Postoperative nausea and vomiting (PONV) con - AANA

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Midazolam, a short-acting benzodiazepine used for pre-operative anxiolysis, may also have pharmacologic prop-erties that could further reduce the incidence of postop-erative nausea and vomiting (PONV) in high-risk patients when included in a multimodal antiemetic protocol. However, concerns remain that the sedating properties of midazolam will delay discharge after short outpatient procedures. A retrospective data analysis (N = 4,057) investigated effects of midazolam on postoperative anti-emetic administration and length of stay following can-cer-related outpatient procedures over 15 months. Fol-lowing initial univariate analysis, a multivariable model adjusting for Apfel score, surgical service, age, length of surgery, and type of anesthesia was created to test these associations. The multivariable analysis demonstrated

that midazolam was associated with reduced need for postoperative antiemetic medications (3.2% lower than no-midazolam group; 95% confidence interval = 0.03%-6.0%, P = .032). Furthermore, the multivariable analysis demonstrated no clinically significant effect on postop-erative length of stay (7.9 minutes shorter in midazolam group; 95% confidence interval = −20 to 4.4, P = .2). In patients for whom midazolam is not otherwise indicated, evidence is insufficient to warrant midazolam adminis-tration solely to prevent PONV. Randomized trials are needed to provide an accurate estimation of the effect size of midazolam for PONV in these patients.

Keywords: Benzodiazepine, cancer, midazolam, outpa-tient, postoperative nausea and vomiting.

Effects of Midazolam on Postoperative Nausea and Vomiting and Discharge Times in Outpatients Undergoing Cancer-Related Surgery

Jennifer R. Majumdar, MSN, CRNA Emily Vertosick, MPHMichael Long, DNP, CRNA Christian Cansino, DNP, CRNA, FNP Melissa Assel, MPH Rebecca Twersky, MD, MPH

Postoperative nausea and vomiting (PONV) con-tinues to be a stressful consequence of outpa-tient surgery despite pharmacologic advances. Patients often find experiencing nausea and vomiting more distressing than postsurgical

pain. Furthermore, PONV can delay recovery and dis-charge in patients undergoing outpatient procedures.1-3

As a result of these complications, substantial research has been generated to establish appropriate pharmaco-logic and nonpharmacologic interventions to reduce the incidence of PONV.

Patients with a higher risk of PONV often require a combination or multimodal approach of 2 or more inter-ventions for effective risk reduction.1,3 Thus, researchers have explored additional nontraditional antiemetics, such as midazolam, that would aid in the multimodal prevention of PONV.4,5

Midazolam is often administered in the perioperative period to reduce anxiety in addition to causing sedation and amnesia. The pharmacologic qualities allow for a rapid onset, short duration, and short half-life. The clini-cal effects of midazolam result from an agonist action on the γ-aminobutyric acid A (GABAA) receptor throughout

the central nervous system. Benzodiazepines do not work directly on the GABA receptor, so there is a physiologic ceiling effect, which contributes to their safety and low toxicity.6,7

Although the exact antiemetic mechanisms remain unknown, researchers postulate that midazolam works on the chemoreceptor trigger zone by reducing the syn-thesis, release, and postsynaptic dopamine.7 It remains debatable whether midazolam reduces dopamine di-rectly or blocks the reuptake of adenosine leading to an adenosine-mediated reduction of dopamine release. Additionally, the binding of midazolam to the GABA benzodiazepine complex may cause dopaminergic neuro-nal activity and the release of 5-hydroxytryptamine. The reduction of PONV may also be a secondary effect of the anxiolytic properties of benzodiazepines.8

Despite literature demonstrating the PONV benefits of midazolam in the perioperative period,4,5 published consensus guidelines have not yet included midazolam as a standard intervention for PONV prevention.1 A small retrospective analysis concluded that midazolam had beneficial antiemetic properties in patients under-going breast cancer-related surgery, but only 48 of the

180 AANA Journal June 2019 Vol. 87, No. 3 www.aana.com/aanajournalonline

patients studied underwent outpatient procedures.9 The study was limited to partial and complete mastectomies and did not include postoperative length of stay, which is a critical value in outpatient surgeries and a clinical concern for anesthesia providers. Also, the researchers did not investigate plastic reconstructive procedures or other types of outpatient cancer surgeries. Therefore, the current literature exhibits a gap in the effect of midazol-am on PONV and length of stay in patients undergoing outpatient cancer surgeries. Our study focused on a large outpatient surgical center where the use of midazolam is high because of the anxiety associated with cancer surgery, enabling us to measure these associations.

The primary aim of this study was to determine whether patients undergoing cancer-related outpatient surgeries who received midazolam intraoperatively had a decreased incidence of postoperative rescue antiemetic administration compared with those patients who did not receive midazolam. The secondary aim examined whether patients who received midazolam had a longer time to discharge compared with patients who did not receive midazolam.

Materials and MethodsFollowing institutional review board approval, we con-ducted a retrospective chart review of a cohort of 4,417 patients who underwent a total of 4,954 outpatient surgical procedures at Memorial Sloan Kettering Cancer Center’s Josie Robertson Surgery Center from January 2016 to March 2017.

Prespecified exclusion criteria excluded patients with preexisting benzodiazepine prescriptions (n = 294), 2 sur-gical procedures on the same day (n = 35), preoperatively placed paravertebral nerve blocks (n = 17), an ASA clas-sification 4 exhibiting substantial comorbidities (n = 7), unexpected admissions to the hospital (n = 6), or receipt of only local anesthesia (n = 1). Also excluded from the analysis were any subsequent secondary procedures per-formed in the same patient at a later date (n = 537).

Patients undergoing general anesthesia received stan-dard prophylactic antiemetics of dexamethasone and ondansetron, and all patients with an Apfel score for PONV of 4 also received aprepitant. Patients undergo-ing monitored anesthesia care (MAC) received pro-phylactic antiemetics based on clinician judgment. In the postanesthesia care unit (PACU), antiemetics were administered for treatment of nausea or vomiting based on the standard-of-care treatment protocol. Prophylactic antiemetics were not administered before opiate admin-istration in the PACU. Data on intraoperative opioid use, in morphine milligram equivalents, were also collected.

The primary aim was to determine whether the in-traoperative administration of midazolam was associated with a reduction in the use of PONV as indicated by use of antiemetic rescue medications in the PACU. To test

this hypothesis, we created logistic regression models for the outcome of rescue medication use in the treatment of PONV. A univariate logistic regression model helped assess the association between midazolam and use of rescue medication for PONV. A multivariable logistic regression model analyzed whether midazolam reduced the use of PONV rescue medication after adjusting for factors that may influence PONV such as Apfel score, surgical service, age, length of surgery, and type of anesthesia (general anesthesia or MAC). Cubic splines were created for age and were included in the multivariable model if significant nonlinearity was identified. It was hypothesized that the effect of midazolam on the use of PONV rescue medication differs depending on the length of surgery, because the effects of midazolam may have dissipated before the post-operative period for patients who have longer surgeries. To test this hypothesis, we tested an interaction between the use of midazolam and operative time.

The secondary study aim was to determine whether the use of intraoperative midazolam increased postoperative length of stay. This was calculated as the time in hours from PACU admission to the time of discharge. Linear regression models were created to test this association. The association was tested using both a univariate model and a multivariable model, which was adjusted for Apfel score, surgical service, age, length of surgery, surgery start time, and type of anesthesia (general anesthesia or MAC). Cubic splines were also included in this multivariable model if significant nonlinearity was identified.

It was hypothesized that intraoperative midazolam use is lower in patients aged 65 years and older. An analysis was conducted on whether the effect of midazolam on the need for postoperative rescue medications for PONV or length of stay differed depending on patient age. An interaction term was added between intraoperative mid-azolam use and patient age in the multivariable models used for the outcomes of use of rescue medications for PONV and length of stay.

We did not include intraoperative opioid use or pro-phylactic antiemetic use in our primary analysis, because opioid and antiemetic use are standardized at our facility and are highly correlated with anesthesia type. However, we performed a sensitivity analysis to confirm that these factors did not influence our results by repeating the anal-yses, including intraoperative opioid use (in morphine milligram equivalents) and dexamethasone and ondanse-tron use (in milligrams) in the multivariable models. All analyses were performed using Stata 15 (StataCorp).

ResultsA total of 4,057 patients were included in our analysis after removing those who met the prespecified exclusion criteria. Patient characteristics are presented in the Table. Most patients received midazolam (76%). The most common dose of midazolam was 2 mg (92%), with 6.0%


of patients receiving less than 2 mg and 1.7% receiving more than 2 mg. Patients under 65 years of age, receiving general anesthesia, and those with ASA scores less than 3, longer operative times, or higher Apfel scores were more likely to receive midazolam. We first investigated whether midazolam administration affected the use of rescue medications for PONV. Most patients did not require any rescue PONV medications (88%). Among the 491 patients who received rescue medications for PONV, the majority (73%) required only 1 dose, while 23% required 2 doses and 4.3% required 3 or more doses.

On univariate analysis, the use of midazolam was asso-ciated with an increased use of PONV rescue medications (13% in midazolam group vs 8.3% in the no-midazolam group, 95% CI = 3.0%-7.2%, P < .0001). However, when controlling for Apfel score, surgical service, age, length of surgery, and type of anesthesia, midazolam was associ-ated with a reduced need for rescue PONV medications (adjusted rate in midazolam group of 11.6% [95% CI =

10.7%-12.6%] vs no-midazolam group of 14.8% [95% CI = 12.1%-17.4%]), a rate of PONV medication use that was 3.2% lower in the midazolam group (95% CI = 0.03%-6.0%, P = .032). In the sensitivity analysis, in-cluding opioid use and preventive antiemetic use, results were similar, with a 3.2% lower risk in the midazolam group (95% CI = 0.04%-6.1%, P = .020).

Longer length of surgery was associated with in-creased use of rescue PONV medications on multivari-able analysis (OR =1.13, 95% CI = 1.11-1.16, P < .0001). There was some evidence that the use of rescue PONV medications also differed by service (P = .066), with higher rates of rescue medication use in plastic surgeries than in breast surgeries (OR =1.43, 95% CI = 0.98-2.08). Thus, the increased use of PONV medications seen on univariate analysis was likely due to differences between services, increased midazolam use, and increased PONV medication use among patients with longer operative times. We then investigated whether midazolam affected

Table. Patient Characteristics by Use of Midazolam (N = 4,057)Abbreviations: IQR, interquartile range; MAC, monitored anesthesia care; MMEs, morphine milligram equivalents.aData are presented as number (%) unless indicated otherwise.bP values were determined by χ2 test for categorical variables and Wilcoxon rank sum test for continuous variables.

No midazolam Midazolam P Characteristic (n = 993)a (n = 3,064)a Valueb

Male sex 53 (5.3) 88 (2.9) .0002

Age, y, median (IQR) 65 (51-74) 52 (44-60) < .0001

ASA score < .0001

1 32 (3.2) 137 (4.5)

2 436 (44) 1,817 (59)

3 525 (53) 1,110 (36)

Surgical service < .0001

Breast 692 (70) 1,545 (50)

Gastric 1 (0.1) 8 (0.3)

Gynecology 107 (11) 508 (17)

Head/neck 57 (5.7) 84 (2.7)

Plastic surgery 125 (13) 906 (30)

Urology 11 (1.1) 13 (0.4)

Type of anesthesia < .0001

General 346 (35) 1,641 (54)

MAC 647 (65) 1,423 (46)

Operative time, min, median (IQR) 79 (62-105) 92 (67-126) < .0001

Apfel score .0002

0 1 (0.1) 1 (< 0.1)

1 11 (1.1) 23 (0.8)

2 107 (11) 277 (9.0)

3 732 (74) 2,128 (69)

4 142 (14) 635 (21)

Intraoperative opioid use, 20 (10-25) 20 (15-40) < .0001 MMEs, median (IQR; N = 4,054)


use of rescue PONV medications differently depending on the length of surgery and found no evidence that this association differed based on operative time (P = .6).

We investigated whether the use of midazolam was as-sociated with an increased length of stay. For our cohort, the median length of stay was 2.6 hours (interquartile range = 2.0-3.6). On univariate analysis, there was a sig-nificant association between midazolam and an increase in postoperative length of stay (3.5 hours in midazolam group vs 3.1 hours in no-midazolam group, 22 minutes longer in midazolam group; 95% CI = 8.6-34, P = .001). However, when controlling for Apfel score, surgical service, surgery start time, operative time and type of an-esthesia, the association was not significant: length of stay 3.4 hours in the midazolam group (95% CI = 3.3-3.5) and 3.5 hours in the no-midazolam group (95% CI = 3.3-3.7), 7.9 minutes shorter in the midazolam group (95% CI = −20 to 4.4, P = .2). The confidence interval was narrow, with an upper bound of a 4.4-minute increase in length of stay, suggesting that we can exclude any clinically relevant increase in discharge time. Operative time was longer for patients receiving midazolam (P < .0001), and use of midazolam differed between services (P < .0001). In the multivariable model, operative time was also as-sociated with an increase in length of stay (15-minute increase in length of stay per 10 minutes’ operative time, 95% CI = 14-17, P < .0001) and there was a significant difference in length of stay between services (P < .0001). The differences between services, and the increased use of midazolam and longer length of stay among patients with longer surgeries is likely the reason for seeing an association between midazolam use and increased length of stay on univariate analysis. When including intraop-erative opioid use and prophylactic antiemetic use in our model as a sensitivity analysis, results were similar, with an 8.1 minute shorter length of stay in the midazolam group (95% CI = −20 - 4.2, P = .2).

We then investigated whether the effect of midazolam differed by patient age. We found no evidence that the effect of midazolam on either use of postoperative PONV rescue medications (P = .6) or length of stay (P = .2) dif-fered by age.

DiscussionOur multivariable analysis controlling for Apfel score, surgical service, age, length of surgery, and type of anes-thesia demonstrated that midazolam was associated with a significantly reduced need for rescue antiemetic medi-cations in the PACU. The administration of midazolam produced no clinically significant effect on the length of PACU stay in this large cohort of outpatients. Because both PONV and length of stay are top clinical concerns in outpatient surgeries, our results are important in re-ducing anesthesia providers’ perceptions that midazolam results in longer PACU stays in outpatients.

This retrospective analysis of ambulatory cancer-related surgical patients suggests the important role that intra-operative administration of midazolam may play toward decreasing PONV rates. Most patients included in this retrospective analysis underwent breast and plastic recon-structive surgeries, which are surgeries that disproportion-ately represent women, who are at higher risk of PONV.3

These findings are consistent with the conclusions of a meta-analysis regarding the effects of midazolam on PONV rates.4,5 The meta-analysis of 12 randomized controlled trials (N = 841) concluded the administration of preoperative or intraoperative intravenous midazolam is associated with a decrease in overall nausea, vomiting, and rescue antiemetic use.4 Another meta-analysis re-ported a reduction in the incidence of PONV in the early, late, and overall recovery period.5 The results indicated that midazolam treatment can prevent nausea and vom-iting in approximately 1 in 3 patients who would oth-erwise experience PONV if given a placebo.5 However, both studies pooled their results from a profoundly het-erogeneous surgical population.

Our results are consistent with those of small studies included in the meta-analysis that examined the impact of midazolam on PONV in ambulatory surgeries.4,5 One study (N = 70) reported a significantly lower incidence of antiemetic rescue medication administration in the mid-azolam group vs placebo in endoscopic outpatient pro-cedures using general anesthesia.10 Our study expanded on these results because our cohort was composed of 51% MAC cases. Furthermore, an additional study (N = 88) reported a decreased frequency of postoperative nausea and increased patient satisfaction compared with a placebo in a prospective study of patients undergo-ing a variety of ambulatory surgeries.11 This study also included only a small number of patients undergoing a variety of procedures, which makes drawing conclusions about the broader population difficult. Our study results are consistent with a retrospective analysis of women undergoing breast surgery that reported significantly higher PONV rates in outpatients with breast cancer who did not receive midazolam.9 In this small study, only 48 of the 196 patients underwent outpatient procedures. A crucial consideration in all outpatient procedures is the length of postoperative stay, and none of these studies addressed the impact of midazolam on this important variable.

The major limitation of the current study is using rescue antiemetic administration as a surrogate for PONV. Although this measure is consistent with the current literature in capturing the rates of PONV, the actual in-cidence may be higher. Furthermore, although the study examined the most common type of outpatient cancer surgeries, it did not include all types of outpatient cancer surgeries. The study also included a higher number of female than male patients, making it difficult to generalize


the results to male patients. Receipt of chemotherapy was not available for inclusion as a covariate. However, receipt of chemotherapy at the time of surgery was rare, because chemotherapy in this cohort is typically given before or after surgery, and likely did not affect our results.

The retrospective study collected data over the period of 15 months, which should address most of the issues of natural fluctuations related to seasonal or diurnal varia-tion but may not have addressed all possible variables. Because of the selection bias possible in a retrospective design, we cannot exclude the possibility of important differences in confounders influencing the relationship between midazolam and outcomes even after multivari-able adjustment. However, these findings can be used to motivate a randomized clinical trial to study the effect of midazolam without the influence of selection bias.

ConclusionOur study focused on a large outpatient cancer surgical center where the use of midazolam is high because of the anxiety associated with these procedures. In addition to midazolam treating preoperative anxiety in a highly anxious patient population, we have observed potential secondary benefits in reducing the need for postopera-tive rescue antiemetics when controlling for Apfel score, surgical service, age, length of surgery, and type of an-esthesia. Additionally, we demonstrated no significant increase in time to discharge after adjusting for these factors. In patients for whom midazolam is not other-wise indicated to treat anxiety, evidence is insufficient to warrant midazolam administration solely to prevent PONV. Randomized trials are needed to provide a more accurate estimation of the effect size of midazolam. Our findings have important clinical implications because both postoperative nausea and vomiting and length of stay are top concerns in outpatient surgeries.

REFERENCES 1. Gan TJ, Diemunsch P, Habib AS, et al; Society for Ambulatory Anes-

thesia. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Anal. 2014;118(1):85-113. doi:10.1213/ANE.0000000000000002

2. Koivuranta M, Laara E, Snare L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia. 1997;52(5):443-449. doi:10.1111/j.1365-2044.1997.117-az0113.x

3. Apfel CC, Korttila K, Abdalla M, et al; IMPACT Investigators. A

factorial trial of six interventions for the prevention of postopera-tive nausea and vomiting. N Engl J Med. 2004;350(24):2441-2451. doi:10.1056/NEJMoa032196

4. Grant MC, Kim J, Page AJ, Hobson D, Wick E, Wu CL. The effect of intravenous midazolam on postoperative nausea and vomiting: a meta-analysis. Anesth Analg. 2016;122(3):656-663. doi:10.1213/ANE.0000000000000941

5. Ahn EJ, Kang H, Choi GJ, Baek CW, Jung YH, Woo YC. The effectiveness of midazolam for preventing postoperative nausea and vomiting: a systematic review and meta-analysis. Anesth Analg. 2015;122(3):664-676. doi:10.1213/ANE.0000000000001062

6. Nagelhout JJ, Elisha S. Nurse Anesthesia. 6th ed. St Louis, MO: Else-vier; 2017.

7. Stoelting RK, Hillier SC. Pharmacology & Physiology in Anesthetic Prac-tice. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

8. Rodolà F. Midazolam as an anti-emetic. Eur Rev Med Pharmacol Sci. 2016;10(3):121-126.

9. Wilson S, Meyer H, Fecho K. Postoperative nausea and vomiting after inpatient and outpatient breast surgery: incidence and effects of midazolam. Ambulatory Surg. 2009;15(4):68-72.

10. Qadirullah, Tariq MA, Iqbal Z. Postoperative nausea and vomiting in ambulatory surgery: comparison of midazolam with normal saline. J Med Sci. 2016;24(3):149-154.

11. Bauer KP, Dom PM, Ramirez AM, O’Flaherty JE. Preoperative intravenous midazolam: benefits beyond anxiolysis. J Clin Anesth. 2004;16(3):177-183. doi:10.1016/j.jclinane.2003.07.003

AUTHORSJennifer R. Majumdar, MSN, CRNA, is a nurse anesthetist at Memorial Sloan Kettering Cancer Center’s Josie Robertson Surgery Center, New York, New York. Email: [email protected].

Emily Vertosick, MPH, is an assistant research biostatistician at Memo-rial Sloan Kettering Cancer Center in the Department of Epidemiology and Biostatistics, New York, NY. Email: [email protected].

Michael Long, DNP, CRNA, is an obstetric nurse anesthetist at Community Health Network, Indianapolis, Indiana. Email: [email protected].

Christian Cansino, DNP, CRNA, FNP, is a nurse anesthetist at Memo-rial Sloan Kettering Cancer Center and an assistant professor of clinical nursing at Columbia University in the Nurse Anesthesia Program, New York, New York. Email: [email protected].

Melissa Assel, MPH, is a research biostatistician at Memorial Sloan Ket-tering Cancer Center in the Department of Epidemiology and Biostatistics. Email: [email protected].

Rebecca Twersky, MD, MPH, is the chief of anesthesia at Josie Rob-ertson Surgery Center at Memorial Sloan Kettering Cancer Center. Email: [email protected].

DISCLOSURESThis research was funded in part through the NIH/NCI Cancer Center Sup-port Grant P30 CA008748. The authors would like to thank Gregory W. Fischer, MD, and Andrew J. Vickers, PhD, for their guidance in the devel-opment of this manuscript. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.


This past January, for the first time in the 20-year history of National CRNA Week, members of the American Association of Nurse Anesthetists (AANA) serving in the military around the world were surprised and delighted to receive packages from home—their AANA home. LTC Benjamin Riley, MNA, CRNA, ANC, USA, pictured on this month’s AANA Journal cover wearing a CRNA Week T-shirt while serving in Afghanistan, was one of the recipients.

The initiative was the brainchild of AANA CEO Randall Moore, DNP, MBA, CRNA, a retired military vet-eran who served for 22 years as an infantryman, combat medic, and CRNA in the US Army Reserve and Illinois National Guard. He was deployed with Forward Surgical Teams in Afghanistan and provided combat casualty care. His CRNA Week initiative was simple and effec-tive: family and friends of military CRNAs could contact Moore and request that CRNA Week merchan-dise be shipped to their loved ones, and just like that the shipment would be sent from the AANA Bookstore.

“I vividly remember how dif-ficult it is to be deployed during the holidays,” said Dr Moore. “I’ve missed two Christmases and two Thanksgivings, and it’s really difficult on both the deployed service member and his/her family. My intention was to demonstrate appreciation from the AANA and myself to the service members who were away from their families during this difficult time. I know it’s just a small token of appre-ciation, but I knew that it would mean a lot to these folks that the AANA appreciates their sacrifice.”

Halfway around the world, LTC Riley was happy to receive his care package. With permission from his commanding officers, he shared the following with the AANA staff: “[O]ne of my coworkers from Mankato, Minnesota, was organizing

CRNA Week items for their hospital and noticed the availability of the T-shirt and travel mug for deployed soldiers. I had no idea who had put my name in for receiving these items and was surprised to receive them. The recognition of deployed soldiers from your own professional organi-zation is great but the real reward comes from having the opportunity to serve your country and fellow soldiers. The most gratifying anes-thesia work I have ever done has been with the military, caring for true patriots who make incredible sacrifices in order to preserve the American way of life.

“My Forward Surgical Team (FST) was under the command of Special Operation Task Force-Afghanistan (SOTF-A). Our objective was to provide medical support to American and allied forces wherever we were needed in Afghanistan,” LTC Riley wrote. “Most of my time in country was spent at Forward Operating Bases where running water and hot meals were a rarity. Getting mail was a luxury that we usually only received when they would push medical resupply shipments from larger bases in country out to our locations. I was happy to have the travel mug to keep my morning cof-

fee warm after shutting down the Jetboil [portable stove], and who couldn’t use an extra T-shirt when you’ve worn your current one for a week without laundering it!”

Dr Moore said that when he joined the Army he really wasn’t looking to make a career of it. “I was looking for adventure and some direction,” he said. “I wanted to be a part of something that was bigger than myself, and military service seemed the best opportunity at that time.” As it turned out, Moore wound up going to anesthesia school while in the Army Reserve.

“Without a doubt, my most mem-orable experiences involved serving with Forward Surgical Teams in Afghanistan providing combat casualty care. It was an incredibly challenging and rewarding experi-ence, and I frequently think about the people we were able to save as well as the patients who didn’t make it,” Dr Moore recalled. “Providing anesthesia care at the top of my education and training was the most rewarding and formative experience of my professional career.

“Only a very small percentage of Americans serve in the military, so I want them to know that the AANA appreciates and honors their service and sacrifice,” Dr Moore said.

LTC Benjamin Riley, MNA, CRNA, ANC, USA

American Association of Nurse Anesthetists CEO Randall Moore, DNP, MBA, CRNA

On the Cover


A patient presented for elective shoulder arthroscopy who had subclavian steal syndrome. The patient’s history included bilateral mastectomy with unilateral lymph node dissection, limiting noninvasive oscillo-metric blood pressure monitoring on the nonoperative side. This history, combined with the necessary surgi-cal positioning and calf blood pressure monitoring, raised the concern of decreased cerebral perfusion

during a general anesthetic in the beach chair position. This report describes the management of this particu-lar case, then reviews the relevant literature regarding cardiovascular and cerebral perfusion monitoring.

Keywords: Axillary lymph node dissection, noninva-sive cardiovascular monitoring, shoulder arthroscopy sitting position, subclavian steal syndrome.

Beach Chair Position in a Patient With Subclavian Steal Syndrome and Axillary Lymph Node Dissection: A Case Report

Capt David J. Krasucki, DNP, CRNA, USAF, NC

This case report aims to review, discuss, and perform a post-hoc analysis of the manage-ment of a patient presenting for elective shoul-der arthroscopy who had subclavian steal syndrome (SSS). Each year approximately 1.4

million shoulder arthroscopies are performed worldwide.1 Many of these are performed in the beach chair position, a position that when combined with general anesthesia reduces cerebral perfusion pressure (Table 1). Beach chair position was first introduced in the 1980s as an alterna-tive to lateral decubitus position for shoulder surgery and is favored because of its reduction in brachial plexus injury and anatomical optimization.2

The major anesthetic concern related to SSS is its po-tential effect on the cerebral circulation. This syndrome is defined as flow reversal in the vertebral artery on the same side as a proximally obstructed subclavian artery (Figure 1). The lesion in the proximal subclavian artery reduces aortic blood flow through the subclavian artery and allows retrograde flow from the circle of Willis to return down the basilar artery, into the vertebral artery, which then backfills the subclavian artery distal to the obstruction.3 This flow reversal steals cerebral circula-tion and perfuses the extremity.

To further complicate matters in this case, the oscil-lometric blood pressure cuff had to be placed on the patient’s calf to avoid the axillary lymph node–dissected arm in accordance with hospital policy. This policy is de-signed to reduce the risk of lymphedema. Lymphedema develops when the lymphatic system is unable to remove accumulated interstitial fluid, and it affects up to 5 million Americans.4 Among breast cancer survivors, the occurrence of lymphedema varies widely.5,6 Regardless, many institutions maintain policies that restrict needle sticks and blood pressure cuffs on axillary lymph node–dissected extremities.

Case SummaryA 65-year-old woman presented for right shoulder ar-

NIBP cuff placement

Distance from circle of

Willis, cmGradient, mm

Hga

Brachial (upper arm) 10-30 8-24

Radial (lower arm) 35-50 27-39

Tibial (calf) 60-80 46-62

Table 1. Noninvasive Blood Pressure (NIBP) Sites and Gradient in Sitting Position a0.77 mm Hg/cm or 1 mm Hg for each 1.25 cm.8

Figure 1. Subclavian Steal Syndrome (SSS)Defined as flow reversal in vertebral artery on ipsilateral side of obstructive lesion in subclavian artery, SSS is demonstrated in left subclavian artery.Abbreviations: L, left; R, right.


throscopy with possible open rotator cuff repair. Her medical history was remarkable for asthma, fibromyalgia, gastroesophageal reflux disease (GERD), Mobitz type 1 atrioventricular block, hypertension, supraventricular tachycardia, irritable bowel syndrome, osteoarthritis, systemic lupus erythematosus, breast cancer treated with bilateral mastectomy with left-sided axillary lymph node dissection, and SSS of unknown laterality. Her medica-tion list included hydrochlorothiazide, melatonin, mul-tivitamin, lansoprazole, pantoprazole, ranitidine, simv-astatin, vitamin B12, cetirizine, and albuterol. Results of preoperative laboratory and cardiac studies were within normal limits. Her ASA physical status was assigned as 2, although 3 previous anesthetic evaluations assigned a physical status of 3.

Her baseline vital signs were as follows: heart rate of 81/min, respiratory rate of 22/min, and blood pressure of 126/84 mm Hg. She was 1.57 m tall and weighed 66 kg, with a body mass index of 26.7 kg/m2. The patient was al-lergic to penicillin and sulfa drugs. She reported a history of aspiration during a sedated colonoscopy secondary to her hiatal hernia and poorly controlled GERD, but no other anesthesia-related complications. She reported activity that required greater than 4 metabolic equiva-lents without dyspnea or angina. Unfortunately, she was not routinely followed up at the institution at which she presented for surgery; consequently, no additional infor-mation regarding her SSS laterality, severity, or treatment was available.

Hospital policy prevented the preoperative registered nurse from obtaining bilateral upper extremity blood pressures because of her history of axillary lymph node dissection. However, she did not report any vertebrobasi-lar symptoms or arm claudication, and it was presumed that she was medically managed based on her medication list. These conclusions pacified some of the major con-cerns of the anesthesia team.

The routine anesthetic for shoulder arthroscopy at the institution is a general anesthetic with an interscalene block. The nonoperative extremity is used for noninva-sive oscillometric blood pressure monitoring and periph-eral intravenous (PIV) catheter placement. The patients are placed in the beach chair position after anesthetic induction and airway management.

Preoperatively, because of the patient’s left axillary lymph node dissection and right-sided shoulder surgery, a left external jugular PIV catheter was placed and an oscillometric blood pressure cuff was placed on the calf. An interscalene block was placed in the right shoulder with mild midazolam and fentanyl sedation. The use of a percutaneously placed radial arterial catheter was ruled out secondary to hospital policy regarding axillary lymph node dissections and needle sticks. Instead, the calf cuff pressure was to be used with compensation made for the hydrostatic gradient. The blood pressure gradient, between the calf and tragus, was estimated to be 45 mm Hg based on an approximate 60-cm height difference (see Table 1). Noninvasive continuous cardiac output and arterial pressure monitoring was achieved using the ClearSight System (Edwards Lifesciences Corp). The finger cuff was placed on the left third digit with the finger-side heart reference sensor attached; the heart-side heart reference sensor was clipped at the level of the heart per the manufacturer’s instruction (Figure 2).7

It is recommended to maintain the patient’s blood pressure within 20% of baseline throughout an anesthetic to ensure adequate end-organ perfusion.2,8 With the pre-operative blood pressure of 126/84 mm Hg and a calcu-lated mean arterial pressure (MAP) of 98 mm Hg noted, the intraoperative goal was to maintain a MAP of at least 78 mm Hg at the circle of Willis; this would require a calf MAP of 123 mm Hg: (123[Calf] – 45[Gradient] = 78), as shown in Table 1.

The patient was brought into the operating room, and

Figure 2. Heart Reference Sensors (HRS) of ClearSight SystemOne sensor is attached to finger cuff, and other is placed at level of the heart (pillow).(Used with permission of Edwards Lifesciences Corp)


monitors were applied. Anesthesia was induced intrave-nously, the trachea was intubated, and the lungs were mechanically ventilated with a tidal volume of 500 mL, respiratory rate of 12/min, positive end-expiratory pres-sure of 5 cm H2O, and inspired oxygen concentration of 60%. Anesthesia was maintained with inhaled 0.9% sevoflurane in an air and oxygen mixture.

Immediately after beach chair positioning and just before the incision was made, the patient experienced moments of hypotension, with calf MAPs of 80 mm Hg or lower. A phenylephrine infusion was initiated and rapidly titrated to 200 μg/min with ephedrine, norepi-nephrine, and vasopressin boluses while the anesthetic concentration was simultaneously reduced. The calf MAP remained between 90 and 95 mm Hg throughout the pro-cedure despite the pharmacologic support. All other vital signs were within normal limits throughout the case. The heart rate ranged from 70 to 85/min in normal sinus rhythm, end-tidal carbon dioxide was 31 to 45 mm Hg, skin temperature ranged from 35.7° to 36.1°C, and pulse oximetry readings were between 96% and 100%.

The ClearSight System measured the MAP 10 to 20 mm Hg lower than the calf oscillometric pressure and provided an estimated stroke volume of 47 to 53 mL and a cardiac index of approximately 2.7 L/min/m2 throughout the procedure. Because the SSS laterality was unknown, it was difficult to trust the data provided by the ClearSight System; however, an oscillometric cuff on that extremity would have been just as vulnerable to any such vasculopa-thy. Regardless, the preoperative plan consisted of clinical responses to the calf oscillometric blood pressure with an adjustment made for the hydrostatic gradient.

Toward the conclusion of the case the patient was allowed to spontaneously ventilate as the anesthetic was reduced during dressing and sling placement. The phen-ylephrine infusion was simultaneously reduced as the anesthetic was decreased, and the oscillometric calf MAP increased to between 95 to 110 mm Hg. After the patient met the established extubation criteria, her trachea was extubated as she remained in the beach chair position.

She was transferred to a stretcher and escorted to the postanesthesia care unit (PACU) for recovery with supplemental oxygen via face mask at 6 L/min. In the PACU a neurologic examination was performed, and the patient was found to be alert and oriented to person, place, and year. She was able to move 3 of her extremities to command, and cranial nerves II through X and cranial nerve XII were intact. The spinal accessory (cranial nerve XI) and right arm were unable to be adequately assessed because of the unilateral interscalene block. No negative se-quelae developed related to her anesthetic or hemodynamic management. She was discharged later that same day.

Discussion• Beach Chair Position. A priority consideration in pa-

tients presenting for elective shoulder surgery is related to their positioning. Blood behaves as fluid in a column; when a patient is in the upright position a blood pressure gradient between the circle of Willis and heart is created (see Table 1). It is often recommended to place an arte-rial line and level the transducer at the patient’s tragus to estimate the blood pressure in the circle of Willis when there are major concerns related to cerebral perfusion.8 Because of this patient’s lack of vertebrobasilar symp-toms, conservative medical management, and history of axillary lymph node dissection, an arterial line was believed to be excessive.

Most publications recommend maintaining blood pressure within 20% of the patient’s preoperative baseline when in a sitting or beach chair position.2,8 However, there is no established “minimally safe” blood pressure in the sitting or beach chair position, and it is presumed to be patient dependent. Awake patients placed in the beach chair or sitting position demonstrated unchanged or slightly increased blood pressures. However, the vasodilatory effects of general anesthesia, coupled with blood pooling in the lower extremities, can cause sudden and severe hypotension after positioning, much like this patient experienced.9

Four case reports have been published in which irre-versible neurologic damage was described due to global cerebral hypoperfusion secondary to the sitting position and hypotension.10 The consequences are substantial; therefore, when one places a patient into the sitting or beach chair position, careful anesthetic, vasopressor, and positioning titration is mandatory to prevent sudden, po-tentially catastrophic, hypotension. The use of the lateral decubitus position to eliminate hydrostatic gradients could have been considered in this case. However, this decision must include both anesthetic and surgical teams and may have been difficult to negotiate.

• Subclavian Steal Syndrome. Subclavian steal syn-drome was first described in the 1960s and has a reported incidence of 0.6% to 6.4%.11 Of individuals with SSS, approximately 5.3% have neurologic symptoms. These include vertebrobasilar symptoms such as vertigo, dizzi-ness, ataxia, and syncope indicating cerebral hypoperfu-sion.12 Additional symptoms that should alert the practitio-ner to SSS include arm ischemia presenting as claudication, paresthesias, or weakness; however, these symptoms are difficult to assess and elicit because of the collateral circula-tion provided by the cerebral circulation.11

Preoperative evaluation of patients with SSS can include comparison of upper extremity blood pressures. A gradient between extremities of greater than 15 to 20 mm Hg has been shown to be a sensitive indicator of subclavian steal; a gradient of 40 mm Hg or greater can be predictive of a partial or complete SSS.3,11 However, computed tomography or magnetic resonance angiogra-phy remain the gold standards for diagnosis.3,11 For most


patients, medical management of comorbidities such as diabetes mellitus, hyperlipidemia, and hypertension may be all that is necessary. For the 1.4% of severe refractory cases, surgical options such as carotid-subclavian bypass grafting or endovascular treatments are available.3,11

Despite the low incidence of severe complications of SSS, several studies described patients who experienced more alarming signs of SSS indicative of brainstem isch-emia.12-14 The severity of these symptoms has been ques-tioned when controlling for anterior cerebral circulation disease15; however, patients with a diagnosis of SSS can be presumed to have systemic atherosclerotic changes, and anesthesia should be diligently managed.

