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Reconsidering the role of decompressive craniectomy for neurological emergencies
Journal of Critical Care 39 (2017) 185–189
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Journal of Critical Care journal homepage: www.jccjournal.org
Reconsidering the role of decompressive craniectomy for neurological emergencies S. Honeybul a,⁎, K.M. Ho b, G.R. Gillett c a b c
Department of Neurosurgery, Sir Charles Gairdner Hospital and Royal Perth Hospital, Western Australia, Australia Department of Intensive Care Medicine and School of Population Health, University of Western Australia, Australia Dunedin Hospital and Otago Bioethics Centre, University of Otago, Dunedin, New Zealand
a r t i c l e
i n f o
Keywords: Decompressive craniectomy Outcome Neurotrauma Ethics
a b s t r a c t Objective: There is little doubt that decompressive craniectomy can reduce mortality. However, there is concern that any reduction in mortality comes at an increase in the number of survivors with severe neurological disability. Method: Over the past decade there have been several randomised controlled trials comparing surgical decompression with standard medical therapy in the context of ischaemic stroke and severe traumatic brain injury. The results of each trial are evaluated. Results: There is now unequivocal evidence that a decompressive craniectomy reduces mortality in the context of “malignant” middle infarction and following severe traumatic brain injury. However, it has only been possible to demonstrate an improvement in outcome by categorizing a mRS of 4 and upper severe disability as favourable outcome. This is contentious and an alternative interpretation is that surgical decompression reduces mortality but exposes a patient to a greater risk of survival with severe disability. Conclusion: It would appear unlikely that further randomised controlled trials will be possible given the significant reduction in mortality achieved by surgical decompression. It may be that observational cohort studies and outcome prediction models may provide data to determine those patients most likely to benefit from surgical decompression. Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decompressive craniectomy for neurological emergencies . . . . . . . . Decompressive craniectomy following ischaemic stroke . . . . . . . . . Decompressive hemicraniectomy following severe traumatic brain injury . The future of decompressive craniectomy . . . . . . . . . . . . . . . . 5.1. Predicting long term outcome following decompressive craniectomy 5.2. Outcome following surgical decompression – what is favourable?. . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The management of patients with severe traumatic brain injury continues to evolve and many therapies that once formed the cornerstone of neurointensive care management are being re-evaluated in the light of clinical evidence for efficacy. For many years, patients were ⁎ Corresponding author at: Consultant Neurosurgeon, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. E-mail address: [email protected] (S. Honeybul).
http://dx.doi.org/10.1016/j.jcrc.2017.03.006 0883-9441/Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.
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routinely hyperventilated [1,2], frequently placed in a barbiturate coma [3,4], or more recently rendered hypothermic [5,6], because it could be clearly demonstrated that these measures consistently reduced intracranial pressure (ICP). Given the strong association between intracranial hypertension and poor outcome [7,8] the rationale was that lowering the intracranial pressure would improve cerebral perfusion, prevent secondary brain injury and therefore improve clinical outcome. However subsequent clinical studies failed to demonstrate clinical benefit and in certain instances, these therapies may have caused harm [1,4,9-11]. Whilst this would seem counterintuitive, studies that
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have investigated the effect that these therapies have on cerebral blood flow, suggest a reason for treatment failure. Notwithstanding the neuroprotective potential of barbiturates and hypothermia [12-15], the mechanism by which these three therapies reduce ICP, is predominantly because of cerebral vasoconstriction and this has been demonstrated by perfusion studies [16-19]. This does not mean that their use has been abandoned, but rather that they are used more selectively and are generally reserved for situations in which the patient is thought unlikely to survive, without therapeutic intervention. A similar re-evaluation may be required for decompressive craniectomy as a treatment for malignant intracranial hypertension, in the light of the results of recent randomised controlled trials. 2. Decompressive craniectomy for neurological emergencies The procedure itself is technically straightforward and first became popular in the early 1970's, predominantly in the context of severe traumatic brain injury (TBI) [20,21] and ischaemic stroke [22]. However, a combination of poor clinical outcomes [23,24] and experimental studies that seemed to suggest that decompression may worsen cerebral oedema, led to its use being almost abandoned in the latter part of that decade [25]. Interest in the procedure returned throughout the 1980s and 1990's and there was a progressive increase in the number of publications reporting surgical intervention, not only in the context of TBI [26,27] and stroke [28,29] but also following other neurological emergencies, such as subarachnoid haemorrhage [30,31], cerebrovenous thrombosis [32,33], severe intracranial infection [34,35], inflammatory demyelination [36,37] and encephalopathy [38,39]. These studies supported the claim that mortality could be reduced and many patients were reported to make a good functional and neurocognitive recovery. However, that was not always the case and there was concern that surgical intervention merely converted death into survival with severe disability and dependency [40]. To address this issue the last decade has seen a number of prospective multicentre randomised controlled trials investigating clinical efficacy of decompressive craniectomy initially in the context of ischaemic stroke [41-43] and more recently in the context severe traumatic brain injury [44,45]. 3. Decompressive craniectomy following ischaemic stroke The evidence obtained from the trials investigating efficacy of decompressive caniectomy in the context of ischaemic stroke, overwhelmingly confirm that the procedure is a lifesaving intervention [41-43]. The pooled analysis of the three European trials that investigated efficacy of decompressive craniectomy in the context of “malignant” middle cerebral artery infarction, in patients under sixty years of age, demonstrated a reduction in mortality from 71% in the medical arm of the trial, to 22% in the surgical arm (Table 1) [46]. However, this reduction in mortality came about as an almost direct result of an increase in the number of patients who survived, with moderately severe disability. The number of survivors with a modified Rankin Scale (mRS) score of 4 (and therefore dependency) was increased from 2% in the medical arm to 31% in the surgical group and the reclassification of this outcome category as favourable, remains controversial [47,48]. The translation of death into survival with severe disability was even more striking in the
