Emergency Medicine Journal Club

Emergency Medicine Journal Club Wednesday, April 27, 2016

The April 2016 Journal Club will be held Wednesday April 27th at Romano’s in

Redlands from 6pm to 9pm. Dinner will be provided. Discussion of articles will begin at roughly 6pm. The topic will be:

Non-procedural sedation uses of ketamine

Is ketamine effective in treating pain? When should we use ketamine to treat asthma?

Is ketamine a safe alternative for treatment of excited delirium? What is the success rate of ketamine when used for DSI?

Should we use ketamine for refractory status epilepticus in children? Does ketamine help with preoxygenation in DSI?

Ketamine for depression?

The following individuals have been assigned to present articles (maximum of 5-10 minutes each). Everyone is expected, however, to have reviewed the articles and to be prepared to critically discuss them. Page Presenter Topic Article

3 Jason Morris Audra Wisham Allen Chiou

Pain management

Sin B, Ternas T, Motov S. The Use of Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med. 2015;22(3):251-257. doi:10.1111/acem.12604.

10 Jen Hughes Brad Alice Andrew Johnson

Pain management

Ahern T, Herring A, Anderson E, Madia V, Fahimi J, Frazee B. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. The American Journal of Emergency Medicine. 2015;33(2):197-201. doi:10.1016/j.ajem.2014.11.010.

15 Matthew Reddoch Darren Brockie Brad Lawing

Pain management

Miller J, Schauer S, Ganem V, Bebarta V. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. The American Journal of Emergency Medicine. 2015;33(3):402-408. doi:10.1016/j.ajem.2014.12.058.

22 Liz Fierro Pain management

Motov S, Rockoff B, Cohen V et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Annals of Emergency Medicine. 2015;66(3):222-229.e1. doi:10.1016/j.annemergmed.2015.03.004.

30 Mari Yasunaga Erik Smith Nellie Ekmekjian

Asthma Allen J, Macias C. The Efficacy of Ketamine in Pediatric Emergency Department Patients Who Present With Acute Severe Asthma. Annals of Emergency Medicine. 2005;46(1):43-50. doi:10.1016/j.annemergmed.2005.02.024.

38 Michael Li Joseph Fargusson Tim Widener

Asthma Kiureghian E, Kowalski J. Intravenous ketamine to facilitate noninvasive ventilation in a patient with a severe asthma exacerbation. The American Journal of Emergency Medicine. 2015;33(11):1720.e1-1720.e2. doi:10.1016/j.ajem.2015.03.066.

40 Stacey White Karan Singh

RSI Patanwala A, McKinney C, Erstad B, Sakles J. Retrospective Analysis of Etomidate Versus Ketamine for First-pass Intubation Success in an Academic Emergency Department. Acad Emerg Med. 2014;21(1):87-91. doi:10.1111/acem.12292.

44 Brad Alice Morgaine Daniels

DSI Weingart S, Trueger N, Wong N, Scofi J, Singh N, Rudolph S. Delayed Sequence Intubation: A Prospective Observational Study. Annals of Emergency Medicine. 2015;65(4):349-355. doi:10.1016/j.annemergmed.2014.09.025.

51 Audra Wisham Sarah Peterson Darren Brockie

Status epilepticus

Ilvento L, Rosati A, Marini C, L'Erario M, Mirabile L, Guerrini R. Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation. Epilepsy & Behavior. 2015;49:343-346. doi:10.1016/j.yebeh.2015.06.019.

55 Whitney Hamptom Sonya Stokes

Agitated Delirium

Hopper A, Vilke G, Castillo E, Campillo A, Davie T, Wilson M. Ketamine Use for Acute Agitation in the Emergency Department. The Journal of Emergency Medicine. 2015;48(6):712-719. doi:10.1016/j.jemermed.2015.02.019.

62 Erik Smith Michael O’Neal

Depression Wilkinson S, Sanacora G. Ketamine: A potential rapid-acting antisuicidal agent?. Depression and Anxiety. 2016. doi:10.1002/da.22498.

69 Liz Fierro Closing Schatzberg A. A Word to the Wise About Ketamine. American Journal of Psychiatry. 2014;171(3):262-264. doi:10.1176/appi.ajp.2014.13101434.

STRUCTURED EVIDENCE-BASED MEDICINE REVIEWS

The Use of Subdissociative-dose Ketamine forAcute Pain in the Emergency DepartmentBilly Sin, PharmD, Theologia Ternas, PharmD, and Sergey M. Motov, MD

AbstractObjectives: Ketamine is a well-known anesthetic with its use trailing back to the 1960s. It hasantagonistic effects at the N-methyl-D-aspartate receptor. There is emerging literature to suggest the useof subdissociative-dose ketamine (SDDK) for pain reduction. This evidence-based review evaluates theevidence regarding the use of SDDK for acute pain control in the emergency department (ED).

Methods: The MEDLINE and EMBASE databases were searched. Randomized controlled trials (RCTs)that described or evaluated the use of SDDK for acute pain in the ED were included. Literature wasexcluded if it was not published in English. Duplicate articles, unpublished reports, abstracts, and reviewarticles were also excluded. Quality assessment and evaluation of literature were evaluated based on theGRADE criteria. The primary outcome of interest in this review was the difference in pain score frombaseline to cutoff time as specified in the studies. Secondary outcome measures were the incidence ofadverse events and reduction in the amount of adjuvant opioids consumed by patients who receivedSDDK.

Results: Four RCTs met the inclusion criteria, which enrolled a total of 428 patients. Three adult trialsand one pediatric trial were identified. The level of evidence for the individual trials ranged from low tomoderate. A significant reduction in pain scores was only found in two of the four trials. One trial founda significant reduction in mean pain scores when ketamine was compared to morphine (p < 0.05).Another trial reported a significant decrease in mean distress scores, favoring SDDK over fentanyl (1.0vs. 2.7, p < 0.05). One trial found a significant reduction in the amount of morphine consumed, favoringketamine over placebo (0.14 mg/kg, 95% confidence interval [CI] = 0.13 to 0.16 mg/kg vs. 0.2 mg/kg, 95%CI = 0.18 to 0.22 mg/kg; p < 0.001). An emergence phenomenon was reported in one trial.

Conclusions: Four RCTs with methodologic limitations failed to provide convincing evidence to eithersupport or refute the use of SDDK for acute pain control in the ED.

ACADEMIC EMERGENCY MEDICINE 2015;22:251–257 © 2015 by the Society for Academic EmergencyMedicine

CLINICAL SCENARIO

You are working in the emergency department(ED) and are caring for a 27-year-old femalewho presents with severe back pain that radi-

ates to her legs. The patient has a past medical his-tory of lumbar radiculopathy. Over the course of24 hours, her pain has progressively worsened andshe is now unable to ambulate due to her pain. Uponphysical examination, you find her neurologic func-tions to be intact. The patient has no known drugallergies. You decide to initiate therapy with 30 mg ofintravenous (IV) ketorolac and 5 mg of oral diazepam.

Unfortunately, the patient’s pain does not improve.You then decide to order two tablets of acetamino-phen 325 mg/oxycodone 5 mg, and trigger pointinjections with 0.25% bupivacaine. Despite the thera-pies, the patient’s pain is still not improving. Youconsult your colleague and a recommendation is madeto use subdissociative-dose ketamine (SDDK). Noticingyour surprise, he states that patients who presentwith acute pain may benefit from the therapy. Afteradmitting the patient for intractable lower back pain,you decide to review the evidence to justify the use ofSDDK for acute painful conditions in the ED.

From the Arnold & Marie Schwartz College of Pharmacy, Long Island University (BS, TT), Brooklyn NY; the Department of Phar-macy, Division of Pharmacotherapy Services, The Brooklyn Hospital Center (BS), Brooklyn NY; and the Department of EmergencyMedicine, Maimonides Medical Center, and SUNY Downstate Medical Center (SMM), Brooklyn, NY.Received September 3, 2014; revisions received October 15 and October 19, 2014; accepted October 19, 2014.There were no sources of support in the form of grants, equipment, or drugs. The authors have no conflicts of interest to disclose.Supervising Editor: Shahriar Zehtabchi, MD.Address for correspondence and reprints: Billy Sin, PharmD; e-mail: [email protected].

© 2015 by the Society for Academic Emergency Medicine ISSN 1069-6563 251

doi: 10.1111/acem.12604 PII ISSN 1069-6563583 251Page 3

INTRODUCTION

The N-methyl-D-aspartate (NDMA) receptor is a ligand-gated channel for the excitatory neurotransmitter gluta-mate.1–5 The stimulation of this receptor has beenthought to increase signals and impulses, which lead tohyperalgesic effects.1–5 Therefore, it was believed thatNMDA antagonists may play a role in pain manage-ment. Ketamine is a well-known anesthetic with antago-nistic effects at the NMDA receptor. Its role as ananalgesic has been well documented in various settingssuch as cancer or palliative care, perioperative care,and chronic therapy for neuropathic pain.6–13 However,the use of ketamine for acute pain is not a commonpractice in the ED. Its use is often a topic of controversydue its ability to cause adverse events such as dissocia-tion and emergence phenomena.2–4,14,15 Recent evidencehas emerged that suggests the use of ketamine in sub-dissociative doses for acute pain control. The objectiveof this review was to answer the following researchquestion: In ED patients with moderate to severe painwho do not respond to conventional therapies, is theadministration of SDDK, compared to placebo, safe andeffective in pain control?

METHODS

Criteria for Considering Studies for the ReviewRandomized controlled trials (RCTs) that described orevaluated the use of SDDK in the ED were selected forthe review.

Participants. Eligible participants included patients ofany age range who presented to the ED for acute painand received at least one dose of SDDK in the ED.Patients who received ketamine in a setting outside theED or for indications other than analgesia wereexcluded.

Intervention. The intervention consisted of the admin-istration of SDDK. Subdissociative dose was defined asdoses below 1 mg/kg/dose as these were the doses usedfor the treatment of postoperative or cancer-associatedpain in published literature.12,13 No restrictions were setfor the route of administration.

Comparison. The comparison consisted of the admin-istration of placebo or other pain medications.

Outcomes. The primary outcome of interest in thisreview was the difference in pain scores from baselineto the cutoff time as specified in the studies. Secondaryoutcomes included the incidence of adverse events andreduction in the amount of adjuvant opioids consumedby patients who received ketamine.

Search MethodsA search of the MEDLINE database from 1970 to May2014 and EMBASE from 1970 to May 2014 was con-ducted. Our search strategies are presented in DataSupplement S1 (available as supporting information inthe online version of this paper). Additional referenceswere identified from a review of literature citations.

Abstracts were screened for relevance, and publicationsrelating to the use of ketamine as an analgesic for acutepain in the ED were identified. Only literature publishedin English that evaluated the use of ketamine for acutepain control in humans were included. Duplicate arti-cles, unpublished reports, abstracts, and review articleswere not considered. The primary search identified atotal of 720 publications. The number of citations wasreduced according to their relevance for this review(Figure 1). Eighteen publications were eliminatedbecause they did not meet inclusion criteria. The searchidentified four RCTs that fulfilled our criteria. We per-formed our review based on these four publications.16–19

Description of Included TrialsOne randomized nonblinded trial and three randomizeddouble-blind trials were identified. All identified trialsadhered to the dose range as specified in this section.Analgesic efficacy was measured by the validated scalesused in the original studies, and safety was measuredby the incidence of adverse events reported in the origi-nal studies. In the literature identified, ketamine wasused for acute pain control due to fracture reduction,dislocation, burns, abscesses, acute trauma, or general-ized pain. Three randomized trials used ketamine as anIV injection with doses ranging from 0.2 to 0.3 mg/kg/dose.16–18 One randomized trial utilized ketamine as anIV infusion at 0.1 mg/kg/hr.19 The characteristics of thestudies included in this review are summarized inTable 1.

Quality Assessment of the Included StudiesFactors that affected study quality, such as randomiza-tion, patient selection, adequacy of blinding, and dura-tion of follow-up, were assessed and evaluated based onthe GRADE criteria.20 Assessment and evaluation wereconducted independently by two reviewers (BS, SMM).In the case of discrepancy, a third reviewer (TT) was

Total number of abstractsidentified

720

22

Nonrelevant abstract, topic,or title.

698

Violation of study design(nonrandomized, observationstudies, case series, survey),inclusion or exclusion criteria(entire article reviewed).

18

4

Figure 1. The process of selecting studies suitable for inclu-sion in the final review.

252 Sin et al. • SUBDISSOCIATIVE-DOSE KETAMINE FOR ACUTE PAIN IN THE ED

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consulted. Subgroup analysis was not possible due tothe heterogeneity of the randomized trials. An assess-ment of the risk and potential biases is summarized inTable 2.

RESULTS

A summary of the outcomes from the included literatureis presented in Tables 3 and 4.16–19 The data collectedfrom a total of 428 patients revealed conflicting resultsand conclusions. In two randomized double-blind trialsconducted by Messenger et al.16 and Galinski et al.,17

no detectable differences in pain scores were observed.In the trial by Messenger et al., evidence of compro-mised blinding was reported.16

Gurnani et al.19 conducted a randomized double-blindtrial which compared ketamine infusion to intermittentmorphine injections for trauma patients. Patients inboth groups were provided with morphine 3 mg IVinjections if a pain score was ≥5 out of 10 or inadequateanalgesia was reported. It was found that patients whoreceived ketamine infusion reported significantly lowerpain scores. The trial also reported other findings ofinterest in patients who received ketamine. First, con-trary to other studies, nausea or vomiting were notreported. Second, rescue therapy was not required. Incomparison, 18 of 20 (90%) patients in the morphinegroup required rescue therapy. Finally, there were noreports of hallucinations, disorientation, or overseda-tion.

Table 1Characteristics of the Studies Included in the Review

Study PopulationComparison [Number of Patients

Assigned] Outcome Design

Messengeret al.,200816

63 patients in a tertiary carehospital

Age range: 14–65 yearsInclusion: reduction for fractureor dislocation, incision,drainage of an abscess.

Exclusion: weight > 130 kg,allergic to study medications,chronic opioid use, substanceabuse, psychiatric disorders,acute intoxication, significantactive cardiac or pulmonarydisease.

Ketamine 0.3 mg/kg IV [32] vs.fentanyl 1.5 lg/kg IV [31]

Primary: incidence andseverity of adverse eventsSecondary: analgesicadequacy based on 10-point pain scale

Randomized,double-blindcontrolledtrial

Galinski etal., 200717

65 patients in five EDsAge range: 18–70 yearsInclusion: severe pain (VASscore of at least 60/100 mm)secondary to trauma.

Excluded: previous use ofopioid, history of psychiatricdisease, respiratory, renal orhepatic failure, ketamineallergy, pregnancy, unable tocommunicate VAS

Ketamine 0.2 mg/kg IV over10 minutes and morphine0.1 mg/kg [33] vs. placebo andmorphine 0.1 mg/kg IV [32]

Primary: VAS and opioidconsumption at 30 minutesSecondary: patientsatisfaction, adverse events

Multicenter,randomized,double-blindtrial

Kennedy etal., 199818

260 pediatric patients in apediatric ED

Age range: 5–15 yearsInclusion: require emergencyfracture or joint reduction

Exclusion: abnormalities ofairway, cardiorespiratory,hepatic, renal or centralnervous systems; history ofpsychoses; alcohol abuse, ornonprescribed narcotic usewithin 6 hours of theprocedure.

Midazolam 0.1 mg/kg IV andfentanyl 0.5 lg/kg IV [130] orketamine 0.5 mg/kg IV [130]every 3 minutes until sedation

Primary: OSBD-RSecondary: parent’s ratingof subjects’ pain, adverseevents, FAS scores

Randomized,nonblindedtrial

Gurnani etal., 200719

40 adult patients in a traumacenter

Age range: not specifiedInclusion: acute musculoskeletaltrauma not requiring surgicalinterventionExclusion: severe shock,hypertension, hepatic, renal,cardiac, or debilitating diseases

Ketamine 0.25 mg/kg IV followedby IV infusion at 0.1 mg/kg/hr[20] vs. morphine 0.1 mg/kg IVfollowed by morphine 0.1 mg/kgIV every 4 hours [20]

Primary: VAS, oxygensaturation, demand foradjuvant analgesia,adverse events

Randomizeddouble-blindpilot trial

FAS = facial affective scale; OSBD-R = Observational Scale of Behavioral Distress–Revised; VAS = visual analogue scale.

ACADEMIC EMERGENCY MEDICINE • March 2015, Vol. 22, No. 3 • www.aemj.org 253

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One randomized trial evaluated the use of SDDK inthe pediatric population.18 Patients who received keta-mine and midazolam were found to have lower distress

scores compared to those who received fentanyl andmidazolam. A higher incidence of vomiting was foundin the ketamine and midazolam group (11 of 130, 8.4%

Table 2Assessment of Risk of Bias in the Available Literature

Reference Randomization BlindingBaseline

Comparison Duration of Follow-up Cointervention

AdequateSample

SizeAttained

AssignedLevel of

Evidence


Yes Double-blind

Yes Until deemed recoveredfrom procedure. Nomention of follow upmethod for dischargepatients.

Both groups receivedpropofol 0.4 mg/kgIV, then 0.1 mg/kgIV every 30 secondsuntil sedation.

No Low


Yes Double-blind

Yes 30 minutes afteradministration of studyinterventions. Nomention of follow-upmethod for dischargepatients.

Both groups receivedmorphine 3 mg IVevery 5 minutesuntil pain relief.

Yes Moderate


Yes No Yes Up to ED discharge.Discharged patient hada 1-week follow-upquestionnaire. Nomention of loss tofollow-up.

Midazolam 0.1 mg/kg (max 2.5 mg) IVevery 3 minutesuntil sedation.

Yes Low


No Double-blind

Yes 24 hours. No mention offollow up method fordischarge patients.

Morphine 3 mg IVwas provided ifinadequateanalgesia reported.

No dataprovided

Low

Table 3Summary of the Difference in Pain Scores From Baseline to the Cutoff Time as Specified in Randomized Trials

Study Parameter Result Conclusion


Pain score duringprocedure(mean � SD)

Ketamine 2.1 � 2.2 vs. fentanyl 2.3 � 2.0(95% CI = –1.3 to 0.8)

No significant difference found


Mean VAS at30 minutes after studyintervention

Ketamine 34.1 (25.6 to 42.6) vs. placebo 39.5(95% CI = 32.4 to 46.6), p > 0.05

No significant difference found


OSBD-R scores duringprocedure (mean � sd)

Ketamine 1.08 � 1.12 vs. fentanyl2.70 � 2.16, p < 0.05 (95% CI not reported)

Patients who received ketamine hadsignificant reduction in mean OSBD-Rscores


Mean VAS throughout24 hours

Results shown in graphic comparison,individual values not reported (95% CI notreported)

Patients who received ketamine had asignificant reduction in mean VAS

OSBD-R = Observational Scale of Behavioral Distress–Revised; VAS = visual analogue scale.

Table 4Summary of the Incidence (%) of Adverse Events in Patients Who Received Ketamine

Study Dizziness Fatigue Nausea Vomiting Neuropsychological

Messenger et al.,200816

0 0 0 0 0

Galinski et al., 200717 0 0 8 (6)* 0 12 (36)†

Kennedy et al., 199818 0 0 0 11 (9) 7 (5)‡

Gurnani et al., 200719 0 0 0 0 2 (10)

*Nausea and vomiting were reported as one category.†Description of the reported neuropsychological events not provided by study authors.‡Emergence phenomenon was observed in all reported events.


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vs. 3 of 130, 2.3%; p = 0.03). An emergence phenome-non was reported in one patient. No detectable differ-ences were found in other adverse events.

Despite the use of subdissociative doses, an emer-gence phenomenon was observed in one pediatricstudy.18 Cases of neuropsychological adverse eventswere reported.17,18 However, with the limited data thatwere provided in the original articles, it was difficult toconclude whether these events were related to dissocia-tion or an emergence phenomenon. All reportedadverse events identified in the randomized trials weretransient and did not require additional medical inter-vention, prolonged observation, or hospitalization.16–19

Two studies reported a reduction in the amount ofadjuvant opioids consumed by patients who receivedketamine. Galinski et al.17 found that at 30 minutes frombaseline, morphine consumption was significantly lowerin patients who received ketamine (0.14 mg/kg, 95%confidence interval [CI] = 0.13 to 0.16) compared to pla-cebo (0.20 mg/kg, 95% CI = 0.18 to 0.22; p < 0.05). Gur-nani et al.19 reported a significant reduction in thenumber of patients who demanded adjuvant morphine,favoring ketamine over placebo (0 of 20, 0% vs. 18 of20, 90%; p < 0.05). The amount of morphine consumedwas not reported by the study authors.

DISCUSSION

Returning to the clinical scenario, this review providessome guidance on the use of SDDK in the ED. Thereview suggests that there is limited evidence to eithersupport or refute the use of SDDK for acute pain con-trol. Ketamine was used as an adjuvant therapy in allrandomized trials identified in this review, which hadsmall sample sizes or various methodologic flaws.16–19

There was evidence of unclear documentation or miss-ing records. Data on the use of adjuvant analgesic ther-apies were lacking.16 Detailed descriptions of reportedadverse events were not available.17 Various pain scoreswere used to analyze analgesic effects. CIs that providedinformation about the point estimates and the degree ofuncertainty for the reported pain scores18,19 or adverseevents16–19 were not consistently presented.

In the trial by Messenger et al.,16 patients whoreceived analgesics at ED arrival were required to havea minimum 30-minute washout period. However, thestudy authors did not present data on the analgesicagents and doses, routes of administration, or times ofadministration. Thus, it was questionable whether thewashout period was sufficient to mitigate potentialeffects of the analgesics that were administered. Of thetrials evaluated in this review, Galinski et al.17 used thelowest dose of ketamine. It is unclear whether this hadan effect on the study results.

Kennedy et al.18 and Gurnani et al.19 reported detect-able differences in pain scores when ketamine was usedas an IV infusion for trauma patients and as an IV injec-tion for pediatric patients. Aside from these two ran-domized trials, the efficacy of SDDK for pain reductionwas also reported in observational studies, case series,a case report, and a survey.

Three observational studies evaluated the use of intra-nasal ketamine as monotherapy for acute pain.21–23 All

three studies reported satisfactory pain reduction formost patients within 30 minutes of therapy. Cases ofneuropsychological adverse events were reported.17,18

Descriptions of neuropsychological events includedmood changes, feelings of “unreality,” “spaced out,”“euphoric,” or “disconnected.” Despite these events, thestudy authors noted that there were no reports of disso-ciation or emergence phenomenon. In a separate obser-vational study by Sharieff et al.,24 ketamine 15 mg IVwas used with propofol for fracture reduction. Of the 20pediatric patients who were enrolled, one reported apain score greater than zero, two reported experiencingdreams, and one reported postprocedure vomiting.

In a case series by Lester et al.,25 satisfactory paincontrol was reported in 19 of 35 (54%) patients whoreceived ketamine as an IV or intramuscular injection.Ketamine was dosed between 0.1 and 0.6 mg/kg/dose.Ineffective analgesia and need for additional opioidswere reported in three of 35 (16%) patients. Mild dys-phoria was reported in one of 35 (2.8%) patients.Incomplete data were noted in 22.8% of cases.

Richards and Rockford26 conducted a survey to deter-mine the level of pain reduction, overall satisfaction,adverse events, and patient willingness to receive futuretreatments with ketamine. Eighteen of 24 patientsreceived ketamine because opioids failed to provideadequate pain relief after 30 minutes. Of the 24 patientswho were enrolled, four reported adverse events.Although the description of adverse events was not pro-vided, the authors stated that emergence phenomenonwas not reported. Sixteen of 24 patients reported will-ingness to be treated with ketamine again. Patient satis-faction was reported at 55%, while physiciansatisfaction was reported at 72%.

An observational study conducted by Ahern et al.27

further confirmed that therapy with SDDK reduced theamount of opioids required for pain reduction. In thisstudy, ketamine 0.5 mg/kg IV was combined with areduced dose of hydromorphone. Within 15 minutes oftherapy, 20 of the 30 patients reported adequate paincontrol.

Herring et al.28 presented a case report which sug-gested that SDDK may decrease ED length of stay. Anadult female presented to the ED with generalized intol-erable pain in the head, chest, and back. A review ofthe patient’s electronic medical records revealed 23 EDvisits within a period of 3 years. All visits were forpain-related complaints. The patient’s visits amountedto a total time of 151 hours in the ED. The average EDlength of stay was more than 6 hours. In her latest visit,ketamine 15 mg IV injection was administered after lo-razepam and morphine failed to provide pain reduction.At 20 minutes postinjection, the patient reported painrelief and was subsequently discharged uneventfully.

Despite various methodologic flaws in the studydesigns, such as small sample sizes,16,17,19 and incom-plete descriptions of adverse events17 or pain scores,19

the clinical trials identified in this review revealed sev-eral promising findings. First, it appears that the use ofSDDK may result in satisfactory pain control, and theincidence of adverse events seems to be limited andadditional medical intervention is usually not required.Second, SDDK may play a role in reducing the need for


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additional opioids. This may mitigate concerns of opioidoveruse in the ED. Finally, most trials reported painreduction within 5 minutes of initiating therapy. Theability to achieve adequate pain control in a reducedamount of time may lead to a decreased ED length ofstay and increased patient satisfaction.

There are other important factors to consider wheninitiating SDDK in the ED. Clinicians need to determineif ketamine is readily available in the ED. It may be nec-essary to retrieve ketamine from the central pharmacy ifa pharmacy satellite or automated dispensing cabinetsare not available. Since it is an anesthetic, hospital poli-cies may require physicians to administer ketamine. IVinjections should be administered over 1 minute to pre-vent respiratory depression. Patients should be periodi-cally monitored for adverse events such as nausea,vomiting, respiratory depression, headache, or disorien-tation.

LIMITATIONS

This review lacked the qualities of a rigorous systematicreview or meta-analysis. Non–English language literaturewas not evaluated. The quality of the review’s findingswas affected by the quality of the original articles. Mostof the trials included small sample sizes and used variousdoses and pain scales to evaluate efficacy. Differentpatient populations were also evaluated. The CIs werenot consistently reported by the original study authors.The combination of these limitations makes it difficult toapply the study findings in a general population.

CONCLUSIONS

This review consisted of four randomized clinical trialsenrolling a total of 428 patients. The data failed to pro-vide convincing evidence to either support or refute theuse of subdissociative-dose ketamine for managementof acute pain in the ED. This review also highlighted theneed for well-designed clinical studies to further exam-ine the potential applicability and benefits of subdisso-ciative-dose ketamine. The decision to initiatesubdissociative-dose ketamine should be based onassessments of potential risks and benefits of therapyon a case-by-case basis.

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23. Yeaman F, Meek R, Egerton-Warburton D, Rosen-garten P, Graudins A. Sub-dissociative dose intra-nasal ketamine for moderate-severe pain in adultemergency department patients. Emerg Med Aus-tralas 2014;26:237–42.

24. Sharieff GQ, Trocinski DR, Kanegaye JT, Fisher B,Harley JR. Ketamine-propofol combinationsedation for fracture reduction in the pediatricemergency department. Pediatr Emerg Care2007;23:881–4.

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27. Ahern TL, Herring AA, Stone MB, Frazee BW.Effective analgesia with low-dose ketamine andreduced dose hydromorphone in ED patients withsevere pain. Am J Emerg Med 2013;31:847–51.

28. Herring AA, Ahern T, Stone MB, Frazee BW. Emerg-ing applications of low-dose ketamine for pain man-agement in the ED. Am J Emerg Med 2013;31:416–9.

Supporting Information

The following supporting information is available in theonline version of this paper:

Data Supplement S1. Search strategy for MEDLINEand EMBASE.


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American Journal of Emergency Medicine 33 (2015) 197–201

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

j ourna l homepage: www.e lsev ie r .com/ locate /a jem

Original Contribution

The first 500: initial experience with widespread use of low-dose
ketamine for acute pain management in the ED☆ ,☆☆ ,★,★★
Terence L. Ahern, MD a,⁎, Andrew A. Herring, MD a,b, Erik S. Anderson, MD a, Virat A. Madia, MD a,Jahan Fahimi, MD a,b, Bradley W. Frazee, MD a,b

a Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CAb Department of Emergency Medicine, University of California, San Francisco, San Francisco CA

a b s t r a c ta r t i c l e i n f o

☆ Prior presentations: Accepted for presentation, Americand Pain Medicine, Annual Pain Medicine Meeting in San Fr☆☆ Conflicts of interest: The authors report no conflicts★ Source of support: None.

★★ Author contributions: TA, EA, VM, AH, JF, and BF cothe trial. All authors participated in the conduct of the triathe work of research assistants. TA, EA, and JF analyzed tscript, and all authors contributed substantially to its revithe manuscript as a whole.

⁎ Corresponding author. Department of EmergencyMediHeath System, 1411 East 31st St, Oakland, CA 94602-1018. Tel437 8322.

E-mail address: [email protected] (T.L. Ahern).

http://dx.doi.org/10.1016/j.ajem.2014.11.0100735-6757/© 2014 Elsevier Inc. All rights reserved.

Article history:
Received 17 September 2014Received in revised form 5 November 2014Accepted 7 November 2014
Objectives: The objective of this study is to describe the clinical use and safety profile of low-dose ketamine (LDK)(0.1-0.3 mg/kg) for pain management in the emergency department (ED).Methods: This was a retrospective case series of consecutive patients given LDK for pain at a single urban ED be-tween 2012 and 2013. Using a standardized data abstraction form, 2 physicians reviewed patient records to de-termine demographics, indication, dose, route, disposition, and occurrence of adverse events. Adverse events
were categorized as minor (emesis, psychomimetic or dysphoric reaction, and transient hypoxia) and serious(apnea, laryngospasm, hypertensive emergency, and cardiac arrest). Additional parameters measured wereheart rate and systolic blood pressure.Results: Five hundred thirty patients received LDK in the ED over a 2-year period. Indications for LDK were di-verse. Median patient age was 41 years, 55% were women, and 63% were discharged. Route of administrationwas intravenous in 93% and intramuscular in 7%. Most patients (92%) received a dose of 10 to 15 mg. Comorbiddiseases includedhypertension (26%), psychiatric disorder (12%), obstructive airway disease (11%), and coronaryartery disease (4%). There was no significant change in heart rate or systolic blood pressure. Thirty patients (6%)met our criteria for adverse events. Eighteen patients (3.5%) experienced psychomimetic or dysphoric reactions.Seven patients (1.5%) developed transient hypoxia. Five patients (1%) had emesis. There were no cases of seriousadverse events. Agreement between abstractors was almost perfect.Conclusion: Use of LDK as an analgesic in a diverse ED patient population appears to be safe and feasible for thetreatment of many types of pain.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction

The Institute of Medicine report, Relieving pain in America: a blue-print for transforming prevention, care, education, and research,highlighted inadequate emergency department (ED) treatment ofpain as a major public health concern [1]. However, strategies to suc-cessfully manage acute pain in a safe and expeditious manner are thesource of considerable debate, and there is wide variation in clinical

anSociety of Regional Anesthesiaancisco, CA, November 2014.of interest.

nceived the study and designedl, data collection, and organizedhe data. TA drafted the manu-sion. TA takes responsibility for

cine, HighlandHospital–Alameda.:+1 510 437 8497; fax:+1510

practice [2]. Current pharmacologic strategies in the ED rely heavilyon monotherapy with opioids; but adverse events such as sedation,bradypnea, hypotension, and tolerance limit their utility in many pa-tients [3-8]. In addition, the epidemic of opioid pain medication misusehas become a nationally recognized problem, and emergency physi-cians have been tasked with carefully assessing opioid administrationand prescriptions [9].More than ever, emergency physicians are consid-ering alternative, complimentary medications, such as ketamine, thatcan be combined with traditional drugs such as opioids and nonsteroi-dal antiinflammatory drugs, to achieve multimodal analgesia in theacute setting.

Ketamine has been used extensively in the ED for procedural seda-tion and rapid sequence intubation. An alternative, off-label, use of keta-mine is for pain control, using subanesthetic dosing—typically 0.1 to 0.3mg/kg. Research conducted over the last 15 years has demonstratedthat such low-dose ketamine (LDK) is safe, effective, and improvespain management when combined with opioid analgesics [10-13].Low-dose ketamine has been shown to potentiate the analgesic effectof opioids, have opioid-sparing effects, and to attenuate developmentof centralized chronic pain states [14-20]. For these reasons, LDK for an-algesia has been widely adopted in the anesthesia, surgical, and

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198 T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197–201

palliative care settings for the treatment of postoperative and chroniccancer-related pain.

Emergency medicine has been slower to incorporate LDK for anal-gesia into routine practice, likely due to lack of familiarity with this in-dication as well as concerns over adverse effects, particularlyemergence phenomena. But a small yet growing body of evidencehas emerged over the last 10 years documenting the successful useof LDK in the ED and prehospital environment [12,21-25]. These stud-ies consistently show that the safety and side effect profile of LDK issimilar to that of opioids and that LDK causes few significantpyschomimetic reactions. In response, some institutions have begunto routinely incorporate LDK into acute painmanagement as a compli-mentary and rescue analgesic. Two years ago, in collaboration withemergency physicians, nursing, and pharmacy staff, we developedan ED-specific LDK protocol to facilitate use for a broad array of painfulconditions in our department.

The aim of this study is to document the clinical use, safety, and sideeffect profile of LDK for pain management in the ED.

2. Methods

2.1. Setting

This retrospective, consecutive case series was conducted in asingle ED at an urban trauma center. We obtained a database, de-rived from our electronic medical record (EMR) (Wellsoft Corpora-tion, Sumerset, NJ), of all patients receiving ketamine in our EDduring a 2-year period from January 2012 to December 2013. This2-year timeframe coincided with an increase in popularity andawareness of ketamine on the part of ED providers after the creationof an ED-specific LDK protocol in 2012. With broad inclusion criteria,the protocol proposed LDK as an agent for analgesia in patients withmany types of acute or chronic pain, either alone or in combinationwith additional pain relieving drugs. The protocol recommendeddoses of 5 to 20 mg intravenous (IV) or 10 to 25 mg intramuscular(IM). There were no absolute contraindications except for known al-lergy to ketamine. Relative contraindications included age youngerthan 18 years, uncontrolled seizure activity, severe signs of elevatedintracranial pressure, renal and/or liver failure, and women who arepregnant or breastfeeding. Patients were not specifically excludedfor having abnormal vital signs (ie, hypertension, tachycardia, orhypoxia), and the ultimate decision whether to order LDK was leftup to provider preference.

Our ED uses computerized drug storage units (Pyxis Corporation,San Diego, CA) and EMRs that permit accurate tracking of departmentdrug ordering and administration, including dosage and route of ad-ministration. To facilitate ease of use and cut down on unnecessarywaste, our pharmacy began stocking preloaded syringes of 15 mg keta-mine for IV administration, which were kept in the drug storage units.Our hospital's institutional review board approved this retrospectivereview.