• Blood Pressure Measurement and Interpretation. Most patients undergoing surgery will have their blood pressure measured via the oscillometric technique. Briefly, this technique employs an appropriately sized cuff placed circumferentially around a patient’s extrem-ity. The cuff’s bladder is inflated with air to a preset value and slowly released. As the cuff pressure is released, os-cillations are detected and the peak amplitude is recorded as the MAP.16 Unfortunately, the systolic and diastolic pressures are determined by manufacturers’ proprietary algorithms, unavailable for public review.16

There are times when an oscillometric-derived blood pressure measurement is inaccurate. For example, cuff placement is an important consideration; a study per-formed in women undergoing cesarean delivery demon-strated markedly variable oscillometric blood pressure values measured at the patient’s ankle and those obtained from the upper arm.17 Atrial fibrillation has also been demonstrated to affect the accuracy of the oscillometric blood pressures18,19 and oscillometric cuffs tend to under-estimate blood pressure compared with manual ausculta-tory methods.20,21 In light of these limitations, the prudent practitioner should remain skeptical when the obtained blood pressure is incongruent with the clinical scenario.

In contrast, the ClearSight System is a noninvasive form

of continuous arterial blood pressure and cardiac output monitoring.22 The underlying science was developed in the 1970s by Penaz23 but has recently gained popularity. It is completely noninvasive and uses a finger cuff placed on the intermediate phalange (Figure 3). The basis of this technology is the volume clamp method, also known as vascular unloading.16,22 The cuff is inflated and adjusted upwards of 1,000 times per second7 to maintain a constant arterial vessel volume by providing equal pressure on the arterial walls, and the volume is assessed continuously by built-in photoplethysmography (Figure 4).22,24

Studies have been performed to determine the accu-racy of this device. Teboul et al24 concluded that “valida-tion studies showed good agreement and trending ability in the perioperative context”, but these results were not as promising in patients with major changes in vascular tone. Similarly, another study concluded that in cases of severe vasoconstriction or peripheral vascular disease, it may be difficult to obtain reliable signals.16 A 2014 study demonstrated a bias (SD) of 3.5 (6.8) mm Hg between oscillometric and ClearSight System technologies.25 Practically, this means that a MAP of 60 mm Hg corre-lates to an oscillometric blood pressure cuff measurement of between 50.1 and 66.9 mm Hg with 95% certainty.26

It is known that even short periods of hypotension can adversely affect end-organ function.27,28 Results of a recent randomized controlled trial demonstrated significantly shorter periods of hypotension in beach chair-positioned patients when continuous blood pres-

Figure 3. ClearSight Cuff Placed on Patient’s Finger, on Intermediate Phalanges7

(Used with permission of Edwards Lifesciences Corp)

Figure 4. Volume Clamp Method of ClearSight CuffCuff is inflated and adjusted (1,000 times per second) to maintain constant arterial vessel volume by providing equal pressure on the arterial walls, and volume is assessed constantly by photoplethysmography.22

(Used with permission of Edwards Lifesciences Corp)


sure monitoring modalities were used compared with intermittent blood pressure modalities.29 More generally, it has been suggested that the use of a continuous nonin-vasive blood pressure monitor can reduce the time spent in hypotensive states by 14 (3) min/h.30 This is precisely the value of this additional monitor: by allowing continu-ous arterial blood pressure monitoring, the patient did not experience prolonged periods of hypotension before interventions could be initiated. A practical method of stepwise escalation of blood pressure modalities is sug-gested by Meidert and Saugel16 (Figure 5).

• Near-Infrared Spectroscopy (NIRS). Institutions that have NIRS cerebral oximeters may consider using them in patients undergoing procedures with a high risk of cerebral hypoperfusion and emboli, such as cardiac surgery.31 This technology uses an adhesive pad placed on the patient’s forehead that emits near-infrared light. This light is attenuated by chromophores, specifically, oxygenated hemoglobin, and thus can calculate the amount of saturated hemoglobin in the cerebral arteries and veins based on the degree of attenuation.32

A 2012 prospective observational study demonstrated a significant correlation between the cerebral oximetry values and MAP of the cerebrum.31 Additionally, a 2010 prospective study demonstrated significant cerebral de-saturation events, defined as 20% or more reduction in baseline NIRS value, in patients placed in the beach chair position compared with the lateral decubitus posi-tion. These desaturations did not occur in the laterally positioned patients, despite the lack of significant hemo-dynamic differences between the groups.33 From these study finding, a practitioner could conclude that, in lieu of an arterial line or an oscillometric blood pressure cuff on the upper extremity, a noninvasive cerebral oximeter could be used to determine adequate cerebral perfusion.

However, results of another study, performed in pa-tients undergoing shoulder surgery with regional anes-thesia and sedation, demonstrated that 99% of the group experienced hypotension, but only 10% experienced cerebral desaturation.34 The authors concluded that the presence of cerebrovascular disease was associated with the cerebral desaturation. Taken together, a NIRS cere-bral oximeter would have been an excellent adjunct to the author’s noninvasive arsenal by providing real-time cerebral perfusion data in a vasculopathic patient in the beach chair position.

• Peripheral Intravenous Catheters and High-Dose Vasopressors. The use of high-dose vasopressors admin-istered through a PIV catheter during this case, both infusions and boluses, demand brief consideration. In the emergency and intensive care departments it has been traditionally taught that a central venous catheter is required for patients receiving vasoactive infusions. This fear stems from extravasation case studies published during the 1950s and 1960s.35,36 However, little, if any,

robust evidence supports this notion. Authors of several recent studies have concluded that the PIV extravasation rate is 2% to 14% with vasoactive infusions.35,36 Factors determined to increase the risk of extravasation included duration of the infusion and the site; sites distal to the antecubital or popliteal fossa and infusions lasting greater than 24 hours increased the risk.35 Central venous cathe-ters, with their associated morbidity (> 15%35), appear to be unnecessary when a larger-caliber vessel is cannulated for short infusions.

• Lymph Node Dissection. The added complexity of a lymph node dissection also necessitates a brief discus-sion. It is recommended by most oncologic associations to avoid needle sticks or blood pressure measurements in the affected limb.37-39 Unfortunately, most of these recommendations are based on low levels of evidence, including individual case reports, some of which date to the early 1920s.5,40 However, these recommendations include the option to place a PIV or arterial line in the affected extremity in patients with difficult intravenous access or surgical site limitations.40 One case study de-scribed a patient in whom lymphedema developed 30 years after mastectomy because of a recent diagnosis of diabetes mellitus and daily finger sticks for glucose management; therefore, the risk related to needle sticks should not be entirely disregarded.41

The risk of using a blood pressure cuff on the lymph node–dissected extremity is unclear because of the

Figure 5. Escalation of Cardiovascular Monitoring Based on Patient or Operative Severity16

Abbreviations: ICU, intensive care unit; OR, operating room.(Reproduced under the terms of the Creative Commons Attribution License [CC BY 4.0] and used with the author’s permission)


paucity of available data. Placing a blood pressure cuff on the affected extremity may be reasonable when you con-sider that one of the principle treatments of lymphedema includes compression stockings, which often generate and maintain pressures well above those of a blood pres-sure cuff.5 Additionally, a case series explored the role of tourniquets in patients undergoing elective hand surgery who had a history of axillary lymph node dissection, and the authors found there was no increase in the incidence of lymphedema.42 It is unclear where this dogma first began, and there is a lack of data to support it. The use of the lymph node–dissected arm for oscillometric blood pressure measurement can be considered an appropriate clinical decision dependent on the patient and the pro-posed surgical intervention.

ConclusionThe objective of this article was to review a unique case and share the post-hoc analysis. The preoperative evalua-tion of these patients can include bilateral upper extrem-ity blood pressure measurement to assess the severity of SSS, as well as a detailed history regarding arm ischemia or vertebrobasilar symptoms. An arterial line with the transducer leveled at the tragus, despite the associated risk of infection and lymphedema, may be warranted in severe cases of SSS (Table 2). Additionally, placement of an oscillometric blood pressure cuff on the lymph node–dissected extremity should be considered in view of the benefits, risks, and recommendations. Based on this literature review, it appears that sole reliance on oscillo-metric blood pressures obtained on a patient’s calf would put a patient such as this at unnecessary risk.

Furthermore, after a review of the literature, it appears

that the Edwards Lifesciences ClearSight System is capable of providing reliable and accurate arterial blood pressure measurements. Because it was unknown which extremity was affected by SSS in the patient described, the gradi-ent between the oscillometric blood pressure and the ClearSight cuff may have been reflective of left arm vas-cular obstruction, a limitation specified by the manufac-turer.43 Due to the complexity of this particular case, the use of both modalities was synergistic: allowing for con-tinuous noninvasive arterial blood pressure monitoring and verification on an unobstructed extremity (the leg).

Managing similar cases using continuous noninvasive arterial blood pressure monitoring and oscillometric cuffs, with or without NIRS technology, may help guide therapy by triangulating adequate perfusion pressures. The prac-titioner must be well versed in all forms of cardiovascular monitoring techniques, their alternatives, and their limita-tions to maintain vigilance for such complex cases.

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12. Peera MA, LoCurto M, Elfond M. A case of Takayasu arteritis causing subclavian steal and presenting as syncope. J Emerg Med. 2011;40(2):158-161. doi:10.1016/j.jemermed.2007.11.031

13. Sharma VK, Chuah B, Teoh HL, Chan BP, Sinha AK, Robless PA. Chronic brainstem ischemia in subclavian steal syndrome. J Clin Neu-rosci. 2010;17(10):1339-1341. doi:10.1016/j.jocn.2010.03.019

14. Smith JM, Koury HI, Hafner CD, Welling RE. Subclavian steal syn-drome. A review of 59 consecutive cases. J Cardiovasc Surg (Torino). 1994;35(1):11-14.

15. Hennerici M, Klemm C, Rautenberg W. The subclavian steal phe-nomenon: a common vascular disorder with rare neurologic deficits. Neurology. 1988;38(5):669-673.

Signs SymptomsImaging to consider

> 15 mm Hg discrepancy in upper extremities

Vertebrobasilar neurologica

Continuous wave Doppler and duplex ultrasonography

Delayed or decreased amplitude pulses in affected side

Arm claudication Transcranial Doppler ultrasonography

Suboccipital bruit Coronary ischemia with internal mammary arterial graft has been used

Magnetic resonance angiography

Atrophic changes to skin/nails on affected side

Computed tomogra-phy angiography

Arm paresthesias

Cool arm

Table 2. Diagnosis, Signs, and Symptoms of Subclavian Steal Syndromea“Drop attacks,” dizziness, diplopia, nystagmus, tinnitus, and hearing loss3,11


16. Meidert AS, Saugel B. Techniques for non-invasive monitoring of arterial blood pressure. Front Med. 2018;4:231. doi:10.3389/fmed.2017.00231

17. Drake MJ, Hill JS. Observational study comparing non-invasive blood pressure measurement at the arm and ankle during caesarean section. Anaesthesia. 2013;68(5):461-466. doi:10.1111/anae.12194

18. Tholl U, Forstner K, Anlauf M. Measuring blood pressure: pitfalls and recommendations. Nephrol Dial Transplant. 2004;19(4):766-770. doi:10.1093/ndt/gfg602

19. Feenstra RK, Allaart CP, Berkelmans GF, Westerhof BE, Smulders YM. Accuracy of oscillometric blood pressure measurement in atrial fibrillation. Blood Press Monit. 2018;23(2):59-63. doi:10.1097/MBP.0000000000000305

20. Bur A, Hirschl MM, Herkner H, et al. Accuracy of oscillometric blood pressure measurement according to the relation between cuff size and upper arm circumference in critically ill patients. Crit Care Med. 2000;28(2);371-376.

21. Landgraf J, Wishner SH, Kloner RA. Comparison of automated oscillometric versus auscultatory blood pressure measurement. Am J Cardiology. 2010;106(3):386-388.

22. ClearSight System hemodynamic monitoring. Edwards Lifesciences website. https://www.edwards.com/gb/devices/hemodynamic-mon-itoring/clearsight?WT.ac=eu_clearsightsystem Originally accessed March 12, 2018. URL updated March 21, 2019.

23. Penaz J. Photoelectric measurement of blood pressure, volume and flow in the finger. In: Digest of the 10th International Conference on Medical and Biological Engineering. Dresden, Germany: Conference on Medical and Biological Engineering; 1973:104.

24. Teboul JL, Saugel B, Cecconi M, et al. Less invasive hemody-namic monitoring in critically ill patients. Intensive Care Med. 2016;42(9):1350-1359. doi:10.1007/s00134-016-4375-7

25. Kim SH, Lilot M, Sidhu KS, et al. Accuracy and precision of continu-ous noninvasive arterial pressure monitoring compared with invasive arterial pressure: a systematic review and meta-analysis. Anesthesiol-ogy. 2014;120(5):1080-1097. doi:10.1097/ALN.0000000000000226

26. Raggi E, Sakai T. Update on finger-application-type noninvasive continuous hemodynamic monitors (CNAP and ccNexfin): physi-cal principles, validation, and clinical use. Semin Cardiothroac Vasc Anesth. 2017;21(4):321-329. doi:10.1177/1089253217708620

27. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraop-erative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiol-ogy. 2013;119(3):507-515. doi:10.1097/ALN.0b013e3182a10e26

28. Lonjaret L, Lairez O, Minville V, Geeraerts T. Optimal perioperative management of arterial blood pressure. Integr Blood Press Control. 2014;7:49-59. doi:10.2147/IBPC.S45292

29. Benes J, Simanova A, Tovarnicka T, et al. Continuous non-invasive monitoring improves blood pressure stability in upright position: randomized controlled trial. J Clin Monit Comput. 2015;29(1):11-17. doi:10.1007/s10877-014-9586-2

30. Chen G, Chung E, Meng L, et al. Impact of noninvasive and beat-to-beat arterial pressure monitoring on intraoperative hemodynamic management. J Clin Monit Comput. 2012;26(2):133-140.

31. Ko SH, Cho YW, Park SH, Jeong JG, Shin SM, Kang G. Cerebral oxygenation monitoring of patients during arthroscopic shoulder sur-gery in the sitting position. Korean J Anesthesiol. 2012;63(4):297-301. doi:10.4097/kjae.2012.63.4.297

32. Roh D, Park S. Brain multimodality monitoring: updated perspec-tives. Curr Neurol Neurosci Rep. 2016;16:56. doi:10.1007/s11910-016-0659-0

33. Murphy GS, Szokol JW, Marymont JH, et al. Cerebral oxygen desatu-ration events assessed by near-infrared spectroscopy during shoulder arthroscopy in the beach chair and lateral decubitus positions. Anesth Analg. 2010;111(2):496-505. doi:10.1213/ANE.0b013e3181e33bd9

34. Yadeau JT, Liu SS, Bang H, et al. Cerebral oximetry desaturation dur-

ing shoulder surgery performed in a sitting position under regional anesthesia. Can J Anaesth. 2011;58(11):986-992. doi:10.1007/s12630-011-9574-7

35. Lewis T, Merchan C, Altshuler D, Papadaopoulos J. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med. 2017;34(1):26-33. doi:10.1177/0885066616686035

36. Dick-Perez R, Herrera S. Peripherally versus centrally administered potent vasopressors in the ICU. American College of Emergency Phy-sicians website. https://www.acep.org/how-we-serve/sections/critical-care-medicine/news/july-2017/peripherally-versus-centrally-adminis-tered-potent-vasopressors-in-the-icu/ Originally accessed March 17, 2018. URL updated March 21, 2019.

37. For people at risk of lymphedema. American Cancer Society web-site. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/lymphedema/for-people-at-risk-of-lymphedema.html Updated July 7, 2016. Accessed January 9, 2018.

38. Hayes SC, Janda M, Cornish B, Battistutta D, Newman B. Lymph-edema after breast cancer: incidence, risk factors, and effect on the upper body function. J Clin Oncol. 2008;26(21):3536-3542. doi:10.1200/JCO.2007.14.4899

39. National Lymphedema Network Medical Advisory Committee. Posi-tion statement of the National Lymphedema Network: lymphedema risk reduction practices. https://lymphnet.org/position-papers Pub-lished May 2012. Originally accessed January 9, 2018. URL updated March 20, 2019.

40. Jakes AD, Twelves C. Breast cancer-related lymphoedema and vene-puncture: a review and evidence-based recommendations. Breast Cancer Res Treat. 2015;154(3):455-461. doi:10.1007/s10549-015-3639-1

41. Brennan MJ, Weitz J. Lymphedema 30 years after radical mastectomy. Am J Phys Med Rehabil. 1992;71(1):12-14.

42. Dawson WJ, Elenz DR, Winchester DP, Feldman JL. Elective hand surgery in the breast cancer patient with prior ipsilateral axillary dis-section. Ann Surg Oncol. 1995;2(2):132-137.

43. McGee WT, Headley JM, Frazier JA, eds. Quick Guide to Cardiopulmo-nary Care. 3rd ed. Irvine, CA: Edwards Lifesciences; 2014.

AUTHORCapt David J. Krasucki, DNP, CRNA, USAF, NC, is currently serving in the United States Air Force assigned to the 60th Surgical Operations Squadron at Travis AFB. His clinical background includes pediatric criti-cal care, cardiac critical care, and extracorporeal life support. He received his bachelor’s degree from University of Delaware and his master’s and doctoral degree from Villanova University.

DISCLOSURESThe author has declared no financial relationships with any commercial entity related to the content of this article. The author did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.

MILITARY DISCLAIMERThe views expressed in this material are those of the author and do not reflect the official policy or position of the US Government, the Depart-ment of Defense, or the Department of the Air Force. This case did not take place at an Air Force military treatment facility.

ACKNOWLEDGMENTSI thank Matthew McCoy, DNP, CRNA; Jessica Poole, DNAP, CRNA; and Mark Schneider, MD, MBA, for their review and comments in the develop-ment of this manuscript. I also thank Agnes S, Meidert, MD, and Bernd Saugel, MD, as well as Edwards Lifesciences Corp for the use of their figures reproduced in this manuscript.


The primary purpose of this proof-of-concept quality improvement effort was to evaluate the practicality of using near-infrared spectroscopy (NIRS) to measure tissue oxygen saturation (Sto2) during total knee arthro-plasty (TKA) with use of a tourniquet. NIRS sensors were applied to the biceps femoris (BF) and gastrocne-mius (GS) muscles of both lower extremities of patients undergoing TKA procedures. For a convenience sample of 15 patients, measurement of Sto2 was attempted at baseline, following subarachnoid block administration, and after tourniquet inflation and deflation.

Mean baseline Sto2 (SD) was 71% (6%) in the BF mus-cle and 66% (7%) in the GS muscle. Significant changes

in Sto2 values were observed following subarachnoid block, tourniquet inflation, and tourniquet deflation. The Sto2 returned to or above baseline in the BF muscle but did not return to baseline in the GS muscle following tourniquet deflation. Changes in tissue oxygen satura-tion resulting from use of a tourniquet can be continu-ously monitored with the use of an NIRS device. Further evaluation of the use of NIRS should be undertaken to determine if it could be used to guide safe duration and pressure limits for tourniquet inflation.

Keywords: Near-infrared spectroscopy, tissue oxygen saturation, total knee arthroplasty, tourniquet.

Use of Near-Infrared Spectroscopy to Measure Tissue Oxygen Saturation During Total Knee Arthroplasty With Use of a Tourniquet

Riley R. Gaines, DNP, CRNAAndi N. Rice, DNP, CRNAJeffrey C. Gadsden, MD, FRCPC, FANZCABrett T. Morgan, DNP, CRNACharles A. Vacchiano, PhD, CRNA, FAAN

According to the American Academy of Orthopedic Surgeons, more than 600,000 total knee arthroplasties (TKAs) are per-formed annually and by 2030 more than 3 million TKAs are expected to be performed.1

Although most of these procedures employ the use of a tourniquet, the inflation pressure and duration vary in practice, and use of a tourniquet has been associated with patient morbidity and occasionally mortality.2-9

Current clinical practice convention for tourniquet use on a lower extremity limits the inflation time to 2 hours at a pressure of 100 mm Hg above the patient’s systolic blood pressure. However, the optimal inflation pressure to enhance visualization and minimize potential tissue injury has never been determined.3,10 The lack of evidence-based guidelines regarding tourniquet use in the clinical setting suggests the need for an objective method to determine safe inflation pressure and time limits.

The use of near-infrared spectroscopy (NIRS) to measure tissue oxygen saturation (Sto2) in the frontal lobe of the brain has been employed in the operating room (OR) for more than 2 decades. However, few studies have examined its use for monitoring lower limb perfusion. Palanca et al11 established that muscle oxygen saturation decreased with increasing lower extremity elevation or decreased perfu-sion and suggested that NIRS may offer a direct measure of

muscle oxygen saturation in the lower extremity. Shadgan et al12 suggested that NIRS-derived Sto2 data could be used to predict the degree of tourniquet-induced injury. Reisman et al13 noted that NIRS appears to be a useful tool for measuring decreasing perfusion pressure over time, which may be a useful indicator of the onset of tissue injury and necrosis. Several studies have employed NIRS to measure Sto2 in the upper extremity during vascular occlusion via tourniquet, the so-called vascular occlusion test.14-17 The rates of descent and ascent of muscle Sto2 during occlusion and reperfusion, respectively, have been used to assess oxygen consumption in skeletal muscle and to define the origin of vascular disease.15

The evidence to date suggests that NIRS may have appli-cation for assessing Sto2 during lower extremity tourniquet use and therefore may serve as an objective guide to deter-mine safe inflation pressure and duration windows. The primary purpose of this pilot quality improvement project was to determine the practicality of using a NIRS device to measure lower extremity Sto2 during TKA procedures using a tourniquet. A secondary aim was to determine if changes in lower extremity Sto2 during tourniquet inflation and deflation could be appreciated using NIRS technology.

MethodsThis quality improvement pilot project was determined


to be exempt by the governing institutional review board. Near-infrared spectroscopy sensors (Equanox Advance Model 8004CA, Nonin Medical Inc) were applied to the biceps femoris (BF) and the gastrocnemius (GS) muscles on both the operative and nonoperative lower extremities of a convenience sample of 15 patients undergoing TKA (Figure 1). The BF sensor on the operative leg was posi-tioned just distal to the tourniquet. Tissue oxygen satura-tion was monitored continuously from all 4 sensors with a precalibrated Model 7600 oximeter (Nonin Medical Inc) by the project participants who had extensive expe-rience with the device, and the data were downloaded to a laptop computer at 1-second intervals.

All patients received a preoperative peripheral nerve block (PNB; adductor canal and posterior capsular), followed by either a subarachnoid block (SAB) admin-istered in the preoperative holding area or general anes-thesia with induction in the OR. Tissue oxygen satura-

tion values were collected at the following times: (1) a 5-minute baseline period in the preoperative holding area before administration of the SAB, (2) following SAB, (3) throughout the intraoperative period following tour-niquet inflation and deflation, and (4) postoperatively during transport to the postanesthesia care unit (PACU) and for the first 10 minutes in the PACU (Table 1).

Following baseline and post-SAB administration data collection, the oximeter sensor leads were disconnected and the patient was transported to the OR. On the pa-tient’s arrival in the OR, the sensor leads were recon-nected and the data download resumed except for the GS muscle of the operative leg, for which the sensor was in the operative field. General anesthesia was then induced for those patients not receiving a SAB; sedation, primarily by means of a propofol infusion, was initiated for those receiving a SAB. A sterile securement dressing (Tegaderm, 3M Co) was placed over the GS muscle sensor on the

Table 1. Flow Chart Showing Data Collection Time PointsAbbreviations: General Induction, general anesthesia begun for patients not receiving a subarachnoid block (4 of 15 patients); OR, operating room; PACU, postoperative anesthesia care unit; PNB, peripheral nerve block placed (all 15 patients); SAB, subarachnoid block placed (11 of 15 patients); SAB + Sedation = intravenous sedation begun for patients receiving a SAB (11 of 15 patients); StO2 Data, tissue oxygen saturation measured and recorded on bilateral lower extremities.

Table 2. Demographic Characteristics (N = 15)

Demographic Value

Age, mean (SD), y 63 (9)

Height, mean (SD), cm 170 (9)

Weight, mean (SD), kg 95 (11)

Body mass index, mean (SD), kg/m2 32 (4)

Gender, No. %

Female 7 (46.7)

Male 8 (53.3)

Surgical extremity, No. %

Left 8 (53)

Right 7 (47)

Anesthesia type, No. %

Subarachnoid block and peripheral 11 (73) nerve block

General anesthesia and peripheral 4 (27) nerve block

Figure 1. Application of Near-Infrared Spectroscopy Sensors to Biceps Femoris and Gastrocnemius MusclesaaNonin Equanox oximeter (Nonin Medical Inc) is in the foreground with its associated signal processors (blue pods). Note that patients who were monitored as part of the project had sensors on both lower extremities.


operative extremity, and a sterile ultrasonography probe cover (Safersonic–US Inc) was placed over the sensor lead and pod using sterile technique. The oximeter cable was then reconnected to the pod through a hole cut in the end of the probe cover, and data collection resumed. The covered sensor lead and pod were fixed in place at the patient’s ankle area with a sterile compression dress-ing (Coban, 3M Co), which was used to exsanguinate the extremity before tourniquet inflation.

A series of paired Student t tests were conducted using statistical analysis software (SPSS version , IBM Corp) to examine differences in Sto2 between and within the BF and GS muscle groups in the operative and nonoperative extremities at baseline and following the SAB, and within the operative extremity at baseline, following tourniquet inflation, and following tourniquet deflation. The level of significance was set at a P value of < .05.

To determine the rate of change of Sto2 from baseline following tourniquet inflation and deflation, we per-formed regression analysis with Sto2 plotted against time and then determined the slope of the line of best fit.

ResultsA convenience sample of 15 consecutive patients admit-ted for TKA had Sto2 measurements recorded. Patient demographics are noted in Table 2. The mean (SD) tourniquet inflation time for these 15 patients was 56.8 (14.9) minutes, with a range of 38.7 to 97.9 minutes. Eleven of the 15 patients had SAB, and the remaining 4 patients underwent general anesthesia. During surgical manipulation of the operative extremity, the monitor cable became disconnected from the oximeter sensor pod

in 4 of 15 patients, preventing complete capture of Sto2 measurements. In 3 of 15 patients the surgical extremity sensor pod itself malfunctioned and prevented complete capture of Sto2 measurements. Therefore, complete Sto2 data from baseline through recovery were available for 8 of the 15 patients evaluated.

A comparison of preoperative baseline mean Sto2 in the BF and GS muscle groups between the nonoperative and operative extremity showed no significant difference (Figure 2). However, preoperative baseline mean Sto2 in the GS muscle group was significantly lower than in the BF muscle group in both extremities.

We examined changes in Sto2 following administra-tion of the SAB because of the expected vasodilation that accompanies block administration. There was a measur-able and significant increase in mean Sto2 in both the BF and GS muscle groups in both extremities following SAB (Figure 3). The overall increase in Sto2 from baseline in both extremities and for both the BF and GS muscle groups following SAB was 10.5%.

Figures 4A and B show changes in mean Sto2 from baseline as a result of tourniquet inflation and tourniquet deflation in the operative leg in the BF and GS muscles for the SAB and the general anesthesia groups. There was a significant decrease from baseline in mean Sto2 on tourni-quet inflation in both muscle groups with both anesthetic types. The average decrease in mean Sto2 across both an-esthetic types was 24% and 27% in the BF and GS muscle groups, respectively. On tourniquet deflation there was a significant increase of 8.6% above baseline in mean Sto2 in the BF muscle in the SAB group, whereas the mean Sto2 simply returned to baseline in the general anesthesia

Figure 2. Comparison of Mean Baseline Preoperative Biceps Femoris (BF) and Gastrocnemius (GS) Muscle Tissue Oxygen Saturation in Nonoperative and Operative Extremity (N = 15)* P < .05 for BF vs GS.

Figure 3. Comparison of Mean Tissue Oxygen Saturation in Biceps Femoris (BF) and Gastrocnemius (GS) Muscles in Nonoperative and Operative Extremities at Baseline and After Subarachnoid Block (SAB) (n = 11)* P < .05 for BF baseline vs BF post block; GS baseline vs GS post block in the nonoperative and operative extremities).


group. Tissue oxygen saturation did not return to baseline in the GS muscle for either the SAB or the general anes-thesia group. The mean Sto2 in the GS muscle was not significantly different on tourniquet deflation than it was while the tourniquet was inflated during the operative procedure for either anesthetic type. The sustained decre-ment in mean Sto2 below baseline in the GS muscle after the tourniquet was deflated was 15% and 20% in the SAB and general anesthesia groups, respectively.

Figure 5 is a comparison of the mean Sto2 at preop-erative baseline and following tourniquet deflation in the in the BF and GS muscles of the operative extremity for the 8 patients who had complete data capture (5 in SAB group and 3 in general anesthesia group). There was a 7% increase in mean Sto2 above baseline in the BF muscle fol-lowing tourniquet deflation; however, Sto2 did not return to baseline after tourniquet deflation in the GS muscle.

The mean Sto2 value in the GS muscle after achieving stability on tourniquet deflation was 17% below baseline.

Table 3 shows the mean time to return to or above baseline in the BF muscle (2 minutes, 28 seconds) or to achieve a stable Sto2 value in the GS muscle (16 minutes, 51 seconds) as well as the rate of change in mean Sto2 expressed as the slope of the line of best fit following tourniquet deflation in the operative extremity. The mean time to achieve a stable Sto2 in the GS muscle fol-lowing tourniquet deflation was, on average, 14 minutes and 23 seconds longer than the time to return to baseline or above in the BF muscle. In addition, the variability associated with the mean time to return to baseline or achieve a stable Sto2 following tourniquet deflation was greater in the GS muscle (SD = 10 minutes, 12 seconds) compared with the BF muscle (SD = 37 seconds). Finally, the mean slope of the line of best fit was 0.301 for the BF muscle and 0.024 for the GS muscle. Figure 6 shows a representative example of the changes from baseline in the BF and GS muscles in a patient with a SAB following tourniquet inflation and deflation. The example demon-strates the consistently higher Sto2 in the BF muscle vs the GS muscle starting at baseline, the increase in Sto2 after placement of the SAB, the decreased Sto2 following tourniquet inflation, and the increase in Sto2 above base-line in the BF muscle and the failure to return to baseline in the GS muscle following tourniquet deflation.

DiscussionThe primary purpose of this pilot project was to deter-mine the practicality of using a NIRS device to measure lower extremity Sto2 during TKA procedures using a

Figure 4. Comparison of Mean Tissue Oxygen Saturation in Biceps Femoris (BF) and Gastrocnemius (GS) Muscles in Operative Extremity at Baseline and After Tourniquet Inflation (T-Up) and Deflation (T-Down), by Anesthesia Group. A. Subarachnoid block group (n = 5). B. General anesthesia group (n = 3).* Figure 4A: P < .05 for Baseline vs T-Up; T-Up vs T-Down; Baseline vs T-Down in BF muscle/Baseline vs T-Up in GS muscle. Figure 4B: P < .05 for Baseline vs T-Up in the BF muscle/Baseline vs T-Up; Baseline vs T-Down in GS muscle.

Figure 5. Comparison of Mean Tissue Oxygen Saturation in Biceps Femoris (BF) and Gastrocnemius (GS) Muscles in Operative Extremity at Baseline and After Tourniquet Deflation (T-Down) in All Patients With Complete Data Capture (n = 8)* P < .05 for Baseline vs T-Down in the BF and GS muscles. Error bars indicate standard deviation.


tourniquet. We were indeed able to acquire Sto2 values using a Nonin Model 7600 oximeter and Model 8004CA sensors at baseline, and following tourniquet inflation and deflation. Our secondary aim was to determine if changes in lower extremity Sto2 during tourniquet infla-tion and deflation could be captured using NIRS technol-ogy. We were able to obtain baseline Sto2 measurements in 15 patients in the BF and GS muscles of both lower extremities and therefore have added to the knowledge base with respect to “normal” Sto2 values in the leg. Our findings of a baseline mean (SD) Sto2 of 65% (7%) in the GS muscle support the findings of Comerota et al,18 who reported a mean (SD) Sto2 in the GS muscle of 65% (19%) in a group of “normal” subjects. In our study, we were able to capture an increase in Sto2 values in both the BF and GS muscles following SAB, presumably associ-ated with the resultant vasodilation. We were also able to capture the predicted decline in Sto2 on tourniquet infla-tion and the consequent reduction in blood flow.

In most of our sample for which we obtained com-plete data, there was an increase in Sto2 above baseline in the BF muscle following tourniquet deflation, which is consistent with the reactive hyperemia after a period of vascular occlusion reported in the literature. Comerota et al18 reported a mean time for Sto2 to return to baseline in the GS muscle of 1.95 minutes in normal subjects after a walking exercise, which was comparable to our finding of a mean time to return to or above baseline in the BF muscle following tourniquet deflation of 2 minutes and 28 seconds. An unexpected finding was the failure of the Sto2 to return to baseline in the operative extremity GS muscle following tourniquet deflation. The mean GS muscle Sto2 during this period was 55%, which was not significantly different than the mean Sto2 achieved following tourni-quet inflation but was significantly lower than baseline. The mean rate-of-change slope in Sto2 calculated for the operative extremity GS muscle following tourniquet deflation in 8 patients was essentially 0 (0.024), further indicating the failure of the Sto2 to return to baseline in the immediate postoperative period. This finding suggests there is incomplete resolution of the regional hypoxia in

the muscles of the lower leg following tourniquet defla-tion in the immediate postoperative period.

The Model 7600 oximeter calculates Sto2 based on a 70% contribution from venous blood and 30% from arte-rial blood and therefore is purported to be a measure of both oxygen supply and demand. Applying this premise to our findings and assuming that oxygen demand would increase following a period of reduced blood flow, ongoing cellular metabolism, and the resultant oxygen debt in-curred during tourniquet inflation suggest that in the BF muscle on tourniquet deflation there is an increase in oxygen delivery; however, there appears to be a de-crease in oxygen delivery in the GS muscle. Contributors to a decreased oxygen delivery to the GS muscle could include any of the following: (1) surgical trauma, edema, pressure created by the wound dressing, and elevation of the extremity; (2) an alteration in local mediator–driven

Table 3. Time for Tissue Oxygen Saturation to Return to or Above Baseline in Biceps Femoris Muscle or to Achieve Stable Value in Gastrocnemius MuscleaEight observations.bRate-of-change slope after tourniquet deflation.

Time, min:s Muscle Mean (SD) Median Range

Biceps femorisa

Time to return or above baseline 2:28 (0:37) 2:00 1:52-3:20

Slopeb 0.301 (0.146) 0.299 0.145-0.596

Gastrocnemiusa

Time to stability 16:51 (10:12) 16:28 4:02-23:48

Slopeb 0.024 (0.028) 0.022 0.002-0.079

Figure 6. Changes From Baseline in Biceps Femoris (BF) and Gastrocnemius (GS) Muscles in a Single Patient With Subarachnoid Block (SAB) After Tourniquet Inflation (T-Up) and Deflation (T-Down)aaBaseline value in this example is the mean of a 5-minute preoperative data collection period. The other data points represent the peak or trough following SAB, T-Up, and T-Down.


vasodilation as a result of tissue injury and/or nerve block; or (3) a “steal” phenomenon whereby increased oxygen consumption in the large upper leg muscles following the period of tourniquet-induced tissue hypoxia results in a reduction in available oxygen to the lower leg muscles. Such a reduction in oxygen delivery could contribute to the muscle weakness, electromyographic changes, and increased pain reported to be caused by mechanical com-pression from a tourniquet.19-21 In this regard, Ejaz et al8 showed that TKA procedures without use of a tourniquet result in better functional outcomes and improved knee range of motion in the early period of rehabilitation.

The primary limitation of this proof-of-concept pilot study is the small number of attempted observations complicated by the even more limited number of com-plete datasets from baseline through tourniquet defla-tion. A larger sample size is not only necessary to verify the apparent failure of Sto2 to return to baseline in the GS muscle in the immediate postoperative period, and perhaps beyond, but also to support evaluation of the effect of longer tourniquet inflation times and patient co-morbidities that could potentially affect lower extremity oxygen supply. We did not collect blood pressure data, and it is possible that episodes of “hypertension” and “hypotension” during tourniquet inflation or on defla-tion could have contributed to changes in perfusion and Sto2. There were several logistical and technical problems associated with the data capture. Maintaining sterility of the operating field with a nonsterile sensor applied to the area of the GS muscle required the development of a technique to enclose the sensor, sensor lead, and its asso-ciated pod within a sterile envelope. The sensor lead with pod was subsequently fixed to the ankle area and exposed to frequent motion and impact during manipulation of the extremity required by the TKA procedure. Despite the careful connection of the pod to the oximeter cable and fixing of the pod to the patient’s ankle area, there were instances in which the cable became disconnected from the pod and in which the sensor pod failed to function, resulting in loss of data transfer.

To determine the value of tissue oximetry as an objec-tive method to make decisions about the safe duration of tourniquet application and inflation pressure would require that a threshold Sto2 value clearly associated with tissue injury and negative patient outcomes be defined. A starting point for establishing that threshold value would be correlation of Sto2 measurements in muscles groups of the lower extremity during varying tourniquet infla-tion periods and pressures to biomarkers of tissue injury such as lactic acid, pH, base deficit, and serum creatine phosphokinase.

ConclusionWe have found that changes in Sto2 resulting from the use of a tourniquet can be continuously monitored with

the use of an NIRS device. Determining the potential ap-plicability of NIRS technology to surgical tourniquet use during TKA procedures is the first step needed toward establishing objective Sto2 guidelines. Further study of the measurement of Sto2 by application of this technol-ogy and correlation with markers of tissue injury could lead to an objective guide to determine safe duration and pressure limits for tourniquet inflation.

