Update on Fluid Management Intravenous Fluid Therapy Using Colloids: New Data, New Controversies D John Doyle MD PhD FRCPC Cleveland Clinic Foundation.

Update on Fluid Management

Intravenous Fluid Therapy Using Colloids:

New Data, New Controversies D John Doyle MD PhD FRCPC

Cleveland Clinic Foundation

September, 2004

This talk can be downloaded from

http://colloidtalk.homestead.com

Goals and Objectives

• To compare and contrast crystalloids and colloids and their use in the perioperative period

• To compare the various HES preparations• To provide an update on the SAFE trial• To present information on the drawbacks of using

crystalloids such as normal saline in large volumes• To present information on fluid resuscitation in a

real clinical case• To present information on immediate versus

delayed fluid resuscitation for hypotensive patients with ongoing blood loss.

Boldt J. New light on intravascular volume replacement regimens: what did we learn from the past three years?. Anesthesia & Analgesia. 97(6):1595-604, 2003 Dec.

Definition of the "ideal" intravascular fluid volume replacement strategy still remains a critical problem. This article analyzes studies on volume replacement by using a MEDLINE search of the past 3 years (from January 1, 2000, to December 12, 2002). Forty original studies in humans with a total of 2454 subjects were identified. Five studies were performed in volunteers (n = 113); the other 35 studies (n = 2341) were performed in a variety of patients (e.g., cardiac surgery, trauma patients, children, and intensive care unit patients). The influence of different volume replacement regimens on coagulation was one of the major topics of interest (16 studies with 1183 subjects), and other studies focused on metabolic state, alterations in macro- and microcirculation, volume distribution, and organ function (e.g., kidney function and splanchnic perfusion). Among all synthetic colloids, hydroxyethyl starch (HES) was the solution most often studied. Two new HES preparations have been approved (Hextend), a balanced hetastarch solution, and a new third-generation HES [130/0.4]). Only two studies used albumin, and no superiority of albumin was found over less expensive synthetic colloids. In almost all studies, the outcome either was no end-point or was not reported. Volume replacement has often been hitherto based on dogma and personal beliefs. Future well performed studies in this area will hopefully help to shed new light on the ideal volume replacement strategy. IMPLICATIONS: By using a MEDLINE search covering the last 3 yr, the present knowledge on volume replacement regimens was analyzed. Forty studies in humans were identified. New hydroxyethyl starch preparations have shed light on this topic, whereas no additional data supporting the use of albumin have been presented

“… no additional data supporting the use of albumin have been presented.”

THIS PART IS NO LONGER TRUE ! (SAFE Trial)

Joachim Boldt (Germany)

Fluid choice for resuscitation of the trauma patient: a review of the physiological, pharmacological, and clinical evidence.

Can J Anesth 2004 51: 500-513.

(May 2004)

Purpose: Volume replacement regimens are discussed very emotionally. Interpretation of the literature is difficult due to variations in study design, patient population, target for volume replacement, endpoints, and type of fluids. Meta-analyses may not be very helpful because all kinds of patients and very old studies are included. The principles and options for volume replacement were reviewed exclusively in trauma patients and studies from the literature focusing on this problem were analyzed.

Source: Using a MEDLINE search, volume replacement therapy in adult trauma patients published in the English language from 1985 to the end of 2002 were identified and analyzed. Studies on prehospital volume replacement, volume replacement in the emergency area or in the operating room, and volume therapy in trauma intensive care unit patients were included.

Principle findings: The age-old crystalloid /colloid controversy has still not been resolved but has been enlarged to a colloid/colloid debate. It is now widely accepted that human albumin could easily be replaced by synthetic colloids for volume replacement in trauma patients. No superiority of a specific volume replacement strategy with regard to outcome was found. However, in several studies outcome was not the major endpoint. Although showing some promising results, the importance of hypertonic solutions for volume replacement in the trauma patient is not yet defined.

Conclusion: The choice of fluid therapy in trauma patients engenders the most controversy and an examination of the body of literature on this subject results in confusion. It is imperative to continue the search for substances that are effective in avoiding the development of post-trauma multi-organ dysfunction syndrome without detrimental side-effects.

Overview

• Physiological basis of fluid therapy

• Colloids and crystalloids

• Sample case

• What is the controversy?

• What are the consequences?

• Massive fluid therapy

• New developments (SAFE trial)

History

Starling EH. Physiological Factors in the Causation of Dropsy

Lancet 1896

Dropsy

The American Heritage® Dictionary of the English Language: Fourth Edition. 2000.

Edema.

No longer in scientific use.

Starling’s Law

Jv = Kf (Pc-Pt) - d (c-t)

Jv fluid flux

Kf filtration constant

d osmotic coefficientP hydrostatic pressure oncotic pressure t tissuec capillary

Fluid Compartments

• ICF Volume is INTRACELLULAR

• ECF Volume is EXTRACELLULAR

• ECF Volume = Plasma Volume +

Interstitial Volume

Fluid Compartments

• Total Body Water (0.6 L/kg)– 2/3 Intracellular (ICF) = 0.4 L/kg– 1/3 Extracellular (ECF) = 0.2 L/kg

• ECF Volume (0.2 L/kg) Plasma Volume (0.05 L/kg) Interstitial Volume (0.15 L/kg)

Ratio of plasma volume to interstitial volume is 1-to-3 [rationale for 3-to-1 replacement of blood losses with crystalloid]

