Samuel A. Tisherman

Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study.

ObjectivePreviously, we documented that mild hypothermia (34°C) induced immediately with reperfusion after ventricular fibrillation cardiac arrest in dogs improves functional and morphologic cerebral outcome. This study was designed to test the hypothesis that a 15-min delay in the initiation of cooling after reperfusion would offset this beneficial effect. DesignProspective, randomized, controlled study. SettingAnimal intensive care unit. SubjectsA total of 22 custom-bred coonhounds. InterventionsEighteen dogs underwent normothermic ventricular fibrillation arrest (no blood flow) of 12.5 mins, reperfusion with brief cardiopulmonary bypass, defibrillation within 5 mins, intermittent positive-pressure ventilation to 20 hrs, and intensive care to 96 hrs. Three groups of six gogs each were studied: group 1, normothermic controls; group 2, core temperature 34°C from reperfusion to 1 hr; and group 3, delayed initiation of cooling until 15 mins after normothermic reperfusion, and 34°C from 15 mins to 1 hr 15 mins after cardiac arrest. Measurements and Main ResultsTympanic membrane temperature (which represented brain temperature) in group 2 reached 34°C at 6 ± 3 (SD) mins after reperfusion; and in group 3 at 29 ± 1 mins after reperfusion. Best overall performance categories achieved (1, normal; 5, brain death) compared with group 1, were better in group 2 (p <.05) but not in group 3 (NS). Similar results were found with best neurologic deficit scores (0%, normal; 100%, brain death), i.e., 44 ± 4% in group 1, 19 ± 15% in group 2 (p<.01), and 38 ± 9% in group 3 (NS). Total brain histologic damage scores (< 30 minimal damage; > 100 severe damage), however, were 150 ± 32 in group 1, 81 ± 13 in group 2 (p<.001 VS. group 1), and 107 ± 17 in group 3 (p<.05 VS. group 1). ConclusionsMild, resuscitative cerebral hypothermia induced immediately with reperfusion after cardiac arrest improves cerebral functional and morphologic outcome, whereas a delay of 15 mins in initiation of cooling after reperfusion may not improve functional outcome, although it may slightly decrease tissue damage. (Crit Care Med 1993;21:1348–1358)

Mild Cerebral Hypothermia during and after Cardiac Arrest Improves Neurologic Outcome in Dogs

We previously found mild hypothermia (34–36°C), induced before cardiac arrest, to improve neurologic outcome. In this study we used a reproducible dog model to evaluate mild hypothermia by head cooling during arrest, continued with systemic cooling (34°C) during recirculation and for 1 h after arrest. In four groups of dogs, ventricular fibrillation (no flow) of 12.5 min at 37.5°C was reversed with cardiopulmonary bypass and defibrillation in ≤5 min, and followed by controlled ventilation to 20 h and intensive care to 96 h. In Study A we resuscitated with normotension and normal hematocrit; Control Group A-I (n = 12) was maintained normothermic, while Treatment Group A-II (n = 10) was treated with hypothermia. In Study B we resuscitated with hypertension and hemodilution. Control Group B-I (n = 12) was maintained no rmo thermic (6 of 12 were not hemodiluted), while Treatment Group B-II (n = 10) was treated with hypothermia. Best overall performance categories (OPCs) achieved between 24 and 96 h postarrest were in Group A-I: OPC 1 (normal) in 0 of 12 dogs, OPC 2 (moderate disability) in 2, OPC 3 (severe disability) in 7, and OPC 4 (coma) in 3 dogs. In Group A-II, OPC 1 was achieved in 5 of 10 dogs (p < 0.01), OPC 2 in 4 (p < 0.001), OPC 3 in 1, and OPC 4 in 0 dogs. In Group B-I, OPC 1 was achieved in 0 of 12 dogs, OPC 2 in 6, OPC 3 in 5, and OPC 4 in 1 dog. In Group B-II, OPC 1 was achieved in 6 of 10 dogs (p < 0.01), OPC 2 in 4 (p < 0.05), and OPC 3 or 4 in 0 dogs. Mean neurologic deficit and brain histopathologic damage scores showed similar significant group differences. Morphologic myocardial damage scores were the same in all four groups. We conclude that mild brain cooling during and after insult improves neurologic outcome after cardiac arrest.

MILD HYPOTHERMIC CARDIOPULMONARY RESUSCITATION IMPROVES OUTCOME AFTER PROLONGED CARDIAC ARREST IN DOGS

Background and Methods.This study was designed to explore the effect of mild cerebral and systemic hypothermia (34°C) on outcome after prolonged cardiac arrest in dogs. After ventricular fibrillation with no flow of 10 min, and standard external CPR with epi-nephrine (low flow) from ventricular fibrillation time of 10 to 15 min, defibrillation and restoration of spontaneous normotension were between ventricular fibrillation time of 16 and 20 min. This procedure was followed by controlled ventilation to 20 hr postarrest and intensive care to 72 hr postarrest. In control group 1 (n = 10), core temperature was 37.5°C; in control group 2 (n = 10), cooling was started immediately after restoration of spontaneous normotension; and in group 3 (n = 10), cooling was initiated with start of CPR. Cooling was by clinically feasible methods. Results.Best overall performance categories achieved (1 = normal; 5 = brain death) were better in group 2 (p = .012) and group 3 (p = .005) than in group 1. Best neurologic deficit scores were 36 ± 14% in group 1, 22 ± 15% in group 2 (p = .02), and 19 ± 18% in group 3 (p = .01). Brain histopathologic damage scores were also lower (better) in groups 2 (p = .05) and 3 (p = .03). Myocardial damage was the same in all three groups. Conclusion.Mild cerebral hypothermia started during or immediately after external CPR improves neurologic recovery. (Crit Care Med 1991; 19:379)

Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs.

