A review of therapeutic hypothermia in traumatic brain injury
Myron Yaster MD, Shawn Jackson MD PhD, and Ethan Sanford MD
Over the past 50 years, an enormous amount of money (millions? billions?) has been spent at the bench and beside to improve outcomes following traumatic brain injury. And yet, despite the enormous investment in time, money, and professional career development, of all of the therapeutic neuroprotective strategies that have been tried in animal and human studies, and there have been many, only hypothermia, and possibly TXA, have been shown to be effective at improving neurologic outcomes.1,2 Unfortunately, even hypothermia, the most studied, has failed to convincingly and consistently demonstrate outcome improvement in human studies.3
My own personal experience with therapeutic hypothermia began with the Reye syndrome epidemic of the 1980s and later as an intensivist in managing TBI. Unfortunately, our efforts to adopt hypothermia were limited by impaired coagulation, arrythmias, hyperglycemia, electrolyte abnormalities, and an increased risk of infection.
Today’s PAAD by Trieu et al.4 is a timely review and an excellent introduction of this topic for practitioners and students on a neuro anesthesia or PICU rotation. I’ve asked Drs. Shawn Jackson and Ethan Sanford, who recently joined the PAAD’s executive council and who are both Board certified in Pediatrics, Anesthesiology, Anesthesiology and Pediatric Critical Care Medicine to assist. Myron Yaster MD
Review article
Trieu C, Rajagopalan S, Kofke WA, Cruz Navarro J. Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury. Anesth Analg. 2023 Nov 1;137(5):953-962. doi: 10.1213/ANE.0000000000006503. Epub 2023 Apr 28. PMID: 37115720
The potential benefits and real harms of hypothermia are readily understood by anesthesiologists who manage patients undergoing deep hypothermic arrest and, conversely, work to avoid hypothermia in the majority of common OR procedures. Hypothermia is a blunt tool which effects the cellular function of every organ system. The possible beneficial effects of decreased cerebral metabolic rate for oxygen consumption and reduced inflammatory response are weighed against deleterious complications including arrhythmia, coagulopathy, poor wound healing, and infection risk.
The data for and against therapeutic hypothermia exists for a variety of pathologies and in all age ranges. Several adult trials of hypothermia after cardiac arrest showed improvement in neurologic outcomes and became a recommended treatment for post-arrest patients with evidence of moderate or severe brain injury. In our pediatric patient population, the most compelling argument for hypothermia comes from the NICU. Newborns who experienced hypoxic ischemic encephalopathy (HIE) had decreased risk of death or disability with hypothermia.5 But not all of the data is supportive of hypothermia. In pediatric patients who have experienced an in-hospital or out-of-hospital cardiac arrest, therapeutic hypothermia failed to demonstrate survival with a favorable functional outcome at 1 year (THAPCA Trials).6,7
But what do we know about hypothermia as it relates to traumatic brain injury? And how does this change our practice as pediatric anesthesiologists? In traumatic brain injury (TBI), the primary injury occurs on impact and secondary injury develops as a result of cell death, inflammation, cerebral edema and intracranial hypertension – all of which may all cause diminished brain perfusion. Factors which exacerbate the inflammatory response, increase metabolic demand, or worsen cellular metabolic states are hypothesized to result in worse neurologic outcome. In this review, the authors enumerate these factors to include fever, hyperglycemia, sustained neuronal hyperexcitability mediated by neurotransmitters, activation of kinase cascades, mitochondrial dysfunction, free radical release, apoptotic cell death, and blood-brain barrier (BBB) derangements.4 Hypothermia reduces cerebral metabolic rate of oxygen consumption, glucose utilization, and intracranial pressure (ICP), all which would seemingly be beneficial for an injured brain at risk for further ischemic injury.8
Hypothermia in the setting of TBI can be utilized as prophyaxis (soon after injury) or as treatment (in the setting of refractory intracranial hypertension). This review outlines available RCTs and the differences in hypothermia protocols utilized. Unfortunately, prophylactic hypothermia has not consistently demonstrated benefit in adults with TBI and is, thus, only recommended as a last line treatment for ICP elevation. Despite this recommendation, hypothermia treatment of refractory increased ICP has only limited supportive evidence and even some data of worsened mortality. What about the kids? Again, sadly, two high-profile multicenter randomized trials have demonstrated no functional neurologic benefit or mortality benefit.
A possible limitation of these studies is differences in protocols. How to induce hypothermia (cool saline, cooling blankets, cold peritoneal lavage, ect); whether to use mild hypothermia (33-36o C) or moderate hypothermia (28-32o C); when to initiate hypothermia; and for how long to continue hypothermia after injury remains unclear.3 Further, how to rewarm and whether hypothermia should be systemic or limited to regional cooling of the brain (which may limit systemic toxicity) is also unclear.9 Harris et al.10 used a “cooling cap” to apply hypothermia solely to the brain. However, the cooling cap failed to induce an adequate cranial temperature, determined by the cranial-bladder gradient, and authors concluded that there was no benefit in mortality or morbidity between the 2 groups.”4
Whether or not HYPOthermia is effective at ameliorating secondary brain injury, it is very clear that HYPERthermia is associated with worsened outcomes after brain injury. A possible reason for discrepancies in studies of hypothermia for cardiac arrest were the larger amount of fever in the standard care arms of earlier studies. Thus, avoidance of fever (<37.5 o C) is always an important element of a comprehensive neuroprotecive strategy. Additionally, a possible problem with hypothermia is the side effect of hypotension with treatment or during rewarming which was noted in the pediatric trials with TBI. Hypotension is well established to correlate with worsened outcomes of TBI and should be avoided.