Where the IV fluid goes

Crystalloids NS, RL

75 % Extravascular

25 % Intravascular/

Plasma Volume

ColloidsAlbumin, HES

Almost 100 %Intravascular/

Plasma Volume

Plasma Volume Expansion

Fluid Loss

• Burns

• Sepsis

Blood Loss

• Hemorrhage

• Surgery

• Trauma

Plasma Volume Expansion

1.0 L NS (0.9%) 0.33 L Plasma Volume

1.0 L Hypertonic Saline (3%, 5%, 7.5%) draws water out from ICF to ECF leading to ECF

1.0 L of Colloid 1.0 L of Plasma Volume

Advantage of Crystalloids

• Inexpensive

• Promote urine output

• Chemically simple

Disadvantages of Crystalloids

• Potential to impair blood supply (e.g. replanted digit or flap)

• Facial edema (especially patient in the prone position)

• Airway edema

• Scleral edema

• GI edema

• Acid base disturbances

Hypertonic Saline

Hypertonic Saline

Currently, only 3% solutions are available "off-the-shelf" in the United States.

In Sweden, a commercially prepared 7.5% solution in combination with 6% dextran 70 (RescueFlow, BioPhausia, Knivsta, Sweden), is available.

“Hypertonic solutions are beneficial in resuscitation from shock and trauma. Compared with isotonic solutions, the lesser volumes are associated with equivalent or improved systemic blood pressure, cardiac output, and survival in experimental animals. A positive cardiac inotropic effect is documented, as is a decrease in systemic vascular resistance.”

Invited CommentaryHypertonic Saline Resuscitation in Anesthesia and SurgeryRobert R Kirby MD and Emilio B Lobato MDCurrent Anesthesiology Reports 2000 2:257-258 (published 1 July 2000)http://www.biomedcentral.com/1523-3855/2/257/abstract

Colloids

• Human serum albumin (5 and 25%)

• Fresh frozen and stored plasma

• HMW hydroxyethyl starch

• LMW hydroxyethyl starch

• Dextrans

• Gelatins

Artificial Colloid Solutions

• Hydroxyethyl Starches (HESs)– LMW (Pentaspan, PentaLyte)– HMW (Hespan, Hextend)

• Dextrans• Gelatins

Artificial colloids, unlike crystalloids, are complex entities that undergo a regulatory approval process similar to that for a drug.

Properties of an Ideal Colloid• Non toxic• Non infective (sterile)• Non allergenic• Not teratogenic or mutagenic• No effect on diagnostic tests• Compatible with medications• No influence on hemostasis• Complete elimination• No storage in tissues• Good shelf life• No special storage requirements• Few very small or very large molecules

Properties of an Ideal Hydroxyethyl Starch (HES)

• Long shelf life and easy storage

• Few very small or very large molecules

• No adverse effects on coagulation

• Can be repeatedly administered

HES Properties• HES are a mixture of differently sized and

differently substituted molecules• A higher degree of molar substation results in poorer

degradation of the HES molecule by alpha amylase• Volume effect exceeds drug concentration:

decreased HES concentration by renal elimination of molecules is compensated by the supply of new molecules (still oncotically active) from the degradation of the larger fragments

Characterizing HES Colloids

• Degree of substitution (molar substitution)

• C2/C6 ratio

• Molecular weight distribution

• Concentration

• Maximum daily dose

• Degradation by amylase

Advantages of Colloids

• Less edema

• Less volume administered

• Less thermal load effect for given level of plasma volume expansion

• Volume administer stays in intravascular space longer

Cytokines

Volume replacement with HES products is associated with decreased release of cytokines (proinflammatory molecules), and other effects that may improve the microcirculation.

“Cytokines are the neurotransmitters of the immune system”

Lang K. Suttner S. Boldt J. Kumle B. Nagel D. Volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major abdominal surgery. Canadian Journal of Anaesthesia. 50(10):1009-16, 2003 Dec. PURPOSE: To investigate the effects of intravascular volume replacement therapy on the inflammatory response during major surgery. METHODS: Thirty-six patients scheduled for elective abdominal surgery were randomized to receive either 6% hydroxyethylstarch (130,000 Dalton mean molecular weight, degree of substitution 0.4; n = 18, HES-group) or lactated Ringer's solution (RL-group; n = 18) for intravascular volume replacement. Fluid therapy was given perioperatively and continued for 48 hr in the intensive care unit. Volume replacement was guided by physiological parameters. Serum concentrations of interleukin (IL)-6, IL-8 and IL-10 and soluble adhesion molecules (sELAM-1 and sICAM-1) were measured after induction of anesthesia, four hours after the end of surgery, as well as 24 hr and 48 hr postoperatively. RESULTS: Biometric and perioperative data, hemodynamics and oxygenation were similar between groups. On average, 4470 +/- 340 mL of HES 130/0.4 per patient were administered in the HES-group compared to 14310 +/- 750 mL of RL in the RL-group during the study period. Release of pro-inflammatory cytokines IL-6 and IL-8 was significantly lower in the HES-group [(peak values) 47.8 +/- 12.1 pg*dL(-1) of IL-6 and 35.8 +/- 11.2 pg*mL(-1) of IL-8 (HES-group) vs 61.2 +/- 11.2 pg*dL(-1) of IL-6 and 57.9 +/- 9.7 pg*mL(-1) of IL-8 (RL-group); P < 0.05]. Serum concentrations of sICAM-1 were significantly higher in the RL-group [(peak values) 1007 +/- 152 ng*mL(-1) (RL-group) vs 687 +/- 122 ng*mL(-1), (HES group); P < 0.05)]. Values of sELAM-1 were similar in both groups. CONCLUSION: Intravascular volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major surgery compared to a crystalloid-based volume therapy. We hypothesize that this is most likely due to an improved microcirculation with reduced endothelial activation and less endothelial damage.