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7. Murphy CG, Winter DC, Bouchier-Hayes DJ. Tourniquet injuries: pathogenesis and modalities for attenuation. Acta Orthop Belg. 2005;71(6):635-645.

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9. Dennis DA, Kittelson AJ, Yang CC, Miner TM, Kim RH, Stevens-Lapsley JE. Does tourniquet use in TKA affect recovery of lower extremity strength and function? A randomized trial. Clin Orthop Rel Res. 2016;474(1):69-77. doi:10.1007/s11999-015-4393-8

10. Sato J, Ishii Y, Noguchi H, Takeda M. Safety and efficacy of a new tour-niquet system. BMC Surg. 2012;12:17. doi:10.1186/1471-2482-12-17

11. Palanca AA, Yang A, Bishop JA. The effects of limb elevation on mus-cle oxygen saturation: a near-infrared spectroscopy study in humans. PM R. 2016;8(3):221-224. doi:10.1016/j.pmrj.2015.07.015

12. Shadgan B, Reid WD, Harris RL, Jafari S, Powers SK, O’Brien PJ. Hemodynamic and oxidative mechanisms of tourniquet-induced muscle injury: near-infrared spectroscopy for the orthopedics set-ting. J Biomed Opt. 2012;17(8):081408-081401. doi:10.1117/1.JBO.17.8.081408

13. Reisman WM, Shuler MS, Kinsey TL, et al. Relationship between near infrared spectroscopy and intra-compartmental pressures. J Emerg Med. 2013;44(2):292-298. doi:10.1016/j.jemermed.2012.06.018

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high altitude. High Alt Med Biol. 2013;14(3):256-262. doi:10.1089/ham.2012.1109

18. Comerota AJ, Throm RC, Kelly P, Jaff M. Tissue (muscle) oxygensaturation (Sto2): a new measure of symptomatic lower-extremityarterial disease. J Vasc Surg. 2003;38(4):724-729. doi:10.1016/S0741-5214(03)01032-2

19. Saunders KC, Louis DL, Weingarden SI, Waylonis GW. Effect of tour-niquet time on postoperative quadriceps function. Clin Orthop Rel Res.1979(143):194-199.

20. Worland RL, Arredondo J, Angles F, Lopez-Jimenez F, Jessup DE.Thigh pain following tourniquet application in simultaneous bilateraltotal knee replacement arthroplasty. J Arthroplasty. 1997;12(8):848-852. doi:10.1016/S0883-5403(97)90153-4

21. Tai TW, Chang CW, Lai KA, Lin CJ, Yang CY. Effects of tourniquetuse on blood loss and soft-tissue damage in total knee arthroplasty: arandomized controlled trial. J Bone Joint Surg Am. 2012;94(24):2209-2215. doi:10.2106/JBJS.K.00813

AUTHORSRiley R. Gaines, DNP, CRNA, practices at Lynchburg General Hospital in Lynchburg, Virginia. At the time this work was being performed she was a

student in Duke University School of Nursing, Nurse Anesthesia Program, Durham, North Carolina.

Andi N. Rice, DNP, CRNA, has practiced in academic institutions, community hospitals, and office-based practices and is a consulting asso-ciate in Duke University School of Nursing, Nurse Anesthesia Program.

Jeffrey C. Gadsden, MD, FRCPC, FANZCA, is an associate professor and chief, Division of Orthopedics, Plastics, and Regional Anesthesiology, and director, Regional Anesthesiology and Acute Pain Medicine Fellow-ship at Duke University Hospital, Durham, North Carolina.

Brett T. Morgan, DNP, CRNA, is an assistant professor and program director at Duke University School of Nursing, Nurse Anesthesia Program.

Charles A. Vacchiano, PhD, CRNA, FAAN, is a professor at Duke Uni-versity School of Nursing, Nurse Anesthesia Program.

DISCLOSURESThe authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.


This retrospective cohort study aimed to explore the study institution’s intraoperative ketamine use during kyphoplasty and compare narcotic requirements in patients who received intraoperative ketamine with those who did not. The authors hypothesized that a single dose of ketamine during kyphoplasty would reduce postoperative narcotic consumption. Included patients underwent kyphoplasty under monitored anesthesia care between 2012 and 2013. Excluded patients were younger than 18 years or had general anesthesia, endotracheal intubation, or major intra-operative complications. Narcotics were converted into morphine equivalents for comparison. Analysis included χ2, correlation analyses, multivariate regres-sion analysis, and analysis of variance. Overall, 279 patients were included. Men were a minority of the sample, 26.2% (73/279). More than 83% of patients

were ASA class 3 (232/279), and more than 50% repaired a single vertebra (154/279). A single dose of ketamine was administered in 15.8% of kyphoplasties, with an average dose of 38.7 mg (range = 2-150 mg). Intraoperative ketamine administration was predictive of decreased intraoperative narcotic requirements (P < .001) but was not associated with decreased post-operative narcotic requirements (P = .442). Patients remained hemodynamically stable in the preoperative and postoperative period. Ketamine did not reduce postoperative narcotic consumption but reduced intra-operative narcotic consumption in this sample.

Keywords: Intraoperative narcotic consumption, ket-amine, kyphoplasty, postoperative narcotic consump-tion, postoperative pain.

Single Dose of Ketamine During Kyphoplasty Procedures Does Not Reduce Postoperative Narcotic Consumption

Seth M. Sharp, MSN, RN, CRNAElisha A. Chance, BSAS, CCRCTorin Karsonovich, DOSteven Cubbison, DOKene T. Ugokwe, MD

Ketamine, first used in 1964 as an intraop-erative anesthetic agent, is a well-established and broadly studied anesthetic and analgesic agent.1-17 Despite an abundance of literature, ketamine’s efficacy to treat perioperative pain

in spinal procedures remains controversial, attributed partly to study heterogeneity and lack of dosing stan-dards.2,3,9,13,14,17 Systematic reviews published in 1999,14 2006,2 and 20119 concluded that ketamine appears to reduce postoperative pain intensity and analgesic consumption without significant side effects. However, Bell’s group2 and Schmid et al14 could not perform meta-analyses on preincisional or perioperative admin-istration, respectively, secondary to vast heterogeneity among the studies. Interestingly, in 2011, Laskowski and colleagues9 performed a focused meta-analysis on peri-operative ketamine use, excluding studies that used any form of regional anesthesia. They reported that the least opioid reduction was found in the most homogeneous groups.9 Devin and McGirt3 were not able to determine optimal postoperative pain protocols in spinal surgery because there was a paucity of evidence and conflict-

ing grade I evidence. Indeed, 7 randomized controlled trials examining ketamine’s analgesic efficacy in spinal procedures have been performed since 1996 with vari-ous study designs, dosing schemes, standard anesthetic techniques, and outcomes.1,6,7,10-12,15 In 2016, results of a retrospective study with historic controls from a level I trauma center in Canada suggested there was no statistical difference in any analyzed category between conventional postoperative therapy and conventional therapy plus ket-amine in patients undergoing spine surgery.16

At the current study institution, ketamine is used ac-cording to the clinician’s discretion. Nurse anesthetists’ and anesthesiologists’ confidence in and comfort with using ketamine vary, which appears to be a national trend.8 Conflicting perceptions attributed to knowledge deficits and fears regarding ketamine, among other reasons, were identified in a 2016 survey of the American Society of Pain Management Nurses.8 Survey respondents included postanesthesia care nurses, nurse anesthetists, and operating room nurses.8 In their survey, Klaess and Jungquist8 identified not only vast differences in ket-amine dosing regimens but also inconsistent use in each


state, where some hospitals administer ketamine and others do not, regardless of size or academic affiliation.

The purposes of this study were to explore the study institution’s intraoperative ketamine use during kyphoplasty and to compare narcotic requirements in patients undergoing kyphoplasty who received ketamine intraoperatively vs those who did not. The authors hy-pothesized that intraoperative ketamine administration during kyphoplasty would reduce postoperative narcotic consumption.

Materials and MethodsAfter institutional review board approval, the authors performed a retrospective chart review of consecutive patients undergoing kyphoplasty at a regional level I trauma center in northeast Ohio. Written informed consent was not required because the authors used pre-existing information from medical records.

Included patients underwent a kyphoplasty procedure (International Classification of Diseases, Ninth Revision procedure code 81.66) under monitored anesthesia care between January 1, 2012, and May 31, 2013. Excluded patients were younger than 18 years, underwent general

anesthesia with endotracheal intubation, had a major in-traoperative complication, or had Advanced Cardiac Life Support initiated intraoperatively.

The authors chose the period from January 2012 to May 2013 because the study institution’s standard an-esthetic technique for kyphoplasty changed from moni-tored anesthesia to general anesthesia on June 1, 2013. For the purposes of this retrospective chart review, an intraoperative complication was defined as a document-ed complication in a patient’s intraoperative record or postoperative progress note. Patients with intraoperative complications were excluded because these conditions would affect narcotic administration.

The following variables were extracted from the elec-tronic medical record: patient demographics, number of vertebrae repaired, surgery duration, ASA class, and hospital length of stay. Also extracted were total narcotic administration 6 hours preoperatively, intraoperatively, and 6 hours postoperatively; mean arterial pressure and heart rate 6 hours preoperatively and 6 hours postopera-tively; intraoperative ketamine administration and total ketamine dose if administered; intraoperative placement of an epidural block; documentation of unwanted events

Table 1. Descriptive Patient CharacteristicsAbbreviation: VAS, visual analog scale. aSignificantly less than no-ketamine group (P = .013).

Overall Ketamine No ketamine Variable (N = 279) (n = 44) (n = 235)

Age, mean (SD), y 77.42 (11.76) 74.75 (12.58) 77.92 (11.56)

Weight, mean (SD), kg 83.86 (112.16) 95.71 (141.60) 81.64 (105.96)

Procedure length, mean (SD), min 59.04 (15.59) 62.48 (18.85) 58.40 (14.87)

VAS pain score, mean (SD) 5.66 (3.23) 6.91 (2.84) 5.43 (3.25)

Hospital stay, mean (SD), d 3.29 (3.14) 3.41 (2.94) 3.26 (3.19)

Morphine equivalents

Preoperative 1.24 (2.81) 1.42 (3.23) 1.20 (2.73)

Intraoperative 12.34 (7.26) 9.85 (7.94)a 12.81 (7.05)

Postoperative 5.78 (9.98) 6.84 (7.43) 5.58 (10.39)

Vertebra repaired, No. (%)

1 154 (55.2) 25 (56.8) 129 (54.9)

2 92 (33) 14 (31.8) 78 (33.2)

3 30 (10.8) 5 (11.4) 25 (10.6)

4 3 (1.1) 0 (0) 3 (1.3)

ASA class, No. (%)

1 2 (0.7) 1 (2.3) 1 (0.4)

2 15 (5.4) 2 (4.5) 13 (5.5)

3 232 (83.2) 37 (84.1) 195 (83.0)

4 30 (10.8) 4 (9.1) 26 (11.1)

Epidural block placement, No. (%)

No 152 (54.5) 27 (61.4) 125 (53.2)

Yes 127 (45.5) 17 (38.6) 110 (46.8)


(dysphoria, hallucinations, delirium, postoperative intu-bation, or death). The final variable obtained from the health record was the highest visual analog scale (VAS) pain score 6 hours postoperatively.

The VAS pain score is a common method of assess-ing patients’ pain. The patient assigns a number for pain intensity from 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. The authors chose a 6-hour postoperative period because ketamine has a half-life less than 6 hours.18 It is unlikely that ketamine administered as a single dose would influence pain scores and narcotic administration after the 6-hour postoperative period. For consistency, the authors applied the 6-hour window to the preoperative period as well.

Data were entered into a spreadsheet (Excel 2010, Microsoft Corp, Redmond, WA) and imported into statis-tical analysis software (SPSS 17.0, SPSS Inc, Chicago, IL) for data analysis. All recorded narcotics were converted into morphine equivalents (MEQ) to allow comparison across groups. Patients who did and who did not receive ketamine intraoperatively were compared with statistical control for confounding variables. Analysis included χ2, correlation analyses, multivariate regression analysis, and analysis of variance. Statistical significance was estab-lished with α ≤ .05.

ResultsOverall, 338 charts were reviewed and 279 patients were included. The most common reason for exclusion was general anesthesia with endotracheal intubation. Two patients were excluded because of a major intraopera-tive complication; neither had received ketamine. Males accounted for a minority of the sample, 26.2% (73/279). More than 83% of patients were ASA class 3 (232/279), and 55.2% were repairing a single vertebra (154/279). Other patient characteristics are displayed by group in Table 1. There were no continuous ketamine infusions

administered in this sample. A preincisional, single dose of ketamine was administered in 15.8% of the kypho-plasties included (44/279). The average ketamine dose among the 44 patients who received it was 38.7 mg, ranging from 2 mg to 150 mg. When ketamine was cal-culated as a weight-based dose, the average dose was 0.53 mg/kg with a range from 0.01 mg/kg to 1.64 mg/kg.

All patients were hemodynamically stable in the preoperative and postoperative periods. Heart rate and mean arterial pressure did not significantly vary between patients who did and did not receive ketamine intraop-eratively. Heart rate and mean arterial pressure in the postoperative period were similar to the preoperative period among all groups, and there were no unwanted events (dysphoria, hallucinations, delirium, intubations, or deaths) documented in the postoperative period. In the 6-hour preoperative period, there was no difference in narcotic consumption between patients who received intraoperative ketamine (1.42 MEQ, SD = 3.23) and pa-tients who did not (1.20 MEQ, SD = 2.73, t [df = 277] = −0.472, P = .637).

Increased intraoperative narcotic consumption was associated with higher preoperative morphine require-ments, longer procedures, younger age, lower ASA class, and male gender (all P < .05). Epidural block placement, postoperative pain scores, and number of vertebrae re-paired were not associated with intraoperative narcotic requirements. Patients who received a single dose of ket-amine required significantly less intraoperative narcotics than patients who did not receive ketamine: 9.85 MEQ (SD = 7.94) vs 12.81 MEQ (SD = 7.05), t (df = 277) = 2.51, P = .013 (Figure).

In multivariate regression analysis with forward selec-tion (Table 2), longer procedures (β = 0.08), younger patients (β = −0.23), and any ketamine use (β = −4.01) was predictive of decreased intraoperative narcotic re-quirements (model F = 20.13, P < .001, R2 = 0.180). Intraoperative placement of an epidural block did not sig-nificantly affect intraoperative narcotic administration. Patients without an epidural block consumed 11.85 MEQ (SD = 6.36) and patients with an epidural consumed 12.93 MEQ (SD = 8.21), t (df = 277) = −1.24, P = .218.

Postoperative narcotic consumption was associated with pain scores, preoperative narcotic requirements, intraoperative narcotic consumption, number of repaired vertebrae, and age (all P < .05). Procedure length, gender, ASA class, weight, and epidural block placement were not associated with postoperative narcotic requirements. The average postoperative narcotic dose was 6.84 MEQ (SD = 7.43) when patients received intraoperative ket-amine, and 5.58 MEQ (SD = 10.39) when patients did not receive intraoperative ketamine (t [df = 277] = −0.77, P = .442; see Figure). Multivariate regression analysis with forward selection (Table 3) revealed that higher preoperative narcotic doses (β = 1.35), higher pain scores

Figure. Mean Intraoperative and Postoperative Narcotic Comparisons in Milligrams of Morphine by Ketamine Administration


(β = 0.06), and greater number of repaired vertebrae (β = 0.167) were predictive of increased narcotic use in the postoperative period (model F = 38.73, P < .001, R2 = 0.301). Receiving an intraoperative epidural block did not significantly affect postoperative narcotic con-sumption. Patients with and without an epidural block consumed similar amounts of postoperative narcotics: 5.90 MEQ (SD = 13.01) vs 5.68 MEQ (SD = 6.49), respec-tively, t (df = 277) = −0.19, P = .853.

DiscussionThe purposes of this retrospective cohort study were to explore the study institution’s intraoperative ketamine use during kyphoplasty and to compare narcotic require-ments in patients who received intraoperative ketamine with those who did not. The authors hypothesized that in-traoperative ketamine administration during kyphoplasty would reduce postoperative narcotic consumption. In the current study observing a homogeneous group of mostly elderly patients with multiple comorbid conditions, a single dose of ketamine during kyphoplasty was not as-sociated with reduced narcotic consumption or reduced VAS pain scores in the 6-hour postoperative period, but it reduced intraoperative narcotic consumption.

Less than one-fourth (16%) of the current sample re-ceived ketamine, and in those who did, the weight-based doses of ketamine administered ranged from 0.01 mg/kg to 1.64 mg/kg. The small percentage of patients receiving ketamine confirms that clinicians at the study institu-tion are divided regarding intraoperative ketamine use. The wide ketamine dosing range found in 44 patients is in accordance with Klaess and Jungquist’s8 2016 survey results that demonstrated administration inconsistencies and a myriad of dosing calculations used in practice.

Despite various study designs across the literature, the

current findings were more in-line with investigators who found no difference in postoperative pain.12,15,16 Nitta and colleagues12 investigated continuous intraoperative and postoperative ketamine administration in spinal surgeries. They reported no difference in patient-controlled analge-sia or VAS pain scores in their prospective, randomized investigation, but they excluded ASA class 3 patients and those who had preoperative analgesia.12 Subramaniam et al15 similarly conducted a prospective, randomized trial of continuous intraoperative and postoperative ketamine infusion in major spine surgeries. They included ASA class 3 and opioid-tolerant patients but also reported no difference in postoperative analgesia.15 The retrospective study by Vaid et al16 of opioid-tolerant adults undergo-ing spinal surgery demonstrated that the addition of a continuous ketamine infusion to a conventional postop-erative pain regimen also did not reduce pain scores and opioid consumption. The current study’s results mirror the findings of Garcia-Navia et al,5 who concluded that single ketamine doses did not reduce postoperative pain or opioid consumption but did reduce intraoperative opioid requirements in gynecologic procedures.

Observations reported in this retrospective chart review are plausible. Ketamine’s short duration of action may provide therapeutic benefit within a limited time-frame,18 with a subsequent “rebound” increase in opioid requirement once the effects have subsided. All ket-amine doses administered in this investigation were preincisional, 1-time doses. This may explain why use of intraoperative narcotics was reduced in the ketamine group, but postoperative narcotic consumption was similar between groups. Another explanation is selection bias; patients who received ketamine intraoperatively may have been opioid tolerant. Preoperative pain scores and data on opioid tolerance were not collected for the

Table 2. Factors Predicting Intraoperative Narcotic Consumption (N = 279)aaR 2 = 0.180.

Unstandardized Standard Standardized Variable β coefficient error β coefficient P

Constant 25.88 3.02 8.58 < .001

Age −0.23 0.03 −0.37 < .001

Ketamine use −4.01 1.10 −0.20 < .001

Procedure length 0.08 0.03 0.17 .002

Table 3. Factors Predicting Postoperative Narcotic Consumption (N = 279)aaR 2 = 0.301.

Unstandardized Standard Standardized Variable β coefficient error β coefficient P

Constant −3.33 1.51 .028

Preoperative narcotics 1.35 0.19 0.38 < .001

Visual analog scale 0.86 0.17 0.28 < .001

Vertebra repaired 1.67 0.70 0.12 .019


current investigation, but 6-hour preoperative narcotic consumption was not significantly different between groups. It is reasonable to assume that most, if not all, patients included in this retrospective chart review were being treated for back pain in the weeks or months before their procedure. Because ketamine use is according to the anesthesiologist’s or nurse anesthetist’s discretion at the study facility, it is likely that patients who received ketamine were under the care of an anesthesiologist or nurse anesthetist who was confident in and comfort-able with the agent. Another consideration is timing of ketamine administration. In the current effort, the in-traoperative ketamine administration was preincisional. Administering ketamine as a continuous infusion during the procedure may have led to better pain management in the postoperative period.1,6,7,10,11

Despite the lack of an opioid-sparing effect in the post-operative period, the results of the current study suggest there is a clinically important opioid-sparing effect intra-operatively. When intraoperative narcotics are reduced, respiratory and airway integrity are preserved. Given the known respiratory depression due to opioid use, ket-amine administration may be a beneficial adjunct to avoid intubation in monitored anesthesia care surgical cases, especially in an elderly population with moderate to high operative risks. Importantly, no hemodynamic instability or adverse events related to intraoperative ketamine use were observed. This is particularly noteworthy given the mostly elderly population with multiple comorbidities.

This retrospective chart review is unique for 4 reasons. First, the authors examined ketamine use in kyphoplasty procedures. A PubMed search using the text terms ket-amine and kyphoplasty yielded no pertinent publications. To the authors’ knowledge, the efficacy of ketamine in ky-phoplasty has not been specifically reported. Second, all 7 randomized controlled trials examining ketamine use in spinal procedures included patients who underwent surgery with general endotracheal anesthesia.1,6,7,10-12,15 The patients examined in the current study had moni-tored anesthesia care; the authors excluded any patients who received general anesthesia. Third, more than 90% of patients included in the current study were ASA class 3 or 4. In all 7 randomized controlled trials, patients with ASA classes 3 and 4 were either excluded1,6-7,12 or represented less than half of all included patients.10,11,15 Fourth, the average patient age was 77 years in the current study. In all 7 randomized controlled trials, 65 years was the average age,6,7,10-12,15 and the maximum age was 75 years.1 Klaess and Junquist’s8 survey respondents indicated that in practice, 55% of patient’s receiving ketamine were 65 years or older. It seems that previ-ously studied populations are not wholly representative of most patients who receive ketamine in practice. The current retrospective cohort study provides enlightening real-world information in an understudied population.

The results warrant ketamine practice standardization and further research in ketamine’s efficacy for the geriat-ric population in a randomized controlled design. Future research could include investigating ketamine efficacy during other monitored anesthesia cases.

Among this study’s limitation is its retrospective nature. As previously mentioned, ketamine use in kypho-plasty procedures at the study facility is according to the clinician’s discretion. Secondary to clinician preference and a lack of practice standardization, there is inherent selection bias. Rationale behind who received and did not receive ketamine, as well as the dose administered, could not be determined. Another limitation is the small sample of patients receiving ketamine intraoperatively, and the wide dosing range observed in the patients who received it. This can be attributed to an absence of widely accepted guidelines regarding optimal dose, route, or length of therapy when ketamine is used off-label as an analgesic8; even the prescribing information acknowl-edges that dosage recommendations cannot be absolutely fixed when used as an anesthetic.18 As mentioned in the discussion, the authors did not collect preoperative pain scores or preoperative opioid tolerance variables. Knowing these patient characteristics may have provided further insight into the results. In the present study, only a 6-hour postoperative period was examined because of the short half-life of ketamine.18 Observing narcotic use for a 24-hour period may have suggested different results, but based on ketamine’s short half-life and the single-dose administration, extending the period to 24 hours may have inappropriately confounded narcotic consumption by collecting data that were not temporally associated with ketamine’s known pharmacokinetics. Despite the limitations, this investigation provides valu-able, clinically meaningful insight into real-world ket-amine use in this understudied patient population.

ConclusionA single, intraoperative, preincisional dose of ketamine did not reduce postoperative narcotic consumption, but reduced intraoperative narcotic administration, without un-wanted side effects in this study group. The results strength-en the need for standardization of ketamine practice.

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[sic] ketamine and morphine for postoperative pain control after lumbar disk surgery. Eur J Pain. 2006;10(7):653-658. doi:10.1016/j.ejpain.2005.10.005

2. Bell RF, Dahl JB, Moore RA, Kalso EA. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;(1):CD004603. doi:10.1002/14651858.CD004603.pub2

3. Devin CJ, McGirt MJ. Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and func-tional outcomes. J Clin Neurosci. 2015;22(6):930-938. doi:10.1016/j.jocn.2015.01.003

4. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice.


Acta Pharmacol Sin. 2016;37(7):865-872. doi:10.1038/aps.2016.5

5. Garcia-Navia JT, Tornero Lopez J, Egea-Guerrero JJ, Vilches Arenas A, Vazquez Gutierrez T. Effect of a single dose of lidocaine and ketamine on intraoperative opioids requirements in patients undergoing elec-tive gynecological laparotomies under general anesthesia. A random-ized, placebo controlled pilot study. Farm Hosp. 2016;40(1):44-51. doi:10.7399/fh.2016.40.1.9339

6. Hadi BA, Al Ramadani R, Daas R, Naylor I, Zelkó R. Remifent-anil in combination with ketamine versus remifentanil in spinal fusion surgery—a double blind study. Int J Clin Pharmacol Ther. 2010;48(8):542-548. doi:10.5414/CPP48542

7. Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth. 1996;43(3):212-215. doi:10.1007/BF03011736

8. Klaess CC, Jungquist CR. Current ketamine practice: results of the 2016 American Society of Pain Management Nursing Survey on Ketamine. Pain Manag Nurs. 2018;19(3):222-229. doi:10.1016/j.pmn.2018.02.063

9. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58(10):911-923. doi:10.1007/s12630-011-9560-0

10. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesi-ology. 2010;113(3):639-646. doi:10.1097/ALN.0b013e3181e90914

11. Nielsen RV, Fomsgaard JS, Siegel H, et al. Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blinded trial. Pain. 2017;158(3):463-470. doi:10.1097/j.pain.0000000000000782

12. Nitta R, Goyagi T, Nishikawa T. Combination of oral clonidine and intravenous low-dose ketamine reduces the consumption of postoperative patient-controlled analgesia morphine after spine surgery. Acta Anaesthesiol Taiwan. 2013;51(1):14-17. doi:10.1016/j.aat.2013.03.003

13. Rivkin A, Rivkin MA. Perioperative nonopioid agents for pain control in spinal surgery. Am J Health Syst Pharm. 2014;71(21):1845-1857. doi:10.2146/ajhp130688

14. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ket-amine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111-125. doi:10.1016/S0304-3959(99)00044-5

15. Subramaniam K, Akhouri V, Glazer PA, et al. Intra- and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake. Pain Med. 2011;12(8):1276-1283. doi:10.1111/j.1526-4637.2011.01144.x

16. Vaid P, Green T, Shinkaruk K, King-Shier K. Low-dose ketamine infu-sions for highly opioid-tolerant adults following spinal surgery: a retro-spective before-and-after study. Pain Manag Nurs. 2016;17(2):150-158.

17. Weinbroum AA. Non-opioid IV adjuvants in perioperative period: Pharmacological and clinical aspects of ketamine and gabapentinoids. Pharmacol Res. 2012;65(4):411-429. doi:10.1016/j.phrs.2012.01.002

18. Ketamine hydrochloride injection [package insert]. Rockford, IL: Mylan Institutional; 2017.

AUTHORSSeth M. Sharp, MSN, CRNA, is a nurse anesthetist in the Department of Anesthesia at Bel-Park Anesthesia Associates in Youngstown, Ohio. Email:[email protected].

Elisha A. Chance, BSAS, CCRC, is a clinical research coordina-tor for the Trauma/Neuroscience Research Department at St Elizabeth Youngstown Hospital in Youngstown, Ohio. Email: [email protected].

Torin Karsonovich, DO, a graduate of Lake Erie College of Osteopathic Medicine in Erie, Pennsylvania, is currently a neurosurgical resident at Advocate BroMenn Medical Center in Normal, Illinois. Email: [email protected].

Steven Cubbison, DO, is a hospitalist in the Department of Internal Medicine at St Elizabeth Boardman Hospital in Boardman, Ohio. Email: [email protected].

Kene T. Ugokwe, MD, is a neurosurgeon in the Department of Neu-rosurgery at St Elizabeth Youngstown Hospital. Email: [email protected].

DISCLOSURESThe authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did discuss off-label use within the article. Disclosure statements are available for viewing upon request.

ACKNOWLEDGMENTSThe authors wish to acknowledge Adam Schneider, P. Jacob Noll, and Kelly Bellia from the Department of Medical Education at St. Elizabeth Youngstown Hospital for their assistance with the study’s literature review, IRB proposal, and data collection. The authors also thank James Graham, PharmD, at St. Elizabeth Youngstown Hospital for his guidance with nar-cotic conversions. Finally, the authors acknowledge David Gemmel, PhD, from the Department of Research at St. Elizabeth Youngstown Hospital and Eric S. Emerick, MA, from Youngstown State University for statistical analysis assistance.


The rapid changes in the US healthcare system have resulted in collateral damage to many healthcare providers. Many of these changes have increased demands placed on providers, resulting in high preva-lence rates of burnout throughout various healthcare specialties. One healthcare specialty that has reported a recent surge in burnout in the United States is the Certified Registered Nurse Anesthetist (CRNA). Despite these concerns, most of the burnout research

on anesthesia providers has focused on anesthesiolo-gists and CRNA-equivalent anesthesia providers from other countries. This is particularly concerning given CRNAs’ critical role in the future of US healthcare delivery. The purpose of this integrated review was to examine, discuss, and synthesize the burnout con-struct related to CRNAs practicing in the United States.

Keywords: Burnout, CRNA, interventions, measurement.

Burnout and the Nurse Anesthetist: An Integrative Review

Brian Del Grosso, MS, CRNAA. Suzanne Boyd, PhD, MSW

Stress is a mental, emotional, and physical strain due to an interaction between personal and professional traits.1 Occupational stress in the healthcare profession is inevitable; how-ever, when the provider uses appropriate cop-

ing strategies, stress can exert beneficial effects such as increased motivation to face challenging situations. When exposure occurs over a prolonged time, it can result in a psychological syndrome known as burnout. Since its first published description in the 1970s, burnout has been extensively studied and recognized as a direct occupa-tional hazard for healthcare providers, with implications for colleagues, patients, and organizations.1,2 For example, various cross-sectional studies have demonstrated that provider burnout can result in physical and mental health problems (eg, depression, headaches, cardiovascular dis-ease), work/family relationship problems, and increased mental health problems (eg, depression, anxiety, sub-stance abuse).3,4 Burnout has also been found to have negative consequences on the health of the organization (eg, increased turnover, decreased job satisfaction, and absenteeism) as well as decreased quality and satisfac-tion of patient care.5-7 Despite the healthcare industry’s attempts to embrace strategies to improve the overall well-being of healthcare providers, interventions to miti-gate burnout have been largely unsuccessful, with recent surveys8 demonstrating burnout trends increasing toward greater than 50% of healthcare providers.1 This increase in burnout has become particularly concerning given that the US healthcare industry is rapidly changing in efforts to improve overall patient delivery of care while decreasing per capita costs.

Among the changes occurring in the healthcare land-scape is the increased utilization of highly trained, highly skilled professionals called advanced clinical providers.

Among advanced clinical providers, one particular group that may be prone to a higher incidence of burnout is Certified Registered Nurse Anesthetists (CRNAs). For more than 150 years, CRNAs have been providing anes-thesia services in the United States and are considered the primary providers in the military and most rural hospi-tals.9 Research continues to demonstrate CRNAs’ ability to provide safe, high-quality, and cost-effective anesthe-sia services.10 However, the increasing demands from political and bureaucratic healthcare changes combined with the demands of a stressful occupation may jeopar-dize this profession’s invaluable contribution. Although it may seem pragmatic to manage this syndrome through interventions aimed at the individual CRNA, the lack of conceptual clarity has created confusion and debate around the phenomenon’s prevalence rates, its factors, and its outcomes. Furthermore, because burnout is understood as an individual’s response to stressors specific to a given work environment, any cultural and occupational factors further limit the concept’s external validity.5,11,12 Although studies evaluating the anesthesia profession have increased over the past 2 decades, there seems to be a paucity of research focusing on CRNAs practicing in the United States. Therefore, the purpose of this integrated review was to examine and discuss burnout in CRNAs practicing in the United States. This review will examine and discuss ongoing conceptual and methodological inconsistencies that have resulted in confusion and debate around the burnout context and its measurements as it relates to the CRNA profession. A review of literature to identify common conceptual and methodological applications and an evaluation of current burnout research related to the anesthesia profession in-cluding CRNA providers practicing in the United States are conducted to identify common trends and gaps. This


review will include these issues, and their implications for future measurement, analysis, and interventions toward addressing CRNA burnout.

Review of Literature • Conceptualization of Burnout. Despite voluminous literature on burnout, conceptually, the term remains vague and overinclusive. For this reason, it seems ap-propriate to review the concept’s key characteristics. A review of consensually accepted characteristics about the concept may help clarify some of its underpinnings, creating a better understanding in evaluating burnout among CRNA providers. Burnout is generally viewed as a psychological phenomenon that emerges from a prolonged response to chronic interpersonal job-related stressors.2 Although the psychological symptoms of burnout were described as early as the 1950s, the concept was adapted into the psychological literature in the 1970s by Freudenberger (1974) and Maslach (1976).2 Despite more than 4 decades of extensive research, the burnout context still provokes much controversy between burnout scholars, which has resulted in confusion and doubt among researchers and practitioners.2,13 Burnout scholars believe some of the concept’s fragmented state may stem from how it was originally introduced into the literature.2 For instance, researchers initially took an inductive methodological approach derived from either a social (eg, Maslach) or clinical (eg, Freudenberger) psy-chological perspective.2 This approach allowed research-ers to describe the phenomenon as well as demonstrate it existed well beyond a few observations; however, its introduction as a social and clinical phenomenon also re-sulted in a lack of attention to its theoretical foundation, leaving researchers struggling to integrate and evaluate a construct without boundaries.2 This resulted in varied meanings of the term, lack of empirical research, and an overexpansion of the concept.2

Despite this early limitation, burnout’s popularity as a topic of research grew and shifted away from its more descriptive phase and toward a more empirical one.2 The shift in research created advancements in theory and methods that provided researchers with more precise defi-nitions and methodological tools for understanding and evaluating burnout.13 With a more enriched understand-ing of burnout and an expanding literature, various mea-sures were proposed.13 The Maslach Burnout Inventory (MBI) was the first standardized measure that helped shape burnout research and remains one of the most uti-lized scales in burnout research in the healthcare profes-sion.14 However, researchers have continued to question the need for MBI’s 3-dimensional approach (emotional exhaustion, depersonalization, and personal accomplish-ment), which has resulted in other measures being pro-posed that conceptualize burnout as a 1-dimensional (eg, the Burnout Measure15) or 2-dimensional (Oldenburg

Burnout Inventory16) view.13 Proponents of the single dimensional assessment tend to argue that studies have predominantly demonstrated the exhaustion dimension having the strongest correlation with burnout, and the additional dimensions are predicated on incidental find-ings that create redundancy, confusion, and lengthy surveys.2 Critics of the single dimensional view argue that empirical studies have provided greater support for a multidimensional approach; conceptualizing burnout as unidimensional fails to distinguish it from related constructs such as exhaustion, work-related stress, and depression, and would lose the ability to properly identify specific factors and outcomes related to burnout.2,13,17 A result of this debate is that the measures used to assess burnout are often closely linked to the author’s assump-tions of the construct.2,13 Therefore, when selecting an ap-propriate instrument to evaluate burnout, the practitioner and researcher must look beyond the instrument’s face value and understand the scale’s conceptual meaning.13 Although some scholars and practitioners still call the MBI and its operational definition the gold standard of burnout measurement, it is important to note that only the exhaustion domain has had general acceptance among scholars as the core representation of burnout.2,13

The increase in standardized measures combined with the contributions from the industrial-organizational psy-chology field has provided conceptual models address-ing the complex relationships between various factors and dimensions of burnout.2,17 Given that burnout is generally accepted as a job-related construct, most of these conceptual models focus on job factors such as job stress (workload, role conflict, and role ambigu-ity), job satisfaction, supervision (social support on the job), and withdrawal (turnover, absenteeism).2 More recently, conceptual models have been based on stress theories, and researchers have started to focus more attention on personality variables (hardiness, locus of control), personal health, and relationships with friends and family.12,13 The increase in attention to the theo-retical foundations of burnout has allowed researchers to integrate empirical results within conceptual frame-works. For instance, models such as the Conservation of Resources theory18 and the Job Demands-Resources model19 are used frequently in the healthcare profession and have consistently demonstrated that burnout is a result of prolonged job-related stress stemming from a mismatch between the demands of the job and the re-sources available to the healthcare provider.2 As burnout became more theory driven, these models became the cornerstone in empirical research on common etiologic factors of burnout: interpersonal, individual, and orga-nizational.2,13,17

The development of such models has generated em-pirical research with stronger theoretical foundations that posit several common characteristics of the causes


and consequences of burnout. First, the consensus has viewed causes of burnout to be situational (eg, job-related), as well as individually related. Additionally, decades of research have found that job-related factors, compared with individual-related factors, have a stronger correlation to burnout, particularly in the exhaustion domain.2,12,13,17 Second, burnout’s harmful effects on the individual, healthcare organizations, and patient health are recognized by many scholars. At the individual level, stress-related health concerns among workers (eg, cardiac disease, headaches) are strongly correlated with the ex-haustion dimension.2,5 Organizationally, studies have consistently demonstrated strong correlation between burnout and withdrawal behaviors such as absenteeism, incivility, and high turnover.6,9 Finally, from a patient care standpoint, the research has been limited and highly variable; however, decreased patient satisfaction and in-creased medical errors have been shown to have strong correlation with burnout.11,13

Despite burnout’s popularity in the literature, concep-tual overlap with other constructs continues to cause con-fusion among providers.2,17 One of the major problems with burnout continues to be construct proliferation, which usually occurs when “new” constructs are theoret-ically or empirically indistinguishable from existing con-structs.20 Although professional use of the term burnout began more than 40 years ago, the concept continues to overlap conceptually with terms that preceded it, such as depression, anxiety, and occupational stress. Although integrating burnout into larger conceptual models (eg, stress models) has created some clarity, debates on the construct’s appropriate dimensions continue to under-mine its empirical distinctiveness.2 Discriminant validity refers to the extent to which measures of distinct con-structs are empirically unrelated.20 Despite some studies using psychometric tests (eg, multitrait-multimethod or confirmatory factor analysis) to empirically demonstrate burnout’s distinctiveness, interpretations can be highly subjective and variable because it is operationalized through measures that predominantly estimate the re-lationship through correlation studies; thus, confusion persists.20 An example is the burnout-depression overlap debate. Depression is clinically defined as feelings of sadness, emptiness, hopelessness, helplessness, and low energy; however, from a theoretical perspective, depres-sion is generalized distress that entails all life’s domains. Burnout, on the other hand, is a work-related phenom-enon involving worker’s complete depletion of energetic resources.21 Criticisms of burnout’s singularity still elicits hundreds of articles and article responses that argue for a more inconclusive construct. This debate represents the extent of confusion about burnout among producers and consumers of the literature.