DESTINY II trial that investigated decompressive craniectomy for patients over 60 years of age [49]. Of the twenty-seven patients who survived following decompressive craniectomy, only two patients achieved a mRS score of 3 and therefore had some degree of independence. Of the remaining twenty-five patients, there was an equal distribution of patients with a mRS of 4 and five and sixteen of these patients had severe aphasia or neuropsychological problems, such that they were unable to answer a relatively simple question regarding retrospective consent (Table 2) [48]. Overall, these trials confirm the ethical concern that decompressive craniectomy reduces mortality, at the expense of survival with severe disability, especially for patients over sixty years of age. The results of recent randomised controlled trials in the context of severe traumatic brain injury have been similar and should therefore be addressed. 4. Decompressive hemicraniectomy following severe traumatic brain injury The DECRA study investigated the role of early bifrontal decompressive craniectomy in the context of diffuse cerebral swelling and it demonstrated that outcomes were worse in those patients in the surgical arm of the trial [44]. The results of the study evoked considerable debate and one of the key criticisms was that the ICP threshold at which patients were randomised (20 mm Hg for N15 min in the hour), was not representative of current clinical practice (which is to intervene at higher ICP thresholds) [50]. This may be a valid observation, however, it fails to acknowledge the trial hypothesis which was that early decompression, would improve cerebral perfusion, reduce secondary insults and improve clinical outcome. Given the relatively low ICP threshold at which patients were enrolled, it is unsurprising that the trial did not demonstrate a survival benefit, for those patients randomised to the surgical arm of the trial. However, the trial did clearly show that at that ICP threshold, (20 mm Hg for N 15 mins/h), there was insufficient ongoing secondary brain injury and therefore any potential benefit obtained from improved cerebral perfusion, was offset by the increasingly well recognised surgical morbidity. Whilst the patients in the trial may not have been representative of current clinical practice, if the trial had shown benefit these patients would have come to represent the clinical practice of the future, which would have had significant impact on neurosurgery [51]. It is in this regard that the results of the recently published RESCUEicp are particularly pertinent, as it was felt to be more reflective of current clinical practice [45]. The trial compared last-tier secondary decompressive craniectomy, with continued medical management in patients with a higher ICP threshold (25 mm Hg for 1 to 12 h despite maximal medical treatment: except for barbiturates). It was conducted over a ten-year period, between 2004 and 2014. Four hundred and nine patients were randomised, amongst 2008 eligible patients, at 52 centres in 20 countries. The results of the trial demonstrated a clear survival benefit in those patients randomised to surgical decompression and these results were consistent with the results of the stroke trials. There were further similarities, in that this reduction in mortality came as an almost direct result of an increase in the number of survivors in either a vegetative state, or with severe disability. At twelve month
Table 2 DESTINY II trial [49]. Table 1 Pooled analysis from the European randomised controlled trials [46]. mRS
Hemicraniectomy n = 51 patients (%)
Conservative n = 42 patients (%)
6 5 4 3 2
11 pts. (22%) 2 pts. (4%) 16 pts. (31%) 15 pts. (29%) 7 pts. (14%)
30 pts. (71%) 2 pts. (5%) 1 pt. (2%) 8 pts. (19%) 1 pt. (2%)
Amongst 27 patients who had decompressive hemicraniectomy • 2 patients mRS - 3 • 25 patients mRS - 4 or 5; • Sixteen of these patients could not answer a question regarding retrospective consent because of severe aphasia or neuropsychological deficits • Amongst the nine patients that 9 that could answer: • Five said Yes • Four said No
S. Honeybul et al. / Journal of Critical Care 39 (2017) 185–189
follow up, there was a small increase, albeit statistically insignificant in the number of patients with a favourable outcome, from 34.6% in the medical arm of the trial, to 42% (p = 0.12) in the surgical arm of the trial. However, this increase was only possible by including patients with upper levels of severe disability within the favourable category, in a similar fashion to the stroke trials, in which mRS of 4 was deemed favourable. Without this re-categorization, the number of patients who survived with lower moderate disability or better (traditionally a favourable outcome), was very similar (32% favourable in the surgical arm of the trial and 28.5% favourable in the medical arm). Like the DECRA trial, the RESCUEicp trial did not address whether decompression is effective in improving neurological recovery in patients with focal intracerebral contusions as N 80% of those enrolled in the latter trial only had diffuse traumatic brain injury. Overall, the results of these studies represent overwhelming evidence for efficacy of decompressive craniectomy as a lifesaving intervention, by reducing refractory intracranial hypertension. However, surgical intervention will not reverse the pathophysiology of the primary neurological insult and any reduction in mortality comes as a result of survival, with significant disability. The question remains as to whether decompressive craniectomy should continue to be used, especially in those neurological conditions in which there is no trial data available. The fact that there were a significant number of severely disabled survivors implies that an ethically oriented study of acceptability of the survival achieved is needed, before the practice is widely extended, to include the other indications that have been suggested. Such a study would include two types of data: (i) prospective data from patients at risk, who may become candidates for such a procedure, with a careful appraisal of their attitudes or advance wishes in relation to the likely outcomes; and (ii) retrospective appraisals from patients and caregivers, of the results achieved and their assessment of whether they justify a shift in management of the type studied. In that way, an informed basis for clinical guidelines could be formulated and debated, in terms of clinical applicability and acceptability. 