Boldt J. Ducke M. Kumle B. Papsdorf M. Zurmeyer EL. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Medicine. 30(3):416-22, 2004 Mar.

OBJECTIVE: Adequate restoration of intravascular volume remains an important maneuver in the management of the surgical patient. Influence of different volume replacement regimens on inflammation/endothelial activation in elderly surgical patients was assessed. DESIGN: Prospective, randomized study. SETTING: Surgical intensive care unit of a university-affiliated hospital. PATIENTS: Sixty-six patients >65 years undergoing major abdominal surgery. INTERVENTIONS: Ringer's lactate (RL; n=22), normal saline solution (NS; n=22) or a low-molecular HES (mean molecular weight 130 kD) with a low degree of substitution (0.4; HES 130/0.4; n=22) were administered after induction of anesthesia until the 1st postoperative day (POD) to keep central venous pressure between 8-12 mmHg. MEASUREMENTS AND RESULTS: C-reactive protein, interleukins (IL-6, IL-8), adhesion molecules [endothelial leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1)] were measured prior to volume therapy at the end of surgery, 5 h after surgery and at the morning of the 1st POD. RL patients received 10,150+/-1,660 ml of RL, NS patients 10,220+/-1,770 ml of NS and the HES-treated group 2,850+/-300 ml of HES 130/0.4 and 2,810+/-350 ml of RL. Hemodynamics were similar in all groups. CRP, IL-6 and IL-8 plasma levels increased significantly higher in both crystalloid groups (IL-6 in the NS group: increase to 407+/-33 pg/ml; RL: increase to 377+/-35 pg/dl) than in the HES-130 treated group (IL-6: increase to 197+/-20 pg/dl). Plasma levels of ELAM-1 and ICAM remained almost unchanged in the HES 130-, but significantly increased in the RL- and NS-treated patients. CONCLUSIONS: In elderly patients, markers of inflammation and endothelial injury and activation were significantly higher after crystalloid- than after HES 130/0.4-based volume replacement regimens.

Concerns with Colloids

• Decreased hemoglobin

• Dilution of plasma proteins

• Dilution of coagulation factors (PT, PTT)

• Pulmonary edema / Tissue Oxygenation

• Allergic reaction

• Renal Issues







• Renal Issues

Boldt J. Priebe HJ. Intravascular volume replacement therapy with synthetic colloids: is there an influence on renal function?. Anesthesia & Analgesia. 96(2):376-82, 2003 Feb.

FINAL PARAGRAPH

In reviewing the literature on HES and kidney function, the general recommendation that “HES should be avoided in ICUs and during the perioperative period” cannot be supported. All HES preparations are not created equally. There are large differences in physicochemical properties between the first-generation HES (Mw, 450 kd; DS, 0.7 [Hetastarch]) and the newest, third-generation HES solution (Mw, 130 kd; DS, 0.4). Although promising results with this rapidly degradable HES preparation have been published regarding patients with moderate to severe kidney dysfunction showing no deterioration in kidney function, large, well controlled, prospective studies demonstrating no adverse effects of this HES preparations on kidney function in the critically ill are missing.







• Renal Issues

Lang K. Boldt J. Suttner S. Haisch G. Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesthesia & Analgesia. 93(2):405-9, 2001 Aug.

The effects of intravascular volume replacement regimens on tissue oxygen tension (ptiO(2)) are not definitely known. Forty-two consecutive patients scheduled for elective major abdominal surgery were prospectively randomized to receive either 6% hydroxyethyl starch (HES) (mean molecular weight 130 kd, degree of substitution 0.4, n = 21) or lactated Ringer's solution (RL, n = 21) for intravascular volume replacement. Fluids were administered perioperatively and continued for 24 h on the intensive care unit to keep central venous pressure between 8 and 12 mm Hg. The ptiO(2) was measured continuously in the left deltoid muscle by using microsensoric implantable partial pressure of oxygen catheters after the induction of anesthesia (baseline, T0), 60 min (T1) and 120 min thereafter (T2), at the end of surgery (T3), and on the morning of the first postoperative day on the intensive care unit (T4). HES 130/0.4 2920 +/- 360 mL and 11,740 +/- 2,630 mL of RL were given to the patients within the study period. Systemic hemodynamics and oxygenation (PaO(2), PaCO(2)) did not differ significantly between the two volume groups throughout the study. From similar baseline values, ptiO(2) increased significantly in the HES-treated patients (a maximum of 59% at T4), whereas it decreased in the RL group (a maximum of -23% at T4, P < 0.05). The largest differences of ptiO(2) were measured on the morning of the first postoperative day. We conclude that intravascular volume replacement with 6% HES 130/0.4 improved tissue oxygenation during and after major surgical procedures compared with a crystalloid-based volume replacement strategy. Improved microperfusion and less endothelial swelling may be responsible for the increase in ptiO(2) in the HES 130/0.4-treated patients. IMPLICATIONS: In patients undergoing major abdominal surgery, a colloid-based (with hydroxyethyl starch [HES] 130/0.4) and a crystalloid-based (with lactated Ringer's solution [RL]) volume replacement regimen was compared regarding tissue oxygen tension (ptiO(2)) measured continuously by microsensoric implantable catheters. The ptiO(2) increased in the HES-treated (+59%) but decreased in the RL-treated (-23%) patients. Improved microcirculation may be the mechanism for the better ptiO(2) in the HES group.