2.2. Study population

We extracted data from electronic systems to include all ED pa-tients for whom ketamine was ordered during the study period.The data included medical record number, arrival date, age, sex, dis-position, and chief complaint. Chief complaints were categorizedinto 7 broad groups of indications for LDK before chart review. Thegroups included muscular-skeletal pain, abdominal pain, chestpain, skin and soft tissue infections, headache, back pain, and other.For the purposes of this study, we defined LDK as a dose less thanor equal to 20 mg IV or 25 mg IM or roughly 0.1 to 0.3 mg/kg in theaverage size adult.

2.3. Data abstraction

After a formal training period and data abstraction pilot trial, a stan-dardized data abstraction formwas used to reviewpatient records inde-pendently by 2 authors. We abstracted ketamine dose (milligram),route of administration (IV or IM) and systolic blood pressure (SBP),and heart rate (HR) at 2 time points: at triage and within 1 hour ofLDK administration.

Detailed review of the clinical chart was done to ascertain the pres-ence or absence of specific, predefined adverse events with one hour ofLDK administration including cardiac arrest, apnea (respiratory rateb10 breaths per minute or need for jaw thrust and/or bag valve maskventilation), hypoxia (oxygen saturation, b90% on room air or N5% de-creased in oxygen saturation from baseline value if N90% at triage), hy-pertensive emergency (SBP, N180 and the acute onset of chest pain,shortness of breath, or severe headache), laryngospasm, emesis,psychomimetic reaction (agitation, hallucinations, or unusual behaviorrecorded by provider), and other (nurse or physician documentationof specific problem related to LDK administration). Lastly, comorbiditiesincluding a history of hypertension, coronary artery disease (CAD), psy-chiatric illness (schizophrenia, bipolar, and depression requiring medi-cation), and chronic obstructive pulmonary disease (COPD) or asthmawere recorded. If not documented in the medical record, each of theseadverse events and comorbidities was assumed to be absent.

Frequentmeetingswere held between abstractors and study coordi-nators to answer questions, resolve disputes, and review identified ad-verse events. A random sample of 10% of charts reviewed wasduplicated to assess interrater reliability.

2.4. Data analysis

We report descriptive statistics and 95% confidence intervals (CIs),where appropriate. Interrater reliability was ascertained through theCohen κ statistic for route of administration and absence or presenceof any adverse events and the Spearman rank correlation for dose of ad-ministration. Statistical analysis was done using Stata version 11(StataCorp, College Station, TX).

3. Results

We found almost perfect agreement between the 2 abstractors: κ=0.98 for route of administration, κ = 0.90 for presence of adverse reac-tion, and r = 0.99 for dose of administration.

The initial database included 683 patients who received ketamine inour ED over the study period.We excluded all cases of ketamine admin-istration that did not meet our definition of LDK (≥20 mg IV or 25 mgIM). Using this definition, 153 cases were excluded from the analysis.The excluded cases primarily comprised ketamine used for conscioussedation and rapid sequence intubation.

This series ultimately included 530 consecutive ED LDK administra-tions, of which 294 (55.5%) were female. The median age was 40 years,and the distribution of patients was fairly even between the second tofifth decades of life (Table 1). Indications for LDK were diverse, andmany of the patients had substantial underlying illness including hyper-tension (26%), psychiatric disorder (12%), COPD (11%), and CAD (4%).Ultimately, near two-thirds (63%) were discharged home from the ED.

Low-dose ketamine was administered IV in the vast majority ofcases (93%) and IM in the remaining cases. Most patient (92%) receiveda single dose of either 10 or 15 mg, although the dose range was 5 to25 mg IV/IM. There was no significant change in SBP and HR within 1hour of LDK administration, as compared with triage values. Mean tri-age SBP and HR was 141 (99% CI, 138-144) and 93 (99% CI, 91-95),whereas SBP and HR within 1 hour of LDK administration were 138(99% CI, 135-141) and 86 (99% CI, 84-88), respectively.

Of 530 LDK cases, only 30 (6%) met our criteria for an adverse event.Each event is specifically detailed in Table 2. Therewere 7 patients (1.5%)

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Table 1Patient characteristics and indications for LDK

No. of patients Percentage (%)

Age (y)19-29 132 2530-39 125 2440-49 120 2250-59 114 2260-69 35 6N70 4 1

SexMale 236 44Female 294 56

DispositionDischarge 335 63Admission 195 37

IndicationsMusculoskeletal pain 63 12Abdominal pain 178 33Chest pain 24 5Skin and softtissue infection

62 12

Back pain 66 12Headache 13 3Othera 124 23

ComorbiditiesHypertension 139 26CAD 21 4COPD 57 11Psychiatric illness b 63 12

a Included chronic pain, sickle cell crisis, genitourinary disorders, painful rashes, psy-chiatric complaints, and other miscellaneous painful complaints.

b Included depression, bipolar disorder, and schizophrenia.

199T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197–201

who developed transient hypoxia, 4 of whom had concurrently received1 to 2 mg of hydromorphone. Most of the 7 had transient oxygendesaturations to between 86% and 92%, and all but 1 patient respondedto 2 L oxygen by nasal cannula. Five patients (1%) had emesis, 3 receivedondansetron for symptomatic relief, and all 5 cleared their airway with-out assistance. There was no evidence of aspiration in any patient.

Eighteen patients (3.5%) experienced psychomimetic or dysphoricreactions (hallucinations, agitation, unusual behavior, or provider docu-mentation of LDK-related patient complaint), none of which were longlasting or led to a change in ultimate disposition. Three patients weregiven lorazepam for symptomatic anxiety or agitation. Most patientsimproved without intervention or after reassurance by nurse or physi-cian. There was 1 case of moderate-to-severe agitation in a 57-year-old man with metastatic cancer who was noted by the nurse to openhis eyes widely and scream while pulling at the gurney side rails afterreceiving ketamine 15 mg IV and fentanyl 50 μg IV; he was treatedwith lorazepam resulting in resolution of his symptoms. Another pa-tient was noted by the nurse to have “a bad dream-like state” and “feltlike she might die in her dream,” after receiving ketamine 10 mg IV.Other notable patient quotations in the medical record included, “Ifeel like a zombie,” “if this is what people feel like on drugs, then Idon't want them,” “my pain is gone, but I feel crazy,” “I feel like I'm fly-ing,” and “you all look like aliens.”

4. Discussion

To our knowledge, this is largest series reported of LDK administra-tion for pain in the ED. We found that LDK is feasible and safe for treat-ment of a wide variety of painful conditions. The adverse event rate was6% overall, but the events were easily identified and dealt with by EDstaff. Furthermore, this adverse event rate is lower than that of opioidmedications in hospitalized patients, although a direct comparison isproblematic [26,27]. None of the adverse events caused harm orchanged disposition. Importantly, no patients experienced apnea,laryngospasm, hypertensive emergency, or cardiac arrest.

Concerns over adverse psychomimetic affects, particularly emer-gence phenomena, have traditionally limited widespread use of LDK inadult ED patients [28]. Our results confirm those of prior smaller studiesof LDK showing that psychomimetic reactions are mostly mild in natureand rarely alter a patient's clinical course [10,12,21-24,29]. In our cohort,18 patients (3.5%) had documented psychomimetic or dysphoric reac-tions within 1 hour of LDK administration. Although 3 patients requiredlorazepam for sedation during the episode,most reactionsweremild andimproved without intervention or with reassurance from ED staff.

It is now apparent that mild dysphoric effects of LDK occasionaloccur with doses lower than what is traditionally considered the disso-ciative range (1-2 mg/kg IV), at which actual emergence phenomenoncan occur. The rate of such reactions in recent prospective studiesranges from 16% to 26% [21,22,30]. It is important to note that the neg-ative reactions are universally short lived and differ substantially fromemergence phenomenon. Our rate of mild dysphoric events is muchlower than described in previous prospective studies; but this is likelydue to the inherent limitations of retrospective chart review, relianceon themedical records for documentation of events, and the sensitivityof screening instruments for such events used in prospective studies.Nonetheless, we suspect that some patients reported the effects as neg-ative experiences primarily because they were taken by surprise. Basedupon our (the investigators) growing experience with LDK, we believethat advising patients about the possibility of psychomimetic effects re-duces the likelihood that the effect will be perceived as negative if it oc-curs. In addition, a prior prospective trial on LDK showed that the samepatient who reports very bothersome dissociative effects might reporthigh satisfaction at discharge [21]. It seems prudent that providerswho administer LDK should routinely coach patients just before admin-istration, reassuring them that any dysphoric reactionwill be short livedand create as calm an environment as possible.

Other types of adverse eventswere infrequent. Seven patients (1.5%)experienced transient oxygen desaturation within 1 hour of ketamineadministration. Of these patients, 4 were given concomitant opioidswith LDK, and all but 1 patient responded quickly with 2 to 4 L nasalcannula oxygen. One patient required 2 hours of bilevel positive airwaypressure (bipap) support; but she had been hypoxic at triage, requiredoxygen support via non-rebreather facemask and bipap before LDK,and was already admitted for a COPD exacerbation. According toprovider's documentation, the indication for LDK in this case was totreat chest pain but, perhaps, more importantly, to facilitate therapyfor hypoxia byway of providing anxiolysis and bronchodilation. Overall,the rate of hypoxia is substantially less than reported in prior prospec-tive research on opioid-based pain protocols in the ED [31]. For exam-ple, in the widely cited “1 + 1” hydromorphone titration protocolstudy, Chang et al [31] found a 5% rate of hypoxia in patients receivinghydromorphone. In addition, their study excluded patients with base-line oxygen saturation less than 95%. However, a direct comparisonwith our heterogeneous cohort is not possible because some patientsmay have been given LDK in spite of their hypoxia.

Similarly, we found a lower rate of emesis in our cohort than whatwas reported in patients receiving hydromorphone in the study ofChang et al [31] (1% vs 7%, respectively). Furthermore, most of our eme-sis cases were in patients who had experienced nausea and/or vomitingbefore receiving LDK (reference, Table 2 for details), whereas such pa-tients would have been excluded from the reporting of emesis in thestudy of Chang et al [31].

We observed no significant change in blood pressure or HRwithin 1hour of administering LDK as comparedwith triage values. Patientswhowere tachycardic, hypertensive, or hypoxic at triage remained so afterreceiving LDK. This is not surprising given the well-established favor-able hemodynamic profile of ketamine [32]. Although these findingssuggest that LDK may be safe in patients who have abnormal vitalsigns, there ismuchuncertainty in this patient population given the lim-itations of retrospective data. Furthermore, our LDK protocol does notexplicitly exclude patients with abnormal vital signs and allows for

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Table 2All 30 adverse events that occurred within 1 hour of LDK bolus, among 530 patients

Adverse eventa Age Sex Disposition Indication Dose Route Comorbiditiesb Details

Hypoxiac

41 F Home Abdominalpain

15 IV LDK given for chronic pelvic pain. Hypoxia noted during LDK administrationrequiring non-rebreather facemask, which resolved within 1 h.Patient had been given 2 mg hydromorphone 45 minutes before LDK.

43 M Admit Abdominalpain

10 IV Hypertension LDK given for abdominal pain. Placed on 2-L nasal cannula after LDK, although nodesaturation was noted.

43 M Admit Abdominalpain

15 IV Depression,hypertension, CAD

LDK given for abdominal pain secondary to diabetic ketoacidosis. 45 min priorreceived 2 mg hydromorphone. SpO2 dropped to 88%, transient2-L NC applied.

42 M Admit Abscess 20 IV LDK given for abscess drainage. 1 h after administration noted to have SpO2 of 88%when asleep, which improved with elevation head of bed.Patient may have had undiagnosed obstructive sleep apnea.

58 M Home Cancer 15 IV LDK and 2 mg hydromorphone given for back pain related to metastatic lesion. SpO2

dropped to 88%, transient 2-L NC applied.48 F Admit COPD 15 IV Hypertension, COPD Patient was admitted for COPD. SpO2 95% on 2-L NC before LDK but dropped to 80%

with increased work of breathing and lethargy obstructivelung disease noted by MD afterward. Placed on bipap for next 2 h then improved.

46 M Admit Trauma 20 IV LDK and 1 mg hydromorphone given for head laceration repair. SpO2 dropped to90%, transient 2-L NC applied.

Emesis21 M Admit Abdominal

pain15 IV LDK and 8 mg ondansetron given for nausea and vomiting in setting of

pyelonephritis. Patient had 2 small episodes of emesis afterward butstated “it's due to not eating.”


15 IV Hypertension LDK, 25 mg benedryl and 4 mg ondansetron given for nausea and vomiting insetting of gastroparesis. Patient had large emesis 45 minafterward, improved with 10 mg metoclopramide.

51 M Home Back pain 15 IV Hypertension LDK, 30 mg ketorolac and 10 mg dexamethasone given for cauda equina syndrome.Patient had small emesis 15 min afterward while lying flatfor electrocardiogram.

22 F Home Chronicpain

15 IV LDK given for chronic abdominal pain and hyperemesis syndrome. Patientcomplained of continued nausea and vomiting after LDK.

75 F Home Fracture 15 IV Hypertension LDK and 1 mg hydromorphone given for humerus fracture. Patient had large emesis10 min afterward, improved with 4 mg ondansetron.

Psychomimetic/dysphoricd

54 M Home Abdominalpain

10 IV After LDK and 2 mg hydromorphone, patient reported, “I feel dizzy.”


5 IV After LDK and 400 mg ibuprofen, patient reported, “I feel dizzy.”


15 IV COPD After LDK and 1 mg hydromorphone, patient stated her pain is improved, but themedicine made her feel “like I'm going to die.”


15 IV Hypertension After LDK, noted that “she does not want ketamine again for pain; that it made herhallucinate.”


15 IV CAD, COPD After LDK and 4 mg morphine, patient reported “pain gone” but “I feel crazy.” Given1 mg lorazepam.


15 IV After LDK and 4 mg morphine, patient noted by nurse to become unresponsive toverbal stimuli. Awakened with sternal rub and began crying.Vital signs normal except for HR of 110. Given 1 mg lorazepam.

22 F Admit Abdominalpain

20 IV After LDK, patient reported “I feel dizzy, but the pain is gone.” Later noted by RN topatting the wall with hand repeatedly with eyes closed. She remained alert andoriented but no explanation offered.

55 F Admit Abscess 10 IV LDK and 25 μg fentanyl given for abscess drainage. Noted to become anxious and wascrying because she “didn't like the effect of the drug.”

42 F Home Back pain 10 IV Hypertension LDK and 2 mg hydromorphone given for back pain. Noted to be very anxious for10 min afterward.

40 F Home Back pain 15 IV After LDK, patient became highly anxious and was crying. Reported “I feel like azombie.” Improved with reassurance by nurse.

57 M Admit Cancer 15 IV After LDK and 50 μg fentanyl, patient noted to have enlarged eyes and be screamingin pain while pulling at side rails. Required 2 mglorazepam and was calmed by MD

65 F Admit Chest pain 15 IV COPD After LDK, noted to be anxious and disoriented by nurse. Patient stated “If this iswhat people feel like on drugs, then I don't want them.”Feelings resolved spontaneously within 10 min.

67 F Admit Chest pain 15 IV Hypertension, coronary Patient did not like feeling of LDK immediately, and the bolus was stopped beforecompletion.

36 M Home Chest pain 15 IV Hypertension Received LDK for asthma exacerbation. Afterward, noted to be more calm and stated“I feel like I'm flying,” then “I'm going to sleep.”

38 F Home Chest pain 10 IV During LDK administration, noted to have “a bad dream-like state,” and “felt like shewas going to die in her dream.”

54 F Home Chest pain 15 IV Hypertension After LDK noted, “I feel weird. I feel funny… What is wrong with me?” Symptomsresolved without intervention.

44 M Home Hematoma 15 IV After LDK and 1 mg hydromorphone, patient reported pain is gone, but “we all looklike aliens.”

43 F Home Sickle cell pain 15 IV Depression, hypertension After LDK, patient became nauseated and flushed feeling. Improved with 25 mgphenergan.

Abbreviations: M, male; F, female; SpO2, oxygen saturation as measured by pulse oximetry; NC, nasal cannula;MD, doctor of medicine; RN, registered nurse.a No patient experienced cardiac arrest, apnea, hypertensive emergency, or laryngospasm.b Significant comorbities abstracted included history of hypertension, pyschiatric illness (depression, bipolar, and schizophrenia), CAD, and COPD.c Hypoxiawas defined as oxygen saturation as measured by pulse oximetry less than 90% or decrease in oxygen saturation more than 5% from triage vital signs.d Pyschomimetic/dysphoric side effectswere defined as hallucinations, agitation, unusual behavior, or registered nurse/doctor of medicine documentation of a specific problem

related to ketamine.

200 T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197–201

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201T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197–201

provider preference, so we cannot account for individual practice pat-terns and must assume some avoided LDK in these situations.

The favorable safety profile of LDK is especially notable given thewide age distribution and prevalence of comorbidities in our cohort(Table 1). To date, prior studies of LDK had rigorous inclusion and exclu-sion criteria and represented a tightly controlled cohort of patients. Webelieve that our cohort represents a typical diverse, urban ED popula-tion,wheremanypatients have chronicmedical and psychiatric disease,substance abuse, and lack of social support. In spite of this, our findingsare consistentwith those of a prior small retrospective study in a similarsetting [25] and recent prospective data [21,22,24,30], showing that LDKis feasible, generally well tolerated, and very safe in the ED.

This study has the usual limitations inherent in a retrospective re-view. Quality of the data was dependent on that of the medical record,particularly nursing documentation. To mitigate this, we focused ondata that were objective and not prone to interpretation or abstractorbias using a standardized abstraction protocol based upon acceptedguidelines for chart reviewmethodology [33]. Our EMRs include exten-sive documentation from nursing and physicians, so it is unlikely thatwe missed any major adverse events (ie, cardiac arrest, apnea, hypoxia,laryngospasm, and hypertensive emergency). Despite this, it is likelyour data underestimate minor adverse events, such as emesis or tran-sient psychomimetic and dysphoric events.

Although emergency physicians should be encouraged by the safetyof LDK in this large and diverse cohort of ED patients, we emphasize thatdata from prospective, randomized blinded trials are needed to defini-tively determine the efficacy, safety, and side effect profile of LDK com-pared with standard opioid analgesics and other opioid adjuncts.

5. Conclusion

Use of LDK alone or in combination with other pain medications as aprimary or rescue analgesic in a diverse ED patient population appears tobe safe and feasible for the treatment of many types of pain. Minorpsychomimetic side effects were observed but easily addressed by EDpersonnel anddid not alter disposition. Other side effects, including eme-sis and hypoxia, appear to be equally or less common than reportedwithopioids. Prospective randomized trials are needed to determine theefficacy and further elucidate the safety and side effect profile of LDK.

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[16] Childers Jr WE, Baudy RB. N-methyl-D-aspartate antagonists and neuropathic pain:the search for relief. J Med Chem 2007;50(11):2557–62.

[17] Corchs F, Mercante JP, Guendler VZ, MashruhaM, Vieira D, BernikM, et al. Sensitivityto aversive stimulation, posttraumatic symptoms and migraines: what do they havein common? Med Hypotheses 2011;77:534–5.

[18] Dickenson AH. NMDA receptor antagonists: interactions with opioids. ActaAnaesthesiol Scand 1997;41:112–5.

[19] Fishman SM. Listening to pain: a physician's guide to improving pain managementthrough better communication. Oxford University Press; 2012.

[20] Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler J, Schmelz M. A newmodel of elec-trically evoked pain and hyperalgesia in human skin: the effects of intravenousalfentanil, S ⊕−ketamine, and lidocaine. Anesthesiology 2001;95(2):395–402.

[21] Ahern T, Herring A, Stone M, Frazee B. Effective analgesia with low-dose ketamineand reduced dose hydromorphone in ED patients with severe pain. Am J EmergMed 2013;31(5):847–51.

[22] Galinski M, Dolveck F, Combes X, Limoges V, Smail N, Pommier V, et al. Managementof severe acute pain in emergency settings: ketamine reduces morphine consump-tion. Am J Emerg Med 2007;25(4):385–90.

[23] Jennings PA, Cameron P, Bernard S, Walker T, Jolley D, Fitzgerald M, et al. Morphineand ketamine is superior to morphine alone for out-of-hospital trauma analgesia: arandomized controlled trial. Ann Emerg Med 2012;59(6):497–500.

[24] Johansson P, Kongstad P, Johansson A. The effect of combined treatment with mor-phine sulfate and low-dose ketamine in the pre-hospital setting. Scand J TraumaResusc Emerg Med 2009;17:61–6.

[25] Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED:a retrospective case series. Am J Emerg Med 2010;28(7):820–7.

[26] Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adversedrug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One 2009;4(2):e4439.

[27] Weiss AJ, Elixhauser A. Characteristics of adverse drug events originating during thehospital stay, 2011. Healthcare Cost and Utilization Project. 2013. Statistical brief#164. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb164.jsp.

[28] Stoddard FJ, Sheridan RL, Saxe GN, King BS, King BH, Chedekel DS, et al. Treatment ofpain in acutely burned children. J Burn Care Rehabil 2002;23(2):135–56.

[29] Porter K. Ketamine in prehospital care. Emerg Med J 2004;21:351–4.[30] Richards JR, Rockford RE. Low-dose ketamine analgesia: patient and physician expe-

rience in the ED. Am J Emerg Med 2013;31(2):390–4.[31] Chang AK, Bijur PE, Gallagher E. Randomized clinical trial comparing the safety and

efficacy of a hydromorphone titration protocol to usual care in the management ofadult emergency department patients with acute severe pain. Ann Emerg Med2011;58(4):352–9.

[32] Weinbraum AA. Non-opioid IV adjuvants in the perioperative period: pharmacolog-ical and clinical aspects of ketamine and gabapentinoids. Pharmacol Res 2012;65(4):411–29.

[33] Gilbert EH, Lowenstein SR, Koziol-Mclain J, Barta D, Steiner J. Chart reviews in emergen-cy medicine research: where are the methods? Ann Emerg Med 1996;27(3):305–8.

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American Journal of Emergency Medicine 33 (2015) 402–408




Original Contribution

Low-dose ketamine vs morphine for acute pain in the ED: a randomized
controlled trial☆,☆☆
Joshua P. Miller, MD a,b,⁎, Steven G. Schauer, DO a,c, Victoria J. Ganem, RN, BSN d, Vikhyat S. Bebarta, MD d

a Department of Emergency Medicine, San Antonio Military Medical Center, Houston, TXb Department of Emergency Medicine, Bergan Mercy Medical Center, Omaha, NEc Department of Emergency Medicine, Bayne-Jones Army Community Hospital, Fort Polk, LAd Air Force En Route Care Research Center, San Antonio Military Medical Center, Houston, TX

a b s t r a c ta r t i c l e i n f o

☆ Grant:We received a research grant from the Office oto support this study (Award No. C.2011.173).☆☆ Meetings: Society for Academic Emergency MedicinMay 2013; oral presentation.⁎ Corresponding author. 8035Hunters Ridge Rd, Lincoln

E-mail addresses: [email protected] (J.P. Miller(S.G. Schauer), [email protected] (V.J. Ganem)(V.S. Bebarta).

http://dx.doi.org/10.1016/j.ajem.2014.12.0580735-6757/© 2014 Elsevier Inc. All rights reserved.

Article history:
Received 29 May 2014Received in revised form 24 December 2014Accepted 24 December 2014
Objectives: To compare the maximum change in numeric rating scale (NRS) pain scores, in patients receivinglow-dose ketamine (LDK) or morphine (MOR) for acute pain in the emergency department.Methods:We performed an institutional review board–approved, randomized, prospective, double-blinded trialat a tertiary, level 1 trauma center. A convenience sample of patients aged 18 to 59 years with acute abdominal,flank, low back, or extremity pain were enrolled. Subjects were consented and randomized to intravenous LDK
(0.3 mg/kg) or intravenous MOR (0.1 mg/kg). Our primary outcome was the maximum change in NRS scores. Asample size of 20 subjects per group was calculated based on an 80% power to detect a 2-point change in NRSscores between treatment groupswith estimated SDs of 2 and anα of .05, using a repeated-measures linearmodel.Results: Forty-five subjects were enrolled (MOR 21, LDK 24). Demographic variables and baseline NRS scores(7.1 vs 7.1) were similar. Ketamine was not superior to MOR in the maximum change of NRS pain scores,MOR=5 (confidence interval, 6.6-3.5) and LDK=4.9 (confidence interval, 5.8-4). The time to achievemaximumreduction in NRS pain scores was at 5 minutes for LDK and 100minutes for MOR. Vital signs, adverse events,provider, and nurse satisfaction scores were similar between groups.Conclusion: Low-dose ketamine did not produce a greater reduction in NRS pain scores comparedwithMOR foracute pain in the emergency department. However, LDK induced a significant analgesic effect within 5 minutesand provided a moderate reduction in pain for 2 hours.

1. Introduction

Pain is the most common complaint for emergency department (ED)visits [1]. Opioids, commonly morphine, are the standard treatment ofmoderate and severe, acute pain in the ED. However, many patientsreport inadequate pain control in the ED [2,3]. Patientswith opioiddepen-dence may present to the ED in anticipation of obtaining treatment withopioids [4]. In addition, the serious adverse effect profile of opioids canbe underappreciated given their common use in the ED. In 2012, theJoint Commission released a Sentinel Event Alert, which stated that opioidanalgesics rank among the drugsmost frequently associatedwith adversedrug events. Of the opioid-related adverse drug events—includingdeaths—that occurred in hospitals and were reported to The Joint

f the Air Force Surgeon General

e Annual Meeting; Atlanta, GA;

, NE 68516. Tel.:+120 887 4579.), [email protected], [email protected]

Commission's Sentinel Event database (2004-2011), 47% were wrongdose medication errors, 29% were related to improper monitoring of thepatient, and 11%were related to other factors, including excessive dosing,medication interactions, and adverse drug reactions [5].

Like opioids, ketamine has analgesic properties [6–9]. Ketamine,however, has a very large therapeutic window. Overdoses from 5 to100 times the therapeutic dose have been reportedwithout adverse out-comes [10]. In addition, the adverse effect profile of ketamine (elevatedpulse and blood pressure, hallucinations, emergence) is much differentfrom that of opioids (decreased pulse, blood pressure, and respiratoryrate, sedation).

The predominant use of ketamine in the ED, as well as the focus ofresearch, has been as a dissociative agent (1.5-2 mg/kg intravenous [IV])to facilitate procedural sedation [11–14]. There were a small number ofnon-ED studies with low-dose ketamine (b0.55 mg/kg IV) from as earlyas the 1970s which reported efficacious analgesia without dissociation[15,16]. More recent studies from the ED and prehospital environmenthave shown that low-dose ketamine, when used alone or in combina-tion, provides safe and efficacious analgesia [8,9,17–19]. These studies,however, are limited in that opioids or sedatives were used in conjunc-tion with low-dose ketamine; patients were treated for chronic pain,not acute pain, or there was no comparison arm.

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Fig. 1. CONSORT diagram. SAMMC, San AntonioMilitaryMedical Center; MOR, morphine;LDK, low-dose ketamine.

403J.P. Miller et al. / American Journal of Emergency Medicine 33 (2015) 402–408

Studies are needed to independently compare the safety and efficacyof opioids to other analgesics, such as ketamine, in order to ensure thatpatients are receiving the safest and most effective pain managementpossible when experiencing acute pain in the ED. Thus far, a prospec-tive, randomized, double-blinded trial comparing low-dose ketaminealone to morphine for the treatment of acute pain in the ED has notbeen reported.

The goal of this studywas to compare the ability of low-dose ketamineand morphine to reduce acute pain as measured by the numeric ratingscale (NRS). In addition, we describe the details of ketamine analgesiaover time in an ED population. Finally, we also sought to examine thereduction of pain as measured by provider and nurse satisfaction scores.

2. Methods

2.1. Study design

Our studywas a prospective, randomized, controlled, double-blinded,superiority trial comparing the efficacy of IV low-dose ketamine to IVmorphine for moderate to severe acute pain in the ED setting. Wehypothesized that ketamine would provide a greater maximum reduc-tion in pain comparedwithmorphine. The Brooke ArmyMedical CenterInstitutional Review Board in San Antonio, TX, approved the study pro-tocol.Written and signed informed consentwas obtained in accordancewith institutional policy.

2.2. Setting

The study was conducted in a military, level 1 trauma center ED,where approximately 80000 ED patients are treated annually. TheED patient population consists of uniformed military personnel(20%) and civilians (80%). Enrollment occurred from February 2012to March 2013.

2.3. Study protocol

A convenience sample of patientswas obtained by a full-time, trained,research nurse coordinator using a standard enrollment protocol.Patients were screened at triage during daytime and evening hours onweekdays. Patients were eligible for inclusion if they were between theages of 18 and 59 years and complained of abdominal, flank, low back,or extremity pain that the EDprovider feltwarranted IVopioid treatment.Patients were excluded if any of the following were met: oxygen satura-tion less than 95%, systolic blood pressure less than 90 mmHg or greaterthan 180 mm Hg, pulse rate less than 50 or greater than 120 beats/min,respiratory rate less than 10 or greater than 30 respirations/min, alteredmental status, intoxication, fibromyalgia or other chronic pain conditionrequiring the use of opioids or tramadol as an outpatient, ischemicheart disease, heart failure or unstable dysrhythmias, use of an opioidor tramadol within 4 hours prior to enrollment, an allergy to morphineor ketamine, required pain medication immediately, pregnant orbreast-feeding, history of chronic oxygen-dependent pulmonary disease,hepatic cirrhosis, or dialysis dependent, presence of intracranial mass, ahistory of psychosis, weight less than 45 kg or greater than 115 kg, orpresence of acute ocular or head trauma.

Eligible patients, in whom opioid analgesia was anticipated, gavewritten consent immediately after triage and the blinded study protocolwas implemented: (1) if the provider prescribed opioid analgesia and(2) if the providerwas agreeable after beingmade aware of the patient'sconsent to the protocol. The trial was open to all patients regardless ofthe provider and nurse caring for the patient. All enrolled patientsgave written consent.

Once enrolled, patients were assigned a random study identificationnumber and an opaque envelope. The envelopes were prepared by theresearch teamand contained the studydrug anddose. Upon enrollment,the research nursewould obtain the assigned opaque envelope and give

it to a trained clinical nursing specialist (CNS). The CNSwould then openthe envelope containing a presigned prescription with the assignedmedication and weight-based dosing. The CNS would obtain the drugfrom the ED dispensing system in an unlabeled syringe, dilute themedication to 10mL (a 20-mL syringe was used if the body weight pre-cluded the medication from fitting into a 10-mL syringe) using normalsaline as indicated, and infuse the medication for 5 minutes. Unusedmedications were disposed of using standard nursing protocols.

An initial dose of ketamine at 0.3 mg/kg of total body weight (maxi-mumdose 25mg)was infused intravenously for 5 minutes, ormorphineat 0.1 mg/kg of total body weight (maximum dose 8 mg) was infusedintravenously for 5 minutes. Completion of the initial infusion was con-sidered time zero. A second dose could be given as early as 20 minutesafter completion of the initial dose and was the same dose as the firstdose. The protocol allowed for midazolam treatment of agitation oremergence reactions and naloxone treatment of evidence of opioidoverdose. All other medication reactions were treated at the provider'sdiscretion. If the patient requested a third dose of pain medication,data collection stopped, the provider was notified, and the patient waseligible for open-label pain medication of the providers choosing (Fig. 1).

Therewas onemajor protocol deviation. The CNS calculated thedoseof the studymedication based on the patient's weight and administeredthe weight-based dose to the patient. The resulting dose was greaterthan the maximum dose allowed by the protocol. There were noadverse events as a result of this deviation, and the deviation wasreported to our institutional review board.

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Table 2NRS pain score: raw change from baseline by treatment group

Time Morphine (95% CI) Low-dose ketamine (95% CI)

T5 −3 (−3.9, −2.1) −4.9 (−5.8, −4)T10 −3.4 (−4.4, −2.5) −4.3 (−5.5, −3.1)T20 −3.3 (−4.4, −2.2) −3.2 (−4.4, −2.1)T40 −4.5 (−5.6, −3.5) −3.7 (−5.2, −2.3)T60 −4.8 (−5.8, −3.8) −3.5 (−5.4, −1.6)T80 −4.4 (−5.9, −2.9) −3.9 (−6.1, −1.6)T100 −5 (−6.6, −3.5) −4.1 (−6.8, −1.5)T120 −5 (−7.1, −2.9) −3.6 (−6.1, −1)

T5was 5 minutes after drug administration. T120was 120 minutes after drug admin-istration and end of our observation period. Bolded texts emphasize time of maxi-mum change in NRS pain score from baseline for each group: morphine (T100) andlow-dose ketamine (T5).

404 J.P. Miller et al. / American Journal of Emergency Medicine 33 (2015) 402–408

2.4. Measures

Our primary outcomemeasurementwas themaximumchange on theverbal NRS pain scale compared with their initial score (baseline). TheNRS was used to measure a patient's subjective level of pain on a scalefrom 0 (representing no pain at all) to 10 (the worst pain imaginable)using whole numbers. This scoring system is commonly used in the EDand correlates well with the visual analog scale [20] and has been usedin clinical trials [20–24]. The NRS score was documented just prior tothe administration of the study drug (time zero). After infusion of thestudy drug was complete, NRS scores were documented at 5, 10, 20,and then every 20minutes thereafter up to 120 minutes.We stopped re-cording NRS scores prior to 120 minutes if the patient was dischargedfrom the ED, underwent procedural sedation, or requested a third doseof the study drug.

The secondary outcomes included levels of agitation or sedationmeasured by the Richmond Agitation-Sedation Scale (RASS), vitalsigns, adverse events, and the need for repeating dosing [25,26].Providers and nurses were surveyed after the patient encounter endedto rate their satisfaction with the study medication. They scored themedication as “very dissatisfied” (1), “somewhat dissatisfied” (2),“neither satisfied nor dissatisfied” (3), “somewhat satisfied” (4), or“very satisfied” (5).

All data were collected by our research nurse and stored in a locked,password encrypted, electronic database (Microsoft Excel, v14;Microsoft, Redmond, WA)

2.5. Data analysis

Power analysis determined that a sample size of at least 20 subjectsper group would achieve 80% power to detect a 2-point change in NRSscores between treatment groups, with estimated group SDs of 2 for a2-sided test with a significance level α of .05 (PASS-NCCS, 2011,Kaysville, UT). We used a repeated-measures linear model with adjust-ments for treatment group, time, and the group by time interactionwithan autoregressive covariance structure (SAS Version 9.3 for Windows;SAS Institute, Cary, NC). Differences between drug groups were testedat each time point with the Sidak method of adjustment applied formultiple testing. All analyses were performed with intention to treat.