Background and Purpose: Mild cerebral hypothermia (34°C) induced immediately after cardiac arrest improves outcome. Deep postarrest hypothermia (15°C) has not been studied. Methods: We used our dog model of normothermic ventricular fibrillation (no blood flow) of 12.5 minutes, reperfusion by brief cardiopulmonary bypass, controlled ventilation to 20 hours, and intensive care to 72 hours. Head surface cooling and bypass cooling were performed from start of reperfusion to 1 hour. Five groups of six dogs each were compared: group I, normothermic controls; group II, deep hypothermia (15°C); group III, moderate hypothermia (30°C); group IV, mild hypothermia (34°C); and group V, mild hypothermia with head surface cooling begun during no flow. Results: In control group I, five dogs remained comatose (overall performance category [OPC] 4) and one severely disabled (OPC 3). In group II, four dogs achieved OPC 4 and two dogs OPC 3 (NS versus group I). Compared with group I, OPCs were better in group III (p<0.05), group IV (p<0.05), and group V (p<0.05). Neurological deficit scores were also better in groups III, IV, and V than in groups I or II (p<0.05). Total brain histological damage scores were better in group III (p=0.02), group IV (p=0.06), and group V (p<0.05) than in group I. In group II, OPC and neurological deficit scores were the same and histological damage scores numerically worse than in group I and all were worse than in groups III, IV, and V (p<0.05). Cardiovascular complications and myocardial morphological damage in groups II and III were worse than in groups I, IV, and V (p<0.05). Conclusions: Mild or moderate cerebral hypothermia induced immediately after cardiac arrest improves cerebral outcome, more likely when initiated during arrest, whereas deep postarrest hypothermia can worsen cerebral and cardiac outcome. (Stroke 1992;23:1454‐1462)

Admission hypothermia and outcome after major trauma.

Objective:Uncontrolled exposure hypothermia is believed to be deleterious in the setting of major trauma. Prevention of hypothermia in the injured patient is currently practiced in both prehospital and in-hospital settings. However, this standard is based on studies of limited patient series that were not designed to identify the independent relationship between hypothermia and mortality. Recent studies suggest that therapeutically applied hypothermia may benefit selected patient subsets. The goal of this study was to evaluate the independent association between admission hypothermia and mortality after major trauma, with adjustment for clinical confounders. Design:Retrospective analysis of a statewide trauma registry. The primary outcome was death at hospital discharge. The key exposure was hypothermia, defined as body temperature ≤35°C at admission. Multivariate regression was used to risk-adjust for age, severity and mechanism of injury, and route of temperature measurement. Additional adjustment for prehospital exposure time and intravenous fluid therapy was also evaluated. Setting:Trauma centers of the Commonwealth of Pennsylvania. Patients:All trauma patients ≥16 yrs of age for the years 2000–2002. Transferred patients were excluded. Patients were excluded if temperature or route of temperature measurement was not known. Both the full cohort and a subset with isolated severe head injury were evaluated. Interventions:None. Measurements and Main Results:Of 38,520 patients, 1,921 (5.0%) were hypothermic at admission. Admission hypothermia was independently associated with increased odds of death in both the full cohort (odds ratio, 3.03; 95% confidence interval, 2.62–3.51) and the subset with isolated severe head injury (2.21; 1.62–3.03), with adjustment for age, severity and mechanism of injury, and route of temperature measurement. Conclusions:Admission hypothermia is independently associated with increased adjusted odds of death after major trauma. The increase in mortality is not completely attributable to physiologic presentation or injury pattern or severity.

Out-of-Hospital Hypertonic Resuscitation Following Severe Traumatic Brain Injury: A Randomized Controlled Trial

CONTEXT Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI). OBJECTIVE To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, placebo-controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients. INTERVENTION A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting. MAIN OUTCOME MEASURE Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or ≤4). RESULTS The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE ≤4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, -4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, -4.0% to 9.7%]; P = .67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P = .88). CONCLUSION Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00316004.

Critical Time Window for Intra-Arrest Cooling With Cold Saline Flush in a Dog Model of Cardiopulmonary Resuscitation

Background— Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. Methods and Results— Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (n=9), mild hypothermia (34°C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (n=8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (P=0.012). Conclusions— Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible.

