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What Is the Evidence Behind Standardized Protocols for Hypothermia in Post Cardiac Arrest?

Cardiac arrest results in over 300,000 deaths per year in North America alone (1). The survival rate of out-of-hospital cardiac arrest is very poor: Less than half of victims who develop return of spontaneous circulation (ROSC) survive to leave the hospital alive. In most patients with ROSC who die within one month of the cardiac arrest, the cause is usually attributed to anoxic brain injury (26). Major advances in CPR and post cardiac arrest care have improved outcomes in select cohorts of patients (2-6). Among these advances is the use of therapeutic hypothermia. Inducing mild therapeutic hypothermia in selected patients surviving out-of-hospital sudden cardiac arrest has a major impact on long-term neurologically intact survival and may prove to be one of the most important clinical advancements in the science of resuscitation (26).

The pathophysiology behind cardiac arrest and ROSC involves a case of whole-body ischemia and subsequent reperfusion injury. This injury mechanism, along the with pre-arrest comorbidities can cause enormous biochemical, structural, and functional insults, which in a complex interrelated process leads to progressive cell destruction, multiorgan dysfunction, neuronal apoptosis, and death(10). Many of these processes are temperature sensitive, and when applied to the post cardiac arrest patient, hypothermia can decrease the area of injury, promote epicardial reflow, decrease myocardial metabolic demand, and preserve intracellular high-energy phosphate stores (11-13).

The following actions are associated with hypothermia:

• Reducing cerebral metabolism (approximately 6-8% per 1ºC)

• Reducing excitatory amino acids (glutamate release)

• Attenuation and/or reversibility of ischemic depolarization of the CNS, leading to membrane stabilization, electrolyte redistribution, and normalization of intracellular water concentration and intracellular pH (stabilization of the blood-brain barrier)

• Attenuation of oxygen free radical production and lipid peroxidation

• Restoration of normal intracellular signaling mechanisms (including calcium modulation) and inhibition of deleterious signaling mechanisms, such as apoptotic signaling

• Restoration of protein synthesis and gene expression

• Inhibition of deleterious inflammatory products (ie, cytokines, interleukins, arachidonic acid cascade end products)

• Attenuation of CSF platelet-activating factor (PAF)

• Inhibition of cytoskeletal breakdown (26)

Until recently, evidence for mild therapeutic hypothermia has lacked sufficient weight as well as advisory panel support that thereby follows to propel it into common practice. Despite its 2005 inclusion in American Heart Association Guidelines for CPR and Emergency Cardiovascular Care, and 2003 advisory statements by the International Liaison Committee on Resuscitation (ILCOR) and the European Resuscitation Council (ERC), hypothermia therapy is largely misunderstood and inconsistently applied (6-8).

A 2011 meta-analysis of randomized controlled trials found that therapeutic hypothermia with conventional cooling methods improved both survival and neurologic outcomes at hospital discharge for patients who experienced cardiac arrest (9).

Two studies published in the February 2002 New England Journal of Medicine demonstrated that induction of mild therapeutic hypothermia for comatose survivors of out-of-hospital cardiac arrest improved overall survival and neurological sequelae. The Hypothermia after Cardiac Arrest Study Group showed that, when applied to unconscious out-of-hospital cardiac arrest patients with ROSC (n=274), mild hypothermia (cooling to 32-34ºC) provided significant improvement in functional recovery at hospital discharge (55% vs 39%; number needed to treat [NNT] = 6) and lower 6-month mortality rate when compared with patients who were not cooled (41% vs 55%) (NNT=7) (2). Bernard et al. examined endpoint of survival to hospital discharge to home or a rehabilitation facility (good outcome) in 77 patients and demonstrated 49% in the hypothermia group compared with 26% in the normothermicgroup (3).

Patients shown to benefit from induced hypothermia include the following:

• Intubated patients with treatment initiated within a 6-hour post cardiac arrest (nonperfusing ventricular tachycardia [VT] or VF) time window

• Those able to maintain a systolic blood pressure >90 mm Hg, with or without pressors, after cardiopulmonary resuscitation (CPR)

• Those in a coma at the time of cooling. Coma is defined as not following commands. Brainstem reflexes and pathological/posturing movements are permissible. Patients with a Glasgow Coma Score (GCS) of 3 are eligible for hypothermia.