3. Results

A total of 45 patientswere enrolled fromMarch toNovember 2012; 21in themorphine arm and 24 in the low-dose ketamine arm. Demographiccharacteristicswere similar between the 2 groups includingmean age, sex,baseline vital signs, chief complaint, and baseline NRS scores (Table 1).

Table 1Patient characteristics by treatment group

Morphine Low-doseketamine

Both treatmentgroups

Age (y), mean (SD) 29 (10) 31 (12) 30 (11)Male sex 9 (43) 14 (58) 23 (51)Vital signs, mean (SD)Systolic blood pressure (mm Hg) 121 (11) 126 (14) 124 (13)Pulse rate (BPM) 74 (11) 76 (11) 75 (11)Respiratory rate (RPM) 18 (3) 18 (3) 18 (3)Oxygen saturations (%) 98 (1) 98 (2) 98 (2)

Baseline NRS pain score, mean (SD) 7.14 (1.5) 7.13 (1.7) 7.14 (1.6)Pain locationAbdomen 15 (71) 15 (65) 30 (68)Back 4 (19) 8 (35) 12 (27)Extremity 2 (10) 0 (0) 2 (5)

All results reported as no. (%) unless otherwise indicated. BPM, beats per minutes; RPM,respirations per minutes.

The primary outcomemeasurementwas themaximum reduction inNRS score from baseline between the 2 groups (Table 2). Themaximumchange in NRS pain score, from baseline, in the low-dose ketaminegroup was 4.9 (95% confidence interval [CI], 5.8-4). The maximumchange in NRS pain score, from baseline, in the morphine group was5 (95% CI, 6.6-3.5). The maximum change in NRS pan score took placeat 5 minutes (T5) in the low-dose ketamine group and at 100 minutes(T100) in the morphine group.

We reported the NRS scores as a percentage change from baselineover time. In the morphine group, there was a steady trend of reducedpain over time. In the ketamine group, there was an initial decrease inpain scores followed by a rapid increase in pain scores within the first20 minutes. However, after the 20-minute mark, the pain decreased bygreater than 50% from baseline in the low-dose ketamine group (Fig. 2).

A seconddosewas administered in 38%of themorphine group vs 54%of the ketamine group (P= .37; Table 3). A third dose was requested for14% of the morphine arm and 25% of the ketamine arm (P= .47).

Richmond Agitation-Sedation Scale scores varied within the first20minutes after drug administration in both groups. There wasminimalvariation from baseline after T20 (Fig. 3).

Significant treatment group differences (mean, 95% CI) in systolicblood pressure (mm Hg) were observed at T5 (23, 9-38) and T10 (14,0-29; Fig. 4). No differences were found in diastolic blood pressure,heart rate, respiratory rate, or oxygen saturations (Figs. 5–8).

Fourteen patients (58%) in the low-dose ketamine group and12 (57%)patients in themorphine group described adverse effects (Table 4). Onepatient in the morphine arm had a transient oxygen desaturation to88%, which resolved after 5 minutes of oxygen via nasal cannula at4 L/min. Two patients in the morphine arm and 3 patients in theketamine arm were treated for nausea. One patient in each group

Fig. 2. Numeric rating scale pain score (mean, SD) as percent change from baseline overtime by treatment group. There were no significant differences at any time point.

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Table 3Repeat dosing of analgesia reported by treatment group

Morphine Low-dose ketamine P Total

Second dose, n (%) .37a

Yes 8 (38) 13 (54) 21 (47)No 13 (62) 11 (46) 24 (53)Total 21 24 45

Third dose, n (%) .47b

Yes 3 (14) 6 (25) 9 (20)No 18 (86) 18 (75) 36 (80)Total 21 24 45

a χ2 Test.b Fisher exact test.

Fig. 4.Mean systolic blood pressure over time with SD. Significant differences in systolicblood pressure were observed at T5 (23 mm Hg; 95% CI, 9-38) and T10 (14 mm Hg; 95%CI, 0-29).


vomited. One patient in the morphine arm was treated for pruritus.Three patients in the ketamine group experienced hallucinations. Nodissociation or emergency reactions were detected. Neither midazolamnor naloxone was given during the study.

Themedianprovider satisfaction scorewas4 (interquartile range [IQR],3-5) for the low-dose ketamine group and 4 (IQR, 4-5) for the morphinegroup (Table 5). The average nursing score was 4 (IQR, 3-5) for the low-dose ketamine group and 5 (IQR, 4-5) for the morphine group (Table 6).

4. Discussion

Low-dose ketamine was not superior to morphine in the maximumchange of NRS pain scores from baseline. However, if alternatives toopioids are going to be prescribed for acute pain in the ED, the analgesicpotential of the alternatives must be comparable to opioids. Our studydemonstrates that ketamine may have comparable analgesic effects;however, more studies are needed.

The maximum reduction in pain scores for low-dose ketamine wasseen immediately after the infusion was complete and was sustainedfor only 5 to 10 minutes. In the morphine group, a similar maximumreduction in pain scores was reached 100 minutes after the infusionwas complete. The rapid decrease in pain provided by low-dose keta-mine is an advantage compared with morphine for the treatment ofacute pain in the ED. However, the inability to sustain this degree ofpain relief over the normal course of an ED stay may require higherdoses of low-dose ketamine infused over a longer duration or the useof adjunctive medications.

The short duration of maximum analgesia likely contributed to theincreased rate of repeat dosing in the ketamine arm (54%) vs the mor-phine arm (38%), although the difference was not statistically significant.

Fig. 3. Box-and-whisker plot of RASS for morphine and low-dose ketamine over time. Thex-axis shows time after the initial infusion of medication was complete.

In the ketamine group, 25% of the patients did not complete the entire120minutes of data collection (assessmentswere stopped for inadequatepain control if the patients requested a third dose of the study drug).These 2 outcomes highlight the poor sustained maximum analgesia oflow-dose ketamine. However, as mentioned above, the safest and mosteffective dose for low-dose ketamine has yet to be established. In addi-tion, because most patients in the ketamine arm received a total of0.6 mg/kg (0.3 mg/kg × 2 separated by at least 20 minutes), a higherinitial dose infused over a longer period of time could lengthen the dura-tion of maximum analgesia. Additional prospective studies to evaluatethis approach are needed.

Despite the inability of low-dose ketamine to sustain its maximumanalgesic effect, there was greater than 50% reduction in pain scoresfor 2 hours at all intervals, after T20. As stated above, 25% of the patientsdid not complete the entire 120-minute observation period, and themajority needed a repeat dose of ketamine. However, an alternatemedication to opioids that can provide a greater than a 50% decreasein acute pain for 2 hours is valuable for clinical use.

We also collected provider and nurse satisfaction scores aftercompletion of the patient's observation period. Both drugs scored similarand well with both the providers and the nurses. The nursing group wasslightly more satisfied with morphine; however, this trend was notclinically significant. Future studies should further evaluate this trend.

In addition to the similarities in pain control between low-doseketamine and morphine, low-dose ketamine was comparable to

Fig. 5.Mean diastolic blood pressure over time with SD. There were no significant dif-ferences at any time point.

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Fig. 6. Mean pulse rate over time with SD. There were no significant differences at anytime point.

Fig. 8.Mean oxygen saturation over timewith SD. There were no significant differences atany time point.


morphine regarding adverse effects as well. We detected a similaradverse effect rate (57% vs 58%) and RASS scores in both arms. Vitalsigns were similar as well, although there were statistically significantdifferences in systolic and diastolic blood pressure between the groups.These differenceswere secondary to both decreases in blood pressure inthe morphine group and increases in blood pressure in the low-doseketamine group. These findings are established effects of these medica-tions and should be anticipated, but are of minimal clinical significance.We did observe dysphoria (4) and hallucinations (3) only in the keta-mine arm. These effects should be anticipated with low-dose ketamine.However, no episodes of dissociation or emergence reactions weredetected. We specifically did not detect more hypoxia, bradycardia, orsedation in the morphine group.

Our results are similar to prior studies that evaluated low-doseketamine alone for the treatment of pain. Hirlinger and Pfenninger [27]demonstrated a decrease in pain scores with 5 minutes of infusion in EDpatients receiving IV low-dose ketamine (0.25 or 0.5 mg/kg) for acutemusculoskeletal injuries. However, this study lacked a control arm. The0.3-mg/kg dose in the study by Persson et al [28] decreased pain scoresimmediately, with the effect starting to decrease at 20 minutes afterinfusion, which was similar to our results. In addition, the patients inthis study, although they had chronic and not acute pain, experienced agreater than 50% decrease in pain scores for 1 hour after infusion, just asin our study. Persson et al also compared low-dose ketamine tomorphineand showed a similar delayed but prolonged analgesic effect.

Fig. 7. Mean respiratory rate over time with SD. There were no significant differences atany time point.

Our study was not the first to evaluate low-dose ketamine in the ED,but it is unique [8,27,29,30]. Although other ED studies have evaluatedlow-dose ketamine as an adjunct to opioid therapy [29,30], as the soleagent without comparison[27], and in a retrospective case series[8],to our knowledge, this is the first randomized, double-blinded studyto compare low-dose ketamine to morphine for acute pain in the ED.In addition, we evaluated low-dose ketamine for the treatment ofmultiple types of pain (trauma, medical) and at multiple anatomicalsites (abdomen, back, extremity). Most studieswith low-dose ketaminein the ED and prehospital setting have evaluated its use in acute trau-matic or musculoskeletal pain [18,27,30,31]. Another unique aspect ofthis study was the use of the RASS score to capture the cognitive andbehavioral effects of the study drugs, although we saw no differencebetween groups.

4.1. Limitations

Therewere several limitations to our study. Our studywas conductedat amilitarymedical center, which has the potential to limit the general-izability of it results. However, only ≈20% of the ED patients areuniformed active military service members. Most of the patients arecivilians who have similar demographic characteristics compared withother civilian EDs at a level 1 trauma and tertiary care centers. In addi-tion, the generalizability of our results may be limited, as our data werecollected from a single medical center.

Table 4Adverse effects reported by total events

Adverse effects Morphine(n = 8)

Low-dose ketamine(n = 12)

Total

Nausea 2 3 5Dysphoria 0 4 4Hallucinations 0 3 3Dizziness 1 2 3Headache 3 0 3Drowsiness 2 0 2Vomiting 1 1 2Lightheaded 1 0 1Decreased oxygen saturation 1 0 1Numbness 0 1 1Pruritus 1 0 1Total 12 14 26

n = number of patients experiencing an adverse effect. Some patients reported multipleadverse effects.

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Table 5Provider Satisfaction Score as assessed by survey after drug administration to evaluateprovider's clinical experience with the analgesic

Satisfaction category (value) Morphine, n (%) Low-dose ketamine, n (%)

Very dissatisfied (1) 0 (0) 2 (8)Somewhat dissatisfied (2) 5 (24) 3 (13)Neither (3) 0 (0) 2 (8)Somewhat satisfied (4) 9 (43) 7 (29)Very satisfied (5) 7 (33) 10 (42)Median value (IQR) 4 (4-5) 4 (3-5)

Results are reported as number of responses and percent of group total.


Our study has a small sample size. Our study required a number ofvery specific inclusion and exclusion criteria as it was a prospectivepain study and one of the study drugs (ketamine) was otherwise usedalmost exclusively for procedural sedation. In addition, the number ofpatients who were able to complete an adequate screening and enroll-ment process while experiencingmoderate to severe acute pain furtherlimited our study population.

We calculated our sample size to detect a 2-point difference in themaximum change from baseline between the 2 groups. Detecting a2-point difference in NRS pain scores is greater thanwhat some authorshave reported as clinically significant (eg, an NRS difference of 1.3) [32].We reported a 0.1 difference in themaximumchange in NRS pain scoresbetween the 2 groups. A larger number of patientswould have providedmore precise data to allow us to determine if a larger differencebetween NRS pain scores was detectable. However, given the smalldifference between the 2 groups in our study, an argument for a similarclinical effect can be made, although our study was not powered todemonstrate this.

The analgesic dose of ketamine is not standardized.We administeredketamine at a dose of 0.3mg/kg. Several studies have reported the use of“low-dose ketamine,” but there aremany differences in the dose and themode of delivery (IM vs IV) between the studies [15–18,27,28,31,33].The studies by Hirlinger and Pfenninger [27] and Persson et al [28]provided the best data to guide our dosing. Both studies correlated IVketamine dose with plasma levels of ketamine. Hirlinger and Pfenningercompared 0.25 and 0.5 mg/kg of ketamine in trauma patients in the ED.Persson et al compared 0.15, 0.3, and 0.45mg/kg in patientswith chronicischemic pain due to lower extremity arteriosclerosis obliterans. Bothstudies cited impairment or adverse neurologic effects with the highestdose. Pain control was adequate, and these neurologic effects were notseen at the 0.25- and 0.3-mg/kg dosing. However, there are no large trialswith data to support a specific dose that maximizes analgesia and avoidsneurologic adverse effects.

Our measure of sedation and agitation has not been validated in theED. The RASS is a validated tool used in the intensive care unit setting toevaluate for both sedation and agitation and is not routinely used in theED [26]. The typical adverse effect profiles of ketamine and morphineare quite different. Ketamine can cause both sedation and psychomotoragitation, whereas morphine can cause sedation. Rather than justreporting a list of adverse reactions, we wanted our blinded research

Table 6Nurse Satisfaction Score as assessed by survey after drug administration to evaluateprovider's clinical experience with the analgesic

Satisfaction category (value) Morphine, n (%) Low-dose ketamine, n (%)

Very dissatisfied (1) 1 (5) 2 (8)Somewhat dissatisfied (2) 2 (10) 2 (8)Neither (3) 1 (5) 4 (17)Somewhat satisfied (4) 4 (20) 7 (29)Very satisfied (5) 12 (60) 9 (38)Median value (IQR) 5 (4-5) 4 (3-5)

Results are reported as number of responses and percent of group total.

nurse to have an objective scoring system that could be used to evaluateall patients, regardless of the study drug they received. In addition, thistool allowed us to quantify and provide a time course for some of themore clinically significant adverse reactions associated with thesemedications (hallucinations, altered sensorium, agitation, emergence,sedation, etc). The RASS score was the best tool that we found forcapturing the adverse effects of both drugs; however, its reliabilityand validity have not been established in the population of patientsenrolled in this study.

We did not obtain serum levels for the drug administered during ourstudy. As mentioned above, prior studies have done this [27,28]. Thesedata would have been helpful to make more specific correlations withthe study drugs and their effects on pain scores and adverse reactions.

We did not obtain long-term followup.We do not know if therewasa difference in the number of patients who returned to the ED for treat-ment of the same pain after their initial encounter. These outcomesshould be evaluated in future ED studies involving low-dose ketamineand morphine for acute pain.

Finally, we did not include patients with chronic pain. This is apatient population that frequents the ED. However, the analgesic effectsas well as adverse effects of ketamine or morphine in this populationmay be different.

5. Conclusions

In ED patients with acute, moderate-severe pain, low-dose ketaminedid not provide a superior maximum reduction in NRS pain scorescompared with morphine. However, these 2 medications produced simi-lar adverse effects, as well as provider and nurse satisfaction scores. Inaddition, low-dose ketamine induced analgesic effects within 5 minutesof infusion and provided a moderate reduction in pain for 2 hours.

Acknowledgments

We would have been unable to complete this study without thecontributions of Steve Ray, RN, CNS; Sarah Abel, RN, CNS; and LeeannZarzabal. We thank Steve Ray, RN, CNS, and Sarah Abel, RN, CNS, fortheir support of the trial and Leeann Zarzabal for statistical support.

References

[1] Todd KH, Ducharme J, Choiniere M, Crandall CS, Fosnocht DE, Homel P, et al. Pain inthe emergency department: results of the pain and emergency medicine initiative(PEMI) multicenter study. J Pain 2007;8:460–6.

[2] Cordell WH, Keene KK, Giles BK, Jones JB, Jones JH, Brizendine EJ. The high preva-lence of pain in emergency medical care. Am J Emerg Med 2002;20:165–9.

[3] Martin JS, Spirig R. Pain prevalence and patient preferences concerning painmanagement in the emergency department. Pflege 2006;19:326–34.

[4] Hansen GR. The drug-seeking patient in the emergency room. EmergMed Clin NorthAm 2005;23:349–65.

[5] Safe use of opioids in hospitals. Sentinel Event Alert 2012:1–5.[6] Hetem LA, Danion JM, Diemunsch P, Brandt C. Effect of a subanesthetic dose of

ketamine on memory and conscious awareness in healthy volunteers. Psychophar-macology 2000;152:283–8.

[7] Smith DC, Mader TJ, Smithline HA. Low dose intravenous ketamine as an analgesic: apilot study using an experimental model of acute pain. Am J Emerg Med 2001;19:531–2.

[8] Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED:a retrospective case series. Am J Emerg Med 2010;28:820–7.

[9] Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED:a retrospective case series. Am J Emerg Med 2011;29:348.

[10] Green SM, Clark R, Hostetler MA, Cohen M, Carlson D, Rothrock SG. Inadvertentketamine overdose in children: clinical manifestations and outcome. Ann EmergMed 1999;34:492–7.

[11] Ellis DY, Husain HM, Saetta JP, Walker T. Procedural sedation in paediatric minorprocedures: a prospective audit on ketamine use in the emergency department.Emerg Med J 2004;21:286–9.

[12] Green SM, Li J. Ketamine in adults: what emergency physicians need to know aboutpatient selection and emergence reactions. Acad Emerg Med 2000;7:278–81.

[13] Green SM, Rothrock SG, Lynch EL, Ho M, Harris T, Hestdalen R, et al. Intramuscularketamine for pediatric sedation in the emergency department: safety profile in1,022 cases. Ann Emerg Med 1998;31:688–97.

[14] Green SM, Sherwin TS. Incidence and severity of recovery agitation after ketaminesedation in young adults. Am J Emerg Med 2005;23:142–4.

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[15] Bovill JG, Dundee JW. Alterations in response to somatic pain associated with anaes-thesia. XX. Ketamine. Br J Anaesth 1971;43:496–9.

[16] Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine adminis-tered in subdissociative doses. Anesth Analg 1971;50:452–7.

[17] Cottingham R, Thomson K. Use of ketamine in prolonged entrapment. J Accid EmergMed 1994;11:189–91.

[18] Jennings PA, Cameron P, Bernard S, Walker T, Jolley D, Fitzgerald M, et al. Morphineand ketamine is superior to morphine alone for out-of-hospital trauma analgesia: arandomized controlled trial. Ann Emerg Med 2012;59:497–503.

[19] JohanssonP, KongstadP, JohanssonA. The effect of combined treatmentwithmorphinesulphate and low-dose ketamine in a prehospital setting. Scand J TraumaResusc EmergMed 2009;17:61.

[20] Berthier F, Potel G, Leconte P, Touze MD, Baron D. Comparative study of methods ofmeasuring acute pain intensity in an ED. Am J Emerg Med 1998;16:132–6.

[21] MohanH, Ryan J,WhelanB,Wakai A. The endof the line? TheVisual Analogue Scale andVerbal Numerical Rating Scale as pain assessment tools in the emergency department.Emerg Med J 2010;27:372–5.

[22] Chang AK, Bijur PE, Davitt M, Gallagher EJ. Randomized clinical trial comparing apatient-driven titration protocol of intravenous hydromorphone with traditionalphysician-drivenmanagement of emergency department patients with acute severepain. Ann Emerg Med 2009;54:561–567.e2.

[23] ChangAK, Bijur PE, Baccelieri A, Gallagher EJ. Efficacy and safety profile of a singledoseof hydromorphone comparedwithmorphine in older adultswith acute, severe pain: aprospective, randomized, double-blind clinical trial. Am J Geriatr Pharmacother 2009;7:1–10.

[24] Birnbaum A, Esses D, Bijur PE, Holden L, Gallagher EJ. Randomized double-blindplacebo-controlled trial of two intravenous morphine dosages (0.10 mg/kg and

0.15 mg/kg) in emergency department patients with moderate to severe acutepain. Ann Emerg Med 2007;49:445–53 [53 e1-2].

[25] Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, et al. TheRichmond Agitation-Sedation Scale: validity and reliability in adult intensive careunit patients. Am J Respir Crit Care Med 2002;166:1338–44.

[26] Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, et al.Monitoring sedation status over time in ICU patients: reliability and validityof the Richmond Agitation-Sedation Scale (RASS). JAMA 2003;289:2983–91.

[27] Hirlinger WK, Pfenninger E. Intravenous analgesia with ketamine for emergency pa-tients. Anaesthesist 1987;36:140–2.

[28] Persson J, Hasselstrom J, Wiklund B, Heller A, Svensson JO, Gustafsson LL. Theanalgesic effect of racemic ketamine in patients with chronic ischemic pain due tolower extremity arteriosclerosis obliterans. Acta Anaesthesiol Scand 1998;42:750–8.

[29] Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose keta-mine and reduced dose hydromorphone in ED patients with severe pain. Am JEmerg Med 2013;31:847–51.

[30] Galinski M, Dolveck F, Combes X, Limoges V, Smail N, Pommier V, et al. Managementof severe acute pain in emergency settings: ketamine reduces morphine consump-tion. Am J Emerg Med 2007;25:385–90.

[31] Porter K. Ketamine in prehospital care. Emerg Med J 2004;21:351–4.[32] Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating

scale of acute pain for use in the emergency department. Acad Emerg Med 2003;10:390–2.

[33] Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenousketamine in cancer patients on morphine therapy: a randomized, controlled,double-blind, crossover, double-dose study. J Pain Symptom Manag 2000;20:246–52.

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PAIN MANAGEMENT AND SEDATION/ORIGINAL RESEARCH

Intravenous Subdissociative-Dose Ketamine Versus Morphinefor Analgesia in the Emergency Department: A Randomized

Controlled TrialSergey Motov, MD*; Bradley Rockoff, MD; Victor Cohen, PharmD; Illya Pushkar, MPH; Antonios Likourezos, MA, MPH;

Courtney McKay, PharmD; Emil Soleyman-Zomalan, MD; Peter Homel, PhD; Victoria Terentiev, BA; Christian Fromm, MD

*Corresponding Author. E-mail: [email protected], Twitter: @smotovmd.

222 Ann

Study objective: We assess and compare the analgesic efficacy and safety of subdissociative intravenous-doseketamine with morphine in emergency department (ED) patients.

Methods: This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years andexperiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric ratingscale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes.Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesiaat 30 and 60 minutes.

Results: Forty-five patients per group were enrolled in the study. The primary change in mean pain scores was notsignificantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95%confidence interval�0.46 to0.77) and 4.1 versus 3.9 at 30minutes (mean difference 0.2; 95% confidence interval�1.19to 1.46; P¼.97). There was no difference in the incidence of rescue fentanyl analgesia at 30 or 60minutes. No statisticallysignificant or clinically concerning changes in vital signswere observed. No serious adverse events occurred in either group.Patients in the ketamine group reported increased minor adverse effects at 15 minutes post–drug administration.

Conclusion: Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectivenessand apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED.[Ann Emerg Med. 2015;66:222–229.]

Please see page 223 for the Editor’s Capsule Summary of this article.

A feedback survey is available with each research article published on the Web at www.annemergmed.com.A podcast for this article is available at www.annemergmed.com.

0196-0644/$-see front matterCopyright © 2015 by the American College of Emergency Physicians.http://dx.doi.org/10.1016/j.annemergmed.2015.03.004

INTRODUCTIONBackground

The provision of adequate, safe, and timely analgesia is acore component of patient care in the emergencydepartment (ED). Ketamine is a noncompetitive N-methyl-D-aspartate and glutamate receptor antagonist thatdecreases central sensitization, “wind-up” phenomena, andpain memory.1,2 As a phencyclidine-like dissociative agent,ketamine possesses a number of pharmacologiccharacteristics useful to the emergency physician. At dosescommonly used for procedural sedation (1 to 1.5 mg/kg),ketamine produces a trancelike cataleptic state, whereas atsubdissociative doses (0.1 to 0.6 mg/kg; most commonly0.3 mg/kg) it maintains potent analgesic and amnesticeffects that are accompanied by preservation of protective

als of Emergency Medicine

airway reflexes, spontaneous respiration, andcardiopulmonarystability.3-5

ImportanceIn subdissociative doses, ketamine has been shown to

confer potent, opioid-sparing effects and to be effective inproviding analgesia for pain that is poorly controlled byopioids in a variety of settings outside of the ED.6-9

Emerging data on the use of subdissociative-dose ketamineas a single agent in out-of-hospital and austere settings,where it has compared favorably to morphine, support arole for ketamine in the analgesic armamentarium ofemergency physicians. Two retrospective studiesdemonstrated that subdissociative-dose ketamine in thedosing range of 0.1 to 0.6 mg/kg, when administered as an

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http://dx.doi.org/10.1016/j.annemergmed.2015.03.004

Motov et al Ketamine Versus Morphine for Analgesia in the Emergency Department

Editor’s Capsule Summary

What is already known on this topicKetamine is a potent analgesic.

What question this study addressedIs ketamine more or less effective than morphine intreating acute pain?

What this study adds to our knowledgeIn this trial, 90 adults with acute pain wererandomized in the emergency department in double-blind fashion to receive either ketamine at 0.3 mg/kgor morphine at 0.1 mg/kg intravenously. Pain scorereductions and the proportion of patients withcomplete pain relief were statistically similar betweengroups, with reasonable power to exclude clinicallyimportant differences. There were no serious adverseevents, although ketamine subjects more frequentlyexperienced dizziness and disorientation.

How this is relevant to clinical practiceThis small but well-designed trial suggests generallysimilar analgesic equivalence between ketamine at0.3 mg/kg and morphine at 0.1 mg/kg intravenously.

adjunct to opioid analgesics, significantly reduced painreported by patients in the ED.10,11

Goals of This InvestigationIn our study, we hypothesize that a subdissociative

dose of ketamine administered as a single agent at0.3 mg/kg will provide relief similar to that of a standarddose of morphine at 0.1 mg/kg for acute moderate tosevere pain in the ED setting. The primary outcome usedto test our hypothesis is the comparative reduction inparticipants’ pain scores at 30 minutes from medicationadministration.

MATERIALS AND METHODSStudy Design

This was a prospective, randomized, double-blind trialcomparing the safety and efficacy of subdissociativeintravenous-dose ketamine with intravenous morphine foracute pain in the ED. This study was approved by theMaimonides Medical Center institutional review board andregistered with clinicaltrials.gov (NCT01835262). Thestudy was conducted and is reported according to theConsolidated Standards of Reporting Trials Group.12


Study Setting and Selection of ParticipantsThe study facility is a 711-bed community teaching

hospital with an annual ED census of more than 120,000visits. Patient screening, enrollment, and data collectionwereperformed by a study investigator (B.R., I.P., and V.T.). EDpharmacy investigators maintained the randomization list,which was generated before commencement of the study,prepared the medication, and delivered it to the nurse caringfor the study participant in a blinded manner.

A convenience sample of patients was enrolled betweenJune 2013 and May 2014. Enrollment occurred at varioustimes of the day when both a study investigator wasavailable for patient enrollment and an ED pharmacist wasavailable for medication preparation.

The study included patients aged 18 to 55 years whopresented to the ED with acute abdominal, flank, back, ormusculoskeletal pain score of 5 or more on a standard 11-point (0 to 10) numeric rating scale and required opioidanalgesia, as determined by the treating attendingphysician.13,14 Acute pain was defined as having an onsetwithin 7 days. Exclusion criteria included pregnancy,breast-feeding, altered mental status, allergy to morphine orketamine, weight less than 46 kg or greater than 115 kg,unstable vital signs (systolic blood pressure <90 or>180 mm Hg, pulse rate <50 or >150 beats/min, andrespiration rate <10 or >30 breaths/min), and medicalhistory of acute head or eye injury, seizure, intracranialhypertension, chronic pain, renal or hepatic insufficiency,alcohol or drug abuse, psychiatric illness, or recent (4 hoursbefore) opioid use.

Each patient was approached by a study investigator foracquisition of written informed consent and HealthInsurance Portability and Accountability Act authorizationafter being evaluated by the treating emergency physicianand determined to meet study eligibility criteria.

In situations in which English was not the participant’sprimary language, a staff interpreter or licensed telephoneinterpreter was used. Baseline pain score was determinedwith an 11-point numeric rating scale (0 to 10), describedto the patient as “no pain” being 0 and “the worst painimaginable” being 10. A patient was eligible for enrollmentif a baseline numeric rating scale score of 5 or greater wasreported. A study investigator then recorded the patient’sbody weight and baseline vital signs.

The on-duty ED pharmacist prepared 0.3 mg/kg ofketamine or 0.1 mg/kg of morphine in 10 mL of normalsaline solution according to the predeterminedrandomization list, which was created in SPSS (version19.0; IBM Corp, Armonk, NY) with block randomizationevery 10 participants, up to 90. The medication wasdelivered to the treating nurse in a blinded fashion and was

Annals of Emergency Medicine 223Page 23

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Ketamine Versus Morphine for Analgesia in the Emergency Department Motov et al

administered by intravenous push during 3 to 5 minutes.The preparing pharmacist, research manager, andstatistician were the only members of the team withknowledge of the study arm to which the participant wasrandomized, leaving the providers, participants, and data-collecting research team blinded to the medication received.Study investigators recorded pain scores, vital signs, andadverse effects at 15, 30, 60, 90, and 120 minutes. Ifpatients reported a pain numeric rating scale score of 5 orgreater and requested additional pain relief, fentanyl 1 m/kgwas administered as a rescue analgesic. Blinding of thepatient, research team, and clinical staff was strictlymaintained by the on-duty ED pharmacist.

All data recorded on data collection sheets, includingsex, demographics, medical history, and vital signs, wereentered into SPSS (version 19.0; IBM Corp) by theresearch manager. Development of the randomization list,confirmation of written consent acquisition for allparticipants, and statistical analyses were conducted by theresearch manager and statistician, who were independent ofany data collection.

Outcome MeasuresThe primary outcome was comparative reduction of

numeric rating scale pain scores between recipients ofketamine and morphine at 30 minutes. The secondaryoutcome was need for rescue analgesia at either 30 or 60minutes. Vital sign changes and adverse events were alsoanalyzed.

Table 1. Demographics and clinical characteristics of patients atenrollment.

Characteristics

Group

Difference (95% CI)Ketamine Morphine

No. of patients 45 45Age, mean (SD), y 35 (9.5) 36 (10.5) �1 (�5.1 to 3.3)SexFemale, No. (%) 30 (67) 28 (62) 5 (�16 to 25)Weight, mean (SD), kg 74 (15.9) 78 (16.6) �4 (�11.4 to 2.2)Blood pressure, mean (SD), mm HgSystolic 125 (18.2) 127 (16.1) �2 (�8.8 to 5.6)Diastolic 76 (13.2) 74 (12.7) 2 (�3.6 to 7.3)Pulse rate, beats/min 79 (14.8) 79 (15.0) 0 (�6.8 to 5.6)Source of pain, No. (%)Abdominal 33 (73) 31 (69) 4 (�15 to 24)Flank 7 (16) 9 (20) �4 (�21 to 12)Other* 5 (11) 5 (11) 0 (�13 to 13)

*Other pain sources include back and musculoskeletal pain.

Primary Data AnalysisData analyses included frequency distributions, paired t

test to assess a difference in pain scores within each group,and independent-sample t test to assess differences in painscores between the 2 groups at the various intervals (SPSS,version 19.0; IBM Corp). Mixed-model linear regression(SAS, version 9.1; SAS Institute, Inc., Cary, NC) was usedto compare changes in pain numeric rating scale across timepoints. This compensated for participants lost to follow-upand allowed all patients’ data to be analyzed on an intention-to-treat principle. A mean contrast test based on the mixed-model linear regression results compared the primaryoutcome difference at 30 minutes relative to time 0. The95% confidence limits for the mean difference in numericrating scale pain score for the ketamine versus morphinegroups at each time point were calculated with 2 estimatemethods for the pooled SD. One method was based on thepooled SD from the bivariate t test comparison at eachspecific time point, whereas the other method was based onthe pooled SD from the repeated-measures ANOVA. The

224 Annals of Emergency Medicine

latter method uses data at all time points and provides amore reliable estimate of the SD. For categorical outcomes(eg, complete resolution of pain), a c2 or Fisher’s exact testwas used to compare rates for categorical outcomes at 30minutes. Percentage differences and 95% confidence limitsbetween the treatment groups were calculated for all timepoints. P<.05 was used to denote statistical significance.

In accordance with the validation by Bijur et al15 of averbally administered rating scale of acute pain in the EDand the comparison by Holdgate et al16 of verbal and visualpain scales, we assumed a primary outcome consisting of aminimal clinically meaningful difference of 1.3 between theketamine and morphine groups at the 30-minute painassessment. Assuming an SD of 3.0, a power analysisdetermined that a repeated-measures ANOVA with asample size of 90 (45 in each group) provided at least 83%power to detect a difference of at least 1.3 at 30 minutes (aswell as at any other interval postbaseline), with an a¼.05.

RESULTSNinety patients (45 ketamine and 45 morphine) were

enrolled in the study. The patients’ mean age was 35 and36 years, respectively (SD¼10 for both groups); 67% and62% were women, respectively. There were no differencesbetween the groups in terms of demographic characteristicsor baseline vital signs, pain scores, or chief complaint(Table 1). The patient flow diagram is illustrated inFigure 1.

As shown in Table 2, patients’ reported pain scores attime 0 were similar in the 2 groups: the mean difference inpain numeric rating scale score for ketamine versusmorphine was 0.1 (95% confidence interval [CI] –0.46to 0.77). Participants received an average dose of either


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130 PatientsApproached

40 PatientsRefused

53%: Requested morphine only34%: Refused to participate in a study10%: Undisclosed Reasons3%: Requested ketamine only

90 PatientsEnrolled

45 RandomizedTo Ketamine

45 RandomizedTo Morphine

45 Available None Excluded

45 Available

43 Available

43 Available

41 Available

45 Available

45 Available

43 Available

43 Available

42 Available

None Excluded

None Excluded

None Excluded

2 lost on follow-up*






Patients available foranalysis at 15 minutes

Patients available forPrimary analysis at

30 minutes

Patients available foradditional analysis at

60 minutes


90 minutes


120 minutes

Figure 1. Participant flow diagram. *Patients were lost to follow-up because of either discharge or transfer from the ED.


21.8 mg (SD¼4.9) of ketamine or 7.7 mg (SD¼1.6) ofmorphine. All patients showed significant reductions inmean pain numeric rating scale score at 15 and 30 minutescompared with baseline. However, there were nostatistically significant differences between the 2 groups ateither point. At 15 minutes, the mean difference in painnumeric rating scale score was –1.0 (95% CI –2.40 to0.31). At 30 minutes, the primary outcome comparison,the mean difference, was 0.2 (95% CI –1.19 to 1.46;P¼.97). The 95% CI for the mean difference at 30minutes according to the mixed-model regression SD was–0.77 to 1.05. The parallel line plots (Figure 2) presentingthe changes in pain numeric rating scale score for eachgroup from baseline to 30 minutes show almost the samepattern of decrease, with the exception of 1 patient in theketamine group who showed an increase from 9 to 10. Thebox plots of the difference likewise show a similar pattern ofcentral tendency and dispersion. As shown in Figure 3,comparison of the pain scores over all time pointsdemonstrates similar mean pain numeric rating scale scoresin the 2 study groups.