Factor VIII

The presence of large, highly substituted molecules are believed to contribute to decreases in Factor VIII after HES administration

Boldt J. Haisch G. Suttner S. Kumle B. Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation. British Journal of Anaesthesia. 89(5):722-8, 2002 Nov.

BACKGROUND: Hydroxyethyl starch (HES) may affect blood coagulation. We studied the effects of a modified, balanced, high-molecular weight [mean molecular weight (MW) 550 kDa], high-substituted [degree of substitution (DS) 0.7] HES preparation (Hextend) on coagulation in patients undergoing major abdominal surgery. METHODS: Patients were allocated randomly to receive Hextend) (n=21), lactated Ringer's solution (RL, n=21) or 6% HES with a low MW (130 kDa) and a low DS (0.4) (n=21). The infusion was started after induction of anaesthesia and continued until the second postoperative day to maintain central venous pressure between 8 and 12 mm Hg. Activated thrombelastography (TEG) was used to assess coagulation. Different activators were used (extrinsic and intrinsic activation of TEG) and aprotinin was added to assess hyperfibrinolytic activity (ApTEG). We measured onset of coagulation [coagulation time (CT=reaction time, r)], the kinetics of clot formation [clot formation time (CFT=coagulation time, k)] and maximum clot firmness (MCF=maximal amplitude, MA). Measurements were performed after induction of anaesthesia, at the end of surgery, 5 h after surgery and on the mornings of the first and second days after surgery. RESULTS: Significantly more HES 130/0.4 [2590 (SD 260) ml] than Hextend) [1970 (310) ml] was given. Blood loss was greatest in the Hextend) group and did not differ between RL- and HES 130/0.4-treated patients. Baseline TEG data were similar and within the normal range. CT and CFT were greater in the Hextend) group immediately after surgery, 5 h after surgery and on the first day than in the two other groups. ApTEG MCF also changed significantly in the Hextend) patients, indicating more pronounced fibrinolysis. Volume replacement using RL caused moderate hypercoagulability, shown by a decrease in CT. CONCLUSION: A modified, balanced high-molecular weight HES with a high degree of substitution (Hextend) adversely affected measures of coagulation in patients undergoing major abdominal surgery, whereas a preparation with a low MW and low DS affected these measures of haemostasis less. Large amounts of RL decreased the coagulation time.

Human Serum Albumin

• Most abundant protein in the plasma

• MW 69,000 daltons

• Prepared from human donor plasma in isotonic saline

• Source of unending controversy

• SAFE study

Hespan (6 % Hydroxyethyl Starch)

• Available as 6% solution in normal saline w/ osmolarity of 310 mOsm/l

• Plasma volume expansion for more than 24 hrs• Like Dextran, can be associated w/ urticarial & anaphylactoid

reactions• Half life for 90% of particles is 17 days, whereas that of

remaining 10% is 48 days• Dosage: - usually 500-1000ml (do not usually exceed

1500ml/day) IV at a rate not to exceed 20ml/kg/hr • Precautions: - Not a substitute for blood or plasma;

Contraindicated in patients with severe bleeding disorders, severe CHF, or renal failure with oliguria or anuria

Hespan and Heparin Mix-upsProblem: A fatal error occurred when a nurse mistakenly selected and administered two heparin 25,000 unit per 500 mL premixed bags instead of HESPAN (hetastarch) for a patient who was actively bleeding. Such mix-ups have been reported on several occasions to USP, ISMP and FDA. Although this is primarily a nomenclature issue (both names include the characters h-e-p-a and n in the same sequence), the drugs are also found in similar IV bags with blue and red labeling. Since Hespan may be used in patients who are actively bleeding, the danger of inadvertent heparin administration is obvious.

Recommendation: Since hetastarch is now manufactured generically by other companies, consider using an alternate to Hespan and refer to hetastarch products by generic name. If Hespan remains in stock, do not store alphabetically next to premixed heparin products. Label products, storage bins, and automated dispensing machine pockets with a reminder about error potential. ISMP has communicated with FDA and the manufacturer about this serious problem.

http://www.ismp.org/MSAarticles/A4Q99Action.html

From: Wilkes: Anesth Analg, Volume 94(3).March 2002.538-544

Hextend (6 % Hydroxyethyl Starch)

HES - Pentaspan

• Synthetic plasma volume expander

• Average MW 200,000 – 300,000 daltons

• Plasma volume expansion exceeds volume of Pentaspan infused – lasting 18-24 h

• 12-24 h improvement in hemodynamic status

• 70% excreted in the urine in 24 hr

• Metabolized by serum amylases

Source: BioTime, Inc.

Case Study

Fluid Management for Craniofacial Resection with Rectus Free-Flap

Case: Craniofacial Resection with Rectus Free-Flap

A 76 year-old male, weighing 81 kg who was 185 cm tall, presented with complaints of facial pain and swelling. The patient had smoked a pack of cigarettes a day for almost 50 years. About 10 years ago, he developed angina while playing tennis. The angina was treated with the beta-blocker atenolol and the patient quit his smoking habit.

