Hypothermia after cardiac arrest: a treatment that works

PURPOSE OF REVIEW: Sudden death from cardiac arrest is a major health problem that still receives too little publicity. Current therapy after cardiac arrest concentrates on resuscitation efforts because, until now, no specific therapy for brain protection after restoration of spontaneous circulation was available. Therapeutic mild or moderate resuscitative hypothermia is a novel therapy with multifaceted chemical and physical effects by preventing or mitigating the derangements seen in the postresuscitation syndrome. RECENT FINDINGS AND SUMMARY: In 2002, two prospective, randomized studies reported improved outcomes when deliberate hypothermia was induced in comatose survivors after resuscitation from cardiac arrest. However, several issues with regard to resuscitative cooling are still unanswered and should be studied further. These include the optimal timing to initiate cooling, the optimal cooling period, the optimal temperature level, and rewarming strategy. Even important questions, such as which cooling technique will be available in the near future that would combine ease of use with high efficacy, are not answered yet.     

Hypothermia and cardiac arrest: the promise of intra-arrest cooling

Over the past several years, the implementation of therapeutic hypothermia has provided an exciting opportunity toward improving survival from out-of-hospital cardiac arrest. There are compelling data to support the prompt use of therapeutic hypothermia for initial survivors from out-of-hospital cardiac arrest, but animal data have suggested that initiation of therapeutic hypothermia during the intra-arrest period may significantly improve outcomes even further. In the first feasibility study in humans, Bruel and colleagues report on the implementation of this intra-arrest approach among patients suffering out-of-hospital cardiac arrest, an exciting prospect that is discussed in the present commentary.     

Combination pharmacotherapy in the treatment of experimental cardiac arrest

Study Objectives

Full recovery after cardiopulmonary resuscitation (CPR) is poor. We hypothesized that the coadministration of epinephrine, a β-blocker such as atenolol, and a calcium sensitizer such as levosimendan during CPR would improve survival and postresuscitation myocardial function.

Methods

Ventricular fibrillation was induced in 60 piglets, which were left untreated for 8 minutes before attempted resuscitation. Animals were randomized into 4 groups (n = 15), to receive epinephrine (group E), epinephrine + atenolol (group E + A), epinephrine + levosimendan (group E + L) and epinephrine + atenolol + levosimendan (group E + A + L) during CPR. Electrical defibrillation was attempted 2 minutes after drug administration.

Results

Five animals in group E survived for 48 hours in comparison to 8 animals in groups E + A and E + L and 12 animals in group E + A + L. Postresuscitation cardiac output was significantly better in the animals of group E + A + L. Troponin I remained significantly lower in groups E + A and E + A + L. Serum astroglial protein (S-100) and neuron-specific enolase values in group E + L and E + A + L were statistically lower than those measured in groups E and E + A during the entire observation period. The neurologic alertness score was higher in group E + A + L compared to groups E and E + A.

Conclusions

The administration of a drug combination of epinephrine + atenolol + levosimendan, when given during CPR, in a pig model of cardiac arrest, results in improved 48-hour survival and improves postresuscitation cardiac function.     

Cerebral cortical perfusion during and following resuscitation from cardiac arrest in dogs

Perfusion of the cerebral cortex during closed chest CPR in dogs, generating systolic pressures of 60 to 70 mmHg, is only 10% of pre-arrest blood flow. In contrast, internal cardiac massage produces normal cortical perfusion rates. Following a 20-min perfusion arrest, during pressure controlled reperfusion, cortical flow rates decay to less than 20% normal after 90 min of reperfusion. This appears to be due to increasing cerebral vascular resistance, and is not due to rising intracranial pressure. The post-arrest cortical hypoperfusion syndrome is prolonged with cortical flow remaining below 20% normal up to 18 hr post arrest. The use of a variety of calcium antagonists, including flunarizine, lidoflazine, verapamil, and Mg²⁺, immediately post-resuscitation maintains cerebral vascular resistance and cortical perfusion at normal levels. A prospective blind trial of the calcium antagonist lidoflazine following a 15-min cardiac arrest in dogs and resuscitation by internal massage, demonstrates amelioration of neurologic deficit in the early post-resuscitation period.     

