- Email: [email protected]
Reconsidering the role of hypothermia in management of severe traumatic brain injury
Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Reconsidering the role of hypothermia in management of severe traumatic brain injury S. Honeybul ⇑ Department of Neurosurgery, Sir Charles Gairdner Hospital and Royal Perth Hospital, Hospital Avenue, Perth, WA 6000, Australia
a r t i c l e
i n f o
Article history: Received 13 December 2015 Accepted 4 January 2016 Available online xxxx Keywords: Hypothermia Intracranial hypertension Severe traumatic brain injury
a b s t r a c t Over the past two decades there has been considerable interest in the use of hypothermia in the management of severe traumatic brain injury. However despite promising experimental evidence, results from clinical studies have failed to demonstrate benefit. Indeed recent studies have shown a tendency to worse outcomes in those patients randomised to therapeutic hypothermia. In this narrative review the pathophysiological rationale behind hypothermia and the clinical evidence for efficacy are examined. There would still appear to be a role for hypothermia in the management of intractable intracranial hypertension. However optimising therapeutic time frames and better management of strategies for complications will be required if experimental evidence for neuroprotection is to be translated into clinical benefit. Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.
1. Introduction
2.1. The Monro–Kellie doctrine
The past two decades has seen enormous interest in the use of hypothermia in the context of severe traumatic brain injury (TBI). The rationale is that therapeutic cooling of the brain can prevent or attenuate some of the secondary brain injury due to damaging inflammatory and neuroexcitatory cascades and elevated intracranial pressure (ICP). Laboratory and animal studies [1–6] have shown promising results however evidence of efficacy in clinical studies has been less forthcoming [7–12]. Indeed, recent trials not only failed to demonstrate benefit but also revealed a tendency towards clinical harm [7,8,11,12]. In view of these results the time may have come to reconsider the role of hypothermia in the management of severe TBI. The aim of this narrative review is to re-examine the pathophysiological rationale behind hypothermia, assess the clinical evidence for efficacy and consider future directions.
Despite considerable advances in the management of TBI we are still bound by the Monro–Kellie doctrine, which was first described over 200 years ago. In 1783 Alexander Monro deduced that the cranium was a ‘‘rigid box” filled with a ‘‘nearly incompressible brain” and that its total volume tends to remain constant [13] (Fig. 1). The doctrine states that any increase in the volume of the cranial contents (the brain, blood or cerebrospinal fluid [CSF]), will elevate ICP. Furthermore, if one of these three elements increases in volume, it must occur at the expense of the volume of the other two elements. In 1824 George Kellie confirmed many of Monro’s early observations [14]. When the brain is injured and starts to swell or there is a mass lesion such as an intracerebral haematoma, in order to maintain cerebral perfusion, compensation is made at the expense of a reduction in the volume of blood and CSF. As the brain becomes progressively more swollen or a mass lesion increases in size these compensatory mechanisms become exhausted and for incrementally smaller increases in volume there are progressively greater increases in pressure until tonsillar herniation occurs. An understanding of this concept is important in order to appreciate how management strategies for patients with severe TBI have evolved over recent years. Throughout the 1980s, patients were routinely hyperventilated [15,16], placed in a barbiturate coma [17,18], or more recently rendered hypothermic because these measures have been shown to consistently reduce ICP. Given the strong association between intracranial hypertension and poor outcome [19,20] the rationale was that by lowering the ICP, cerebral perfusion would be improved and this in turn would prevent
2. The pathophysiology of TBI In order to appreciate the pathophysiological rationale and possible limitations for hypothermia in the context of neurotrauma there are two concepts that require consideration: firstly, the Monro–Kellie doctrine, and secondly, the concept of neuroprotection. ⇑ Tel.: +61 8 9346 1132; fax: +61 8 9346 3824. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jocn.2016.01.002 0967-5868/Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
2