At the time of diagnosis, the patient reported that his infrequent angina attacks responded quickly to sublingual nitroglycerine tablets. He described his exercise tolerance as good, being able to climb three flights of stairs before "getting pooped". The patient took no other medications and had no allergies.

Diagnosis

A diagnosis of squamous cell carcinoma of the maxillary sinus was made bymagnetic resonance imaging and confirmed by biopsy following a workup.

Surgical Plan SURGERY

The surgical plan was to undertake a 10-hour craniofacial resection of the right maxilla and orbit and to replace the defect with a rectus muscle free-flap using microvascular techniques. A three litre blood loss is expected.

• 10-hour craniofacial resection

• 3 L expected blood loss

Preoperative Tests

Laboratory results included a hemoglobin concentration of 130 g/L, a creatinine of 99 mmol/L. Vital signs, serum electrolytes, electrocardiogram and chest X-ray were all unremarkable.

· Hb 130 g/L · Creatinine 99 mmol/L

Coronary Artery Disease

Although this patient appeared to be in fairly good shape, with good exercise tolerance, he had known coronary artery disease.

Because of his coronary artery disease, most anesthesiologists would not allow his hemoglobin to drop significantly below 100 g/L.

Blood Volume Estimate

Using 65 mL/kg as a blood volume estimate, his blood volume (BV) was calculated to be about 5300 mL.

ABL=2(5300) x (130-100)/(130+100)=1400 mL (approx.)

This suggests that with appropriate fluid replacement using crystalloid or colloid, the patient could lose up to about 1400 mL of blood, before a transfusion of packed red blood cells would likely become necessary. If serial blood samples were taken from an arterial line, it would be possible to know exactly when a minimum acceptable hemoglobin or hematocrit had been reached.

ABL Formula

The allowable blood loss (ABL) was estimated using the following formula:

ABL=2BV x (Starting Hb-Allowable Hb)/(Starting Hb+Allowable Hb)

ABL=2(5300) x (130-100)/(130+100)=1400 mL (approx.)

Two options to replace ongoing blood losses

• 4:1 with a crystalloid such assaline or Ringer’s lactate solutionor

• 1:1 with a colloid such as Pentaspan(10% pentastarch in 0.9% sodium chloride injection)

This is given in order to keep the patient isovolemic.

Rule of Thumb One often used "rule of thumb" is to replace

initial blood losses with crystalloid such as saline on a 4:1 basis until blood losses reach 15-20% of blood volume. Replace subsequent losses 1:1 with a colloid such asPentaspan (to keep patient isovolemic) until the hemoglobin or hematocrit falls below the "transfusion trigger".

Rule of thumb: Start Colloids at 15 - 20% Blood Volume Loss

Example (20% blood loss rule of thumb)

77 kg man

Blood volume estimated at 65 ml/kg x 77 kg = 5 liters

20% blood volume = 1 liter of blood

Crystalloid replacement for 1 liter blood is 3-4 liters

Thus, consider starting a colloid after 3-4 liters of crystalloid given to replace lost blood

Transfusion Trigger

In this case, a transfusion trigger of 100 g/L would be used because of thepatient's cardiopulmonary disease. In a much younger patient without anyknown cardiopulmonary disease, the trigger level might be set at 80 or even 70 g/L, depending on clinical judgement.

Preoperative Fluid Deficits

Preoperative fluid deficits are often estimated using the 4-2-1 rule. For an 81 kg patient this amounts to about 130 mL/hr. Assuming that the patient has been NPO for about 10 hours preoperatively and has had no IV prior togoing to the OR, the preoperative fluid deficit would be about 130 mL/hr x 10 hrs = 1300 mL. Many anesthesiologists attempt to replace this deficit over about a two hour span at the beginning of the case.

4-2-1 Rule

• 4 ml/kg/hr for first 10 kg• 2 ml/kg/hr for next 10 kg• 1 ml/kg/hr thereafter

EXAMPLES10 kg 40 ml/hr

20 kg 60 ml/hr

30 kg 70 ml/hr

40 kg 80 ml/hr

70 kg 120 ml/hr

Maintenance Fluid Requirements

Maintenance fluid requirements would amount to about 130 mL/hr

Third Space Losses

Third space losses include both evaporative losses from surgical area and fluid that enters the interstitium as a result of tissue trauma. For a case such as this one, a reasonable estimate of the third space losses would be about 4 mL/kg/hr or about 320 mL/hr.

Remember

• Preoperative fluid deficit anticipated at

1300 mL

• Third space losses of 320 mL/hr expected

• Maintenance fluid requirements of

130mL/hr expected

Desired Fluid Therapy 1

Run the IV at 450 mL/hour (130 mL/hr maintenance + 320 mL/hr third space loss replacement) throughout course of treatment.

In addition, for the first two hours add 650 mL/hr to the above amount to replace the 1300 mL deficit over 2 hours. The infusion rate will then be 1100 mL/hr (=450 mL/hr + 650 mL/hr) for the first two hours.

Desired Fluid Therapy 2

Switch predominately to Pentaspan 1:1 to replace the ABL of 1400 mL, with use of crystalloids as judged clinically appropriate by anesthesiologist.

Transfuse packed cells when hemoglobin falls below the "transfusion trigger" of 100 g/L.