At 15 minutes, more patients reported completeresolution of pain (numeric rating scale¼0) in the ketaminegroup (percentage difference¼31%; 95% CI 13% to49%). However, this difference was no longer present at 30minutes (percentage difference¼3%; 95% CI –16% to


21%). All of the patients who reported complete resolutionof pain did so with the analgesic benefit of the studymedication and without the use of a rescue analgesic doseof fentanyl during these measurement intervals. There wereno statistically significant differences between the groups inthe proportion of patients reporting a 3-point or morereduction in pain numeric rating scale score. There was alsono significant difference between the 2 groups with respectto use of rescue fentanyl analgesia at 30 minutes(percentage difference¼7%; 95% CI –3% to 16%) or at 60minutes (percentage difference¼–5%; 95% CI –18% to9%). At 120 minutes, the ketamine group requiredsignificantly more rescue fentanyl (percentagedifference¼17%; 95% CI 1% to 34%) (Table2).

No serious or life-threatening adverse events occurred ineither medication group; these included, but were notlimited to, respiratory distress, seizures, and cardiac arrest.There were no changes in vital signs that were clinicallyconcerning or required intervention (Table E1, availableonline at http://www.annemergmed.com). All adverseeffects were transient and did not require treatment.

A statistically significant difference was observed in thenumber of ketamine patients who reported any adverseeffects immediately after the medication injection and at15 minutes (percentage difference¼38%; 95% CI 18% to57%). This difference in adverse effects diminished to



Table 2. Pain trends.

TimeInterval*

Group


Pain NRS, mean (SD)Baseline 8.6 (1.5) 8.5 (1.5) 0.1 (�0.46 to 0.77)15 3.2 (3.5) 4.2 (2.9) �1.0 (�2.40 to 0.31)30 4.1 (3.2) 3.9 (3.1) 0.2 (�1.19 to 1.46)†

60 4.8 (3.2) 3.4 (3.0) 1.4 (0.13 to 2.75)90 4.8 (3.1) 3.9 (3.1) 0.9 (�0.37 to 2.28)120 3.9 (2.9) 3.7 (2.9) 0.2 (�1.09 to 1.46)Complete resolution of pain,No. (%)

15 20 (44) 6 (13) 31 (13.1 to 49.2)30 12 (27) 11 (24) 3 (�16.3 to 20.7)60 9 (21) 12 (27) �6 (�25.6 to 11.6)90 7 (16) 9 (21) �5 (�21.5 to 12.2)120 9 (22) 9 (21) 1 (�17.7 to 18.8)Reduction of 3D NRS,No. (%)

15 34 (75) 31 (69) 6 (�12.3 to 25.6)30 33 (73) 31 (69) 4 (�14.7 to 23.6)60 25 (58) 33 (77) �19 (�38.5 to 1.3)90 23 (54) 33 (77) �23 (�43.3 to –3.2)120 29 (71) 33 (79) �8 (�27.0 to 11.3)Fentanyl rescue incidence,No. (%)

15 0 0 030 4 (9) 1 (2) 7 (�2.9 to 16.3)60 4 (9) 6 (14) �5 (�18.1 to 9.0)90 5 (11) 5 (12) �1 (�13.1 to 14.1)120 12 (29) 5 (12) 17 (0.8 to 34.2)

NRS, Numeric rating scale.*Minutes from time of medication injection.†95% CI –0.77 to 1.05 is based on the SD from the mixed-model regression.


equivalence with morphine at the 30-minute interval(Table 3). The most common adverse effects reported byketamine patients were dizziness, disorientation, moodchanges, and nausea. Dizziness and nausea were alsoreported by morphine patients.

LIMITATIONSThis was a single-center study in which patients were

enrolled as a convenience sample according topredetermined inclusion and exclusion criteria. Sample sizewas near minimum for adequate power (80%). There was apotential for unblinding because some participantsexhibited ketamine-specific reactions such as nystagmus.Patient enrollment was restricted to time frames in whichboth a member of the research team and pharmacy teamwere available.

DISCUSSIONSubdissociative ketamine has been shown to mitigate

pain and reduce opioid consumption in patients withchronic pain (neuropathic pain), cancer pain, and acute


postoperative pain, as demonstrated in the anesthesia andsurgical literature.17-20 There have been several publishedretrospective studies and prospective trials examiningketamine used for analgesia in ED patients. Lester et al10

evaluated 35 patients who received subdissociativeketamine for analgesia and reported that 19 patients (54%)experienced pain relief after opioid analgesics had failed.Richards and Rockford11 evaluated 24 patients whoreceived subdissociative ketamine and reported an overallreduction in pain score of 5 points (8.9 [SD¼2.1] to 3.9[SD¼3.4]); however, 18 patients (75%) had receivedopioid analgesics before ketamine. In addition, 55% ofpatients reported satisfaction with subdissociative ketamineanalgesia and 67% stated that they would choose ketamineanalgesia again.11 Neither study reported significant adverseeffects in the ketamine recipients. Several prospectiverandomized trials examined the analgesic effect ofsubdissociative ketamine and morphine combination onpatients with traumatic and nontraumatic pain. An out-of-hospital study by Johansson et al21 demonstrated statisticalimprovement in pain reduction by 4.4 points with the useof morphine-ketamine combination in comparison to 3.1points with morphine alone. The 3-arm trial by Beaudoinet al22 that evaluated 2 different doses of subdissociativeketamine-morphine combinations compared withmorphine alone for ED analgesia showed a clinicallysignificant decrease in pain intensity for more than 50% ofpatients who received morphine (0.1 mg/kg) and ketamine(0.15 or 0.3 mg/kg) combination compared with themorphine-only group. In addition, the authors concludedthat morphine combined with ketamine at a dose of0.3 mg/kg had more efficacious analgesic effect than acombination using a ketamine dose of 0.15 mg/kg.22 Last,Miller et al23 conducted the first randomized controlledsuperiority trial directly comparing subdissociativeketamine to morphine for acute pain in the ED. The resultsshowed that ketamine administered at a dose of 0.3 mg/kgketamine did not provide a superior maximum reduction innumeric rating scale pain scores compared with morphineat 0.1 mg/kg.

In our prospective, randomized, double-blind trial, wecompared single subdissociative-dose ketamine with single-dose morphine for ED patients experiencing acute severepain. Our study suggests that subdissociative ketamine is aseffective as morphine in relieving pain at 15 and 30 minutes.The subdissociative ketamine group had a larger proportionof patients who reported complete resolution of pain(numeric rating scale score¼0), without the use of analgesicfentanyl rescue, at 15 minutes (44% versus 13%); however,there was no difference between the groups in painresolution or change in pain scores at 30 minutes. There was


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Figure 2. Parallel line and box plots of pain scores: baseline versus 30 minutes. The parallel line plots contrast the change in eachpatient’s pain numeric rating scale score from baseline to 30 minutes in the ketamine versus the morphine group, whereas the boxplots show the overall group changes in pain numeric rating scale score between the ketamine and morphine groups.

Table 3. Adverse effects.

Time Interval

Group*


Report of any adverse effectPostinjection 33 (73) 23 (51) 22 (2.2 to 42.2)


also no difference in the proportion of patients who reporteda 3-point or more reduction in pain numeric rating scalescore at either interval. These findings suggest thatsubdissociative ketamine is as effective as morphine in thereduction of acute pain within 15minutes of administration.

No participants in either group experienced clinicallyconcerning adverse events or changes in vital signs.However,the subdissociative ketamine recipients did experience astatistically significant increase in adverse effects immediately

Figure 3. Reported pain numeric rating scale score with 95%CI bars.


postinjection and at the 15-minute interval, with highpercentages of participants experiencing dizziness anddisorientation compared with the morphine recipients

15 min 31 (69) 14 (31) 38 (18.2 to 57.4)30 min 16 (36) 15 (33) 3 (�17.9 to 22.3)Most common adverse effectsDizzinessPostinjection 24 (53) 14 (31) 22 (1.8 to 42.6)15 min 19 (42) 9 (20) 22 (3.2 to 41.3)30 min 8 (18) 6 (13) 5 (�10.9 to 19.8)DisorientationPostinjection 13(29) 1 (2) 27 (12.4 to 40.9)15 min 5 (11) 0 11 (1.7 to 20.5)30 min 1 (2) 0 2 (�2.2 to 6.6)Mood changesPostinjection 6 (13) 1 (2) 11 (0 to 22.2)15 min 5 (11) 0 11 (1.7 to 20.5)30 min 1 (2) 0 2 (�2.2 to 6.6)NauseaPostinjection 4 (9) 4 (9) 0 (�12.1 to 12.1)15 min 8 (18) 5 (11) 7 (�8.2 to 21.5)30 min 6 (13) 9 (20) �7 (�22.4 to 9.1)

*Data are presented as No. (%).



(Table 3). These findings are consistent with those ofprevious trials of ketamine and opioid combinationregimens. Ahern et al24 found that 24 of 30 out-of-hospitalpatients (80%) receiving an intravenous combination ofhydromorphone (0.5mg) and ketamine (15mg) experiencedan adverse effect, with dizziness being the most common.These results were observed again in the study by Beaudoinet al,22 in which 9 of 20 (45%) of the morphine (0.1 mg/kg)and ketamine (0.3mg/kg) group reported lightheadedness ordizziness. We believe further investigation of ketamine doseranges and duration of infusion will help to diminish theadverse effects experienced by patients while maintaininganalgesic efficacy similar to that of morphine.

Subdissociative-dose intravenous ketamine administeredat 0.3 mg/kg provides analgesic effectiveness and apparentsafety comparable to that of intravenous morphine forshort-term treatment of acute moderate to severe pain inthe ED.

The authors acknowledge John Marshall, MD, for hissupport and guidance; Cierra Treu, PharmD, Anil Jacob,PharmD, and Erica Colgan, PharmD, for medicationadministration to study patients; and Tamar Motov, RN, andNicolette Tedeschi, RN, for assistance with patient screeningand enrollment.

Supervising editor: Steven M. Green, MD

Author affiliations: From the Department of Emergency Medicine(Motov, Rockoff, Pushkar, Likourezos, Soleyman-Zomalan,Terentiev, Fromm), the Department of Pharmacy (Cohen, McKay),and the Office of Research Administration (Homel), MaimonidesMedical Center, Brooklyn, NY; the Long Island University School ofPharmacy, Brooklyn, NY (Cohen); and the Department of Medicine,Albert Einstein College of Medicine, Bronx, NY (Homel).

Author contributions: SM, VC, IP, AL, ES-Z, and CF conceived thestudy, designed the trial, and obtained research funding. SM, BR,AL, and CF supervised the conduct of the trial and data collection.BR, IP, CM, and VT undertook recruitment of patients andmanaged the data, including quality control. AL and PH providedstatistical advice on study design and data analysis. BR drafted thearticle, and all authors contributed substantially to its revision. SMtakes responsibility for the paper as a whole.

Funding and support: By Annals policy, all authors are required todisclose any and all commercial, financial, and other relationshipsin any way related to the subject of this article as per ICMJE conflictof interest guidelines (see www.icmje.org). The authors have statedthat no such relationships exist and provided the following details:This research was funded, in part, by an unrestricted grant fromthe New York Department of Health’s Empire Clinical ResearchInvestigator Program.

Publication dates: Received for publication October 24, 2014.Revision received February 20, 2015. Accepted for publicationMarch 3, 2015. Available online March 26, 2015.


Presented at the New York American College of EmergencyPhysicians conference, July 2014, Bolton Landing, NY; the Societyfor Academic Emergency Medicine national conference, May 2014,Dallas, TX; and the Society for Academic Emergency Medicine Mid-Atlantic regional conference, February 2014, Philadelphia, PA.

REFERENCES1. Guirimand FM, Dupont XM, Brasseur LM, et al. The effects of ketamine

on the temporal summation (wind-up) of the RIII nociceptive flexionreflex and pain in humans. Anesth Analg. 2000;90:408-414.

2. Schmid R, Sandler A, Katz J. Use and efficacy of low-dose ketamine inthe management of acute postoperative pain: a review of currenttechniques and outcomes. Pain. 1999;82:111-125.

3. Galinski MM, Dolveck FM, Combes XM, et al. Management of severeacute pain in emergency settings: ketamine reduces morphineconsumption. Am J Emerg Med. 2007;25:385-390.

4. Strigo I, Duncan G, Bushnell C, et al. The effects of racemic ketamineon painful stimulation of skin and viscera in human subjects. Pain.2005;113:255-264.

5. Smith D, Mader T, Smithline H. Low dose intravenous ketamine as ananalgesic: a pilot study using an experimental model of acute pain. AmJ Emerg Med. 2001;19:531-532.

6. Jennings PP, Cameron PM, Bernard SM, et al. Morphine and ketamineis superior to morphine alone for out-of-hospital trauma analgesia: arandomized controlled trial. Ann Emerg Med. 2012;59:497-503.

7. Mitchell A, Fallon M. A single infusion of intravenous ketamineimproves pain relief in patients with critical limb ischaemia: results of adouble blind randomised controlled trial. Pain. 2002;97:275-281.

8. Aida SM, Yamakura TM, Baba HM, et al. Preemptive analgesia byintravenous low-dose ketamine and epidural morphine in gastrectomy:a randomized double-blind study. Anesthesiology.2000;92:1624-1630.

9. Sadove MM, Shulman MM, Hatano SM, et al. Analgesic effects ofketamine administered in subdissociative doses. Anesth Analg.1971;50:452-457.

10. Lester LM, Braude DM, Niles CM, et al. Low-dose ketamine foranalgesia in the ED: a retrospective case series. Am J Emerg Med.2010;28:820-827.

11. Richards JM, Rockford RM. Low-dose ketamine analgesia: patient andphysician experience in the ED. Am J Emerg Med. 2013;31:390-394.

12. Schulz KF, Altman DG, Moher D; for the CONSORT Group. CONSORT2010 statement: updated guidelines for reporting parallel grouprandomised trials. Trials. 2010;11:32.

13. Serlin R, Mendoza T, Nakamura Y, et al. When is cancer pain mild,moderate or severe? grading pain severity by its interference withfunction. Pain. 1995;61:277-284.

14. Li K, Harris B, Hadi S, et al. What should be the optimal cut points formild, moderate, and severe pain? J Palliat Med. 2007;10:1338-1346.

15. Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administerednumerical rating scale of acute pain for use in the emergencydepartment. Acad Emerg Med. 2003;10:390-392.

16. Holdgate A, Asha S, Craig J, et al. Comparison of a verbal numericrating scale with the visual analogue scale for the measurement ofacute pain. Emerg Med Australas. 2003;15:441-446.

17. Urban M, Ya Deau J, Wukovits B, et al. Ketamine as an adjunct topostoperative pain management in opioid tolerant patients after spinalfusions: a prospective randomized trial. HSS J. 2007;4:62-65.

18. Jouguelet-Lacoste J, La Colla L, Schilling D, et al. The use ofintravenous infusion or single dose of low-dose ketamine forpostoperative analgesia: a review of the current literature. Pain Med.2015;16:383-403.

19. Finkel J, Pestieau S, Quezado Z. Ketamine as an adjuvant fortreatment of cancer pain in children and adolescents. J Pain.2007;8:515-521.


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20. Schwartzman R, Alexander G, Grothusen J. The use of ketamine incomplex regional pain syndrome: possible mechanisms. Expert RevNeurother. 2011;11:719-734.

21. Johansson P, Kongstad P, Johansson A. The effect of combinedtreatment with morphine sulphate and low-dose ketamine in aprehospital setting. Scand J Trauma Resusc Emerg Med. 2009;17:1-5.

22. Beaudoin F, Lin C, Guan W, et al. Low-dose ketamine improves painrelief in patients receiving intravenous opioids for acute pain in the

Images in Emerg

The Annals Web site (www.annemerghundreds of emergency medicine-re

discussion and diagnosis, in 18 categoriand test your diagnostic skill toda

Neurology/Neuros

“Long-Term Survival Following CompTransection” by Gautschi and Zellweger, Ap


emergency department: results of a randomized, double-blind, clinicaltrail. Soc Acad Emerg Med. 2014;21:1193-1202.

23. Miller J, Schauer S, Ganem V, et al. Low-dose ketamine vs morphinefor acute pain in the ED: a randomized controlled trial. Am J EmergMed. 2015;33:402-408.

24. Ahern T, Herring A, Stone M, et al. Effective analgesia with low-doseketamine and reduced dose hydromorphone in ED patients withsevere pain. Am J Emerg Med. 2013;31:847-851.

ency Medicine

med.com) contains a collection oflated images, complete with briefes. Go to the Images pull-down menuy. Below is a selection from theurgery Images.

lete Medulla/Cervical Spinal Cordril 2007, Volume 49, #1, pp. 540, 545.



















PEDIATRICS/ORIGINAL RESEARCH

The Efficacy of Ketamine in Pediatric Emergency DepartmentPatients Who Present With Acute Severe Asthma

Joseph Y. Allen, MD, FAAP

Charles G. Macias, MD, FAAP

From the Department of Pediatrics, Section of Emergency Medicine, Baylor College ofMedicine, Houston, TX.

Study objective:We determine whether a continuous infusion of ketamine can decrease the severity ofa moderately severe acute asthma exacerbation by a clinically significant 2 points using a 15-pointPulmonary Index scoring scale.

Methods: A double-blinded, randomized, placebo-controlled trial was performed to evaluate patientsaged 2 to 18 years who presented to a pediatric emergency department with an acute asthmaexacerbation. Exclusion criteria included temperature greater than 39�C (102�F), focal infiltrate onradiograph, or any glucocorticoid use in the last 72 hours. Eligible patients received 3 treatments withalbuterol, ipratropium bromide, and a dose of oral or parenteral glucocorticoids. If the Pulmonary Indexscore remained 8 to 14, enrollment proceeded. All enrolled patients received continuous nebulizedalbuterol at 10 mg/hour and were randomized to receive an intravenous bolus of 0.2 mg/kg ofketamine, followed by a 2-hour ketamine infusion at 0.5 mg/kg per hour or an equal-volume regimenwith normal-saline placebo. A Pulmonary Index score was performed on patients at 0, 30, 60, 90, and120 minutes.

Results: Sixty-eight patients were enrolled, with 33 randomized to the ketamine infusion and 35randomized to placebo. Mean ages of patients enrolled, chronic severity of asthma, and duration ofsymptoms before presentation were similar between groups. At enrollment, the mean Pulmonary Indexscore in the placebo group was 10.3G1.1 versus 10.5G1.5 for the ketamine group (difference ofmeans 0.2; 95% confidence interval [CI] �0.5 to 0.8). Sixty-two patients completed the entire 2-hourinfusion protocol. No significant difference between groups was seen in rate of improvement in thePulmonary Index score at completion. The mean decrease in the Pulmonary Index scores at the end ofthe infusion was 3.6G1.3 in the placebo group versus 3.2G2.0 in the ketamine group (difference ofmeans 0.4; 95% CI �0.4 to 1.3). No short-term adverse effects necessitating discontinuation of theinfusion or adverse behavioral impacts at 48 hours after discharge were noted.

Conclusion: We conclude that ketamine given at 0.2 mg/kg followed by an infusion of 0.5 mg/kg perhour for 2 hours provided no incremental benefit to standard therapy in this cohort of children with amoderately severe asthma exacerbation. [Ann Emerg Med. 2005;46:43-50.]

0196-0644/$-see front matterCopyright ª 2005 by the American College of Emergency Physicians.doi:10.1016/j.annemergmed.2005.02.024


Asthma is one of the most common chronic childhoodillnesses, affecting 10% of children in the United States.1 Itsmorbidity and mortality have increased during the last 20 years,and hospitalization rates have doubled for children 1 to 4 yearsold.1 During this same period, the absolute number ofemergency department visits for asthma has increased by 36%,resulting in more than 600,000 visits per year to emergencydepartments (EDs) by children younger 14 years.2

Children with an acute asthma exacerbation benefit frominhaled albuterol or ipratropium bromide for bronchodilation.3

Volume 46, no. 1 : July 2005

Oral or parenteral glucocorticoids at a dose of 1 to 2 mg/kgaddress the inflammatory component and can further reduceadmission rates.4-6 Adjunct medicines that have been investi-gated to reduce bronchoconstriction in children with a severeexacerbation include nebulized dexamethasone,7 intravenousterbutaline,8 and intravenous magnesium sulfate.9,10

Occasionally, a severe asthma exacerbation can progress torespiratory failure, necessitating mechanical ventilation. Forthese patients, additional bronchodilation can be obtained byusing the dissociative anesthetic ketamine for induction. Inanimal models, ketamine has been shown to inducebronchodilation by several mechanisms: preventing the reuptake


Ketamine for Pediatric Patients With Asthma Allen & Macias


What is already known on this topic

Asthma is a common chronic childhood illness, resultingin more than 600,000 emergency department (ED) visitsper year for children younger than 14 years.

What question this study addressed

Using a 15-point Pulmonary Index scoring scale tomeasure improvement, what is the efficacy of ketamineas an addition to standard therapy for pediatric patientswho present to the ED with a moderately severe asthmaexacerbation?

What this study adds to our knowledge

Thirty-three patients were randomized to ketamine and35 to placebo. The 2 groups had similar improvement inPulmonary Index during the study period. Therefore,ketamine, as provided in this study, did not produce anyclinically important improvement beyond standardtherapy.

How this might change clinical practice

This study provides fairly compelling evidence againstthe use of this strategy of ketamine administration forasthma unresolved by initial treatment with standardtherapy. Study of alternative dosing strategies forketamine for pediatric patients with asthma may still bewarranted.

of circulating catecholamines to increase bronchodilation,11

blocking calcium influx,12 and directly relaxing smooth muscleby reducing vagally mediated bronchoconstriction.13

ImportanceThe reported efficacy of a ketamine infusion in children has

been previously limited to case reports. In 1971, Betts andParkin14 first reported ketamine being used successfully forbronchodilation of a child with an asthma exacerbation. Huberet al reported measurable bronchodilation in intubated patientsusing a loading dose of 0.1 mg/lb.11 Sarma later reportedavoiding intubation in 2 adults using a ketamine infusion of0.15 mg/kg per hour,12 whereas Nehama et al15 reportedsuccessful bronchodilation of an intubated infant at a rate of 0.2mg/kg per hour. The range of published successful dosingstrategies of ketamine infusions, as well as the patient cohortswho received it, has varied significantly.16-19

One randomized trial by Howton et al20 evaluated ketaminein patients with an acute asthma exacerbation; however, noadditional measurable bronchodilation was noted when it wasadded to standard therapy. Several limitations of the study makeit difficult to generalize these results to the pediatric population.The study did not include pediatric patients. Second, theloading dose had to be reduced from 0.2 to 0.1 mg/kg because


of dysphoria observed in the first patients who received it.Finally, the scoring scale used required peak flow measurementsas markers of improvement, which can be difficult for youngchildren to perform.

Goals of This InvestigationWe sought to determine whether an intravenous bolus of

ketamine at 0.2 mg/kg, followed by a continuous 2-hourparenteral infusion of ketamine at 0.5 mg/kg per hour, added tostandard therapy for pediatric patients 2 to 18 years of age whopresented to an ED with a moderately severe asthma exacer-bation could improve symptoms as measured by a previouslyvalidated asthma scoring scale.


This study was a randomized, double-blinded, placebo-controlled trial. Written, informed consent was obtained fromall patients’ parents or guardians, as well as assent from allpatients older than 12 years before enrollment in the study. Thestudy was approved by the Baylor College of Medicineinstitutional review board for April 2002 until April 2004.Additional approval was required and obtained from the TexasChildren’s Hospital Sedation Oversight Committee about theuse of ketamine for nonsedation purposes.

Setting and Selection of PatientsEnrollment occurred at a freestanding, urban, tertiary-care,

children’s hospital ED from November 2002 through March2004. Patients aged 2 to 18 years who were triaged as having anacute episode of wheezing were evaluated by a nurse, arespiratory therapist, and a physician (resident, pediatricemergency medicine fellow, or attending physician). Theinstitution uses a reactive airways disease protocol for up to 3treatments with nebulized albuterol (2.5 mg/dose, with up to 3nebulized treatments of ipratropium bromide 500 mg/dose).Alternatively, an equivalent 6-puff dose of albuterol (90 mg/puff) by a metered-dose inhaler with a spacer with an equivalent2-puff dose (18 mg/dose) of ipratropium bromide may be usedin the same protocol. During this time, patients also received a 2mg/kg dose of prednisone or intravenous methylprednisolone(maximum 80 mg). During the study period, there was anationwide shortage of methylprednisolone. Our institutionutilized intravenous dexamethasone 0.4 mg/kg (maximum15 mg) as the equivalent of methylprednisolone. After 3treatments, physicians reevaluated the need for additional therapy.

Once the patients received 3 treatments with albuterol,ipratropium bromide, and their dose of oral or parenteralglucocorticoids, the primary investigator used a previouslyvalidated 15-point scoring scale called the Pulmonary Index21 toevaluate and score the severity of their asthma exacerbation(Table 1). Previous literature identified scores of 8 or greater asmoderate to moderately severe exacerbations.9 If the patientsscored from 8 to 14, then enrollment would proceed. Toeliminate interobserver variability, only the primary investigator

Volume 46, no. 1 : July 2005Page 31

Allen & Macias Ketamine for Pediatric Patients With Asthma

Table 1. Pulmonary Index.

Respiratory Rate (Breaths/Min)Inspiratory/

Expiratory Ratio

Accessory

Muscle Use

Oxygen

SaturationScore \6 y O6 y Wheezing

0 \30 \20 None 2:1 None 99%–100%1 31-45 21-35 End expiration 1:1 C 96%–98%2 46-60 36-50 Entire expiration 1:2 CC 93%–95%3 O60 O50 Entire breath (none) 1:3 CCC \93%

evaluated and enrolled patients. Treating physicians or respira-tory therapists would attempt to notify the investigator when apatient appeared to require continuous nebulization therapywith albuterol. Enrollment occurred primarily between 7 AM

and 11 PM when the primary investigator was available, as wellas from 11 PM to 7 AM if the primary investigator was present.

To precisely determine the effect the ketamine infusionwould have on reducing acute asthma severity, strict exclusioncriteria were established to minimize effects of potentialconfounders. Patients with temperature greater than 39�C(102�F) or a focal infiltrate on chest radiograph were excluded.Any use of oral, parenteral, or inhaled glucocorticoids withinthe previous 72 hours precluded enrollment. Patients with ahistory of prematurity, bronchopulmonary dysplasia, coexistingprimary parenchymal pulmonary disease (such as cystic fibrosis)or coexisting congenital heart diseases, known hypertension,psychotic disorders, pregnancy, and allergy to ketamine werealso excluded.

InterventionsAll enrolled patients received nebulized albuterol at 10 mg/

hour delivered by an aerosol facemask using 100% oxygen at 8L/min. Using a predetermined randomization list generatedfrom coin flips by the institutional pharmacy, the patients werethen allocated to receive either a 0.2 mg/kg bolus of intravenousketamine during 1 to 2 minutes, followed by a 0.5 mg/kg perhour continuous infusion of ketamine for 2 hours, or anequivalent volume of normal-saline placebo as determined bythis pregenerated list. The infusion and bolus were delivered insyringes labeled only with the patient’s name and rate ofinfusion, and their contents were blinded to the nurse, treatingphysician, investigator, and patient. The patients were observedin the ED during the entire infusion. Additional treatmentmedications such as ipratropium bromide, magnesium sulfate,and terbutaline were withheld during the 2-hour infusion. APulmonary Index score, as well as pulse rate, blood pressure, andoral or axillary temperature, was recorded at 0, 30, 60, 90, and120 minutes by the primary investigator. Continuous pulseoximetry, cardiac monitoring, and blood pressure monitoringwere performed during the entire infusion. Data describingpatient characteristics, including age, race, sex, episodes ofprevious ED visits or inpatient stays for asthma, ICUadmissions, the presence of family history of asthma, andduration of symptoms before presentation, were collected onstandardized data-collection forms.


Enrolled patients could be removed from the study beforecompletion of the infusion if their status deteriorated andrequired more aggressive therapy, as determined by theattending physician. The attending physician could also removethe patient if further continuous albuterol therapy was notwarranted because of clinical improvement. They could also beremoved from the study if adverse effects became intolerable orif the parents wished the study to be discontinued. A finalPulmonary Index score was given at withdrawal, and the reasonfor withdrawal was recorded.

After the infusion was completed, clinical management wasleft to the discretion of the attending physician. The patient’sdisposition and triage severity of inpatient care setting (whenapplicable) were tracked. The primary investigator also recordeda guess as to whether the patients received ketamine based ontheir behaviors during the infusion to assess the impactpsychological effects manifested during the infusion had onblinding. Attempts were made to reach all patients by telephonewithin 48 hours of discharge using a standardized form thatinquired about their clinical status and recorded the number ofrevisits to their primary care provider or ED.

Primary Data AnalysisThe primary outcome to be assessed was clinical improve-

ment as measured by a clinically significant reduction of thePulmonary Index score by 2 points, as previously reported byScarfone et al.9 In this population of patients with a similardegree of illness at presentation, the SD of the difference was1.97 points. Setting an a of 0.05 and a power of 80% (b=0.20)resulted in the need to enroll 17 patients per group, for a total of34 patients who would complete the protocol. We anticipatedthat 35% to 50% of patients enrolled would not finish theentire 2-hour ketamine infusion. To insure adequate power, wedoubled the sample-size enrollment requirements of 68 patientstotal. Additionally, the increased sample size allowed thedetection of a reduced ketamine effect size or a larger SD.Student’s t tests were used to compare continuous variablesbetween the 2 groups. Repeated measures of analysis of variancewere used to assess the effect of time, group allocation, and theinteraction between the groups. For patients who did not haveall data points available, the last value was brought forward tothe missing time points for analysis in an intent-to-treat fashion.c2 Analysis was performed on categoric variables betweengroups. At the completion of enrollment, an analysis ofcovariance was performed to examine the interaction of



Table 2. Patient characteristics.

Variable

Placebo

(N=35)

Ketamine

(N=33)

Difference in Means

or Proportions

95% CI for

Difference

Mean age (y) 6.5 (G3.8) 5.7 (G4.3) 0.8 �1.2 to 2.7Sex, male (%) 20 (57) 21 (64) 7 �14 to 28Ethnicity, No. (%)

Black 15 (42.9%) 14 (42.4%) 0.5% �19% to 21%Hispanic/Latino 16 (45.7%) 13 (39.4%) 6.7% �15% to 29%White 3 (8.6%) 3 (9.1%) 0.5% �13% to 14%Asian 1 (2.9%) 2 (6.1%) 3.2% �10% to 16%Other 0 1 (3.0%) 3.0% �8% to 14%

patient weight and the efficacy of ketamine in bronchodilation.Analyses were performed on Minitab 11.12 (State College, PA),and Statistical Package for the Social Sciences (SPSS, Inc.,Chicago, IL), version 12.0.

RESULTSThe patient-tracking database used in the ED retrospectively

identified 694 patients aged 2 to 18 years during the enrollmentperiod who were noted to have the diagnosis of reactive airwaysdisease, wheezing, or status asthmaticus and who were admittedto the hospital from the ED. Of these, 135 patients were listedwith a primary or secondary diagnosis of status asthmaticus. Aconvenience sample of 72 patients who met inclusion criteriawas approached for enrollment, with 68 patients consenting toparticipate. Mean time from administration of glucocorticoidsto starting the ketamine infusion was 30 minutes. There were35 patients in the placebo group and 33 patients in theketamine infusion group. The mean age for the study cohortwas 6.1G4.0 years, with 60% of enrolled being malepatients (Figure E1, available at http://www.mosby.com/AnnEmergMed). The intervention and placebo groups weresimilar with respect to age, sex, and ethnicity, as shown inTable 2. Chronic severity of disease as measured by reported EDvisits or in admissions within the past year because of asthmaexacerbations, a reported family history of asthma or atopy, andin classification of chronic asthma severity using published


guidelines22 were similar between groups as well. Finally,duration of illness between groups before presentation wassimilar to ensure that neither was potentially more catechol-amine depleted. The mean Pulmonary Index scores of the 2groups were similar at enrollment (10.3G1.1 in the placebogroup and 10.5G1.5 in the ketamine group; a difference ofmeans was 0.2; 95% confidence interval [CI] �0.5 to 0.8).These results are summarized in Table 3.

Patient tracking is shown in Figure 1. Five patients werewithdrawn after the 90-minute Pulmonary Index score, and1 was withdrawn after the 60-minute Pulmonary Index scorewas taken, resulting in 62 patients who completed the infusion.There was no difference in the mean Pulmonary Index score atany interval, nor was there any significant difference in the meandecrease in the Pulmonary Index score during the 2-hour periodbetween the intervention and control groups. Figure 2 graph-ically shows the mean Pulmonary Index scores for each group at0, 30, 60, 90, and 120 minutes. At time 120, the PulmonaryIndex scores decreased by 3.6G1.3 points in the placebo groupand 3.2G2.0 points in the ketamine group (difference of means0.4; 95% CI �0.4 to 1.3). For the 6 patients who did not haveall data points available, the last value collected was broughtforward for analysis of variance testing. No differences in thedegree of improvement of hypoxia, tachypnea, tachycardia, orblood pressure were noted. A trend was noted in that the heavierchildren (O35 kg) seemed to receive more bronchodilation

Table 3. Comparison of asthma severity between groups.

Variable

Placebo

(N=35)

Ketamine

(N=33)

Difference in Means

or Proportions

95% CI for

Difference

ED visits for asthma in previous year 0.8 1.0 �0.2 �0.7 to 0.3Previous asthma hospitalizations 0.5 (G0.8) 0.5 (G0.8) 0 �0.4 to 0.4Previous ICU admissions for asthma 0.1 (G0.3) 0.03 (G0.2) 0.07 �0.04 to 0.2Presence of a family history of asthma/atopy, No. (%) 23 (65.7%) 18 (54.6%) 11.1% �12% to 34%Chronic asthma severity, No. (%)D

Mild, intermittent 13 (37%) 10 (30%) 7% �14% to 28%Mild, persistent 22 (63%) 22 (67%) 4% �16% to 24%Moderate, persistent 0 1 (3%) 3% �8% to 14%Severe, persistent 0 0 d d

Duration of coughing, hours 14.7 15.7 1 �5.2 to 7.2Duration of wheezing, hours 10.9 11.5 0.6 �3.6 to 4.6Duration of increased work of breathing, hours 7.1 7.7 0.6 �1.7 to 2.9Oxygen saturation at presentation 93.2% 94.1% �0.9 �2.4 to 0.5Pulmonary Index score at enrollment 10.3 10.5 0.2 �0.5 to 0.8


http://www.mosby.com/AnnEmergMed

http://www.mosby.com/AnnEmergMed


Figure 1. Patient flow algorithm.

from ketamine because their mean Pulmonary Index scoresdecreased slightly more than their lighter counterparts duringthe 2-hour infusion. Figure 3 shows the change in thePulmonary Index score from time 0 to time 120 by subject.