S. Honeybul / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Whilst this notion seemed counterintuitive, the negative effects that these interventions have on cerebral blood flow suggest a reason for treatment failure. Notwithstanding the potential neuroprotective effects of barbiturates [21] and hypothermia [4,6,22], the predominant mechanism by which these three therapeutic modalities can rapidly reduce ICP after TBI is cerebral vasoconstriction. Hyperventilation reduces the arterial carbon dioxide which in turn alkalinizes the CSF and induces a reflex vasoconstriction [15]. Barbiturates and hypothermia depress neuronal activity and reduce cerebral metabolism, which leads to a reduction in cerebral blood flow and blood volume due to autoregulatory flow metabolism coupling [23–25]. The subsequent reduction in cerebral blood flow has been clearly shown in several studies [15,23–27]. In view of the well known deleterious effect that ischaemia has on outcome [28] it is perhaps not entirely surprising that, although these measures reduce ICP, they do not necessarily provide long-term clinical benefit [2,7–9,15,29]. Fig. 1. The Monro–Kellie doctrine. (i) In normal physiological circumstances any increase in volume of the constituent components of the intracranial compartment does not cause a significant increase in ICP because of compensatory decrease in volume of either blood or CSF. (ii) Partially compensated intracranial hypertension. As the brain progressively swells initial compensation is at the expense of blood and CSF. (iii) Decompensated intracranial hypertension. As the cerebral swelling worsens or a mass lesion enlarges there comes a point when the compensatory mechanisms start to fail and for smaller increases in swelling there are incrementally greater increases in ICP. CSF = cerebrospinal fluid, ICP = intracranial pressure.
secondary brain injury and improve clinical outcome. However, several clinical studies failed to show these therapeutic interventions provided benefit and in certain circumstances may have resulted in a worsened outcome [11,15,17].
2.2. Cerebral neuroprotection Traditionally primary brain injury has been defined as occurring at the moment of impact and secondary injury follows thereafter and consists of a wide range of molecular and cellular pathophysiological mechanisms. However it is now realised that there is considerable overlap between the two processes and a substantial amount of cell death that occurs many hours later is due to a series of deleterious inflammatory and neurochemical processes that are initiated at the time of injury [30–32]. This concept is well illustrated by the glutamate neuroexcitatory cascade which is one of many such responses initiated at the time of injury and amplified by secondary insults such as hypoxia and hypotension [33] (Fig. 2).
Fig. 2. A simplified schematic representation of the neuroexcitatory cascade. The primary injury triggers a massive uncontrolled release of the neurotransmitter glutamate which triggers the cascade leading to cytotoxic and apoptotic cell death. The cascade is reinforced by secondary insults.
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
S. Honeybul / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
A substantial amount of time and money has been invested into research regarding possible mechanisms whereby some of the damaging consequences of these neuroexcitatory and inflammatory cascades can, at the very least, be somewhat attenuated. Indeed this was in part the rationale behind the extensive use of steroids in the 1980s for patients with severe TBI given the favourable response that can be achieved in the management of vasogenic oedema secondary to tumours. However the Corticosteroid Randomization After Significant Head injury (CRASH) study clearly demonstrated that not only was this not beneficial, but mortality was actually increased [34]. Since that time the use of steroids has largely been abandoned and this has been the fate of many pharmacological agents that showed early promise in the laboratory setting [32,35–38]. It is in this regard that hypothermia has been thought to have a possible role in neuroprotection because many of these pathophysiological cascades are temperature-sensitive and hypothermia could potentially act in a blanket fashion by affecting several deleterious pathways at the same time [22]. There is no doubt that in the laboratory setting hypothermia has been shown to suppress free radical and antioxidant production, stabilise cell membranes and reduce the neuroexcitotoxicity and inflammatory response [1,3,4,6,22]. In addition a number of animal studies have demonstrated that hypothermia may be clinically beneficial if induced either immediately or within 2 hours of injury [6,19,39]. Unfortunately this preclinical evidence has not been translated into practice.
