Death and taxes are two hard facts we face in this world. Facts pertinent to the pediatric intensivist and intensive care unit (ICU) nurse include strong evidence that fever after cardiac arrest and other pediatric brain insults is associated with worse outcomes.(1-3) However, it is our nature to push the boundaries of critical care and innovate, especially in pediatric brain injury, where morbidity and mortality rates are high and targeted therapies are few and far between.(4) Groundwork for the exploration of therapeutic hypothermia for neuroprotection in critical care began with case reports of phenomenal outcomes in cold-water drowning and cardiopulmonary bypass patients.(5,6) Blockbuster neonatal and adult hypoxic-ischemic disease trials proclaimed the start of the hypothermia era.(7-9) Since those publications appeared, hypothermia has become standard of care in neonates. However, clarity was muddled after publication of a trial showing that targeted temperature management (TTM) at 36°C was as effective as a temperature target at 33°C in adults with out-of-hospital cardiac arrest of presumed cardiac etiology.(10)
What about hypothermia for children surviving cardiac arrest? This heterogeneous group deserves a high quality trial of its own, rather than a simple extrapolation of studies in other patient populations. Differing from both neonatal asphyxia (only approximately one-third of these newborns require cardiopulmonary resuscitation) and witnessed adult out-of-hospital cardiac events, pediatric arrests are most frequently due to asphyxia rather than cardiac events, exhibit asystole rather than ventricular arrhythmia as the presenting rhythm, and are often unwitnessed—all indicators of unfavorable outcomes.(11) Still, no other intervention packed the power of multiple mechanisms of action and track record of hypothermia.(12)
Facts are being elucidated regarding the utility of therapeutic hypothermia for neuroprotection following cardiac arrest in children. Hypothermia has a history of use in children with arrest due to drowning, part of a package of aggressive supportive care measures that included hyperventilation, steroids, and intracranial pressure monitoring and treatment, whose effectiveness was later debunked.(13) More recently, a systematic review analyzed three pediatric cardiac arrest observational studies and found no difference in mortality rates or neurological outcome whether children received hypothermia or normothermia; these findings led to a call for prospective randomized trials.(14)
We now have results from the out-of-hospital cohort of the multicenter Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) trial.(15) Enrollment targets were met (n=295 subjects) and subjects were enrolled within six hours of return of circulation in order to facilitate timely transition to temperature assignment. Eligibility criteria reflected the heterogeneous nature of the problem; the study included children of all ages (48 hours to 18 years) whose cardiac arrest was due to any etiology and who were comatose on assessment for the study. The investigators found that hypothermia (33°C for 48 hours) compared to controlled normothermia (36.8°C) did not improve the composite primary outcome of one-year survival with favorable outcome (20% vs. 12%; p=0.14). The point estimate for the primary outcome was in favor of hypothermia, and a secondary outcome survival analysis demonstrated a difference in favor of hypothermia (supplementary data, p=0.04). Subgroup analyses were not provided.
There will undoubtedly be vigorous discussions among providers regarding the clinical implications of these data. Perhaps similar to the traumatic brain injury and neonatal asphyxia trials, people will ponder the sample size (i.e., would more subjects have led to a significant difference?) and the delivery of hypothermia (i.e., was 48 hours enough?). Others may say the data prove it is time to forget about hypothermia and focus on the delivery of controlled normothermia. While we have these discussions, we also eagerly await the THAPCA in-hospital study results to provide additional insights.
Where does all of this leave clinicians today? First, we need to ensure that basic but critical post-resuscitation care goals are communicated and stringently met. This includes the need to manage patient temperature with the same intensive regard as blood pressure in post-resuscitation management, with continuous monitoring and active fever prevention.(16,17) Many children are hypothermic (30°C to 36°C) following the return of circulation; slow (one to two days) passive rewarming toward TTM goals may prevent overwarming, although some children with poikilothermia may eventually require active rewarming. At temperatures <30°C, brief active rewarming may be indicated to prevent arrhythmias and other adverse effects. To achieve these goals, sites may consider implementing a post-arrest checklist that includes nursing and physician action items, such as timing and location of a continuous temperature monitoring probe and use of temperature managing measures (i.e., a cooling blanket), among other recommendations to treat post-resuscitation syndrome.(18) We need to continually reassess whether our treatment goals are being met. Intensivists and nurses who participated in the THAPCA trials and/or care for children requiring temperature control know that even TTM targeting normothermia is hard work, so regular education and practice or simulation of these measures should be standardized.
Although there are no definitive data on the time window for continuous temperature monitoring and measurement, we should consider TTM for three to five days post-arrest, to cover the period when the brain may be most vulnerable to secondary insults and continued neuronal death.(19) Serum brain biomarkers and noninvasive neurological testing should be validated prospectively, as they may prove helpful in assisting in trial stratification, assessing theragnostics, or determining when therapeutic interventions can be weaned.(20-22) Finally, this is only the beginning of a revolution in resuscitation. The plain and simple fact is that we, as clinicians, researchers and funding agencies, need to advance our commitment to helping children and their families recover to their best potential.
1. Bembea M, Nadkarni V, Diener-West M, et al. Temperature patterns in the early post-resuscitation period after pediatric in-hospital cardiac arrest. Pediatr Crit Care Med. 2010 Nov;11(6):723-730.
2. Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008;122:491-499.
3. Natale JE, Joseph JG, Helfaer MA, Shaffner DH. Early hyperthermia after traumatic brain injury in children: risk factors, influence on length of stay, and effect on short-term neurologic status. Crit Care Med. 2000;28:2608-2615.
4. Moreau JF, Fink EL, Hartman ME, et al. Hospitalizations of children with neurological disorders in the United States. Pediatr Crit Care Med. 2013 Oct;14(8):801-810.
5. Siebke H, Rod T, Breivik H, Link B. Survival after 40 minutes; submersion without cerebral sequeae. Lancet. 1975;1:1275-1277.
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7. Shankaran S, Laptook AAR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353:1574-1584.
8. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.
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14. Scholefield B, Duncan H, Davies P, et al. Hypothermia for neuroprotection in children after cardiopulmonary arrest. Cochrane Database Syst Rev. 2013;2:CD009442.
15. Moler FW, Silverstein FS, Holubkov R, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015 May 14;372(20):1898-1908.
16. Topjian AA, French B, Sutton RM, et al. Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest. Crit Care Med. 2014;42:1518-1523.
17. Kleinman ME, Chameides L, Schexnayder SM, et al. Pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2010 Nov;126(5):e1361-e1399.
18. Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79:350-379.
19. Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ. Early neurodegeneration after hypoxia-ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis. 2001 Apr;8(2):207-219.
20. Fink EL, Berger RP, Clark RSB, et al. Serum biomarkers of brain injury to classify outcome after pediatric cardiac arrest. Crit Care Med. 2014 Mar;42(3):664-674.
21. Subbaswamy A, Hsu AA, Weinstein S, Bell MJ. Correlation of cerebral near-infrared spectroscopy (cNIRS) and neurological markers in critically ill children. Neurocrit Care. 2009;10(1):129-135.
22. Hansen G, Grimason M, Collins JW, Wainwright MS. Selective head cooling for the treatment of neurologic complications of acute liver failure in a newborn with disseminated herpes infection. Springerplus. 2013 Oct 29;2:572.