• Burnout Among Anesthesia Providers. Advancements that have helped improve patient safety combined with

healthcare reforms have resulted in highly demanding, stressful work environments that can expose the anesthe-sia provider to numerous stressors.3,11,22 Concerns about burnout’s impact on anesthesia providers and their pa-tients have led to an increased empirical focus on burnout by both practitioners and scholars.5 Some of these studies have demonstrated that anesthesia providers not only are experiencing this syndrome but are at a particularly higher risk than other healthcare specialties. For example, a 2016 Medscape physician lifestyle report found that anesthesiologists ranked third, behind critical care phy-sicians and emergency medicine physicians, in burnout symptoms.11 Most studies of burnout among anesthesia providers have relied on self-reported surveys; the results have yielded wide variation in burnout prevalence rates, determinants, and consequences. However, there have been some obvious factors that seem to have a higher correlation toward burnout in the profession. Nyssen et al22 completed a systematic review that demonstrated time constraints, work overload, clinical task complex-ity, fear of harming the patient, workplace environment, lack of job control, and family constraints as common factors that contributed to anesthesia provider burnout. In a systematic review, Sanfilippo et al11 found high workload to be a primary factor toward burnout among anesthesiologists, residents, and CRNAs. Other studies have demonstrated that burnout negatively affects the an-esthesia provider’s mental and physical health, giving rise to various psychosomatic symptoms. De Oliveira et al23 surveyed more than 1,500 residents from various US hos-pitals and found burnout to be positively correlated with alcohol and cigarette consumption. Studies that evaluated how burnout affects the anesthesia provider’s occupation demonstrated that burnout negatively affected healthcare systems in ways that were associated with poorer patient safety and quality of care. Kluger et al24 and de Oliveira et al23 found burnout to be negatively correlated with job satisfaction and positively correlated with lower quality of care. Sociodemographic characteristics that can con-tribute to anesthesia provider burnout include hospital type, gender, age, and support network. Results have not been consistent; for example, the review by Sanfilippo et al11 found only one study that reported women being at higher risk of burnout, whereas other studies either found no correlation or higher risk of burnout in men.

Despite research demonstrating several common themes among various anesthesia providers, burnout is an individual experience that is specific to the work context and influences such as the occupational environ-ment (eg, work setting, managerial support), professional background (eg, nurses, advanced clinical providers, physicians), demographic variables (eg, sex, race, ex-perience), and personality traits, all of which can vastly influence data outcomes.2,5 For example, Chiron and col-leagues6 demonstrated that junior French anesthesiolo-


gists scored higher on emotional exhaustion compared with senior anesthesiologists, whereas Meeusen and coworkers25 demonstrated older Dutch nurse anesthe-tists scored higher on emotional exhaustion compared with younger nurse anesthetists. Although organizational factors are considered the primary factors resulting in burnout among anesthesia providers, various types of factors can be dependent on situational variables. For example, Lederer et al26 found that job-related factors leading to burnout among Austrian anesthesiologists in-cluded limited complexity of work, lack of time control, and lack of ability to participate; in contrast, the study by Morais et al1 found job-related factors such as strained work relationships, unskilled leaders, work overload, and surgeon attitudes resulted in burnout among Portuguese anesthesiologists. Therefore, valid concerns can be raised of the possibility that situational variables can act as moderators and create inaccurate assumptions and in-terventions of burnout without greater context-specific research. For these reasons, we sought articles that ex-amined burnout among practicing CRNAs.

Review of CRNA Burnout• Method of Literature Search. The reviewers undertook a comprehensive literature search using the following data-bases: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, PsycARTICLES, and Google Scholar. We followed Torraco’s27 suggestions for an integrated review. We used the PICOS approach (Population, Intervention, Comparison, Outcomes, and Study Design; Table 1) to guide our criteria for our primary search. This included empirical burnout re-search that focused specifically on CRNAs practicing in the United States. Additionally, the criteria included English-language articles published in peer-reviewed journals from January 1974 to February 2018. The wide date range was reflective of burnout articles appearing as early as 1974 and the hope to capture the extent of empirical studies since burnout was first introduced. Our search focused around keywords and medical subject headings (MeSH) that included perioperative wellness, perioperative burnout, perioperative stress, anesthesia well-ness, anesthesia burnout, anesthesia stress, anae* AND burnout, anae* AND stress, anes* AND burnout, and anes*

AND stress. Additional searches included secondary literature reviews and primary journals: AANA Journal, Anesthesia & Analgesia, Current Opinion in Anesthesiology, and Anesthesia.

The initial search revealed 38 potential articles based on keywords and MeSH terms. Additional sources were then reviewed and, as displayed in the Figure, a total of 46 potential articles were found. The abstracts were reviewed for eligibility, and 28 articles were removed because they were outside the United States, involved anesthesia trainees, or included only anesthesiologists. The remaining 18 articles were reviewed in their entirety to ensure they met our strict criteria, and 3 systematic review articles and 13 articles that assessed burnout with instruments that measured occupational stress were removed. Although the exhaustion dimension of burnout has been theoretically linked to occupational stress, empirical research has demonstrated these authors’ mea-sures tend to have different dimensions.2 For this reason, we believed it was best practice to exclude articles that measured burnout through stress measures.

• Results. The results of the literature search yielded only 2 studies—Hyman et al5 and Elmblad et al28—that directly measured burnout of CRNAs in the United States (Figure).

Hyman et al5 examined work-related factors and re-sources correlated with burnout in various perioperative providers, such as surgeons, resident physicians, nurses, CRNAs, and anesthesiologists, who worked in the same operating room. They used an online survey that consist-ed of a modified MBI-Human Services Survey14 and the Social Support and Personal Coping Survey. Of the 145 respondents, 20% were CRNAs, with an average age of 44 years and 51% male. The results of the survey demonstrat-ed the CRNA median burnout score (2.45) was higher compared with nursing (2.2) and other personnel (2.1), was that of similar to physicians (2.45), and lower com-pared with residents (4.05). Of the 3 dimensions, CRNAs scored lower on depersonalization (1.25) than emotional exhaustion (2.45). Several limitations of this study are worth mentioning. First, Hyman and colleagues5 did not mention the score cutoff for burnout. Second, the authors modified the MBI-Human Services Survey by asking pro-viders to focus on the past 2 to 4 weeks vs the past year as recommended by Maslach.14 They also increased the

Table 1. PICOS: Population, Intervention, Comparison, Outcomes, and Study DesignAbbreviation: CRNAs, Certified Registered Nurse Anesthetists.(Adapted with permission from Torraco,27 2005.)

PICOS Characteristics of studies included for the comprehensive search

Participants CRNAs actively practicing in the United States in any setting

Intervention Assessment of burnout

Comparison None

Outcomes Risk of burnout evaluated either by subscales or overall burnout

Study design Empirical studies that used a burnout measurement scale


interval range from 6 to 9. Both these changes can cause reliability and validity issues with the instrument. Third, it was unclear how work-related factors and resources correlated with the MBI dimensions for CRNAs or with the demographics (eg, age, gender).

In the study by Elmblad et al,28 the authors used the Copenhagen Burnout Inventory29 and the Nursing Incivility Scale to evaluate the influence of workplace in-civility on burnout in 385 Michigan CRNAs. The survey respondents primarily consisted of women (69%), more than half (52%) of whom worked greater than 40 hours per week in hospital settings (76%). The authors demon-strated that CRNAs experienced “moderate” burnout levels (median = 42.8) and found the correlation between work-place incivility and burnout to be statistically significant (P < .0001).28 Elmblad et al28 demonstrated a direct linear relationship between workplace incivility and burnout. The study’s limitations that are worth noting included a limited response rate (22.6%) as well as whether other work-relat-ed factors or provider demographics had influence on the providers’ burnout levels were not mentioned.

DiscussionThe burnout context has been extensively studied for more than 4 decades and is no longer considered an

emerging problem but an occupational hazard in the healthcare industry. Given public expectations that healthcare delivery should be seamless, safe, and free from adverse events combined with administrative pro-duction pressures and the complex management for an aging population, the anesthesia provider is particularly prone to burnout. CRNAs are critical to the success of US healthcare reform. However, provider burnout may have a negative impact not only on this profession’s ability to manage the increasing demands of such changes, but to the healthcare system as a whole. Furthermore, the CRNA profession may be prone to additional and unique stressors such as ongoing political battles that question the profession’s integrity coupled with an occupational setting that tends to place CRNA providers between the field of nursing and medicine; these stressors can ulti-mately lead to one feeling undervalued. For example, a 2016 American Association of Nurse Anesthetists (AANA) survey demonstrated that 43% of their members found the political nature of the occupation to be stress-ful and 33% felt they were treated with a lack of respect.30 Therefore, the primary objective of our integrated review was to evaluate the potential impact that burnout may have on CRNAs in the United States. Although in the past 2 decades an increasing amount of burnout literature

Figure. PRISMA Diagram of CRNA Burnout Empirical Study Searcha Abbreviations: AANA, American Association of Nurse Anesthetists; CINAHL, Cumulative Index to Nursing & Allied Health Literature; CRNAs, Certified Registered Nurse Anesthetists; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. aPsycINFO.


has focused on the anesthesia provider, to the best of our knowledge, this is the first article that takes a more focused review.

Based on the search criteria (See Figure), our literature inquiries yielded only 2 studies of burnout in CRNAs in the United States, thus validating our assumption of the paucity of burnout research that focuses on CRNAs who deliver anesthetic care in the United States. Although these results were not surprising given that the profes-sion has historically focused more on the clinical aspects of patient care, this gap is particularly concerning when considering that an estimated 34% of the AANA member-ship in 2016 reported experiencing work-related stress.30 To help address this gap, we took a more pragmatic ap-proach toward reviewing burnout’s conceptualization, its methods, and its effects on the anesthesia profession as a whole. We identified several consensual agreements among burnout scholars related to the construct’s under-

pinnings. First, burnout is the result of prolonged stress at work caused by a mismatch between the demands associated with the job and the resources of the pro-vider. Second, burnout causes are generally divided into situational (job-related) and individual factors. Third, compared with individual-related factors, job-related factors have a stronger correlation with the dimensions of burnout that result in various negative outcomes affect-ing the providers’ professional and personal relationships as well as their overall health and the health of their or-ganization and patients. Fourth, regardless of one’s theo-retical view of burnout, exhaustion is widely considered the central quality of burnout and the most obvious man-ifestation of this negative trait affect. Finally, selection of burnout measures is directly linked to how the researcher views burnout; therefore, selection of measures should be viewed beyond the scale’s face value.

• Measurement Considerations. Many of the criticisms

MeasureBurnout

definitionDimensional

view FormatPsychometric

quality Key features

Staff Burnout Scale for Health Professionals, 198034

Physical and emotional exhaustion involving the development of negative job attitudes, poor professional self-concept, and loss of empathetic concern for patients

One dimension that assesses the adverse cognitive, psychophysiologic, behavioral, and affective reactions of burnout

Thirty items on a 6-point, Likert-type scale; 20 items assess burnout and 10 items assess truthful-ness of answers. Single composite score.

Internal consis-tency coefficient ranges from 0.82 to 0.93. Validity studies found burnout correlated positively with turnover, absen-teeism, tardiness, discipline, and alcoholism.

Lacks theoretical foundation. Not widely used. Sam-ple sizes of valid-ity studies were small. Correlation coefficients sub-stantially differed across studies.

Maslach Burnout Inventory, 198614

A syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment that can occur among individuals who do “people” work

Three dimensions that assess emo-tional exhaustion (EE), deperson-alization (DP), and personal accom-plishment (PA)

Twenty-two items on a 7-point, Likert-type scale; each dimension is evaluated indi-vidually. Authors recommend scor-ing separately, but studies have used an averaged single composite score.

Internal consis-tency coefficient ranges from 0.71 to 0.90. Validity studies predomi-nantly found EE negatively cor-related with job satisfaction and control and posi-tively correlated with various work factors (workload).

Lacks theoretical foundation. Most highly used and compared mea-sure of burnout. Designed spe-cifically for human services profes-sion.

The Burnout Measure, 198815

A state of physical, emotional, and mental exhaustion caused by long-term involvement in situations that are emotionally demanding

One dimension that assesses emotional exhaus-tion

Twenty-one items scored on a 7-point, Likert-type scale. Single com-posite score.

Internal consis-tency coefficients 0.88-0.95. Valid-ity studies found burnout correlated negatively with job satisfaction, perceived control, and social support and had a positive correlation with poor health, job demands, and stressors.

Lacks theoretical foundation. Sec-ond most widely used scale with thousands of subjects. Debates exist whether scale measures only 1 dimen-sion. Has a short 10-item version called Burnout Measure-S.35

Table 2. Summary of Common Burnout Measurement Tools


of burnout as a construct have yet to be convincingly re-solved. This ongoing lack of agreement has left the field without definitive boundaries and with a wide variation in measurement tools that are commonly seen in today’s literature. A lack of a common operational definition of burnout complicates efforts to establish criterion valid-ity. To advance the understanding of any organizational construct, we must also be able to appropriately measure and analyze it. A focus on core research principles, such as building on existing models and frameworks with strong psychometric properties, may provide an easier path toward understanding burnout in the CRNA profes-sion.31 For instance, one aspect to consider is related to the amount of psychometric research (eg, inter-item reli-ability, test-retest consistency, factor analysis) involved in developing the measures (ie, questions). The Burnout Measure15 and the MBI14 are 2 of the few measures of burnout that have undergone numerous psychometric validity studies.2 Additional measures are sometimes reported; however, many of them have limited to no

psychometric testing, which limits their accuracy in mea-suring burnout.2 For example, the widespread establish-ment of do-it-yourself instruments that have appealing headings such as “how burned out are you?” or “what’s your burnout score?” Likewise, modification (eg, adding or deleting) of validated scales can also have an impact on the scale’s psychometric properties and the potential loss of its accuracy.32 Therefore, providers should use common healthcare-specific measurement scales (Table 214-16,29,33-35) that are grounded in strong foundational theory and psychometric evalution.2,31,32

Despite the pleas to use well-validated scales to measure burnout, even the scales mentioned in Table 2 pose limita-tions that continue to create a diverse group of risk factors and consequences, which result in a clouded delineation of the concept from similar negative effects (eg, depres-sion, anxiety). For instance, without definitive concep-tualization of burnout, each scale is based on how the author conceptualizes burnout, and selection of a particu-lar scale implies acceptance of the definition provided by

Copenhagen Burnout Inventory, 200529

State of physical, emotional, and mental exhaustion that results from long-term involvement in work situations that are emotionally demanding

Three dimen-sions that assess personal burnout (PB), work-related burnout (WRB), and client-related burnout (CRB)

Nineteen items scored on a 5-point Likert-type scale. PB (6 items), WRB (7 items), and CRB (6 items) Single com-posite score.

Internal consis-tency coefficient of 0.85. Validity studies found positive correlation between burnout and job satisfac-tion, absenteeism, sleep distur-bances, drug use, and intention to quit.

Based on “Situ-ational Model of Illness.” Instru-ment developers believe that core of burnout is fatigue and exhaustion. Designed to mea-sure burnout over time. Primarily used in international stud-ies. Free.

Oldenburg Burnout Inventory,16 1999

Psychological syndrome that may emerge when employees are exposed to a stressful working environment, with high job demands and low resources

Two dimensions that assess exhaustion (affec-tive, physical, and cognitive) and dis-engagement.

Sixteen items scored on a 4-point Likert-type scale. Exhaus-tion (8 items) and disengagement (8 items). Single mean score.

Internal consis-tency coefficient ranges from 0.85 to 0.87. Positive correlation with job demands and negatively cor-related with job resources. Score high in exhaus-tion indicates poor coping; high in dis-engagement indi-cates poor working conditions.

Based on the Job-Demands Resources (JD-R) model. Uses both positively and negatively worded items. Highly debated on engagement and burnout relation-ship. Free.

Shirom-Melamed Burnout Measure,33 2003

Affective reaction to prolonged exposure to occupational stress in which job demands exceed an individual’s adaptive resources

Three dimensions that assess emo-tional exhaustion (EE), physical fatigue (PF), and cognitive weari-ness (CW)

Fourteen items scored on a 7-point Likert-type scale. Each sub-scale is averaged and scored sepa-rately.

Internal consis-tency coefficient ranges from 0.85-0.87. Valid-ity studies found that burnout has a positive correla-tion with physical and mental illness and is negatively correlated with job resources.

Based on Con-servation of Resources (COR) theory. Evaluates how individual has felt in past 30 days. Limited studies on reli-ability and validity. Strong correlation evaluating health outcomes related to burnout.

Table 2. Summary of Common Burnout Measurement Tools (continued)


the test authors. For example, use of the Shirom-Melamed Burnout Measure33 implies a multidimensional view of burnout that consists of emotional exhaustion, physi-cal fatigue, and cognitive weariness. Another caution to consider is that most empirical research heavily relies on correlational studies that collect subjective, self-reported data. Although some strong and interesting findings have come from this research, it is prone to various limitations of response bias, such as the inability to validate one’s true feelings or the lack of introspective ability of the provider.2,32 Because burnout is considered a progressive process, a third caution worth mentioning is related to researchers predominantly using a cross-sectional study design, which does not permit a test of causal hypoth-eses, even though these links are usually assumed and discussed. Ultimately, no scale is perfect; however, by following the common concept ideas of burnout, strong core research principles, and selection of a measurement tool that best fits to that provider’s work environment may help mitigate some of these limitations.

• Interventions and Future Implications. Despite the advancements and ongoing interests in burnout research, large systematic reviews30-32 continue to demonstrate inconsistent results in alleviating provider burnout. Although there is a general consensus among burnout scholars that occupational stressors are the primary factors of provider burnout, most interventional ap-proaches use an individual-directed strategy.36,37 The current hierarchal nature of healthcare organizations places providers in an environment with limited control over stressors, which limits the effect of individual-directed strategies.2 Panagioti et al38 demonstrated that organizational strategies such as increasing control over schedule or reducing one’s workload had moderate effects in decreasing burnout; however, because these types of interventions tend to involve greater complexity and costs, they remain limited. Without effective inter-ventions, burnout may continue to rise, causing reduced quality of care and patient satisfaction and having detri-mental effects on the provider and healthcare system as a whole. Therefore, research must first focus on CRNA burnout to identify and evaluate how key occupational and professional characteristics correlate with burnout factors, its consequences, and its prevalence before at-tempting interventional approaches.

Our review illustrates that not only is research related to the CRNA profession vastly limited but also a wide variation of burnout factors and consequences greatly hinders the accuracy of appropriate interventions. Therefore, future research will benefit from conducting context-specific research that incorporates unique CRNA job-related characteristics. For instance, CRNAs function in a variety of practice models, which can create such qualitative job-related stressors as role ambiguity, role conflict, and various social dynamics (eg, incivility, social

support). Additionally, CRNAs function in a variety of occupational settings, which also has been shown to have variable burnout characteristics and prevalence rates. Although much of burnout research has focused on job-related factors, people do not simply elicit a re-sponse to the job, but rather bring unique qualities to the job.2 Therefore, future research must also evaluate how individual characteristics such as demographics (eg, gender, age, family life) and personality (eg, hardi-ness, resilience, self-esteem) influence burnout. A major limitation to current empirical research is the high reli-ance on cross-sectional design; therefore, future research must also focus on more direct statistical methods, such as multivariate analyses, in the hope of evaluating and analyzing the extent to which hypothesized variables contribute to provider burnout. As previously mentioned, most burnout studies use self-reported surveys, so future studies would benefit from also including objective assessments to avoid influencing factors such as a pro-vider’s current emotional affective state. Having a greater understanding of the direct relationship between causes and consequences of burnout will allow greater manage-ment of interventions.

ConclusionAlthough theoretical and empirical work related to both the burnout context and the CRNA profession paints a daunting and discouraging picture, the profession has shown its resilience through its 150-year history of de-livering anesthesia services in a safe and high-quality fashion. Our overall findings support our initial pre-sumption of the gaps in burnout research in CRNAs, which suggest there is much work to be done. Because theoretical knowledge tends to transfer from academ-ics to practitioners at the concept level, the ongoing criticisms related to the construct’s conceptualization will only continue to create empirical redundancies. Our lit-erature review, however, clearly shows enough evidence supporting that the phenomenon has widespread nega-tive impact. An effective way to improve CRNA burnout, from an organizational standpoint, is to measure it, develop and implement interventions, and then measure again. However, for burnout research to advance in the CRNA profession, it must not only increase but also provide context-specific data of how this phenomenon affects CRNAs practicing in the United States. This re-search becomes even more imperative when one exam-ines the current and future direction of healthcare. The healthcare industry is undergoing a massive and sweep-ing culture change. Healthcare organizations are merging to form large, volume-based accountable care organiza-tions. In hopes of maintaining relevance, the profession must look beyond the ability of providing cost-effective, high-quality care and must enhance our individual well-being through identifying such hindrances as burnout.


After all, if we cannot take care of ourselves, who will take care of our patients?

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38. Panagioti M, Panagopoulou E, Bower P, et al. Controlled interven-tions to reduce burnout in physicians: a systematic review and meta-analysis. JAMA Intern Med. 2017;177(2):195-205. doi:10.1001/jamainternmed.2016.7674

AUTHORSBrian Del Grosso, MS, CRNA, has been a CRNA at Atrium Health in Char-lotte, North Carolina, for the past 10 years. He is currently a fourth-year Health Services Research PhD student at the University of North Carolina Charlotte. Email: [email protected].

A. Suzanne Boyd, PhD, MSW, is an associate professor of social work and program faculty, Health Services Research Doctoral Program at the University of North Carolina Charlotte, School of Social Work. Email: [email protected].



Assessment of pulmonary dysfunction is vital to anesthetists. Measurements including the gradient between the alveolar partial pressure of oxygen (PAo2) and the arterial partial pressure of oxygen (Pao2), called the PAo2 - Pao2 , and the ratio of the Pao2 to the fraction of inspired oxygen (FIo2) (Pao2/FIo2 ratio) are useful in determining the extent of acute lung injury. A literature review via MEDLINE using the terms PAo2 - Pao2 , Pao2/FIo2 ratio, and pulmonary dysfunction was performed to identify articles on the use of these measures in the perioperative period. Both measures have been found to predict clinical outcomes in most settings. We also developed a mathematical model to calculate values of the PAo2 - Pao2 and the Pao2/

FIo2 ratio. In model results, as in clinical findings, both respond appropriately to reflect worsening pulmonary dysfunction when shunt or diffusion barrier (alveolar Po2 – pulmonary capillary partial pressure of oxygen) is increased. However, both are also sensitive to the FIo2. The increase in the Pao2/FIo2 ratio as the FIo2 increases is particularly problematic because it could disguise a deterioration in the patient’s pulmonary status. The PAo2 - Pao2 and the Pao2/FIo2 ratio should be used with an understanding of their limitations.

Keywords: PAo2 - Pao2, Pao2/FIo2 ratio, pulmonary dysfunction.

Role of Alveolar-Arterial Gradient in Partial Pressure of Oxygen and PaO2/Fraction of Inspired Oxygen Ratio Measurements in Assessment of Pulmonary Dysfunction

David E. Harris, PhD, RN Maribeth Massie, PhD, MS, CRNA

Measures of pulmonary dysfunction are important to anesthetists caring for patients in the operating suite and assess-ing patients preoperatively. Such mea-surements allow quantification of the

level of pulmonary dysfunction1 and identification of patients who are critically ill in the preoperative or post-operative periods.2,3 In the operating suite, serial determi-nations of measures of pulmonary dysfunction facilitate assessment of the impact of interventions such as denitro-genation,4 changes in position,5 or changes in ventilator settings6 on pulmonary function.

Several measurement tools including the gradient between the alveolar partial pressure of oxygen (PAo2) and the arterial partial pressure of oxygen (Pao2), ex-pressed as the PAo2 - Pao2 (or the AaDo2),7 and the ratio of the Pao2 to the fraction of inspired oxygen (FIo2)—the Pao2/FIo2 ratio—can be used to quantify pulmonary dysfuncton.1,2 Increasing values of the PAo2 - Pao2 and

decreasing values of the Pao2/FIo2 ratio suggest deterio-rating pulmonary function (Table 1).

This article provides a review and critical evaluation of representative articles on the use of the PAo2 - Pao2 and the Pao2/FIo2 ratio as measures of pulmonary dys-function with an emphasis on the perioperative period. Articles were identified via MEDLINE searches using the terms PAo2 - Pao2, Pao2/FIo2 ratio, and Pao2. We under-take this review because diseases that increase shunt (eg, atelectasis), or the diffusion barrier for oxygen from the alveoli to the blood (eg, pulmonary edema, pulmonary fibrosis, and heart failure), as well as factors other than pulmonary dysfunction (eg, changes in FIo2 and PCO2) can have an impact on these parameters. A review of these factors will demonstrate the clinical importance of these measures and facilitate their effective use.

History and Review of Literature• PAo2 - Pao2. The alveolar gas equation was first pro-

Table 1. Measures of Pulmonary Dysfunction and Response to Worsening DysfunctionAbbreviations: FIO2, fraction of inspired oxygen; PAO2 - PaO2, alveolar-arterial gradient in partial pressure of oxygen.

Measure of pulmonary dysfunction Response to worsening dysfunction

PAO2 - PaO2 Increases

PaO2/FIO2 ratio Decreases


posed by Wallace Fenn in 19468:PAo2 = FIo2 (PB – PH2O) – PACO2/R

wherePB (barometric [atmospheric] pressure) = 760 mm Hg

at sea levelPH2O (vapor pressure of water) = 47 mm Hg at body

temperature and PB = 760 mm HgPACO2 (alveolar PCO2) = PaCO2 under most circum-

stancesR (respiratory coefficient) = 0.8 for people consuming

a standard diet9

This equation allows the calculation of the Po2 in the alveoli and reflects the following facts. (1) The partial pressure of inhaled oxygen = FIo2 × Barometric pres-sure. (2) Inhaled oxygen is diluted by water vapor as the inhaled gas is humidified in the airways. (3) Oxygen is replaced on virtually a molecule-for-molecule basis by carbon dioxide (CO2) in the alveoli. Because the Pao2 can be measured from arterial blood, calculation of the PAo2 allows the determination of the PAo2 - Pao2.

In animal models the PAo2 - Pao2 increased in venti-lated dogs subjected to near-drowning, an effect attrib-uted to increased right-to-left shunt or areas of low ven-tilation to perfusion matching (V/Q) caused by flooded alveoli.10 Also in ventilated dogs, PAo2 - Pao2 fell as the alveolar partial pressure of carbon dioxide (PACO2) was increased via hypoventilation, an effect the authors at-tributed to either the dilation of airways responsible for collateral ventilation or the decreased affinity of hemo-globin for oxygen (right-shift in the oxygen-hemoglobin dissociation curve) caused by increased PACO2 (and increasing PaCO2) or acidosis (Bohr effect).11

Similar changes occur in humans. When healthy human participants varied their PaCO2 levels by changing their level of ventilation, the PAo2 - Pao2 fell as PaCO2 in-creased.7 In a second study, the PAo2 - Pao2 increased as the FIo2 was increased in patients with chronic obstruc-tive pulmonary disease (COPD), suggesting that caution should be used in the interpretation of the PAo2 - Pao2 when the FIo2 changed.12 And in a third study, when healthy human participants used a rebreathing system with a CO2 absorber to induce hypoxia, reduction of the PAo2 caused a narrowing of the PAo2 - Pao2.

13 Because the FIo2 is a driver of the PAo2, this result extends to healthy patients the findings reported earlier for patients with COPD on the impact of the FIo2 on PAo2 - Pao2.

12 The PAo2 - Pao2 also allows risk stratification in

pulmonary disease and in the perioperative period. For patients hospitalized with community-acquired pneu-monia, those with PAo2 - Pao2 90 mm Hg or higher had lower survival rates that those with lower PAo2 - Pao2 values.14 Similarly, another study of patients with community-acquired pneumonia found that patients who died had an average PAo2 - Pao2 at admission of 181 mm Hg and a Pao2/FIo2 ratio of 139, whereas those who

survived had a lower average admission PAo2 - Pao2 (107 mm Hg) and a higher Pao2/FIo2 ratio (169).15 Thus, the PAo2 - Pao2 is useful in assessing prognosis in patients with community-acquired pneumonia.

In patients with end-stage liver disease and portal hypertension being prepared for liver transplant, the PAo2 - Pao2 increased as the severity of the liver disease increased, with PAo2 - Pao2 of 27 mm Hg on room air in those with the most severe disease. The negative impact of end-stage liver disease on pulmonary function was attributed to high intra-abdominal pressures, pleural effusion, and interstitial pulmonary edema.16 During surgery, higher PAo2 - Pao2 (average PAo2 - Pao2 = 80.9 mm Hg at FIo2 of 0.4) were found in patients undergoing liver transplant if those patients also demonstrated shunt determined by echocardiography after injection of saline with air bubbles.17

The PAo2 - Pao2 has also been used to assess the impact of positive end-expiratory pressure (PEEP) on oxygen-ation in patients undergoing laparoscopic prostatectomy in whom Trendelenburg positioning and the introduction of gas into the peritoneal cavity might compromise venti-lation. A PEEP of 10 cm H2O produced the lowest PAo2 - Pao2 but at the expense of elevated airway pressure. The authors concluded that 7 cm H2O of PEEP produced adequate oxygenation without this unwanted result. The PAo2 - Pao2 values varied with surgical times but were generally in the range of 80 to 125 mm Hg at FIo2 of 0.5.18

Postoperatively, the PAo2 - Pao2 was found to cor-relate with increasing shunt in patients after open heart surgery19 and has been used to compare the level of pul-monary dysfunction after coronary artery bypass grafting in patients whose procedures were performed with and without a bypass pump. Patients whose procedures were performed off-pump had lower PAo2 - Pao2 than those performed on-pump.20

• Pao2/FIo2 Ratio. The Pao2/FIo2 ratio has gained popularity as a simple measure of pulmonary dysfunction among critically ill patients that can be used to predict disease outcome. Among patients with trauma, when pa-tients with acute lung injury were classified by the Pao2/FIo2 ratio, patients with severe injury (Pao2/FIo2 ratio < 100) had much higher mortality rates than those with less severe dysfunction (Pao2/FIo2 ratio > 250).21 Similarly, a Pao2/FIo2 ratio less than 250 was used as one criterion for defining hypoxia in patients admitted to the hospital with community-acquired pneumonia. Hypoxia was then employed as part of a combined measure (along with vital signs and chest radiography results) that predicted the ne-cessity for invasive respiratory or vasopressor support.22 However, the Pao2/FIo2 ratio is not always useful for pre-dicting clinical outcomes. In patients receiving mechani-cal ventilation for hypoxic respiratory failure, this ratio failed to predict successful extubation.23 The FIo2 was not specified and probably varied in these 3 studies.


Despite its limitations, the importance of the Pao2/FIo2 ratio as a predictor of clinical outcomes in criti-cally ill patients is illustrated by its inclusion in the cur-rently accepted definition of acute respiratory distress syndrome (ARDS), the Berlin Definition (Table 2). The level of ARDS was then used to suggest appropriate treat-ment.1 Because both the FIo2 and the level of PEEP can influence the Pao2/FIo2 ratio, some authors have recom-mended standardizing these to improve on the Berlin Definition of ARDS.24 This serves as a reminder that the impact of the FIo2 on the Pao2/FIo2 ratio must be consid-ered whenever this ratio is used.

The categories of the Pao2/FIo2 ratio used to define the severity of ARDS (see Table 2) have seen wide ap-plication. A Pao2/FIo2 ratio less than 202 at 3 hours after admission to the intensive care unit (ICU) was found to predict increased mortality in cardiac surgical patients.2 In brain-dead patients being considered for lung trans-plant, a Pao2/FIo2 ratio less than 200 was deemed to indicate unacceptably poor lung function.25 A Pao2/FIo2 ratio below 300 was used to define acute lung injury in patients with acute brain injury undergoing dilatational tracheostomy. In this retrospective analysis, one-third of the patients met the Berlin Definition of ARDS pre-operatively and one-tenth of the patients with ARDS experienced intraoperative hypoxia. The average Pao2/FIo2 ratio improved from the preoperative to the postop-erative period, and the procedure was deemed safe.3

Several studies used the Pao2/FIo2 ratio to investigate the impact of specific anesthesia interventions on intra-operative pulmonary dysfunction. Two studies evaluated obese patients undergoing laparotomy under general anesthesia, who are at particular risk of intraoperative impairment of oxygenation from compression atelectasis and resultant increased intrapulmonary shunt.4,26 The authors found that these patients maintained their Pao2/FIo2 ratio when diffusion atelectasis was minimized by avoiding the use of nitrous oxide, either by using 50% oxygen and 50% nitrogen in isoflurane anesthesia4 or by using xenon in oxygen anesthesia.26

The Pao2/FIo2 ratio has also been used to assess the impact of intraoperative ventilation strategies during 1-lung ventilation. One study searched for a ventilation strategy that avoids excessive tidal volumes and airway pressures during 1-lung ventilation. Higher tidal volume

ventilation (tidal volume = 8 mL/kg of ideal body weight) was compared with lower tidal volume ventilation (5 mL/kg of ideal body weight) with PEEP adjusted to maintain similar airway plateau pressures. The Pao2/FIo2 ratio was lower with the low tidal volume regimen, so this approach did not produce a benefit.6 A meta-analysis in-cluded studies comparing the Pao2/FIo2 ratio of patients undergoing thoracotomy and 1-lung ventilation with pressure-controlled ventilation vs volume-controlled ventilation and studies comparing conventional ventila-tion (tidal volume ≥ 7 mL/kg ideal body weight) with protective ventilation (tidal volume ≤ 6 mL/kg ideal body weight).27 Neither pressure-controlled ventilation nor protective ventilation improved intraoperative oxygen-ation as measured by the Pao2/FIo2 ratio.27

The Pao2/FIo2 ratio has also been used to assess the impact of ventilation strategy on blood oxygenation for patients under general anesthesia in the sitting posi-tion. Use of the sitting position for patients undergoing shoulder arthroscopy reduces anatomical distortion but can compromise cerebral perfusion. Cerebral perfusion can be maintained by inducing mild hypercapnia via hypoventilation, but this, in turn, can produce atelectasis and impaired oxygenation. A study of healthy patients undergoing shoulder arthroscopy under general anesthe-sia in the sitting position with sevoflurane maintenance without nitrous oxide compared the Pao2/FIo2 ratios of patients ventilated to normocapnia with those venti-lated to mild hypercapnia (end-tidal CO2 = 45 mm Hg). There was no decrease in the Pao2/FIo2 ratio with mild hypercapnia while regional brain oxygen saturation was maintained, suggesting a benefit for mild hypercapnia for this procedure.5

Another use of the Pao2/FIo2 ratio in patients under general anesthesia involved burn patients with ARDS maintained on a regimen of high-frequency oscillatory ventilation in the burn unit and transported to the op-erating suite for burn excision or wound grafting. The authors found that continuing high-frequency oscillatory ventilation in the operating suite did not result in a sig-nificant fall in Pao2/FIo2 ratio.28

Discussion of State of the ArtFor the anesthetist, the most important questions about the Pao2/FIo2 ratio and the PAo2 - Pao2 are the following.

Table 2. Values of PaO2/FIO2 Ratio for Acute Respiratory Distress Syndrome (ARDS) Categories in Berlin Definition of ARDS1,a

Abbreviation: FIO2, fraction of inspired oxygen. aAll measurements are in the presence of positive end-expiratory pressure ≥ 5 cm H2O.

ARDS severity PaO2/FIO2 ratio

Mild 200-300

Moderate 100-200

Severe ≤ 100


(1) What are the normal values of these parameters? (2) How do these values respond to changes in ventilator settings, age, and pulmonary disease? (3) What are the values of concern? To inform the discussion of these questions, we created a mathematical model that uses accepted pulmonary function equations (Table 3) to compute the Pao2/FIo2 ratio and the PAo2 - Pao2 (Table 4). These equations reflect the facts that (1) the oxygen content of the arterial blood is a weighted average of the content of the blood oxygenated in the pulmonary capil-laries and the oxygen content of the shunted blood9 and (2) there is an empirical relationship between hemoglo-bin saturation and Po2.