Out-of-hospital Hypertonic Resuscitation After Traumatic Hypovolemic Shock A Randomized, Placebo Controlled Trial

Objective: To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock. Background: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury. Methods: Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium. Inclusion criteria: injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ⩽ 70 mm Hg or systolic blood pressure 71–90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern. Results: A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival—HSD: 74.5% (0.1; 95% confidence interval [CI], −7.5 to 7.8); HS: 73.0% (−1.4; 95% CI, −8.7–6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality—HSD: 10% (5.2; 95% CI, 0.4–10.1); HS: 12.2% (7.4; 95% CI, 2.5–12.2); and NS: 4.8%, P < 0.01]. Conclusion: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial. Clinical Trial Registration: Clinical Trials.gov, NCT00316017

Clinical Practice Guideline: Endpoints of Resuscitation

STATEMENT OF THE PROBLEM Severely injured trauma victims are at high risk of development of the multiple organ dysfunction syndrome (MODS) or death. To maximize chances for survival, treatment priorities must focus on resuscitation from shock (defined as inadequate tissue oxygenation to meet tissue O2 requirements), including appropriate fluid resuscitation and rapid hemostasis. Inadequate tissue oxygenation leads to anaerobic metabolism and resultant tissue acidosis. The depth and duration of shock leads to a cumulative oxygen debt. Resuscitation is complete when the oxygen debt has been repaid, tissue acidosis eliminated, and normal aerobic metabolism restored in all tissue beds. Many patients may appear to be adequately resuscitated based on normalization of vital signs, but have occult hypoperfusion and ongoing tissue acidosis (compensated shock), which may lead to organ dysfunction and death. Use of the endpoints discussed in this guideline may allow early detection and reversal of this state, with the potential to decrease morbidity and mortality from trauma. Without doubt, resuscitation from hemorrhagic shock is impossible without hemostasis. Fluid resuscitation strategies before obtaining hemostasis in patients with uncontrolled hemorrhage, usually victims of penetrating trauma, remain controversial. Withholding fluid resuscitation may lead to death from exsanguination, whereas aggressive fluid resuscitation may disrupt the clot and lead to more bleeding. “Limited,” “hypotensive,” and/or “delayed” fluid resuscitation may be beneficial, but clinical trials have yielded conflicting results. This clinical practice guideline will focus on resuscitation after achieving hemostasis and will not address the issue of uncontrolled hemorrhage further. Use of the traditional markers of successful resuscitation, including restoration of normal blood pressure, heart rate, and urine output, remain the standard of care per the Advanced Trauma Life Support Course. When these parameters remain abnormal, i.e., uncompensated shock, the need for additional resuscitation is clear. After normalization of these parameters, up to 85% of severely injured trauma victims still have evidence of inadequate tissue oxygenation based on findings of an ongoing metabolic acidosis or evidence of gastric mucosal ischemia. This condition has been described as compensated shock. Recognition of this state and its rapid reversal are critical to minimize risk of MODS or death. Consequently, better markers of adequate resuscitation for severely injured trauma victims are needed. This guideline committee sought to evaluate the current state of the literature regarding use of potential markers and related goals of resuscitation, focusing on those that have been tested in human trauma victims. This manuscript is part of an ongoing process of guideline development that includes periodic (every 3–4 years) review of the topic and the recommendations in light of new data. The goal is for these guidelines to assist clinicians in assuring adequate resuscitation of trauma patients, ultimately improving patient outcomes.

Hypothermia and minimal fluid resuscitation increase survival after uncontrolled hemorrhagic shock in rats.

OBJECTIVE To test the hypothesis that protective-preservative moderate hypothermia during uncontrolled hemorrhagic shock (UHS) in rats increases survival. DESIGN Randomized outcome study in rats. MATERIALS AND METHODS UHS phase I of 90 minutes, with initial withdrawal of 3 mL/100 g of blood plus tail amputation, was followed by hemostasis and all-out resuscitation phase II from 90 to 150 minutes, and observation phase III to 72 hours. Forty male rats under light anesthesia and spontaneous breathing were randomized into four groups: Group 1 received no fluid resuscitation during UHS and normothermia (37.5 degrees C) throughout. Group 2 received no fluid resuscitation and hypothermia (30 degrees C) from 15 to 120 minutes. Group 3 received lactated Ringers solution to maintain mean arterial pressure at 40 mm Hg during UHS and normothermia. Group 4 received lactated Ringers solution to a mean arterial pressure of 40 mm Hg during UHS and hypothermia from 15 to 120 minutes. RESULTS UHS phase I was survived by 0 of 10 rats in group 1, 7 of 10 in group 2, 5 of 10 in group 3, and 10 of 10 in group 4 (p < 0.01 for group 1 vs. 2, 3, or 4; p < 0.05 for group 4 vs. 3). Survival to 72 hours was achieved by 0 of 10 rats in group 1, 3 of 10 in group 2 (p < 0.001 vs. group 1), 1 of 10 in group 3, and 7 of 10 in group 4 (p < 0.001 vs. group 1, and p < 0.01 vs. group 3). All 72-hour survivors were neurologically normal. Necropsies in rats that died early during phase III showed edema and gastrointestinal hemorrhages. CONCLUSIONS Moderate hypothermia or limited (hypotensive) fluid resuscitation --best both combined--increases survival during and after UHS in rats.