5. The future of decompressive craniectomy. It would appear unlikely that further randomised controlled trials comparing surgical decompression with standard medical therapy will be possible, given the significant reduction in mortality that has now been clearly demonstrated. In most institutions, surgical intervention is only performed when patients have either failed, or are in the process of failing medical management and randomising patients in these circumstances, is problematic. This was clearly demonstrated in the RESCUEicp trial, in which 73 of the 196 patients randomised to receive medical therapy were surgically decompressed. Whilst it is difficult to determine the effect this has on the trial interpretation, as the authors stated, the observed treatment effect may be somewhat diluted [44]. In view of these difficulties, an alternative approach may be required when considering ongoing investigation into clinical efficacy of the procedure. It is in this regard that observation cohort studies are useful, to clarify two key issues. Firstly, additional work is required to predict which patients are most likely to benefit from surgical decompression. Secondly, how do competent individuals feel about survival with severe disability. 5.1. Predicting long term outcome following decompressive craniectomy Predicting outcome following severe traumatic brain injury is important, for many reasons. It can form the basis of discussions with family members regarding outcome expectations, the continuation of ongoing management strategies, or in certain circumstances consideration may need to be given to the instigation of palliative treatment. It can also guide clinicians, who sometimes need to make decisions regarding the appropriate allocation, of what can be scarce and expensive resources. However, when considering the decision to perform a
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decompressive craniectomy the ethical imperative to consider prognosis, prior to the clinical decision to intervene is strengthened in the light of the current evidence, not only about the clinical outcomes but also about the wishes of informed people within society. It has now been clearly established, that dichotomising outcome into life or death will fail to recognise that surgical decompression significantly increases the likelihood of survival with severe disability and dependence. This must be incorporated into the decision-making paradigm, when considering whether that outcome would be considered acceptable to the person on whom the procedure is to be performed. Traditionally, prognosis has been considered based on individual clinical parameters such as age, initial post resuscitation conscious level, pupillary reaction and extracranial injuries (a surrogate marker for hypoxia and hypotension). Individual radiological features are also known to have prognostic significance and over the years several mathematical prognostic models have been developed, most of which have been based on relatively small numbers, with limited follow up and have tended to focus on survival as the primary end point [52]. However, improvements in data collection and statistical analysis have enabled the development of sophisticated prediction models that have been based on large patient samples. The CRASH (corticosteroid randomization after significant head injury) collaborators model is one such model [53] that was developed from the data collected on the 10,000 patients in the CRASH trial that investigated the use of steroids following TBI [54]. It is a readily available, user friendly, web-based application that provides a predicted risk of unfavorable outcome at 6 months (favourable outcome is defined by the Glasgow outcome scale of either severely disabled, vegetative state or dead). The model has recently been validated [55] and studies have demonstrated that the predicted percentage risk, can be used as a surrogate index of injury severity with which to stratify patients according to injury severity [56-58] (See Fig. 1). It can be applied to patients who have a primary decompression following evacuation of a mass lesion, or to patients who develop intractable intracranial hypertension and require a secondary decompressive procedure. There are limitations when applying population based data to individual cases [59], however, presenting the data in this fashion, does provide an objective assessment of the most likely outcome following surgical intervention. Once the prediction of an unfavorable outcome is N 80% the most likely outcome if the patient survives is either severe disability or a vegetative state. The authors of the model clearly state the information provided should only be used to support and not replace clinical judgment, however, this type of data presentation may act as prompt to direct discussions regarding realistic outcome expectations and the acceptability or otherwise, of that outcome for the person on whom the procedure is being considered. This leads on the final consideration, regarding the definition of favourable outcome. 5.2. Outcome following surgical decompression – what is favourable? Traditionally, favourable outcome has been defined as 0–3 on the mRS and moderate disability or better on the Glasgow outcome Scale. The implication would appear to be, that the aim of the procedure is to leave survivors with some degree of independence, compatible with what most regard as an acceptable quality of life. However, in the pooled analysis of the three European stroke studies it was stated that “on the basis of increasing experience of long term outcome in patients with a space occupying infarction, most investigators feel obliged to define a score of 4 on the mRS as favourable”. The basis of this obligation is not defined and ethically it seems highly questionable. Based on this recategorization the RESCUEicp investigators went on to include upper severe disability in the definition of favourable outcome. However, this is also contentious. The DESTINY-S investigated the opinion amongst physicians regarding disability and treatment in malignant middle cerebral artery infarction [60]. The study specifically addressed the issue of favourable outcome and whilst there was a relatively poor
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Fig. 1. The prediction of an unfavorable outcome at six months (x axis) and the observed outcome at eighteen months amongst the 144 patients who had had a decompressive craniectomy for intractable intracranial hypertension. Numbers within the bar chart represent absolute patient numbers. (Reproduced by kind permission Journal of Neurosurgery Publishing Group).
