Pre-hospital torso-warming modalities for severe hypothermia

[Ace844]

Hi All,

With the abundance of so many of our professional "coleagues" from the grate abyss to our north, i decided to look into some of their literature and saw this article which at this time of year may be useful..

Pre-hospital torso-warming modalities for severe hypothermia: a comparative study using a human model

Michele V. Hultzer, MD;*† Xiaojiang Xu, PhD;† Claudia Marrao, MSc;† Gerald Bristow, MD;† Alex Chochinov, MD;‡ Gordon G. Giesbrecht, PhD†*

Received: June 7, 2005; final submission: Aug. 27, 2005; accepted: Oct. 4, 2005

This article has been peer reviewed.

Can J Emerg Med 2005;7(6):378-86

*Department of Anesthesia, Faculty of Medicine, University of Manitoba, Winnipeg, Man.

†Laboratory for Exercise and Environmental Medicine, Health, Leisure and Human Performance Research Institute, Winnipeg, Man.

‡Department of Emergency Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Man.

ABSTRACT

Objective: To compare 5 active torso-warming modalities in a human model of severe hypothermia with shivering heat production inhibited by intravenous meperidine.

Methods: Six subjects were cooled on 6 different occasions each, in 8°C water, for 30 minutes or to a core temperature of 35°C. Spontaneous warming was the first torso-warming modality to be tested for every subject, and results served both as a comparative control and for determination of the meperidine dose for subsequent trials. Meperidine (1.5 mg/kg) was administered during the final 10 minutes of immersion to suppress shivering. Subjects were removed from the water, dried and insulated for 30 minutes, followed by 120 minutes of 1) forced-air warming with either a 600-W heater and commercial soft warming blanket; or 2) a 600-W heater and rigid cover; or 3) an 850-W heater and rigid cover; or 4) a charcoal heater on the chest; or 5) direct body-to-body contact with a normothermic partner. Supplemental meperidine (to a maximum cumulative dose of 3.2 mg/kg) was administered as required to inhibit shivering.

Results: The initial post-cooling afterdrop was approximately 1.0°C. After 30 minutes, core temperature continued to drop by 0.45°C in spontaneous and body-to-body warming modalities. This post-warming afterdrop was significantly less with 600-W heater and rigid cover and the charcoal heater (0.26°C) and the least with 850-W heater and rigid cover (0.17°C). Core rewarming rates were highest using 850-W heater and rigid cover (1.45°C/hr), with charcoal heating and 600-W rigid heater (0.7°C/hr), 600-W heater and blanket (0.57°C/hr) and body-to-body warming (0.52°C/hr) being more effective than spontaneous warming (0.36°C/hr).

http://www.caep.ca/004.cjem-jcmu/004-00.cj...005/v76.378.htm

[flight-lp]

Porta-warmer, one of the greatest inventions since sliced bread!!!!!!!!!!! 8)

http://www.allmed.net/catalog/item/1262

[bravofoxtrot]

Guess it was a human trial...I don't know how they find people to do these things...8 degrees Celsius...no thanks.

[Dustdevil]

Guess it was a human trial...I don't know how they find people to do these things.

This is how:

• Hey, if I get to pick my body-to-body partner in Canada, I think I might have to give it a try too!

[Ace844]

Hi All,

Here's another study with some great phys info for hypothermic trauma pt's, although the study was an animal study it does make some good points.

Hope this helps,

ACE844

(Does the Rate of Rewarming from Profound Hypothermic Arrest Influence the Outcome in a Swine Model of Lethal Hemorrhage?

[Original Articles)

Alam, Hasan B. MD; Rhee, Peter MD, MPH; Honma, Kaneatsu MD, PhD; Chen, Huazhen MD; Ayuste, Eduardo C. MD; Lin, Tom MD; Toruno, Kevin BS; Mehrani, Tina BS; Engel, Caroline BA; Chen, Zheng MD, PhD

From the Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland (H.B.A., P.R., K.H., H.C., E.C.A., T.L., K.T., T.M., C.E., Z.C.); Department of Surgery, Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts (H.B.A.); Los Angles County-University of Southern California Medical Center, Los Angeles, California (P.R.)

Submitted for publication October 15, 2004.

Accepted for publication November 16, 2005.

Data presented at the Annual Meeting of the American Association for the Surgery of Trauma, September 29–October 4, 2004, Maui, Hawaii.

This work was supported by a research grant (RO1 HL71698 to H.B.A.) from the National Institutes of Health.

Address for Reprints: Hasan B. Alam, MD, FACS, Massachusetts General Hospital. Division of Trauma, Emergency Surgery, and Surgical Critical Care. 165 Cambridge Street, Suite 810. Boston, MA 02114; email:hbalam@partners.org.]

Abstract

Background: Rapid induction of profound hypothermic arrest (suspended animation) can provide valuable time for the repair of complex injuries and improve survival. The optimal rate for re-warming from a state of profound hypothermia is unknown. This experiment was designed to test the impact of different warming rates on outcome in a swine model of lethal hemorrhage from complex vascular injuries.

Methods: Uncontrolled lethal hemorrhage was induced in 40 swine (80–120 lbs) by creating an iliac artery and vein injury, followed 30 minutes later (simulating transport time) by laceration of the descending thoracic aorta. Through a thoracotomy approach, a catheter was placed in the aorta and hyperkalemic organ preservation solution was infused on cardiopulmonary bypass to rapidly (2°C/min) induce profound (10°C) hypothermia. Vascular injuries were repaired during 60 minutes of hypothermic arrest. The 4 groups (n = 10/group) included normothermic controls (NC) where core temperature was maintained between 36 to 37°C, and re-warming from profound hypothermia at rates of: 0.25°C/min (slow), 0.5°C/min (medium), or 1°C/min (fast). Hyperkalemia was reversed during the hypothermic arrest period, and blood was infused for resuscitation during re-warming. After discontinuation of cardiopulmonary bypass, the animals were recovered and monitored for 6 weeks for neurologic deficits, cognitive function (learning new skills), and organ dysfunction. Detailed examination of brains was performed at 6 weeks.