29

Two models using similar equations have been de-veloped previously. In both models, the Pao2/FIo2 ratio rose continuously as the FIo2 increased when the shunt was 0.02 of the cardiac output,30,31 as is the case in the model reported here (see Table 4, lines 1-5). The model we present includes 2 features not found in the other models cited: (1) It allows variation of the diffusion barrier across the respiratory membrane (as defined in Table 3) and (2) it computes both the Pao2/FIo2 ratio and the PAo2 - Pao2, allowing comparisons of these measures.

• Normal Values of Pao2/FIo2 Ratio and PAo2 - Pao2—and Their Response to Changes in Ventilator Settings. Measurements of the PAo2 - Pao2 in healthy participants were reported more than 50 years ago. These reports were before the Pao2/FIo2 ratio was in use, but the ratio could be calculated from the data provided in these studies. The results (Table 5) demonstrate that both the Pao2/FIo2 ratio (approximately 450 at FIo2 of 0.21) and the PAo2 - Pao2 (< 10 mm Hg at FIo2 of 0.21 for younger

patients) increase as the FIo2 increases.32,33 These experi-mental measurements are in remarkably good agreement with our model results (see Table 4), suggesting that our model results are clinically meaningful. The PAo2 - Pao2 increases and the Pao2/FIo2 ratio decreases with increas-ing age (see Table 5).32,33

The impact of changes in the FIo2 on both the Pao2/FIo2 ratio and the PAo2 - Pao2 even without changes in pulmonary function are of clinical importance. The in-crease in PAo2 - Pao2 as the FIo2 is increased12,13,32 could lead a practitioner to conclude that a patient’s pulmonary status was deteriorating when it was not. However, the increase in the Pao2/FIo2 ratio as the FIo2 is increased, both in experimental work32 and in models,30,31 falsely suggests improved pulmonary function. The model pre-sented here replicates these results. As the FIo2 increased from 0.2 to 1.0 in the normal case, the PAo2 - Pao2 rose from 5 to 45 mm Hg, and the Pao2/FIo2 ratio rose from 440 to 618 (see Table 4, lines 1-5). This phenomenon undoubtedly had an impact on the results of several clinical studies discussed in this article and complicates the application of Pao2/FIo2 ratio values in the Berlin Definition of ARDS (see Table 2). One solution that has been suggested to this problem is reporting the Pao2/FIo2 ratio only at a very high FIo2.

24,34 To understand the clinical importance of the impact

of FIo2 on measures of pulmonary dysfunction, consider a patient receiving mechanical ventilation at a lower FIo2 in the ICU transported to the operating suite for general anesthesia. If the FIo2 used in the operating suite is higher than that used in the ICU (as might often be the case), this could cause absorption atelectasis, increased

Table 3. Equations and Assumptions9,29 Used to Generate Model Results Displayed in Table 4

Equation 1QT × CaO2 = Qs × CvO2 + (QT – Qs) × CcO2

Where

QT = Cardiac output CaO2 = Oxygen content of the arterial capillary blood Qs = Shunted blood flow CvO2 = Oxygen content of the venous capillary blood CcO2 = Oxygen content of the pulmonary capillary bloodEquation 2

Hemoglobin saturation = ([23,400{(PO2)3 + 150 PO2}−1] + 1)−1

Equation 3Oxygen content = (1.36 × Hemoglobin concentration × Hemoglobin saturation) + (PO2 × 0.0031)

Equation 4DB = PAO2 – PCO2

Where DB = Oxygen diffusion barrier between alveoli and pulmonary capillaries PAO2 = Alveolar partial pressure of oxygen PCO2 = PO2 in pulmonary capillaries perfusing ventilated alveoliModel assumptions DB = 0 in the normal lung but can be varied in the model Qs = 0.02 of the cardiac output in the normal lung but can be varied in the model


shunt, and worsening pulmonary dysfunction. However, if the anesthetist relied on the Pao2/FIo2 ratio to assess pulmonary dysfunction, found a constant or slightly lower level of this parameter in the operating suite com-pared with the value calculated in the ICU, and ignored the expected increase in the Pao2/FIo2 ratio as the FIo2 increased, the deterioration in this hypothetical patient’s pulmonary function might be missed. In this case, a calculation of the PAo2 - Pao2 would be a more appropri-ate measure because it would reveal the deterioration in function when the Pao2/FIo2 ratio did not.

The PACO2 (and thus the PaCO2) also influences both the Pao2/FIo2 ratio and the PAo2 - Pao2. In our model, the Pao2/FIo2 ratio falls (from 528 to 470) and the PAo2 - Pao2 also falls slightly (from 30 to 28 mm Hg) as the PaCO2 rises from 35 mm Hg to 55 mm Hg (see Table 4, lines 6-8). Experimental work in dogs11 and in humans7 found an inverse relationship between PACO2 and the PAo2 - Pao2, suggesting that the PAo2 - Pao2 rather than the Pao2/FIo2 ratio should be used to assess pulmonary function as the PaCO2 changes. Interestingly, the de-creases in PAo2 - Pao2 as the PACO2 increased were much

larger in these studies than could be accounted for by our model alone, suggesting that this effect may indeed be caused by a right-shift in the oxygen-hemoglobin dis-sociation or the dilation of some airways as suggested by the authors of the study in dogs.11

• Impact of Shunt and Diffusion Barrier. Shunt, al-though low in the normal lung,7 becomes substantial and reduces Pao2 when atelectasis is present, as might occur with retained secretions35 under general anesthe-sia or from chronic bronchitis. The model presented here shows that increasing shunt from 0.05 to 0.4 of the cardiac output will cause a widening of the PAo2 - Pao2 from 69 to 173 mm Hg and reduce the Pao2/FIo2 ratio from 415 to 155 at an FIo2 of 0.4 (see Table 4, lines 9-13). Confirmation of the impact of shunt on measures of pulmonary dysfunction is found in the previously cited experimental work in dogs, in which atelectasis and shunt induced by near-drowning caused a widening of the PAo2 - Pao2

10 and in studies of patients after open heart surgery in whom a widening of the PAo2 - Pao2 was seen as a sign of increased shunt.19 In ARDS, a syndrome in which al-veolar collapse causes increased shunt and reduced Pao2,

Model FIO2

PaCO2, mm Hg Shunt

DB, mm Hg

PAO2, mm Hg

PCO2, mm Hg

CcO2, mL

O2/100 mL blood

CaO2 mL

O2/100 mL

bloodPaO2,

mm HgPaO2/FIO2

PAO2 - PaO2,

mm Hg1 0.2 40 0.02 0 93 93 20.11 20.02 88 440 5

2 0.4 40 0.02 0 235 235 21.09 20.98 205 513 30

3 0.6 40 0.02 0 378 378 21.56 21.44 339 565 39

4 0.8 40 0.02 0 520 520 22.01 21.88 479 599 41

5 1 40 0.02 0 663 663 22.45 22.31 618 618 45

6 0.4 35 0.02 0 241 241 21.11 21.00 211 528 30

7 0.4 45 0.02 0 229 229 21.07 20.96 199 498 30

8 0.4 55 0.02 0 216 216 21.02 20.91 188 470 28

9 0.4 40 0.05 0 235 235 21.09 20.81 166 415 69

10 0.4 40 0.1 0 235 235 21.09 20.52 122 305 113

11 0.4 40 0.2 0 235 235 21.09 19.96 86 215 149

12 0.4 40 0.3 0 235 235 21.09 19.39 71 178 164

13 0.4 40 0.4 0 235 235 21.09 18.82 62 155 173

14 0.4 40 0.02 25 235 210 21.00 20.89 183 458 52

15 0.4 40 0.02 50 235 185 20.90 20.79 161 403 74

16 0.4 40 0.02 75 235 160 20.78 20.67 142 355 93

17 0.4 40 0.02 100 235 135 20.63 20.52 122 305 113

18 0.4 40 0.02 150 235 85 19.93 19.84 72 180 163

Table 4. Model Resultsa: Impact of FIO2, PCO2, Shunt, and Diffusion Barrier on PaO2/FIO2 Ratio and PAO2 - PaO2Abbreviations: CaO2, oxygen content of the arterial capillary blood; CcO2, oxygen content of the pulmonary capillary blood; DB, diffusion barrier (PAO2-PCO2); FIO2, fraction of inspired oxygen; PAO2, alveolar partial pressure of oxygen; PAO2 - PaO2, alveolar-arterial gradient in partial pressure of oxygen; shunt, fraction of cardiac output.aInput variables are the FIO2, PACO2, shunt, and DB. The PO2 in the venous blood was held constant at 40 mm Hg. The equations used are described in Table 3. Lines 1 to 5 show the impact of increasing the FIO2 in the otherwise healthy patient. Lines 6 to 8 show the impact of increasing PCO2 also in the healthy patient. Lines 9-13 show the impact of increasing shunt. Lines 14 to 18 show the impact of increasing DB.


the Pao2/FIo2 ratio has become a major measure of the degree of pulmonary dysfunction (ie, shunt).1

In the model presented here, both the PAo2 - Pao2 and the Pao2/FIo2 ratio respond to increases in shunt at a constant FIo2 by indicating poorer pulmonary function. Thus, it is reasonable that prevention of both an increase in the PAo2 - Pao2

18 and a decrease in the Pao2/FIo2 ratio4 have been used in clinical settings as indicators that specific ventilation strategies prevent atelectasis and increased shunt under general anesthesia. Thus, either would seem an adequate measure of pulmonary dysfunc-tion at a constant FIo2 if shunt is the major concern.

Oxygen transport from the alveolus to the pulmo-nary capillary is perfusion limited in the normal lung but becomes diffusion limited with a resultant increased diffusion barrier in patients with pulmonary diseases including pulmonary fibrosis as well as interstitial pneu-monia, autoimmune diseases,35 and heart failure.36 Both the PAo2 - Pao2 and the Pao2/FIo2 ratio respond appropri-ately to increasing levels of diffusion barrier for oxygen between alveoli and pulmonary capillaries (defined in Table 3) in the model presented here. As the diffusion barrier increases from 25 to 150 mm Hg, the PAo2 - Pao2 rises from 52 to 163 mm Hg and the Pao2/FIo2 ratio falls from 458 to 189 (see Table 4, lines 14-18), so either measure provides an assessment of worsening pulmonary dysfunction of this type at a constant FIo2.

• Values of Concern for PAo2 - Pao2 and Pao2/FIo2 Ratio. In the Berlin Definition, ARDS is associated with Pao2/FIo2 ratios less than 300 (see Table 2), so values this low are certainly of concern for any patient. To translate this into PAo2 - Pao2, note that a Pao2/FIo2 ratio of 305

correlates with an PAo2 - Pao2 equal to 113 mm Hg when pulmonary dysfunction is modeled by increased shunt or diffusion barrier (see Table 4, lines 10 and 13). Although PAo2 - Pao2

18 and Pao2/FIo2 ratio26 values in this range can occur intraoperatively, even less dramatic changes indicate deteriorating pulmonary function and may ne-cessitate intervention.4 These findings suggest that serial determinations of measures of pulmonary dysfunction may be warranted, particularly in patients at risk by per-sisting disease or the nature of the surgical procedure.

ConclusionThis article reviews the use of the PAo2 - Pao2 and the Pao2/FIo2 ratio as measures of pulmonary dysfunction. The broad use of these parameters in the laboratory, ICU, and operating suite demonstrates their popularity. and the predictive value of these indexes in many clinical set-tings suggests their importance. The factors influencing these parameters are summarized in Table 6.

The PAo2 - Pao2 expresses a physiologic phenomenon: the gradient in partial pressure of oxygen between the al-veolus and the arterial blood. The Pao2/FIo2 ratio, although it does not reflect an aspect of physiology, is easy to calcu-late and to understand. These facts and the finding that in-creases in Pao2/FIo2 ratio as the FIo2 increases could mask deterioration in pulmonary function probably contribute to the PAo2 - Pao2 being identified as a “very relevant” measure of acute lung injury in animal models, whereas the Pao2/FIo2 ratio less than 200 is deemed “somewhat relevant”.37 In model results (see Table 4, lines 9-18), as in experimental and clinical findings, both respond ap-propriately to reflect worsening pulmonary dysfunction

Table 6. Summary of Factors Affecting PaO2/FIO2 Ratio and PAO2 - PaO2Abbreviations: FIO2, fraction of inspired oxygen; ↓, decreased; ↑, increase

Factor PaO2/FIO2 ratio PAO2 - PaO2

Increasing intrapulmonary shunt ↓ ↑

Increasing diffusion barrier ↓ ↑

Increasing age ↓ ↑

Increasing FIO2 ↑ ↑

Increasing PaCO2 ↓ ↓

Table 5. Normal Values of PAO2 - PaO2 and PaO2/FIO2 Ratio Reproduced or Computed From Published Sources32,33 Abbreviations: FIO2, fraction of inspired oxygen; PAO2 - PaO2, alveolar-arterial gradient in partial pressure of oxygen.

Age, y FIO2 PAO2 - PaO2, mm Hg PaO2/FIO2 ratio

< 40 0.21 1 443

> 40 1 31 624

> 60 0.21 14 414

> 60 1 56 597

15-40 0.21 8.1 460

41-75 0.21 13.9 426


when shunt or diffusion barrier are increased at a fixed FIo2. Thus, both are useful in identifying patients who are at risk of poor outcomes and in determining the impact of a particular procedure. However, both are also sensi-tive to the FIo2. The increase in the Pao2/FIo2 ratio as the FIo2 increases, even in the absence of changes in patient condition (see Table 4, lines 1-5), is particularly problem-atic because it could mask a deterioration in the patient’s pulmonary status. Thus, the PAo2 - Pao2 and the Pao2/FIo2 ratio are both useful measures of pulmonary function, but the anesthetist should use these measures with a full un-derstanding of their limitations.

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6. Rozé H, Lafargue M. Perez P, et al. Reducing tidal volume and increas-ing positive end-expiratory pressure with constant plateau pressure during one-lung ventilation: effect on oxygenation. Br J Anaesth. 2012;108(6):1022-1027. doi:10.1093/bja/aes090

7. Bradford JM Jr, Ingram RH, Davis JA, Finlay GD. Relationship of alveolar CO2 and o2 pressures to AaDo2 in normal subjects. J Appl Physiol. 1974;37(2)139-144. doi:10.1152/jappl.1974.37.2.139

8. Curran-Everett D. A classic learning opportunity from Fenn, Rahn, and Otis (1946): the alveolar gas equation. Adv Physiol Educ. 2006;30:58-62. doi:10.1152/advan.00076.2005

9. West JW. Respiratory Physiology: The Essentials. 9th ed. New York, NY: Lippincott Williams & Wilkins; 2012.

10. Modell JH, Moya F, Williams HD, Weibley TC. Changes in blood gasses and A-aDo2 during near drowning. Anesthesiology. 1968;39(3)456-465.

11 Ingram RH Jr, Finlay GD, Bradford JM Jr. Relationship of AaDo2 to airway PCO2 in dog lungs. J Appl Physiol. 1976;40(5)720-724. doi:10.1152/jappl.1976.40.5.720

12. Mithoefer JC, Keighley JF, Cook WR. The AaDo2 and venous admix-ture at varying inspired oxygen concentrations in chronic pulmonary disease. Crit Care Med. 1978;6(3):131-135.

13. Hoffstein V, Duguid N, Rebuck AS. Estimation of changes in alve-olar-arterial oxygen gradient induced by hypoxia. J Lab Clin Med. 1984;104(5):685-692.

14. Moammar MQ, Azam HM, Blamoun AI, et al. Alveolar-arterial oxygen gradient, pneumonia severity index and outcomes in patients hospitalized with community acquired pneumonia. Clin Exp Pharmacol Physiol. 2008;35(9):1032-1037. doi:10.1111/j.1440-1681.2008.04971.x

15. Nicolini A, Ferraioli G, Ferrari-Bravo M, Barlascini C, Santo M, Ferrera L. Early non-invasive ventilation treatment for respiratory

failure due to severe community-acquired pneumonia. Clin Respir J. 2016;10(1):98-103. doi:10.1111/crj.12184

16. Sun YW, Hua R, Huo YM, et al. The characteristics of respiratory func-tion and pulmonary hemodynamics in patients with portal hypertension. J Dig Dis. 2012;13(2):75-81. doi:10.1111/j.1751-2980.2011.00555.x

17. Kim JA, Lee JJ, Kim CS, Chung IS, Gwak MS, Kim GS. Does gen-eral anesthesia with inhalation anesthetics worsen hypoxemia in patients with end-stage liver disease and an intrapulmonary shunt? Transplant Proc. 2011;43(5):1665-1668. doi:10.1016/j.transpro-ceed.2011.03.056

18. Lee HJ, Kim KS, Jeong JS, Shim JC, Cho ES. Optimal positive end-expiratory pressure during robot-assisted laparoscopic radical pros-tatectomy. Korean J Anesthesiol. 2013;65(3):244-250. doi:10.4097/kjae.2013.65.3.244

19. Sari A, Okuda Y, Takashita H, Oda T. Factors affecting A-aDo2 after open-heart surgery. Anesth Analg. 1976;55(3):315-321.

20. e Silva AM, Saad R, Stirbulov R, Rivetti LA. Off-pump versus on-pump coronary artery revascularization: effects on pulmonary function. Interactive Cardiovasc Thoracic Surg. 2010;11:42-45. doi:10.1510/icvts.2009.229617

21. Offner PJ, Moore EE. Lung injury severity scoring in the era of lung protective mechanical ventilation: the Pao2/FIo2 ratio. J Trauma. 2003;55(2):285-289. doi:10.1097/01.TA.0000078695.35172.79

22. Charles PG, Wolfe R, Whitby M, et al; Australian Community-Acquired Pneumonia Study Collaboration. SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis. 2008;47(3):375-384. doi:10.1086/589754

23. El Khoury MY, Panos RJ, Ying J, Almoosa KF. Value of the Pao2:Fio2 ratio and Rapid Shallow Breathing Index in predicting successful extubation in hypoxemic respiratory failure. Heart Lung. 2010;39(6):529-536. doi:10.1016/j.hrtlng.2009.10.020

24. Villar J, Perez-Mendez L, Blanco J, et al; Spanish Initiative for Epide-miology, Stratification, and Therapies for ARDS (SIESTA) Network. A universal definition of ARDS: the Pao2/Fio2 ratio under a standard ven-tilatory setting—a prospective, multicenter validation study. Intensive Care Med. 2013;39(4):583-592. doi:10.1007/s00134-012-2803-x

25. Najafizadeh K, Arab M, Radpei B, et al. Age and sex predict Pao2/Fio2 ratio in brain-dead donor lungs. Transplant Proc. 2009;41(7):2720-2722. doi:10.1016/j.transproceed.2009.06.146

26. Abramo A, Di Salvo C, Foltran F, Forfori F, Anselmino M, Giunta F. Xenon anesthesia improves respiratory gas exchanges in morbidly obese patients. J Obes. 2010:421593. doi:10.1155/2010/421593

27. Liu Z, Liu X, Huang Y, Zhao J. Intraoperative mechanical ventilation strategies in patients undergoing one-lung ventilation: a meta-analy-sis. 2016;5:1251. doi:10.1186/s40064-016-2867-0

28. Walia G, Jada G, Cartotto R. Anesthesia and intraoperative high-frequency oscillatory ventilation during burn surgery. J Burn Care Res. 2011;32(1):118-123. doi:10.1097/BCR.0b013e318204b38c

29. Severinghaus JW. Simple, accurate equations for human blood o2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol. 1979;46(3):599-602. doi:10.1152/jappl.1979.46.3.599

30. Whitely JP, Gavaghan DJ, Hahn CEW. Variation of venous admixture, SF6 shunt, Pao2, and the Pao2/Fio2 ratio with Fio2. Br J Anaesth. 2002;88(6):771-778. doi:10.1093/bja/88.6.771

31. Aboab J, Louis B, Jonson B, Brochard L. Relation between Pao2/FIo2 ratio and FIo2: a mathematical description. Intensive Care Med. 2006;32(10):1494-1497. doi:10.1007/s00134-006-0337-9

32. Kanber GJ, King FW, Eshchar YR, Sharp JT. The alveolar-arterial oxygen gradient in young and elderly men during air and oxygen breathing. Ame Rev Respir Dis. 1968;97(3):376-381.

33. Mellemgaard K. The alveolar-arterial oxygen difference: its size and components in normal man. Acta Physiol Scand. 1966;67(1):10-20. doi:10.1111/j.1748-1716.1966.tb03281.x

34. Karzai W, Klein U. FIo2 and studies on oxygenation during one-lung ventilation. Br J Anaesth. 2012;108(6):644.

35. West JW. Respiratory Pathophysiology: The Essentials. 6th ed. New York, NY: Lippincott Williams & Wilkins; 2003.


36. Agostoni PG, Guazzi M, Bussotti M, Grazi M, Palermo P, Marenzi G .Lack of improvement of lung diffusing capacity following fluid with-drawal by ultrafiltration in chronic heart failure. J Am Coll Cardiol.2000;36(5):1600-1604. doi:10.1016/S0735-1097(00)00929-3

37. Matute-Bello G, Downey G, Moore BB, et al; Acute Lung Injury inAnimals Study Group. An official American Thoracic Society work-shop report: features and measurements of experimental acute lunginjury in animals. Am J Respir Cell Mol Biol. 2011;44(5):725-738.doi:10.1165/rcmb.2009-0210ST

AUTHORSDavid E. Harris, PhD, RN, is a faculty member at the University of New England Nurse Anesthesia Program in Portland, Maine where he teaches

advanced physiology, advanced pathophysiology, and other basic science content. Email: [email protected].

Maribeth Massie, PhD, MS, CRNA, is program director of the Colum-bia University School of Nursing Nurse Anesthesia Program. She is the American Association of Nurse Anesthetists Region 1 director for 2017 to 2019.



Opioid-induced pruritus is prevalent after neuraxial administration of opioid. A number of preventive mea-sures have been reported; however, only a few studies evaluated treatment strategies for established pruritus. The pharmacokinetics and pharmacodynamic profiles of nalbuphine make this drug ideal for the treatment of established pruritus. The primary outcome of this sys-tematic review and meta-analysis was the incidence of pruritus after neuraxial opioid administration. Sec-ondary outcomes were the incidence of sedation and postoperative nausea and vomiting. Pooled estimates were reported by calculating the risk ratio (RR) with 95% confidence interval (CI). Five trials consisting of 494 patients were included for analysis. There was a

low quality of evidence that nalbuphine was effective in reducing the incidence of pruritus compared with active control (RR, 0.59; 95% CI, 0.38 to 0.93; P = .02). Conversely, there was no difference between the inci-dence of sedation (RR, 1.06; 95% CI, 0.42 to 2.71; P = .90) and postoperative nausea and vomiting (RR, 1.58, 95% CI, 0.75 to 3.31; P = .23). Although large studies are needed to decrease heterogeneity across studies, the current review showed that nalbuphine appears to reduce the incidence of opioid-induced pruritus.

Keywords: Epidural, morphine, nalbuphine, opioid-induced pruritus, spinal.

Use of Nalbuphine for Treatment of Neuraxial Opioid-Induced Pruritus: A Systematic Review and Meta-Analysis

Tito D. Tubog, DNAP, CRNA Jennifer L. Harenberg, MS, CRNAKristina Buszta, MSN, CRNAJennifer D. Hestand, MSNA, CRNA

The addition of opioids in a neuraxial blockade contributes to a number of clinical advan-tages, including enhanced analgesic effects, profound sensory blockade, and rapid sensory and motor recovery.1,2 However, the addition

of opioid in spinal or epidural anesthesia causes adverse side effects such as pruritus, which is troublesome to many patients and is a factor of low patient satisfaction scores. Neuraxial opioid-induced pruritus (OIP) is a com-mon side effect, with a prevalence rate ranging between 50% and 100% despite prophylactic measures.3,4 Some pharmacologic agents including ondansetron, naloxone, diclofenac, propofol, droperidol, and gabapentin have been studied for the prevention and treatment of OIP.3 Nalbuphine is one of the agents that has been studied, and results from clinical trials demonstrated that prophy-lactic nalbuphine might reduce the incidence of pruritus. Yet, studies evaluating pharmacologic treatments of pruri-tus have been scarce and report conflicting results.

The efficacy of nalbuphine has been postulated based on its pharmacologic profiles. Nalbuphine is a μ-receptor antagonist and a κ-receptor agonist.5-7 The activation of the κ opioid receptors accounts for its utility as a treat-ment agent for pruritis. Although some clinical studies have reported on the use of nalbuphine prophylactically, only a few studies have evaluated the effect of nalbuphine

as a treatment of established pruritus. The results of these studies are clinically relevant and add to the treatment regimen of pruritus.

The objective of this systematic review and meta-anal-ysis was to evaluate the efficacy of nalbuphine in treating OIP after the administration of a neuraxial opioid.

MethodsThis systematic review with meta-analysis was conducted following the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.8 The clinical PICO (Patient, Intervention, Comparison, and Outcome) question that guided the search of the literature was, In patients with a neuraxial opioid, how does nalbuphine affect the inci-dence of neuraxial OIP?

• Search Strategy and Study Selection. The following key terms were used to search for evidence with appro-priate Boolean mechanics: nalbuphine, epidural, spinal, opioid-induced pruritus, and neuraxial. The electronic databases searched were MEDLINE (PubMed), Google Scholar, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Review Database, Embase, and Scopus. Gray literature databases including www.clini-caltrials.gov, conference abstracts, and poster presenta-tions were explored to reduce reporting bias. Additional


studies were retrieved using the ancestry approach. The last search for evidence was performed on June 7, 2018.

The titles and abstracts of relevant results were evalu-ated using predetermined inclusion criteria. A discus-sion among the authors resolved any disagreement on included articles. The full text of each relevant article was obtained, and data were extracted for analysis.

• Inclusion and Exclusion Criteria. The authors evalu-ated the abstracts based on the following 3 inclusion cri-teria identified before the literature search: randomized controlled trials (RCTs) evaluating the use of nalbuphine as a treatment of established neuraxial OIP compared with active control, use of nalbuphine regardless of route of administration, and English-language peer-reviewed articles. The studies were excluded if they involved non-neuraxial administration route of opioids, retrospective studies, descriptive articles, editorials, or case reports.

• Data Extraction. A pilot-studied and standardized

data extraction template was used to tabulate the results of each study. The following information was obtained from each trial: the total number of participants; ASA physical status classification; the incidence of neuraxial OIP after treatment; the dose and type of opioid used; the dose, route, and timing of nalbuphine administra-tion; types of surgical procedures; types of neuraxial techniques; incidence of sedation as defined by the trial’s authors; the rate of postoperative nausea and vomiting (PONV); and other adverse effects.

• Assessment of Risk of Bias. Two authors appraised the included RCTs and assessed the methodologic quality of each study according to the Risk of Bias algorithm out-lined in the Cochrane Handbook for Systematic Reviews of Intervention.9 The evaluators assessed the quality of the study or report based on random sequence generation; allocation concealment; blinding of participants, per-sonnel, and outcomes assessors; incomplete outcomes

Figure 1. PRISMA Flowchart of Literature Screening and Study SelectionAbbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.


data; selective reporting; and other sources of bias. Two independent authors rated the study as “high risk,” “low risk,” or “unclear risk,” and each evaluator was instruct-ed to identify the reasons for each rating. Another review author resolved any discrepancies or disagreements in the appraisal of the quality of the studies.

• Summary of Measures and Statistical Analysis. The primary outcome was the incidence of neuraxial OIP. The overall number of patients with pruritus after treatment (defined by the trial’s authors) with nalbuphine and the other active control medications reported in each study was used to pool estimates of pruritus incidence. To mini-mize observational bias due to different methods used to determine the presence and absence of pruritus, we considered data classified as mild, moderate, and severe pruritus to be pruritus events. The secondary outcomes were the incidence of sedation and the rate of PONV.

The incidence of neuraxial OIP, sedation, and PONV was estimated by calculating the pooled risk ratio (RR) with 95% confidence interval (CI). The random-effects model was used to pool the estimates anticipating methodologic and clinical heterogeneity of data. For the binary endpoint, a significant effect compared with placebo needed a 95% CI not to include one.

If any data were not explicitly reported, study authors were contacted for additional raw data. In RCTs with multiarm groups, data were processed individually. Moreover, in studies when opioids were administered initially in the subarachnoid space and followed by an epidural infusion, the opioid used in the latter section of the anesthesia technique was counted as the type of anesthetic and dosage of opioid used for that RCT. Trials with data not suitable for meta-analysis were described qualitatively in the review.

Heterogeneity was assessed using I2 statistics. As de-scribed in the Cochrane Handbook for Systematic Reviews of Intervention, the following model was used in determin-ing heterogeneity: an I2 statistic of 0% to 40% indicated low heterogeneity; 30% to 60%, moderate heterogeneity; 50% to 90%, substantial heterogeneity; and 75% to 100%, considerable heterogeneity.10 For exploration of clinical

and methodologic heterogeneity, a priori subgroup and sensitivity analyses were designed. Subgroup analyses in-vestigated the incidence of neuraxial OIP in obstetric and nonobstetric surgery, lipophilic and hydrophilic opioids, and the epidural and subarachnoid routes of opioid administration. A sensitivity analysis was performed by removing studies with a high risk of bias one study at a time. If results from sensitivity analysis were unchanged, we concluded that the risk of bias did not influence the effect estimates.

The overall quality of evidence was rated using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach.10 The GRADE method categorizes outcomes as “high,” “moderate,” “low,” or “very low.” Because all evidence included in this review was from RCTs, the baseline quality of evi-dence was graded as “high.” Consequently, an outcome was downgraded by 1 level for serious concerns and 2 levels for very serious concerns about the risk of bias as-sessment, inconsistency, imprecision, indirectness, and high probability of publication bias.

ResultsThe initial search yielded 58 RCTs. After a comprehen-sive review of the titles and abstracts, 5 studies11-15 were included in the review and meta-analysis. The flowchart in Figure 1 details the search of the review.

The opioids used either intrathecally or via the epi-dural space were preservative-free morphine and fentanyl. Different opioid dosages were administered. The dose of nalbuphine differed, and the route of administration varied after confirming the presence of pruritus using a self-invented Likert scale assessment tool. Propofol, naloxone, ondansetron, chlorpheniramine, and diphenhydramine were the active controls examined in all studies. Table 1 summarizes the characteristics of the included studies.

• Primary Outcome: Incidence of Neuraxial Opioid-Induced Pruritus. The primary endpoint of the current meta-analysis is presented in Figure 2. Five studies11-15

consisting of 494 patients were evaluated for the efficacy of nalbuphine to treat neuraxial pruritus (see Figure 2).

Figure 2. Forest Plot of Incidence of Neuraxial Opioid-Induced PruritusAbbreviations: M-H, Mantel-Haenszel; Random, random-effects model.


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5


Pooled estimates of the rate of pruritus were significantly lower in the nalbuphine group compared with active control (RR, 0.59; 95% CI, 0.38 to 0.93; P = .02). An I2 statistic of 62% suggested substantial heterogeneity. A priori tests were performed to elucidate the causes of sub-stantial heterogeneity and variations across all studies.

Four RCTs involving 466 patients who underwent ce-sarean delivery demonstrated that nalbuphine was more effective compared with active control in treating pruri-tus (RR, 0.51; 95% CI, 0.32 to 0.81; P = .004; I2 = 60%).12-

15 Only one RCT was done in a nonobstetric setting, consisting of 28 patients.11 This study demonstrated no difference in success rate in nalbuphine vs ondansetron.

When aggregate data from 4 studies using preserva-tive-free morphine were combined, nalbuphine was not effective in treating pruritus (RR, 0.53; 95% CI, 0.28 to 1.01; P = .05; I2 = 62%).11,13-15 Only one RCT12 used fentanyl, and therefore no meta-analysis was conducted.

Three studies12-14 administered opioid in the sub-arachnoid space. Pooled estimates showed that patients treated with nalbuphine had fewer episodes of pruritus compared with active control (RR, 0.50; 95% CI, 0.34 to 0.90; P = .02, I2 = 62%). Only a single trial15 admin-istered opioid via the epidural space, and 1 study11 did not clearly identify the number of subjects who received opioids in the subarachnoid or epidural space.

• Secondary Outcomes. Figures 3 and 4 illustrate the forest plot of the secondary outcomes, which are the in-cidence of sedation and PONV. Two studies13,14 reported the incidence of sedation as defined by the trial’s authors (see Figure 3). The use of nalbuphine did not affect the number of patients who were considered sedated (RR,

1.06; 95% CI, 0.42 to 2.71; P = .90; I2 = 54%).Aggregate data from 3 RCTs demonstrated no differ-

ence in the incidence of PONV (RR, 1.58; 95% CI, 0.75 to 3.31; P = .23; I2 = 38%; see Figure 4).13-15

• Risk of Bias. All studies were rated as low risk of random sequence generation. Two clinical trials reported adequate allocation concealment. Blinding of participants and study assessors were sufficient in 4 trials. The risks of bias of included studies are shown in Figure 5.

• Quality of Findings. The quality of findings table was generated using GRADEpro software (Table 2). In this review, we drew our conclusions regarding the overall efficacy of nalbuphine on the treatment of established neuraxial OIP based on 5 studies consisting of 494 pa-tients. We downgraded the evidence of the incidence of pruritus to low quality because of potential publication bias, the existence of clinical and methodologic hetero-geneity, and imprecision. However, we found the quality of evidence for the frequency of sedation and PONV was moderate because of the small effect size.

DiscussionSeveral significant findings emerged from this meta-analysis. The administration of nalbuphine to treat established pruritus after neuraxial opioid was effective at a statistically significant level compared with active control. We found that the number of patients success-fully treated with nalbuphine was higher compared with intravenous (IV) chlorpheniramine (47% vs 38%), di-phenhydramine (83% vs 57%), propofol (92% vs 57%), and naloxone (80% vs 40%). Successful treatment of established pruritus required different nalbuphine doses

Figure 3. Forest Plot of Incidence of SedationAbbreviations: M-H, Mantel-Haenszel; Random, random-effects model.

Figure 4. Forest Plot of the Incidence of Postoperative Nausea and VomitingAbbreviations: CI, confidence interval; M-H, Mantel-Haenszel; Random, random-effects model.


and treatment protocols. Alhashemi et al14 administered 3 dosing regimens of IV nalbuphine, with subsequent doses given 30 minutes after the first dose if pruritus per-sisted. The first dosing regimen was 5 mg intravenously followed by a 10-mg IV dose if itchiness persisted. If the second dose of nalbuphine was ineffective, the patient received a third IV dose of 10 mg.14 One study used nalbuphine at 5 mg throughout the entire study, and 2 additional treatments using the same dose were adminis-tered 30 minutes after the first dose if pruritus symptoms continued.15 Three studies administered 3 mg13 or 4 mg12,13 of nalbuphine at 8-hour12 intervals if symptoms persisted. The variability in the doses and the frequency of nalbuphine make it challenging to make recommenda-tions on an effective nalbuphine dose for the treatment of established pruritus.

The incidence of sedation was similar between na-lbuphine and the active control groups. Although this outcome was based on only 2 RCTs13,14 combined, the finding is congruent with the reports in the previous review suggesting no increase in sedation with low-dose (4-mg) nalbuphine.16,17 However, this result should be cautiously interpreted because the studies did not de-scribe how sedation was measured, which could intro-duce bias in the results.

The effect of nalbuphine on PONV was not statisti-cally significant. In this review, we found no difference in PONV between use of nalbuphine and active control. Our finding is not similar to previous reports demon-strating an increased incidence of PONV.18 Our find-ings, although coming from only 3 RCTs, are promising because decreased PONV would improve patient satisfac-tion after opioid administration.

Postoperative pain scores were not estimated because of inadequate data to pool. However, Charuluxananan and colleagues13 reported no clinically significant decrease of pain score between their nalbuphine and propofol groups. As in the study by Cohen et al,15 pain scores before and after treatment of nalbuphine remained the same.13 These outcomes were incongruent with previous RCTs and case reports demonstrating a reversal in pain control with the use of nalbuphine.19-21 In some reports, investigators re-corded an increase in pain intensity with nalbuphine.

There are limitations to this review. We acknowledge that sample sizes and effect sizes of the studies included in this meta-analysis are small; hence, we recommend that extrapolation of the results should be guided follow-ing their limitations. In this review, we included studies comparing nalbuphine with a variety of active control agents. Although pooling the data from these studies yielded a statistically significant outcome, a clinically significant implication is limited because of the absence of head-to-head comparison with either a standard phar-macologic treatment of established pruritus or consistent active control. The pooled estimates showed substantial

variation across studies in which none of the a priori sub-group analyses explained the presence of heterogeneity. In addition, with the different dosages used in included studies, we could not determine the most effective dose for pruritus treatment. Furthermore, publication bias was not explored by visual inspection of the funnel plot for symmetrical configuration and by using an Egger regres-sion test because of the small number of studies included in the review, because this may introduce inaccurate findings.22,23

Because of a small to moderate effect size and the overall quality of the evidence (GRADE), we recommend future large, randomized, double-blind studies comparing nalbuphine with placebo and active control. Estimating the effects of nalbuphine compared with placebo tests the real efficacy of nalbuphine. In all studies included in the review, assessment of the presence and absence of pru-ritus was quantified using different metrics, from asking the patient to using a Likert scale. This inconsistency may have created variations across studies, as evidenced by high I2 statistics. We did not include a subgroup analysis of the instruments used to assess pruritus because of the number of studies included. Use of a universal method of assessing pruritus may minimize heterogeneity. Our rec-

Figure 5. Risk of Bias Summary: Review Authors’ Judgements About Each Risk of Bias Item for Each Included Study Legend: Green = low risk of bias, white = unclear risk of bias, red = high risk of bias


ommendation is to use the numeric rating scale, similar to the pain scale with 2 opposing anchors. An ordinal assessment of the pruritus score obtained from a numeric rating scale will provide a more reliable assessment tool of the incidence and severity of pruritus and a clinically significant difference.24

ConclusionNalbuphine was successfully used to treat patients with neuraxial OIP. The addition of nalbuphine as part of the anesthesia plan in patients receiving neuraxial opioid may reduce the incidence of OIP and improve patient satisfaction. However, because of the small sample sizes and the substantial heterogeneity of results, we caution the extrapolation of the outcomes to clinical practice until large randomized studies are conducted.