Of the 6 patients who were removed before completion, 2received the placebo infusion. Magnesium sulfate was used on1 patient who was later admitted to the ICU and remainedhospitalized for 16 days. The other patient in the placebo cohortimproved to the degree that continuous albuterol therapy wasno longer required, and the patient was subsequently dischargedfrom the ED. The other 4 patients removed before completionwere from the ketamine cohort. Two required intravenousterbutaline and increased dosages of nebulized albuterol becauseof worsening bronchoconstriction. They were admitted to ICUsettings, from which they were discharged 3 and 4 days later,respectively. The other 2 patients were removed for improve-ment and no longer required continuous albuterol therapy.They were later discharged from the ED. No patients in eithergroup were removed for dysphoria, laryngospasm, salivation, orintolerance of adverse effects. No patients in either grouprequired intubation.

A secondary outcome explored was the disposition for theenrolled patients after completion of the study. The patientscould be discharged home directly from the ED, admitted to aregular ward, or to higher-triage-level inpatient settings thatincluded the intermediate care and ICUs. Although the study


was not powered to detect differences in this secondaryoutcome, the ketamine and placebo groups were similar inadmission rates and higher-triage-level inpatient requirements.Table 4 shows the patient disposition.

For 58 patients, the primary investigator logged a ‘‘guess’’ asto what the patient received and guessed correctly in 37 of the58 patients (64%; 95% CI 50% to 76%) enrolled. The patientwas asked at each scoring interval an age-appropriate queryabout how they felt. An inquiry of parental perceptions about

Figure 2. Mean improvement in Pulmonary Index score, with SDshown at each point during infusion. PI, Pulmonary Index.



Figure 3. This is a parallel line plot showing the change in Pulmonary Index score by subject. There are 33 patients on the left of thedividing line who received ketamine and 35 patients on the right who received the placebo infusion. The marker - signifies thePulmonary Index score at time 0 for each patient. The vertical line emanating from each marker displays its change over the timeduring which the patients received the infusion.

the child’s temperament while receiving the infusion was alsoperformed as each point.

Finally, to determine whether ketamine caused any long-term adverse effects, attempts to contact the family by telephoneafter discharge were made using a standardized questionnaire toassess for the need for a primary care physician or ED revisitwithin 48 hours after discharge from the hospital. Of the 58patients who were contacted, 1 patient visited the primary carephysician for a scheduled reexamination and needed nosubsequent medical intervention. One patient returned to theED but was treated and discharged. No families reported anynightmares, dysphoria, or long-term abnormal change inbehaviors.

LIMITATIONSThere are several limitations to this study. The first is that

the bronchodilatory effects of ketamine on patients could not bestudied alone. A randomized trial that involved only the use ofketamine without concomitant b agonists in children withasthma would be the best way to isolate and observe their

Table 4. Disposition of enrolled patients.

Disposition,

No. (%)

Placebo

(N=35)

Ketamine

(N=33)

Difference in

Proportions

95% CI for

Difference

Home 6 (17%) 7 (21%) 4% �14% to 22%General ward 18 (51%) 13 (39%) 12% �10% to 35%Intermediatecare unit

10 (29%) 10 (30%) 1% �18% to 20%

ICU 1 (3%) 3 (9%) 6% �9% to 21%


bronchodilatory properties. However, because nebulizedb agonists are considered standard therapy for asthmaexacerbations, it would be unethical to withhold albuterolin a study design.

A second limitation involved the sensitivity of the scoringscale in detecting changes in improvement. Because a clinicallysignificant improvement has been previously defined andadditional patients beyond the required 34 were enrolled whocompleted the infusion, it is unlikely that the Pulmonary Indexscore failed to detect these clinical differences as defined a priori.The Pulmonary Index score has components that are subjective,resulting in interobserver variability in measurements. Becauseyoung children cannot effectively perform objective measure-ments of improvements such as peak flow testing, all scales thatmeasure respiratory distress in young children will have inherentsubjectivity on clinical characteristics. The fact that thePulmonary Index score has been previously validated also madeit appealing to use.

The use of a single evaluator was selected to eliminate thisvariability; however, it is important to recognize that thismethod may reduce generalizability if this investigator assessedchildren with asthma differently from other physicians. It isunlikely that this differing assessment occurred to a significantextent because the decision to treat patients with continuousalbuterol was made by the attending physician and not theinvestigator, which further suggests that Pulmonary Index scoresof greater than 8 given by the primary investigator wereappropriate in identifying the cohort of more severely illchildren with asthma.



Another limitation of this study is the use of a conveniencesample for enrollment that may lead to a sampling bias. With asingle investigator enrolling and scoring patients, it was verydifficult to evaluate all patients who may have been potentialcandidates or to perform a detailed comparison of enrolledpatients with those who were not. Patients were recruitedprimarily from 7 AM until 11 PM, with 6 patients being enrolledafter 11 PM. This disparity in times of enrollment may createbias if the patient population who had an acute asthmaexacerbation during the time when the primary investigator wasnot available was different from those who presented when hewas able to enroll them. Randomization into treatment andplacebo groups can reduce some of the bias a conveniencesample creates.

There were 6 patients who had the infusion discontinued forimprovement or deterioration before the 2-hour completionand did not have all data points collected. It is possible that thissubset of patients was different from the rest of the cohort.Analysis of variance testing using the last value brought forwardfor these 6 patients, as well as excluding them entirely, revealednearly identical results between the 2 groups. Additionally, allthe patients who were removed for improvement went homeand all those who were removed for deterioration were admittedto ICU settings in equal ratios in both groups, suggesting thatany bias their removal may add is minimal. Two patients in theketamine cohort and 1 in the placebo cohort received metered-dose inhalers rather than nebulization. These numbers were toosmall to indicate whether this was of statistical significance,although the clinical impact of receiving metered-dose inhalersrather than nebulizer therapy should be negligible.23

Additionally, when analysis of variance testing was performed,there was no difference in results if they were included or not.

Ketamine has been shown to induce nystagmus anddysphoria that could unblind the primary investigator. With thedosing regimen used in this study, nystagmus was not seen, eventhough ketamine has known effects on the central nervoussystem. No patients withdrew because of intolerable adverseeffects. The guess as to what the enrolled patient received wascorrect only 64% of the time, further suggesting that at thesedoses unblinding was not a significant issue. The limitation thata single investigator performed these evaluations may add biasin this assessment.

DISCUSSIONThe successful use of ketamine as a continuous infusion for

the treatment of children with a severe asthma exacerbation wasfirst reported more than 30 years ago.14 Previously describedcase series have reported the successful use of ketamine in themanagement of patients with asthma exacerbations that wererecalcitrant to traditional therapies; however, the dosingregimens and severity of patient illness varied significantlybecause some patients were intubated.11,12,15-19 In contrast, ourrandomized trial found that ketamine added no additionalbenefit to standard therapy for nonintubated children with amoderately severe asthma exacerbation, even though our dosing


regimen was greater than several of those that reportedsuccess.11,12,15

Although it was a negative study outcome, the previouslypublished randomized trial of ketamine for asthma by Howtonet al20 was difficult to generalize to children, given its exclusionof patients younger than 18 years and dysphoria that resulted inthe lowering of the bolus dose. In choosing our dose, we soughtto maximize the risk-benefit ratio of a ketamine infusion innonintubated children. We thought that dysphoria reported byHowton et al20 with a bolus of 0.2 mg/kg was evidence that apharmacologic effect of ketamine was occurring. We believedthat combining the evidence from their dosing regimen (whichwas ultimately lower than that in this trial) with the previouslydescribed yet limited successful case reports that ultimatelyresulted in the selection of this dosing regimen would lead toadditional measurable bronchodilation while minimizingdysphoria and laryngospasm in children who already were inrespiratory distress.

There are several possibilities for a lack of additionalmeasurable effect. The most likely cause is that the dose givenwas too low for measurable bronchodilation, despite the factthat it was within the ranges described in successful case series.This may reflect the uncertainty of relying on case series fordetermining clinical efficacy of a therapeutic intervention.Another possibility is that ketamine may be effective only ifgiven in a bolus because its peak effects may fade after 10 to 15minutes; however, repeated bolus dosing may instead representan issue of total dose given rather than rate of administration.Finally, it may be that the therapeutic benefit of albuterol at 10mg/hour is greater than the bronchodilation produced by thisketamine regimen. This effect is more notable in the youngerchildren who received smaller absolute doses of ketaminebecause analysis of covariance testing revealed that heavierchildren (O35 kg) seemed to have more bronchodilationattributable to the ketamine infusion. This result may alsoindicate a relative underdosing of albuterol for the largerpatients because all children received nebulized albuterol at10 mg/hour. Despite this possibility, all enrolled patients werewithin range of dosing for continuous albuterol therapy, and nopublished data exist showing that higher-dose albuterol issuperior for children with a severe asthma exacerbation.

Because there may be a dose dependency and time effect ofketamine, more rapid infusion and increased dosages may allowa change to be more easily detected with concomitant albuteroladministration for patients with a moderately severe asthmaexacerbation. However, there may be a limit to the maximumtolerable and ethical doses that can be given to this cohort ofawake, nonintubated children. The case series reported byPetrillo et al19 emphasizes the need for clinicians to consider therisk-benefit ratio of using higher doses. Even though it reportedsuccessful bronchodilation with its regimen of 1 mg/kg loadfollowed by a 0.75 mg/kg per hour, it unfortunately alsoresulted in a 40% rate of adverse effects, with 3 of the 10patients needing the infusion discontinued from therapyprematurely. Additionally, it may be that higher doses of



ketamine in attempts to bronchodilate may oversedate a child andcreate the false impression of an emergency need for intubation.Therefore, it may be that subsequent studies should focus on thecohort of most severe asthmatic patients for whom intubationappears imminent to more favorably balance the risks and benefitsof these higher-dose ketamine infusions.

In RetrospectEliminating the exclusionary criteria of the use of inhaled

steroids would have allowed more patients to be enrolled. Giventhat there is a multitude of delivery mechanisms and dosingstrategies for the various forms of inhaled glucocorticoids,significant confounders would have been added to determinethe effect of ketamine. Multiple enrollers and establishmentof interrater reliability could increase enrollment. Creatingand validating a scale for asthma with smaller intervals todetect smaller clinically significant differences would behelpful as well.

We conclude that ketamine given at 0.2 mg/kg, followed byan infusion of 0.5 mg/kg per hour for 2 hours, provided noincremental benefit to standard therapy in this cohort ofchildren with a moderately severe asthma exacerbation.

The authors would like to thank the TCH Pharmacy for theirassistance with drug preparation; the physicians, respiratorytherapists, and nurses who were involved in rapid identification ofpotential patients; Roland Tadoum, MS, for assistance withhistograms; and E. O’Brien Smith, PhD, for statistical analysis.

Supervising editor: David M. Jaffe, MD

Author contributions: JYA and CGM conceived the study,designed the trial, and obtained departmental funding. JYAand CGM supervised the conduct of the trial and datacollection. JYA performed all the patient enrollment, datacollection, and data entry. JYA and CGM performed all dataanalysis. JYA drafted the manuscript, and CGM contributedsubstantially to its revision. JYA and CGM take responsibility forthe paper as a whole.

Funding and support: This study was intradepartmentallyfunded by the Department of Pediatrics, the Section ofEmergency Medicine. No outside funding sources were used.

Publication dates: Received for publication April 27, 2004.Revisions received September 15, 2004, and January 21,2005. Accepted for publication February 4, 2005. Availableonline May 31, 2005.

Presented as an abstract at the American Academy of Pediat-rics National Conference, San Francisco, CA, October 8, 2004.

Reprints not available from the authors.

Address for correspondence: Joseph Y. Allen, MD, TexasChildren’s Hospital, 6621 Fannin St. MC 1-1481,Houston, TX 77030; 832-824-5497, fax 832-825-5424;E-mail [email protected].


REFERENCES1. Werner HA. Status asthmaticus in children: a review. Chest. 2001;

119:1913-1929.2. Surveillance for asthma: United States, 1980-1999. MMWR Morb

Mortal Wkly Rep. 2002;51:1-13.3. Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute

asthma treatment: an evidence based evaluation. Chest. 2002;121:1977-1987.

4. Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acuteasthma in infants and toddlers: a controlled clinical trial. Pediatrics.1990;86:350-356.

5. Scarfone RJ, Fuchs SM, Nager AL, et al. Controlled trial of oralprednisone in the emergency department treatment of children withacute asthma. Pediatrics. 1993;92:513-518.

6. Barnett P, Caputo GL, Baskin M, et al. Intravenous versus oralcorticosteroids in the management of acute asthma in children.Ann Emerg Med. 1997;29:212-217.

7. Scarfone RJ, Loiselle JM, Wiley JF, et al. Nebulized dexamethasoneversus oral prednisone in the emergency treatment of asthmaticchildren. Ann Emerg Med. 1995;26:480-486.

8. Stephanopolous DE, Monge R, Schell KH, et al. Continuousintravenous terbutaline for pediatric status asthmaticus. Crit CareMed. 1998;26:1744-1748.

9. Scarfone RJ, Loiselle JM, Joffe MD, et al. A randomized trial ofmagnesium in the emergency department treatment of children withasthma. Ann Emerg Med. 2000;36:572-578.

10. RoweBH,Bretzlaff JA, BourdonC, et al. Intravenousmagnesiumsulfatetreatment for acute asthma in the emergency department: a systematicreview of the literature. Ann Emerg Med. 2000;36:181-190.

11. Huber FC, Reves JG, Gutierrez J, et al. Ketamine: its effect onairway resistance in man. South Med J. 1972;65:1176-1180.

12. Sarma VJ. Use of ketamine in severe asthma. Acta AnaesthesiolScand. 1992;36:106-107.

13. Brown RH, Wagner EM. Mechanisms of bronchoprotection byanesthetic induction agents. Anesthesiology. 1999;90:822-828.

14. Betts EK, Parkin CE. Use of ketamine in an asthmatic child. AnesthAnalg. 1971;50:420-421.

15. Nehama J, Pass R, Bechtler-Karsch A, et al. Continuous ketamineinfusion for the treatment of refractory asthma in a mechanicallyventilated infant: case report and review of the pediatric literature.Pediatr Emerg Care. 1996;12:294-297.

16. Fisher M. Ketamine hydrochloride in severe bronchospasm.Anesthesiology. 1977;32:771-772.

17. Strube PJ, Hallam PL. Ketamine by continuous infusion in statusasthmaticus. Anesthesiology. 1986;41:1017-1019.

18. Rock MJ, Reyes de la Rocha S, L’Hommedieu CS, et al. Use ofketamine in asthmatic children to treat respiratory failure refractoryto conventional therapy. Crit Care Med. 1996;14:514-516.

19. Petrillo T, Fortenberry JD, Linzer JF, et al. Emergency departmentuse of ketamine in pediatric status asthmaticus. J Asthma. 2001;38:657-664.

20. Howton JC, Rose J, Duffy S, et al. Randomized, double-blindplacebo controlled trial of ketamine in acute asthma. Ann EmergMed. 1996;27:170-175.

21. Becker AB, Nelson NA, Simons ER. The pulmonary index:assessment of a clinical score for asthma. Am J Dis Child. 1984;138:574-576.

22. National Institutes of Health. National Asthma Education andPrevention Program Clinical Practice Guidelines: Expert PanelReport 2: Guidelines for the Diagnosis and Management of Asthma.National Institutes of Health, National Heart, Lung, and BloodInstitute; 1997. NIH Publication 97-4501.

23. Leversha AM, Campanella SG, Aickin RP, et al. Costs andeffectiveness of spacer versus nebulizer in young children withmoderate and severe acute asthma. J Pediatr. 2000;136:497-502.


American Journal of Emergency Medicine 33 (2015) 1720.e1–1720.e2




Case Report

Intravenous ketamine to facilitate noninvasive ventilation in a patient
with a severe asthma exacerbation
Abstract

Despite advances inoutpatient treatment andan improvedunderstand-ing of the pathophysiology, asthma continues to be a significant source ofmorbidity and mortality in the United States. Although there is certainly acomponent of chronic inflammation, the majority of the symptoms inacute asthma exacerbations can be reversed with proper medications andmanagement. Reversingbronchoconstrictionandavoidingmechanical ven-tilation should be the goals of the emergency physician and the intensivistto avoid intubation and to view this intervention as a last resort.

We describe a case of ketamine administration and utilization ofnoninvasive positive pressure ventilation (NIPPV) to avoid mechanicalventilation in a patient with a severe asthma exacerbation.

A 36-year-old man in extremis presented to the emergency depart-mentwith a severe asthma exacerbation and alteredmental status. Dis-sociative state was achieved using aliquots of ketamine to facilitateNIPPV and medication administration. In less than 1 hour, the patientexhibited significant improvement and did not require intubation.

Although large studies on the benefits of NIPPV and ketamine in thesetting of asthma are lacking, this case suggests that a strategy ofsubdissociative doses of ketamine with NIPPV could be considered as aninitial step in the management of status asthmaticus before intubation.

Despite advances in outpatient treatment and an improved under-standing of the pathophysiology, asthma continues to be a significantsource of morbidity and mortality in the United States [1]. In 2007,there were 3447 deaths due to asthma; 3262 of those were amongadults. Although there is certainly a component of chronic inflamma-tion, the majority of the symptoms in acute asthma exacerbations canbe reversed with proper medications and management [2]. Reversingbronchoconstriction and avoiding mechanical ventilation should bethe goals of the emergency physician and the intensivist to avoid intu-bation and to view this intervention as a last resort.

The patient is a 36-year-old African American man who presented toour emergency department (ED) in severe respiratory distress. Per medics,the patient returned to his group home after taking a walk and developingsevere dyspnea. By the time Emergency Medical Services arrived on scene,the patient was minimally responsive, was bradypneic, and had an initialpulse oximeter reading of 70%. An attempt at intubation was performedby the paramedic without medications. This attempt failed, as the stimula-tion of the laryngoscope caused the patient to gag and move.

On arrival to the ED, the patient’s history was limited given his clinicalcondition; but the patient had visited our ED 20months prior and had a his-toryof asthmaanddepressivepsychosis. At that time, thepatienthaddeniedprevious intubations but admitted to several previous hospitalizationswithout mention of intensive care unit–level care. Vital signs were rectal

0735-6757/© 2015 Elsevier Inc. All rights reserved.

temperature of 35.1°C, heart rate of 124 beats per minute, respiratory rateof 26 breaths per minute, blood pressure of 147/87 mm Hg, and pulseoximetry of 98% on 10-L/min facemask with concurrent albuterol adminis-tration. Given his respiratory distress, a room air pulse oximeter readingwas not obtained. On physical examination, the patient was sitting uprightin a tripod position, perspiring profusely, andwas unable to speak. His respi-ratory examination revealedmarkedly diminished breath sounds bilaterally,prolongation of the expiratory phase, and accessory muscle usage.

Immediately on arrival, the patient was started on nebulized albute-rol and ipratropium. Throughout his ED stay, the patient was also given125 mg methylprednisolone, 2 g magnesium sulfate, epinephrine0.3 mg intramuscularly times 3 doses, and a 2000-mL bolus of isotonicsodium chloride solution.Within minutes, the decision wasmade to at-tempt bilevel positive airway pressure ventilation (BiPAP) given the pa-tient’s altered mental status with potential for rapid deterioration andapnea. Just before BiPAP attempts, a point-of-care venous blood gasreturned that showed a pH of 7.08, pCO2 of 67, and a lactic acid level of79.0 mg/dL (8.769 mmol/L). A chest radiograph was obtained thatshowed hyperinflated lungs with no evidence of pneumothorax, pulmo-nary consolidation, or other etiology to explain the patient’s presentation.

Our initial attempts at BiPAP failed, as the patient would push away therespiratory therapist and was becoming increasingly agitated. Intubationequipment was brought to the bedside, and a 50-mg bolus of ketaminewas given. The patient dissociated, and the BiPAPwas applied with contin-uous albuterol solution flowing. After 10 minutes, an arterial blood gas(ABG) was drawn that showed a pH of 7.17, pCO2 of 63, and a PaO2 of 305with an FIO2 of 100%. Several repeat boluses of 50 mg ketamine weregiven at approximately 5- to 10-minute intervals while the patient wason BiPAP to a total dose of 300 mg. After 40 minutes, an ABG showed apH of 7.21, pCO2 of 59, and lactic acid level of 24.0 mg/dL (2.664 mmol/L).After this point, no further ketamine was needed because the patient wasable to tolerate the BiPAP and participate in his care. At 120 minutes, hisABG showed a pH of 7.35 and pCO2 of 45. The patient was admitted to themedical intensive care unit on BIPAP, switched to nasal cannula, anddischarged home from the general medical floor approximately 48 hoursafter his arrival to the ED in good condition.

Ketamine and noninvasive positive pressure ventilation (NIPPV) havebothbeenproposed as adjunctive therapies for themanagement of severeasthma exacerbations. Though a 2012 Cochrane review found insufficientdata to recommend NIPPV for status asthmaticus, this conclusion may beattributed to the lack of high-quality studies on the topic. Likewise,although ketamine exhibits physiologic effects that are beneficial in thesettingof asthma [3–5]and thereare case reports andsmall studies showingbenefit [6–8], large randomized studies showing benefit are lacking.

In this case, the patient presented to us in a state that would haveotherwise required mechanical ventilation. We believe that ketamine

Page 38




1720.e2 E. Kiureghian, J.M. Kowalski / American Journal of Emergency Medicine 33 (2015) 1720.e1–1720.e2

and NIPPV provided time for our standard therapies to take effect, re-verse the bronchoconstriction, and thereby avoid intubation. The pa-tient had an uncomplicated hospital stay and was rapidly discharged,presumably because of the acute management. Further studies mayhelp elucidate the role for these agents in the avoidance of mechanicalventilation in severe asthma exacerbations.

Emeen Kiureghian, DO⁎

J. Michael Kowalski, DODepartment of Emergency Medicine, Einstein Medical Center, 5501 Old

York Road, Korman B-9, Philadelphia, PA 19141⁎Corresponding author

E-mail address: [email protected]


References

[1] Akinbami LJ, Moorman JE, Liu X. Asthma prevalence, health care use, and mortality:United States 2005-2009. Natl Health Stat Report 2011, Jan 12;32:1–14.

[2] Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, Meckler GD, editors.Tintinalli’s emergency medicine: a comprehensive study guide. New York, NY:McGraw-Hill; 2011.

[3] L’Hoomedieu CS, Arens JJ. The use of ketamine for the emergency intubation ofpatients with status asthmaticus. Ann Emerg Med 1987;16:568–71.

[4] Sato T, Hiroa K, Matsuki A, Zsigmond EK, Rabito SF. The relaxant effect of ketamine onguinea pig airway smooth muscle is epithelium-independent. Anesth Analg 1997;84:641–7.

[5] Sato T, Matsuki A, Zsigmond EK, Rabito SF. Ketamine relaxes airway smooth musclecontracted by endothelin. Anesth Analg 1997;84:900–6.

[6] Betts EK, Parkin CE. Use of ketamine in an asthmatic child: a case report. Anesth Analg1971;50:420–1.

[7] Petrillo TM, Fortenberry JD, Linzer JF, Simon HK. Emergency department use ofketamine in pediatric status asthmaticus. J Asthma 2001;38:657–64.

[8] Shlamovitz GZ, Hawthorne T. Intravenous ketamine in a dissociating dose as a tempo-rizing measure to avoid mechanical ventilation in adult patient with severe asthmaexacerbation. J Emerg Med 2011;41(5):492–4.

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BRIEF REPORT

Retrospective Analysis of EtomidateVersus Ketamine for First-passIntubation Success in an AcademicEmergency Department

Asad E. Patanwala, PharmD, Courtney B. McKinney, PharmD, Brian L. Erstad, PharmD, and John C.Sakles, MD

AbstractObjectives: The objective of this study was to compare first-pass intubation success between patientswho received etomidate versus ketamine for rapid sequence intubation (RSI) in the emergencydepartment (ED).

Methods: This was a retrospective analysis of prospectively collected data recorded in a qualityimprovement database between July 1, 2007, and December 31, 2012. The study was conducted in anacademic ED in the United States. All patients who received etomidate or ketamine as part of RSI wereincluded. The primary outcome measure was first-pass success. A multivariate analysis was conducted todetermine if sedative type was associated with first-pass success, after adjusting for potentialconfounders and baseline differences.

Results: The final cohort consisted of 2,098 RSI procedures using either etomidate (n = 1,983) orketamine (n = 115). First-pass success occurred in 77.0% of patients in the etomidate group and 79.1% ofpatients in the ketamine group (difference = –2.1%; 95% CI = –5.5% to 9.8%). In the multivariate analysis,after adjusting for potential confounders, sedative type was not associated with first-pass success (oddsratio = 0.89; 95% CI = 0.5 to 1.5; p = 0.632).

Conclusions: Etomidate and ketamine are associated with equivalent first-pass success when used inRSI. Ketamine may be an appropriate alternative to etomidate for RSI in the ED.

ACADEMIC EMERGENCY MEDICINE 2014; 21:88–91 © 2013 by the Society for Academic EmergencyMedicine

Rapid sequence intubation (RSI) is the mainstayof airway management in critically ill emergencydepartment (ED) patients. With the possible

exception of patients who are unconscious and unre-sponsive, all patients needing RSI require the use of asedative agent prior to neuromuscular blockade. Theintent of the sedative is to render the patient uncon-scious and unaware, while the paralytic facilitates pas-sage of the tracheal tube via muscular relaxation. Moststudies evaluating intubation conditions or success rateshave traditionally focused on comparisons of neuromus-cular blockers.1,2 However, the sedative used may alsoinfluence intubating conditions and success rates bypotentiating the effect of the neuromuscular blocker;

reducing the time to maximal neuromuscular blockade;and affecting diaphragmatic, laryngeal, and pharyngealreactivity to the intubation stimulus.3–5

In previous systematic reviews and registry studies,the effect of the paralytic on intubation conditions wasmodified based on the sedative used.2,5 This suggeststhat sedative selection could also influence intubationsuccess, which is a more clinically relevant outcomecompared to intubation conditions.6 A previous studyby Jabre et al.,7 in which the primary focus was organfailure, reported intubation conditions and difficultybetween etomidate and ketamine, but first-pass intuba-tion success has not been evaluated as an outcome. Thecomplications related to intubation (such as hypoxemia,

From the Department of Pharmacy Practice & Science (AEP, CBM, BLE) and the Department of Emergency Medicine (JCS),College of Pharmacy, University of Arizona, Tucson, AZ; and the Department of Pharmacy Services, Intermountain MedicalCenter (CBM), Salt Lake City, UT.Received May 6, 2013; revision received August 2, 2013; accepted August 2, 2013.Presented at the Society of Critical Care Medicine, Puerto Rico, January 2013.The authors have no relevant financial information or potential conflicts of interest to disclose.Supervising Editor: Robert F. Reardon, MD.Address for correspondence and reprints: Asad E. Patanwala, PharmD; e-mail: [email protected].

88 PII ISSN 1069-6563583 doi: 10.1111/acem.12292ISSN 1069-6563 © 2013 by the Society for Academic Emergency Medicine

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aspiration, bradycardia, and cardiac arrest) increase asthe number of intubation attempts increase.6,8 There-fore, it is important that intubation success is achievedon the first-pass, and studies are needed to ascertain ifketamine use is associated with a reduction in intuba-tion success compared to etomidate before it can beroutinely recommended.

The primary goal of this study was to compare first-pass RSI success in ED patients who received etomidateversus ketamine. We hypothesized that there is no dif-ference in first-pass success between the two agents.

METHODS

Study DesignThis was retrospective analysis of prospectively col-lected data recorded in a quality improvement databasebetween July 1, 2007, and December 31, 2012. The intentof the database is to evaluate resident performance,medications, and devices used for intubation in the ED.This study was granted exemption by the institutionalreview board.

Study Setting and PopulationThe study was performed in a 61-bed academic tertiarycare ED with a census of approximately 75,000 patient-visits annually. Emergency physicians (EPs) primarilyperform all intubations. During each intubation, physi-cians have access to a standardized intubation medica-tion box containing the sedative etomidate, and theneuromuscular blockers succinylcholine, rocuronium,and vecuronium. Ketamine is available as an alternativeagent via controlled access cabinets located in the ED.Sedative and neuromuscular blocker selection is primar-ily dependent on physician preference. All patients whounderwent RSI in the ED were included. Patients wereexcluded if RSI was performed using a sedative otherthan etomidate or ketamine or if vecuronium was usedfor neuromuscular blockade instead of succinylcholineor rocuronium.

Study ProtocolThe EP performing the intubation recorded data pro-spectively using a standardized data collection form,which was completed following the intubation. Phar-macy, billing, and admission records were used toidentify any intubations performed without corre-sponding data forms, in which case the operators werecontacted for form completion. Data collected includedpatient age, sex, trauma status (trauma or nontrauma),failure of prehospital intubation (failed or notattempted), presence of any difficult airway characteris-tics (blood or vomit in the airway, short neck, cervicalcollar, small mandible, obesity, airway edema, facialtrauma, or large tongue), laryngoscopy device used,reason for device selection (standard, anticipate diffi-cult airway, or educational reasons), reason for intuba-tion (airway protection, respiratory failure, cardiacarrest, patient control, hypoxia), level of physiciantraining (classified by postgraduate year [PGY] of resi-dency training), medications used, and number of intu-bation attempts. The data were then entered into theelectronic database program HanDBase 4.0 for the

iPad (DDH Software, Wellington, FL) with subsequenttransfer to Excel for Windows 2010 (Microsoft, Red-mond, WA).

The primary outcome measure was first-pass success.The definitions of intubation attempt and intubation suc-cess were similar to those used in previous investiga-tions.9 An intubation attempt was defined as theinsertion and subsequent removal of the laryngoscopicdevice from the patient’s mouth, regardless of whetheran attempt was made to pass a tracheal tube. Intubationsuccess was defined as correct placement of the trachealtube into the trachea, which was confirmed by end-tidalCO2 capnometry, pulse oximetry, chest auscultation,observation of chest excursion, absence of epigastricsounds, and misting of the endotracheal tube.9

Data AnalysisPatients were categorized into two groups based on thesedative used for intubation: etomidate or ketamine.Demographic and intubation data were comparedbetween the two groups. An unpaired Student’s t-testwas used to compare continuous, normally distributedvariables. Normality was determined by visually inspect-ing the data. Fisher’s exact test was used to comparecategorical variables. A multivariate logistic regressionanalysis was performed to determine the effect of seda-tive agent on first-pass success, after adjusting for con-founders. Potential confounders that were included inthe model were age, sex, paralytic used, trauma status,reason for intubation, device used, failure of prehospitalintubation, reason for device selection, difficult airwayparameters, and physician training. These were selectedbased on previous studies evaluating intubation successin this setting, and all variables were forced into themodel.1,9 Age was categorized in the model as youngerthan 18, 18 to 65, and older than 65 years, since it didnot meet the assumption of linearity in the log-odds.Difficult airway characteristics were entered into themodel as ordinal variables. The model was checked forinteractions and model fit was assessed by the Hosmer-Lemeshow goodness-of-fit test. No interactions wereidentified, allowing for all potential variables to beadded in the same model. All statistical analyses wereperformed using Stata version 12 (StataCorp, CollegeStation, TX) with significance for all analyses defined apriori as p < 0.05.

RESULTS

During the study period there were 2,258 RSIs per-formed in the ED. Of these, 113 were performed withsedatives other than etomidate or ketamine, 42 wereperformed with paralytics only, and five were per-formed with paralytics other than succinylcholine orrocuronium. Therefore, the final cohort consisted of2,098 intubations using either etomidate (n = 1,983) orketamine (n = 115). Overall, most intubations wereperformed by EPs (n = 2,019), followed by medical stu-dents or paramedics (n = 59) and physicians from otherspecialties (n = 20). The mean (�SD) patient age was45.6 (�22.5) years, 63.5% of the patients were male, andthe proportion of trauma patients was 44.0%. Compari-son of baseline patient demographics and intubation

ACADEMIC EMERGENCY MEDICINE • January 2014, Vol. 21, No. 1 • www.aemj.org 89

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parameters between the etomidate and ketamine groupsis provided in Table 1.

First-pass success occurred in 77.0% of patients in theetomidate group and 79.1% of patients in the ketaminegroup (difference = –2.1; 95% CI = –5.5 to 9.8). In the mul-tivariate analysis, after the potential confounders andbaseline differences were adjusted for, ketamine use wasnot associated with a reduction in first-pass success(odds ratio = 0.89; 95% CI = 0.5 to 1.5; p = 0.632) com-pared to etomidate. The data fit the model well (Hosmer-Lemeshow goodness-of-fit, p = 0.944).

DISCUSSION

First-pass intubation success is highly desirable becausecomplications increase as the number of attemptsincreases.6,8 Previous studies have primarily focused onthe effects of neuromuscular blockers, since they are

directly responsible for muscular relaxation for passageof the tracheal tube.1 However, the sedative used canaffect this outcome by a variety of potential mecha-nisms. For instance, the response to the intubation stim-ulus, such as diaphragmatic movement and coughing,can be influenced by the sedative used.3 Also, the onsettime of neuromuscular blockade can be modified by thesedative.4 This is particularly important in the context ofour study because ketamine has a longer onset of effectcompared to etomidate. Therefore, if intubation isattempted prior to maximal neuromuscular blockade,intubation success could be affected.