Should we stop pursuing hypothermia as a treatment modality in brain injury? Hopefully not. Rather than focusing on the hypothermia protocol, future studies may focus on specific populations. A RCT of adults with cardiogenic shock requiring ECMO demonstrated improved outcomes with hypothermia. Such distinct populations where the risk is elevated, but complications (arrhythmia, hypotension, ease in implementing cooling and rewarming) may be better managed with an ECMO circuit. Currently, an adaptive trial of hypothermia for out-of-hospital cardiac arrest in children is enrolling in an attempt to find a hypothermia protocol to improve outcomes. We believe such work is justified given the potential to prevent a devastating outcome, though admittedly enthusiasm must someday wain if lack of positive results persist.
Perhaps more germane to our anesthesia practice, is whether active rewarming should be performed for children who present with hypothermia after traumatic injury and are going to the OR. We’ve been in the uncomfortable position of titrating rewarming in these circumstances as the surgeon clamors for rewarming to avoid a component of the trauma triad of death. We all recognize the importance of normothermia to avoid hemorrhagic complications is crucial, but these are not normal patients coming for elective surgery. If we are trying to preserve brain function, actively rewarming and certainly hyperthermia may be detrimental. Until evidence is available, we likely must have direct conversations to weigh trauma risk versus neurologic risk. For now, avoiding hyperthermia and maintaining blood pressure should be the priority.
Are you using therapeutic hypothermia in your practice for traumatic brain injury, ICP management, and/or post CPR brain “rescue”? Send your responses to Myron who will post in a Friday Reader response.
References
1. Hirst TC, Klasen MG, Rhodes JK, Macleod MR, Andrews PJD: A Systematic Review and Meta-Analysis of Hypothermia in Experimental Traumatic Brain Injury: Why Have Promising Animal Studies Not Been Replicated in Pragmatic Clinical Trials? J Neurotrauma 2020; 37: 2057-2068
2. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019; 394: 1713-1723
3. Cooper DJ, Nichol AD, Bailey M, Bernard S, Cameron PA, Pili-Floury S, Forbes A, Gantner D, Higgins AM, Huet O, Kasza J, Murray L, Newby L, Presneill JJ, Rashford S, Rosenfeld JV, Stephenson M, Vallance S, Varma D, Webb SAR, Trapani T, McArthur C: Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. Jama 2018; 320: 2211-2220
4. Trieu C, Rajagopalan S, Kofke WA, Cruz Navarro J: Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury. Anesth Analg 2023; 137: 953-962
5. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574-84
6. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Clark AE, Browning B, Pemberton VL, Page K, Shankaran S, Hutchison JS, Newth CJ, Bennett KS, Berger JT, Topjian A, Pineda JA, Koch JD, Schleien CL, Dalton HJ, Ofori-Amanfo G, Goodman DM, Fink EL, McQuillen P, Zimmerman JJ, Thomas NJ, van der Jagt EW, Porter MB, Meyer MT, Harrison R, Pham N, Schwarz AJ, Nowak JE, Alten J, Wheeler DS, Bhalala US, Lidsky K, Lloyd E, Mathur M, Shah S, Wu T, Theodorou AA, Sanders RC, Jr., Dean JM: Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med 2015; 372: 1898-908
7. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Browning B, Pemberton VL, Page K, Gildea MR, Scholefield BR, Shankaran S, Hutchison JS, Berger JT, Ofori-Amanfo G, Newth CJ, Topjian A, Bennett KS, Koch JD, Pham N, Chanani NK, Pineda JA, Harrison R, Dalton HJ, Alten J, Schleien CL, Goodman DM, Zimmerman JJ, Bhalala US, Schwarz AJ, Porter MB, Shah S, Fink EL, McQuillen P, Wu T, Skellett S, Thomas NJ, Nowak JE, Baines PB, Pappachan J, Mathur M, Lloyd E, van der Jagt EW, Dobyns EL, Meyer MT, Sanders RC, Jr., Clark AE, Dean JM: Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N Engl J Med 2017; 376: 318-329
8. Rivera-Lara L, Zhang J, Muehlschlegel S: Therapeutic hypothermia for acute neurological injuries. Neurotherapeutics 2012; 9: 73-86
9. Dietrich WD, Bramlett HM: Therapeutic hypothermia and targeted temperature management in traumatic brain injury: Clinical challenges for successful translation. Brain Res 2016; 1640: 94-103
10. Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, Easley K: Discrete cerebral hypothermia in the management of traumatic brain injury: a randomized controlled trial. J Neurosurg 2009; 110: 1256-64