Hypothermia after cardiac arrest: beneficial, but slow to be adopted

Survivors of cardiac arrest due to ventricular tachycardia or ventricular fibrillation have improved neurologic outcomes if they are cooled to a core body temperature of 32°C to 34°C for 24 hours as soon as possible after reaching the hospital.     

Vasopressin and epinephrine in the treatment of cardiac arrest: an experimental study

Background

Epinephrine remains the drug of choice for cardiopulmonary resuscitation. The aim of the present study is to assess whether the combination of vasopressin and epinephrine, given their different mechanisms of action, provides better results than epinephrine alone in cardiopulmonary resuscitation.

Methods

Ventricular fibrillation was induced in 22 Landrace/Large-White piglets, which were left untreated for 8 minutes before attempted resuscitation with precordial compression, mechanical ventilation and electrical defibrillation. Animals were randomized into 2 groups during cardiopulmonary resuscitation: 11 animals who received saline as placebo (20 ml dilution, bolus) + epinephrine (0.02 mg/kg) (Epi group); and 11 animals who received vasopressin (0.4 IU/kg/20 ml dilution, bolus) + epinephrine (0.02 mg/kg) (Vaso-Epi group). Electrical defibrillation was attempted after 10 minutes of ventricular fibrillation.

Results

Ten of 11 animals in the Vaso-Epi group restored spontaneous circulation in comparison to only 4 of 11 in the Epi group (p = 0.02). Aortic diastolic pressure, as well as, coronary perfusion pressure were significantly increased (p < 0.05) during cardiopulmonary resuscitation in the Vaso-Epi group.

Conclusion

The administration of vasopressin in combination with epinephrine during cardiopulmonary resuscitation results in a drastic improvement in the hemodynamic parameters necessary for the return of spontaneous circulation.     

Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis

OBJECTIVE: Only a few patients survive cardiac arrest with favorable neurologic recovery. Our objective was to assess whether induced hypothermia improves neurologic recovery in survivors of primary cardiac arrest. DATA SOURCE: Studies were identified by a computerized search of MEDLINE, EMBASE, CINAHL, PASCAL, the Cochrane Controlled Trial Register, and BIOSIS. STUDY SELECTION: We included randomized and quasi-randomized, controlled trials of adults who were successfully resuscitated, where therapeutic hypothermia was applied within 6 hrs after arrival at the emergency department and where the neurologic outcome was compared. We excluded studies without a control group and studies with historical controls. DATA EXTRACTION: All authors of the identified trials supplied individual patient data with a predefined set of variables. DATA SYNTHESIS: We identified three randomized trials. The analyses were conducted according to the intention-to-treat principle. Summary odds ratios were calculated using a random effects model and translated into risk ratios. More patients in the hypothermia group were discharged with favorable neurologic recovery (risk ratio, 1.68; 95% confidence interval, 1.29-2.07). The 95% confidence interval of the number-needed-to-treat to allow one additional patient to leave the hospital with favorable neurologic recovery was 4-13. One study followed patients to 6 months or death. Being alive at 6 months with favorable functional neurologic recovery was more likely in the hypothermia group (risk ratio, 1.44; 95% confidence interval, 1.11-1.76). CONCLUSIONS: Mild therapeutic hypothermia improves short-term neurologic recovery and survival in patients resuscitated from cardiac arrest of presumed cardiac origin. Its long-term effectiveness and feasibility at an organizational level need further research.     