Results: All the normothermic animals died, whereas survival rates for slow, medium and fast re-warming from hypothermic arrest were 50, 90, and 30%, respectively (p < 0.05 slow and medium warming versus normothermic control, p < 0.05 medium versus fast re-warming). All the surviving animals were neurologically intact, displayed normal learning capacity, and had no long-term organ dysfunction.

Conclusions: Rapid induction of hypothermic arrest maintains viability of brain during repair of lethal vascular injuries. Long-term survival is influenced by the rate of reversal of hypothermia.

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Uncontrolled hemorrhage remains the leading cause of preventable death in military 1 and civilian trauma.2–4 The typical cardiopulmonary resuscitation strategies do not change the outcome in this setting 5–7 unless the source of hemorrhage can be rapidly controlled. A large number of these injuries are potentially reparable, but most patients die before definitive care can be rendered.8 Often the limiting factor is the period of normothermic ischemia that can be tolerated by the brain (5 minutes)9,10 and the heart (about 20 minutes).11 Strategies that can prevent cerebral and myocardial damage long enough to gain control of hemorrhage and restore intra-vascular volume could be life saving. This requires an entirely new approach to the problem, with emphasis on rapid total body preservation, repair of injuries during metabolic arrest, and controlled resuscitation. The feasibility of using profound hypothermia to induce a state of “suspended animation” has clearly been established in numerous preclinical experiments.12 However, before this concept can be applied in clinical practice the optimal methods for the induction, maintenance, and reversal of profound hypothermia must be clearly identified.

Using large animal models of complex vascular injuries, our group has demonstrated that profound hypothermia (10°C) can be induced for repair of injuries through an emergency thoracotomy approach 13 to achieve >75% long term survival, even after 60 minutes of uncontrolled hemorrhage.14 The surviving animals in these experiments displayed normal cognitive functions, no neurologic deficits, and no significant long-term organ dysfunction. We now know that maximum benefit is achieved when profound hypothermia is induced very rapidly (2°C/min).15 However, the optimal rate of re-warming after a period of hypothermic arrest (for repair of injuries) has not been established. Unless carefully controlled, restoration of normal flow and reversal of hypothermia can have adverse side effects. Reperfusion injury has been well described in heart 16 and brain 17 after periods of low flow such as cardiac surgery or cardiac arrest. In the brain, calcium overload in the mitochondria, free radical injury, and a “no-flow” phenomenon may all play a role in postresuscitation dysfunction.18 After 60 minutes of hypothermic circulatory arrest or low flow bypass, cerebral oxygen consumption and metabolism may take 2 to 4 hours to recover and the cerebral vascular resistance can stay elevated for almost 8 hours.19,20 There is also data to suggest that active re-warming may cause a mismatch between cerebral oxygen delivery and demand.21 Thus it is logical to re-warm gradually when protective hypothermia is induced for elective surgical procedures, traumatic brain injury, or cardiac arrest. However, trauma patients are clearly different and the potential benefits of prolonged hypothermia (slow re-warming) must be weighed against its risks (e.g. coagulopathy). The current experiment was therefore designed to study the impact of different rates of re-warming on outcome after profound hypothermic arrest, in a clinically relevant porcine model of uncontrolled hemorrhage and soft tissue injuries.

MATERIALS AND METHODS

The institutional Animal Care and Use Committee approved this study. All the research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations related to experiments involving animals. The study adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996 edition. Strict aseptic technique was used for all surgical procedures.

Animal Preparation

A total of 40 (n = 10/group) female Yorkshire swine (wt 80–120 lbs, Tom Morris Farms, Reistertown, MD) were anesthetized with intra-muscular injection of ketamine (10 mg/kg) and inhaled isoflurane (4–5%). After placement of endotracheal tubes, isoflurane was reduced to 0.5 to 1%. The animals were allowed to breathe spontaneously through a Narkomed M ventilator (North American Dräger, Telford, PA). A temperature probe was inserted in the pharynx. The right carotid artery and external jugular vein were cannulated with a 22G angio-catheter and 9F introducer sheath respectively, and a 7.5F oximetric thermodilution pulmonary artery catheter (Baxter Health Care Corp., Irvine, CA) was positioned in the pulmonary artery. The catheters were attached to a hemodynamic monitoring platform (Hewlett Packard, Paolo Alto, CA), and Baxter system (Explorer, Baxter, Edwards Critical Care, Irvine, CA) was used for continuous monitoring of blood pressure, mixed venous oxygen saturation, and pulmonary artery catheter parameters (measured and derived). A left anterior lateral thoracotomy was performed through the fourth intercostal space. The animals were paralyzed (Pancuronium) and switched to full ventilator support, and minute ventilation was adjusted to keep Paco2 between 35 to 40 mm Hg. The fraction of inspired oxygen (FiO2) was kept at the lowest possible level to maintain pulse oximetry readings above 95%. Arterial and mixed venous blood samples were analyzed on Nova Stat Profile Ultra (Nova Biomedical, Waltham, MS). Complete blood counts and serum biochemical measurements were performed by the Diagnostic Services & Comparative Medicine laboratory (Uniformed Services University, Bethesda, MD).

