Outcome Prediction after Cardiac Arrest Treated with Hypothermia

Rationale: Clinical and electrophysiological prognostic markers of brain anoxia have been mostly evaluated in comatose survivors of out hospital cardiac arrest (OHCA) after standard resuscitation, but their predictive value in patients treated with mild induced hypothermia (IH) is unknown. The objective of this study was to identify a predictive score of independent clinical and electrophysiological variables in comatose OHCA survivors treated with IH, aiming at a maximal positive predictive value (PPV) and a high negative predictive value (NPV) for mortality. Methods: We prospectively studied consecutive adult comatose OHCA survivors from April 2006 to May 2009, treated with mild IH to 33-34_C for 24h at the intensive care unit of the Lausanne University Hospital, Switzerland. IH was applied using an external cooling method. As soon as subjects passively rewarmed (body temperature >35_C) they underwent EEG and SSEP recordings (off sedation), and were examined by experienced neurologists at least twice. Patients with status epilepticus were treated with AED for at least 24h. A multivariable logistic regression was performed to identify independent predictors of mortality at hospital discharge. These were used to formulate a predictive score. Results: 100 patients were studied; 61 died. Age, gender and OHCA etiology (cardiac vs. non-cardiac) did not differ among survivors and nonsurvivors. Cardiac arrest type (non-ventricular fibrillation vs. ventricular fibrillation), time to return of spontaneous circulation (ROSC) >25min, failure to recover all brainstem reflexes, extensor or no motor response to pain, myoclonus, presence of epileptiform discharges on EEG, EEG background unreactive to pain, and bilaterally absent N20 on SSEP, were all significantly associated with mortality. Absent N20 was the only variable showing no false positive results. Multivariable logistic regression identified four independent predictors (Table). These were used to construct the score, and its predictive values were calculated after a cut-off of 0-1 vs. 2-4 predictors. We found a PPV of 1.00 (95% CI: 0.93-1.00), a NPV of 0.81 (95% CI: 0.67-0.91) and an accuracy of 0.93 for mortality. Among 9 patients who were predicted to survive by the score but eventually died, only 1 had absent N20. Conclusions: Pending validation in a larger cohort, this simple score represents a promising tool to identify patients who will survive, and most subjects who will not, after OHCA and IH. Furthermore, while SSEP are 100% predictive of poor outcome but not available in most hospitals, this study identifies EEG background reactivity as an important predictor after OHCA. The score appears robust even without SSEP, suggesting that SSEP and other investigations (e.g., mismatch negativity, serum NSE) might be principally needed to enhance prognostication in the small subgroup of patients failing to improve despite a favorable score.

Postmortem biochemical investigations in hypothermia fatalities.

Despite the progress made during the past several decades in forensic pathology, the possibilities for the postmortem diagnosis of hypothermia remains relatively limited. Aside from histology and immunohistochemistry, numerous authors have investigated the postmortem biochemistry of hypothermia fatalities. Several biochemical markers (e.g., glucose, electrolytes, hormones, ketone bodies, and neurotransmitters) and various biological samples (e.g., blood, urine, heart, liver, skeletal muscle as well as pericardial and cerebrospinal fluids) have been proposed as potentially useful markers to improve the insufficient diagnostic efficacy of macroscopic and microscopic findings. The aim of this article is to review the medicolegal literature covering the postmortem biochemical investigations that are associated with hypothermia cases as well as report our own research results on this topic where possible.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Postmortem diagnosis of hypothermia.

The identification of hypothermia as the cause of death has always been somewhat problematic in forensic pathology because of unspecific, inconstant, or even negative macroscopic and microscopic findings. Though the simultaneous presence of frost erythema, Wischnewski spots, hemorrhages into the synovial membrane, bloody discoloration of synovial fluid of the knee, and basal vacuolization of the renal tubular epithelial cells has been indicated as strongly supportive of fatal hypothermia, their absence does not allow the diagnosis of hypothermia to be ruled out. Postmortem biochemical investigations are valuable in detecting adaptation responses to cold stress and metabolic changes that occur following cold exposure. However, ethanol intoxication prevents appearance of adaptation responses to cold, rendering the diagnosis less obvious. Immunohistochemistry, postmortem imaging, and molecular pathology have shown promising results, although at present, they do not provide pathognomonic signs of fatal hypothermia. The aim of this article is to present a review of the literature covering the significance of different postmortem investigations that are associated with hypothermia fatalities.