response rate, most of those that did respond did not feel that a mRS of 4 was favourable. More recently the ORACLE (Opinion Regarding Acceptable outCome folLowing decompressive hemicraniectomy for ischaemic stroke) study, addressed the issue of consent for decompressive hemicraniectomy amongst a large cohort of healthcare workers, most of whom felt that survival with a mRS of 4 would be unacceptable [61]. That finding concurs with a prior study that investigated the opinion amongst healthcare workers, regarding the acceptability of severe disability following severe TBI [62]. In view of these findings, the time has come for a broader debate, on the goals of surgical intervention and the acceptability or otherwise of ongoing use of a procedure, that in certain circumstances is highly likely to leave a person severely disabled and dependent. This is especially relevant, given the increase in the number of vegetative survivors in the surgical arm of the RESCUEicp trial and the numbers of survivors in the DESTINY II trial who were dependent and unable to communicate. The tangible and intangible cost of these outcomes is considerable and warrants careful deliberation. It must be acknowledged that many of those who survive learn to adapt and accept a level of disability, that they might previously have felt to be unacceptable [63,64]. There is also little doubt that society benefits knowing that considerable efforts are made to protect its members when they are at their most vulnerable [65]. The difficulty comes when it is no longer clear that we are doing the best for an individual by our attempt to rescue, as is the case where we save them to survive with what they may feel to be unacceptable disability. Society may also need to reconsider the value of survival at any cost for one individual if use of the procedure is to continue and perhaps expand to include other pathological conditions. The considerations are not only financial, but also personal and ethical and they require us to exercise well-considered judgment about our actions moral values and responsibilities.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Funding No funding has been received for this work.
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decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke 2007;38:2506–17. Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB, et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurol 2009;8:326–33. Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D'Urso P, et al, the DECRA Trial Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;364:1493–502. Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375:1119–30. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, et al, DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007;6:215–22. Puetz V, Campos CR, Eliasziw M, Hill MD, Demchuk AM, Calgary Stroke Program. Assessing the benefits of hemicraniectomy: what is a favourable outcome? Lancet Neurol 2007;6:580–1. Honeybul S, Ho KM, Gillett G. Outcome following decompressive hemicraniectomy for malignant cerebral infarction: ethical considerations. Stroke 2015;46:2695–8. Jüttler E, Unterberg A, Woitzik J, Bösel J, Amiri H, Sakowitz OW, et al, DESTINY II Investigators. Hemicraniectomy in older patients with extensive middle-cerebralartery stroke. N Engl J Med 2014;370:1091–100. Timmons SD, Ullman JS, Eisenberg HM. Craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;365:373. Honeybul S, Ho KM, Lind CR. What can be learned from the DECRA study. World Neurosurg 2013;79:159–61. Perel P, Edwards P, Wentz R, Roberts I. Systematic review of prognostic models in traumatic brain injury. BMC Med Inform Decis Mak 2006;6:38. Perel P, Arango M, Claydon T, Edwards P, Komolafe E, Poccock S, et al, MRC CRASH Trial Collaborators. Predicting outcome after brain injury: practical prognostic models based on a large cohort of international patients. BMJ 2008;336:425–9. Roberts I, Yates D, Sandercock P, Farrell B, Wassenberg J, Lomas G, et al, CRASH trial collaborators. 