Hemorrhage Protocol

Two standardized longitudinal (medial and lateral) lacerations were made in the common iliac artery by passing a number 15 scalpel blade through the arterial walls.22 A venous injury was simultaneously created by performing a 50% transection of a large branch of the internal iliac vein (uncontrolled arterial and venous hemorrhage). Animals were kept in shock for 30 minutes (simulating transport time to the hospital) before creating a 2-cm descending aortic laceration that caused lethal uncontrolled hemorrhage, which in previous experiments had resulted in 100% mortality unless hemorrhage was rapidly controlled or hypothermic arrest induced. After 5 minutes of hemorrhage from the aortic laceration, a catheter was placed into the aorta for the induction of hypothermic metabolic arrest as described below. The total blood loss before induction of hypothermia ranged between 1,000 to 1,500 mL (approximately 50% of estimated blood volume). The shed blood was saved for auto-transfusion in all animals. During the 60 minutes of hypothermia (10°C) the injured branch of iliac vein was ligated and the arterial lacerations were repaired using running 6-0 monofilament sutures.

Induction of Asanguineous Hyperkalemic Hypothermic Metabolic Arrest 13–15

A 24 F double lumen catheter (Cardeon, Cupertino, Calif) was inserted through the aortic laceration. Standard cardiopulmonary bypass (CPB) equipment was utilized for this experiment: roller pumps and heat exchanger (Sarns Inc., Ann Arbor, MI), membrane oxygenator, nonheparin bonded circuit tubing and reservoir (Gish Biomedical Inc., Santa Ana, CA). The reservoir was primed with 3 L of cold (2°C) high potassium (70 mEq/L) organ preservation solution (Unisol-I “intracellular type” UHK, Organ Recovery Systems Inc, Charleston, SC). Heparin (100 units/kg) and dexamethasone (0.25 mg/kg) were added to the reservoir. Flow was started at 500 mL/min through the aortic catheter, which resulted in instantaneous cardioplegic arrest. A 36F venous cannula was inserted into the right atrium to initiate full cardiopulmonary bypass at 3 to 4 L/min, and the temperature of the heat exchanger was adjusted to achieve a cooling rate of 2°C/min. When the core temperature reached 20°C, 2 L of reservoir fluid were exchanged for a lower potassium fluid (Unisol-I “intracellular type”, 25 meq/L, ULK, Organ Recovery Systems Inc.). Once the core temperature reached 10°C, flow rates were reduced to 10 to 20 mL/kg/min and heat exchanger adjusted to maintain this temperature. The reservoir fluid was exchanged (1 L every 15 minutes for a total of 4 L) with potassium-free extracellular perfusate fluid (Unisol-E, Organ Recovery Systems Inc.) to restore normal extra-cellular milieu. At the start of the warming phase, reservoir was drained to 0.5 L and 0.5 L of purchased pig whole blood in citrate dextrose solution (Tom Morris Farms, Md) was added. The flow rates were increased to 3 to 4 L/min and temperature of the aortic return adjusted to achieve the desired re-warming rates. This typically required a gradient of 5°C and 10°C above the core body temperatures in the slow and medium warming groups respectively. In the fast warming group, this gradient varied between 10 to 20°C, with the maximum temperature of the re-infused blood occasionally reaching 38°C. As the core temperature increased, whole blood (maximum of 4000 mL) was introduced gradually to keep up with the increasing oxygen demands, and electrolyte and acid base abnormalities were corrected as needed. Typically, spontaneous cardiac activity resumed with the reversal of hyperkalemia and hypothermia. Internal cardioversion was performed if required and mechanical ventilation was re-started. After a brief period of stabilization, the animals were gradually taken off the CPB and protamine sulfate was administered to reverse heparin. A dose of dexamethasone (0.25 mg/kg) was given intravenously, and autologus shed blood was infused over the next 2 hours. All the incisions were repaired, and the animals were taken off the ventilator once the normal respiratory drive had returned (typically 2–3 hours). Intra-muscular injections of buprenorphine hydrochloride (0.3 mg) were given for pain control, and cefazolin was administered for peri-operative antibiotic coverage (24 hours). All the animals (hypothermic and normothermic) were treated in an identical fashion (injuries, fluids, CPB flow rates, blood transfusion, drugs, etc.) except for the differences in maintenance of core temperatures.

Postoperative Laboratory Measurements

In the surviving animals, blood was drawn weekly for measurement of complete blood count, electrolytes, liver enzymes (bilirubin, alkaline phosphatase, aminotransferases), renal function tests (creatinine, urea nitrogen), markers of cell damage (creatine kinase, lactate dehydrogenase, uric acid), pancreatic enzymes (amylase), and nutritional parameters (serum protein, albumin, globulin, triglyceride, cholesterol, lipoproteins).

Measurement of Circulating Cytokines and Immune Markers Using ELISA

Venous blood samples were obtained at the following time points: before operation (baseline), 30 minutes of hemorrhagic shock, start and end of profound hypothermic period, end of warming period, end of experiment, and weeks 1, 3, and 6 after the experiment (surviving animals). The serum was separated by centrifuging blood samples at 3,000 pm for 15 minutes and saved at -80°C. The experiments for IL-6, IL-10, IL-1[beta], TGF-1[beta], and HSP70 were done according to manufacturer's protocol. Briefly, 100 µL of standards and serum samples (diluted 1:1) for IL-10, IL-1[beta] (BioSource, Camarillo, CA) and HSP70 (Stressgen, Victoria, Canada), IL-6 (diluted 1:2) (R&D System, Minneapolis, Minn), 200 µL of standards and serum samples for TGF-1[beta] (diluted 1:2) (BioSource, Camarillo, Calif) were incubated in 96-well microtiter plates coated with those antibodies at 4°C overnight for IL-10, IL-1[beta], and TGF-1[beta], at room temperature 3 hours for HSP70 and 2 hours for IL-6. The optical density of each well was determined with a microplate reader set at 450 nm (Dynatech Laboratories, Billingshurst, UK). The concentrations of these cytokines were determined by interpolation from a standard curve. Results were expressed as nanograms of antigen per milliliter for HSP70, picograms of antigen per milliliter for IL-6, IL-10, IL-1[beta], and TGF-1[beta].