Sivilotti et al.5 evaluated the effect of a wide range ofsedatives on intubation success in a multicenter observa-tional study. They found that collectively, thiopental,methohexital, and propofol were associated withimproved first-pass success, compared to other sedativessuch as etomidate, ketamine, and benzodiazepines. They

Table 1Demographics and Intubation Characteristics of Etomidate Versus Ketamine Groups

CharacteristicEtomidate (n = 1,983)

n (%; 95% CI)Ketamine (n = 115)n (%; 95% CI)

Age group (yr)*<18 171 (8.6; 7.4–9.9) 23 (20.0; 13.1–28.5)18 to 65 1,415 (71.4; 69.3–73.3) 71 (61.7; 52.2–70.6)>65 397 (20.0; 18.3–21.9) 21 (18.3; 11.7–26.5)

Sex*Female 711 (35.9; 33.7–38.0) 55 (47.8; 38.4–57.3)Male 1,272 (64.2; 62.0–66.3) 60 (52.2; 42.7–61.6)

Trauma*Medical 1,081 (54.5; 52.3–56.7) 94 (81.7; 73.5–88.3)Trauma 902 (45.5; 43.3–47.7) 21 (18.3; to 11.7–26.5)

Prehospital intubationNot attempted 1,870 (94.3; 93.2–95.3) 113 (98.3; 93.9–99.8)Failed 113 (5.7; 4.7–6.8) 2 (1.7; 0.2–6.1)

Paralytic usedRocuronium 1,006 (50.7; 48.5–53.0) 57 (49.6; 40.1–59.0)Succinylcholine 977 (49.3; 47.0–51.5) 58 (50.4; 41.0–59.9)

Reason for intubation*Airway protection 1,407 (71.6; 68.9–72.9) 56 (48.7; 39.3–58.2)Respiratory failure 315 (16.0; 14.3–17.6) 49 (42.6; 33.4–52.2)Cardiac arrest 43 (2.2; 1.6–2.9) 1 (0.9; 0.0–4.7)Patient control 171 (8.7; 7.4–9.9) 3 (2.6; 0.5–7.4)Hypoxia 29 (1.5; 1.0–2.1) 6 (5.2; 1.9–11.0)

Device used*Direct laryngoscopy 951 (48.0; 45.7–50.2) 41 (35.7; 26.9–45.1)GlideScope 556 (28.0; 26.1–30.1) 28 (24.4; 16.8–33.2)C-MAC 415 (20.9; 19.2–22.8) 35 (30.4; 22.2–39.7)Other 61 (3.1; 2.4–3.9) 11 (9.6; 4.9–16.5)

Reason for device selection*Standard 1,230 (62.0; 59.8–64.2) 57 (49.6; 40.1–59.0)Difficult 485 (24.5; 22.6–26.4) 31 (27.0; 19.1–36.0)Education 268 (13.5; 12.0–15.1) 27 (23.5; 16.1–32.3)

Operator level of trainingNonphysician (medical students and paramedics) 57 (2.9; 2.2–3.7) 2 (1.7; 0.2–6.1)PGY1 411 (20.7; 19.0–22.6) 27 (23.5; 16.1–32.3)PGY2 754 (38.0; 35.9–40.2) 42 (36.5; 27.7–46.0)PGY3 722 (36.4; 34.3–38.6) 42 (36.5; 27.7–46.0)Attending 39 (2.0; 1.0–2.1) 2 (1.7; 0.2–0.6)

Difficult airway characteristics*None 722 (36.4; 34.3–38.6) 45 (39.1; 30.2–48.7)1 586 (29.6; 27.6–31.6) 41 (35.7; 26.9–45.1)2 289 (14.6; 13.1–16.2) 18 (15.7; 9.6–23.6)3 or more 386 (19.5; 17.7–21.3) 11 (9.6; 4.9–16.5)

PGY = postgraduate year.*Significant difference between groups.

90 Patanwala et al. • EFFECT OF SEDATIVES ON INTUBATION SUCCESS

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hypothesized that the former group of sedatives producea deeper plane of anesthesia, thereby facilitating intuba-tion before complete neuromuscular blockade is achievedwith paralytics alone. However, these former agents areseldom used for emergency intubation because of thepotential for adverse effects such as hypotension. Ourstudy builds on the results of Sivilotti et al. by focusingon etomidate and ketamine, two of the most commonlyused sedatives for this indication due to their favorablehemodynamic profile. In addition, we included importantconfounders such as the intubation device used, whichhas recently been shown to be highly predictive of intu-bation success.10 Thus, our results are pertinent in an erain which video laryngoscopy is common.

In a recent randomized controlled trial by Jabre at al.,7

655 patients who required emergency intubation weregiven either etomidate or ketamine for induction. Therewas no difference between groups with regard to thedevelopment of organ failure, which was the primaryoutcome. Although intubation success was not an out-come in this study, the difficulty of intubation was mea-sured and was found to be comparable between the twogroups. However, since this was not the focus of thestudy, important confounders were not measured. Ourstudy is unique because we measured first-pass success,which was our primary outcome. We were unable tomeasure adverse effects, which is an important consider-ation in terms of sedative selection. However, the muchlarger study by Jabre et al.7 did not show differences inadverse effects, and these agents are considered to havesimilar safety profiles. Thus, given the fact that multipleintubation attempts are associated with an increase inadverse effects, we felt that first-pass success was themost important outcome to study.

LIMITATIONS

The study has a few limitations related to its design.The results should be extrapolated with caution to non-academic EDs. There is a possibility for measurementbias because physicians performing each intubationcompleted the data forms themselves. Ideally, an inde-pendent observer would collect this information. How-ever, our main outcome variable was intubationattempts, and it is very unlikely that this variable wouldbe erroneously documented. Some data collection formswere not completed immediately after the intubationsand required the senior investigator (JCS) to contactindividual physicians as part of a quality improvementprocess. Although this was done as quickly as possible,the delay in recording information in these cases couldhave led to recall bias. Nonetheless, the senior investi-gator verified information provided against medicalrecords to ensure accuracy of documentation. It is pos-sible that there was selection bias with regard to keta-mine and etomidate. There were many more patients inthe etomidate group, but we included all patients tominimize the potential for selection bias. Ideally, a ran-domized controlled trial would overcome this bias.However, we adjusted for differences between groupsand performed the necessary model diagnostics. Inaddition, there could be individual variation between

operators, but we could not stratify the results by oper-ator because there were more than 150 operators in thedatabase. Also, operator success could improve withnumber of previous intubations. Nonetheless, weincluded level of training as a surrogate for operatorskill. We did not have dosing information of the paralyt-ics, which could influence intubation conditions. Therewere several baseline differences between groups.However, we adjusted for this in our multivariatemodel. Finally, it is possible that there are additionalconfounders that were not included in our model. How-ever, we have included the most likely variables, basedon previous studies that could affect our outcome.

CONCLUSIONS

Etomidate and ketamine were associated with equiva-lent first-pass success in this retrospective review. Aprospective randomized trial of first-pass success isneeded to confirm these findings.

References

1. Patanwala AE, Stahle SA, Sakles JC, Erstad BL.Comparison of succinylcholine and rocuronium forfirst-attempt intubation success in the emergencydepartment. Acad Emerg Med. 2011;18:10–4.

2. Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuroni-um versus succinylcholine for rapid sequence induc-tion intubation. Cochrane Database Syst Rev. 2008(2):CD002788.

3. Fuchs-Buder T, Sparr HJ, Ziegenfuss T. Thiopentalor etomidate for rapid sequence induction withrocuronium. Br J Anaesth. 1998;80:504–6.

4. Gill RS, Scott RP. Etomidate shortens the onset timeof neuromuscular block. Br J Anaesth. 1992;69:444–6.

5. Sivilotti ML, Filbin MR, Murray HE, Slasor P, WallsRM. Does the sedative agent facilitate emergencyrapid sequence intubation? Acad Emerg Med.2003;10:612–20.

6. Sakles JC, Chiu S, Mosier J, Walker C, Stolz U. Theimportance of first pass success when performingorotracheal intubation in the emergency depart-ment. Acad Emerg Med. 2013;20:71–8.

7. Jabre P, Combes X, Lapostolle F, et al. Etomidateversus ketamine for rapid sequence intubation inacutely ill patients: a multicentre randomised con-trolled trial. Lancet. 2009; 374:293–300.

8. Mort TC. Emergency tracheal intubation: complica-tions associated with repeated laryngoscopicattempts. Anesth Analg. 2004;99:607–13.

9. Mosier J, Chiu S, Patanwala AE, Sakles JC. A com-parison of the GlideScope video laryngoscope to theC-MAC video laryngoscope for intubation in theemergency department. Ann Emerg Med. 2013;61:414–20.

10. Sakles JC, Mosier JM, Chiu S, Keim SM. Trachealintubation in the emergency department: a compari-son of GlideScope(R) video laryngoscopy to directlaryngoscopy in 822 intubations. J Emerg Med.2012;42:400–5.

ACADEMIC EMERGENCY MEDICINE • January 2014, Vol. 21, No. 1 • www.aemj.org 91

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AIRWAY/ORIGINAL RESEARCH

Delayed Sequence Intubation: A Prospective Observational StudyScott D. Weingart, MD*; N. Seth Trueger, MD, MPH; Nelson Wong, MD; Joseph Scofi, MD; Neil Singh, MD; Soren S. Rudolph, MD

*Corresponding Author. E-mail: [email protected], Twitter: @emcrit.

Volume 6

Study objective:We investigate a new technique for the emergency airway management of patients with altered mentalstatus preventing adequate preoxygenation.

Methods: This was a prospective, observational, multicenter study of patients whose medical condition led them toimpede optimal preintubation preparation because of delirium. A convenience sample of emergency department andICU patients was enrolled. Patients received a dissociative dose of ketamine, allowing preoxygenation with high-flownonrebreather mask or noninvasive positive pressure ventilation (NIPPV). After preoxygenation, patients were paralyzedand intubated. The primary outcome of this study was the difference in oxygen saturations after maximal attempts atpreoxygenation before delayed sequence intubation compared with saturations just before intubation. Predeterminedsecondary outcomes and complications were also assessed.

Results: A total of 62 patients were enrolled: 19 patients required delayed sequence intubation to allow nonrebreathermask, 39 patients required it to allow NIPPV, and 4 patients required it for nasogastric tube placement. Saturationsincreased from a mean of 89.9% before delayed sequence intubation to 98.8% afterward, with an increase of 8.9% (95%confidence interval 6.4% to 10.9%). Thirty-two patients were in a predetermined group with high potential for criticaldesaturation (pre–delayed sequence intubation saturations�93%). All of these patients increased their saturations post–delayed sequence intubation; 29 (91%) of these patients increased their post–delayed sequence intubation saturations togreater than 93%. No complications were observed in the patients receiving delayed sequence intubation.

Conclusion: Delayed sequence intubation could offer an alternative to rapid sequence intubation in patients requiringemergency airway management who will not tolerate preoxygenation or peri-intubation procedures. It is essentiallyprocedural sedation, with the procedure being preoxygenation. Delayed sequence intubation seems safe and effectivefor use in emergency airway management. [Ann Emerg Med. 2015;65:349-355.]

Please see page 350 for the Editor’s Capsule Summary of this article.

A podcast for this article is available at www.annemergmed.com.

0196-0644/$-see front matterCopyright © 2014 by the American College of Emergency Physicians.http://dx.doi.org/10.1016/j.annemergmed.2014.09.025


Preoxygenation and denitrogenation allow a safe buffer ofoxygen to avoid hypoxemia during the apneic period of rapidsequence intubation.1 However, some patients struggle againsttraditional means of preoxygenation because of altered mentalstatus. In these patients, we would be forced to proceed with rapidsequence intubation without the safety buffer of a large oxygenreservoir. Many of them will become hypoxemic during the apneicperiod and then require bag-valve-mask ventilation, with itsattendant increased risks of gastric insufflation and aspiration.

In contrast to rapid sequence intubation, the technique ofdelayed sequence intubation temporally separates administrationof the induction agent from the administration of the musclerelaxant to allow adequate preintubation preparation.2 Theinduction agent chosen is one that allows the continuation ofspontaneous breathing and the retention of airway reflexes. Theprototypical agent for this purpose is ketamine, a dissociative

5, no. 4 : April 2015

NMDA receptor antagonist. In the space of this separation, thepatient can be preoxygenated and denitrogenated, and anynecessary peri-intubation procedures can be performed. Only aftercompletion of these crucial actions would the patient be paralyzedand intubated.

ImportancePatients who are intubated without adequate preoxygenation

will have less apneic tolerance and are at risk for precipitousdesaturation during intubation.1 If the patient’s preintubationoxygen saturation is less than or equal to 93%, he or she willlikely continue to desaturate during the apneic period.3 Patientswith inadequate preoxygenation and denitrogenation will havemuch shorter times until desaturation during intubationattempts.1 A technique to allow adequate preparation ofdelirious or combative patients for intubation could decreasethe risk of hypoxemia and reduce peri-intubation morbidity andmortality.4



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350

Delayed Sequence Intubation Weingart et al


What is already known on this topicAdequate preoxygenation is difficult or evenimpossible in some patients with agitated delirium.

What question this study addressedThis small, observational study addresses whether abrief period of sedation with ketamine wouldimprove ventilation and preoxygenation beforeintubation.

What this study adds to our knowledgePostsedation oxygen saturations were successfullyincreased in the majority of patients.

How this is relevant to clinical practiceDelayed sequence intubation provides a feasibleoption for preoxygenation in the patient with alteredmental status resistant to standard preoxygenation.Clinical outcomes were not assessed, and arandomized trial is warranted.

Goals of This InvestigationOur aim was to investigate the technique of delayed sequence

intubation in a cohort of emergency department (ED) andcritical care patients requiring emergency airway management inregard to improvement in preoxygenation and safety.


This was a prospective, observational study of patients whosemedical condition or mental status led them to impede optimalpreoxygenation, denitrogenation, or preintubation procedures. Aconvenience sample of patients was enrolled during thestudy period. Clinicians made attempts to preoxygenate anddenitrogenate the study participants. If these patients did not allowthe necessary preintubation preparations because of delirium,ketamine was administered until they became dissociated. At thispoint, preoxygenation and any necessary procedures wereperformed. After adequate preparation, in most cases the patientsthen received muscle relaxants and were intubated.

The study design complied with the recommendations ofthe Strengthening the Reporting of Observational Studies inEpidemiology statement.5 This study was approved by ourinstitutional review board, as well as the Danish data protectionagency; consent beyond what was standardly obtained forintubation was deemed unnecessary because delayed sequenceintubation was considered usual care in these institutions.

SettingThe study was conducted at 3 institutions: a US 540-bed Level I

trauma center, a US 1,100-bed quaternary referral center, and a

Annals of Emergency Medicine

Danish 1,200-bed Level I trauma center. This was primarily a studyof ED patients; patients intubated in the ICU immediately onadmission from the ED were also included at one of the study sites.

Selection of ParticipantsPatients included in this trial were undergoing emergency airway

management. Patients were aged 18 years or older, spontaneouslybreathing, and not predicted by clinicians to have an anatomicallydifficult airway requiring awake intubation. Delayed sequenceintubation was performed on patients who remained uncooperativeaftermaximal attempts of traditionalmeans of preoxygenation. Lackof cooperation included any of the following: verbal statements ofinability to tolerate a mask or procedure, tearing off the mask, orinability to remain in the stretcher or bed. Attempts to performpreoxygenation included calm reassurance, help holding the mask,and explanations of the importance of preoxygenation. In mostcases, delayed sequence intubationwas performed after 3 attempts tofacilitate standard preoxygenation.

InterventionsPatients undergoing delayed sequence intubation received

titrated ketamine in a dose sufficient to achieve a dissociated statewith continued spontaneously breathing and maintenance ofairway reflexes (Figure 1). The recommended initial dose ofketamine was 1 mg/kg; additional aliquots of 0.5 mg/kg wereadministered until the patient was in a dissociated state.

Once the dissociated statewas achieved, the patientswere placed inan at least 30-degree head-up (semi-Fowler) positioning. They thenreceived preoxygenation and denitrogenation with high-flow oxygen,usingnonrebreathermasks. If the nonrebreathermaskwas insufficientto raise the pulse oximeter saturation to greater than or equal to 95%,the patients began receiving noninvasive positive pressure ventilation(NIPPV), with continuous positive airway pressure settings of 5 to 15cmH2O,withnomandatory rate (spontaneous breath trigger). At thispoint, any procedures clinicians deemed necessary were performed,such as nasogastric tube placement.

After 3 minutes of denitrogenation, patients then received amuscle relaxant (succinylcholine or rocuronium) and beganreceiving nasal cannula apneic oxygenation, and intubation attemptsweremade45 to 60 seconds afterward. In some cases, if the cliniciansdeemed the patient’s improvement after preoxygenation was soprofound that intubationwas no longer necessary, the procedurewasdelayed and the patient was allowed to emerge from dissociation.This was predicated on clinical judgment and not part of our delayedsequence intubation protocol. In these patients, the post–delayedsequence intubation oxygen saturation for the primary outcomewas at 3 minutes after the administration of ketamine (the timemuscle relaxants would have been administered).

Outcome MeasuresThe primary outcome of this study was the difference in

oxygen saturations after maximal attempts at preoxygenationbefore delayed sequence intubation compared with saturationsjust before intubation. Maximal attempts at preoxygenation

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Figure 1. Elaboration of the procedure of delayed sequence intubation.

Weingart et al Delayed Sequence Intubation

included attempting to verbally persuade the patient to keep onthe oxygen mask or NIPPV mask or to allow the procedureand, if that failed, gently holding the mask on the patient’sface, without straps. The 2 points for the oxygen saturationswere defined as the saturation just before the decision toproceed with ketamine administration (pre–delayed sequenceintubation) compared with the oxygen saturation just beforemuscle relaxant administration (post–delayed sequenceintubation). Predetermined secondary outcomes included thenumber of patients with pre–delayed sequence intubationsaturations likely to progress to critical desaturation (�93%)and their post–delayed sequence intubation saturations,3 thenumber of successful nasogastric tube placements in patientswho would not tolerate attempts at this procedure during theirpreintubation preparations, and the number of successfuldenitrogenations (defined as �3 minutes of tidal volumebreathing while continuously exposed to a high-FiO2 sourcewithout any room-air breaths6). Complications associatedwith delayed sequence intubation were tracked as well; thepredetermined complications included pre–muscle relaxantapnea (defined as any apnea from 10 seconds after the


administration of ketamine until the administration of musclerelaxant), peri-intubation emesis, and peri-intubation cardiacarrest or mortality (within 3 hours of intubation).

Primary Data AnalysisDescriptive statistics were assessed with means (SD). Mean

differences between the saturations pre– and post–delayedsequence intubation were assessed with a paired t test because thedata were normally distributed. Data were also analyzed withnonparametric methods (Wilcoxon signed rank test), with nodifference in results. Computer analysis was performed withSPSS (version 22; IBM Corporation, Armonk, NY).

RESULTSSixty-four patients with delayed sequence intubation were

included from May 2011 to December 2013 (Figure 2). Twopatients were excluded because the pulse oximeterwould not registera post–delayed sequence intubation oxygen saturation. Both of thesepatients had arterial blood gases sent from their arterial lines at thispoint; the SaO2 values of these blood gases were both 100% andneither of these patients had any complications.


Figure 2. Enrollment and flow through the study.


The Table summarizes the characteristics of the remaining 62study patients. The mean patient age was 54 years; 33% werewomen. The Table also shows the patients’ underlying condition,the primary reason for intubation, and the reason delayed sequenceintubation was needed. Fifty-five patients were intubated in anED setting; 7, in an ICU. The mean total dose of ketamineadministered to facilitate delayed sequence intubation was 112mg.For the 42 patients with available weight data, the mean total dosewas 1.4 mg/kg.

Saturations increased from a mean of 89.9% before delayedsequence intubation to 98.8% afterward, with an increase of 8.9%(95% confidence interval 6.4% to 10.9%). Figure 3 shows thesaturation changes of the individual patients. Thirty-two patientswere in the predetermined group with high potential for criticaldesaturation (pre–delayed sequence intubation saturations�93%). All of these patients increased their saturationspost–delayed sequence intubation; 29 (91%) of them increasedtheir post–delayed sequence intubation saturations to greaterthan 93%. All but 1 of these patients received NIPPV forpreoxygenation during delayed sequence intubation.

Four patients with upper gastrointestinal bleeding receiveddelayed sequence intubation to allow the placement of a nasogastrictube to drain their gastric blood before intubation; all 4 of thesepatients had successfully placed tubes confirmed by postintubationradiography. Of the 19 patients who received delayed sequence


intubation to allow nonrebreather mask preoxygenation ordenitrogenation, all were successfully denitrogenated for the3-minute period.

Two patients were not intubated post–delayed sequenceintubation. Both of them were asthmatic, with altered mentalstatus. After administration of ketamine, both of these patientstolerated NIPPV. They received nebulized asthma medicationsand steroids. The clinicians deemed that the patients’ respiratorystatus improved sufficiently post–delayed sequence intubationthat intubation could be avoided. Both of these patients emergedwith continued improved respiratory status and were able to beadmitted to the hospital, receiving NIPPV. They weresubsequently discharged without the need for intubation.

No patients had pre–muscle relaxant apnea, peri-intubationemesis, cardiac arrest, or death. Two patients’ oxygen saturationsdecreased from the pre– to the post–delayed sequence intubationperiods. The first patient’s saturation decreased from 99% to 98%;the second patient’s, from 95% to 93%. Both of these patientswere receiving preoxygenation by nonrebreather masks withoutnasal cannula oxygen during their dissociation.

LIMITATIONSThis was not a randomized trial and therefore it is unknown

what the patient outcomes would have been in these cases if


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Table. Characteristics of study patients.

Characteristics All Patients (N[62)

Age, mean, y 54Range, y 18–79Female, % 33Location of intubation, PtsED 55Critical care unit 7Condition leading to need for intubation, PtsPneumonia 20Asthma 7Acute pulmonary edema 3Chronic obstructive pulmonary disease 1Acute lung injury 8Anaphylaxis 2Smoke inhalation 2Sepsis encephalopathy 2Hepatic encephalopathy 8UGIB 6Cardiogenic shock 1Trauma 2Primary reason for intubation, Pts (%)Oxygenation (type I) failure 42 (68)Ventilatory (type II) failure 2 (3)Airway protection 18 (29)Reason for DSI, Pts (%)Intolerance of nonrebreather mask 19 (31)Intolerance of NIPPV 39 (63)Intolerance of nasogastric tube placement for UGIB 4 (6)

Pts, Patients; UGIB, upper gastrointestinal bleeding; DSI, delayed sequenceintubation.

Figure 3. Oxygen saturations (SpO2) pre– and post–delayedsequence intubation for the 62 enrolled patients. Blue dotsindicate pre-DSI saturation and red dots indicate post-DSIsaturation. When there was no change during the dissociativeperiod, a red dot indicates both saturations. The oxygensaturations of the 32 patients whose pre-DSI saturation wasless than 93% (red line) can be seen on the left side of the plot.


delayed sequence intubation had not been used. We collectedpatients as a convenience sample when the clinician deemed thatdelayed sequence intubation would have been beneficial; hence,there may be inherent selection bias. It is possible that a delayedsequence intubation was performed at one of these centers but thepatient was not enrolled in the study. This is unlikely because allintubations were reviewed by a research associate specifically toscreen for missed delayed sequence intubation.

All delayed sequence intubations were supervised by clinicianswith extensive experience with ketamine sedation in adults;clinicians lacking familiarity with the medication may not havethe same results. Furthermore, the study authors performedmany of these intubations and may have given a higher level ofcare and attention because of a vested interest in good outcomes.

The study was small; there may be rare complications that willemerge only on the performance of larger trials, though areassurance of safety can be extrapolated from the complicationrate of ketamine for procedural sedation in adults.7 The safety ofNIPPV in this cohort cannot be applied to all patients withaltered mental status, such as obtunded or brain-injured patients.Although no patients in this cohort had tachycardia orhypertension necessitating treatment, these adverse events arepotentially those of ketamine. Only adult patients were included;the safety and efficacy of delayed sequence intubation in thepediatric population is unknown, though there have been casereports of its use.8,9


DISCUSSIONIn this prospective trial, we found that delayed sequence

intubation allowed the provision of preoxygenation anddenitrogenation to a patient population who would otherwisehave been resistant to these important procedures. Traditionally,these patients would have proceeded directly to rapid sequenceintubation, exposing them to the risks of peri-intubation bag-valve-mask ventilation such as gastric insufflation and aspiration.In patients with physiologic shunting, inadequate recruitmentand preoxygenation can lead to severe hypoxemia and peri-intubation cardiac arrest. In this study, delayed sequenceintubation was demonstrated to be effective and withoutobserved complications in these patient groups during emergencyairway management.

Delayed sequence intubation is often conflated with NIPPVpreoxygenation. Although the 2 complement each other,delayed sequence intubation can be performed with standardpreoxygenation as well. In this trial, 39 patients receivedpreoxygenation with NIPPV; the remaining 23 patientsachieved adequate preoxygenation and denitrogenation withnonrebreather mask alone.

There is a belief that NIPPV is contraindicated in patients withaltered mental status. Although some ICUs have begun to challengethis prohibition in many classes of patients,10-12 the traditionalreasons for the contraindication are not applicable to delayedsequence intubation. Ketamine-induced dissociation leads to theretention of airway reflexes and spontaneousbreathing, in contrast toother causes of altered mental status.13 We believe this is a safepractice during the fewminutes of preoxygenation as long as patientsare carefullymonitored by advanced airwaypractitioners throughoutthe delayed sequence intubation-preoxygenation.



In this study, a dose of 1 to 1.5 mg/kg was usually sufficient todissociate patients requiring emergency airway management.Many of the complications of ketamine, such as hypersalivation,are dose dependent.13 Because ketamine will show its full clinicaleffects within seconds, it is logical to administer a smaller initialdose, such as 1 mg/kg, and then administer continued aliquots of0.5 mg/kg until dissociation is achieved. In patients in whomimmediate control is needed, a larger dose can be administeredinitially because even in 10-fold overdose spontaneous breathingand airway reflexes are retained.13

In 2 of the delayed sequence intubations, the patients werejudged by the clinicians to not require intubation after ketamineadministration. Both of these were asthmatic patients who hadsignificant improvement after beginning to receive NIPPV.Although this is not a recommended aspect of delayed sequenceintubation, it bears future study. Other trials have examined theuse of sedation to facilitate the provision of NIPPV.14 Ketaminemay serve a similar role, but this trial is only suggestive of thispossibility. If a clinician opts to attempt this technique, werecommend administering an antiemetic such as ondansetron15

because, although peridissociation emesis from ketamine has notbeen reported in adults, postdissociation emesis is common.7 Ifsuch patients are allowed to emerge from sedation and are still inrespiratory distress, they can be intubated with standard rapidsequence intubation technique because there will have alreadybeen an extensive period of preoxygenation.

The oxygen saturations of 2 of the patients minimallydecreased while they were receiving denitrogenation. If duringdelayed sequence intubation there is a precipitous decrease inoxygen saturation, proceeding to standard rapid sequenceintubation is likely the best course. These patients will likely bedesaturating as a result of the continued effects of physiologicshunting, so a device incorporating positive end expiratorypressure should be used when reoxygenation of the patient isattempted (bag-valve-mask with positive end expiratory pressurevalve, ventilator, etc).1

The trial researchers have explored the use of other agents tofacilitate delayed sequence intubation, such as dexmedetomidine,droperidol, and remifentanil. However, they require furtherstudy before they can be recommended for this purpose. Incontrast to ketamine, these agents require provision of anadditional induction agent at administration of the musclerelaxant to ensure amnesia and adequate sedation. Some havesuggested that standard induction agents such as etomidate orpropofol or sedation agents such as midazolam could also be usedfor delayed sequence intubation. We strongly recommend againstthis because the nonapnea-inducing dosages of these agents maybe very different in a patient requiring resuscitation than onereceiving elective procedural sedation.16

Delayed sequence intubation will not be commonly neededbecause most patients are able to tolerate peri-intubationpreparation without additional sedation. Therefore, because itwill not be performed often, if delayed sequence intubation isneeded it is imperative to perform the procedure in a regimentedfashion. All equipment for preoxygenation, intubation, and the


possibility of difficult intubation should be at the bedside beforeketamine administration. Medications for rapid sequenceintubation should be drawn up and present at the bedside,including additional ketamine. A clinician should carefullyobserve the patient from the moment ketamine is administereduntil the endotracheal tube is placed and confirmed. Suction andventilation devices should be prepared before the administrationof ketamine.

Ketamine may cause a few seconds of transient apnea after initialrapid administration. Though ketamine-induced prolonged apneahas not been reported in the adult literature,7 we cannot exclude thepossibility of this rare complication. In the event this occurs, werecommend the immediate administration of a muscle relaxant(succinylcholine or rocuronium), which will place the patient inthe same situation as if standard rapid sequence intubation hadbeen performed. A similar circumstance is ketamine-inducedlaryngospasm. Although relatively common in pediatrics, it has beenreported only once in the adult cohort.17 Most situations of upperairway obstruction in adult ketamine dissociations are actually due topoor airway positioning, not laryngeal spasm. If actual laryngospasmoccurs during delayed sequence intubation, the muscle relaxantshould be administered, allowing standard rapid sequence intubation.

Additional information and media about delayed sequenceintubation can be found at http://emcrit.org/dsi/.

Delayed sequence intubation could offer an alternative torapid sequence intubation in patients requiring emergency airwaymanagement who will not tolerate preoxygenation or peri-intubation procedures. It is essentially procedural sedation, withthe procedure being preoxygenation. Using this technique, aresuscitationist retains a higher degree of control when intubatinga delirious patient. The traditional alternative is to progress torapid sequence intubation without adequate preparation, whichmay result in morbidity. Randomized controlled trials of thistechnique would be welcome, but would be difficult, given thispatient population. Delayed sequence intubation seems safe andeffective for use in emergency airway management.

The authors acknowledge Alex Manini, MD, PhD, and DavidShriger, MD, for their statistical advice and the FOAM communityfor encouragement and feedback.

Supervising editor: Gregory W. Hendey, MD

Author affiliations: From the Division of Emergency Critical Care,Department of EmergencyMedicine, Stony Brook UniversityMedicalCenter, Stony Brook, NY (Weingart); the Section of EmergencyMedicine, University of Chicago, Chicago, IL (Trueger); theDepartment of Emergency Medicine, Massachusetts GeneralHospital, Boston, MA (Wong); the Department of EmergencyMedicine, Icahn School of Medicine at Mount Sinai, New York, NY(Scofi); the Division of Critical Care Medicine, Montefiore MedicalCenter, New York, NY (Singh); and the Centre of Head andOrthopaedics, Department of Anaesthesia, Copenhagen UniversityHospital, Rigshospitalet, Denmark (Rudolph).

Author contributions: SDW was responsible for the overall studyand statistical review, was the principal investigator, collated


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comments from other authors, prepared the final article, had fullaccess to all the data in the study, and takes responsibility for theintegrity of the data and the accuracy of the data analysis. ST, JS,and NS were responsible for data collection. SDW and SSR wereresponsible for analysis and interpretation of the data and forstudy design. All authors critically reviewed the article. SDW takesresponsibility for the paper as a whole.

Funding and support: By Annals policy, all authors are required todisclose any and all commercial, financial, and other relationshipsin any way related to the subject of this article as per ICMJE conflictof interest guidelines (see www.icmje.org). The authors have statedthat no such relationships exist.

Publication dates: Received for publication August 7, 2014.Revision received September 16, 2014. Accepted for publicationSeptember 26, 2014. Available online October 23, 2014.

Presented as an abstract at the Society of Airway ManagementScientific Assembly, September 2012, Toronto, Canada.

REFERENCES1. Weingart SD, Levitan RM. Preoxygenation and prevention of

desaturation during emergency airway management. Ann Emerg Med.2012;59:165-175.e1.

2. Weingart SD. Preoxygenation, reoxygenation, and delayed sequenceintubation in the emergency department. J EmergMed. 2011;40:661-667.

3. Davis DP, Hwang JQ, Dunford JV. Rate of decline in oxygen saturationat various pulse oximetry values with prehospital rapid sequenceintubation. Prehosp Emerg Care. 2008;12:46-51.

4. Heffner AC, Swords DS, Neale MN, et al. Incidence and factorsassociated with cardiac arrest complicating emergency airwaymanagement. Resuscitation. 2013;84:1500-1504.

5. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reportingof Observational Studies in Epidemiology (STROBE) statement:

Advertising in Annals of

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guidelines for reporting observational studies. J Clin Epidemiol.2008;61:344-349.

6. Baraka AS, Taha SK, Aouad MT, et al. Preoxygenation: comparisonof maximal breathing and tidal volume breathing techniques.Anesthesiology. 1999;91:612-616.

7. Strayer RJ, Nelson LS. Adverse events associated with ketamine forprocedural sedation in adults. Am J Emerg Med. 2008;26:985-1028.

8. Lollgen RM, Webster P, Lei E, et al. Delayed sequence intubationfor management of respiratory failure in a 6-year-old child in apaediatric emergency department. Emerg Med Australas. 2014;26:308-309.

9. Schneider ED, Weingart SD. A case of delayed sequence intubation ina pediatric patient with respiratory syncytial virus. Ann Emerg Med.2013;62:278-279.

10. Mani R. Noninvasive ventilation for hypercapnic respiratory failure inCOPD: encephalopathy and initial post-support deterioration of pHand PaCO2 may not predict failure. Indian J Crit Care Med. 2005;9:217-224.

11. McNeill G, Glossop A. Clinical applications of non-invasive ventilationin critical care. Cont Educ Anaesth Crit Care Pain. 2012;12:33-37.

12. Scala R. Hypercapnic encephalopathy syndrome: a new frontier fornon-invasive ventilation? Respir Med. 2011;105:1109-1117.

13. Green SM, Roback MG, Kennedy RM, et al. Clinical practice guidelinefor emergency department ketamine dissociative sedation: 2011update. Ann Emerg Med. 2011;57:449-461.

14. Senoglu N, Oksuz H, Dogan Z, et al. Sedation during noninvasivemechanical ventilation with dexmedetomidine or midazolam: arandomized, double-blind, prospective study. Curr Ther Res Clin Exp.2010;71:141-153.

15. Langston WT, Wathen JE, Roback MG, et al. Effect of ondansetron onthe incidence of vomiting associated with ketamine sedation inchildren: a double-blind, randomized, placebo-controlled trial. AnnEmerg Med. 2008;52:30-34.

16. Shafer SL. Shock values. Anesthesiology. 2004;101:567-568.17. Burnett AM, Watters BJ, Barringer KW, et al. Laryngospasm and

hypoxia after intramuscular administration of ketamine to a patient inexcited delirium. Prehosp Emerg Care. 2012;16:412-414.

Emergency Medicine

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Epilepsy & Behavior 49 (2015) 343–346


Epilepsy & Behavior

j ourna l homepage: www.e lsev ie r .com/ locate /yebeh

Ketamine in refractory convulsive status epilepticus in children avoidsendotracheal intubation

Lucrezia Ilvento a,1, Anna Rosati a,1, Carla Marini a, Manuela L'Erario b, Lorenzo Mirabile b, Renzo Guerrini a,⁎a Pediatric Neurology Unit, Children's Hospital “A. Meyer”, University of Florence, Italyb Intensive Care Unit, Children's Hospital “A. Meyer”, University of Florence, Italy

⁎ Corresponding author at: Pediatric Neurology Unit,University of Florence, Viale Pieraccini 24, 50139 Firenzefax: +39 055 5662329.