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. Honeybul S, Ho KM, Lind CR, Gillett GR. Validation of the CRASH model in the prediction of 18-month mortality and unfavorable outcome in severe traumatic brain injury requiring decompressive craniectomy. J Neurosurg 2014;120:1131–7. Honeybul S, Ho KM, Lind CRP, Gillett GR. The retrospective application of a prediction model to patients who have had a decompressive craniectomy for trauma. J Neurotrauma 2009;26:2179–83. Honeybul S, Ho KM, Lind CRP, Gillett GR. Observed versus predicted outcome for decompressive craniectomy: a population based study. J Neurotrauma 2010;27: 1225–32. Honeybul S, Ho KM. Predicting long-term neurological outcomes after severe traumatic brain injury requiring decompressive craniectomy: a comparison of the CRASH and IMPACT prognostic models. Injury 2016;47:1886–92. Honeybul S, Ho KM, Lind CR, Gillet GR. Decompressive craniectomy for neurotrauma: the limitations of applying an outcome prediction model. Acta Neurochir 2010;152:959–64. Neugebauer H, Creutzfeldt CJ, Hemphill 3rd JC, Heuschmann PU, Jüttler E. DESTINYS: attitudes of physicians toward disability and treatment in malignant MCA infarction. Neurocrit Care 2014;21:27–34. Honeybul S, Ho KM, Blacker DW. ORACLE stroke study: opinion regarding acceptable outcome following decompressive hemicraniectomy for ischemic stroke. Neurosurgery 2016;79:231–6. Honeybul S, Ho K, O'Hanlon S. Access to reliable information about long-term prognosis influences clinical opinion on use of lifesaving intervention. PLoS One 2012;7: e32375. Larach DR, Larach DB, Larach MG. A life worth living: seven years after craniectomy. Neurocrit Care 2009;11:106–11. Honeybul S, Gillett GR, Ho KM, Janzen C, Kruger K. Is life worth living? Decompressive craniectomy and the disability paradox. J Neurosurg 2016;125:775–8. Honeybul S, Gillett GR, Ho KM, Lind CR. Neurotrauma and the rule of rescue. J Med Ethics 2011;37:707–10.
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Reconsidering the role of decompressive craniectomy for neurological emergencies S. Honeybul a,⁎, K.M. Ho b, G.R. Gillett c a b c
Department of Neurosurgery, Sir Charles Gairdner Hospital and Royal Perth Hospital, Western Australia, Australia Department of Intensive Care Medicine and School of Population Health, University of Western Australia, Australia Dunedin Hospital and Otago Bioethics Centre, University of Otago, Dunedin, New Zealand
a r t i c l e
i n f o
Keywords: Decompressive craniectomy Outcome Neurotrauma Ethics
a b s t r a c t Objective: There is little doubt that decompressive craniectomy can reduce mortality. However, there is concern that any reduction in mortality comes at an increase in the number of survivors with severe neurological disability. Method: Over the past decade there have been several randomised controlled trials comparing surgical decompression with standard medical therapy in the context of ischaemic stroke and severe traumatic brain injury. The results of each trial are evaluated. Results: There is now unequivocal evidence that a decompressive craniectomy reduces mortality in the context of “malignant” middle infarction and following severe traumatic brain injury. However, it has only been possible to demonstrate an improvement in outcome by categorizing a mRS of 4 and upper severe disability as favourable outcome. This is contentious and an alternative interpretation is that surgical decompression reduces mortality but exposes a patient to a greater risk of survival with severe disability. Conclusion: It would appear unlikely that further randomised controlled trials will be possible given the significant reduction in mortality achieved by surgical decompression. It may be that observational cohort studies and outcome prediction models may provide data to determine those patients most likely to benefit from surgical decompression. Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decompressive craniectomy for neurological emergencies . . . . . . . . Decompressive craniectomy following ischaemic stroke . . . . . . . . . Decompressive hemicraniectomy following severe traumatic brain injury . The future of decompressive craniectomy . . . . . . . . . . . . . . . . 5.1. Predicting long term outcome following decompressive craniectomy 5.2. Outcome following surgical decompression – what is favourable?. . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The management of patients with severe traumatic brain injury continues to evolve and many therapies that once formed the cornerstone of neurointensive care management are being re-evaluated in the light of clinical evidence for efficacy. For many years, patients were ⁎ Corresponding author at: Consultant Neurosurgeon, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. E-mail address: [email protected] (S. Honeybul).
http://dx.doi.org/10.1016/j.jcrc.2017.03.006 0883-9441/Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.