Neurologic Testing

Neurologic testing was done during the postoperative period using a scoring system that has previously been published.13 This score took into account level of consciousness, behavior, feeding, cranial nerves, motor/sensory functions, and co-ordination.

Cognitive Function (learning capacity)

We used a method of training that is based upon the concept of operant conditioning. A detailed description, rationale, and validation of this method have already been published.14 Briefly, we relied on the strong “rooting behavior,” and excellent color perception that is normally found in swine. During the training, animals were presented with three colored boxes, all contained food but only one (blue box) could be opened. They were expected to open the blue box to obtain food in the shortest possible period of time without making any mistakes. Their performance was compared with 15 normal animals that were used to establish this protocol.

We monitored the number of sessions taken to learn the task, time taken to finish the task (max. 300 seconds) during each session, and a composite performance score that was calculated as follows:

+2 = opens blue box

+1 = touches blue box but does not open it

+1 = does not approach the other two boxes

+0 = smells either of the other two boxes

-1 = tries to open either of the other two boxes

The maximum score possible was +3 (opening of blue box without ever approaching the other two boxes). Each false attempt earned a negative mark (no maximum). The session ended as soon as the blue box was opened or at 300 seconds.

Brain Fixation and Histology

Six weeks postexperiment, in vivo fixation of brains was performed under anesthesia by infusion of ice cold saline followed by 4% buffered paraformaldehyde. The brains were then kept in the same fixative overnight at 4°C, dissected, and examined for gross lesions. Brain blocks were embedded in paraffin and 10 um frontal sections of cortical, striatal and hippocampal areas were cut and stained with hematoxylin and eosin and examined for ischemic changes.

Statistical Analysis

All data are presented as group means ± SEM. The SPSS statistical software program (SPSS/Windows, SPSS Inc., Chicago, IL) was used. One-way ANOVA with Dunnett's test for multiple comparisons was performed for all continuous variables, and [chi]2 and Fisher's exact tests were used to compare the survival rates. Significance was defined as p < 0.05.

RESULTS

Hemodynamic and Physiologic Parameters

Uncontrolled hemorrhage from iliac arterial and venous injuries caused a rapid drop in mean arterial pressure (MAP) and cardiac output in all animals (Fig. 1A, Table 1). The animals remained profoundly hypotensive (no palpable pulse), with low cardiac output (CO), and decreased oxygen delivery (DO2) during the 30 minutes of normothermic shock (Table 1). Aortic laceration caused massive hemorrhage and decreased the MAP to about 20 mm Hg. Infusion of cold hyperkalemic fluid into the aorta resulted in cessation of spontaneous cardiac activity. Hemodynamic parameters, markers of tissue ischemia and selected electrolyte changes during different phases of the experiment are shown in Table 1. The hypothermic animals developed significantly less metabolic acidosis (serum lactate, base excess, and pH) compared with normothermic controls.

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[Email Jumpstart To Image] Fig. 1. (A) Representative Mean Arterial Pressure (MAP) readings during the experiment. One randomly selected animal from each experimental group. ( Representative core body temperature readings during the experiment. One randomly selected animal from each experimental group.

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[Email Jumpstart To Image] Table 1 Selected Intra-Operative Measurements

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Re-Warming Rates

The cooling rates were the same in all the hypothermic animals. After 60 minutes of profound hypothermia, re-warming was started and the temperature of aortic return was adjusted to achieve the desired re-warming rates. The maximum temperature that could be generated in the heat exchanger was 42°C. But the temperature of the blood that was re-infused into the aorta (even with maximum heating) was never above 38°C. The rate of warming was not constant during the entire period. It automatically slowed down as the temperature gradient between the core body temperature and the heat exchanger decreased (Fig. 1B). The times taken to re-warm back to baseline temperatures in the three hypothermia groups were:

* Slow warming: Early (up to 20°C) = 38.9 ± 0.9 minutes. Total (10°C-baseline) = 105.5 ± 1.7 minutes.

* Medium warming: Early (up to 20°C) = 19.3 ± 1.0 minutes. Total (10°C-baseline) = 61.6 ± 2.2 minutes.

* Fast warming: Early (up to 20°C) = 13.3 ± 0.9 minutes. Total (10°C-baseline) = 50.0 ± 1.5 minutes.

Postoperative Laboratory Measurements

The biochemical abnormalities during the postoperative period were transient. These included an increase in the levels of liver aminotransferases, serum creatine kinase, lactate dehydrogenase, and serum creatinine (Table 2). All of these returned to baseline over a period of about 1 week.

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[Email Jumpstart To Image] Table 2 Selected Postoperative Laboratory Measurements

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Measurement of Circulating Cytokines and Immune Markers

Among the markers measured, two were specifically influenced by hypothermia. Proinflammatory IL-6 increased in all groups compared with baseline, but the increase was significantly attenuated in the hypothermic groups. Furthermore, the circulating levels of IL-6 were inversely proportional to the rate of re-warming (Fig. 2A). Protective heat shock protein 70 (HSP-70) increased markedly after re-warming, with the highest increase seen in medium warming group (Fig. 2B). Other cytokines (data not shown) were influenced by hemorrhage, surgical insult, and use of cardiopulmonary bypass but not specifically by induction or reversal of hypothermia.

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[Email Jumpstart To Image] Fig. 2. Levels of circulating: (A) Interlukin-6, and Heat shock protein 70 (HSP-70) in different experimental groups. Data presented as group means ± SEM. *, p < 0.05 compared with the no cooling group at the same time point. ^, p < 0.05 compared with its own baseline value. Warming rates for the groups are: control = no cooling or warming, slow warming = 0.25°C/min, medium warming = 0.5°C/min, fast warming = 1.0°C/min. Sampling time points are: B = baseline, AH = after 30 minutes of uncontrolled hemorrhage, SH = Start of 60 minutes period of profound hypothermia (10°C), EH = end of 60 minutes period of profound hypothermia (10°C), EW = end of warming period, EE = end of experiment (death, or successful detachment from cardiopulmonary bypass and ventilator), W1–6 = postoperative weeks 1 through 6.