E-mail address: [email protected] (R. Guerrini).1 These authors contributed equally to the manuscript.

http://dx.doi.org/10.1016/j.yebeh.2015.06.0191525-5050/© 2015 Elsevier Inc. All rights reserved.

a b s t r a c t
a r t i c l e i n f o
Article history:
Revised 9 June 2015Accepted 10 June 2015Available online 16 July 2015
Keywords:KetamineStatus epilepticusRefractory status epilepticusConventional anestheticsChildrenEndotracheal intubation

Objective: The purpose of this study was to report on the efficacy and safety of intravenous ketamine (KE) in re-fractory convulsive status epilepticus (RCSE) in children and highlight its advantages with particular reference toavoiding endotracheal intubation.Methods: Since November 2009, we have used a protocol to treat RCSE including intravenous KE in all patientsreferred to the Neurology Unit of the Meyer Children's Hospital.Results: From November 2009 to February 2015, 13 children (7 females; age: 2 months–11 years and 5 months)received KE. Eight patients were treated once, two were treated twice, and the remaining three were treated3 times during different RCSE episodes, for a total of 19 treatments. Most of the RCSE episodes were generalized(14/19). A malformation of cortical development was the most frequent etiology (4/13 children). Ketamine wasadministered from a minimum of 22 h to a maximum of 17 days, at doses ranging from 7 to 60 mcg/kg/min,obtaining a resolution of the RCSE in 14/19 episodes. Five patients received KE in lieu of conventional anesthetics,
thus, avoiding endotracheal intubation. Ketamine was effective in 4 of them. Suppression-burst pattern was ob-served after the initial bolus of 3 mg/kg in the majority of the responder RCSE episodes (10/14).Conclusions: Ketamine is effective in treating RCSE and represents a practical alternative to conventional anes-thetics for the treatment of RCSE. Its use avoids the pitfalls and dangers of endotracheal intubation, which isknown to worsen RCSE prognosis.
This article is part of a Special Issue entitled “Status Epilepticus”.
1. Introduction

Status epilepticus (SE) is a life-threatening emergency traditionallydefined as ‘an acute epileptic condition characterized by continuous sei-zures for at least 30 min, or by 30 min of intermittent seizures withoutfull recovery of consciousness between seizures’ [1]. Convulsive SE is themost common and harmful form. Based on improved understanding ofpathophysiology, there is now consensus that any seizure lasting longerthan 5 min should be treated as SE [2].

Status epilepticus lasting longer than 120min and not responding tofirst-line (benzodiazepines) and second-line (midazolamat a high dose,phenytoin, and phenobarbital) antiepileptic drugs (AEDs) is defined as“refractory” and requires Intensive Care Unit (ICU) treatment [3]. The

Children's Hospital “A. Meyer”,, Italy. Tel.: +39 055 5662573;

term “super-refractory” defines SE that continues, or recurs, for 24 hor longer or recurs after withdrawal of anestheticpropofol infusion syn-drome therapy [3]. Evenwith current best practice, neurological sequelaeoccur in N50% of children with refractory convulsive status epilepticus(RCSE) [4,5]. The mortality rate of RCSE ranges between 2.7 and 5.2%and increases up to 5–8%when only data from ICU are taken into account[4,5]. Refractory convulsive status epilepticus is generally treated withcoma induction with high-dose midazolam or thiopental or propofol[6–8]. However, the high risk of “propofol infusion syndrome” often limitsits use in children [9].

Increasing evidence indicates that ketamine (KE), a potent N-methyl-D-aspartate antagonist, may be effective in treating RCSE [10]. Compared toconventional anesthetics, KE has neither cardiac nor respiratory depressantproperties. Its administration, therefore, does not imply emergentendotracheal intubation, a prognostic factor of increased morbidity andmortality risk in critically ill adults and children [11–13].

Here, we report our experience using KE in a treatment protocolfor children with RCSE, extending our initial series of patients [14] andincluding those children inwhomKEwas administered prior to conven-tional anesthetics.

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344 L. Ilvento et al. / Epilepsy & Behavior 49 (2015) 343–346

2. Material and methods

Since November 2009, our Pediatric Neurology Unit at the MeyerChildren's Hospital (Florence, Italy) has used a treatment protocol forRCSE including intravenous KE infusion. S(+)-ketamine (Ketanest S®;Parke-Davis, Freiburg, Germany) was the isoform we used untilNovember 2011. We subsequently started using racemic KE(Ketamina®, Molteni S.p.A., Italy) as the only form of the drug availableat our hospital.

Since January 2013, to avoid mechanical ventilation, we have usedKE (Ketamina®, Molteni S.p.A., Italy) before considering conventionalanesthetics.We have set as primary endpoint the control of both electri-cal and clinical seizures under continuous video-EEG recording.

By protocol, we administer 2 boluses of 2–3 mg/kg each of KE 5 minapart, immediately followed by continuous infusion of 5–10mcg/kg/min.Based on both the clinical and electrographic response, we then increasethe dose every 10min or longer, using 2 to 10mcg/kg/min increments, upto 60 mcg/kg/min [14]. We administer add-on midazolam at 1mcg/kg/min to prevent emergent side effects such as hallucinations. Rou-tine blood tests are performed regularly.

We collected clinical and EEG features of all patients treated withKE, including age at diagnosis, sex, type of SE, etiology, age at onsetand duration of SE, type and doses of additional AEDs and conven-tional anesthetics (when applicable), sequence of drug administra-tion, tolerability, and outcome.

The pediatric ethics committee of the Tuscany region approved thestudy. Written informed consent of the parents was required beforeKE administration.

3. Results

Between November 2009 and February 2015, 68 consecutive pa-tients were admitted for SE, and 29 of them were transferred to theICU because of RCSE. Thirteen children (7 female) received intravenousKE. Eight patientswere treated once, twowere treated twice, and the re-maining threewere treated 3 times during different RCSE episodes, for atotal of 19 treatments (Table 1). Ten RCSE episodes were treated with

Table 1Clinical, demographic, and EEG data of 13 children with refractory convulsive status epilepticu

Case no. Sex Age Neurologicalexamination

Diagnosis Etiolo

1 F 2 months Severe CI, quadriparesis EE Unkno2a F 16 months Severe CI, quadriparesis EE Unkno2b F 26 months Severe CI, quadriparesis EE Unkno3a F 26 months Severe CI, quadriparesis EE Unkno3b F 3 years and 4 months Severe CI, quadriparesis EE Unkno4 F 2 years and 6 months Severe CI, quadriparesis EE Sindro5a M 4 years and 8 months Severe CI, quadriparesis EE Mitoc5b M 7 years Severe CI, quadriparesis EE Mitoc5cd M 9 years Severe CI, quadriparesis EE Mitoc6 M 5 years CI, hemiparesis EE MELA7 F 7 years and 9 months Normal FE FCD8a F 8 years and 2 months Severe CI, quadriparesis FE Type 18b F 11 years and 2 months Severe CI, quadriparesis FE Type 18cd F 11 years and 5 months Severe CI, quadriparesis FE Type 19 M 9 years and 7 months Normal FIRES Undefi10 M 10 years and 5 months Normal FIRES Undefi11d F 6 months CI, hemiparesis EE Hemim12d M 3 years and 3 months Severe CI, quadriparesis EE Malfo13d M 4 months Severe CI,

quadriparesisEE Unkno

Legend: BS, burst suppression pattern; CI, cognitive impairment; EE, epileptic encephalopathyepilepsy syndrome; GC, generalized convulsive; i.v., intravenous; KE, ketamine; M, male; Mmyoclonus; SE, status epilepticus; SG, secondary generalization.

a First treatment with ketamine.b Second treatment with ketamine.c Third treatment with ketamine.d Cases treated with KE without endotracheal intubation.

S(+)-ketamine, while racemic KE was administered in the remaining9. Patients' ages at the time of treatment ranged from 2 months to11 years and 5 months (mean: 5 years and 3 months; median: 3 yearsand 4 months).

A history of epilepsy preceding RCSE was present in 11 patients;SE had previously occurred in 7. Most of the RCSEs were generalized(14/19), and the most frequent etiology was a cerebral malformation(4/13 children).

The initial therapy for SEwas startedwithin amedian of 15min fromadmission (range: 10–45 min). Ketamine was applied within a mediantime of 7 days (range: 5 h–26 days). The median KE dose was 30mcg/kg/min (mean: 33.6± 4.5mcg/kg/min; range: 7–60mcg/kg/min).In 14/19 treatments, KE was administered after conventional intrave-nous anesthetics: midazolam, 8 pts (mean: 3.2 ± 1.9 mcg/kg/min; me-dian: 3 mcg/kg/min); propofol, 4 pts (mean: 4.1 ± 1.8 mg/kg/h;median: 4.5 mg/kg/h); thiopental, 4 pts (mean: 7.8± 3.7mg/kg/h;me-dian: 9 mg/kg/h). Median duration of KE administration was 3 days(mean: 4.2 ± 1.9 days; range: 1–17 days).

The use of KEwas associated with resolution of RCSE in 14 episodes;a burst suppression EEG pattern was obtained in 10. In the remaining 4episodes, resolution of the RCSE was obtained through the appearanceof delta activity and a rapid, progressive reduction in seizure frequency(maximum: 8 per day).

In 5 children (2 females; age range: 4 months–11 years and5 months), KE was administered in lieu of conventional anesthetics,thus, avoiding mechanical ventilation. In all of them, the maximumdose infusion was 60 mcg/kg/min (range: 7–60 mcg/kg/min; median:20 mcg/kg/min) for a maximum of 4 days (range: 1–4 days, median:2 days). Status epilepticus control was obtained in 4/5 individuals.The only nonresponder was completely seizure-free for 8 h with 20mcg/kg/min of KE, yet, daily seizures recurred during and after thedrug withdrawal.

Among the 19 RCSE episodes, 5were not controlled by KE. In 2 of the5 no responders, SE, which became eventually life-threatening, wassuccessfully treated by surgical removal of focal cortical dysplasia.

During KE administration, a slight increase of saliva productionoccurred in all patients. A transient, mild increase of liver enzymes

s treated with KE.

gy Seizure typesduring SE

KE dosage(mcg/kg/min)

EEG after i.v. KE KEefficacy

wn Focal, My 40 BS Yeswn My 27 BS Yeswn Focal, My 55 BS Yeswn Focal +/− SG 20 BS Yeswn Focal +/− SG 30 BS Yesme Rett Focal, My, GC 50 BS Yeshondrial disease Focal, My, GC 10 Transitory BS Nohondrial disease Focal, My, GC 30 Theta–delta activity Yeshondrial disease Focal, My, GC 10 Transitory BS NoS Focal +/− SG 40 Theta–delta activity Yes

Focal 10 No change Nomultilobar FCD Focal +/− SG 60 No change Nomultilobar FCD Focal +/− SG 50 No change Nomultilobar FCD Focal +/− SG 60 BS and delta activity Yesned Focal +/− SG 40 BS Yesned Focal +/− SG 60 BS Yesegalencephaly Focal +/− SG 20 BS Yes

rmative Focal +/− SG 7 Theta–delta activity Yeswn Focal, My 20 BS Yes

; F, female; FCD, focal cortical dysplasia; FE, focal epilepsy; FIRES, febrile infection-relatedELAS, Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; My,

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345L. Ilvento et al. / Epilepsy & Behavior 49 (2015) 343–346

occurred in 4 children who had also received phenobarbital. No addi-tional adverse events were observed, in particular, no psychotomimeticchanges, respiratory depression, or hemorrhagic cystitis occurred.

Follow-up brain MRI was performed 3 to 12 months (median: 6.5months) after KE treatment in 6 patients. Two patients, both with an un-known progressive disorder, exhibited worsening of preexisting brain at-rophy, which we attributed to the underlying condition; 2 patients withfebrile infection-related epilepsy syndrome (FIRES) exhibited mild atro-phic changes, a likely consequence of the causative encephalopathy;and no change occurred in the remaining 2 patients.

4. Discussion

Our series (Class IV of evidence), although small, provides furtherevidence of the efficacy of KE for treating RCSE in children and its safetyprofile [14]. Status epilepticus resolution was obtained in 14/19 RCSEepisodes, and none of the 13 patients experienced serious adverseevents. In 2 of the 5 RCSE episodes in which the drug was ineffective,resolution of the SE, even after the failure of conventional anesthetics,was obtained only with surgical treatment. Ketamine was also effectivein 4/5 children that received it prior to conventional anesthetics, thus,avoiding the risks of endotracheal intubation in the management ofRCSE. Thus, we believe that KE therapy should be considered beforeconventional anesthetics in the treatment algorithms of RCSE.

Status epilepticus is a significant cause of morbidity andmortality inthe pediatric population [4,5].Management of SE includes systemic sup-port of airway and circulation, seizure control, prevention of recurrence,and treatment of the underlying cause. The underlying etiology is themain determinant factor of mortality [4], whereas the main cause ofdeath is an acute respiratory distress syndrome, which is regarded as ei-ther the result of prolonged and continuous infusion of high-dose anes-thetics or the complication of the late phase of RCSE [11,13].

There are a general consensus over the first and second lines oftreatment of SE. Although the types of drugs are similar in differentcountries, the algorithm/protocols may differ, as well as between insti-tutions. Conversely, there is currently no definitive data or consensus toguide both the optimal choice of therapy and treatment goals for RCSE[3,6–8]. Refractory convulsive status epilepticus is generally treatedwith coma induction using high-dosemidazolam or conventional anes-thetics such as thiopental or propofol [6,8], although the high risk ofpropofol infusion syndrome is often a limitation to the use of this drugin children [9]. While conventional anesthetics are effective, their intra-venous administration is associated with hypotension, myocardial de-pression, and low cardiac output that require ICU admission. All thesedrugs also require endotracheal intubation,which represents a negativeprognostic factor of morbidity and mortality [11–13].

Between 15 and 39% of emergent endotracheal intubations in adultsare associatedwith one ormore complications, including severe hypox-emia, hemodynamic collapse, and death [11,13]. In the pediatric popu-lation, the complication rate is even higher, and acute deteriorationcan occur rapidly as a result of age-related differences in physiology,oxyhemoglobin dissociation, oxygen consumption, and pulmonarymechanics [12].

Because of its sympathomimetic action, KE has no cardiac depres-sant properties and does not cause hypotension [15]. Owing to its phar-macological properties, KE use does not necessarily require amineadministration or mechanical ventilation. Large doses of KE and rapidintravenous boluses may cause hallucinations, which are less frequentin children than in adults and can be reduced with benzodiazepinepremedication [15]. Ketamine has neuroprotective properties bypreventing transduction of signals to destructive intracellular mecha-nisms through the blocking of NMDA receptors [15,16].

Differences between the drug's two isomers have been reportedwith regard to their anesthetic potency and EEG effects [17,18]. In ourseries, response-adjusted dosage did not result in different dosages of

the two drug preparations, in different rates of adverse events or typesof EEG patterns.

Experimental models suggest that, with continuing seizures,inhibitory γ-aminobutyric acid (GABAA) receptors are internalizedin clathrin-coated vesicles, and excitatory N-methyl-D-aspartate(NMDA) receptors are mobilized to the membrane [19,20]. Thisreceptor-trafficking results in decreased inhibitory control and in-creased excitation that may foster sustained SE [19,20]. Conven-tional anesthetics, which all act on GABAA receptors, will,therefore, be less active, making higher doses necessary, whichwill in turn enhance their untoward effects, especially hypoten-sion, and, thus, require vasopressor administration [13]. In this sce-nario, NMDA modulating molecules such as KE represent anattractive alternative in status epilepticus [10]. The literature hasprovided good evidence for the potential benefit and low adverseevents of KE, in both the adult and pediatric populations withRCSE. However, the heterogeneity of prior treatments, time to KEadministration (which is always considered after conventional an-esthetic failure), and KE dosage and duration make available infor-mation on seizure responsiveness difficult to interpret.

Our pediatric series shows that treatment with KE in RCSE is effec-tive and safe, and its use should be considered before thiopental andpropofol, unless specific contraindications to KE exist. Based on theseencouraging results, we have designed a national multicenter random-ized sequential trial, which has been approved by the Italian MedicinesAgency and includes ten pediatric hospitals (EudraCT number 2013-004396-12; ClinicalTrial.gov identification number: NCT02431663).

Acknowledgments

Wewould like to thankDebora DiMaina, Elisa Nacci, and the teamofEEG technicians of the Neurophysiology Laboratory for their technicalsupport, especially concerning the extensive data acquisition andhandling.

Conflict of interest

The authors have stated that they had no interests thatmight be per-ceived as posing a conflict or bias.

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[14] Rosati A, L'Erario M, Ilvento L, Cecchi C, Pisano T, Mirabile L, et al. Efficacy and safetyof ketamine in refractory status epilepticus children. Neurology 2012;79:2355–8.

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The Journal of Emergency Medicine, Vol. 48, No. 6, pp. 712–719, 2015Copyright � 2015 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2015.02.019

This study wasthe University of

RECEIVED: 17 FeACCEPTED: 21 F

Pharmacology inEmergency Medicine

KETAMINE USE FOR ACUTE AGITATION IN THE EMERGENCY DEPARTMENT

Austin B. Hopper, BS,* Gary M. Vilke, MD,*† Edward M. Castillo, PHD, MPH,*† Ashleigh Campillo, BS,*

Timothy Davie, MD,*‡ and Michael P. Wilson, MD, PHD*†

*Department of Emergency Medicine Behavioral Emergencies Research (DEMBER) Lab, University of California, San Diego, San Diego,California, †Department of Emergency Medicine, University of California, San Diego, San Diego, California, and ‡Department of Emergency

Medicine, Maricopa Integrated Health System, Phoenix, Arizona

Reprint Address:Michael P. Wilson, MD, PHD, Department of Emergency Medicine, University of California, San Diego, 200 West Arbor Drive,San Diego, CA 92103

, Abstract—Background: Emergency physicians regu-larly encounter agitated patients. In extremely agitatedand violent patients, the onset of many traditional medica-tions is relatively slow and often requires additional medica-tion. Ketamine is frequently used in emergency departments(EDs) for procedural sedation and intubation, but hasrecently been suggested as a treatment for acute agitation.Objectives: We sought to examine the use of ketamine inthe treatment of acute agitation in an ED setting, includingvital sign changes as a result of this medication. Methods:This is a structured review of an historical cohort of patientsover 7 years at two university EDs. Patients were included ifthey received ketamine as treatment for acute agitation.Abstracted data included age, vital signs including hypoxia,any additional medications for agitation, and alcohol/drugintoxication. Results: Ketamine was administered for agita-tion on 32 visits involving 27 patients. Preadministration sys-tolic blood pressure was 131 ± 20 mm Hg, with an averagepostadministration increase of 17 ± 25 mm Hg. The averagebaseline heart rate was 98 ± 23 beats/min, with an averageincrease of 8 ± 17 beats/min. No patients became hypoxic;62.5% of patients required additional calming medication.Alcohol or drug intoxication was present in 40.6% of pa-tients. Conclusions: We found ketamine was used rarely,but had few major adverse effects on vital signs even in apopulation with 21.9% alcohol intoxication. However, ahigh proportion (62.5%) of patients required additional

approved by the institutional review board ofCalifornia, San Diego prior to data collection.

bruary 2014; FINAL SUBMISSION RECEIVED: 15 Jaebruary 2015

712

pharmacologic treatment for agitation, implying thatadministering ketamine is useful only for initial control ofsevere agitation. � 2015 Elsevier Inc.

, Keywords—ketamine; agitation; aggression; control;vital signs

INTRODUCTION

Emergency physicians regularly encounter agitated pa-tients in the emergency department (ED) (1–11).Causes of ED-based agitation are numerous, rangingfrom psychosis to intoxication (2–5,8). Although verbalde-escalation is recommended as first-line treatment, insome cases this can be ineffective and medication admin-istration may be required to prevent these patients fromharming themselves or others (10,12). However, manyof these medications have a relatively slow onset,require empiric dosing, and often require additionalmedication for calming (10,13).

Ketamine is a dissociative agent acting through anta-gonism of glutamate N-methyl-D-aspartate receptors,which causes a trance-like state resulting in analgesiaand amnesia (14). It is frequently used in EDs for proce-dural sedation as well as an induction agent for intuba-tion, but has only recently been proposed as a treatmentfor agitation. Dissociative anesthesia occurs in 1–2 min

nuary 2015;

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Ketamine Use for Acute Agitation in the Emergency Department 713

intravenously and approximately 3 min in intramuscularadministration (14,15).

In particular, ketamine has been proposed as an alter-native to traditional antipsychotic treatment in the treat-ment of severe acute agitation (13,16,17). TheAmerican College of Emergency Physicians’ WhitePaper on Excited Delirium Syndrome describes thebenefits of ketamine as a fast-acting medication inagitated and violent patients with a low rate of side effects(18). The rapid onset of ketamine, under 5 min, comparesfavorably to haloperidol and droperidol, in which peaksedation can take more than 20 min (19,20). Most ofthe literature focuses on the traditional uses of ketaminefor procedural sedation primarily involving children orinduction for intubation. Little published research hasbeen done on its use for the treatment of acute agitationin EDs, though one prehospital case series has shownsignificant decreases in oxygen saturation afteradministration (21).

The oxygen desaturations in this case series are puz-zling, particularly because ketamine is thought by mostemergency physicians to have few effects on vital signs.However, ketamine has been noted to worsen tachycardiaand hypertension in nonagitated patients, and may be amild respiratory depressant at high doses, with respira-tory drive depressed approximately 15–22% (15,22,23).Post administration, dysphoric emergence phenomenahave been reported to occur in 10–20% of adult patientssedated with ketamine, though these are often mild andcan be treated with low doses of midazolam (21). Adjunc-tive use of benzodiazepines may be dispreferred inchildren, however, studies have shown no difference be-tween midazolam and placebo groups in rates of recoveryagitation and that benzodiazepines may increase the riskof adverse airway events in children (22,24).

Objectives

The purpose of this study is to examine the efficacy andsafety of ketamine in the treatment of acute agitation inan ED setting. Given a recent report that ketamine usein the prehospital setting was associated with a surprisingnumber of oxygen desaturations, the primary measure-ment of interest was any increases or decreases in vitalsigns after ketamine, particularly oxygen saturation (21).

MATERIALS AND METHODS

Study Design and Setting

This is an historical cohort study at two university EDs, oneurban academic teaching hospital, and one suburban com-munity hospital. Combined, these EDs treat approximately65,000 patients per year. This study was approved by thelocal institutional review board prior to data collection.

Selection of Participants

The cohort was identified by a keyword search of the elec-tronic medical record (EMR) for all patients who receivedketamine between September 15, 2004 and June 6, 2012.Patients were included if ketamine was administered astreatment for acute agitation. Agitation was defined,following recent American Association for EmergencyPsychiatry BETA project guidelines, as ‘‘an extremeform of arousal that is associated with increased verbaland motor activity’’ (25). This definition was operationallyadapted for use by including situations where the patientwas noted to be physically aggressivewith staff, require re-straints, or have increased verbal/motor activity interferingwith treatment. Patients were excluded if they received ke-tamine for any other reason, including procedural sedationor intubation, or if the chart was irretrievable.

The following variables were queried from the EMR:age, sex, and chief complaint. The following data werethen abstracted by blinded research associates: patient vi-tal signs (heart rate, blood pressure, respiratory rate, andoxygen saturation), route/dose/time of ketamine adminis-tration, previous administration of antipsychotics or ben-zodiazepines, additional calming medication within 3 h,alcohol levels measured via serum alcohol/breathalyzer,and urine toxicology lab results when available. If avail-able, preadministration vital signs were recorded as closeto the initial administration of ketamine as possible. Ifavailable, postadministration vitals were recorded forboth the lowest and highest values of a particular vitalsign parameter that were recorded within 4 h of adminis-tration. Additional calming medication was defined asadditional antipsychotics, benzodiazepines, or ketamineadministered for agitation within 3 h of the initial doseof ketamine. Although 3 h is not based on the half-lifeof ketamine, this figure has been used in other agitation in-vestigations of this type (26–29). All records wereevaluated by a minimum of three researchers who weretrained on use of the EMR. At least 2 research assistantsevaluated the EMR for each patient visit and selectedthose cases where ketamine was given for agitation;once all researchers had completed their review, theresults were compared. Full consensus between theresearchers was required for inclusion. Patients selectedfor inclusion subsequently had their EMR furtherevaluated for return to the ED for exacerbation of anypsychiatric issues after administration of ketamine.

Data Collection and Processing

All data were entered into a standardized computer work-sheet using Excel 2010 (Microsoft, Redmond, WA), andthen checked for nonsensical values. Change in vital signswithin 4 h after administration of ketamine was calculated

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Table 1. Summary of Patient Gender, Age, and DischargeDiagnosis

Case GenderAge,Years Discharge Diagnosis*

1 M 10 Agitation (autism/tuberous sclerosis)2 F 9 Head trauma3 M 36 Alcohol intoxication4 M 31 Polysubstance intoxication5 M 20 Leg pain (autism)6 M 34 Polysubstance intoxication7† F 24 Ovarian cyst (autism)8 M 40 Primary psych & polysubstance

intoxication9 M 41 Polysubstance intoxication10 M 28 Amphetamine intoxication11† F 24 Finger pain (autism)12† F 24 Ovarian cyst (autism)13† F 24 Ovarian cyst (autism)14 M 56 Head trauma (developmental delay)15 M 49 Anticholinergic delirium16 M 50 Seizure17† F 24 Ovarian cyst (autism)18 M 53 Amphetamine intoxication19 F 30 Suicide attempt20 F 40 Chronic pain21 F 19 Polysubstance intoxication22 M 12 Antipsychotic medication change

(autism)23 M 53 AIDS-related encephalitis24 M 31 Chronic pain25 M 34 Primary psych26 M 77 Dementia27 M 53 Primary psych & cocaine intoxication28 F 37 End-stage renal disease29 F 26 Primary psych & alcohol intoxication30 M 26 Alcohol intoxication31 F 71 Dementia32 M 47 Alcohol intoxication

* Parentheses after the diagnosis contains conditions indicatedto be exacerbating agitation or impeding treatment.† These five cases represent the same patient on different visitsto the emergency department.

714 A. B. Hopper et al.

relative to the baseline vital sign preadministration withineach patient to prevent small changes in baseline vital signsfrom skewing the analysis across patients. Four hourspostmedication administration was chosen, as this hasbeen used in other investigations of this type and is appro-ximately equal to two half-lives of ketamine (t1/2 = 2.17 h)(23,26–29). Hypoxia after administration of ketamine wasdefined as an oxygen saturation of <90%.

Outcome Measures

The primary outcomemeasures were change in vital signspostadministration and the need for any additional calm-ing medication. Vital sign changes were calculated withina particular patient, as noted above.

Primary Data Analysis

Descriptive statistics were used to evaluate patient char-acteristics such as age, gender, change in vitals, ketaminedose, and proportions of patients who received additionalcalming medication within 3 h.

RESULTS

Over the study period, 459 patients who received keta-mine in the ED were identified. Thirty-two casesinvolving 27 patients met study inclusion and exclusioncriteria and were subjected to further analysis. Theremaining 427 patient visits received ketamine for non-agitation-related causes, primarily for procedural seda-tion or induction of intubation. One autistic, nonverbalpatient who was uncooperative with treatment receivedketamine on five separate visits. The age range of thestudy group was from 9 to 77 years (average age of35 6 16 years; 20 males). Weight was recorded in fivepatient visits. Discharge diagnoses, age, and gender foreach patient are listed in Table 1.

A total of 17 patient visits received intramuscular(i.m.) ketamine, and 15 received intravenous (i.v.) admin-istration. In 18 (56.2%) cases, a patient received medica-tion for agitation prior to being administered ketamine,most often a combination of an antipsychotic and abenzodiazepine. On 20 patient visits (62.5%), additionalcalming medication was utilized, most often additionalketamine. In eight (25%) visits, both pre- and postadmi-nistration medication was required. Thirteen patients in-toxicated with alcohol or other substances (40.6%)required additional calming medication at a higher ratethan those who were not (84.6% vs. 47.4%). A summaryof medication and intoxication can be found in Table 2. Inno cases were dysphoric emergence reactions noted, andin no cases did patients return to the ED for noted exacer-bations of psychiatric conditions due to ketamine.

There were sufficient data to evaluate postadminis-tration change in systolic blood pressure (SBP) in 22visits with an average preadministration SBP of131 6 20mmHg.Within 4 h of administration, the high-est recorded SBP for each patient showed an average in-crease of 17 6 25 mm Hg from the patient’s baseline.The lowest recorded SBP in the same time period showedan average drop of 14 6 24 mmHg. Change in heart ratewas evaluated in 25 cases; the average preadministrationheart rate was 98 6 23 beats/min. The average highestincrease from baseline was 8 6 17 beats/min, and thelargest decrease was 10 6 18 beats/min. Twenty-twocases provided oxygen saturation data in which the pread-ministration average was 98 6 2%. Postadministrationaverage highest increase was 1.1 6 1.7%, and averagelargest decrease was 0.6 6 2.2%. No patients becamehypoxic; the lowest oxygen saturation after administra-tion was 94%. A summary of change in SBP and heartrate can be found in Table 3.

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Table 2. Medication Administered and Urine Toxicology/Breathalyzer Results

Case Prior Medication Initial Ketamine Dose Additional Medical Intervention Intoxication†

1 150 mg i.m. +00:50 Ketamine 150 mg i.m.2 40 mg i.m. +00:13 Ketamine 40 mg i.m.

+00:35 Ketamine 40 mg i.m.+00:50 Ketamine 60 mg i.m.+01:02 Midazolam 2 mg i.m.

3 200 mg i.m. BAL 245 mg/dL4 160 mg i.v. +01:00 Olanzapine 10 mg i.m. BAL 119 mg/dL

Benzodiazepines‘‘Mushrooms’’

5 �00:17 Lorazepam 2 mg i.m. 200 mg i.m.200 mg i.m.

6 100 mg i.m. +00:10 Ketamine 100 mg i.m.+00:30 Haloperidol 5 mg i.v.+00:45 Midazolam 2 mg i.v.

‘‘Alcohol’’‘‘Cocaine’’

7 60 mg i.v. +00:27 Ketamine 60 mg i.v.8 �00:44 Haloperidol 10 mg p.o.

�01:41 Lorazepam 1 mg p.o.�02:47 Haloperidol 5 mg p.o.

320 mg i.m. +00:13 Haloperidol 5 mg i.v.+00:13 Lorazepam 2 mg i.v.

CocaineOpiates

9 140 mg i.v. +00:07 Haloperidol 5 mg i.v.+02:18 Midazolam 5 mg i.v.

BAL 344 mg/dLOxycodone

10 400 mg i.v. +00:40 Diazepam 10 mg i.v.+01:22 Midazolam 5 mg i.v.

AmphetaminesBenzodiazepines

11 �01:17 Clonazepam*† 200 mg i.m.12 200 mg i.m. +01:25 Ketamine 100 mg i.v.13 200 mg i.m. +00:25 Ketamine 100 mg i.m.

+02:50 Ketamine 200 mg i.m.14 �01:11 Lorazepam 2 mg i.v.

�01:22 Haloperidol 5 mg i.v.100 mg i.v.

15 �00:13 Droperidol 2.5 mg i.v.�00:54 Haloperidol 5 mg i.v.�00:54 Midazolam 4 mg i.v.�00:54 Lorazepam 2 mg i.v.

100 mg i.v.

16 �00:22 Midazolam 2 mg i.m.�00:20 Midazolam 2 mg i.m.

120 mg i.v.

17 �01:10 Lorazepam 2 mg i.v.�01:40 Lorazepam 2 mg i.v.

100 mg i.v.

18 �00:20 Lorazepam 2 mg i.m.�00:52 Haloperidol 5 mg i.m.�01:21 Lorazepam 2 mg i.m.�02:15 Diphenhydramine 50 mg i.m.�02:15 Lorazepam 2 mg i.m.�02:32 Haloperidol 5 mg i.m.

50 mg i.v. +02:18 Ketamine 30 mg i.v.+02:48 Ketamine 20 mg i.v.

‘‘Methamphetamine’’

19 �00:03 Haloperidol 10 mg i.m.�00:03 Lorazepam 2 mg i.m.�00:03 Diphenhydramine 50 mg i.m.�00:28 Lorazepam 2 mg i.m.�00:55 Clozapine 100 mg p.o.

200 mg i.v.

20 �00:15 Lorazepam 2 mv i.v.�00:45 Droperidol 2.4 mg i.m.�00:45 Lorazepam 2 mg i.m.

300 mg i.m.

21 �00:05 Midazolam 10 mg i.m.* 200 mg i.m. BAL 233 mg/dLMethamphetamines

22 �00:18 Droperidol 2.25 mg i.m.�00:18 Lorazepam 2 mg i.m.

400 mg i.m. +01:04 Lorazepam 2 mg i.v.+01:52 Lorazepam 3 mg i.v.

23 200 mg i.m. +00:34 Lorazepam 2 mg i.v.24 �00:56 Lorazepam 1 mg i.v.

�01:56 Droperidol 1.25 mg i.v.50 mg i.v.

25 �00:00 Lorazepam 2 mg i.v.�00:16 Droperidol 2.25 mg i.v.�00:16 Lorazepam 2 mg i.v.�00:32 Lorazepam 1 mg i.v.

100 mg i.v. +02:24 Ketamine 100 mg i.v.+02:24 Diazepam 10 mg i.v.

‘‘Soma/Ambien overdose’’

26 �00:10 Lorazepam 1 mg i.v. 100 mg i.v. +00:15 Ketamine 50 mg i.v.27 �00:05 Lorazepam 2 mg i.m. 150 mg i.m. +00:20 Lorazepam 1 mg i.m. Cocaine28 50 mg i.m.

(Continued )


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Table 2. Continued

Case Prior Medication Initial Ketamine Dose Additional Medical Intervention Intoxication†

29 160 mg i.m. +00:41 Ketamine 240 mg i.m.+01:29 Droperidol 1.25 mg i.v.

BAL 079 mg/dL

30 150 mg i.m. +00:40 Lorazepam 2 mg i.v.+01:10 Ketamine 50 mg i.v.+01:44 Haloperidol 5 mg i.v.+01:56 Lorazepam 2 mg i.v.

31 �01:56 Haloperidol 5 mg i.m.�01:56 Lorazepam 2 mg i.m.

40 mg i.v. +00:15 Ketamine 20 mg i.v. Oxycodone

32 �01:18 Droperidol 2.25 mg i.v.�01:56 Lorazepam 2 mg i.v.�02:41 Haloperidol 5 mg i.m.�02:53 Lorazepam 2 mg i.m.

100 mg i.v. +00:07 Ketamine 100 mg i.v.+00:27 Midazolam 10 mg i.v.+01:22 Midazolam 1 mg/h i.v.+01:27 Midazolam 5 mg i.v.+01:37 Midazolam 5 mg i.v.+01:47 Midazolam 5 mg i.v.

BAL 284 mg/dL

BAL = blood alcohol level.‘‘�’’ and ‘‘+’’ for prior medication and additional medical intervention indicate time in relation to initial ketamine dose.Quotation marks indicate physician-reported patient use/intoxication.* Medication reported to be given shortly prior to arrival. Time indicated is triage time in relation to ketamine administration time.† Clonazepam dose not indicated.