3. Clinical studies concerning hypothermia Over the past decade there have been a number of high quality trials that have investigated the clinical efficacy of hypothermia however none have demonstrated convincing benefit. Some of the earlier trials have been criticised due to methodological flaws which is in some part justified. In the National Acute Brain Injury Study: Hypothermia (NABISH:H 1) there was some variability in intercenter protocols and expertise and there was a high incidence of hypotension, hypovolaemia and electrolyte imbalance in the treatment group [9]. The Hutchison paediatric trial showed a higher death rate and incidence of poor neurological outcome in the hypothermia group (23 [21%] of 108 patients in the hypothermia group died versus 14 [12%] in the normothermia group). However there were some randomisation discrepancies, a short cooling period of only 24 hours and a fairly rapid rewarming with few facilities for treating rewarming complications [11]. The subsequent trials were methodologically more robust however they have also failed to demonstrate benefit. The NABISH II trial investigated early cooling within 2 hours of injury and the outcomes were worse in the hypothermia group although this was not statistically significant [10]. The ‘‘Cool Kids” trial was stopped on the grounds of futility because hypothermia initiated early, used globally for 48–72 hours and with a slow rewarming, did not improve mortality at 3 months. Indeed, there was again a non-statistical increase in mortality in the hypothermia group (six [15%] of 39 patients in the hypothermia group versus two [5%] in the normothermia group) [7]. Finally, the most recent trial was a multicentre trial conducted by Andrews et al [8]. It not only failed to show that hypothermia provided clinical benefit but also that there was a tendency to cause harm such that the trial also had to be halted early [18]. Sixty-nine (36.5%) of the 192 patients in the control group achieved a favourable outcome compared with 49 patients (25.7%) in the hypothermia arm of the trial. In addition, there was again an increased mortality in the hypothermia group (68 [34.9%] in the hypothermia group died versus 51 [26.6%] in the normothermia group).
3
This was a well-conducted study and whilst there may be some discussion regarding methodology the pragmatic approach aimed to investigate efficacy in the context of routine clinical practice. As such the results require careful consideration given that, as noted by the authors in their exclusion criteria, patients were excluded if they were already receiving therapeutic hypothermia. The implication would be that a number of centres have already adopted hypothermia into their routine clinical practice. Given the findings of this study this practice may need to be reconsidered in much the same way that the routine use of hyperventilation and barbiturate therapy has been re-evaluated over recent years.
4. Future directions It is perhaps premature to abandon the use of hypothermia however based on the clinical evidence available it is perhaps time to reconsider the direction of future research. The difficulties revolve around a number of key issues. In the first instance, the fundamental management strategies regarding timing, target temperature, duration and rewarming have yet to be determined. Secondly the question remains as to whether any clinical benefit is likely to be offset by the well-documented detrimental effect of complications [40]. 4.1. Management strategies Amongst the various strategies that require consideration the time between injury and initiating cooling would seem to be one of the most important issues. The animal studies that demonstrated the neuroprotective effect of hypothermia have commenced cooling either directly after trauma or within 2 hours [3,22,39]. Thereafter most of the harmful cascades will have been initiated. Whilst there is no doubt that hypothermia can lower the ICP due to its effect on cerebral blood flow, in order to provide neuroprotection cooling must be initiated as soon as possible in order to prevent rather than treat the subsequent cerebral insults [39]. This may limit the use of cooling in many trauma situations because of delays in resuscitation, transfer and initial clinical and radiological assessment. At the time of writing an ongoing trial is investigating pre-hospital hypothermia and hopefully this will provide some insight into the future role of hypothermia [41]. If some degree of benefit is demonstrated then more work will be required to establish optimal management strategies regarding target temperature, duration and rewarming protocols. Conversley, if it fails to show benefit than the role of hypothermia in the context of neurotrauma may have to be seriously reconsidered. 4.2. Complications It is becoming increasingly apparent that the use of hypothermia causes significant complications and these will require better management if evidence from experimental studies is to be translated into clinical practice. Most notable complications include electrolyte disturbances, cardiac arrhythmias, coagulopathy and infections, most notably pneumonia [40]. There have also been significant complications associated with rewarming and the subsequent rebound intracranial hypertension [11,12]. Finally there are the significant implications when considering the altered metabolism of many of the drugs that are routinely used in the intensive care environment such as morphine, midazolam propofol, vecuronium and phenytoin to name but a few. These drugs all have significant side effects in themselves and altered metabolism, half-life and interactions may have subtle deleterious effects on outcome [32].