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routinely hyperventilated [1,2], frequently placed in a barbiturate coma [3,4], or more recently rendered hypothermic [5,6], because it could be clearly demonstrated that these measures consistently reduced intracranial pressure (ICP). Given the strong association between intracranial hypertension and poor outcome [7,8] the rationale was that lowering the intracranial pressure would improve cerebral perfusion, prevent secondary brain injury and therefore improve clinical outcome. However subsequent clinical studies failed to demonstrate clinical benefit and in certain instances, these therapies may have caused harm [1,4,9-11]. Whilst this would seem counterintuitive, studies that
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have investigated the effect that these therapies have on cerebral blood flow, suggest a reason for treatment failure. Notwithstanding the neuroprotective potential of barbiturates and hypothermia [12-15], the mechanism by which these three therapies reduce ICP, is predominantly because of cerebral vasoconstriction and this has been demonstrated by perfusion studies [16-19]. This does not mean that their use has been abandoned, but rather that they are used more selectively and are generally reserved for situations in which the patient is thought unlikely to survive, without therapeutic intervention. A similar re-evaluation may be required for decompressive craniectomy as a treatment for malignant intracranial hypertension, in the light of the results of recent randomised controlled trials. 2. Decompressive craniectomy for neurological emergencies The procedure itself is technically straightforward and first became popular in the early 1970's, predominantly in the context of severe traumatic brain injury (TBI) [20,21] and ischaemic stroke [22]. However, a combination of poor clinical outcomes [23,24] and experimental studies that seemed to suggest that decompression may worsen cerebral oedema, led to its use being almost abandoned in the latter part of that decade [25]. Interest in the procedure returned throughout the 1980s and 1990's and there was a progressive increase in the number of publications reporting surgical intervention, not only in the context of TBI [26,27] and stroke [28,29] but also following other neurological emergencies, such as subarachnoid haemorrhage [30,31], cerebrovenous thrombosis [32,33], severe intracranial infection [34,35], inflammatory demyelination [36,37] and encephalopathy [38,39]. These studies supported the claim that mortality could be reduced and many patients were reported to make a good functional and neurocognitive recovery. However, that was not always the case and there was concern that surgical intervention merely converted death into survival with severe disability and dependency [40]. To address this issue the last decade has seen a number of prospective multicentre randomised controlled trials investigating clinical efficacy of decompressive craniectomy initially in the context of ischaemic stroke [41-43] and more recently in the context severe traumatic brain injury [44,45]. 3. Decompressive craniectomy following ischaemic stroke The evidence obtained from the trials investigating efficacy of decompressive caniectomy in the context of ischaemic stroke, overwhelmingly confirm that the procedure is a lifesaving intervention [41-43]. The pooled analysis of the three European trials that investigated efficacy of decompressive craniectomy in the context of “malignant” middle cerebral artery infarction, in patients under sixty years of age, demonstrated a reduction in mortality from 71% in the medical arm of the trial, to 22% in the surgical arm (Table 1) [46]. However, this reduction in mortality came about as an almost direct result of an increase in the number of patients who survived, with moderately severe disability. The number of survivors with a modified Rankin Scale (mRS) score of 4 (and therefore dependency) was increased from 2% in the medical arm to 31% in the surgical group and the reclassification of this outcome category as favourable, remains controversial [47,48]. The translation of death into survival with severe disability was even more striking in the
DESTINY II trial that investigated decompressive craniectomy for patients over 60 years of age [49]. Of the twenty-seven patients who survived following decompressive craniectomy, only two patients achieved a mRS score of 3 and therefore had some degree of independence. Of the remaining twenty-five patients, there was an equal distribution of patients with a mRS of 4 and five and sixteen of these patients had severe aphasia or neuropsychological problems, such that they were unable to answer a relatively simple question regarding retrospective consent (Table 2) [48]. Overall, these trials confirm the ethical concern that decompressive craniectomy reduces mortality, at the expense of survival with severe disability, especially for patients over sixty years of age. The results of recent randomised controlled trials in the context of severe traumatic brain injury have been similar and should therefore be addressed. 4. Decompressive hemicraniectomy following severe traumatic brain injury The DECRA study investigated the role of early bifrontal decompressive craniectomy in the context of diffuse cerebral swelling and it demonstrated that outcomes were worse in those patients in the surgical arm of the trial [44]. The results of the study evoked considerable debate and one of the key criticisms was that the ICP threshold at which patients were randomised (20 mm Hg for N15 min in the hour), was not representative of current clinical practice (which is to intervene at higher ICP thresholds) [50]. This may be a valid observation, however, it fails to acknowledge the trial hypothesis which was that early decompression, would improve cerebral perfusion, reduce secondary insults and improve clinical outcome. Given the relatively low ICP threshold at which patients were enrolled, it is unsurprising that the trial did not demonstrate a survival benefit, for those patients randomised to the surgical arm of the trial. However, the trial did clearly show that at that ICP threshold, (20 mm Hg for N 15 mins/h), there was insufficient ongoing secondary brain injury and therefore any potential benefit obtained from improved cerebral perfusion, was offset by the increasingly well recognised surgical morbidity. Whilst the patients in the trial may not have been representative of current clinical practice, if