From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.

OBJECTIVES: Therapeutic hypothermia has been recommended for postcardiac arrest coma due to ventricular fibrillation. However, no studies have evaluated whether therapeutic hypothermia could be effectively implemented in intensive care practice and whether it would improve the outcome of all comatose patients with cardiac arrest, including those with shock or with cardiac arrest due to nonventricular fibrillation rhythms. DESIGN: Retrospective study. SETTING: Fourteen-bed medical intensive care unit in a university hospital. PATIENTS: Patients were 109 comatose patients with out-of-hospital cardiac arrest due to ventricular fibrillation and nonventricular fibrillation rhythms (asystole/pulseless electrical activity). INTERVENTIONS: We analyzed 55 consecutive patients (June 2002 to December 2004) treated with therapeutic hypothermia (to a central target temperature of 33 degrees C, using external cooling). Fifty-four consecutive patients (June 1999 to May 2002) treated with standard resuscitation served as controls. Efficacy, safety, and outcome at hospital discharge were assessed. Good outcome was defined as Glasgow-Pittsburgh Cerebral Performance category 1 or 2. MEASUREMENTS AND MAIN RESULTS: In patients treated with therapeutic hypothermia, the median time to reach the target temperature was 5 hrs, with a progressive reduction over the 18 months of data collection. Therapeutic hypothermia had a major positive impact on the outcome of patients with cardiac arrest due to ventricular fibrillation (good outcome in 24 of 43 patients [55.8%] of the therapeutic hypothermia group vs. 11 of 43 patients [25.6%] of the standard resuscitation group, p = .004). The benefit of therapeutic hypothermia was also maintained in patients with shock (good outcome in five of 17 patients of the therapeutic hypothermia group vs. zero of 14 of the standard resuscitation group, p = .027). The outcome after cardiac arrest due to nonventricular fibrillation rhythms was poor and did not differ significantly between the two groups. Therapeutic hypothermia was of particular benefit in patients with short duration of cardiac arrest (<30 mins). CONCLUSIONS: Therapeutic hypothermia for the treatment of postcardiac arrest coma can be successfully implemented in intensive care practice with a major benefit on patient outcome, which appeared to be related to the type and the duration of initial cardiac arrest and seemed maintained in patients with shock.

Hyperkalemia. A prognostic factor during acute severe hypothermia.

When hypothermic patients appear to be dead, the decision to resuscitate may be difficult due to lack of reliable criteria of death. To discover useful prognostic indicators, we reviewed the hospital charts of nine hypothermic victims of snow avalanches (group A: median value of rectal temperature, 29.6 degrees C; range, less than 12 degrees C to 34 degrees C) and of 15 patients with hypothermia following acute drug intoxication and/or cold exposure (group B: 28.8 degrees C; range, 25.5 degrees C to 32 degrees C. In group A, plasma potassium level on admission was extremely high (14.5 mmol/L; range, 6.8 to 24.5 mmol/L) compared with that obtained in group B (3.5 mmol/L; range, 2.7 to 5.3 mmol/L). All patients in group A were in cardiorespiratory arrest. None could be successfully resuscitated despite effective rewarming by cardiopulmonary bypass or peritoneal lavage. In contrast, all of the patients in group B recovered from hypothermia, including two in cardiorespiratory arrest. Thus, extreme hyperkalemia during acute hypothermia appears to be a reliable marker of death. It might be used to select those patients in whom heroic resuscitation efforts can be useful.

Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study

OBJECTIVES: Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. DESIGN: Prospective study, from December 2004 to October 2006. SETTING: 32-bed medico-surgical intensive care unit, university hospital. PATIENTS: Comatose patients with out-of-hospital CA. INTERVENTIONS: TH to 33 +/- 1 degrees C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. MEASUREMENTS AND MAIN RESULTS: We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC > 25 mins survived, as compared to 65.7% with time to ROSC < or = 25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. CONCLUSIONS: Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.

Oxidative Stress and Antioxidant Activity in Hypothermia and Rewarming. Can RONS Modulate the Beneficial Effects of Therapeutic Hypothermia?

Hypothermia is a condition in which core temperature drops below the level necessary to maintain bodily functions. The decrease in temperature may disrupt some physiological systems of the body, including alterations in microcirculation and reduction of oxygen supply to tissues. The lack of oxygen can induce the generation of reactive oxygen and nitrogen free radicals (RONS), followed by oxidative stress, and finally, apoptosis and/or necrosis. Furthermore, since the hypothermia is inevitably followed by a rewarming process, we should also consider its effects. Despite hypothermia and rewarming inducing injury, many benefits of hypothermia have been demonstrated when used to preserve brain, cardiac, hepatic, and intestinal function against ischemic injury. This review gives an overview of the effects of hypothermia and rewarming on the oxidant/antioxidant balance and provides hypothesis for the role of reactive oxygen species in therapeutic hypothermia.

An evaluation of the Swiss staging model for hypothermia using case reports from the literature.

BACKGROUND: Core body temperature is used to stage and guide the management of hypothermic patients, however obtaining accurate measurements of core temperature is challenging, especially in the pre-hospital context. The Swiss staging model for hypothermia uses clinical indicators to stage hypothermia. The proposed temperature range for clinical stage 1 is <35-32 °C (95-90 °F), for stage 2, <32-28 °C (<90-82 °F) for stage 3, <28-24 °C (<82-75 °F), and for stage 4 below 24 °C (75 °F). However, the evidence relating these temperature ranges to the clinical stages needs to be strengthened. METHODS: Medline was used to retrieve data on as many cases of accidental hypothermia (core body temperature <35 °C (95 °F)) as possible. Cases of therapeutic or neonatal hypothermia and those with confounders or insufficient data were excluded. To evaluate the Swiss staging model for hypothermia, we estimated the percentage of those patients who were correctly classified and compared the theoretical with the observed ranges of temperatures for each clinical stage. The number of rescue collapses was also recorded. RESULTS: We analysed 183 cases; the median temperature for the sample was 25.2 °C (IQR 22-28). 95 of the 183 patients (51.9 %; 95 % CI = 44.7 %-59.2 %) were correctly classified, while the temperature was overestimated in 36 patients (19.7 %; 95 % CI = 13.9 %-25.4 %). We observed important overlaps among the four stage groups with respect to core temperature, the lowest observed temperature being 28.1 °C for Stage 1, 22 °C for Stage 2, 19.3 °C for Stage 3, and 13.7 °C for stage 4. CONCLUSION: Predicting core body temperature using clinical indicators is a difficult task. Despite the inherent limitations of our study, it increases the strength of the evidence linking the clinical hypothermia stage to core temperature. Decreasing the thresholds of temperatures distinguishing the different stages would allow a reduction in the number of cases where body temperature is overestimated, avoiding some potentially negative consequences for the management of hypothermic patients.

Ethanol-induced hypothermia in rats is antagonized by dexamethasone

The effect of dexamethasone on ethanol-induced hypothermia was investigated in 3.5-month old male Wistar rats (N = 10 animals per group). The animals were pretreated with dexamethasone (2.0 mg/kg, ip; volume of injection = 1 ml/kg) 15 min before ethanol administration (2.0, 3.0 and 4.0 g/kg, ip; 20% w/v) and the colon temperature was monitored with a digital thermometer 30, 60 and 90 min after ethanol administration. Ethanol treatment produced dose-dependent hypothermia throughout the experiment (-1.84 ± 0.10, -2.79 ± 0.09 and -3.79 ± 0.15oC for 2.0, 3.0 and 4.0 g/kg ethanol, respectively, 30 min after ethanol) but only the effects of 2.0 and 3.0 g/kg ethanol were significantly antagonized (-0.57 ± 0.09 and -1.25 ± 0.10, respectively, 30 min after ethanol) by pretreatment with dexamethasone (ANOVA, P<0.05). These results are in agreement with data from the literature on the rapid antagonism by glucocorticoids of other effects of ethanol. The antagonism was obtained after a short period of time, suggesting that the effect of dexamethasone is different from the classical actions of corticosteroids