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Survival and Neurologic Outcome

Six week survival rates and the results of cognitive function evaluation are shown in Figures 3 and 4, respectively. All of the normothermic control animals were found to be clinically brain dead on reversal of anesthesia. Interestingly, half of the animals in this group regained excellent cardiac function and were easily taken off CPB. In the hypothermic animals, the outcome was dramatically influenced by the rate of re-warming. The survival in slow and medium re-warming groups was significantly better than the normothermic controls (p = 0.03 and p = 0.0001 for slow and medium warming groups, respectively). When compared with the fast re-warming group, survival in slow and medium re-warming groups improved by 166% and 300%, respectively, but this was statistically significant only for the medium re-warming (p = 0.65 and p = 0.02 for slow and medium warming groups, respectively). Histologic examination of brains at 6 weeks revealed no ischemic damage in any of the surviving swine.

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[Email Jumpstart To Image] Fig. 3. Survival rates (%) in different groups. * p < 0.05 compared with normothermic control group. # p < 0.05 medium versus fast warming groups. Survival in slow warming group was not statistically different from medium or fast warming groups.

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[Email Jumpstart To Image] Fig. 4. Cognitive function testing: (A) Performance scores, ( Time taken to accomplish the task. Data from the first five training sessions are presented as group means ± SEM. Control = normal animals, Hypothermic = animals that survived profound hypothermia (regardless of re-warming rates). The calculation of performance score is described in the Material and Methods section.

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Slow Warming

Five animals survived for 6 weeks and were neurologically intact and showed normal learning capacity. There were no delayed complications in these animals. One animal could not be taken off the CPB and one died resulting from irreversible ventricular fibrillation. Another animal sustained acute lung injury (Pao2/FiO2 ratio of 112) and died 1 hour after discontinuation of CPB because of hypoxia. Two animals died unexpectedly on the third postoperative day, most likely because of sudden cardiac arrhythmias.

Medium Warming

Nine out of 10 animals survived for 6 weeks. They were all neurologically intact and showed normal learning capacity. One developed a deep thoracotomy wound infection that progressed to empyema and septic pericarditis resulting in death 3 weeks after the experiment. Although neurologically intact, this animal was not healthy enough to undergo the training protocol.

Fast Warming

Only three animals survived for 6 weeks. However, they had no neurologic deficits and showed normal learning capacity. There were 2 intra-operative deaths; 1 animal developed uncontrolled pulmonary hypertension and could not be taken off CPB, and 1 had cardiac arrest after discontinuation of CPB. Another 2 animals died in the early (3 hours) postoperative period secondary to acute lung injury (severe hypoxia), and cardiogenic shock respectively. Two more animals died resulting from unknown reasons on postoperative days 1 and 13.

DISCUSSION

The current study is part of a series of experiments, designed to systematically identify the optimal strategy for the induction, maintenance, and reversal of profound hypothermia. Our aim was to generate clinically meaningful information by using a realistic model (uncontrolled hemorrhage in large animals, open body cavities, major vascular injuries, operative trauma, repair of lethal injuries), and by monitoring for delayed complications. We have recently reported that the outcome in this model of complex injuries is significantly influenced by the rate of cooling, with the best outcome associated with very rapid induction of hypothermia.15 The findings from the current study demonstrate that the rate of re-warming is equally important, with best outcome when hypothermia is reversed at a rate of 0.5°C/min.

The rationale behind the development of this animal model has been published previously 13–15 and only a few salient points need to be discussed. A combination of major vascular injuries above and below the diaphragm was chosen because it is associated with almost certain death in clinical practice. We decided to use an open chest approach for the induction of hypothermia because patients in profound hemorrhagic shock (after penetrating truncal trauma) are candidates for emergency department thoracotomy as a life saving measure. The overall survival after this procedure is approximately 7.0%, but it decreases to <1% when there are multiple sources of hemorrhage (especially below the diaphragm).23 We reasoned that it is logical to use the open chest approach to; (1) control hemorrhage and repair injuries rapidly (without hypothermia) if possible, or (2) induce hypothermia if the patient is potentially salvageable but the time required to repair the injuries is more than what the brain can tolerate. In this highly selected group of patients, we believe that profound hypothermia should be induced rapidly, maintained for the shortest possible period of time, and then actively reversed. Although we utilized a roller pump for the induction of hypothermia, Dr. Safar's group at the University of Pittsburgh has demonstrated convincingly that other methods (such as retrograde aortic flush through a femoral approach) are equally effective.12

The optimal strategy for the utilization of protective hypothermia (rate of induction, depth, duration, etc.) obviously depends upon the clinical setting. Application of hypothermia in elective surgery or after ventricular fibrillation is fundamentally different from its use in traumatic shock. In elective surgery hypothermia is induced before ischemia-reperfusion. In sudden cardiac arrest victims, induction of even mild hypothermia after the restoration of normal flow improves neurologic outcome, most likely by blunting the reperfusion injury.24,25 However, in trauma, hypothermia can only be induced after the onset of shock/ischemia and it must be maintained during the periods of surgical interventions, ongoing shock (prolonged low flow), and resuscitation. It is also important to point out that induced hypothermia and hypothermia secondary to shock may be very different entities. Induced hypothermia is therapeutic in nature whereas hypothermia seen in severely traumatized patients, is a sign of tissue ischemia and failure of homeostatic mechanisms to maintain normal body temperature. A comparison of hypothermic trauma patients with hypothermic cardiothoracic surgery patients has clearly shown decreased levels of energy substrates and higher lactate levels in the trauma patients,26 indicating that while therapeutic cooling is a beneficial adjunct to cardiac surgery, hypothermia associated with shock is a maladaptive consequence of injury. Controlled induction of hypothermia causes a decrease in oxygen demand, which is clearly advantageous during periods of ischemia. In contrast, hypothermia seen during severe shock is a marker of cellular hypoxia and indicates a grave prognosis.27,28 It has also been shown that hypothermia is associated with an increase in acute mortality after trauma, and active re-warming can decrease resuscitation fluid requirements in these patients.29