Cerebral cortical microvascular flow during and following cardiopulmonary resuscitation after short duration of cardiac arrest

AIM: To examine changes in cerebral cortical macro- and microcirculation and their relationship to the severity of brain ischaemia during and following resuscitation from a short duration of cardiac arrest. METHODS: Bilateral cranial windows were created in eight domestic pigs weighing 41+/-1 kg, exposing the frontoparietal cortex for orthogonal polarization spectral imaging together with estimation of cortical-tissue partial pressure of carbon dioxide, a quantitator of the severity of cerebral ischaemia. After 3 min of untreated ventricular fibrillation, cardiopulmonary resuscitation was begun and continued for 4 min before defibrillation. Aortic pressure, end-tidal and cortical-tissue partial pressure of carbon dioxide, and cortical microcirculatory blood flow in vessels of less and more than 20 microm in diameter were continuously measured. RESULTS: Cerebral microcirculatory blood flow progressively decreased over the 3-min interval that followed onset of ventricular fibrillation. Chest compression restored cortical microvascular flow to approximately 40% of the pre-arrest value. Following return of spontaneous circulation, microvascular flow velocity was restored to baseline values over 3 min. Reversal of cerebral ischaemia with normalisation of cerebral cortical-tissue partial pressure of carbon dioxide occurred over 7 min after resuscitation. Cortical microcirculatory blood flow in microvessels less than 20 microm was highly correlated with flow in vessels more than 20 microm together with mean aortic pressure and end-tidal partial pressure of carbon dioxide. CONCLUSION: Cerebral cortical microcirculatory flow ceased only 3 min after onset of cardiac arrest. Flow was promptly restored to 40% of its pre-arrest value after start of chest compression. After resuscitation, both macro- and microcirculatory flows were fully restored over 3 min, but cerebral ischaemia reversed more slowly.     

Cardiac arrest secondary to indomethacin-induced renal failure: a case report

Acute renal failure secondary to nonsteroidal anti-inflammatory agents is an uncommon occurrence, but may have serious or even lethal consequences. We present one such reaction resulting in cardiac arrest in a 59-year-old diabetic treated with indomethacin. Since presenting symptoms may be vague and unimpressive, one must consider this potential complication to make an early diagnosis and intervene appropriately. In addition when prescribing anti-inflammatory drugs such as indomethacin, one should be cautious in patients who are predisposed to the development of acute renal failure. Risk factors that should be considered are preexistent hepatorenal dysfunction, extracellular fluid volume contraction, and concomitant use of nephrotoxic drugs.     

The lactate:pyruvate ratio following open cardiac surgery in children

Objective To explore the relationship between lactate:pyruvate ratio, hyperlactataemia, metabolic acidosis, and morbidity. Design and setting Prospective observational study in the paediatric intensive care unit (PICU) of a university hospital. Patients Ninety-seven children after open cardiac surgery. Most children (94%) fell into low-moderate operative risk categories; observed PICU mortality was 1%. Interventions Blood was sampled on admission for acid-base analysis, lactate, and pyruvate. Metabolic acidosis was defined as standard bicarbonate lower than 22 mmol/l, raised lactate as higher than 2 mmol/l, and raised lactate:pyruvate ratio as higher than 20. Measurements and results Median cardiopulmonary bypass and aortic cross-clamp times were 80 and 46 min. Metabolic acidosis occurred in 74%, hyperlactataemia in 42%, and raised lactate:pyruvate ratio in 45% of children. In multivariate analysis lactate:pyruvate ratio increased by 6.4 in children receiving epinephrine infusion and by 0.4 per 10 min of aortic cross-clamp. Duration of inotropic support increased by 0.29 days, ventilatory support by 0.27 days, and PICU stay by 0.42 days, for each 1 mmol/l increase in lactate. Neither standard bicarbonate nor lactate:pyruvate ratio were independently associated with prolongation of PICU support. Conclusions Elevated lactate:pyruvate ratio was common in children with mild metabolic acidosis and low PICU mortality. Hyperlactataemia, but not elevated lactate:pyruvate ratio or metabolic acidosis, was associated with prolongation of PICU support. Routine measurement of lactate:pyruvate ratio is not warranted for children in low-moderate operative risk categories. Funded in part by a grant from the Institute of Child Health, University of Cape Town (M.H.)     