REFERENCES 1. Pöpping D, Elia N, Wenk M, Tramèr M. Combination of a reduced

dose of an intrathecal local anesthetic with a small dose of an opioid: a meta-analysis of randomized trials. Pain. 2013;154(8):1383-1390. doi:10.1016/j.pain.2013.04.023

2. Saxena A, Arava S. Current concepts in neuraxial administration of opioids and non-opioids: an overview and future perspectives. Indian J Anaesth. 2004;48(1):13-24.

3. Kumar K, Singh SI. Neuraxial opioid-induced pruritus: an update. J Anaesthesiol Clin Pharmacol. 2013;29(3):303-307. doi:10.4103/0970-9185.117045

4. Davies GG, From R. A blinded study using nalbuphine for pre-vention of pruritus induced by epidural fentanyl. Anesthesiology. 1988;69(5):763-765.

5. Kjellberg F, Tramèr MF. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol. 2001;18(6):346-357.

6. Zeng Z, Lu J, Shu C, et al. A comparison of nalbuphine with mor-phine for analgesic effects and safety: meta-analysis of randomized controlled trials. Sci Rep. 2015;5:10927. doi:10.1038/srep10927

7. Jannuzzi RG. Nalbuphine for treatment of opioid-induced pruritus: a systematic review of literature. Clin J Pain. 2016;32(1):87-93. doi:10.1097/AJP.0000000000000211

8. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097

9. Higgins JP, Green S. Guide to the contents of a Cochrane protocol and review. In: Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration; 2011. http://handbook.cochrane.org/ Accessed March 29, 2019.

10. Ryan R, Hill S. How to GRADE the quality of the evidence. Version 3.0. Cochrane Consumers and Communication Group; December 1, 2016. http://cccrg.cochrane.org/author-resources. Accessed March 29, 2019.

11. Cruz-Ferretti U, Llanes-Garza H, López-Cabrera N, et al. Comparison of the efficacy and safety of 4 mg of ondansetron vs. 4 mg of nalbu-phine for the treatment of neuraxial morphine-induced pruritus. Med Univ. 2014;16(64):105-148.

12. Mohd Salleh SK, Kamaruzaman E, Md Zain J, Zainuddin K, Abdul Manap N, Yahya N. Nalbuphine vs. chlorpheniramine in reducing intrathecal opioidinduced pruritus in parturients undergoing lower-segment caesarean section. Brunei Int Med J. 2012;8(3):128-134.

13. Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg. 2001;93(1):162-165. doi:10.1097/00000539-200107000-00032

14. Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C. Treatment of intrathecal morphine-induced pruritus following Cae-

Table 2. Summary of Findings: Key Outcomes of Nalbuphine on Treatment of Neuraxial Opioid-Induced Pruritusa

Abbreviations: RCT, randomized controlled trial; RR, risk ratio.aPatient or population: neuraxial opioid-induced pruritus; setting: postoperative; intervention: nalbuphine; comparison: active control.bRisk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).cGRADE (Grading of Recommendation, Assessment, Development and Evaluation) Working Group grades of evidence10: High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.dModerate heterogeneity. eSmall sample size.


sarean section. Can J Anaesth. 1997;44(10):1060-1065. doi:10.1007/BF03019227

15. Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nal-buphine is better than naloxone for treatment of side effects afterepidural morphine. Anesth Analg. 1992;75(5):747-752.

16. Moustafa AA, Baaror AS, Abdelazim IA. Comparative study betweennalbuphine and ondansetron in prevention of intrathecal morphine-induced pruritus in women undergoing cesarean section. Anesth Essays Res. 2016;10(2):238-244. doi:10.4103/0259-1162.167839

17. Zaglol MA. Prophylactic intravenous ondansetron and nalbu-phine for reduction of subarachnoid fentanyl-induced pruritus inpatients undergoing elective cesarean delivery. Med J Cairo Univ.2009;77(1):577-581.

18. Charuluxananan S, Kyokong O, Somboonviboon W, Narasethakamol A, Promlok P. Nalbuphine versus ondansetron for prevention ofintrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg. 2003;96(6):1789-1793.

19. Blaise GA, Nugent M, McMichan JC, Durant PA. Side effects of nalbu-phine while reversing opioid-induced respiratory depression: reportof four cases. Can J Anaesth. 1990;37(7):794-797. doi:10.1007/BF03006539

20. Jaffe RS, Moldenhauer CC, Hug CC Jr, Finlayson DC, Tobia V, KopelME. Nalbuphine antagonism of fentanyl-induced ventilatory depres-sion: a randomized trial. Anesthesiology. 1988;68(2):254-260.

21. Ramsay JG, Higgs BD, Wynands JE, Robbins R, Townsend GE. Earlyextubation after high-dose fentanyl anaesthesia for aortocoronarybypass surgery: reversal of respiratory depression with low-dose nal-

buphine. Can Anaesth Soc J. 1985;32(6):597-606.

22. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnelplot, researchers could not visually identify publication bias. J ClinEpidemiol. 2005;58(9):894-901.

23. Thornton A, Lee P. Publication bias in meta-analysis: its causes andconsequences. J Clin Epidemiol. 2000;53(2):207-216.

24. Lee JS, Hobden E, Stiell IG, Wells GA. Clinically important change inthe visual analog scale after adequate pain control. Acad Emerg Med.2003;10(10):1128-1130. doi:10.1197/S1069-6563(03)00372-5

AUTHORSTito D. Tubog, DNAP, CRNA, is employed by Texas Wesleyan University, Fort Worth, Texas. Email: [email protected].

Jennifer L. Harenberg, MS, CRNA, is employed by Texas Wesleyan University and Denver Health Medical Center, Denver, Colorado.

Kristina Buszta, MSN, CRNA, is employed by Texas Wesleyan Univer-sity and the University of Colorado Hospital, Denver, Colorado.

Jennifer D. Hestand, MSNA, CRNA, is employed by Texas Wesleyan University.


Author’s Correction Dosing

In the April 2019 issue the authors correct

the midazolam dosing in the figure on

page 148 and again in the first line of

page 150, by changing the dosing of

midazolam instead of the printed “0.3 mg/

kg” to read “0.03 mg/kg IV midazolam”

and “midazolam dose of 0.03 mg/kg

intravenously” respectively. The correct

dosing of 0.03 mg/kg midazolam is

previously mentioned in the article on page

147 under the “Midazolam” heading. See

Collins S, Schedler P, Veasey B, Kristofy A,

McDowell M. Prevention and treatment of

laryngospasm in the pediatric patient:

a literature review. AANA Journal. 87(2),

145-151. The online version of the article

has been corrected.


Millions of children every year undergo seemingly safe general anesthetics for surgical procedures and imaging studies. Anesthetic agents have been shown to cause detrimental effects on brain cell survival and cognitive function in animals. As a result, the safety of general anesthetics in children is an active field of investigation. The objective of this review is to evaluate the human research on anesthesia neurotoxicity in the young child. Three databases were searched for stud-ies on anesthesia exposure in infants and children. Pos-itive clinical outcomes in several studies showed no dif-ference in cognitive function between children exposed and unexposed to anesthesia. Research findings also

demonstrated negative clinical outcomes following anesthesia exposure, including physical changes on magenetic resonance imaging such as lower gray mat-ter density in the occipital cortex and cerebellum; lower scores on performance IQ, listening comprehension, and expressive language; overrepresentation in the lowest fifth percentile of academic achievement; and increased risk of learning disabilities. More studies are needed that simultaneously measure cognitive func-tion, physical changes, and disability risk to learn how these factors interact in the human brain.

Keywords: General anesthesia, neurotoxicity, pediatrics.

Anesthesia Exposure in the Young Child and Long-term Cognition: An Integrated Review

Audrey Rosenblatt, MSN, CRNA Michael Kremer, PhD, CRNA, CHSE, FNAP, FAAN Barbara Swanson, PhD, RN, FAANRavi Shah, MD

Millions of children every year undergo general anesthetics for surgical proce-dures and imaging studies.1 The safety of general anesthetics in children has become an active field of investigation

since anesthetic agents have been shown to cause detri-mental effects on brain cell survival and cognitive func-tion in animals.2 The preclinical evidence for anesthetic neurotoxicity in humans, derived from in vitro and in vivo animal studies, raises concern that the clinical use of anesthetic agents in children might lead to adverse long-term neurodevelopmental outcomes. It remains unclear whether animal data can be extrapolated to humans.

Observational studies in humans have demonstrated mixed outcomes related to cognitive function in children who undergo anesthesia. In several studies, positive clini-cal outcomes were demonstrated by the finding of no dif-ference in cognitive function between children exposed and unexposed to anesthesia.3-18 Negative clinical out-comes following anesthesia exposure included physical changes on MRI, such as lower gray matter density in the occipital cortex and cerebellum; lower scores on per-formance IQ, listening comprehension, and expressive language; over-representation in the lowest 5th percentile of academic achievement; and increased risk for learning disability.19-37 Although these effects were not demon-strated consistently across studies, these results were compelling and warrant additional investigation.

Many organizations have issued recommenda-

tions about the use of anesthesia in young children. Smart Tots (Strategies for Mitigating Anesthesia-related Neurotoxicity in Tots), the research initiative of the International Anesthesia Research Society, issued a 2014 consensus statement suggesting postponing surgeries and procedures that can be reasonably delayed until after age 3 years because of the potential risk of anes-thetics to the developing brain (http://smarttots.org/about/consensus-statement/). However, anesthetizing and sedating children is rarely optional, and often pro-cedures cannot be delayed safely. The Anesthetic and Life Support Drugs Advisory Committee of the Food and Drug Administration (FDA) states in committee proceedings that it would be unethical to allow chil-dren to undergo medical procedures without adequate sedation.38 In December 2016 the FDA issued a “Drug Safety Communication” stating that anesthetics used in children less than 3 years old may affect the development of children’s brains, with specific focus on procedures lasting longer than 3 hours.39

The purpose of this integrated review is to synthesize extant human literature on anesthesia exposure in young children and its impact on long-term cognitive function. The review questions are as follows:

1. What are the long-term effects of anesthesia expo-sure on the neurologic development of children?

2. If anesthesia is correlated with negative effects on long-term neurologic development, does age at exposure make a significant difference?


3. If anesthesia is correlated with negative effects of long-term neurologic development, does duration or fre-quency of exposure make a significant difference?

MethodsAn integrated review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure).40

• Procedure. Comprehensive literature searches of the electronic databases of Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, and Scopus were conducted using the keywords neurotox*, neuro-cognit*, cognit*, pediatric*, neonat*, premature, child*, infant*, newborn*, baby, babies, anesthe*, anaesthe*, an-

aesthe*, anaesthe*, and sedat* as well as associated MeSH (Medical Subjects Headings) or Boolean phrases. This generated a list of potentially relevant articles that were stored in Legacy RefWorks (ProQuest LLC). Duplicates were deleted, with near-match duplicates screened by a single reviewer. Two reviewers screened titles in a double-blind process. A single reviewer searched the authors of the articles included in the review, screened the citation lists for relevant articles, and retrieved abstracts and full articles in the manner described for the previous steps. This process created a list of 26 articles. Fifteen ar-ticles were added to the review after the initial screening process through database alerts for search terms.

• Inclusion and Exclusion Criteria. Experimental

Figure. PRISMA Flow Diagram of Literature ReviewAbbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.


studies examining anesthesia exposure in humans aged birth to 24 years and conducted between January 2000

and July 2018 were included. All anesthesia exposure types, duration, and surgical indications, except cardiac

SourceAge at exposure Outcome measures/results

Bartels,41 2009

< 3 y Educational achievement: Dutch CITO elementary test Twins exposed to anesthesia at < 3 y old had significantly lower educational achievement scores. Monozygotic twins discordant for anesthesia exposure at < 3 y old had no significant difference in educational attainment. Monozygotic twins discordant for exposure between 3 and 12 y had significantly poorer learning-related outcomes than did twins when neither received anesthesia before age 12 y.

Block,20 2012 Infancy Educational achievement: Iowa test scores Greater representation in lowest fifth percentile, lower than expected normative value, duration of anesthesia correlated negatively with scores.

Clausen,4 2017

Youngest age at exposure: 2.4 y; varies by oral cleft type

Educational achievement: Danish national ninth grade testing Compared with controls, children with cleft palate had significantly lower scores, whereas children with cleft lip and with cleft lip and palate showed statistically insignificant differences from controls. Children with cleft lip had youngest exposure age and those with cleft lip and palate had the greatest number of surgeries; thus, authors conclude that there is no evidence of anesthesia-related neurotoxicity in this study.

Flick,24 2011 < 2 y Total cognitive scale, memory subscale California Achievement Test: math, reading, phonics, written, spelling subscale Multiple, but not single, anesthesia/surgery exposures were associated with decrements in group-administered achievement and cognition tests.

Glatz,26 2017 < 4 y Educational achievement: Swedish Ninth Grade Register Single and multiple exposures to anesthesia were associated with lower school grades. Divided into age cohorts, a small difference was found in children exposed at 37-48 mo. Outcomes were affected by type of surgery. There was no association between exposure and grades below the 10th percentile.

Graham,27 2016

0-2 y Educational achievement: Early Development Instrument (EDI) Exposed children < 2 y of age did not differ in EDI scores compared with matched unexposed controls. No association between single or multiple anesthesia exposures and EDI scores.

2-4 y Exposed children aged between 2 and 4 y showed a decreased EDI score compared with matched unexposed controls. A single exposure was associated with deficits for communication/general knowledge.

Hansen,9 2013

< 3 mo Educational achievement: Danish national ninth grade testing No significant difference in test scores for children exposed or unexposed before age 3 mo.

Hansen,8 2011

Infancy Educational achievement: Danish national ninth grade testing No significant difference in test scores after adjusting for known confounders in children exposed or unexposed in infancy.

Hu,28 2017 < 3 y Educational achievement: Stanford/Otis-Lennon School Ability Test (OLSAT), Learning disability based on formulas from academic testing Multiple, but not single, exposures were associated with an increased frequency in learning disabilities, and decreases in cognitive ability and academic achievement. A single anesthesia exposure did not correlate to a difference in total cognitive ability; however, the language and reading scores were decreased in this group.

Schneuer,33 2018

< 48 m Australian Version of the Early Development Instrument (AvEDI), New South Wales Department of Education National Assessment Program–Literacy and Numeracy (NAPLAN) Children exposed to general anesthesia were more likely to be categorized as developmentally high risk on the AvEDI. No associations were found when the analyses were restricted to children with a single anesthesia exposure and a single hospitalization. Children exposed to general anesthesia were more likely to score below the national minimum standard in numeracy and reading. When adjusted for a single anesthesia exposure and single hospitalization, numeracy remained significantly lower.

Wilder,35 2009

< 4 y Learning disability based on formulas from academic testing Multiple, but not single, anesthetics were associated with an increased risk of learning disability. Longer cumulative anesthesia exposure increased risk of learning disability.

Williams,36 2014

Infancy Educational achievement: new standards reference examination reading, math, writing No association between spinal anesthesia exposure and very poor academic achievement defined as scoring below the fifth percentile. Small but significant decreases in math and reading scores in the group exposed to spinal anesthesia.

Table 1. Academic Assessment as an Outcome Measure


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studies, were included. All studies in which outcomes in-volved long-term cognitive function or brain development with measurement at any age were included.

Excluded from this analysis were general review ar-ticles, in vitro and animal studies, publications prior to 2000, non-English language publications, and studies that did not measure cognition or brain development. Studies exclusively of children with congenital cardiac disease undergoing cardiac surgery were excluded, except when cardiac surgery was a small portion of the surgical cohort as a whole. Also excluded were studies on sedation performed in the intensive care unit, drug toxicities, prescription medications, substance abuse, and fetal (obstetric), adult, and geriatric populations.

ResultsForty-one articles were included in this review.

• Long-term Effects of Anesthesia Exposure. Outcome measures were divisible into 4 main categories: aca-demic assessment, behavioral assessment and disability outcomes, brain studies, and neurologic testing using a validated neurologic assessment. Some studies found that anesthesia exposure correlated with subsequent deficits, whereas others found no correlations.

Twelve studies used academic assessment measures (Table 1).a Anesthesia exposure was found to negatively correlate with academic assessment in 9 of these studies, especially for multiple exposures and increased dura-tion of exposure, with some caveats.20,24,26-28,33,35,36,41 These findings were demonstrated for children aged 0 to 4 years old at exposure, and negative outcomes were correlated with exposure to both general and awake regional anesthesia. Three of these studies found a dif-ference only after multiple exposures but not after single exposure.24,28,35 One was a twin study that attributed the difference between exposed and unexposed twin pairs to a capture of genetic difference.41 Two studies found older ages to be associated with decreased academic achieve-ment: 2 to 4 years and 37 to 48 months at exposure.26,27

Nineteen articles measured behavioral assessments and learning disabilities (Table 2).b Eleven studies found increased inattention and increased diagnosis of be-havioral, learning, or developmental disorders in the exposed group with some caveats.c Five of these studies demonstrated differences after multiple but not single an-esthetics.17,24,28,34,35 One study was underpowered,42 and 1 was the twin study referenced earlier.41 Eight studies did not find an association between anesthesia exposure and changes in behavior.6,10,12-15,29,42 Two studies looked exclusively at autism, which was not affected by anes-thesia.6,12 Five of these studies used the Child Behavior

Spr

ung,

34

2012

< 2

yD

SM

-IV c

riter

ia a

pplie

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sch

ool r

ecor

ds f

or A

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ympt

oms

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ting

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ria

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tiple

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not

sin

gle,

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sure

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sulte

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ease

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k of

late

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velo

pmen

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,14 2

016

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BC

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ehav

ior

Rat

ing

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ntor

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Exe

cutiv

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nctio

n (B

RIE

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Ove

rall,

no

sign

ifica

nt d

iffer

ence

bet

wee

n ex

pose

d an

d un

expo

sed

sibl

ing

pairs

. A g

reat

er n

umbe

r of

exp

osed

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ldre

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d ab

norm

al s

core

s on

the

C

BC

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tern

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ing

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blem

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bsca

le.

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shki

n,15

20

17<

4 y

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enta

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vey

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ldre

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pose

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tiple

sho

rt g

ener

al a

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hetic

s ha

d ra

tes

of n

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deve

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aliti

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alen

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rat

es in

the

gen

eral

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ulat

ion

as

repo

rted

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he li

tera

ture

.

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ner,

17

2018

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RIE

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ts o

f ch

ildre

n re

port

ed g

reat

er p

robl

ems

on a

ll sc

ales

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CL

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e ex

pose

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tiple

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gle,

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es w

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ifica

ntly

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her

for

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gly

and

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tiply

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osed

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ldre

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mpa

red

with

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xpos

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ontr

ols.

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pro

port

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of c

hild

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with

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orm

al s

core

s on

th

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BC

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naliz

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blem

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bsca

le w

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chi

ldre

n w

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e an

d m

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le e

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ures

com

pare

d w

ith u

nexp

osed

con

trol

s.

Wild

er,35

20

09<

4 y

Lear

ning

dis

abili

ty b

ased

on

rese

arch

ers’

for

mul

as f

rom

aca

dem

ic t

estin

g M

ultip

le, b

ut n

ot s

ingl

e, a

nest

hetic

s as

soci

ated

with

an

incr

ease

d ris

k of

lear

ning

dis

abili

ty.

Long

er c

umul

ativ

e an

esth

esia

exp

osur

e in

crea

sed

risk

of le

arni

ng d

isab

ility

.

Tab

le 2

. B

ehav

iora

l A

sses

smen

t an

d L

earn

ing

Dis

abili

ties

Abb

revi

atio

ns: A

DH

D,

atte

ntio

n-de

ficit/

hype

ract

ivity

dis

orde

r; D

SM

-IV,

Dia

gnos

tic a

nd S

tatis

tical

Man

ual o

f M

enta

l Dis

orde

rs,

Four

th E

ditio

n; I

CD

-9,

Inte

rnat

iona

l Cla

ssifi

catio

n of

D

isea

ses,

Nin

th R

evis

ion.

a References 4, 8, 9, 20, 24, 26-28, 33, 35, 36, and 41.b References 6, 10, 12-15, 17, 21-24, 28-30, 32, 34, 35, 41, and 42. c References 17, 21-24, 28, 30, 32, 34, 35, and 42.


Assessment (PANDA) project.7,14,17 The MASK study was the only one of these to examine multiple anesthetics, and they demonstrated some neuropsychological domains were affected by multiple exposures, but these results should be interpreted cautiously.17

Eight studies, all of which examined children who were exposed to anesthesia at less than 5 years old, found differences in outcomes, particularly in listening compre-hension, performance IQ, and receptive and expressive language.11,19,25,26,29,31,37,46 One of these, which is an outlier in exposure type, examined patients who received ketamine as a solo anesthetic and found that greater than 3 exposures resulted in lower test scores.37 Zhang et al18 demonstrated a decrease in IQ scores following anesthe-sia for school-aged children, but the IQ scores recovered to baseline by 1 year postoperatively. Petrackova et al45 stratified participants into early (0-8 days) and late expo-sure (3-10 months) groups, and they found no differences between these exposure groups but did not compare them with population norms. One study’s findings were sensi-tive to missing data, which hindered interpretation.46 Two studies examined duration of anesthesia; 1 demonstrated that anesthesia duration was associated with incremen-tal decreases in developmental test scores, and another found differences in procedures lasting longer than 35 minutes but not less than 35 minutes.11,31 Two studies of infants found that single surgeries for full-term infants, or preterm infants at term-equivalent age did not alter outcomes; however, surgeries for preterm infants before term-equivalent age were correlated with decreased per-formance and verbal IQ.3,25

• Age at Exposure. The articles included in this review had a range of ages for anesthesia exposure, from preterm to 10 years old, and outcomes were measured at ages 2 through 19 years. Three studies of children exposed to anesthesia after age 5 years found no long-term behav-

SourceAge at exposure Outcome measures/results

Backeljauw,19 2015

< 4 y MRI Lower gray matter density in occipital cortex and cere

Conrad,5 2017

< 7 y MRI, height, and head circumference Height, head circumference, and global brain variables did not significantly correlate with number of operations or hours of exposure to anesthesia for children with cleft lip, cleft lip and palate, and cleft palate. Increased frontal lobe volume was correlated with more surgeries for the sample as a whole but was not correlated with hours of exposure to anesthesia.

Green,43 2015

Mean age at death: exposed group = 23 d; unexposed group = 9 d

Autopsy: histopathology Gliosis more prevalent in exposed group—confirmed by immunohistochemical staining for glial fibrillary acidic protein

Taghon,44 2015

< 2 y Functional MRI Early anesthesia does not affect accuracy, response time, or activation patterns.

Table 3. Brain Studies as Outcome MeasureAbbreviation: MRI, magnetic resonance imaging.

a References 3, 5, 7, 10, 11, 14, 16-19, 25, 26, 29, 31, 37, 45, and 46.

Checklist (CBCL) or a general parental survey.10,14,15,29,42

Four studies assessed brain structure in pediatric pa-tients who underwent anesthesia (Table 3).5,19,43,44 Two studies examined brain magnetic resonance images of children exposed to anesthesia.5,19 Both studies showed differences in brain structures for the exposed cohort, but the anatomical areas affected differed. Backeljauw et al19 found lower gray matter density in the occipital cortex and cerebellum, which correlated with lower scores for performance IQ and language comprehension. Conrad et al5 found that although global brain variables were not significantly different for the sample as a whole, the number of surgeries was positively correlated with frontal lobe volume and negatively correlated with verbal IQ for a surgical subset of this group. Histopathologic findings of central nervous system changes on autopsy showed gliosis, a nonspecific reactive change of glial cells in response to damage in the central nervous system, was more prevalent in the group exposed to anesthesia.43 Testing with functional MRI showed no differences in accuracy, response time, or activation patterns in the pre-frontal cortex and caudate nucleus but did show activa-tion differences in other structures for children exposed to anesthesia.44 Overall, all 4 studies showed differences in the brains of children exposed to anesthesia, but the significance of these findings is unknown.

Seventeen studies used direct neurologic testing (Table 4).a Seven studies that varied widely in design and age of exposure showed no significant differences for children exposed or unexposed to a single anesthestic.3,5,7,10,14,16,17 These results included 3 large-scale trials: the General Anesthesia vs Awake Spinal Anesthesia (GAS) study, the Mayo Anesthesia Safety in Kids (MASK) study, and one of the studies from the Pediatric Anesthesia Neurodevelopement


ioral difficulties or cognitive effects, with the exception of decreased motor function in children exposed between 3 and 10 years of age, and an interim drop in IQ scores, which recovered to baseline 1 year postoperatively.10,16,18 Most of the studies focused on children less than 5 years old at exposure, with a single study extending to 7 years of age. Several studies focused on exposure in infancy. Under the age of 4 years, many studies found an associa-tion between a single anesthesia exposure and decreased cognitive function, increased incidence of behavioral disorders, and developmental brain changes as discussed earlier.19-23,26,28-31,33,43 However, the findings do not con-sistently show that younger children (infants or neonates) are at greater risk than older children (2- to 4-year-olds). Two studies found that the vulnerable age was the older portion of their cohorts.26,27 This is at odds with the pre-vailing belief that younger age at exposure is associated with greater risk and may constitute a critical window.

• Duration and Frequency of Exposure. Research find-ings suggested an association between duration of expo-sure and negative outcomes on IQ performance, behavior, and brain development. Indeed, most studies that includ-ed multiple anesthetics found changes with multiple ex-posures.17,21,24-26,28,33-35,37 Longer cumulative anesthesia exposure was associated with increased risk of behavioral abnormalities, learning disability, decreased educational achievement, and decreased total and expressive language scores.11,20,21,31,35 It is unclear if the impact is specifically related to duration (cumulative time in a single exposure) or frequency (discrete number of times that a patient is anesthetized) or whether it is a combination of both.

DiscussionThe purpose of this integrated review was to describe the literature associated with anesthesia exposure in the young child and its long-term effects on brain develop-ment and cognition. The findings were mixed, likely reflecting study heterogeneity with respect to design, population, surgical procedure, outcome measures, age at exposure, age at outcome assessment, and anesthesia exposure (duration, frequency, and anesthesia type: seda-tion, general, or regional). Although this heterogeneity addresses small gaps in the literature, it precludes rep-lication of findings and hinders synthesis. Additionally, differential sensitivity of the outcome measures used by multiple investigators limits cross-study comparisons. Some studies were retrospective, thus hindering the ex-plication of causal relationships. These clinical data are also limited by several confounding factors, including the presence of comorbid conditions, varying degrees of surgical stress, the inclusion of previous-generation volatile anesthetic gases such as halothane, and the lack of modern monitoring techniques such as end-tidal gas monitoring and pulse oximetry. Surgical stress, the systemic response to tissue injury, characterized by acti-

vation of the sympathetic nervous system and immuno-logic, hematologic, and endocrine responses, may have an impact on the developing human brain independent of the anesthesia exposure. Anesthesia could potentially either ameliorate or aggravate this impact.

The studies generally concluded that academic perfor-mance is negatively correlated with anesthesia exposure, especially for multiple exposures and increased duration of exposure. Academic performance is influenced by social and financial factors limiting efforts to explicate the effects of anesthesia exposure. Despite this limitation, academic performance is often measured because it repre-sents the intersection of behavior, attention, learning, and intelligence. The methods of these studies varied greatly, with outcome measures ranging across a variety of stan-dardized testing, from the benchmark examinations taken by all students at set intervals in their education to the academic grades assigned by their individual teachers, and across the range of elementary through high school educa-tion. Several studies, 2 of which did not find any achieve-ment gap on testing, found increased nonattainment of academic scores, that is, scores on standardized academic tests were missing.4,8,9,26 Although the cause of nonattain-ment is unknown, the authors of these studies suggest that higher rates of nonattainment may indicate disability, which prohibits a student from taking these examinations.

Behavioral findings were mixed, but those that re-ported negative clinical findings found associations with increased anesthesia exposures and duration, with some studies showing differences after single exposure as well. The CBCL was used in 5 studies.10,14,17,29,42

Other measures, such as medical diagnoses, International Classification of Diseases, Ninth Revision coding, and formula calculations for performance were more consis-tently associated with negative clinical findings than the CBCL.21-24,28,30,34,35 Because the CBCL is unique in that it measures parental and teacher observations, the variation in findings may be tool specific.10,14,17,29,42

Awake regional anesthesia has been proposed for pediatric populations to avoid exposure to general an-esthesia. Two studies examined outcomes after awake regional anesthesia.7,36 In the only randomized con-trolled trial included in this review, Davidson et al7 compared the administration of awake regional anes-thesia or general anesthesia in infants and found no differences in neurodevelopmental outcomes at 2 years of age. Williams et al36 compared children exposed and unexposed to awake spinal anesthesia and found a small but significant decrease in math and reading scores in exposed children. This finding suggests that correlations between anesthesia and negative outcomes may not be due to anesthesia drug exposure but rather to other factors, such as medical burden or a side effect of surgery and anesthesia, such as surgical stress or hypotension, which is yet undescribed.


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Using awake regional anesthesia as an alternative to general anesthesia is problematic for practical reasons, because it is effective for only a limited range of pro-cedures and patients. Indeed, most regional anesthesia performed in children is placed after induction of general anesthesia and is intended to enhance postoperative re-covery. The failure rate for awake regional procedures is not insignificant; the GAS study found a 19% failure rate for awake regional techniques.7 There are no offsetting findings in the literature to support the use of awake re-gional anesthesia to avoid exposure to general anesthesia.

Direct neurologic testing or performance IQ testing administered by trained personnel appears to be the most sensitive measure for detecting small changes in exposed children, since they allow for granular ex-amination of the neuropsychological domains that may be affected. Compared with other outcome measures, direct neurologic testing is expensive and time consum-ing. The studies that have large numbers of participants and use direct neurologic testing were secondary analy-ses of existing databases originally created for other purposes, thus limiting conclusion validity.10,11,26,29 Three large-scale studies (GAS, PANDA, and MASK) all used these robust outcome measures.7,14,17 The strength of these studies in design and outcomes measured, and the fact that none of them found a correlation between a single anesthesia exposure and decreased cognitive function, is promising for the safety of healthy children having a single outpatient surgery.

Future studies should use standardized outcome measures to facilitate cross-study comparisons and thus advance our knowledge. Also, studies designed to eluci-date the differential effects of anesthesia frequency and duration are needed. Since adverse cognitive effects may not be detectable in every patient, future studies should incorporate latent class analysis in patient risk stratifi-cation to facilitate the development of decision-making algorithms.

REFERENCES 1. DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Discharge

Survey: 2005 annual summary with detailed diagnosis and proce-dure data. Vital Health Stat 13. 2007;(165):1-209.

2. Sinner B, Becke K, Englehard K. General anaesthetics and the developing brain: an overview. Anaesthesia. 2014;69(6):1009-1022. doi:10.1111/anae.12637

3. Birajdar S, Rao BS, McMichael J. Neurodevelopmental outcomes of neonates undergoing surgery under general anesthesia for malrota-tion of intestines. Early Hum Dev. 2017;109:32-36. doi:10.1016/j.earlhumdev.2017.04.003

4. Clausen NG, Pedersen DA, Pedersen JK, et al. Oral clefts and aca-demic performance in adolescence: the impact of anesthesia-related neurotoxicity, timing of surgery, and type of oral clefts. Cleft Palate Craniofacial J. 2017;54(4):371-380. doi:10.1597/15-185

5. Conrad AL, Goodwin JW, Choi J, Block RI, Nopoulos P. The relationship of exposure to anesthesia on outcomes in children with isolated oral clefts. J Child Neurol. 2017;32(3):308-315. doi:10.1177/0883073816681257.

6. Creagh O, Torres H, Rivera K, Morales-Franqui M, Altieri-Acevedo War

ner,

17

2018

< 3

y

WA

SI,

Wid

e R

ange

Ass

essm

ent

of M

emor

y &

Lea

rnin

g-2,

CTP

P-II

, D-K

EFS

, Com

preh

ensi

ve T

est

of P

hono

logi

cal P

roce

ssin

g, B

eery

Mot

or C

oord

inat

ion,

B

eery

Vis

ual M

otor

Inte

grat

ion,

Bee

ry V

isua

l Per

cept

ion,

Gro

oved

Peg

boar

d Te

st, C

olor

ado

Lear

ning

Diffi

culti

es Q

uest

ionn

aire

A

nest

hesi

a ex

posu

re w

as n

ot a

ssoc

iate

d w

ith d

efic

its in

gen

eral

inte

llige

nce.

Mul

tiple

exp

osur

es t

o an

esth

esia

wer

e as

soci

ated

with

dec

reas

ed

proc

essi

ng s

peed

and

fin

e m

otor

abi

litie

s. P

aren

ts r

epor

ted

incr

ease

d fr

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ncy

of p

robl

ems

in r

eadi

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d m

ultip

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Tabl

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or C

hild

ren.


G, Warner D. Previous exposure to anesthesia and autism spectrum disorder (ASD): a Puerto Rican population-based sibling cohort study. Bol Asoc Med P R. 2015;107(3):29-37.

7. Davidson AJ, Disma N, de Graaff JC, et al; GAS Consortium. Neuro-developmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multi-centre, randomised controlled trial. Lancet. 2016;387(10015):239-250. doi:10.1016/S0140-6736(15)00608-X

8. Hansen TG, Pedersen JK, Henneberg SW, et al. Academic per-formance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114(5):1076-1085. doi:10.1097/ALN.0b013e31820e77a0

9. Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth. 2013;23(10):883-890. doi:10.1111/pan.12225

10. Ing CH, DiMaggio CJ, Whitehouse AJ, et al. Neurodevelopmental outcomes after initial childhood anesthetic exposure between ages 3 and 10 years. J Neurosurg Anesthesiol. 2014;26(4):377-386.

11. Ing C, Hegarty MK, Perkins JW, et al. Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability. Br J Anaesth. 2017;119(3):532-540. doi:10.1093/bja/aew413

12. Ko WR, Huang JY, Chiang YC, et al. Risk of autistic disorder after exposure to general anaesthesia and surgery: a nationwide, retrospec-tive matched cohort study. Eur J Anaesthesiol. 2015;32(5):303-310. doi:10.1097/EJA.0000000000000130

13. Ko W-R, Liaw Y-P, Huang J-Y, et al. Exposure to general anesthesia in early life and the risk of attention deficit/hyperactivity disorder devel-opment: a nationwide, retrospective matched-cohort study. Paediatr Anaesth. 2014;24(7):741-748. doi:10.1111/pan.12371

14. Sun LS, Li G, Miller TL, et al. Association between a single gen-eral anesthesia exposure before age 36 months and neurocogni-tive outcomes in later childhood. JAMA. 2016;315(21):2312-2320. doi:10.1001/jama.2016.6967

15. Terushkin V, Brauer J, Bernstein L, Geronemus R. Effect of gen-eral anesthesia on neurodevelopmental abnormalities in children undergoing treatment of vascular anomalies with laser surgery: a retrospective review. Derm Surg. 2017;43(4):534-540. doi:10.1097/DSS.0000000000001003

16. Yang HK, Chungh DS, Hwang JM. The effect of general anesthesia and strabismus surgery on the intellectual abilities of children: a pilot study. Am J Ophthalmol. 2012;153(4):609-613. doi:10.1016/j.ajo.2011.09.014

17. Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to proce-dures requiring general anesthesia: the Mayo Anesthesia Safety in Kids (MASK) study. Anesthesiology. 2018;129(1):89-105. doi:10.1097/ALN.0000000000002232

18. Zhang Q, Peng Y, Wang Y. Long-duration general anesthesia influ-ences the intelligence of school age children. BMC Anesthesiol. 2017;17(1):170. doi:10.1186/s12871-017-0462-8

19. Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics. 2015;136(1):e1-e12. doi:10.1542/peds.2014-3526

20. Block RI, Thomas JJ, Bayman EO, Choi JY, Kimble KK, Todd MM. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117(3):494-503.