Exclusion criteria are in part based on theoretical increases in risk. Many studies have reported increased but nonsignificant increases in risk. Patients for whom hypothermia may carry increased risk include those with the following conditions:

• Recent major surgery within 14 days - Hypothermia may increase the risk of infection and bleeding.

• Systemic infection/sepsis - Hypothermia may inhibit immune function and is associated with a small increase in risk of infection.

• Patients in a coma from other causes (drug intoxication, preexisting coma prior to arrest)

• Patients with a known bleeding diathesis or with active ongoing bleeding - Hypothermia may impair the clotting system. Check prothrombin time/partial thromboplastin time (PT/PTT), fibrinogen value, and D-dimer value at admission. (Note: Patients may receive chemical thrombolysis, antiplatelet agents, or anticoagulants if deemed necessary in the treatment of the primary cardiac condition.)

• Patients with a valid DNR order (26)

Induced hypothermia after PEA, asystole, or in-hospital arrest has not been fully studied. One large cohort study of cardiac arrest patients found that TH was not associated with good outcome in nonshockable patients (15). Further investigation is needed, and the practitioner should consider the most likely etiology of the cardiac arrest, and apply TH accordingly.

In most centers, the patient is cooled by using an induced hypothermia protocol for 24 hours to a goal temperature of 32-34ºC. According to an observational study of 151 patients, the risk of death increases for each degree over 37 during the first 48 hours after arrest (OR 2.26; 95% CI 1.24-4.12) (16). The goal is to reach the target temperature as quickly as possible, which can usually be achieved within 3-4 hours of initiating cooling. A prospective observational study of 49 consecutive post-cardiac arrest patients found that a shorter time to reach the goal temperature correlated with improved neurologic outcome (17), although two randomized trials reported no improvement in functional outcomes for subjects cooled in the ambulance compared to those cooled in the emergency department (18-19).

Although no randomized trials in humans have directly compared different durations of TH after cardiac arrest, clinical studies that have shown benefit have used this time frame (2 degrees C per hour (18, 22, 23). The rate of temperature reduction using this method has been found to be comparable or even faster that that achieved with endovascular heat exchange catheters such as : Celsius Control System (Innercool, Inc, San Diego, CA) and Cool Line System (Alsius, Inc, Irvine, CA – this catheter is used at Monte) which are devices typically placed in the femoral vein. They are associated with a low rate of complications and a tighter control of target temperature regulation (24).

In clinical practice the combination of intravascular and surface cooling is commonly used (4, 5).

Once cooling measures have begun, sedation and suppression of shivering must be carried out in order to avoid a delay in achieving goal temperatures. Parenteral narcotic analgesia can be provided with morphine or fentanyl; sedation can be maintained with agents such as midazolam or propofol.

As per UpToDate, a propofol infusion at 30mcg/kg/min is preferred, and can be titrated (based on shivering and not necessarily sedation, to a maximum of 50mcg/kg/min. If that is ineffective, 0.1mcg/kg boluses of fentanyl may be added. Buspirone (serotonin 1A partial agonist) and meperidine also appear to lower the shivering threshold. However the proconvulsant effects of a meperidine metabolite make this drug less appealing. Additionally, meperidine is not recommended in renal dysfunction, which is a common finding in post cardiac arrest patients. While very effective at suppressing shivering, continuous neuromuscular blockade can mask seizures, therefore continuous EEG monitoring is needed (27). Use of an endovascular technique along with buspirone and surface warming may avert shivering without the need for paralysis.

Core body temperature should be monitored during TH. The gold standard is central venous temperature, with esophageal measurement being an accurate alternative. Bladder temperature may be inaccurate if urine output is less that 0.5 ml/kg/hr, and rectal measurements may lag behind acute temperature changes (27).

Other critical care interventions as per Scott Weingart MD/ EM Crit: include keeping HOB >30 degrees, DVT/ GI prophylaxis, glycemic control (ie. 65 (80 better) for cerebral perfusion, Euoxemia (keep 02sat95% to decrease cerebral free radical formation), Eucapnia (35-38), Keep hgb >7-8, maybe 10 if showing s/s poor tissue oxygenation (ie. no decrease on serial lactate), central venous 02 sat >70. Low TV ventilation, increase PEEP , inotropes prn, may need balloon pump, maybe ECMO, consider STEMI- PCI lab

Rewarming is begun 24 hours after the time of initiation of cooling (ie, NOT from the time the target temperature is achieved) (26).