Remember

• Run IV at 450 mL/hr. throughout treatment course to replace intra-op fluid losses

• Add 650 mL/hr over first two hours to replace pre-op deficit

• Add Pentaspan to replace ABL of 1400 mL

• Transfuse with packed cells when transfusion trigger of 100 g/L of hemoglobin is reached

Final Note

Note: These are starting points only. Most anesthesiologists would insert a CVP line, an arterial line and a Foley catheter in this patient to further guide fluid therapy. Fluid delivery may have to be increased should oliguria or hypotension occur.

The Colloid Controversy

The Colloid Controversy

“As colloids are not associated with improved survival and are considerably more expensive than crystalloids, it is hard to see how their continued use outside the randomized controlled trial in subsets of patients of particular concern can be justified.”

Schierhout and Roberts BMJ 316: 961-964, 1998

Cochrane Review

Misuse of Evidence-Based Medicine

“This paper exhibits all the worst abuses of evidence based medicine. It is written without insight into the subject being considered, and the results have been used to produce a sweeping generalisation which is scientifically inept.”

Wyncoll, DJA, Beale, J and McLuckie, A. BMJ 317: 278-279, 1998.

Key Clinical Questions

• Is there any benefit to the use of Pentaspan

over Hespan / Hextend?

• Are there any differences in outcome

between albumin and HES ?

• What are the consequences of prolonged

use of HES ?

Key Clinical Questions

• What should be the appropriate resuscitation protocol for various situations ?

• What is the role of hypertonic solution in acute fluid resuscitation ?

• What are the advantages/disadvantages of commercially available HES ?

ALBUMIN OR SALINE? FINDINGS FROM THE

SAFE STUDY

Key Point:

A large, randomized, double-blind clinical trial has shown that albumin and saline have the same safety and efficacy for fluid resuscitation in most critically ill patients. Only those with traumatic brain injury fared worse with albumin.


SAFE STUDY

In 1998, a Cochrane analysis compared albumin with other fluid resuscitation methods. After analyzing 24 randomized controlled trials, the authors concluded that albumin does not reduce mortality and, in some cases, may increase it. They therefore recommended that albumin not be used outside of clinical trials.

Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240.


SAFE STUDY

In response to these findings, Wilkes and Navickis performed a meta-analysis of 55 trials. Although their data set included many of the same trials that the Cochrane group used, Wilkes and Navickis found that albumin had no significant effect on mortality. They stated that their findings supported albumin’s safety but added the caveat that well-designed clinical trials were needed.

Wilkes MM, Navickis RJ. Patient survival after human albumin administration: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;135:149-164.


SAFE STUDY

Recently, Australian and New Zealand researchers took on the colloid/crystalloid debate by conducting a randomized, controlled, double-blind trial comparing albumin and saline in almost 7,000 critically ill patients. “Saline versus Albumin Fluid Evaluation (SAFE)” Study. The SAFE study found that:

•Albumin and saline are clinically equivalent. •The only increase in mortality with albumin occurred in patients with traumatic brain injury.

Finfer S. Does albumin kill? Results of a randomized control of 7,000 patients. Presented at: 33rd Critical Care Congress; February 22, 2004; Orlando, Fla.


SAFE STUDY

The patients were randomized to receive fluid resuscitation with 4% albumin or 0.9% saline solution. The amount and rate of fluid administration was left to the discretion of the treating clinician; however, the study equipment was carefully designed so that the ICU staff could not tell which fluid was being given. Study treatments were continued until patient discharge or death, or until 28 days after initial randomization.


SAFE STUDY

The primary end point was 28-day all-cause mortality. Secondary outcomes included survival time, proportion of new organ failures, duration of mechanical ventilation or renal replacement therapy, and length of hospital and ICU stay.

There were 3,473 evaluable patients in the albumin group and 3,460 in the saline group. Both groups were well matched for baseline characteristics and APACHE II scores.


SAFE STUDY

During the first four days of treatment, patients in the albumin group received less fluid than did patients in the saline group; however, the difference was not as great as had been expected: The ratio of albumin to saline was 1:1.38 liters.

Also during the first four days, patients in the albumin group received more packed red blood cells (a mean of 79 mL more per patient) than did those in the saline group.

The net daily positive fluid balance for this period was greater in the saline group than in the albumin group by about 1 liter.


SAFE STUDY

There were 726 deaths in the albumin group and 729 deaths in the saline group. Thus, the 28-day mortality rate was almost identical: 20.9% versus 21.1%.

No significant differences in outcome were noted when the three subgroups of patients were analyzed separately. However, when patients with traumatic brain injury were separated from the rest of the trauma group, there were 21 more deaths in patients given albumin than in those given saline.

There was no treatment difference in trauma patients without brain injury.


SAFE STUDY

NOW PUBLISHED

NEJM 2004 350:2247-2246

May 27, 2004

Large Volume Fluid Resuscitation

What is Massive Fluid Resuscitation?

• No strict definition• Over 10 liters of crystalloid / colloid (?)

• Usually involves an unstable patient

• May involve massive transfusion

What is a Massive Transfusion?Massive transfusion is the replacement of more than one blood volume (about 65 ml/kg) with blood components within several hours.

(Some authors say 10 units of blood in under 24 hours).