DISCUSSION

Several case reports have documented the potential useful-ness of ketamine in severe agitation (13,21,30,31). Theputative advantages of this medication for agitationinclude rapid onset, the preservation of airway reflexes,

Table 3. Patient Vitals Pre- and Postadministration of Ketamine

Case Ketamine Dose (mg)

Systolic Blood Pressure (mm

Predose Postdose (High) Pos

1 1502 40 112 1085 400 124 1797 60 128 908 320 120 1519 140 137 13711 20012 200 148 15513 20014 100 107 14915 100 134 11816 12017 100 133 13518 50 119 14519 200 117 13620 300 155 16123 200 101 16924 50 111 11725 100 137 15726 100 143 17527 150 195 18528 50 132 16229 160 138 15130 150 134 14431 40 131 18432 100 120 144

Postdose vitals contain highest and lowest recorded values within 4 h ofnot included; blank spaces are indicative of that vital not being charted

and the ability to administer either i.m. or i.v., whichmay itself be particularly useful if i.v. access is not easilyobtained. In addition, sedation is often achieved reliablywith one dose (23). Compared to other agents, the half-life of ketamine is relatively short, potentially allowingmore rapid disposition of agitated patients (23).

Hg) Heart Rate (Beats/min)

tdose (Low) Predose Postdose (High) Postdose (Low)

86 104 104108 93 102 102172 80 91 7090 121 115 115

113 120 98 78114 119 107 98

72 114 108107

107 122 88104 59 86 56118 112 124 117

111 109 8597 78 98 69

116 87 106 78131 99 135 107115 85 77 64126 116 132 98117 86 80 80121 118 123 94125 70 97 82140 75 112 63135 94 99 80114 147 131 125114 103 95 6591 76 76 69

101 150 143 113

ketamine administration. Cases where vitals were not charted arein that specific case.

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Potential disadvantages of ketamine include the fact thatpatients who are in a dissociative state are unable to partic-ipate in their own care (4,5,10). Ketamine also does nottreat the underlying cause of agitation, and if the etiologyof the agitation persists, patients may require multipledoses of additional calming medications. In this study, forinstance, patients with substance/alcohol intoxicationneeded calming medication at higher rates. Finally, thereis evidence from at least one double-blind placebo-controlled trial that subanesthetic doses of ketamine mayworsen psychosis, which may make use of this medicationinappropriate in patients who have a psychiatric cause oftheir illness (32).

Little has been published on the use of ketamine foragitation. Roberts & Geeting described in a case studythe successful treatment of an acutely agitated and violentpatient with i.m. ketamine without major adverse effects,and a case series by Le Cong et al. reported that ketamineprovided adequate sedation in agitated psychiatric pa-tients who had not responded to treatment with benzodi-azepines, without any major adverse effects (13,30).However, these report did not follow long term toconfirm any worsening of psychosis after administration.

Much of the ED literature has focused on changesin vital signs. Burnett et al. report on several patientsadministered ketamine in the prehospital setting whohad surprising decreases in oxygen saturations (21). Interms of other vital sign parameters, increases in bloodpressure and heart rate are frequently seen, but are rarelyclinically significant (15). This is true in the study aboveas well, in which increases in blood pressure and heartrate are frequently present but not noted as significant.In four cases, the highest recorded blood pressure afterketamine administration was lower than the predoseSBP; this trend was also seen in heart rate in eight cases.In these cases, the effect of calming during an agitatedepisode on vitals may outweigh any changes induced byketamine. Additionally, in no cases were significantchanges in oxygen saturation noted, and no patientsbecame hypoxic, contrary to the results seen in prehos-pital literature.

Slightly over half of the cases (62.5%) required addi-tional medication for agitation after receiving ketamine,suggesting ketamine alone in the dose used is often notenough to resolve agitation. This is not unexpected astypically, ketamine was being used to gain rapid andsafe control of severely agitated patients to facilitate amore structured medical evaluation. As ketamine hasnot been proposed specifically as a treatment for agitationfrom undertreated psychiatric illnesses or even sympa-thomimetic drug intoxication, but rather as a means topermit initial work-up of an agitated patient, it is perhapsnot surprising to find that the majority of patients requiredadditional medications.

Of interest, there were eight cases (Table 2: patients14, 15, 16, 18, 19, 20, 24, and 25) where multiple dosesof an antipsychotic or a benzodiazepine were givenwithout resolution of agitation. Once given ketamine,these patients either did not require additional calmingmedication at all or did not need it within 3 h. Two ofthese patients, 18 and 19, received a ‘‘B-52’’ consistingof haloperidol, lorazepam, and diphenhydramine, tradi-tionally thought to be extremely effective in sedatingagitated patients, yet still required ketamine to resolveagitation. This may highlight ketamine’s usefulnesswith severely agitated patients, as well as introducingketamine as a potential alternate medication forpatients nonresponsive to traditional pharmacologicalinterventions.

Limitations

The retrospective, case series nature of this study maysuffer from selection bias, as patients were not prospec-tively randomized and enrolled in treatment arms. Thesmall patient population of the study also limits the abil-ity to generalize to other populations. Incomplete chart-ing led to a lack of vitals for several of the patients,decreasing our ability to further evaluate ketamine’s re-ported effects on vital signs. A patient’s weight is notroutinely included in ED charts, and so precludes furtherevaluation of the appropriateness of dosing in most cases.

CONCLUSIONS

Relative to other pharmacologic treatments for agitation,ketamine is infrequently used in the ED. We found thatketamine was used without any major adverse effectson vital signs, even in a population with 21.9% alcoholintoxication. However, a high proportion (62.5%) of pa-tients required additional pharmacologic treatment fortheir agitation, implying that ketamine itself is not anideal treatment for the underlying cause of agitation,but rather a means of initial management of severe agita-tion. A prospective study is warranted to further clarifythe safety and efficacy of the use of ketamine in thissituation.

Acknowledgments—Portions of these data were presented at theNational Update on Behavioral Emergencies conference, Or-lando, Florida, 2013.

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31. Svenson JE, Abernathy MK. Ketamine for prehospital use: newlook at an old drug. Am J Emerg Med 2007;25:977–80.

32. Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic dosesof ketamine stimulate psychosis in schizophrenia. Neuropsycho-pharmacology 1995;13:9–19.

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DEPRESSION AND ANXIETY 0:1–7 (2016)

ReviewKETAMINE: A POTENTIAL RAPID-ACTING

ANTISUICIDAL AGENT?

Samuel T. Wilkinson, M.D. and Gerard Sanacora, M.D., Ph.D.∗

Ketamine has attracted widespread attention as a potential rapid-acting antide-pressant. There is also considerable interest in its use for the rapid treatmentof patients deemed at risk for suicide. Here, we review the available evidence(open-label and randomized controlled trials) that examine the effects of ke-tamine on suicidal ideation (SI). Overall, data suggest that ketamine has a rapidalbeit transient effect in reducing SI, though some studies had mixed results atdifferent time points or using different assessments. Weaknesses to the existingliterature include the small sample sizes of the studies, the exclusion of patientswith significant SI at baseline from many of the studies, and the potential func-tional unblinding when participants are randomized to saline as placebo. Theevidence supporting the clinical use of ketamine for SI is very preliminary. Al-though ketamine appears to a promising therapeutic option in a context wherethere is a great unmet need (i.e., patients at imminent risk of suicide), furthercontrolled trials are needed to allow for meaningful clinical recommendations.Depression and Anxiety 0:1–7, 2016. C© 2016 Wiley Periodicals, Inc.

Key words: ketamine; suicidal ideation; suicide; depression; antidepressant

Department of Psychiatry, Yale School of Medicine, NewHaven, Connecticut

Contract grant sponsor: GS reports grants from Brain and Behav-ior Research Foundation, grants from National Institute of MentalHealth, during the conduct of the study; personal fees from Aller-gan, personal fees from Alkermes, grants and personal fees fromAstraZeneca, personal fees and other from BioHaven Pharmaceu-ticals, grants and personal fees from Hoffman La-Roche, grantsand personal fees from Janssen, grants and personal fees fromMerck, grants and personal fees from Naurex, personal fees fromServier Pharmaceuticals, personal fees from Taisho Pharmaceuti-cals, personal fees from Teva, personal fees from Vistagen, grantsfrom Bristol-Myers Squibb, grants from Eli Lilly & Co.; nonfinancialsupport from Sanofi–Aventis, outside the submitted work. In addi-tion, GS has a patent 8778979, “Glutamate agents in the treatmentof mental disorders” licensed to BioHaven Pharmaceuticals.

∗Correspondence to: Gerard Sanacora, Yale School ofMedicine, 100 York Street, STE 2J, New Haven, CT 06511.E-mail: [email protected] for publication 28 January 2016; Revised 3 March 2016;Accepted 4 March 2016

DOI 10.1002/da.22498

INTRODUCTIONForty-two thousand seven hundred and seventy-threedeaths by suicide were reported in the United States in2014, making suicide the 10th leading cause of deathof Americans of all ages.[1] For individuals aged 15– 44years, suicide is among the top three causes of mortalityworldwide.[2, 3] Beyond the devastating impact of suicide-related mortality on individuals and families, there arealso tremendous economic and public health concernsassociated with suicide attempts. More than 490,000hospital visits related to suicide attempts or self-harmbehavior were recorded in the United States for 2013,and the economic cost of suicide death, related mostlyto loss of productivity in the United States, being esti-mated to be greater than $44 billion annually.[4] Alreadyaware of the tremendous societal burden related to sui-cidal behavior,the US Surgeon General released a Callto Action to Prevent Suicide in 1999 calling for a re-newed effort to identify and develop better treatmentsand suicide prevention methods.[5] Unfortunately, de-spite these efforts, suicide rates have not decreased sincethe 1950s,[6] but have paradoxically been increasing overthe past 10 years.[1]

Published online in Wiley Online Library(wileyonlinelibrary.com).

C© 2016 Wiley Periodicals, Inc.Page 62

2 Wilkinson and Sanacora

Although not all suicides are associated with mentalillness, it is estimated that approximately 90% of indi-viduals who commit suicide suffer from a treatable psy-chiatric disorder,[7, 8] most commonly a mood disorder.Generally, the longer time spent in a depressive episode,the higher the chance of suicide.[9] Evidence surround-ing the efficacy of the currently available standardtreatments for mood disorders in treating suicidalideation (SI) presents a complex picture, with some evi-dence suggesting an overall benefit of the treatments[10]

and other studies suggesting an age-related acute wors-ening of SI with treatment initiation.[11–13] However, ineither case, it is clear that the currently available stan-dard antidepressant treatments do not provide a robustand rapid relief of SI.

The existing treatment options for patients assessed tobe at acute risk for suicide are limited. Current manage-ment of patients deemed at acute risk of suicide usu-ally consists of hospitalization plus pharmacotherapy,psychotherapy, electroconvulsive therapy (ECT) or acombination thereof. Significant evidence supports a re-duction in the long-term risk of suicide in mood disor-ders associated with lithium treatment,[14] though it hasnot been shown to be effective in the acute setting.[15]

Clozapine has received an FDA-approved indicationfor “reducing the risk of recurrent suicidal behavior,”but this is primarily based on data from patients diag-nosed with schizophrenia or schizoaffective disorder, andnot patients with mood disorders, which constitute thelargest portion of patients who commit suicide.[16] Fur-ther, clozapine has not been shown to decrease SI in theacute setting. Even ECT, considered the most highlyefficacious antidepressant treatment, may not provide areduction in SI for 1–2 weeks.[17] Moreover, hospitaliza-tion, which is designed to provide a safe environmentfor patients, is not completely effective in preventingsuicide. Although uncommon, suicide among inpatientsremains one of the most commonly reported sentinelevents.[18] These facts highlight the need for the devel-opment of more effective means of identifying those atrisk for suicide and for the introduction of novel effectivetherapeutic approaches with more rapid rates of onset ofantisuicidal action.[19, 20]

In 2000, Berman et al.[21] first reported that ketamine,an N-methyl-D-aspartic acid antagonist, possesses rapid-acting antidepressant properties. Since then, several ran-domized placebo-controlled trials and case series haveconfirmed that the drug produces a rapid onset, transientantidepressant response in both treatment-resistant de-pression (TRD) unipolar and bipolar depression.[22–26]

Given the rapid-acting nature of ketamine and the re-ports of high rates of efficacy in TRD, the potential util-ity of the drug in the acute treatment of suicidal patientswith mood and other disorders has gained great inter-est. Here, we review the evidence for ketamine’s effectson SI in patients with mood disorders. We first reviewevidence gleaned from open-label trials and case series,followed by evidence from randomized controlled trialsexamining ketamine’s general antidepressant properties.

We later consider whether the effects of ketamine onsuicide are independent of the drug’s effects on mood ingeneral and review the limited evidence specifically at-tempting to address the antisuicidal effect of ketamine.The promise and limitations of this approach as a treat-ment of suicidal thinking and behavior are considered.Except where noted, all protocols reviewed utilize an in-travenous infusion of 0.5 mg/kg ketamine over 40 min.

OPEN-LABEL AND NATURALISTIC TRIALSSeveral open-label and naturalistic studies examin-

ing either single-dose or repeated-dose administrationshave attempted to gain insight into the potential anti-suicidal effects of ketamine (see Table 1). A study of 33medication-free inpatients with Major Depressive Dis-order (MDD, treatment-resistant) undergoing a single,open-label IV ketamine infusion, designed to assess an-tidepressant effects of ketamine, showed a reduction inSI in all scales employed in the study (Montgomery–Asberg Depression Rating Scale [MADRS], HamiltonDepression Rating Scale [HDRS], Beck Depression In-ventory [BDI], and Beck Scale for SI [SSI]).[27] Pre–posteffect sizes were largest at 40 min (d = 1.05), dimin-ishing to moderate magnitude effect sizes at 230 min(d = 0.45). However, it should be noted that these effectsizes were much larger when considering only the 10patients with high baseline SI (defined as SSI score >3)in the analysis: d = 2.36 at 40 min and d = 1.27 at 230min. Notably, the participants in this study had stableSI as measured by the SSI for a mean period of 8 daysprior to treatment. Thakurta et al.[28] also reported on27 inpatients with TRD (�2 failures of antidepressants)who were given a single ketamine infusion after a 2-weekwashout of other antidepressant medications in India. SIwas reported to be reduced in the immediate period fol-lowing treatment (40–230 min) as assessed by the SSIand the HDRS, but this reduction was not sustained24 hr following treatment. An additional open-labelstudy of 26 medication-free patients with TRD under-going a single intravenous ketamine infusion reportedMADRS-SI scores1 were significantly reduced 24 hr fol-lowing treatment compared to baseline levels (pre–posteffect size d = 1.37).[29] Implicit measures (IAT2) of SIwere also significantly reduced in a subset of 10 patientswho completed the assessment in a pre–post comparison(d = 1.36). Notably, the decrease in SI was not shownto be independent of the overall reduction in depressionsymptoms in this study. A subset of 10 patients in thestudy who received six total infusions each, given threetimes per week, maintained a significant reduction in SI

1MADRS item 10: Suicidal Thoughts. Representing the feeling thatlife is not worth living, that a natural death would be welcome, suicidalthoughts, and the preparations for suicide.2IAT — Implicit Association Test, tests implicit cognitive associationsbetween concepts such as “Death” and “Me” or “Escape” and “Me”.It has been shown to a good predictor of future behavior in certainsocially stigmatized domains (i.e., prejudicial attitudes based on race).

Depression and AnxietyPage 63

Review: Effects of Ketamine on Suicidal Ideation 3

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for the duration of the treatment. However, it should benoted that subjects with “highly active” SI were excludedfrom participation in this study. In another study of 24TRD medication-free participants treated with six serialinfusions of ketamine over 2 weeks, Murrough et al.[30]

noted a significant decrease in SI (MADRS-SI item) at2 hr compared to baseline in both patients ultimatelyconsidered to be treatment responders and nonrespon-ders (defined at 24 hr by 50% decrease in symptoms).Approximately 70% of responders had relapsed by 4weeks following the final infusion; there is no mentionof the duration of ketamine’s effects on SI. Rasmussenet al.[31] reported on 10 TRD participants (both inpa-tients and outpatients) who were treated with ketamineIV 0.5 mg/kg over an extended 100 min infusion pe-riod in addition to treatment as usual (i.e., concomitantantidepressants). Participants continued to receive in-fusions until remission was achieved or four infusions(provided twice weekly) were given. Changes in explicitmeasures of SI were significant as assessed by the SSI andthe SSF (Suicide Status Form) in a pre–post comparison;reduction in SI was correlated with reduction in overalldepressive symptoms.

There are two open-label, naturalistic studies explor-ing the use of ketamine treatments in emergency depart-ment (ED) settings. Larkin and Beautrais[32] treated 14patients with significant SI recruited from the ED with0.2 mg/kg ketamine delivered IV over 1–2 min alongwith treatment as usual. They reported that SI decreasedsignificantly in all patients at the 40-, 80-, 120-, and240-min time points after ketamine administration usingthe MADRS-SI, and no evidence of recurrence was de-tected during the 10-day follow-up period. Another trialof 49 medication-free patients presenting to the ED ofImam Hossein hospital in Tehran for SI received a sin-gle dose of 0.2 mg/kg ketamine, delivered IV over 1 minalong with treatment as usual.[33] The investigators re-ported a significant decrease in SSI scores over the 2-hrperiod following ketamine dosing, and 94% of the pa-tients reported no SI at day 10. Although these two stud-ies provide some evidence to suggest the feasibility andpotential benefits of using ketamine in the ED setting totreat SI, the value of these studies is markedly limited byshortcomings in the study designs, including small sam-ple sizes, lack of diagnostic specificity, no comparisongroups or historical subject comparisons, and the uniquechoice of dosing compared to other existing studies.

RANDOMIZED CONTROLLED TRIALSIn their original study of ketamine in medication-

free outpatients with MDD, Berman et al.[21] specifi-cally noted significant decreases in SI HDRS-SI item(not adjusted for multiple comparisons) shortly follow-ing a single ketamine infusion in their original reporton the drug’s antidepressant efficacy (see Table 1). Sincethat report, there have been several other accounts ofsecondary analyses attempting to gain insight into the re-lationship between ketamine and SI using data from ran-

domized controlled ketamine studies that were not orig-inally designed to examine effects on SI. Ballard et al.[34]

examined the data from three placebo (saline)-controlledRCTs including participants with both MDD and bipo-lar disorder, and one open-label study conducted at theNIMH. In the total sample of 133 subjects, after con-trolling for both depression and anxiety symptom clus-ters in a regression model, ketamine exerted an effect onSI that was independent of its effects on depression andanxiety. Restricting the analysis to 57 subjects who par-ticipated in a randomized study and demonstrating thepresence of some SI at baseline (HDRS SI item score>0), there was again evidence of an independent ef-fect of ketamine on SI. Thus, this evidence suggests thatketamine exerted an independent effect on SI as opposedto this effect being mediated solely by an overall reduc-tion in depressive or anxiety symptoms. Overall, this sec-ondary analysis suggests that ketamine’s effects on SImay in fact be independent of its effects on other de-pression or anxiety symptoms. Moreover, further anal-ysis from the same datasets using a slightly broader def-inition of SI found ketamine to have significant effectson SI rating on all scales, with the exception of the totalscore of the SSI, but there were significant effects notedas measured by the abbreviated SSI5 scale.[35] Consis-tent with the previous reports showing large effects ofa single ketamine infusion on SI, a recent study ran-domizing 30 patients with MDD to ketamine infusionplus escitalopram or saline infusion plus escitalopramat Beijing Chao-Yang Hospital,[36] found the subjectsin the ketamine/escitalopram group had lower explicitmeasures of SI (as measured by Quick Inventory of De-pressive Symptomatology [QIDS] SI item) compared tothe placebo/escitalopram group from 1 to 72 hr follow-ing treatment, with Cohen’s d ranging from 1.05 to 2.24during this time period. These participants were outpa-tients and, other than the concomitant initiation of esc-italopram on the first treatment day, were free of otherpsychotropic medication.

Analyzing data from 57 outpatients with TRD as-sessed using explicit measures (a composite measure ofSI scores from various scales) and implicit measures (de-rived from an IAT) of SI at baseline and 24 hr following asingle infusion of ketamine or midazolam, Price et al.[37]

reported SI scores 24 hr postinfusion were reduced inthose receiving ketamine compared to midazolam in ex-plicit measures, but difference between groups at 24 hrusing two variants of IAT measures, identified in the pre-vious open-label study, did not reach statistical signifi-cance in omnibus analyses. Notably, subjects with “seri-ous and imminent” SI were excluded from participation.Also, in this study the decrease in explicit measures ofSI appeared to be explained by the overall decrease indepressive symptoms.

Murrough et al.[38] recently completed the only ran-domized trial thus far designed specifically to assessthe effect of ketamine on SI. A sample of 24 subjectswith significant SI (13 with MDD, 7 with bipolar dis-order, 3 with PTSD) recruited from both inpatient and



outpatient settings were randomized to a single-dose in-fusion of intravenous ketamine or 0.045 mg/kg intra-venous midazolam (active control) over 40 min, addedon to their existing medication regimen. Although thislikely underpowered study failed to show a significanteffect of ketamine treatment on the primary outcomemeasure (group difference in SSI at 24 hr), the ketaminetreatment group had lower SSI scores at 48 hr and theMADRS-SI item (secondary outcome) was significantlylower in the ketamine group at 24 hr but not at 48 hr.

Overall, data from RCTs suggest that ketamine hasa rapid effect in reducing SI, though some studies hadmixed results at different time points or using differentassessments. However, it should be noted that there areseveral major weaknesses regarding the quality of dataavailable evaluating the antisuicidal effect of ketaminegenerated from these studies. One weakness of this lit-erature is that, with the exception of Murrough et al.,[38]

these RCTs were designed primarily to test ketamine’santidepressant effects and, in many cases, patients withclinically meaningful SI, or thought to be at imminentrisk of suicide, were excluded from participation. Fur-ther, it should be emphasized that most studies measuredSI only as a secondary outcome, and some measured SIby a single scale item that is part of a general depressionscale, rather than a scale designed to measure SI (theSSI). Among patients receiving ketamine, the individualSI items of the MADRS, HDRS, and BDI have beenshown to correlate with the abbreviated five-item SSI,but not with the full scale.[35]

Another weakness of these studies is that most are gen-erally of small sample size, limiting their power to detectgroup differences. Nonetheless, despite this limitation,there is converging evidence that ketamine may rapidlyreduce SI. A third significant limitation is the potentialfunctional unblinding that may occur due to the disso-ciative properties of ketamine. It is quite probable thatmost subjects become functionally unblinded; evidencefor this is seen in the extremely low placebo responserates seen where saline infusion is used as the control.More recently, some trials have used midazolam as anactive comparator to reduce the amount of functionalunblinding. Although it is unclear whether using mida-zolam as the active comparator completely resolves theproblem of unblinding, these trials generally have higherplacebo response rates and, hence, lower between-groupeffect sizes, but still appear to show meaningful differ-ences with ketamine treatment.

DISCUSSIONThe collective existing data provide intriguing prelim-

inary evidence suggesting that ketamine may produceuniquely rapid effects on SI. However, both the open-label and placebo-controlled trials have many limitationsthat restrain our ability to draw firm conclusions at thispoint in time. Fortunately, the results of several clinicaltrials evaluating the efficacy of ketamine or esketamine(S-enantiomer) to stabilize patients in need of hospital-

ization due to risk of suicide (clinical trials identifier:NCT02133001, NCT02299440) or outpatients withsignificant SI (NCT02094898; NCT01700829) shouldprovide more reliable data related to ketamine’s antisui-cidal effects in the relatively near future.

Although, as discussed in the introduction, there is agreat unmet need for more robust and rapidly actingantisuicidal treatments, the evidence to date support-ing the clinical use of ketamine for this purpose is ex-tremely preliminary. Any consideration of the clinicaluse of ketamine should weigh heavily the known risks ofthe treatment approach (can we reference another pa-per in this issue?), the limited evidence of efficacy, andany possible delays it may cause in receiving establishedtreatments for reducing the risks of SI and behavior, suchas ECT, lithium, or clozapine. Moreover, there remainslittle data of strategies for maintaining the antisuicidalproperties of ketamine, and concerns exist regarding therepeated administration of ketamine.[39] Finally, all stud-ies reviewed examined the effects of ketamine on suicidalideation, not on suicidal behavior; whether ketamine’s ef-fects on SI translate into effects on suicidal behavior hasnot been studied.

There is also significant interest in the question ofwhether ketamine’s effect on SI is independent of its gen-eral antidepressant effects (i.e., pseudospecificity). Theissue of pseudospecificity could impact the path to FDAapproval of ketamine or related medications for use inthe treatment of SI or behavior. The FDA has consid-ered claims for drug effects in psychiatric illnesses to bepseudospecific if it is found to be artificially narrow (i.e.,focusing on a particular aspect or symptom of an illness)in the absence of any empirical evidence to support sucha restricted focus.[40] For example, to evaluate the claimsof pseudospecificity with regard to negative symptoms inschizophrenia, the FDA asked the following questions:(1) Are negative symptoms phenomenologically distinctfrom other symptoms of schizophrenia?; and (2) do theyhave a course that is distinct from other symptoms?[41]

It could be assumed that the agency will take a simi-lar view on claims of antisuicidal effects of ketamine orrelated compounds in mood disorders. To date, the lit-erature on whether ketamine has a specific effect on SI orwhether reductions in SI are mediated by an overall re-duction in general depression symptoms is inconclusive.Although some data suggest the antisuicidal effect to bepresent across different diagnostic groups, it is limitedby the relatively small sample sizes and the fact that theparticipants enrolled in the studies had minimal or nobaseline SI. Larger controlled studies are clearly neededto more definitively address this question.

In sum, ketamine (at least at 0.5 mg/kg i.v. infused over40 min) appears to represent a promising treatment forpatients with SI. However, more data are clearly needed,especially in patients with elevated baseline levels of SI,prior to making any meaningful clinical recommenda-tions on the utility of the treatment. Although there aresome interesting data suggesting the effects of ketaminemay reduce SI independently of its more general effects



on mood and anxiety, this will need to be examined ingreater detail in future studies in order to address theissue of pseudospecificity. Future studies will also needto determine if ketamine-induced effects on SI and be-havior will be generalizable to patients who do not sufferprimarily from a mood disorder (i.e., PTSD, obsessive-compulsive disorder, alcohol abuse). Other drugs withputative rapid-acting antidepressant effects also in devel-opment will be subjected to similar concerns, and will re-quire studies designed to specifically address the uniqueaspects of SI and behavior to establish efficacy and pos-sible FDA approvals. As with all treatments, the risks ofketamine must be weighed against potential benefits inconsidering future development of the treatment strat-egy in the clinical setting.

Acknowledgments. This work was supported bya grant from the National Institute of Mental Health,5R25MH071584-09 (STW), and by the ConnecticutDepartment of Mental Health and Addiction Services(GS).

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Commentary

A Word to the Wise About Ketamine

Recent reports of an acute antidepressant effect for intravenous ketamine,a schedule III agent used in anesthesia and pain clinics, have generated con-siderable hope and enthusiasm among both researchers and clinicians (1–4). Theresponse partly reflects hope that a new mechanism of antidepressant action hasbeen discovered and highlights the scarcity of agents that clinicians can administerto produce immediate effects on mood. Positive initial research reports (includingthe recent article in the Journal by Murrough et al. [4]) have unintentionally en-gendered growing off-label clinical use of ketamine in emergency rooms, specialtypain clinics and, most recently, free-standing private psychiatry clinics. If ketaminewere a new drug, then the Food and Drug Administration would have requiredhundreds more patients to be rigorously studied before an approval for generaldistribution. However, because ketamine was already approved as an anesthe-tic, any physician can legally prescribe it. Some practitioners have even com-missioned pharmacists to compound intranasal and other formulations. Thisunbridled enthusiasm needs to be tempered by a more rational and guardedperspective.

We Need To Know More About Acute and Longer-Term Efficacy and Risks

The data on clinical response to ketamine as an antidepressant are still rela-tively limited. The study by Murrough et al. (4) was the largest to date but stillincluded only 47 patients treated with the drug. Will the data hold up in othercontrolled trials? The antidepressant effects of ketamine are generally short lived,lasting less than 1 week, although longer than its half-life. Unfortunately, to datewe have no idea what we should do for follow-up therapy. In a recent report (3),repeated ketamine administration every few days appeared to be effectiveover a 2-week period with no clear tachyphylaxis to either the antidepressantor depersonalization effect, but that does not address what to do beyond 2weeks, including dealing with the risk for dependence since ketamine is a drug ofabuse.Ketamine produces feelings of depersonalization and even psychosis (1–4), and

it was previously used to test hypotheses regarding dopamine and glutamate inschizophrenia. In their study, Murrough et al. (4) undertook stringent patient eval-uations to decrease the risk of psychotic reactions, but such evaluationsmay not beoccurring in other settings. Clinicians outside a research setting generally do nothave the resources to screen patients similarly.

We Need To Know More About the Mechanism of Action of the Mood-Elevating Effects

The antidepressant effect has been thought to reflect ketamine’s glutamatergicproperties, specifically its blocking ofN-methyl-d-aspartic acid (NMDA) receptors,which should be a clue for follow-up therapy. However, other currently availableagents (covering a variety of glutamatergic actions) have proven unsuccessful inantidepressant trials either as monotherapy or in combination with ketamine(5–7). Investigational agents have been mixed in their effects, with glycine par-tial or full agonists that act essentially as NMDA agonists also being effectivefor depression (unpublished 2012 report by R.M. Burch; 8, 9). This suggests

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that NMDA antagonism may not be the primary mechanism of action forketamine in major depression. Recent reports have indicated that ketaminehas effects on intracelluar mTor that could account for its antidepressantproperties (10).Stimulants and opiates have long been associated with short-term, although

generally clinically ineffective, therapeutic effects and problems with abuse.Ketamine has both opiate and stimulant effects (11, 12). It is a strong promoterof catecholamine, particularly dopamine, turnover (12), and its monoaminergicproperties are similar to cocaine or amphetamine. Ketamine also has mu opioidreceptor properties, consistent with its use for anesthesia and treatment of pain.This mechanism may be similar to the antidepressant effects of buprenorphine(13), although a study in healthy individuals did indicate that the effects ofketamine on responses to alcohol were not blocked by the mu antagonist nal-trexone (14). To our knowledge, such a study has not been conducted indepressed patients. It is interesting that Rodriguez et al. (15) recently reportedthat ketamine given intravenously was similarly effective in refractory obsessive-compulsive disorder (OCD). This was reminiscent of a double-blind, placebo-controlled study by Koran et al. (16)a few years ago that reported that oralmorphine improved OCD symptoms1 day after administration—an effectthat lasted 5 days. Comparison studiesagainst stimulants and opioids wouldbe helpful for assessing ketamine’smechanismof action for acutely elevatingmoodand its potential for providing overall benefit in the treatment of depression.

Should Clinicians Prescribe Ketamine for Patients With Refractory Depression?

Without more data on what ketamine can do clinically, except to produce briefeuphoriant effects after acute administration, and knowing it can be a drug ofabuse, it is difficult to argue that patients should receive an acute trial of ketaminefor refractory depression. Some ketamine investigators have argued for not using itoutside of a hospital setting (17), but without extensive experience and a follow-upstrategy, is even that themost prudent strategy? I would argue that waiting until weunderstand more about its effects and risks makes most sense. Patients have notbenefitted in the past from the overuse of short-term treatments such as stimulantsand opiates. The results have been toxicity and dependence from the immediatetreatment and a failure to recommend and follow through with more definitivelonger-term treatments required for patients with depression. The recent ketaminestudies are exciting, and they open up important avenues for investigation thatshould be supported; however, until we know more, clinicians should be waryabout embarking on a slippery ketamine slope.

References

1. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A ran-domized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch GenPsychiatry 2006; 63:856–864

2. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z,Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr: A randomized add-on trial of anN-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67:793–802

3. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS,Iosifescu DV: Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013; 74:250–256

Until we know more, cliniciansshould be wary about embarkingon a slippery ketamine slope.

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4. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A,Charney DS, Mathew SJ: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142

5. Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, Caloro M, Telesforo CL, Caltagirone SS,Panaccione I, Simonetti A, Demontis F, Serra G, Girardi P: The role of memantine in the treatment ofpsychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNSDrugs 2012; 26:663–690

6. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, Moaddel R, Wainer I,Luckenbaugh DA, Manji HK, Zarate CA Jr: Course of improvement in depressive symptoms to a single in-travenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlledstudy. Neuropsychopharmacology 2012; 37:1526–1533

7. Barbee JG, Thompson TR, Jamhour NJ, Stewart JW, Conrad EJ, Reimherr FW, Thompson PM, Shelton RC: Adouble-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J Clin Psychiatry 2011; 72:1405–1412

8. Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA,Luckenbaugh DA: A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blockerin major depression. Biol Psychiatry 2013; 74:257–264

9. Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, Tun R, Huang KH, Chang YC, Lane HY, Tsai GE:Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry2013; 74:734–741

10. Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M, Li X-Y, Aghajanian G, Duman RS: mTOR-dependent synapseformation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329:959–964

11. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects ofketamine in depressed patients. Biol Psychiatry 2000; 47:351–354

12. Tan S, Lam WP, Wai MS, Yu WH, Yew DT: Chronic ketamine administration modulates midbrain dopaminesystem in mice. PLoS ONE 2012; 7:e43947

13. Bodkin JA, Zornberg GL, Lukas SE, Cole JO: Buprenorphine treatment of refractory depression. J Clin Psy-chopharmacol 1995; 15:49–57

14. Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D’Souza DC: Potentiation oflow-dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.Neuropsychopharmacology 2006; 31:1793–1800

15. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, Flood P, Simpson HB: Randomizedcontrolled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuro-psychopharmacology 2013; 38:2475–2483

16. Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M: Double-blind treatment with oral mor-phine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 2005; 66:353–359

17. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ: Ketamine for depression: where do we go from here?Biol Psychiatry 2012; 72:537–547

ALAN F. SCHATZBERG, M.D.

From Stanford University School of Medicine, Stanford, Calif. Address correspondence to Dr. Schatzberg([email protected]). Commentary accepted for publication January 2014 (doi: 10.1176/appi.ajp.2014.13101434).

Dr. Schatzberg has received consulting fees from Bay City Capital, BrainCells, CeNeRx, Cervel, Eli Lilly,Genentech, Gilead, Jazz, Lundbeck/Takeda, McKinsey, Merck, MSI, Naurex, Neuronetics, Novadel, Pharma-NeuroBoost, Sunovion, Synosia, and Xhale. He has equity in Amnestix, BrainCells, CeNeRx, Cervel, Corcept (co-founder), Delpor, Forest Labs, Merck, Neurocrine, Novadel, Pfizer, PharmaNeuroBoost, Somaxon, Synosia,Titan, and Xhale. He is a named inventor on pharmacogenetic use patents on prediction of antidepressantresponse and glucocorticoid antagonists in psychiatry, and he has received speakers’ honoraria from Merck.Dr. Freedman has reviewed this commentary and found no evidence of influence from these relationships.

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