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
4
S. Honeybul / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
In summary whilst the use of hypothermia as a neuroprotectant has been established in experimental models, clinical benefit in patients with TBI has not been demonstrated. Despite these discouraging results it is perhaps premature to consider abandoning this therapy. There is no doubt that hypothermia has a role in the context of intractable intracranial hypertension however its use must be tempered with the realisation that this may come at a cost in terms of outcome. What remains to be established is the therapeutic time frame and optimal management strategies that are most likely to be beneficial and this must be the focus of future research [41]. Conflicts of Interest/Disclosures The author declare that he has no financial or other conflicts of interest in relation to this research and its publication. References [1] Chatzipanteli K, Alonso OF, Kraydieh S, et al. Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J Cereb Blood Flow Metab 2000;20:531–42. [2] Clifton GL, Jiang JY, Lyeth BG, et al. Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 1991;11:114–21. [3] Dietrich WD, Alonso O, Busto R, et al. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994;87:250–8. [4] Sutcliffe IT, Smith HA, Stanimirovic D, et al. Effects of moderate hypothermia on IL-1 beta-induced leukocyte rolling and adhesion in pial microcirculation of mice and on proinflammatory gene expression in human cerebral endothelial cells. J Cereb Blood Flow Metab 2001;21:1310–9. [5] Clark RS, Kochanek PM, Marion DW, et al. Mild posttraumatic hypothermia reduces mortality after severe controlled cortical impact in rats. J Cereb Blood Flow Metab 1996;16:253–61. [6] Koizumi H, Povlishock JT. Posttraumatic hypothermia in the treatment of axonal damage in an animal model of traumatic axonal injury. J Neurosurg 1998;89:303–9. [7] Adelson PD, Wisniewski SR, Beca J, et al. Paediatric Traumatic Brain Injury Consortium. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol 2013;12:546–53. [8] Andrews PJ, Sinclair HL, Rodriguez A, et al. Eurotherm3235 trial collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015;373:2403–12. [9] Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;22:556–63. [10] Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011;10:131–9. [11] Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;5:2447–56. [12] McIntyre LA, Fergusson DA, Hébert PC, et al. Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003;11:2992–9. [13] Monro A. Observations on the structures and functions of the nervous system. Edinburgh: W. Creech; 1783. [14] Kellie G. An account with some reflections on the pathology of the brain. Edinburgh Med Chir Soc Trans 1824;1:84–169. [15] Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the injured brain: more harm than benefit. Crit Care Med 2010;38:1348–59.
[16] Heffner JE, Sahn SA. Controlled hyperventilation in patients with intracranial hypertension. Application and management. Arch Intern Med 1983;143:765–9. [17] Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosur 1988;69:15–23. [18] Rea GL, Rockswold GL. Barbiturate therapy in uncontrolled intracranial hypertension. Neurosurgery 1983;12:401–4. [19] Juul N, Morris GF, Marshall SB, et al. Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg 2000;92:1–6. [20] Marmarou A, Anderson R, Ward JD. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 1991;75: s59–66. [21] Koerner IP, Brambrink AM. Brain protection by anesthetic agents. Curr Opin Anaesthesiol 2006;19:481–6. [22] Sahuquillo J, Vilalta A. Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr Pharm Des 2007;13:2310–22. [23] Kassell NF, Hitchon PW, Gerk MK, et al. Alterations in cerebral blood flow, oxygen metabolism, and electrical activity produced by high dose sodium thiopental. Neurosurgery 1980;7:598–603. [24] Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 1954;179:85–8. [25] Sakoh M, Gjedde A. Neuroprotection in hypothermia linked to redistribution of oxygen in brain. Am J Physiol Heart Circ Physiol 2003;285:H17–25. [26] Nordström CH, Messeter K, Sundbärg G, et al. Cerebral blood flow, vasoreactivity, and oxygen consumption during barbiturate therapy in severe traumatic brain lesions. J Neurosurg 1988;68:424–31. [27] Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991;75:731–9. [28] Manley G, Knudson MM, Morabito D, et al. Hypotension, hypoxia, and head injury: frequency, duration, and consequences. Arch Surg 2001;136:1118–23. [29] Ward JD, Becker DP, Miller JD, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg 1985;62:383–8. [30] Reilly PL. Brain injury: the pathophysiology of the first hours. ’Talk and Die revisited’. J Clin Neurosci 2001;8:398–403. [31] Sahuquillo J, Poca MA, Amoros S. Current aspects of pathophysiology and cell dysfunction after severe head injury. Curr Pharm Des 2001;7:1475–503. [32] Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 2014;15:1216–36. [33] Nicholls DG, Ward MW. Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci 2000;23:166–74. [34] Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004;364:1321–8. [35] Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics 2010;7:115–26. [36] Nichol A, French C, Little L, et al. EPO-TBI Investigators and the ANZICS Clinical Trials Group. Erythropoietin in traumatic brain injury (EPO-TBI): a doubleblind randomised controlled trial. Lancet 2015;386:2499–506. [37] Schouten JW. Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. Curr Opin Crit Care 2007;13:134–42. [38] Wright DW, Yeatts SD, Silbergleit R, et al. NETT Investigators. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014;371:2457–66. [39] Markgraf CG, Clifton GL, Moody MR. Treatment window for hypothermia in brain injury. J Neurosurg 2001;95:979–83. [40] Marion D, Bullock MR. Current and future role of therapeutic hypothermia. J Neurotrauma 2009;26:455–67. [41] Nichol A, Gantner D, Presneill J, et al. Protocol for a multicentre randomised controlled trial of early and sustained prophylactic hypothermia in the management of traumatic brain injury. Crit Care Resusc 2015;17:92–100.
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Reconsidering the role of hypothermia in management of severe traumatic brain injury S. Honeybul ⇑ Department of Neurosurgery, Sir Charles Gairdner Hospital and Royal Perth Hospital, Hospital Avenue, Perth, WA 6000, Australia
a r t i c l e
i n f o
Article history: Received 13 December 2015 Accepted 4 January 2016 Available online xxxx Keywords: Hypothermia Intracranial hypertension Severe traumatic brain injury
a b s t r a c t Over the past two decades there has been considerable interest in the use of hypothermia in the management of severe traumatic brain injury. However despite promising experimental evidence, results from clinical studies have failed to demonstrate benefit. Indeed recent studies have shown a tendency to worse outcomes in those patients randomised to therapeutic hypothermia. In this narrative review the pathophysiological rationale behind hypothermia and the clinical evidence for efficacy are examined. There would still appear to be a role for hypothermia in the management of intractable intracranial hypertension. However optimising therapeutic time frames and better management of strategies for complications will be required if experimental evidence for neuroprotection is to be translated into clinical benefit. Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.
1. Introduction
2.1. The Monro–Kellie doctrine
The past two decades has seen enormous interest in the use of hypothermia in the context of severe traumatic brain injury (TBI). The rationale is that therapeutic cooling of the brain can prevent or attenuate some of the secondary brain injury due to damaging inflammatory and neuroexcitatory cascades and elevated intracranial pressure (ICP). Laboratory and animal studies [1–6] have shown promising results however evidence of efficacy in clinical studies has been less forthcoming [7–12]. Indeed, recent trials not only failed to demonstrate benefit but also revealed a tendency towards clinical harm [7,8,11,12]. In view of these results the time may have come to reconsider the role of hypothermia in the management of severe TBI. The aim of this narrative review is to re-examine the pathophysiological rationale behind hypothermia, assess the clinical evidence for efficacy and consider future directions.