Some Sources of Massive Blood Loss

from www.trauma.org

(trauma image bank)

Earthquakes

Car Accidents

Penetrating Trauma

28 yr old male, motorcycle collision, fall over pieces of wood. The patient was haemodynamically normal, conscious, just demanding the removal of the stick. Nevertheless, he was submitted to an emergent left thoracotomy, and left laparotomy. The piece of wood was just located behind the sternum and in front of the heart with no major vascular or cardiac injury found, only a perforation of the diaphragm. Intraabdominally, the piece passed between the left lobe of the liver and the

spleen with no further injury. We found this almost unbelievable! Source: Luis Filipe Pinheiro, Viseu, Portugal

Penetrating Trauma

from www.trauma.org (trauma image bank)

Widened Mediastinum from Aortic Tear

from www.trauma.org (trauma image bank)

Massive Fluid Resuscitation: Sources of Trouble

• Not enough experience (lack of proactive management)

• Not enough help

• Not enough lines

• Not enough fluid warmers

• Not monitoring coagulation

Massive Fluid Resuscitation: Things to Look Out For

• Hypothermia

• Hypocalcemia and hypomagnesemia

• Coagulopathy

• Acidosis

• Severe anemia

• Airway edema

Predicting Life-Threatening Coagulopathy in the Massively Transfused Trauma Patient

Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 1997 May;42(5):857-61

CONCLUSION: Postinjury life-threatening coagulopathy in the seriously injured requiring massive transfusion is predicted by persistent hypothermia and progressive metabolic acidosis.

What Mechanisms Lead to Coagulopathy in Massive Transfusions?

Coagulation defects develop primarily from dilution of protein coagulation factors and platelets when crystalloid, colloid and red blood cells are used to replace lost volume.

Hypothermia frequently also plays a role.

Massive Fluid Resuscitation Using Plasma-Poor Red Cells

“Hypofibrinogenemia develops first followed by other coagulation factor deficits and later by thrombocytopenia. Therefore the use of fresh frozen plasma (FFP) is the primary intervention to treat abnormal bleeding encountered in the replacement of massive blood loss with plasma-poor red cells.” Replacement of massive blood loss. Hiippala S. Vox Sang 1998;74 Suppl 2:399-407

Characteristics of Coagulopathy with Massive Transfusions

Coagulopathy associated with massive transfusion is characterized clinically by microvascular bleeding or oozing from the mucosa, wound and puncture sites.

Surgeons will complain that clot formation ins impaired.

How Should Coagulopathy From Massive Transfusions Ideally be Treated?

Empirical formulas using ratios of various components to volume administered are often inadequate to appropriately treat or prevent coagulopathy of massive transfusion.

Treatment should include restoration of systemic perfusion, maintenance of normal temperature and blood component therapy supported by laboratory tests.

Consequences of Using Plasma-Poor Red Cells

• Plasma-poor red cells are now commonly used instead of whole blood or packed red blood cells to supply hemoglobin during blood loss.

• Since the plasma content of plasma-poor red cells is rather small, a deficit of plasma and coagulation factors develops earlier than during transfusion of whole blood or packed red blood cells .

Are Prophylactic Platelets and FFP Indicated in Massive Transfusion?

“Platelets should not be routinely administered during massive transfusion. While thrombocytopenia may develop in massively transfused patients, administration of platelets should be reserved for the patient exhibiting microvascular bleeding and a platelet count less than 50 x 109/L. Platelet transfusion may be necessary for patients with intermediate platelet counts (50-100 x 109/L) if it is determined the risk for more bleeding is significant.”

[http://www.asahq.org/ProfInfo/Transfusion/Massive.html]

“As the development of thrombocytopenia is a highly individual phenomenon, the transfusion of platelets should be guided by repeatedly determined platelet counts.” Replacement of massive blood loss. Hiippala S. Vox Sang 1998;74 Suppl 2:399-407


“FFP also should not be administered prophylactically for massive transfusion. In the massively transfused patient, clinical bleeding associated with coagulation factor deficiencies is unlikely until factor levels fall below 20 percent of normal. In the clinical setting, this usually does not occur until greater than one blood volume has been replaced and the PT and PTT are less than 1.5 times control values. In the event the PT and PTT cannot be obtained in a timely fashion, FFP may be administered for correction of microvascular bleeding in patients transfused with more than one blood volume.”

[http://www.asahq.org/ProfInfo/Transfusion/Massive.html]


Another Viewpoint on Massive Blood Transfusions

“In the past, prophylactic fresh-frozen plasma (FFP) and platelets transfusion has been said to have no place. However, relying on a specific biological diagnosis of the hemostatic defect is an unrealistic view in high bleeding rate situations.”

“Considering the time scale for laboratory screening and blood components availability, the use of FFP is advocated as soon as one blood volume has been replaced.”

“ If platelet counts and units may be more easily obtained, platelets transfusion may be guided by repeatedly determined platelet counts.”

Massive blood transfusion, blood volume expansion and hemostasisHématologie. Vol. 6, Issue 3, May - June 2000: 191-7, Reviewshttp://www.john-libbey-eurotext.fr/articles/hma/6/3/191-7/en-resum.htm

Minimal Volume Resuscitation

Recent studies have shown possible adverse Recent studies have shown possible adverse outcomes with aggressive fluid resuscitation and outcomes with aggressive fluid resuscitation and restoration of blood pressure prior to control of restoration of blood pressure prior to control of bleeding source, esp. in penetrating torso trauma.bleeding source, esp. in penetrating torso trauma.