21. Chemaly M, El-Rajab M, Ziade FM, Naja ZM. Effect of one anesthetic exposure on long-term behavioral changes in children. J Clin Anesth. 2014;26(7):551-556. doi:10.1016/j.jclinane.2014.03.013

22. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospec-tive cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-291. doi:10.1097/ANA.0b013e3181a71f11

23. DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113(5):1143-1151. doi:10.1213/

ANE.0b013e3182147f42

24. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery [pub-lished correction appears at Pediatrics. 2012;129(3):595]. Pediatrics. 2011;128(5):e1053-e1061. doi:10.1542/peds.2011-0351

25. Gano D, Andersen SK, Glass HC, et al. Impaired cognitive perfor-mance in premature newborns with two or more surgeries prior to term-equivalent age. Pediatr Res. 2015;78(3):323-329. doi:10.1038/pr.2015.106

26. Glatz P, Sandin RH, Pedersen NL, Bonamy AK, Eriksson LI, Granath F. Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr. 2017;171(1):e163470. doi:10.1001/jamapediatrics.2016.3470

27. Graham MR, Brownell M, Chateau DG, Dragan RD, Burchill C, Fran-soo RR. Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years: a retrospec-tive matched cohort study. Anesthesiology. 2016;125(4):667-677. doi:10.1097/ALN.0000000000001245

28. Hu D, Flick RP, Zaccariello MJ, et al. Association between expo-sure of young children to procedures requiring general anesthe-sia and learning and behavioral outcomes in a population-based birth cohort. Anesthesiology. 2017;127(2):227-240. doi:10.1097/ALN.0000000000001735

29. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in lan-guage and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476-485. doi:10.1542/peds.2011-3822

30. Ing C, Sun M, Olfson M, et al. Age at exposure to surgery and anesthesia in children and association with mental disorder diagnosis. Anesth Analg. 2017;125(6):1988-1998. doi:10.1213/ANE.0000000000002423

31. Naumann HL, Haberkern CM, Pietila KE, et al. Duration of expo-sure to cranial vault surgery: associations with neurodevelopment among children with single-suture craniosynostosis. Paediatr Anaesth. 2012;22(11):1053-1061. doi:10.1111/j.1460-9592.2012.03843.x

32. Nestor KA, Zeidan M, Boncore E, et al. Neurodevelopmental out-comes in infants undergoing general anesthesia. J Pediatr Surg. 2017;52(6):895-900. doi:10.1016/j.jpedsurg.2017.03.008

33. Schneuer FJ, Bentley JP, Davidson AJ, et al. The impact of general anesthesia on child development and school performance: a popula-tion-based study. Pediatr Anesth. 2018;28(6):528-536. doi:10.1111/pan.13390

34. Sprung J, Flick RP, Katusic SK, et al. Attention-deficit/hyperactiv-ity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc. 2012;87(2):120-129. doi:10.1016/j.mayocp.2011.11.008

35. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804. doi:1097/01.anes.0000344728.34332.5d

36. Williams RK, Black IH, Howard DB, et al. Cognitive outcome after spinal anesthesia and surgery during infancy. Anesth Analg. 2014;119(3):651-660. doi:10.1213/ANE.0000000000000288

37. Yan J, Li YR, Zhang Y, Lu Y, Jiang H. Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: a pro-spective preliminary clinical study. J Child Neurol. 2014;29(10):1333-1338. doi:10.1177/0883073813517508

38. Anesthetic and Life Support Drug Advisory Committee (ALSDAC), Federal Drug Administration. Overview of the March 10, 2011 ALS-DAC meeting to discuss the neurotoxicity of anesthetic and sedative drugs in juvenile animals. 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anestheti-cAndLifeSupportDrugsAdvisoryCommittee/UCM245769.pdf

39. Food and Drug Administration. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Decem-ber 14, 2016. https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm Accessed April 9, 2019.

40. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS One. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097


41. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive per-formance in children: no evidence for a causal relationship. Twin ResHum Genet. 2009;12(3):246-253. doi:10.1375/twin.12.3.246

42. Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiol-ogy. 2009;110(4):805-812. doi:10.1097/ALN.0b013e31819c7124

43. Green MS, Aman MM, Stevens L, et al. Histopathological observa-tions in the brains of children exposed to inhalational anestheticagents: a retrospective autopsy-based study. Minerva Anestesiol.2015;81(12):1329-1337.

44. Taghon TA, Masunga AN, Small RH, Kashou NH. A comparison offunctional magnetic resonance imaging findings in children with andwithout a history of early exposure to general anesthesia. PaediatrAnaesth. 2015;25(3):239-246. doi:10.1111/pan.12606.

45. Petrackova I, Zach J, Borsky J, et al. Early and late operation of cleftlip and intelligence quotient and psychosocial development in 3-7years. Early Hum Dev. 2015;91(2):149-152. doi:10.1016/j.earlhum-dev.2014.12.015

46. de Heer IJ, Tiemeier H, Hoeks SE, Weber F. Intelligence quotientscores at the age of 6 years in children anaesthetised before the age of5 years. Anaesthesia. 2016;72(1):57-62. doi:10.1111/anae.13687.

AUTHORSAudrey Rosenblatt, MSN, CRNA, is employed by Rush University College

of Nursing in Chicago, Illinois, and Ann & Robert H. Lurie Children’s Hos-

pital of Chicago, Chicago, Illinois. Email: [email protected].

Michael Kremer, PhD, CRNA, CHSE, FNAP, FAAN, is executive co-

director of the Rush Center for Clinical Skills and Simulation and a profes-

sor in the Rush University College of Nursing.

Barbara Swanson, PhD, RN, FAAN, is an assistant dean, professor, and

director of the PhD in Nursing Science Program in the Rush University

College of Nursing.

Ravi Shah, MD, is the director, Chronic Pain Treatment Program, Ann

& Robert H. Lurie Children’s Hospital of Chicago.

DISCLOSURESThe authors have declared no financial relationships with any commercial

entity related to the content of this article. The authors did not discuss

off-label use within the article. Disclosure statements are available for

viewing upon request.


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Employment OpportunitiesMednax Services, Inc. 169United Anesthesia Associates 229University of Arkansas for Medical Sciences 221

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AANA Journal CourseClarifying the Confusion of Adult Emergence Delirium

Col Shawna Greiner, PhD, CRNA, USAF, NCMichael J. Kremer, PhD, CRNA, CHSE, FNAP, FAAN

ObjectivesAt the completion of this activity, the learner will be able to:

1. Identify the populations most at risk of emergenceand postoperative delirium.

2. Classify emergence delirium.3. Identify other phenomenon that can present similar

to emergence delirium.4. Select factors that may increase risk or exacerbate

emergence delirium.5. Differentiate between common anesthesia related

toxicities, postoperative delirium, and emergencedelirium.

IntroductionAlthough emergence delirium (ED) is well studied and understood in children, research findings pertaining to adults are contradictory, with an inadequate amount of evidence to guide practice. The definition of ED is unclear in the literature,1 and the reported incidence of ED is widely variable, ranging from 1.8% to 75%.2,3

Emergence delirium is a dangerous and costly occurrence in patients of all ages, and it is most prevalent in healthy pediatric patients and in younger adults.3-5 Postoperative delirium (POD) is typically noted in older patients with multiple comorbidities.6,7 Emergence delirium and POD

share some risk factors; both can be triggered by noxious stimuli encountered during the perioperative period, in-cluding surgery, medications, noise, and light, but they are distinctly different phenomena. There is a continuum of delirium that surgical patients may experience starting with ED that may progress to POD and postoperative cognitive decline.8,9 The distinction between ED and POD is important since prevention and treatments differ, yet the 2 phenomena are often referred to synonymously in the literature.

There is an increasing awareness of ED in adults, especially in military members who have been involved in combat or conflicts.3,10 Current literature does not adequately discriminate between ED, other deliria, or similarly presenting drug toxicities and medical condi-tions. Without an accurate differential diagnosis, the potential treatment choices for ED are unclear, and some options can exacerbate delirium. This course will discuss the similarities and differences of other phenomena that present similarly to ED, and describe evidence-based treatment options from an integrative literature review and a Delphi study.

Delphi Study Methods The authors obtained institutional review board approval

To date, researchers studying emergence delirium in adults have not adopted a consensus on the terminol-ogy for the phenomenon, a formalized definition, a measurement tool or standardized differential diag-nosis to distinguish emergence delirium from postop-erative delirium, anticholinergic or serotonergic toxici-ties, and other physiologic issues that may present on emergence from anesthesia. This lack of a consensus in emergence delirium research and differential diag-nostic tools is confounding findings and preventing

improved patient outcomes. Information from an integrative review of the literature in conjunction with a Delphi study was used to develop a standardized dif-ferential of similarly presenting phenomena to assist clinicians in determining appropriate interventions for patients who appear to have emergence delirium.

Keywords: Adult, differential diagnosis, emergence delirium.

The AANA Journal Course is published in each issue of the AANA Journal. Each article includes objectives for the reader and sources for additional reading. A 5-question open-book exam for each course is published on www.AANALearn.com and will remain live on the site for a period of 3 years. One continuing education (CE) credit can be earned by successfully completing the examination and evaluation. Each exam is priced at $35 for members and $21 for students but can be taken at no cost by using one of the six free CEs available annually to AANA members as a benefit of membership. For details, go to www.AANALearn.com. This educational activity is being presented with the understanding that any conflict of interest has been reported by the author(s). Also, there is no mention of off-label use for drugs or products.


and conducted a Delphi study to determine the definition of ED, to identify an appropriate assessment tool, and to highlight key concepts that could be used for future development of an adult ED assessment tool. A 3-round Delphi study composed of (1) automated telephone open-ended questions, (2) online relevance rating with com-ments, and (3) online relevance ranking with comments was conducted. The wording of the instructions, survey layout, confidence ratings, and scaling of the items were developed from themes identified during the integrative review per Delphi and survey development methods. Because of gaps identified during the literature review, the surveys were framed to determine the definition, appro-priate terminology, and key concepts of adult ED.

The 12 open-ended questions and survey items were developed using standard survey development methods. Perioperative clinicians including 2 anesthesiologists, 2 Certified Registered Nurse Anesthetists (CRNAs), 2 operating room nurses, and 2 postanesthesia care unit nurses reviewed each survey used for the 3 rounds of the Delphi for clarity, readability, and relevance. The first round of open-ended questions was formulated based on information gleaned through a integrative literature review. The second and third rounds of the Delphi study were generated from participant responses during the study and audited by associate investigators for clarity and readability. The surveys were created in Qualtrics software (SAP). As each round of the Delphi was com-pleted, open-ended responses were thematically coded, and quantitative data were analyzed using descriptive statistics and Cronbach α in SPSS version 22 (IBM Corp).

Nineteen purposively sampled perioperative profes-sionals were recruited, including 6 anesthesiologists, 7 CRNAs, 3 operating room nurses, and 3 recovery room nurses. By the end of the study, 13 (68%) of the par-ticipants remained. All participants met the criteria to be considered ED experts. For each round of the Delphi, all participants received feedback on their individual responses and the group responses. The participants were encouraged to provide rationale when they were in disagreement with the group or changed their mind regarding their individual responses.

Confusion About Emergence DeliriumIssues that confound our understanding of ED in the adult population include a lack of agreement on the fol-lowing items:

• a name• a definition• an assessment tool• a differential diagnosis• prevention and treatmentAmbiguous terminology and the absence of a set ED

definition limit our understanding of ED, resulting in the use of various terms to identify what may be ED. Other

terms used to describe delirium occurring during emer-gence from anesthesia are emergence agitation (primar-ily for pediatric patients), recovery room delirium, and POD. These terms are often used interchangeably but may not be synonymous with ED. Postoperative delirium is an example; it is likely that this is a related but differ-ent phenomenon.

A variety of ED measurement tools that were not identified, created without a validation process, devel-oped for use with pediatric patients, or used to monitor patient sedation and agitation in intensive care units were noted in current literature.1,11-16 To date, only the Pediatric Anesthesia Emergence Delirium tool has undergone construct and content validation for ED. Studies that validated the use of the Pediatric Anesthesia Emergence Delirium for adults involved participants who were military nurse anesthetists caring for military service members who were combat veterans.10 Many of these patients had preexisting mental health issues, such as anxiety, depression, and posttraumatic stress disorder (PTSD). It is possible that ED is being misidentified in practice and research, leading to inappropriate treatment and conflicting evidence without consistent use of a vali-dated adult assessment tool.

Lack of use of an adult-specific ED assessment tool hinders clear discernment between ED and similar phe-nomena. A clinical differential diagnosis that includes ED and does not consider other similar phenomena has led to imprecise ED prevention and treatment strategies. Some descriptions of ED based on the literature review and Delphi study follow.

Emergence Delirium Emergence delirium is in a subset of delirium catego-rized as substance/medication-induced delirium.9,17 It is described as an altered level of consciousness, disorien-tation, agitation, hyperactivity and/or hypoactivity, and thrashing and violent behavior with the potential to harm self or others, and it is prevalent in pediatric patients or adults under 40 years of age.3,10,14,16 According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), delirium is a neurocognitive disor-der characterized by a deficit in cognitive function that is acquired.17 There are 5 diagnostic criteria, 4 elements, and 5 characteristics used for the differential diagnosis of the different types of delirium found in the DSM-5 under neurocognitive disorders, specifically the subcategories of substance intoxication delirium, medication-induced delirium, delirium due to medical conditions, and de-lirium due to multiple other causes.

Distinctions between ED, delirium resulting from drug toxicities, delirium due to another medical condi-tion (hypoxia, metabolic derangements, and dehydra-tion), and POD characterize prevention and helpful vs harmful interventions. Medications delivered during


anesthesia can cause ED as seen in pediatric patients. Drugs that are commonly taken by adult patients interact with perioperative medications and can exacerbate other phenomena such as toxicities and POD that are under-diagnosed and misdiagnosed as ED. One example is the 400% rise in antidepressant prescriptions from 1988 to 2011, and polypharmacy involving psychoactive drugs, which can exacerbate these similar diagnoses such as drug toxicities.18 The clinical presentation of these deliria is similar to ED, but when the differential diagnosis does not result in an ED diagnosis, treatment specific to the identified delirium is required.

In addition to the physical ramifications of ED, there is an increased cost to patients, their families, and surgi-cal facilities. Patients who experience ED may remove in-dwelling catheters or tubes, injure themselves, or dehisce wounds or disrupt sutures, resulting in hemorrhage ne-cessitating surgical repair.1,16 Adult patients with ED re-quired up to 6 times more nursing resources than typical patients recovering from anesthesia.1 Those patients who experienced the hypoactive form of ED, in which the patient is sedate and unresponsive or mute, averaged 2 more days of hospitalization than their peers.15,19 This form of ED was likely to result in POD and ongoing com-plications, specifically cognitive and physical deteriora-tion that eventually required long-term care.9,20

• Defining Factors. There is no consistent definition of adult ED. Delphi study participants suggested this adult ED definition: “behavior after exposure to anesthe-sia in which a patient demonstrates or exhibits anxiety, restlessness, confusion, and combativeness.” The types of anesthetics most commonly associated with ED that were identified by study participants were any general anesthetic and inhaled anesthetics. Inhaled anesthetics were also indicated in several studies,21-24 specifically sevoflurane.11,12,25

Most clinicians assert that the onset of ED occurs as the patient awakens from anesthesia, although the exact time of onset varies. The literature review and the Delphi study described ED onset as occurring during either emergence or recovery from anesthesia. The literature review and the Delphi study results described ED as a short-lived reaction to perioperative events.

• Risk Factors. Identified ED risk factors included du-ration of anesthesia more than 1.5 hours, type of surgery, medical conditions, psychological issues, smoking, social alcohol use, and medications. Cases that required greater than 1 hour to complete increased the potential for ED. The types of surgery in which ED was more likely to occur included surgeries of the abdomen; breast; and ear, nose, and throat. The literature described other factors for ED as irritants (external and indwelling medical equipment), hypoxia, or a sense of suffocation and pain.

There was agreement between the literature and the Delphi study participants that fear, depression, anxiety

state and/or trait, PTSD, or trauma3,10,22,26 were more likely to exist in patients who experienced ED. The Delphi study participants added the risk factors of a history of sexual trauma or abuse and a prior history of ED. A prospective correlational study of ED in military members found ED rates of 20% in patients with combat experience and 17.5% in patients without psychological issues, and the authors noted that 50% of patients had anxiety, depression, and/or PTSD.10

The incidence of ED in military members and veterans is higher than in their civilian counterparts of the same age, ranging from 20% to 75%3,10 and 1.8% to 54%,2,4 respectively. Possible contributors to these higher rates include deployment to a combat area, underlying psychi-atric issues, psychotropic medications, and the formerly prescribed antimalarial, mefloquine.27,28

Drugs and drug interactions were cited as exacerbat-ing factors in both the literature and the Delphi study. Findings included perioperative medications adminis-tered, drug interactions, individual responses to anesthe-sia, and longer exposure times to anesthetics, but there was no consensus regarding specific triggering agents for ED. Many of the medications identified in the literature can be related to medical conditions and drug toxicities. Serotonin toxicity is exacerbated by a variety of anti-depressants, cocaine, and fentanyl.29,30 Anticholinergic toxicity can be related to risk of postoperative nausea and vomiting, anxiety, or scopolamine and benzodiaz-epines.13,14 Guidelines for diagnosing delirium recom-mend ruling out these 2 drug toxicities; both toxicities are common yet underdiagnosed because of provider unawareness.30,31 Neuromuscular relaxants1,15 and me-floquine were also identified as exacerbating factors and likely reflect other medical issues such as hypoxia secondary to inadequate oxygenation and ventilation and neurologic and/or psychological issues related to meflo-quine damage.

Mefloquine chemoprophylaxis was standard practice for personnel who served in conflicts where malaria is common, such as the Middle East, until 2009, when permanent neurologic sequelae were noted.32 Six years of mefloquine prescription statistics indicate that at least 150,000 veterans32,33 received this drug for 5 to 20 months. The neurologic and psychiatric side effects of mefloquine are very similar to ED and include abnormal dreams, anxiety, paranoia, agitation, confusion, memory impairment, and hallucinations.32 There is also a correla-tion between PTSD and mefloquine.32 The likely influ-ence of mefloquine in the military and veterans is a vari-able that has not been accounted for in most ED research.

• Diagnosis and Treatment. Treatment suggestions are limited by conflicting information regarding ED and by the probable misdiagnosis of ED. Currently, there is a lack of evidence for the prevention and treatment of ED, and the Food and Drug Administration (FDA) has not


approved any medications for its treatment. The correct diagnosis, determined by differential diag-

nosis, can be guided by information from the literature review and Delphi study. Predictive factors for adult ED include male gender, a younger age (< 40 years of age), history of smoking or social alcohol consumption, long-term use of benzodiazepines or antidepressants, preexisting mefloquine treatment, combat or deployment experience, depression, anxiety state and/or trait, PTSD, intraoperative inhaled anesthesia, fracture repairs, otolar-yngologic surgery, urologic surgery, gastric tubes, Foley catheters, endotracheal tubes, severe pain, and longer duration of surgery.4,5,16,22,24,26,34,35

The Pediatric Anesthesia Emergence Delirium tool is used to assess ED in pediatric patients and may have some limitations for the adult population, but it has been validated for use in adults.10 The Richmond Agitation-Sedation tool and the Confusion Assessment Method for the ICU (Intensive Care Unit; CAM-ICU) have the limita-tion of not being validated for use in ED, but were used to assess ED in most of the studies conducted within the past 5 years.4,5,16,24,25 Emergence delirium is the appropri-ate diagnosis if the patient has the identified predictive factors, POD and drug toxicities have been ruled out, and the Pediatric Anesthesia Emergence Delirium criteria have been met or findings from the combined Richmond Agitation-Sedation and CAM-ICU are consistent with ED.

Despite the lack of consensus and research findings regarding ED in adults, there are a few evidence-sup-ported recommendations for prevention and treatment. However, it is important to note that many of the current double-blind, randomized controlled studies excluded patients with a history of alcohol use or any psychologi-cal illness, although these patients typically are consid-ered to be at risk of ED.

The incidence of ED in adults is lower in institutions that provide extensive preoperative education and offer emotional support in lieu of benzodiazepine premedica-tion24,34 and avoid administration of inhaled anesthet-ics.5,21-24 When inhaled anesthetics were used instead of total intravenous anesthesia, patients who received a con-tinuous infusion of dexmedetomidine or remifentanil or a bolus of dexmedetomidine (0.5-1 μg/kg) or an N-methyl-d-aspartate (NMDA) agonist such as ketamine (0.5 mg/kg) at induction or 5 to 10 minutes before emergence were less likely to experience ED.4,25,36-38 The dosing for the con-tinuous infusion was 0.4 to 1 μg/kg/h and 0.25 to 1 μg/kg/min, respectively.11,39-41 Patients who received dexmedeto-midine had less postoperative pain, nausea, and vomiting. Newer case reports describe reversal of ED with dexme-detomidine, 0.5 to 1 μg/kg, when midazolam treatment, reassurance, and the presence of a family member failed.42 There is no current evidence that supports physostigmine as a treatment; it is likely that agitation that is reversed by this drug is unidentified anticholinergic toxicity.31,43

Similar PhenomenaPostoperative delirium and serotonergic and anticho-linergic toxicities can have signs that mimic ED. Other physiologic issues commonly experienced by patients during the perioperative period that can present as ED include hypoxia, inadequate reversal of neuromuscular blockade, pain, and metabolic derangements. An accu-rate differential diagnosis is essential because inappropri-ate treatments will exacerbate the presenting condition.

Postoperative delirium and anticholinergic and se-rotonin toxicities share the signs of agitation, rest-lessness, anxiety, confusion, and disorientation with ED.10,29,35,44,45 There are other distinguishing signs that can be used to identify ED in adults and to assist in ap-propriate clinical interventions. The Figure compares phenomena that can present as ED.

• Postoperative Delirium. Postoperative delirium is both costly and dangerous. The average cost of postopera-tive delirium is $2,947 per affected patient, annualized to $2 billion each year.19 Patients with POD have the poten-tial for up to 3 times higher morbidity and mortality within 6 months, related to ensuing progressive cognitive decline and other medical issues such as stroke and sepsis.8,14

In contrast to ED, POD primarily affects older adults and occurs after initial recovery from anesthesia up to 24 hours or even days after surgery.9,20,45,49 Inouye50 de-scribed delirium in older adults as resulting from triggers that are a combination of preexisting vulnerabilities and noxious stimuli in the Multifactorial Model of Delirium of Older Persons. This theoretical model is the primary theoretical framework for POD literature. There are some studies that identified older adults with ED,1 but the as-sessment tools used were developed and validated for intensive care sedation and agitation. Established POD risk factors include a lack of acetylcholine, excessive do-pamine, proinflammatory cytokines, γ-aminobutyric acid deficiency (linked to substance abuse), sensory impair-ments, sleep deficits, lack of familiarity with the environ-ment, social isolation, loss of cognitive reserve associated with aging, constipation, indwelling catheters, smoking, anesthetic neurotoxicity, coexisting comorbidities (eg, hypertension, diabetes), dehydration, metabolic derange-ments, infection, inflammation, hypoxia, hypercapnia or hypocapnia, inadequate perfusion, and pharmacologic interactions.7,46,47,49

Because pharmacologic treatments of POD can lead to poorer long-term outcomes and can exacerbate and prolong adverse outcomes, current POD clinical practice guidelines by the American Geriatrics Society (AGS) Expert Panel on Postoperative Delirium in Older Adults recommend first employing prevention.47 Prophylaxis of POD includes orienting the patient to the perioperative area, allowing the use of hearing aids and glasses before surgery and on emergence reorienting the patient to his or her environment after surgery, presence of family or


a friend during recovery from anesthesia, adjusting the environment, encouraging fluid and nutritional intake, avoiding constipation, promoting early activity, cognitive stimulation, nonpharmacologic sleep hygiene before and after surgery, and providing oxygenation. Avoid anes-thetic neurotoxicity by using age-appropriate (chrono-logic or physiologic age) anesthetic doses, maintaining a mean arterial pressure close to the patient’s awake levels, and considering avoiding a deep anesthetic. Also impor-tant is adequate pain control,6,46,47 preferably nonopioid options such as acetaminophen doses of 650 mg if the patient is older than 65 years and 1,000 mg if younger, or use of dexmedetomidine, 0.1 μg/kg/h. If narcotics must be used, avoid meperidine.48 The analgesic and antiinflammatory properties of ketamine decrease the incidence of POD; the recommendation is to give a single dose of 0.5 to 1 mg/kg before the incision. Gabapentin and celecoxib may also have a role,47,49 but more research is needed. In older adults, several medications potentiate POD. Whenever possible, avoid all tricyclic antidepres-sants, anticholinergics (using only glycopyrrolate), an-tihistamines, benzodiazepines (especially midazolam), chlorpromazine, corticosteroids, histamine H2 receptor antagonists, meperidine,46 minimizing sedative hypnot-ics, and medications that increase serotonin (to avoid serotonin toxicity),47 in addition to following the current AGS Beers Criteria Update Expert Panel as a guide of medications to avoid.49 When POD occurs, determina-tion of the underlying causes, including dehydration, infection, hypoxemia, and alcohol or drug withdrawal should be considered. As a last resort for a patient with POD who is in jeopardy of harming self or others, re-straints or pharmacologic treatment can be employed, such as haloperidol dosed in 0.5- to 1-mg increments every 30 minutes for a maximum of 20 mg/24 h, but this may result in worse patient outcomes.47,49 Other drugs that may be effective in treating POD are chlorpromazine and benzodiazepines, which have yielded inconsistent outcomes. Another possible pharmacologic interven-tion is the benzodiazepine lorazepam, 0.5 mg, every 30 minutes for a maximum dose of 6 mg in 24 hours, which also may worsen the delirium and impair full recovery.49

• Anticholinergic Toxicity. Anticholinergic toxicity shares similar characteristics with ED. In fact, delirium is caused by anticholinergic drugs in healthy adults.31 Therefore, it is useful to rule out this diagnosis in pa-tients who have received antiemetics, antihistamines, antiparkinsonian agents, benzodiazepines, opioids, sco-polamine, atropine, promethazine, droperidol, halo-peridol, halothane, etomidate, propofol, or ketamine.43,44 However, there are no current user-friendly diagnostic criteria and many presentations, a difficulty that compli-cates identifying anticholinergic toxicity.

Although some treatments for ED are useful for an-ticholinergic toxicity, others can further exacerbate the

problem if anticholinergic toxicity is misdiagnosed as ED. One treatment, physostigmine, is useful because it can reverse anticholinergic crisis. But, if a patient has anticho-linergic toxicity and is treated for ED with some recom-mended drugs, such as propofol, ketamine, or droperidol, then anticholinergic toxicity could be amplified.31,43 Signs and symptoms specific to anticholinergic toxicity that can be used for diagnostic differentiation and directing treat-ment are anhidrosis, mydriasis, constipation, an urge to urinate, and a sense of bladder fullness. A confounding factor is that many patients emerging from anesthesia cannot coherently verbalize the last 3 symptoms.

Patients with anticholinergic toxicity usually respond to treatment with physostigmine. It is important to note there is a high incidence of nausea and vomiting with this treatment. Appropriate adult intravenous dosing is 0.5 to 2 mg given over 5 minutes not to exceed 1 mg/min and may be repeated in 20 to 30 minutes if symptoms resurge.44 It is important to have atropine ready to treat cholinergic responses. Benzodiazepines can be used to relieve some of the signs and symptoms of anticholinergic toxicity, but they do not treat the underlying pathology.

• Serotonergic Toxicity. Like anticholinergic toxic-ity, serotonin toxicity can present similarly to ED. Some medications that can trigger or potentiate serotonergic toxicity are synthetic phenylpiperidine opioids (fentanyl, alfentanil, sufentanil, meperidine, methadone, dextro-methorphan, and tramadol), amphetamines, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin or serotonin-norepinephrine reuptake inhibitors, lithium, buspirone, and L-tryptophan; other potential triggers are cocaine, MDMA (Ecstasy), and bath salts.29,30 A thor-ough preoperative examination and history can provide clinicians with useful diagnostic information.

Serotonin toxicity is a physiologic reaction to an excess of serotonin in synaptic clefts that presents as motor and mental excitability with altered levels of consciousness that resembles ED. The clinical features of serotonin toxicity are demonstrated in the Figure. Some of the motor and autonomic effects, specifically myoclonus, hyperthermia, flushing, diaphoresis, and mydriasis29 are not present in adults with ED. This toxicity is reliably diagnosed using the Hunter Serotonin Toxicity Criteria29 (see Figure). The primary treatments of serotonin toxicity are avoiding further administration of triggering agents, supportive care, sedation with benzodiazepines (eg, lorazepam, 2-4 mg, or diazepam, 5 to 10 mg, IV repeated every 8 to 10 minutes as needed), cyproheptadine in a 12-mg loading dose fol-lowed by 2 mg by mouth or gastric tube every 2 hours for a maximum of 32 mg/d if the patient is hemodynamically labile, and providing neuromuscular relaxation and intuba-tion for hyperthermic or critically ill patients.29,30

ConclusionInformation regarding adult ED is not conclusive with


PREDICTIVE FACTORS

■ Male, younger age ■ History of smoking or social alcohol drinking ■ Long-term use of benzodiazepines or antidepressants■ Pre-existing mefloquine regimen, combat or deployment experience,

depression, anxiety state and/or trait, PTSD Intraoperative inhaled anesthesia ■ Longer surgical durations (greater than 1.5 hours)■ Types of surgery: Fracture repairs, otolaryngological surgery, urological

surgery ■ Presence of gastric tubes, foley catheters, endotracheal tubes ■ Severe pain, previous experienced ED

■ Lack of acetylcholine, excessive dopamine, proinflammatory cytokines ■ Gamma-aminobutyric acid deficiency (linked to substance abuse), smoking■ Sensory impairments, sleep deficits, lack of familiarity with the environment,

social isolation■ Anesthetic neurotoxicity (too much anesthetic for age), inadequate

perfusion from hypotension■ Loss of cognitive reserve associated with aging or substance abuse ■ Coexisting comorbidities: Hypertension, diabetes, dehydration, metabolic

derangements, infection, inflammation, hypoxia, hyper or hypocapnia ■ Irritants: Constipation, full bladder, indwelling catheters■ Pharmacological interactions

High risk medications: Parkinson's medications; trihexyphenidyl (Artane), benztropine mesylate (Cogentin), biperiden (Akineton); antipsychotics and antidepressants such as clomipramine (Anafranil), chlorpromazine (Thorazine), clozapine (Clozaril), fluphenazine (Prolixin), loxapine (Loxitane), olanzapine (Zyprexa), perphenazine (Trilafon), pimozide (Orap), quetiapine (Seroquel), thioridazine (Mellaril), thiothixene (Navane), trifluoperazine (Stelazine), chloridiazepoxide (Librium), amitriptyline (Elavil, Endep), amoxapine (Asendin), clomipramine (Anafranil,) desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil); antispasmodics belladonna, dicyclomine (Bentyl), hyoscyamine (Levsin); overactive bladder medications oxybutynin (Ditropan), darifenacin (Enablex), solifenacin (Vesicare), fesoterodine (Toviaz), tolterodine (Detrol), trospium (Sanctura); muscle relaxants such as cyclobenzaprine (Flexeril), dantrolene (Dantrium), carisoprodol (Soma), methocarbamol (Robaxin), orphenadrine (Norflex), tizanidine (Zanaflex); motion sickness medications such as meclizine (Antivert); belladonna; dicyclomine (Bentyl); hyoscyamine (Levsin); loperamide (Imodium); scopolamine, diphenhydramine (Benadryl), or promethazine (Phenergan).

A person taking monoamine oxidase inhibitors (furazolidone, isocarboxazid, linezolid, phenelzine, selegiline, Syrian rue, tranylcypromine), tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine), serotonin or serotonin-norepinephrine reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, venlafaxine), triptans (almotriptan, dihydroergotamine, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan), levomethorphan, levorphanol, pentazocine, pethidine, tapentadol, the antiparkinsonian L-dopa, mirtazapine, trazadone, lithium, buspirone, phentermine, bupropion, risperidone, nefazodone, trazodone, granisetron, ondansetron, chlorpheniramine, ciprofloxacin, ritonavir, fluconazole, citalopram, methadone, oxycodone, tramadol, metoclopramide, amphetamines, bath salts, cocaine, dextromethorphan, ecstasy, LSD, L-tryptophan, St. John’s wort (Hypericum perforatum).

Serotonergic ToxicityEmergence Delirium Postoperative Delirium Anticholinergic Toxicity

■ Provide extensive preoperative education and emotional support ■ Minimize or avoid benzodiazepines through reassurance and preoperative

education■ Avoid inhaled anesthetics or combine with

• Continuous infusion of dexmedetomidine 0.4-1 μg/kg/hr or remifentanil 0.25-1 μg/kg/min or

• Bolus of dexmedetomidine (0.5-1 mcg/kg) or ketamine (0.5 mg/kg) on induction or 5-10 minutes before emergence

■ Orient and educate the patient to the perioperative area ■ Instruct the patient on non-pharmacological sleep hygiene before surgery

and promote after surgery■ Encouraging fluid and nutritional intake per the enhanced recovery protocol

before and after surgery■ Allow the use of hearing aids and glasses before surgery and on

emergence■ Consider using ketamine 0.5-1 mg/kg before incision for the

antiinflammatory properties ■ Avoid anesthetic neurotoxicity by using age (chronologic or physiologic)

appropriate anesthetic doses■ Maintain a mean arterial pressure near the patients’ awake levels■ Ensure adequate pain control using non-opioid options whenever possible

• Acetaminophen 1000 mg unless >65 years old then 650 mg or dexmedetomidine 0.1mcg/kg/hr

■ Provide oxygen during recovery from anesthesia■ Reorienting the patient to their environment after surgery■ Allow the presence of family or a friend during recovery from anesthesia■ Adjust the environment (e.g. quiet with mid-level lighting)■ Avoiding constipation■ Promoting early activity■ Provide cognitive stimulation■ Avoid all tricyclic antidepressants, anticholinergics (use only glypyrrolate),

antihistamines, benzodiazepines (especially midazolam), chlorpromazine, corticosteroids, H2 receptors antagonists, meperidine, minimizing sedative hypnotics, and medications that increase serotonin, follow current AGS Beers Criteria

PREVENTIVE STRATEGIES

COMMON PRESENTING S/S Disoriented, RestlessAgitated, Anxious, Confused, Delusions, Hallucinations, Calling Out, Amnesia, Hypoactivity

DIFFERENTIATING S/S young, healthy, violent, thrashing, traumatic past or military deployment history. older age, altered sleep and sensory perception or after recovery within 24 hours of surgery, possible continuation from ED

Anhidrosis, mydriasis, constipation, an urge to urinate and a sense of bladder fullness.

If the patient is on any of the medications above avoid administering atropine, scopolamine, diphenhydramine (Benadryl), or promethazine (Phenergan) during the perioperative period.

ASSESSMENT TOOLS

Pediatric Anesthesia Emergence Delirium scale or Richmond Agitation Sedation Scale with Confusion Assessment Method for Intensive Care Patients. A score of 10 or greater on this PAED indicates ED.

TREATMENT

■ Address triggers such as anxiety, pain, hypoxia and catheters

■ Provide reassurance ■ Allow the presence of a loved one ■ Bolus with dexmedetomide 0.5–1 mcg/kg

Mini-Mental State Exam and the Confusion Assessment Method

Treat underlying causes to include dehydration, infection, hypoxemia, and alcohol or drug withdrawal. Haldoperidol dosed in 0.5-1 mg increments every 30 minutes for a maximum of 20 mg per 24 hours if the patient is harming self or others and treating the underlying cause has failed.

1)

2) Avoid or stop the triggering agentsProvide supportive care (hydration, cooling, neuromuscular relaxation and intubation) and sedate with benzodiazepines (e.g. lorazepam 2-4 mg or diazepam 5-10 mg IV repeated every 8-10 minutes as needed)

3) Load with cyproheptadine 12 mg then 2 mg by mouth or gastric tube every 2 hours up

to 32 mg/day

None

Physostigmine 0.5-2 mg over 5 minutes or 1mg/minute, repeat every 20-30 minutes as needed.Benzodiazepines can be used, but do not relieve the underlying cause.

Hunter Serotonin Toxicity Criteria

This algorithm was created using these sources4,6,7,9-11,14,16,20-31,34-46,48-50

*Boolean terms or and and

Figure. Algorithm for Differential Diagnosis of Emergence Delirium (ED)aAbbreviations: AGS, American Geriatrics Society; L, levo; LSD, lysergic acid diethylamide; PAED, Pediatric Anesthesia Emergence Delirium tool; POD, postoperative delirium; PTSD, posttraumatic stress disorder; S/D, signs and symptoms.


PREDICTIVE FACTORS

■ Male, younger age ■ History of smoking or social alcohol drinking ■ Long-term use of benzodiazepines or antidepressants■ Pre-existing mefloquine regimen, combat or deployment experience,

depression, anxiety state and/or trait, PTSD Intraoperative inhaled anesthesia ■ Longer surgical durations (greater than 1.5 hours)■ Types of surgery: Fracture repairs, otolaryngological surgery, urological

surgery ■ Presence of gastric tubes, foley catheters, endotracheal tubes ■ Severe pain, previous experienced ED

■ Lack of acetylcholine, excessive dopamine, proinflammatory cytokines ■ Gamma-aminobutyric acid deficiency (linked to substance abuse), smoking■ Sensory impairments, sleep deficits, lack of familiarity with the environment,

social isolation■ Anesthetic neurotoxicity (too much anesthetic for age), inadequate

perfusion from hypotension■ Loss of cognitive reserve associated with aging or substance abuse ■ Coexisting comorbidities: Hypertension, diabetes, dehydration, metabolic

derangements, infection, inflammation, hypoxia, hyper or hypocapnia ■ Irritants: Constipation, full bladder, indwelling catheters■ Pharmacological interactions

High risk medications: Parkinson's medications; trihexyphenidyl (Artane), benztropine mesylate (Cogentin), biperiden (Akineton); antipsychotics and antidepressants such as clomipramine (Anafranil), chlorpromazine (Thorazine), clozapine (Clozaril), fluphenazine (Prolixin), loxapine (Loxitane), olanzapine (Zyprexa), perphenazine (Trilafon), pimozide (Orap), quetiapine (Seroquel), thioridazine (Mellaril), thiothixene (Navane), trifluoperazine (Stelazine), chloridiazepoxide (Librium), amitriptyline (Elavil, Endep), amoxapine (Asendin), clomipramine (Anafranil,) desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil); antispasmodics belladonna, dicyclomine (Bentyl), hyoscyamine (Levsin); overactive bladder medications oxybutynin (Ditropan), darifenacin (Enablex), solifenacin (Vesicare), fesoterodine (Toviaz), tolterodine (Detrol), trospium (Sanctura); muscle relaxants such as cyclobenzaprine (Flexeril), dantrolene (Dantrium), carisoprodol (Soma), methocarbamol (Robaxin), orphenadrine (Norflex), tizanidine (Zanaflex); motion sickness medications such as meclizine (Antivert); belladonna; dicyclomine (Bentyl); hyoscyamine (Levsin); loperamide (Imodium); scopolamine, diphenhydramine (Benadryl), or promethazine (Phenergan).