Similar to the previous studies by our group 13–15 there was a remarkable absence of any long-term organ dysfunction in animals that survived the hypothermic arrest. We feel that induction of profound hypothermia was the primary reason for cellular protection, with the organ preservation fluids providing some additional benefits. Infusion of organ preservation fluids without hypothermia (normothermic controls) was clearly not sufficient to prevent injury in the organs that are extremely sensitive to ischemia such as brain and heart. However, other organs (kidneys, liver, pancreas, bowel, muscle, etc.) were fairly well preserved in the normothermic control group, suggesting that the organ preservation fluids used during this experiment also provided a degree of cellular protection. Another possible explanation is that the hemorrhagic shock, before infusion of organ preservation solutions, was not severe enough to cause multiple organ dysfunction. These findings however suggest that universal tissue preservation (in vivo) for procurement of multiple transplantable organs may be another exciting application of the “suspended animation” strategy.30

This study was not designed to identify the specific mechanisms by which hypothermia protected the cells during ischemia and reperfusion. It is well known that biological reactions are influenced by alterations in temperature. The Q10 (temperature coefficient) can be defined as the factor by which the rate of a biochemical reaction changes for a 10°C alteration in temperature.31 For the whole body Q10 is about 2.0, suggesting a 50% reduction in metabolism for every 10°C decrease in body temperature.32 Brain Q10 has been reported to be as high as 4.6 for humans 33 and cerebral metabolic rate has been shown to decrease by 5% for every 1°C drop in temperature, reaching 10% of normal at 15°C. In this experiment, there was no measurable oxygen consumption during the 60 minutes of hypothermic arrest. However, cellular metabolism was not completely abolished as evidenced by an increase in serum lactate during this period (Table 1). Hypothermia has been shown to modulate numerous pathways in biological systems. For example it decreases the oxidative stress proteins and inflammatory response after ischemia-reperfusion.34,35 We noted a decrease in pro-inflammatory cytokine IL-6, and an increase in protective heat shock protein-70 (HSP-70) levels in the hypothermic animals. Although clearly favorable, it is not clear whether these changes were the cause or the effect of decreased cellular injury. Other investigators have shown that induction of hypothermia can attenuate organ injury and improve survival following hemorrhagic shock with 36 or without 37 significant changes in the inflammatory pathways.

Clinical studies have shown that during periods of rapid warming, pharyngeal, esophageal, tympanic, rectal and bladder temperatures can all underestimate the brain temperature.38 The difference between the measured and true brain temperature can be as much as 2°C, with fairly significant variations between different areas of the brain.39 To avoid over heating, we closely monitored the temperature of the blood that was returned to the animals on CPB, and stopped active re-warming when the pharyngeal temperatures reached 35°C. In addition, the maximum temperature of the aortic return was kept below 38°C even in the fast warming animals. Despite all of these precautions, it is possible that a mismatch between oxygen delivery and demand at the tissue level (because of rapid re-warming) may have caused cellular injury. The fact that slow warming animals did not have the best outcome was somewhat surprising. This group however, required bypass twice as long as the medium warming group, which may have contributed to the poor outcome. The best outcome was achieved with a warming rate of 0.5°C/min, which restored normothermia safely without an excessively long period of cardiopulmonary bypass. However, it must be pointed out that only the survival difference between the medium and fast re-warming reached statistical significance.

There are numerous clinical advantages of using acellular organ preservation fluids during the induction and maintenance of hypothermia. It decreases the use of precious blood products, and overcomes the issues of cross match, availability, cost, limited shelf life, and potential transmission of diseases. Profound hypothermia increases blood viscosity and the potential for micro-vascular thrombosis, which is markedly decreased by the use of acellular fluids (hemodilution). During profound hypothermia, hardly any oxygen is given up by the red blood cells at the tissue level because of a shift in oxygen disassociation cure to the left, and an increase in serum pH. Therefore, there is no physiologic need for a high hemoglobin level during this period. For all of these reasons, blood transfusion was delayed in our model until all the vascular injuries had been repaired, and higher oxygen delivery was needed to meet the increasing metabolic demands (re-warming period). The organ preservation fluids used in this experiment contained various electrolytes, impermeant anions (lactobionate and gluconate) to prevent cell swelling, Dextran 40 to provide oncotic pressure and decrease interstitial edema, adenosine as a substrate for ATP regeneration, buffers, anti-oxidants, and small amounts of glucose and sucrose.40

The physiologic and therapeutic effects of hypothermia have been well known for more than 60 years.41,42,43 Since its early description, controlled induction of hypothermia for cellular protection has become common practice in numerous surgical settings, such as operations on the heart, brain, spine, and for the ex vivo preservation of organs for transplantation. No clinical studies have been conducted to test the potential benefits of hypothermia in trauma patients. However, numerous preclinical studies have established that mild to moderate hypothermia can significantly delay the onset of cardiac arrest (2–4 folds)44–46 and improve survival 47–49 after hemorrhagic shock. Rapid induction of deep/profound hypothermia can improve outcome after massive blood loss 50–52 even with no flow to the brain for up to 120 minutes in canine models.53–55