Despite considerable advances in the management of TBI we are still bound by the Monro–Kellie doctrine, which was first described over 200 years ago. In 1783 Alexander Monro deduced that the cranium was a ‘‘rigid box” filled with a ‘‘nearly incompressible brain” and that its total volume tends to remain constant [13] (Fig. 1). The doctrine states that any increase in the volume of the cranial contents (the brain, blood or cerebrospinal fluid [CSF]), will elevate ICP. Furthermore, if one of these three elements increases in volume, it must occur at the expense of the volume of the other two elements. In 1824 George Kellie confirmed many of Monro’s early observations [14]. When the brain is injured and starts to swell or there is a mass lesion such as an intracerebral haematoma, in order to maintain cerebral perfusion, compensation is made at the expense of a reduction in the volume of blood and CSF. As the brain becomes progressively more swollen or a mass lesion increases in size these compensatory mechanisms become exhausted and for incrementally smaller increases in volume there are progressively greater increases in pressure until tonsillar herniation occurs. An understanding of this concept is important in order to appreciate how management strategies for patients with severe TBI have evolved over recent years. Throughout the 1980s, patients were routinely hyperventilated [15,16], placed in a barbiturate coma [17,18], or more recently rendered hypothermic because these measures have been shown to consistently reduce ICP. Given the strong association between intracranial hypertension and poor outcome [19,20] the rationale was that by lowering the ICP, cerebral perfusion would be improved and this in turn would prevent
2. The pathophysiology of TBI In order to appreciate the pathophysiological rationale and possible limitations for hypothermia in the context of neurotrauma there are two concepts that require consideration: firstly, the Monro–Kellie doctrine, and secondly, the concept of neuroprotection. ⇑ Tel.: +61 8 9346 1132; fax: +61 8 9346 3824. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jocn.2016.01.002 0967-5868/Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
2
S. Honeybul / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Whilst this notion seemed counterintuitive, the negative effects that these interventions have on cerebral blood flow suggest a reason for treatment failure. Notwithstanding the potential neuroprotective effects of barbiturates [21] and hypothermia [4,6,22], the predominant mechanism by which these three therapeutic modalities can rapidly reduce ICP after TBI is cerebral vasoconstriction. Hyperventilation reduces the arterial carbon dioxide which in turn alkalinizes the CSF and induces a reflex vasoconstriction [15]. Barbiturates and hypothermia depress neuronal activity and reduce cerebral metabolism, which leads to a reduction in cerebral blood flow and blood volume due to autoregulatory flow metabolism coupling [23–25]. The subsequent reduction in cerebral blood flow has been clearly shown in several studies [15,23–27]. In view of the well known deleterious effect that ischaemia has on outcome [28] it is perhaps not entirely surprising that, although these measures reduce ICP, they do not necessarily provide long-term clinical benefit [2,7–9,15,29]. Fig. 1. The Monro–Kellie doctrine. (i) In normal physiological circumstances any increase in volume of the constituent components of the intracranial compartment does not cause a significant increase in ICP because of compensatory decrease in volume of either blood or CSF. (ii) Partially compensated intracranial hypertension. As the brain progressively swells initial compensation is at the expense of blood and CSF. (iii) Decompensated intracranial hypertension. As the cerebral swelling worsens or a mass lesion enlarges there comes a point when the compensatory mechanisms start to fail and for smaller increases in swelling there are incrementally greater increases in ICP. CSF = cerebrospinal fluid, ICP = intracranial pressure.
secondary brain injury and improve clinical outcome. However, several clinical studies failed to show these therapeutic interventions provided benefit and in certain circumstances may have resulted in a worsened outcome [11,15,17].
2.2. Cerebral neuroprotection Traditionally primary brain injury has been defined as occurring at the moment of impact and secondary injury follows thereafter and consists of a wide range of molecular and cellular pathophysiological mechanisms. However it is now realised that there is considerable overlap between the two processes and a substantial amount of cell death that occurs many hours later is due to a series of deleterious inflammatory and neurochemical processes that are initiated at the time of injury [30–32]. This concept is well illustrated by the glutamate neuroexcitatory cascade which is one of many such responses initiated at the time of injury and amplified by secondary insults such as hypoxia and hypotension [33] (Fig. 2).
Fig. 2. A simplified schematic representation of the neuroexcitatory cascade. The primary injury triggers a massive uncontrolled release of the neurotransmitter glutamate which triggers the cascade leading to cytotoxic and apoptotic cell death. The cascade is reinforced by secondary insults.