(Minimal volume fluid resuscitation : Aim for MAP of 40 mm Hg or a SBP of 60 to 80 mm Hg)

Immediate Versus Delayed Fluid Resuscitation for Hypotensive Patients With Penetrating Torso Injuries

Bickell, W.H., et al, N Engl J Med 331:1105, 1994

Prospective trial of 598 patients with penetrating torso

trauma and systolic BP < 90 mm Hg

Standard resuscitation vs limited resuscitation (until

time of surgical intervention)

Limited resuscitation

375 mls IV fluid

Initial BP 72 mm Hg systolic

30% mortality

23% complication rate

Standard Resuscitation

2,480 mls IV fluid

Initial BP 78mm Hg systolic

38% mortality (p=0.04)

30% complication rate

Comment by Dr. Edward CrosbyTwo solitudes are evolving regarding the optimum timing and scale of fluid administration after penetrating trauma. One view is that immediate fluid resuscitation should be avoided in victims of penetrating trauma, since restoration of the blood pressure may promote further hemorrhage. This may result in the need for massive blood transfusion with resultant dilutional coagulopathy, and technical surgical difficulties. The opposing (and more conventional) view is that fluid resuscitation should be started immediately since the longer the period of shock the greater the risk of developing multiple system organ failure. An argument against fluid restriction is that the blood pressure at presentation is an important factor influencing survival following trauma with the incidence of multisystem complications correlating with the duration and intensity of shock. An additional concern is that, should there be barriers to rapid surgical intervention, non-resuscitated patients may exsanguinate while awaiting operation. The majority of patients assessed by Bickell were in hospital within 30 min of reported injury and entered the operating room in less than one hour of hospital time. Finally, it must be recognized that the reviewed studies (animal and human) address models and clinical situations relating to penetrating injury and are not generalizable to the patient population with blunt traumatic injury.

Pentastarch:How much? How long?

“ WARNING: General: Administration of large volumes of PENTASPAN® will decrease haemoglobin concentration and dilute plasma proteins excessively. Administration should be kept below the recommended ceiling of 2000 mL in 24 hours (see Dosage and Administration)”

HES and Massive Blood Transfusions

“Hydroxyethyl starch (HES) solutions are frequently used and differ in their pharmacological properties.”

“An acquired von Willebrand syndrome may result from the infusion of high molecular weight (MW) or of large volumes of medium MW HES solutions.”

“ HES solutions infusions should be restricted according to recommended dose limits.”

Massive blood transfusion, blood volume expansion and hemostasisHématologie. Vol. 6, Issue 3, May - June 2000: 191-7, Reviewshttp://www.john-libbey-eurotext.fr/articles/hma/6/3/191-7/en-resum.htm

World J Surg 1998 Jan;22(1):2-5

Use of pentastarch solution in the treatment of patients with hemorrhagic hypovolemia: randomized phase II study in the emergency room.

Younes RN, Yin KC, Amino CJ, Itinoshe M, Rocha e Silva M, Birolini D

This study evaluates the hemodynamic effects of the administration of 10% pentastarch solution (PS) during the initial treatment of hypovolemia in trauma patients. This prospective randomized phase II study included trauma patients admitted to the emergency room with hemorrhagic hypovolemia: systolic blood pressure (SBP) < 90 mmHg. Upon admission, the patients were randomized to receive 10% PS (n = 12) or isotonic 0.9% NaCl solution (IS) (n = 11), infused intravenously in 250-ml boluses, repeated until SBP > 100 mmHg. Blood pressure, infused volumes necessary to maintain SBP, and overall survival rates were determined and compared between groups.

World J Surg 1998 Jan;22(1):2-5

Use of pentastarch solution in the treatment of patients with hemorrhagic hypovolemia: randomized phase II study in the emergency room.

Younes RN, Yin KC, Amino CJ, Itinoshe M, Rocha e Silva M, Birolini D

SBP increased significantly following either IS (from 64.4 +/- 9.2 mmHg to 111.1 +/- 6.3 mmHg), or PS (from 63.7 +/- 10.6 mmHg to 108.1 +/- 9.8 mmHg) when compared to admission values (p < 0.05). Endovenous volumes infused were greater (p = 0.001) in IS patients (1420 +/- 298 ml) than in PS patients (356 +/- 64 ml). No blood was transfused into PS patients, compared to 370 +/- 140 ml of red blood cells transfused into IS patients (p = 0.015). Mortality rates were similar in the two groups (p = 0.725). We concluded that PS is a safe, efficient method for inducing hemodynamic recovery of hypovolemic trauma patients, with a clear reduction in the intravenous volumes required for acute resuscitation.

Arellano Pentaspan Study (currently in the review process)

Primary Objective To compare the effect of Pentaspan® vs 5% albumin in doses up to 45

ml/kg on laboratory indices of coagulation among patients undergoing major plastic surgical procedures.

Secondary Objective To compare the efficacy of Pentaspan® to 5% human albumin as a

plasma volume expander using clinical indices of intravascular volume status.

Hypotheses

Patients receiving Pentaspan® will not have clinically significant differences in laboratory indices of coagulation compared to patients receiving 5% human albumin.

Patients receiving Pentaspan® will require less colloid volume administration than patients receiving 5% human albumin to maintain similar levels of intravascular volume.

The End

Update on Fluid Management Intravenous Fluid Therapy Using Colloids: New Data, New Controversies D John Doyle MD PhD FRCPC Cleveland Clinic Foundation.

Documents

studies n

volume distribution

original studies

new data

new light

new hes preparations

safe trial slide

present information