The complexity of this experimental model, while providing clinical realism, adds many variables that can influence the results. Animals were subjected to a number of insults, such as: surgical trauma, vascular injuries, uncontrolled hemorrhage, cardiopulmonary bypass, hypothermia, re-warming, and blood transfusion. Various drugs were also administered, some of which (heparin, steroids, organ preservation fluids, and epinephrine) have the potential to modulate cellular injury and influence survival. To control for all of these variables we included the normothermic group, where animals were treated in an identical fashion compared with the hypothermic animals, except for differences in temperature modulation. It should be emphasized that this group served as an experimental control and was not meant to represent the clinical standard of care. As animals in all the experimental groups were subjected to identical injuries, and were given the same doses of fluids, blood and drugs, we believe that the differences in survival can safely be attributed to the different rates of re-warming. Another limitation of this model is an absence of solid organ injuries, which may be difficult to control in the presence of hypothermia-related coagulopathy. We tested only three rates of warming and it is entirely possible that other rates may give very different results. Despite these limitations, the data clearly demonstrates that rapid induction of profound hypothermia following massive hemorrhage can prevent death, and that rapid re-warming (during a period of sub-optimal oxygen delivery) is detrimental. Although these animals were subjected to lethal injuries and lost about 50% of total blood volume before induction of hypothermia, it should be pointed out that because of the short duration of shock (especially after aortic injury) the degree of metabolic acidosis was relatively modest. Others have shown that induction of profound hypothermia can improve short-term survival (up to 96 hours) even in the setting of very severe metabolic acidosis (pH<6.9, Base deficit <15 mmol/L, lactate >14 mmol/L) as a result of cardiac arrest from prolonged hemorrhage.56 However, it remains unknown whether hypothermia can also be used to improve long term survival in the setting of prolonged anaerobic metabolism, and we are conducting experiments to answer this question.

In summary, using a swine model of lethal hemorrhage we have demonstrated that profound hypothermia can be safely induced through a thoracotomy approach to preserve the viability of key organs, including brain, during repair of multiple vascular injuries. Our data also suggest that the rate of re-warming from hypothermia may be an important variable in determining the long-term survival.

ACKNOWLEDGMENTS

We acknowledge the invaluable guidance provided by Norman Rich, MD, David Burris, MD, and John R. Kirkpatrick, MD, and excellent support by Amal Nadel, MS, Adam Seufert, BS, Ryan Inocencio, BS, Nanna Ariaban, BS, and Tiffani Slaughter, BS during this project. We would also like to acknowledge the help provided by the technicians and veterinarians of the Center for Laboratory Animal Medicine.

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***DISCUSSION

Dr. Larry M. Gentilello (Dallas, TX): Dr. Alam has presented a paper that I believe is very important, because severely injured trauma patients, who present with hemorrhagic shock that has progressed to the point of pulselessness, have almost no hope of survival; therefore, the potential application of hypothermia in this setting is one of the most important questions in resuscitation research.

Laboratory studies to optimize suspended animation techniques, therefore, are extremely important in the group in Bethesda and in Pittsburgh have done a lot to bring the days when we will see a clinical trial closer and closer.

Now, the purpose of this study was to determine the optimal re-warming rate after induced hypothermia, and the authors concluded that a medium rate of re-warming was best. But I have a few concerns about the model that I'd like to express before I can accept these results. Trauma patients with shock, who have progressed to the point of cardiac arrest, have usually reached a point of severe metabolic exhaustion.

Even if the bleeding is successfully controlled, blood pressure cannot be stabilized, improvements are only transient and death usually occurs shortly thereafter. I bring that up, because in this study, it's not clear that the model resulted in metabolic failure. At the end of the 30-minute shock period, cardiac output was still 2.5 liters, and the lactate levels had only risen to 1.4. That's not severe shock for a pig. Most, 30 minutes later, will be looking for food.

Now, it's true that you then induced an aortic injury, and that dropped the blood pressure a bit more, but then only a few minutes later you induced hypothermia. By that time, the lactate level had risen to a value that was still less than four.

Now, my trauma patients who come with pulseless, exsanguinating hemorrhage have lactate levels of 15 or 20, and I think that's a very different type of patient. It's not clear that your animals couldn't have been resuscitated by putting a clamp on the injury and giving them back some fluids.

An additional concern has to do with the procedures for the normothermic control group, which really wasn't mentioned in the presentation. At the end of the shock period, their aorta was flushed with an acellular fluid with a potassium level of 70 mcq per liter until their hemoglobin was down to two.

This is the normothermic control group. Then they were placed on cardiopulmonary bypass with a flow rate of a half a liter per minute that gave them a blood pressure of 15 for 30 minutes. I don't understand that as a control group, because we don't manage our patients that way. They seem doomed to failure. It's not a surprise that all of them were brain dead when they were allowed to awaken from anesthesia.

My final concern has to do with the statistical analysis. You compared all three re-warming rate groups with this doomed control group instead of comparing each re-warming rate group with each other. If the purpose was to determine which re-warming rate was best, each one of those re-warming rate groups should have been compared with one another. So with those reservations, I have three questions.

The first is, we talk about suspended animation, but if someone has really gotten to the point of a lactate of 20 and pulseless exsanguinating hemorrhage, it may not be suspended animation. It may be suspended de-animation. Then when you warm them back up, you still have someone in irreversible shock, and that's why the model is critical.

Second, can you please explain the rationale for the control group of flushing out their blood, keeping them normothermic and at a blood pressure of 15 for 30 minutes and using them for controls.

Finally, when I did the statistical analysis, just a simple chi-square comparing your slow re-warming rate with the medium rate that you said was best, the p value I got was 0.3.

When I compared your medium with your fast re-warming rate, I also got a p value of about 0.3. That's just an estimate. So there were no statistically significant findings with respect to your primary hypothesis.