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
S. Honeybul / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
A substantial amount of time and money has been invested into research regarding possible mechanisms whereby some of the damaging consequences of these neuroexcitatory and inflammatory cascades can, at the very least, be somewhat attenuated. Indeed this was in part the rationale behind the extensive use of steroids in the 1980s for patients with severe TBI given the favourable response that can be achieved in the management of vasogenic oedema secondary to tumours. However the Corticosteroid Randomization After Significant Head injury (CRASH) study clearly demonstrated that not only was this not beneficial, but mortality was actually increased [34]. Since that time the use of steroids has largely been abandoned and this has been the fate of many pharmacological agents that showed early promise in the laboratory setting [32,35–38]. It is in this regard that hypothermia has been thought to have a possible role in neuroprotection because many of these pathophysiological cascades are temperature-sensitive and hypothermia could potentially act in a blanket fashion by affecting several deleterious pathways at the same time [22]. There is no doubt that in the laboratory setting hypothermia has been shown to suppress free radical and antioxidant production, stabilise cell membranes and reduce the neuroexcitotoxicity and inflammatory response [1,3,4,6,22]. In addition a number of animal studies have demonstrated that hypothermia may be clinically beneficial if induced either immediately or within 2 hours of injury [6,19,39]. Unfortunately this preclinical evidence has not been translated into practice.
3. Clinical studies concerning hypothermia Over the past decade there have been a number of high quality trials that have investigated the clinical efficacy of hypothermia however none have demonstrated convincing benefit. Some of the earlier trials have been criticised due to methodological flaws which is in some part justified. In the National Acute Brain Injury Study: Hypothermia (NABISH:H 1) there was some variability in intercenter protocols and expertise and there was a high incidence of hypotension, hypovolaemia and electrolyte imbalance in the treatment group [9]. The Hutchison paediatric trial showed a higher death rate and incidence of poor neurological outcome in the hypothermia group (23 [21%] of 108 patients in the hypothermia group died versus 14 [12%] in the normothermia group). However there were some randomisation discrepancies, a short cooling period of only 24 hours and a fairly rapid rewarming with few facilities for treating rewarming complications [11]. The subsequent trials were methodologically more robust however they have also failed to demonstrate benefit. The NABISH II trial investigated early cooling within 2 hours of injury and the outcomes were worse in the hypothermia group although this was not statistically significant [10]. The ‘‘Cool Kids” trial was stopped on the grounds of futility because hypothermia initiated early, used globally for 48–72 hours and with a slow rewarming, did not improve mortality at 3 months. Indeed, there was again a non-statistical increase in mortality in the hypothermia group (six [15%] of 39 patients in the hypothermia group versus two [5%] in the normothermia group) [7]. Finally, the most recent trial was a multicentre trial conducted by Andrews et al [8]. It not only failed to show that hypothermia provided clinical benefit but also that there was a tendency to cause harm such that the trial also had to be halted early [18]. Sixty-nine (36.5%) of the 192 patients in the control group achieved a favourable outcome compared with 49 patients (25.7%) in the hypothermia arm of the trial. In addition, there was again an increased mortality in the hypothermia group (68 [34.9%] in the hypothermia group died versus 51 [26.6%] in the normothermia group).
3
This was a well-conducted study and whilst there may be some discussion regarding methodology the pragmatic approach aimed to investigate efficacy in the context of routine clinical practice. As such the results require careful consideration given that, as noted by the authors in their exclusion criteria, patients were excluded if they were already receiving therapeutic hypothermia. The implication would be that a number of centres have already adopted hypothermia into their routine clinical practice. Given the findings of this study this practice may need to be reconsidered in much the same way that the routine use of hyperventilation and barbiturate therapy has been re-evaluated over recent years.