The rewarming phase may be the most critical, as constricted peripheral vascular beds start to dilate. Peripheral hyperemia may cause hypotension. The literature recommends rewarming slowly at a temperature of 0.3-0.5ºC every hour. Rewarming will take approximately 8 hours.

Rewarming with any device or approach:

• Remove cooling blankets (and ice if still in use). The goal is to have the patient warm at about 0.3-0.5ºC per hour up to a target of 36°C. One method is to set the water temperature in the cooling device to 35°C and then increase the water temperature by 0.5°C every 1-2 hours until a stable core body temperature of 36°C has been reached for 1 hour.

• Maintain the paralytic agent and sedation until the patient’s temperature reaches 35°C. If infusing, discontinue the paralytic agent first. The sedation may be discontinued at the practitioner’s discretion.

• Monitor the patient for hypotension secondary to vasodilatation related to rewarming.

• Discontinue potassium infusions.

• The goal after rewarming is normothermia (ie, avoidance of hyperthermia) (26)

References

1. Nichol G. Thomas E. Callaway CW et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008; 300: 1423

2. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346-549.

3. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. Feb 21 2002;346 (8):557-63.

4. Sunde K, Pytte M, Jacobsen D. et al. Implementation of a standardized treatment protocol for post resuscitation care after out-of hospital cardiac arrest. Resuscitation 2007; 73:29

5. Rittenberger JC, Guyette FX, Tisherman SA, et al. Outcomes of a hospital wide plan to improve care of comatose survivors of cardiac arrest. Resuscitation 2008; 79: 198

6. Nolan JP, Deakin CD, Soar J, et al. European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support. Resuscitation. Dec 2005;67 Suppl 1:S39-86..

7. Arrich J, European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study Group. Clinical application of mild therapeutic hypothermia after cardiac arrest. Crit Care Med. Apr 2007;35(4):1041-7.

8. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. Dec 2005;33(12):2744-51.

9. Seupaul RA, Wilbur LG. Evidence-based emergency medicine. Does therapeutic hypothermia benefit survivors of cardiac arrest? Ann Emerg Med. Sep 2011;58 (3):282-3.

10. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. Dec 2005;33(12):2744-51.

11. Hammer MD, Krieger DW. Hypothermia for acute ischemic stroke: not just another neuroprotectant. Neurologist. Nov 2003;9(6):280-9.

12. [Best Evidence] Den Hertog HM, van der Worp HB, Tseng MC, Dippel DW. Cooling therapy for acute stroke. Cochrane Database Syst Rev. Jan 21 2009;CD001247.

13. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. Dec 13 2005;112(24 Suppl):IV1-203.

14. Wright WL, Geocadin RG. Postresuscitative intensive care: neuroprotective strategies after cardiac arrest. Semin Neurol. Sep 2006;26(4):396-402.

15. Hovdenes J, Laake JH, Aaberge L, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest: experiences with patients treated with percutaneous coronary intervention and cardiogenic shock. Acta Anaesthesiol Scand. Feb 2007;51(2):137-42.

16. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med. Sep 10 2001;161(16):2007-12.

17. Wolf B, Machill K, Schumacher D et al. Early achievementof mild therapeutic hypothermia and the neurologic outcome after cardiac arrest. Int J Cardiol 2009; 133:233

18. Bernard SA, Smith K, Cameron P et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial Circulation 2010; 122: 737

19. Castren M, Nordberg P, Svensson L et al. Intra-arrest transnasal evaporative cooling: a randomized pre-hospital multicenter study. Circulation 2010; 122: 729

20. Tomte O, Deaegni T, Mangschau A et al. A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors. Crit Care Med 2011; 39: 443

21. Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care. Aug 24 2007;11(4):R91

22. Kim F, Olsufka M, Longstreth WT Jr, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation. Jun 19 2007;115(24):3064-70..

23. Kliegel A, Losert H, Sterz F, et al. Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest--a feasibility study. Resuscitation. Mar 2005;64(3):347-51.

24. Holzer M, Mullner M, Sterz F, et al. Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach. Stroke. Jul 2006;37(7):1792-7. Epub 2006 Jun 8.

25. Robinson J, Charlton J, Seal R et al. Esophageal, rectal, axillary, tympanic and pulmonary artery temperatures during cardiac surgery Can J Anaesth 1998 45: 317

26. . Adler, Jonathan MD. Therapeutic Hypothermia. Nov. 2011

27. . Rittenberger J, Callaway C. Post Cardiac Arrest Management in Adults. Oct. 2012

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