Dr. William B. Long (Portland, OR): I just wanted to ask about your choice of fixed rates of re-warming versus flexible re-warming. Most neurosurgeons and cardiac surgeons who do hypothermic circulatory arrest for certain surgeries use the venous return to adjust the water bath, keeping it 7 to 10 degrees higher than the return temperature. You chose a fixed rate of re-warming. I am curious as to whether or not your re-warming methodology is a local institutional protocol, or is it based on previous research that you have done.

Dr. Frederick A. Moore (Houston, TX): I had the privilege of reading your manuscript, and while you didn't discuss the cytokine data, one of the things that was kind of surprising to me is that you looked at circulating heat shock protein 70.

First question, why would you ever look at that? Secondly, it was most elevated in the medium re-warming group, and if that was really the mechanism, how would you propose that this heat shock protein 70 circulating in the blood would result in better survival?

Dr. Lawrence H. Pitt (San Francisco, California): Clearly, the length of time of shock was chosen probably for many studies to allow for possible survival in the resuscitation, partly in keeping with Dr. Gentilello's question, how long of a shock will always lead to death? Are there markers for that population, so that every patient who shows up in an emergency room with apparently this kind of injury is beyond resuscitation, and one would save a lot of energy? Do you have markers that preclude any of these resuscitations from resulting in survival?

Dr. Hasan B. Alam (Washington, DC): Advocating the use of hypothermia in a room full of trauma surgeons is like throwing bait in the water when swimming with sharks. So let me start by thanking all of you for being so kind.

Dr. Gentilello, you brought up a very important point about the metabolic state of these animals when hypothermia was induced, and whether it correlates with clinical reality. To a large extent I agree with your comment that these animals were not in a state of “irreversible shock,” with base deficits of -20 and lactate levels above 10. However, it must be pointed out that these animals had lost 50 to 60% of total blood volume. There are two main reasons why the metabolic acidosis was not more severe. About half of the blood was lost because of the initial iliac artery and vein injury, which is a survivable injury in swine. The remainder of the blood loss was because of the descending aortic laceration, which is 100% fatal. Hypothermic arrest was induced 35 minutes after the iliac and only 5 minutes after the aortic injury. Thus, because of the relatively short duration of shock, the degree of lactic acidosis did not accurately reflect the magnitude of blood loss. Secondly, swine normally have very high base excess, and compared to humans it is rather difficult to create profound metabolic acidosis in swine.

Now, let's look at the rationale behind the design of our model. It is true that we could have fixed the injuries in this model without hypothermic arrest, because we knew exactly where the injuries were, and surgical exposure was not an issue. However, in clinical practice a combination of major vascular injuries, above and below the diaphragm, associated with a blood pressure of less than 20 mm Hg, and ongoing rapid hemorrhage is almost always fatal. Theoretically, these injuries can be repaired with good outcome if viability of brain and heart can be maintained long enough to obtain surgical control of the bleeding, and restore intra vascular volume. Preclinical studies have already established that induction of hypothermia can improve the outcome after uncontrolled hemorrhage. However, before it can be translated into clinical practice, the optimal strategy for the induction, maintenance and reversal of hypothermia must be clearly identified. To achieve this goal we plan to perform a series of six experiments, systematically evaluating various aspects of induced hypothermia. In this experiment, which is second the series, we used a model of severe, uncontrolled, but salvageable hemorrhage. Once the optimal strategy has been established, we will apply it in increasingly severe models. This will include even larger volumes of blood loss and much longer duration of shock. The goal at that stage will be to determine whether hypothermia can be utilized to bring the animals back from the point of no return, the so called “state of irreversible shock”.

You questioned the relevance of the control group. The normothermic control animals were treated in an identical fashion compared to the hypothermic animals, except for differences in temperature modulation. This was included as an experimental control and was not meant to represent the clinical standard of care. This group controlled for the administration of organ preservation fluids, drugs and blood, as well as the use of bypass for resuscitation. All of these variables have the potential to improve outcome. In the absence of this experimental control group, an improved outcome in the hypothermic animals could not have been attributed to the cooling itself. For statistical analysis, all the hypothermic groups were compared to this normothermic control group, which is completely appropriate. The survival rates in slow and medium re-warming groups were statistically superior to the control group. You are correct in pointing out that not all of the survival differences between various re-warming groups reached statistical significance. However, the threefold improvement in survival between the fast and medium re-warming was not only statistically significant, but also clinically meaningful.

Dr. Long asked about the re-warming rates. We actually did not go for a fixed rate of re-warming. The warming rate varied, as shown in the presentation, because of the changing gradient between the animals and the re-infused blood. The maximum gradient was kept at about 10 degrees for the slow warming and about 15 degrees for fast re-warming animals. In all groups, the gradient decreased as the animals re-warmed back to the baseline temperatures.

Dr. Moore, the heat-shock protein was measured as part of a sub project that my co-investigator Dr. Chen is performing to evaluate the impact of hypothermia on immune/inflammatory system. It is difficult to determine whether the observed improvement in HSP-70 and IL-6 profiles were the cause or effect of decreased cellular injury. Although interesting, monitoring these changes were not the primary goal of our project.

Dr. Pitt, your question was fairly similar to what Dr. Gentilello asked, addressing the severity of the model, and whether the duration of shock was long enough to be universally fatal. We have previously shown that induction of hypothermia can result in greater than 75% survival even after 60 minutes of normothermic shock. The current study was designed specifically to identify the optimal rate of re-warming, and not to test the outer limits of hypothermic arrest. We are addressing this question in a stepwise fashion. Currently we are using models that mimic rapid, lethal hemorrhage following penetrating torso trauma. Once the optimal strategy has been identified, the obvious next step would be to test it in models of increasing duration and severity of shock. I hope to report back to this audience in the near future about the maximum limits of this approach, and whether induction of hypothermia can reverse otherwise irreversible shock.