Role of nitric oxide in hypoxia-induced hyperventilation and hypothermia: participation of the locus coeruleus

Hypoxia elicits hyperventilation and hypothermia, but the mechanisms involved are not well understood. The nitric oxide (NO) pathway is involved in hypoxia-induced hypothermia and hyperventilation, and works as a neuromodulator in the central nervous system, including the locus coeruleus (LC), which is a noradrenergic nucleus in the pons. The LC plays a role in a number of stress-induced responses, but its participation in the control of breathing and thermoregulation is unclear. Thus, in the present study, we tested the hypothesis that LC plays a role in the hypoxia-induced hypothermia and hyperventilation, and that NO is involved in these responses. Electrolytic lesions were performed bilaterally within the LC in awake unrestrained adult male Wistar rats weighing 250-350 g. Body temperature and pulmonary ventilation (VE) were measured. The rats were divided into 3 groups: control (N = 16), sham operated (N = 7) and LC lesioned (N = 19), and each group received a saline or an NG-nitro-L-arginine methyl ester (L-NAME, 250 µg/µl) intracerebroventricular (icv) injection. No significant difference was observed between control and sham-operated rats. Hypoxia (7% inspired O2) caused hyperventilation and hypothermia in both control (from 541.62 ± 35.02 to 1816.18 ± 170.7 and 36.3 ± 0.12 to 34.4 ± 0.09, respectively) and LC-lesioned rats (LCLR) (from 694.65 ± 63.17 to 2670.29 ± 471.33 and 36 ± 0.12 to 35.3 ± 0.12, respectively), but the increase in VE was higher (P<0.05) and hypothermia was reduced (P<0.05) in LCLR. L-NAME caused no significant change in VE or in body temperature under normoxia, but abolished both the hypoxia-induced hyperventilation and hypothermia. Hypoxia-induced hyperventilation was reduced in LCLR treated with L-NAME. L-NAME also abolished the hypoxia-induced hypothermia in LCLR. The present data indicate that hypoxia-induced hyperventilation and hypothermia may be related to the LC, and that NO is involved in these responses.

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia.

The principal cause of mortality in patients with acute liver failure (ALF) is brain herniation resulting from intracranial hypertension caused by a progressive increase of brain water. In the present study, ex vivo high-resolution 1H-NMR spectroscopy was used to investigate the effects of ALF, with or without superimposed hypothermia, on brain organic osmolyte concentrations in relation to the severity of encephalopathy and brain edema in rats with ALF due to hepatic devascularization. In normothermic ALF rats, glutamine concentrations in frontal cortex increased more than fourfold at precoma stages, i.e. prior to the onset of severe encephalopathy, but showed no further increase at coma stages. In parallel with glutamine accumulation, the brain organic osmolytes myo-inositol and taurine were significantly decreased in frontal cortex to 63\% and 67\% of control values, respectively, at precoma stages (p<0.01), and to 58\% and 67\%, respectively, at coma stages of encephalopathy (p<0.01). Hypothermia, which prevented brain edema and encephalopathy in ALF rats, significantly attenuated the depletion of myo-inositol and taurine. Brain glutamine concentrations, on the other hand, did not respond to hypothermia. These findings demonstrate that experimental ALF results in selective changes in brain organic osmolytes as a function of the degree of encephalopathy which are associated with brain edema, and provides a further rationale for the continued use of hypothermia in the management of this condition.

Keeping cool in acute liver failure: rationale for the use of mild hypothermia.

Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF.