Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Qatar Clinical Neuroscience Conference
What is wrong with the tenets underpinning current management of severe traumatic brain injury? Randall M. Chesnut Departments of Neurological Surgery and Orthopaedics and Sports Medicine, Harborview Medical Center, School of Medicine, and School of Global Health, University of Washington, Seattle, Washington Address for correspondence: Randall M. Chesnut, M.D., F.C.C.M., F.A.C.S., Department of Neurological Surgery, Harborview Medical Center, Mailstop 359766, 325 Ninth Ave., Seattle, Washington 98104-2499. [email protected]
The results of a recent randomized controlled trial comparing intracranial pressure (ICP) monitor–based treatment of severe traumatic brain injury (sTBI) to management without ICP monitoring prompt this skeptical reconsideration of the scientific foundation underlying current sTBI management. Much of current practice arises from research performed under conditions that are no longer relevant today. The definition of an episode of intracranial hypertension is incomplete, and the application of a fixed, universal ICP treatment threshold is poorly founded. Although intracranial hypertension is a valid indicator of disease severity, it remains to be demonstrated that lowering ICP improves outcome. Furthermore, sTBI has not been categorized on the basis of underlying pathophysiology despite the current capability to do so. Similar concerns also apply to manipulation of cerebral perfusion with respect to maintaining universal thresholds for contrived variables rather than tailoring treatment to monitored processes. As such, there is a failure to either optimize management approaches or minimize associated treatment risks for individual sTBI patients. The clinical and research TBI communities need to reassess many of the sTBI management concepts that are currently considered well established. Keywords: traumatic brain injury; intracranial pressure; intracranial hypertension; cerebral perfusion pressure; cerebral pressure autoregulation; neurological critical care
Introduction The purpose of this article is to present an alternative and skeptical look at many of the tenets that are held fundamental in the management of severe traumatic brain injury (sTBI), starting with intracranial pressure (ICP). Many clinicians and researchers have recently had their clinical opinions shaken by the publication of a randomized controlled trial (RCT) that suggested that guideline-based, ICP monitor– driven management did not produce outcomes superior to those achieved through aggressive treatment based on serial imaging and clinical examination without ICP monitoring.1 Although the ICP monitor–based approach produced satisfactory outcomes with significantly greater efficiency, the fact that the outcomes were not improved with monitoring was surprising and disappointing. Why did the most commonly recommended ICP monitor–
based treatment approach not produce the expected superiority in recovery? ICP monitoring and management Regarding the evolution of the current status of sTBI management, sTBI was essentially divided into two categories in the 1950s and early 1960s. The first category was treatable brain injury, consisting of patients with intracranial mass lesions amenable to surgical evacuation. The other, larger group was essentially untreatable because it did not include surgical pathology. Indeed, those patients with surgical options were shifted into the latter group following surgery. Other than basic support, the recovery became similar to a natural history study. Subsequently, primarily driven by the emergence of ICP monitoring, the treatable and untreatable sTBI cohorts were merged into a single category (i.e., doi: 10.1111/nyas.12482
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treatable sTBI), where there was a treatment strategy applicable to all patients. The advent of ICP monitoring was associated with, and attributed to, an approximately 50% decrease in the mortality, and an associated decrease in morbidity, from sTBI.2–4 However, it is necessary to examine such attribution more closely. The adoption of ICP monitoring had many influences. As noted above, it integrated all sTBI into the treatable category. It also invoked medical management of ICP and all of its ramifications. On a wider scale, the involvement of neurocritical care in an intensive care unit (ICU) setting pari passu included intensive care management of systemic variables, ranging from oxygenation and ventilation through infectious disease and nutrition. Over the same time course of the adoption of ICP monitoring, numerous developments were occurring in the areas of prehospital care, emergency department management, trauma surgery, and rehabilitation, and one of the most important developments in TBI treatment was becoming readily available—computed tomography (CT) imaging. Therefore, although the improvement in sTBI outcome tends to be attributed to ICP monitoring, the proper attribution is to an amalgamation of all of the above. Differentiating the contribution of any one element to this change requires an RCT. However, the only published RCT to date did not show the expected association of improved outcome with ICP monitor–based treatment, suggesting that ICP monitoring is not independently responsible for many of the beneficial changes attributed to it. To a great extent, the current concept of ICP has become oversimplified. Succinctly put, it can be summarized as “less than 20 mmHg is good and greater than 20 mmHg is bad.” That such a gross oversimplification closely resembles commonly held dogma is concerning. The evolution of current ICP treatment is largely based on practice and research from the late 1960s through the early 1990s, as exemplified in publications from the Traumatic Coma Databank.3,5–13 It is notable, however, that during this period there was concern that elevated systolic blood pressure drove intracranial hypertension and therefore much effort was directed toward “keeping the patient dry” and minimizing fluid resuscitation. Such under-resuscitation resulted in the routine maintenance of mean arterial pressures (MAPs) at approximately 70 mmHg. The MAP interacts with the
What is wrong with current brain injury management?