4. Future directions It is perhaps premature to abandon the use of hypothermia however based on the clinical evidence available it is perhaps time to reconsider the direction of future research. The difficulties revolve around a number of key issues. In the first instance, the fundamental management strategies regarding timing, target temperature, duration and rewarming have yet to be determined. Secondly the question remains as to whether any clinical benefit is likely to be offset by the well-documented detrimental effect of complications [40]. 4.1. Management strategies Amongst the various strategies that require consideration the time between injury and initiating cooling would seem to be one of the most important issues. The animal studies that demonstrated the neuroprotective effect of hypothermia have commenced cooling either directly after trauma or within 2 hours [3,22,39]. Thereafter most of the harmful cascades will have been initiated. Whilst there is no doubt that hypothermia can lower the ICP due to its effect on cerebral blood flow, in order to provide neuroprotection cooling must be initiated as soon as possible in order to prevent rather than treat the subsequent cerebral insults [39]. This may limit the use of cooling in many trauma situations because of delays in resuscitation, transfer and initial clinical and radiological assessment. At the time of writing an ongoing trial is investigating pre-hospital hypothermia and hopefully this will provide some insight into the future role of hypothermia [41]. If some degree of benefit is demonstrated then more work will be required to establish optimal management strategies regarding target temperature, duration and rewarming protocols. Conversley, if it fails to show benefit than the role of hypothermia in the context of neurotrauma may have to be seriously reconsidered. 4.2. Complications It is becoming increasingly apparent that the use of hypothermia causes significant complications and these will require better management if evidence from experimental studies is to be translated into clinical practice. Most notable complications include electrolyte disturbances, cardiac arrhythmias, coagulopathy and infections, most notably pneumonia [40]. There have also been significant complications associated with rewarming and the subsequent rebound intracranial hypertension [11,12]. Finally there are the significant implications when considering the altered metabolism of many of the drugs that are routinely used in the intensive care environment such as morphine, midazolam propofol, vecuronium and phenytoin to name but a few. These drugs all have significant side effects in themselves and altered metabolism, half-life and interactions may have subtle deleterious effects on outcome [32].
Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002
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In summary whilst the use of hypothermia as a neuroprotectant has been established in experimental models, clinical benefit in patients with TBI has not been demonstrated. Despite these discouraging results it is perhaps premature to consider abandoning this therapy. There is no doubt that hypothermia has a role in the context of intractable intracranial hypertension however its use must be tempered with the realisation that this may come at a cost in terms of outcome. What remains to be established is the therapeutic time frame and optimal management strategies that are most likely to be beneficial and this must be the focus of future research [41]. Conflicts of Interest/Disclosures The author declare that he has no financial or other conflicts of interest in relation to this research and its publication. References [1] Chatzipanteli K, Alonso OF, Kraydieh S, et al. Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J Cereb Blood Flow Metab 2000;20:531–42. [2] Clifton GL, Jiang JY, Lyeth BG, et al. Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 1991;11:114–21. [3] Dietrich WD, Alonso O, Busto R, et al. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994;87:250–8. [4] Sutcliffe IT, Smith HA, Stanimirovic D, et al. Effects of moderate hypothermia on IL-1 beta-induced leukocyte rolling and adhesion in pial microcirculation of mice and on proinflammatory gene expression in human cerebral endothelial cells. J Cereb Blood Flow Metab 2001;21:1310–9. [5] Clark RS, Kochanek PM, Marion DW, et al. Mild posttraumatic hypothermia reduces mortality after severe controlled cortical impact in rats. J Cereb Blood Flow Metab 1996;16:253–61. [6] Koizumi H, Povlishock JT. Posttraumatic hypothermia in the treatment of axonal damage in an animal model of traumatic axonal injury. J Neurosurg 1998;89:303–9. [7] Adelson PD, Wisniewski SR, Beca J, et al. Paediatric Traumatic Brain Injury Consortium. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol 2013;12:546–53. [8] Andrews PJ, Sinclair HL, Rodriguez A, et al. Eurotherm3235 trial collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015;373:2403–12. [9] Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;22:556–63. [10] Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011;10:131–9. [11] Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;5:2447–56. [12] McIntyre LA, Fergusson DA, Hébert PC, et al. Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003;11:2992–9. [13] Monro A. Observations on the structures and functions of the nervous system. Edinburgh: W. Creech; 1783. [14] Kellie G. An account with some reflections on the pathology of the brain. Edinburgh Med Chir Soc Trans 1824;1:84–169. [15] Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the injured brain: more harm than benefit. Crit Care Med 2010;38:1348–59.
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Please cite this article in press as: Honeybul S. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.01.002