the trial had shown benefit these patients would have come to represent the clinical practice of the future, which would have had significant impact on neurosurgery [51]. It is in this regard that the results of the recently published RESCUEicp are particularly pertinent, as it was felt to be more reflective of current clinical practice [45]. The trial compared last-tier secondary decompressive craniectomy, with continued medical management in patients with a higher ICP threshold (25 mm Hg for 1 to 12 h despite maximal medical treatment: except for barbiturates). It was conducted over a ten-year period, between 2004 and 2014. Four hundred and nine patients were randomised, amongst 2008 eligible patients, at 52 centres in 20 countries. The results of the trial demonstrated a clear survival benefit in those patients randomised to surgical decompression and these results were consistent with the results of the stroke trials. There were further similarities, in that this reduction in mortality came as an almost direct result of an increase in the number of survivors in either a vegetative state, or with severe disability. At twelve month
Table 2 DESTINY II trial [49]. Table 1 Pooled analysis from the European randomised controlled trials [46]. mRS
Hemicraniectomy n = 51 patients (%)
Conservative n = 42 patients (%)
6 5 4 3 2
11 pts. (22%) 2 pts. (4%) 16 pts. (31%) 15 pts. (29%) 7 pts. (14%)
30 pts. (71%) 2 pts. (5%) 1 pt. (2%) 8 pts. (19%) 1 pt. (2%)
Amongst 27 patients who had decompressive hemicraniectomy • 2 patients mRS - 3 • 25 patients mRS - 4 or 5; • Sixteen of these patients could not answer a question regarding retrospective consent because of severe aphasia or neuropsychological deficits • Amongst the nine patients that 9 that could answer: • Five said Yes • Four said No
S. Honeybul et al. / Journal of Critical Care 39 (2017) 185–189
follow up, there was a small increase, albeit statistically insignificant in the number of patients with a favourable outcome, from 34.6% in the medical arm of the trial, to 42% (p = 0.12) in the surgical arm of the trial. However, this increase was only possible by including patients with upper levels of severe disability within the favourable category, in a similar fashion to the stroke trials, in which mRS of 4 was deemed favourable. Without this re-categorization, the number of patients who survived with lower moderate disability or better (traditionally a favourable outcome), was very similar (32% favourable in the surgical arm of the trial and 28.5% favourable in the medical arm). Like the DECRA trial, the RESCUEicp trial did not address whether decompression is effective in improving neurological recovery in patients with focal intracerebral contusions as N 80% of those enrolled in the latter trial only had diffuse traumatic brain injury. Overall, the results of these studies represent overwhelming evidence for efficacy of decompressive craniectomy as a lifesaving intervention, by reducing refractory intracranial hypertension. However, surgical intervention will not reverse the pathophysiology of the primary neurological insult and any reduction in mortality comes as a result of survival, with significant disability. The question remains as to whether decompressive craniectomy should continue to be used, especially in those neurological conditions in which there is no trial data available. The fact that there were a significant number of severely disabled survivors implies that an ethically oriented study of acceptability of the survival achieved is needed, before the practice is widely extended, to include the other indications that have been suggested. Such a study would include two types of data: (i) prospective data from patients at risk, who may become candidates for such a procedure, with a careful appraisal of their attitudes or advance wishes in relation to the likely outcomes; and (ii) retrospective appraisals from patients and caregivers, of the results achieved and their assessment of whether they justify a shift in management of the type studied. In that way, an informed basis for clinical guidelines could be formulated and debated, in terms of clinical applicability and acceptability. 5. The future of decompressive craniectomy. It would appear unlikely that further randomised controlled trials comparing surgical decompression with standard medical therapy will be possible, given the significant reduction in mortality that has now been clearly demonstrated. In most institutions, surgical intervention is only performed when patients have either failed, or are in the process of failing medical management and randomising patients in these circumstances, is problematic. This was clearly demonstrated in the RESCUEicp trial, in which 73 of the 196 patients randomised to receive medical therapy were surgically decompressed. Whilst it is difficult to determine the effect this has on the trial interpretation, as the authors stated, the observed treatment effect may be somewhat diluted [44]. In view of these difficulties, an alternative approach may be required when considering ongoing investigation into clinical efficacy of the procedure. It is in this regard that observation cohort studies are useful, to clarify two key issues. Firstly, additional work is required to predict which patients are most likely to benefit from surgical decompression. Secondly, how do competent individuals feel about survival with severe disability. 5.1. Predicting long term outcome following decompressive craniectomy Predicting outcome following severe traumatic brain injury is important, for many reasons. It can form the basis of discussions with family members regarding outcome expectations, the continuation of ongoing management strategies, or in certain circumstances consideration may need to be given to the instigation of palliative treatment. It can also guide clinicians, who sometimes need to make decisions regarding the appropriate allocation, of what can be scarce and expensive resources. However, when considering the decision to perform a