Thrombolysis using plasminogen activator and heparin reduces cerebral no-reflow after resuscitation from cardiac arrest: An experimental study in the cat

Objective Successful resuscitation of the brain requires complete microcirculatory reperfusion, which, however, may be impaired by activation of blood coagulation after cardiac arrest. The study addresses the question of whether postischemic thrombolysis is effective in reducing cerebral noreflow phenomenon.Design 14 adult normothermic cats were submitted to 15-min cardiac arrest, followed by cardiopulmonary resuscitation (CPR) and 30 min of spontaneous recirculation. The CPR protocol included closed-chest cardiac massage, administration of epinephrine 0.2 mg/kg, bicarbonate 2mEq/kg per 30 min, and electrical defibrillation shocks.Interventions During CPR, animals in the treatment group (n=6) received intravenous bolus injections of 100 U/kg heparin and 1 mg/kg recombinant tissue type plasminogen activator (rt-PA), followed by an infusion of rt-PA 1mg/kg per 30 min.Measurements and results Microcirculatory reperfusion of the brain was visualized by labeling the circulating blood with 300 mg/kg of 15% fluorescein isothiocyanate albumin at the end of the recirculation period. Areas of cerebral noreflow — defined as the absence of microvascular filling — were identified by fluorescence microscopy at eight standard coronal levels of forebrain, and expressed as the percentage of total sectional area. One animal in the treatment group was excluded from further analysis because of intracerebral hemorrhage due to brain injury during trepanation. Autopsy revealed the absence of intracranial, intrathoracic, or intra-abdominal bleeding in all the other animals. In untreated animals (n=8), no-reflow affected 28±13% of total forebrain sectional areas, and only 1 out of 8 animals showed homogeneous reperfusion (i.e., no-reflow <15% of total forebrain sectional areas). Thrombolytic therapy (n=5) significantly reduced no-reflow to 7±5% of total forebrain sectional areas and all treated animals showed homogeneous reperfusion at the microcirculatory level.Conclusions The present data demonstrate that thrombolytic therapy improves microcirculatory reperfusion of the cat brain when administered during reperfusion after cardiac arrest.Presented in part at the 1994 Annual Meeting of the American Society of Anesthesiologists, 18 October 1994, Washington, DC, and at the 39th Annual Meeting of the German Association of Thrombosis and Hemostasis, 17 February 1995, Berlin, Germany     

Therapeutic hypothermia following cardiac arrest: a review of the evidence

Aims and objectives: This paper aims to undertake a review on the current evidence available on therapeutic hypothermia (TH) following cardiac arrest. Background: The use of TH has been associated as a potential treatment for a number of medical conditions including head injury and cerebral vascular accidents. Within the past decade, there have been numerous studies focusing upon the use of hypothermia following cardiac arrest. This paper evaluates the research on the use of TH following cardiac arrest and provides recommendations for clinical practice. Evidence from randomized controlled trials that are reviewed in this paper found that neurological outcome and mortality were significantly improved following inducing hypothermia following cardiac arrest. Search strategies: The following databases were accessed: Bandolier, Embase, Medline, Science Direct, CINAHL, Blackwell Synergy, Nursing Collection, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the National Electronic Library for Health. The following key words were used to search the databases: ‘Therapeutic hypothermia’, ‘Induced hypothermia’, ‘cooling post cardiac arrest’ and ‘post cardiac arrest care’. Inclusion and exclusion criteria: Only evidences published within the past 10 years and written in English were included. Studies on TH for the treatment of raised intracranial pressure were excluded. Conclusions: All adult patients who have return of spontaneous circulation and remain unconscious following cardiac arrest should be considered for TH between 32°C and 34°C for at least 12–24 h as this will improve patient mortality and morbidity. Acute hospitals need to devise policies and guidelines on the use of TH following cardiac arrest that include methods on how to achieve effective cooling by cold i.v. infusions, ice packs or purchasing specific cooling mattresses.