A person taking monoamine oxidase inhibitors (furazolidone, isocarboxazid, linezolid, phenelzine, selegiline, Syrian rue, tranylcypromine), tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine), serotonin or serotonin-norepinephrine reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, venlafaxine), triptans (almotriptan, dihydroergotamine, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan), levomethorphan, levorphanol, pentazocine, pethidine, tapentadol, the antiparkinsonian L-dopa, mirtazapine, trazadone, lithium, buspirone, phentermine, bupropion, risperidone, nefazodone, trazodone, granisetron, ondansetron, chlorpheniramine, ciprofloxacin, ritonavir, fluconazole, citalopram, methadone, oxycodone, tramadol, metoclopramide, amphetamines, bath salts, cocaine, dextromethorphan, ecstasy, LSD, L-tryptophan, St. John’s wort (Hypericum perforatum).

Serotonergic ToxicityEmergence Delirium Postoperative Delirium Anticholinergic Toxicity

■ Provide extensive preoperative education and emotional support ■ Minimize or avoid benzodiazepines through reassurance and preoperative

education■ Avoid inhaled anesthetics or combine with

• Continuous infusion of dexmedetomidine 0.4-1 μg/kg/hr or remifentanil 0.25-1 μg/kg/min or

• Bolus of dexmedetomidine (0.5-1 mcg/kg) or ketamine (0.5 mg/kg) on induction or 5-10 minutes before emergence

■ Orient and educate the patient to the perioperative area ■ Instruct the patient on non-pharmacological sleep hygiene before surgery

and promote after surgery■ Encouraging fluid and nutritional intake per the enhanced recovery protocol

before and after surgery■ Allow the use of hearing aids and glasses before surgery and on

emergence■ Consider using ketamine 0.5-1 mg/kg before incision for the

antiinflammatory properties ■ Avoid anesthetic neurotoxicity by using age (chronologic or physiologic)

appropriate anesthetic doses■ Maintain a mean arterial pressure near the patients’ awake levels■ Ensure adequate pain control using non-opioid options whenever possible

• Acetaminophen 1000 mg unless >65 years old then 650 mg or dexmedetomidine 0.1mcg/kg/hr

■ Provide oxygen during recovery from anesthesia■ Reorienting the patient to their environment after surgery■ Allow the presence of family or a friend during recovery from anesthesia■ Adjust the environment (e.g. quiet with mid-level lighting)■ Avoiding constipation■ Promoting early activity■ Provide cognitive stimulation■ Avoid all tricyclic antidepressants, anticholinergics (use only glypyrrolate),

antihistamines, benzodiazepines (especially midazolam), chlorpromazine, corticosteroids, H2 receptors antagonists, meperidine, minimizing sedative hypnotics, and medications that increase serotonin, follow current AGS Beers Criteria

PREVENTIVE STRATEGIES

COMMON PRESENTING S/S Disoriented, RestlessAgitated, Anxious, Confused, Delusions, Hallucinations, Calling Out, Amnesia, Hypoactivity

DIFFERENTIATING S/S young, healthy, violent, thrashing, traumatic past or military deployment history. older age, altered sleep and sensory perception or after recovery within 24 hours of surgery, possible continuation from ED

Anhidrosis, mydriasis, constipation, an urge to urinate and a sense of bladder fullness.

If the patient is on any of the medications above avoid administering atropine, scopolamine, diphenhydramine (Benadryl), or promethazine (Phenergan) during the perioperative period.

ASSESSMENT TOOLS

Pediatric Anesthesia Emergence Delirium scale or Richmond Agitation Sedation Scale with Confusion Assessment Method for Intensive Care Patients. A score of 10 or greater on this PAED indicates ED.

TREATMENT

■ Address triggers such as anxiety, pain, hypoxia and catheters

■ Provide reassurance ■ Allow the presence of a loved one ■ Bolus with dexmedetomide 0.5–1 mcg/kg

Mini-Mental State Exam and the Confusion Assessment Method

Treat underlying causes to include dehydration, infection, hypoxemia, and alcohol or drug withdrawal. Haldoperidol dosed in 0.5-1 mg increments every 30 minutes for a maximum of 20 mg per 24 hours if the patient is harming self or others and treating the underlying cause has failed.

1)

2) Avoid or stop the triggering agentsProvide supportive care (hydration, cooling, neuromuscular relaxation and intubation) and sedate with benzodiazepines (e.g. lorazepam 2-4 mg or diazepam 5-10 mg IV repeated every 8-10 minutes as needed)

3) Load with cyproheptadine 12 mg then 2 mg by mouth or gastric tube every 2 hours up

to 32 mg/day

None

Physostigmine 0.5-2 mg over 5 minutes or 1mg/minute, repeat every 20-30 minutes as needed.Benzodiazepines can be used, but do not relieve the underlying cause.

Hunter Serotonin Toxicity Criteria

This algorithm was created using these sources4,6,7,9-11,14,16,20-31,34-46,48-50

*Boolean terms or and and

aThis algorithm was created using references 4, 6, 7, 9-11, 14, 16, 20-31, and 34-48.


regard to its definition, applicable assessment tools, ter-minology, differential diagnosis for similar phenomena, and treatment. Some of these concerns were clarified by a review of the literature and a Delphi study, whereas other questions need further study. In the Delphi study, the definition most agreed on by the experts was “be-havior after an exposure to anesthesia in which a patient demonstrates or exhibits anxiety, restlessness, confusion, and combativeness.” Prevention through the actions pre-viously discussed is the most beneficial for the patient.

It is still unclear which assessment tool is most appro-priate for differentiating ED, but until there is a reliable and valid adult tool, the Pediatric Anesthesia Emergence Delirium scale is supported in both the literature review and the Delphi. An alternative presented in the literature is the Richmond Agitation-Sedation Scale combined with the CAM-ICU. Additionally, it is important to consider other phenomena that can appear to be adult ED through the use of more standardized differential diagnostic tools such as the one provided in the Figure.

Physiologic issues, POD, and anticholinergic and serotonergic toxicities must be carefully ruled out by differentiating signs that are unique to each diagnosis. If a patient presents as experiencing ED, the practitioner should evaluate for the presence of common adult ED predictors. When ED is ruled in, address the triggering physical issue (eg, hypoxia, pain, anxiety, catheters), provide reassurance, or allow a loved one to be present. If ED continues, treat with a bolus of dexmedetomidine.

For POD, if the patient is physiologically or chrono-logically older than 65 years of age or has other comor-bidities such as hypertension, diabetes, sensory depriva-tion, substance abuse, or diseases that cause metabolic derangements or dehydration, these conditions must be considered in the differential diagnosis. Prevention is the most effective strategy to limit the occurrence of POD and results in improved patient outcomes. Note that POD can be delirium that persists beyond the usual timeframe for recovery from anesthesia and responds to treatment with antipsychotics.

Anticholinergic toxicity may manifest for patients who have received the medications discussed earlier. Evaluate for the presence of the signs and symptoms unique to this diagnosis, which are anhidrosis, mydriasis, constipation, and bladder fullness (if possible to assess). The treatment is administration of physostigmine following the guide-lines provided.

Finally, serotonergic toxicity is triggered by many of the medications we administer during an anesthetic. Follow the Hunter Serotonin Toxicity Criteria if a patient is displaying any of the signs specific to this toxicity, to include diaphoresis, muscle rigidity, clonus, ocular clonus, hyperreflexivity, tremors, shivering, vomiting, or diarrhea. In the event that serotonergic toxicity is ruled in, remove the offending drug and provide supportive

care, benzodiazepines, and cyproheptadine. Awareness of how to differentiate these similar phe-

nomena and incorporating an algorithm, such as the one provided in this article, for a thorough and consistent differential diagnosis can lead to improved patient out-comes and interventions for adults with ED. There is a need for research to develop an adult ED assessment tool that investigates patient outcomes when an algorithm like the one provided in this article is implemented.

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AUTHORSCol Shawna Greiner, PhD, CRNA, USAF, NC, practices at 60th Medical Group at Travis Air Force Base and was an assistant professor who has taught for military nurse anesthesia programs. For 25 years, she has served in the US Navy and now the Air Force. Dr Greiner has authored and coau-thored peer-reviewed publications focused on ethics, deployment experi-ences of mothers, military mental health stigma, and emergence delirium.

Michael J. Kremer, PhD, CRNA, CHSE, FNAP, FAAN, received undergraduate degrees in psychology and nursing from Northern Illinois University in DeKalb, Illinois; his anesthesia education was at St John’s Hospital/University of Illinois-Springfield in Springfield, Illinois. Dr Kre-mer is a Certified Healthcare Simulation Educator and is a fellow in the National Academies of Practice, the Institute of Medicine of Chicago, and the American Academy of Nursing.

DISCLOSURESThe authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did discuss off-label use within the article. Disclosure statements are available for viewing upon request.

MILITARY DISCLAIMERThe views presented here are those of the authors and are not to be con-strued as official or reflecting the views of the Department of Defense, Air Force, or the Uniformed Services University of the Health Sciences.


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July 15, 2019 - July 19, 2019, Massachusetts; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” Sea Crest Beach Hotel, Falmouth (Cape Cod), MA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/capecod/19jma.html.

July 15, 2019 - July 20, 2019, Washington; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” Alaskan Explorer via Hubbard Glacier Cruise, aboard ms Oosterdam, Roundtrip from Seattle, WA. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/alaska/19emjakc.html.

July 17, 2019 - July 20, 2019, South Carolina; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Trauma Anesthesia.” Marriott Resort & Spa at Grande Dunes, Myrtle Beach, SC. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/myrtlebeach/19jmb.html.

July 22, 2019 - July 25, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Opal Sands Resort, Clearwater Beach, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/clearwater/19jcw.html.

July 22, 2019 - July 27, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” 7-Day Western Caribbean Cruise, aboard Allure of the Seas, Roundtrip from Fort Lauderdale, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com.

July 24, 2019 - July 27, 2019, Oregon; Northwest Anesthesia Seminars - 20 CEC. “Pediatric Anesthesia Update.” The Nines Hotel, Portland, OR. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/portland/19jpo.html.

August 1, 2019 - August 4, 2019, California; Northwest Anesthesia Seminars - 24 CEC. “Anesthesia Update.” Hotel Solamar, San Diego, CA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/sandiego/19asd.html.

August 1, 2019 - August 4, 2019, California; Northwest Seminars - 20 CEC. “Current Topics in Emergency Medicine.” Paséa Hotel & Spa, Huntington Beach, CA. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/huntingtonbeach/19emahb.html.

August 5, 2019 - August 9, 2019, Canada; Northwest Anesthesia Seminars - 20 CEC. “Clinical Topics in Anesthesia.” The Rimrock Resort Hotel, Banff, Alberta, Canada. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/banff/19aca.html.

August 5, 2019 - August 10, 2019, Alaskan Cruise; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” Vancouver to Seward via the Inside Passage Cruise, aboard ms Noordam, Vancouver, British Columbia, Canada to Seward, Alaska. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/alaska/19aakc.html.

August 9, 2019 - August 9, 2019, Illinois; American Association of Nurse Anesthetists - 7.25 CEC. “2019 Ultrasound-Guided Peripheral Nerve Blocks - A Focused Review and Clinical Applications.” Hyatt Regency, Chicago, IL. (847) 655-8797; email, [email protected]; www.aana2019.com.

August 9, 2019 - August 9, 2019, Illinois; American Association of Nurse Anesthetists - 4 CEC. “2019 Ultrasound Based Acute and Chronic Pain Procedural Workshop - MORNING.” Hyatt Regency, Chicago, IL. (847) 655-8797; email, [email protected]; www.aana2019.com.

August 9, 2019 - August 9, 2019, Illinois; American Association of Nurse Anesthetists - 4 CEC. “2019 Ultrasound Based Acute and Chronic Pain Procedural Workshop - AFTERNOON.” Hyatt Regency, Chicago, IL. (847) 655-8797; email, [email protected]; www.aana2019.com.

August 9, 2019 - August 9, 2019, Illinois; American Association of Nurse Anesthetists - 7.25 CEC. “2019 AANA Peer Assistance and Wellness Pre-Congress Workshop.” Hyatt Regency, Chicago, IL. 222 S Prospect Ave, Park Ridge, IL 60068; (847) 655-8797; email, [email protected]; www.aana2019.com.

August 9, 2019 - August 13, 2019, Illinois; American Association of Nurse Anesthetists - 22.5 CEC. “2019 Nurse Anesthesia Annual Congress.” Hyatt Regency, Chicago, IL. (847) 655-8797; email, [email protected]; www.aana2019.com.

August 12, 2019 - August 16, 2019, Montana; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” The Lodge at Whitefish Lake, Whitefish (Glacier National Park), MT. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/whitefish/19emawf.html.

August 19, 2019 - August 23, 2019, Alaska; Northwest Seminars - 20 CEC. “Current Topics in Emergency Medicine.” The Lakefront Anchorage, Anchorage, AK. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/alaska/19emaakl.html.

August 20, 2019 - August 28, 2019, Italy; Northwest Anesthesia Seminars - 20 CEC. “Clinical Concerns in Anesthesia.” 11-Night Amalfi Coast & Greek Isles Cruise, aboard Celebrity Edge, Roundtrip from Rome (Civitavecchia), Italy. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/europe/19aagc.html.

August 21, 2019 - August 24, 2019, Massachusetts; Northwest Anesthesia Seminars - 24 CEC. “Anesthesia Update.” Royal Sonesta, Boston, MA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/boston/19abst.html.

September 2, 2019 - September 2, 2019, Nevada; Northwest Anesthesia Seminars - 8 CEC. “Business Concepts in Healthcare.” The Palms Casino Resort, Las Vegas, NV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/businessconcepts/19BUS.html.

September 3, 2019 - September 6, 2019, Nevada; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” The Palms Casino Resort, Las Vegas, NV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/vegas/19slv.html.


September 5, 2019 - September 8, 2019, New Mexico; New Mexico Association of Nurse Anesthetists - 24 CEC. “September in Santa Fe 2019: NMANA Anesthesia Conference.” Hotel Santa Fe, Santa Fe, NM. Laura Moritz, 1080 Ayers Rd, Moneta, VA 24121; (336) 577-8450; email, [email protected]; http://www.nmana.org/.

September 9, 2019 - September 12, 2019, Nevada; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” The Palms Casino Resort, Las Vegas, NV. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/vegas/19emslv.html.

September 9, 2019 - September 12, 2019, Tennessee; Med City Anesthesia Seminars - 20 CEC. “Current Topics In Anesthesia.” Hilton Nashville Downtown, Nashville, TN. Karissa Goodrich, PO Box 711, Saint Charles, MN 55972; (800) 558-0217; email, [email protected]; www.medcityanesthesiaseminars.com.

September 9, 2019 - September 13, 2019, Hungary; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” The Ritz-Carlton, Budapest, Hungary. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/budapest/19sbh.html.

September 12, 2019 - September 15, 2019, Alabama; Northwest Anesthesia Seminars - 24 CEC. “Relevant Topics in Anesthesia.” The Lodge at Gulf State Park, a Hilton Hotel, Gulf Shores, AL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/gulfshores/19sal.html.

September 13, 2019 - September 15, 2019, Alabama; Lower Alabama Continuing Education Seminars, Inc. - 20 CEC. “2019 Fall Beach Break.” Perdido Beach Resort, Orange Beach, AL. Laura Lesley, 6218 Fox Branch, Trussville, AL 35173; (205) 642-8052; email, [email protected]; www.lacesinc.com.

September 15, 2019 - September 15, 2019, Maine; Encore Symposiums - 8 CEC. “Encore Symposiums’ Pharmacology CPC Review Course.” Cliff House, Cape Neddick, ME. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

September 16, 2019 - September 19, 2019, Maine; Encore Symposiums - 23 CEC. “New England at the Cliff House Encore Symposium.” Cliff House, Cape Neddick, ME. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

September 16, 2019 - September 19, 2019, Maine; Med City Anesthesia Seminars - 20 CEC. “Current Topics In Anesthesia.” The Samoset Resort on the Ocean, Rockport, ME. Karissa Goodrich, PO Box 711, Saint Charles, MN 55972; (800) 558-0217; email, [email protected]; www.medcityanesthesiaseminars.com.

September 16, 2019 - September 20, 2019, California; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Tenaya Lodge, Fish Camp (Yosemite National Park), CA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/yosemite/19syp.html.

September 16, 2019 - September 26, 2019, Europe - Iberian Adventure Cruise; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” 12-Night Iberian Adventure Cruise, aboard ms Nieuw Statendam, from Amsterdam, the Netherlands to Civitavecchia (Rome), Italy. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/europe/19saic.html.

September 18, 2019 - September 21, 2019, Arizona; Northwest Anesthesia Seminars - 20 CEC. “Current Anesthesia Practice.” Hilton Sedona Resort at Bell Rock, Sedona, AZ. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/sedona/19saz.html.

September 19, 2019 - September 22, 2019, South Carolina; Northwest Anesthesia Seminars - 20 CEC. “Relevant Topics in Anesthesia.” The Westin Hilton Head Island Resort & Spa, Hilton Head Island, SC. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/hiltonhead/19shh.html.

September 21, 2019 - September 22, 2019, Illinois; American Association of Nurse Anesthetists - 12 CEC. “Ultrasound Guided Peripheral Nerve Block Workshop - 2019 Fall.” American Association of Nurse Anesthetists, Park Ridge, IL. (847) 655-8797; email, [email protected]; www.aana.com/meetings.

September 23, 2019 - September 26, 2019, Arizona; Northwest Seminars - 20 CEC. “Pediatric Emergency Medicine.” Hilton Sedona Resort at Bell Rock, Sedona, AZ. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/sedona/19emsaz.html.

September 23, 2019 - September 26, 2019, California; Cornerstone Anesthesia Conferences - 21 CEC. “Anesthesia Update in Wine Country.” Fairmont Sonoma Mission Inn & Spa, Sonoma, CA. Jayme Reuter, PO Box 7214, Houston, TX 77248; (281) 836-0777; email, [email protected]; www.CornerstoneAnesthesiaConferences.com.

September 23, 2019 - September 26, 2019, Maine; Summit Anesthesia Seminars, LLC - 20 CEC. “Fall Foliage in Bar Harbor.” Bar Harbor Inn & Spa, Bar Harbor, ME. Rebecca Sullivan, PO Box 215, New Stanton, PA 15672; (888) 676- CRNA; email, [email protected]; www.summitanesthesiaseminars.com.

September 23, 2019 - September 27, 2019, Wyoming; Northwest Anesthesia Seminars - 20 CEC. “Clinical Anesthesia Update.” Hotel Terra, Teton Village, WY. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/tetons/19swy.html.

September 30, 2019 - October 3, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Anesthesia Update.” Ritz-Carlton, Amelia Island, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/ameliaisland/19sai.html.

October 3, 2019 - October 6, 2019, Tennessee; Northwest Anesthesia Seminars - 20 CEC. “Anesthesia Spectrum.” The Park Vista, a Doubletree Hotel, Gatlinburg, TN. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/gatlinburg/19oga.html.

October 4, 2019 - October 5, 2019, Colorado; Colorado Association of Nurse Anesthetists - 9 CEC. “2019 CoANA Fall Anesthesia Update and Business Meeting.” The Stanley Hotel, Estes Park, CO. Kate Jansky, 12011 Tejon Street, Suite 700, Westminster, CO 80234; (303) 433-4446; email, [email protected]; www.CoANA.org.

October 4, 2019 - October 6, 2019, Georgia; Georgia Association of Nurse Anesthetists - 16 CEC. “Georgia Association Symposium, GAS2019.” The Westin Buckhead Atlanta, Atlanta, GA. Laura Moritz, 1080 Ayers Rd, Moneta, VA 24121; (336) 577-8450; email, [email protected]; www.GANA.org.


October 5, 2019 - October 5, 2019, Virginia; Nurse Anesthesiology Faculty Associates - 8 CEC. “Ultrasound Guided Vascular Access Workshop.” Nurse Anesthesiology Faculty Associates, Richmond, VA. Suzanne Wright, Box 980226, Richmond, VA 23298; (804) 828-6734; fax (804) 828-0581; email, [email protected]; www.nafa-va.org.

October 6, 2019 - October 11, 2019, Mexico; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Hyatt Ziva Los Cabos, Los Cabos, Mexico. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/cabo/19omx.html.

October 7, 2019 - October 10, 2019, Rhode Island; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Gurney’s Newport Resort & Marina, Newport, RI. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/newport/19onp.html.

October 7, 2019 - October 11, 2019, Utah; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” SpringHill Suites Springdale Zion National Park, Springdale, UT. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/zion/19emout.html.

October 13, 2019 - October 13, 2019, Massachusetts; Encore Symposiums - 8 CEC. “Encore Symposiums’ Pharmacology CPC Review Course.” Chatham Bars Inn, Chatham, MA. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

October 13, 2019 - October 16, 2019, South Carolina; Valley Anesthesia, Inc - 20 CEC. “Valley Anesthesia’s CE for the CRNA 2019.” Charleston Harbor Beach Resort, Charleston, SC. Scott Schaus, 5 Penn Plaza, Suite 2375, New York, NY 10001; (651) 395-0777; email, [email protected]; www.valleyanesthesia.com.

October 14, 2019 - October 17, 2019, Massachusetts; Encore Symposiums - 23 CEC. “Discover Cape Cod 2019 Encore Symposium.” Chatham Bars Inn, Chatham, MA. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

October 14, 2019 - October 17, 2019, Missouri; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Kansas City Marriott Downtown, Kansas City, MO. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/kansascity/19okc.html.

October 14, 2019 - October 18, 2019, Hawaii; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” Hyatt Regency Maui, Lahaina, Maui, HI. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/maui/19emohi.html.

October 19, 2019 - October 22, 2019, Louisiana; Valley Anesthesia, Inc - 20 CEC. “Valley Anesthesia’s CE for the CRNA 2019.” The Ritz-Carlton, New Orleans, LA. Scott Schaus, 5 Penn Plaza, Suite 2375, New York, NY 10001; (651) 395-0777; email, [email protected]; www.valleyanesthesia.com.

October 24, 2019 - October 27, 2019, Arizona; Arizona Association of Nurse Anesthetists - 20 CEC. “AZANA Sun & Sedona 2019 Conference.” Poco Diablo Resort, Sedona, AZ. Laura Moritz, 1080 Ayers Rd, Moneta, VA 24121; (336) 577-8450; email, [email protected]; www.AZCRNA.com.

October 28, 2019 - October 31, 2019, Virginia; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Salamander Resort & Spa, Middleburg, VA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/virginia/19ova.html.

November 2, 2019 - November 3, 2019, Arizona; Encore Symposiums - 14 CEC. “Sedona Red Rock CPC Review Course.” Hilton Sedona Resort at Bell Rock, Sedona, AZ. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106-3608; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

November 2, 2019 - November 16, 2019, Saudi Arabia; SpiekermannTravel - 20 CEC. “Current Issues in CRNA Practice.” Multiple locations in Arabian Peninsula. Michael Rieker, Nurse Anesthesia Program, 525 Vine St, Ste 230, Winston-Salem, NC 27101; (336) 716-1411; email, [email protected]; http://www.mideasttrvl.com/.

November 3, 2019 - November 9, 2019, Jamaica; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” Casa Maria Hotel, Port Maria, Jamaica. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/jamaica/19emnja.html.

November 4, 2019 - November 7, 2019, Arizona; Encore Symposiums - 23 CEC. “Sedona Red Rock & Grand Canyon Adventure 2019.” Hilton Sedona Resort at Bell Rock, Sedona, AZ. Nancy LaBrie, RN, 1907 Loch Lomond Ct, Winston-Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

November 4, 2019 - November 7, 2019, California; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” The Ritz-Carlton, Half Moon Bay, CA. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/halfmoonbay/19emnhm.html.

November 7, 2019 - November 10, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Keys in Anesthesia.” Margaritaville Key West Resort, Key West, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/keywest/19nkw.html.

November 8, 2019 - November 10, 2019, Florida; Frank Moya Continuing Education Programs - 20 CEC. “48th Annual Refresher Course for Nurse Anesthetists.” The Hilton Hotel, Disney Springs Resort Area, Orlando Lake Buena Vista, FL. Frank Moya, MD, 1828 SE First Avenue, Ft Lauderdale, FL 33316; (954) 763-8811; fax (954) 762-9111; email, [email protected]; www.currentreviews.com.

November 9, 2019 - November 12, 2019, Arizona; Valley Anesthesia, Inc - 20 CEC. “Valley Anesthesia’s CE for the CRNA 2019.” Hyatt Regency, Scottsdale, AZ. Scott Schaus, 5 Penn Plaza, Suite 2375, New York, NY 10001; (651) 395-0777; email, [email protected]; www.valleyanesthesia.com.

November 10, 2019 - November 15, 2019, Hawaii; Northwest Anesthesia Seminars - 20 CEC. “Relevant Topics in Anesthesia.” Hyatt Regency Maui, Lahaina, Maui, HI. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/maui/19nhi.html.

November 10, 2019 - November 15, 2019, Jamaica; Northwest Anesthesia Seminars - 20 CEC. “Reviews for Anesthesia Professionals.” Casa Maria Hotel, Port Maria, Jamaica. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/jamaica/19nja.html.


November 14, 2019 - November 17, 2019, Florida; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” Margaritaville Resort & Marina, Key West, FL. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/keywest/19emnkw.html.

November 17, 2019 - November 21, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” 7-Night Eastern Caribbean Cruise, aboard ms Nieuw Amsterdam, Roundtrip from Fort Lauderdale, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/caribbean/19necc.html.

November 17, 2019 - November 22, 2019, Turks & Caicos Islands; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Beaches Turks & Caicos Resort Villages & Spa, Providenciales, Turks and Caicos Islands. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/turks/19ntc.html.

November 21, 2019 - November 24, 2019, New Mexico; Northwest Anesthesia Seminars - 24 CEC. “Current Challenges in Pain Management.” Hotel Albuquerque at Old Town, Albuquerque, NM. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/albuquerque/19nnm.html.

December 2, 2019 - December 5, 2019, Bahamas; International Seminars, LLC - 20 CEC. “Nurse Anesthesia Update.” Atlantis, Paradise Island, Bahamas. Barbara McNulty, 1828 SE First Avenue, Ft Lauderdale, FL 33316; (954) 763-2233; fax (954) 762-9111; email, [email protected]; www.nurseanesthetist.com.

December 3, 2019 - December 6, 2019, California; Northwest Seminars - 20 CEC. “Emergency Medicine Update.” Sofitel Los Angeles at Beverly Hills, Los Angeles, CA. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/losangeles/19emdla.html.

December 3, 2019 - December 6, 2019, Georgia; Northwest Anesthesia Seminars - 24 CEC. “Current Topics in Anesthesia.” Hyatt Regency Savannah, Savannah, GA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/savannah/19dga.html.

December 5, 2019 - December 8, 2019, Texas; Northwest Anesthesia Seminars - 24 CEC. “Current Challenges in Pediatric Anesthesia.” Hyatt Regency San Antonio Riverwalk, San Antonio, TX. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/sanantonio/19dtx.html.

December 5, 2019 - December 8, 2019, West Virginia; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” The Greenbrier Resort, White Sulphur Springs, WV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/whitesulphursprings/19dwv.html.

December 8, 2019 - December 13, 2019, Aruba; Northwest Anesthesia Seminars - 24 CEC. “Topics in Anesthesia.” The Hyatt Regency Aruba Resort, Palm Beach, Aruba. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/aruba/19dar.html.

December 9, 2019 - December 9, 2019, Nevada; Northwest Anesthesia Seminars - 8 CEC. “Business Concepts in Healthcare.” Encore at Wynn Las Vegas, Las Vegas, NV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/businessconcepts/19BUS.html.

December 10, 2019 - December 13, 2019, Nevada; Northwest Anesthesia Seminars - 20 CEC. “Cardiothoracic and Vascular Anesthesia Update.” Encore at Wynn Las Vegas, Las Vegas, NV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/vegas/19dlv.html.

December 12, 2019 - December 15, 2019, Florida; Northwest Seminars - 20 CEC. “Topics in Emergency Medicine.” The Palms Hotel & Spa, Miami (South Beach), FL. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/miami/19emdsb.html.

December 16, 2019 - December 19, 2019, Florida; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” The Palms Hotel & Spa, Miami (South Beach), FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/miami/19dsb.html.

December 30, 2019 - January 4, 2020, Florida; Northwest Anesthesia Seminars - 20 CEC. “Current Anesthesia Practice.” 7-Night Eastern Caribbean/New Years Cruise, aboard Celebrity Edge, Roundtrip from Fort Lauderdale, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/caribbean/19decc.html.

January 6, 2020 - January 10, 2020, Costa Rica; Southwest Anesthesia & Medical Seminars - 20 CEC. “Medical Spanish for Healthcare Professionals.” Margaritaville Beach Resort, Playa Flamingo, Costa Rica. Richard Saucier, 4466 North Saddle View Drive, Tucson, AZ 85750; (614) 582-3393; fax (520) 749-3491; email, [email protected]; www.swamseminars.com.

January 9, 2020 - January 12, 2020, Florida; Northwest Anesthesia Seminars - 24 CEC. “Current Topics in Anesthesia.” Key Largo Bay Marriott Beach Resort, Key Largo, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/keylargo/20jfl.html.

January 13, 2020 - January 15, 2020, California; C & H Educational Systems - 20 CEC. “The California Wine Country Anesthesia Update 2020.” The Fairmont Sonoma Mission Inn, Sonoma, CA. Catherine Wagner, 130 Mackinaw Dr, Twin Lakes, CO 81251-9736; (719) 486-3558; email, [email protected]; www.homestead.com/chedusys/index.html.

January 16, 2020 - January 24, 2020, Australia; Northwest Anesthesia Seminars - 24 CEC. “Clinical Concerns in Anesthesia.” 11-Night Great Barrier Reef Cruise, aboard Celebrity Solstice, Roundtrip from Sydney, Australia. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com.

January 18, 2020 - January 19, 2020, Louisiana; Encore Symposiums - 14 CEC. “Encore Symposiums’ CPC Review Course.” Windsor Court Hotel, New Orleans, LA. Nancy LaBrie, 1907 Loch Lomond Ct, Winston-Salem, NC 27106-3608; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

January 19, 2020 - January 23, 2020, Florida; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” 7-Night Eastern Caribbean Cruise, aboard ms Zuiderdam, Roundtrip from Fort Lauderdale, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com.

January 20, 2020 - January 23, 2020, Louisiana; Encore Symposiums - 21 CEC. “Taste of New Orleans 2020 Encore Symposiums.” Windsor Court Hotel New Orleans, New Orleans, LA. Nancy LaBrie, 1907 Loch Lomond Ct, Winston Salem, NC 27106; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

January 28, 2020 - February 1, 2020, Cayman Islands; destinationCME - 27 CEC. “Anesthesia Camp Grand Cayman 2020.” The Ritz-Carlton, Grand Cayman, Cayman Islands. John E. Ellis, MD, 1700 East 56th Street, Suite 3801, Chicago, IL 60637; (773) 417-0075; email, [email protected]; http://destinationcme.com/.

February 1, 2020 - February 7, 2020, Colorado; Amedco LLC - 25 CEC. “Concepts in Anesthesiology Conference 2020.” Steamboat Grand, Steam Boat Springs, CO. Peter Sabel, 90 W County Road C, Suite 300, Little Canada, MN 55117; (800) 871-0326; email, [email protected]; http://www.conceptsinanesthesiology.com.

February 3, 2020 - February 7, 2020, California; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” The Ritz-Carlton, Lake Tahoe (Truckee), CA. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/tahoe/20flt.html.

February 3, 2020 - February 7, 2020, Costa Rica; Southwest Anesthesia & Medical Seminars - 20 CEC. “Medical Spanish for Healthcare Professionals.” Margaritaville Beach Resort, Playa Flamingo, Costa Rica. Richard Saucier, 4466 North Saddle View Drive, Tucson, AZ 85750; (614) 582-3393; fax (520) 749-3491; email, [email protected]; www.swamseminars.com.

February 3, 2020 - February 7, 2020, Hawaii; Northwest Seminars - 20 CEC. “Critical Care: The Team Approach.” Grand Hyatt Kauai Resort & Spa, Koloa, Kauai, HI. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/kauai/20ccfhi.html.

February 4, 2020 - February 7, 2020, Nevada; Northwest Anesthesia Seminars - 20 CEC. “Hot Topics in Anesthesia.” Encore at Wynn Las Vegas, Las Vegas, NV. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/vegas/20flv.html.

February 9, 2020 - February 14, 2020, Dominican Republic; Northwest Anesthesia Seminars - 20 CEC. “Relevant Topics in Anesthesia.” Iberostar Grand Hotel Bávaro, Punta Cana, Dominican Republic. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/dominicanrepublic/20fdr.html.

February 10, 2020 - February 14, 2020, Colorado; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” The Westin Snowmass Resort, Snowmass Village, CO. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/snowmass/20fco.html.

February 15, 2020 - February 16, 2020, California; Encore Symposiums - 14 CEC. “Encore Symposiums’ CPC Review 2020.” Omni Rancho Las Palmas Resort & Spa, Rancho Mirage, CA. Nancy LaBrie, 1907 Loch Lomond Ct., Winston-Salem, NC 27106-3608; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

February 20, 2020 - February 23, 2020, Arizona; Northwest Seminars - 20 CEC. “Current Topics in Emergency Medicine.” Arizona Biltmore, A Waldorf Astoria Resort, Phoenix, AZ. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/phoenix/20emfaz.html.

February 20, 2020 - February 23, 2020, South Carolina; Northwest Anesthesia Seminars - 20 CEC. “Current Challenges in Anesthesia.” The Francis Marion Hotel, Charleston, SC. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/charleston/20fsc.html.

February 26, 2020 - February 29, 2020, Florida; Northwest Anesthesia Seminars - 20 CEC. “Current Topics in Anesthesia.” Hyatt Regency Grand Cypress, Orlando, FL. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/orlando/20for.html.

March 2, 2020 - March 5, 2020, Hawaii; Northwest Anesthesia Seminars - 24 CEC. “Anesthesia Update.” The Fairmont Orchid, Waimea, Kona, HI. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/hawaii/20mhi.html.

March 12, 2020 - March 15, 2020, Texas; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” Dallas/Addison Marriott Quorum by the Galleria, Dallas, TX. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/dallas/20mtx.html.

March 12, 2020 - March 18, 2020, New Zealand & Australia Cruise; Northwest Anesthesia Seminars - 20 CEC. “Clinical Concerns in Anesthesia.” 10-Day New Zealand and Australia Cruise, aboard Celebrity Solstice, Auckland, New Zealand to Sydney, Australia. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com.

March 14, 2020 - March 15, 2020, Florida; Encore Symposiums - 14 CEC. “Encore Symposiums’ CPC Review 2020.” La Playa Beach & Golf Resort, Naples, FL. Nancy LaBrie, 1907 Loch Lomond Ct., Winston-Salem, NC 27106-3608; (336) 768-9095; fax (336) 768-9055; email, [email protected]; www.escrnas.com.

March 15, 2020 - March 20, 2020, Costa Rica; Northwest Anesthesia Seminars - 20 CEC. “Anesthesia Topics.” Westin Resort & Spa, Playa Conchal, Costa Rica. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/costarica/20mcr.html.

March 16, 2020 - March 20, 2020, Colorado; Northwest Anesthesia Seminars - 20 CEC. “Topics in Emergency Medicine.” The Westin Snowmass Resort, Snowmass, CO. NWS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.northwestseminars.com/snowmass/20emmco.html.

March 19, 2020 - March 22, 2020, Arizona; Northwest Anesthesia Seminars - 24 CEC. “Topics in Anesthesia.” The Westin La Paloma Resort and Spa, Tucson, AZ. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com/tucson/20maz.html.

April 6, 2020 - April 10, 2020, Bermuda; Northwest Anesthesia Seminars - 20 CEC. “Topics in Anesthesia.” Fairmont Southampton, Southampton, Bermuda. NWAS, 1412 N 5th Ave, Pasco, WA 99301; (800) 222-6927; fax (509) 547-1265; email, [email protected]; www.nwas.com.

www.aana.com/aanajournalonline AANA Journal June 2019 Vol. 87, No. 3 IBC

Postoperative nausea and vomiting (PONV) con - AANA

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