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decompressive craniectomy the ethical imperative to consider prognosis, prior to the clinical decision to intervene is strengthened in the light of the current evidence, not only about the clinical outcomes but also about the wishes of informed people within society. It has now been clearly established, that dichotomising outcome into life or death will fail to recognise that surgical decompression significantly increases the likelihood of survival with severe disability and dependence. This must be incorporated into the decision-making paradigm, when considering whether that outcome would be considered acceptable to the person on whom the procedure is to be performed. Traditionally, prognosis has been considered based on individual clinical parameters such as age, initial post resuscitation conscious level, pupillary reaction and extracranial injuries (a surrogate marker for hypoxia and hypotension). Individual radiological features are also known to have prognostic significance and over the years several mathematical prognostic models have been developed, most of which have been based on relatively small numbers, with limited follow up and have tended to focus on survival as the primary end point [52]. However, improvements in data collection and statistical analysis have enabled the development of sophisticated prediction models that have been based on large patient samples. The CRASH (corticosteroid randomization after significant head injury) collaborators model is one such model [53] that was developed from the data collected on the 10,000 patients in the CRASH trial that investigated the use of steroids following TBI [54]. It is a readily available, user friendly, web-based application that provides a predicted risk of unfavorable outcome at 6 months (favourable outcome is defined by the Glasgow outcome scale of either severely disabled, vegetative state or dead). The model has recently been validated [55] and studies have demonstrated that the predicted percentage risk, can be used as a surrogate index of injury severity with which to stratify patients according to injury severity [56-58] (See Fig. 1). It can be applied to patients who have a primary decompression following evacuation of a mass lesion, or to patients who develop intractable intracranial hypertension and require a secondary decompressive procedure. There are limitations when applying population based data to individual cases [59], however, presenting the data in this fashion, does provide an objective assessment of the most likely outcome following surgical intervention. Once the prediction of an unfavorable outcome is N 80% the most likely outcome if the patient survives is either severe disability or a vegetative state. The authors of the model clearly state the information provided should only be used to support and not replace clinical judgment, however, this type of data presentation may act as prompt to direct discussions regarding realistic outcome expectations and the acceptability or otherwise, of that outcome for the person on whom the procedure is being considered. This leads on the final consideration, regarding the definition of favourable outcome. 5.2. Outcome following surgical decompression – what is favourable? Traditionally, favourable outcome has been defined as 0–3 on the mRS and moderate disability or better on the Glasgow outcome Scale. The implication would appear to be, that the aim of the procedure is to leave survivors with some degree of independence, compatible with what most regard as an acceptable quality of life. However, in the pooled analysis of the three European stroke studies it was stated that “on the basis of increasing experience of long term outcome in patients with a space occupying infarction, most investigators feel obliged to define a score of 4 on the mRS as favourable”. The basis of this obligation is not defined and ethically it seems highly questionable. Based on this recategorization the RESCUEicp investigators went on to include upper severe disability in the definition of favourable outcome. However, this is also contentious. The DESTINY-S investigated the opinion amongst physicians regarding disability and treatment in malignant middle cerebral artery infarction [60]. The study specifically addressed the issue of favourable outcome and whilst there was a relatively poor
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Fig. 1. The prediction of an unfavorable outcome at six months (x axis) and the observed outcome at eighteen months amongst the 144 patients who had had a decompressive craniectomy for intractable intracranial hypertension. Numbers within the bar chart represent absolute patient numbers. (Reproduced by kind permission Journal of Neurosurgery Publishing Group).
response rate, most of those that did respond did not feel that a mRS of 4 was favourable. More recently the ORACLE (Opinion Regarding Acceptable outCome folLowing decompressive hemicraniectomy for ischaemic stroke) study, addressed the issue of consent for decompressive hemicraniectomy amongst a large cohort of healthcare workers, most of whom felt that survival with a mRS of 4 would be unacceptable [61]. That finding concurs with a prior study that investigated the opinion amongst healthcare workers, regarding the acceptability of severe disability following severe TBI [62]. In view of these findings, the time has come for a broader debate, on the goals of surgical intervention and the acceptability or otherwise of ongoing use of a procedure, that in certain circumstances is highly likely to leave a person severely disabled and dependent. This is especially relevant, given the increase in the number of vegetative survivors in the surgical arm of the RESCUEicp trial and the numbers of survivors in the DESTINY II trial who were dependent and unable to communicate. The tangible and intangible cost of these outcomes is considerable and warrants careful deliberation. It must be acknowledged that many of those who survive learn to adapt and accept a level of disability, that they might previously have felt to be unacceptable [63,64]. There is also little doubt that society benefits knowing that considerable efforts are made to protect its members when they are at their most vulnerable [65]. The difficulty comes when it is no longer clear that we are doing the best for an individual by our attempt to rescue, as is the case where we save them to survive with what they may feel to be unacceptable disability. Society may also need to reconsider the value of survival at any cost for one individual if use of the procedure is to continue and perhaps expand to include other pathological conditions. The considerations are not only financial, but also personal and ethical and they require us to exercise well-considered judgment about our actions moral values and responsibilities.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Funding No funding has been received for this work.
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