lower breakpoint of cerebral pressure autoregulation, which is approximately 50 mmHg, according to the cerebral perfusion pressure (CPP) calculation CPP = MAP – ICP. This means that, when MAPs are maintained around 70 mmHg and CPPs below 50 mmHg bring increased risk of ischemia, ICPs greater than 20 mmHg will risk cerebral hypoperfusion. Under current management schemes, however, MAP is managed to keep the CPP greater than 60 mmHg. As a result, sTBI patients tend to have MAPs closer to 90 mmHg. In addition, modern ICU sedative management of sTBI patients frequently involves agents, such as propofol or dexmedatomidine, that lower the cerebral metabolic rate, therefore decreasing the ischemic risks of CPPs below 50 mmHg. Under current management, the necessity of maintaining an ICP less than 20 mmHg for the purposes of avoiding cerebral ischemia is greatly lessened. It must be remembered that ICP is an epiphenomenon, reflecting a large variety of nonexclusive underlying pathophysiological processes. There are many pathways to an ICP of 30 mmHg. Differentiating these pathways requires the use of different tests and monitors, and managing them requires different treatments. It is unlikely that our current approach of treating all sTBI patients in a similar fashion is consistent with such concepts. The ICP threshold of 20 mmHg is highly deserving of questioning. Despite conducting several thorough literature searches, the author of this article was unable to determine the origin of the adoption of this ICP threshold into sTBI management. The use of a single value is not trivial. Is it actually expected that the same threshold be used for all injuries? Should the diffusely swollen brain be treated at the same threshold as the brain following evacuation of a subdural hematoma? Should a 15-year-old patient have the same threshold as a 60-year-old patient? In addition, is it reasonable to believe that the ICP threshold is constant over the duration of treatment, not varying with recovery time and serial management? With respect to the interaction of duration and threshold, is an ICP greater than 20 mmHg for 10 min the same as an ICP greater than 30 mmHg for 2 minutes? Although maintenance of CPP is critical, maintaining a target value does not require an absolute threshold of ICP. Frank and open examination of the underpinnings of such current management concepts adds further weight
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to the idea that we have vastly oversimplified the understanding and management of ICP. With respect to the ICP treatment threshold, it must be remembered that modern studies that have attempted to determine the critical threshold have used data derived from patients who were concomitantly being treated using a particular threshold value.10,14–17 For obvious reasons, there have been no natural history studies. Unfortunately, there have been no sufficiently powered, randomized investigations of the effects of using different ICP treatment thresholds on outcome. Therefore, although many studies have supported 20–25 mmHg as a relevant threshold, they have been confounded by the above factors to the extent of not being definitive. These difficulties are reflected in the analysis of a recent paper that suggests that the response to ICP management predicts outcome from sTBI.18 This paper retrospectively reviewed 388 patients who received an ICP monitor, and the definition of intracranial hypertension was an ICP > 25 mmHg for 1 h or more. These patients received at least one treatment for ICP over the first 3 days and were examined for 2-week survival. It was found that the 2-week mortality rate was significantly improved in those patients who responded to ICP management. In addition, a regression analysis toward determining the predictors of 2-week mortality found that a positive response to ICP treatment was independently predictive. The authors concluded that lowering ICP improves outcome. Unfortunately, the definitions used in this paper make such a result almost self-fulfilling; the definition of intracranial hypertension involved a fairly mild dose of elevated ICP, which put a large collection of patients into the group requiring treatment. The responders group included only those patients who had 0 h of ICP > 25 mmHg following treatment, while the rest were placed into the nonresponders group, as were those patients dying within 3 days posttreatment. The result of such definitions is that almost any patient with a TBI of any degree of severity would be categorized into the nonresponders group. On closer analysis, therefore, this paper most likely examined the association of the severity of injury with outcome and does not provide strong evidence that a response to ICP management per se is anything other than an indicator of TBI severity. This paper illustrates not only the tenuousness of the belief that managing ICP strongly influences outcome, but also 76
demonstrates the difficulties of carrying out such research. If the pathophysiological events thought to underlie sTBI are closely examined with respect to the treatments that are currently used to manage intracranial hypertension, none of the treatments specifically address pathophysiological processes (Fig. 1). Their use is phenomenologically based on their influence on intracranial hypertension, meaning that they are focused on avoiding secondary insults rather than treating primary brain injury. Although this is very important and has resulted in remarkable improvement in recovery from sTBI, it also implies that none of these treatments are absolutely necessary in the treatment of sTBI in general. Therefore, the concept of primum non nocere must be kept in mind when choosing treatment modalities, and in attempting to improve recovery, avoiding overtreatment is important. One fundamental problem relates to a method of defining an event of intracranial hypertension. As noted above, the most common method is to define it as any reading above a set threshold.4,15,18,19 The speciousness of this definition is suggested by the likelihood that any given non-sTBI individual will exceed such a threshold several times per day during the course of routine daily activities and will not require treatment or suffer related untoward consequences. Some studies have used a closely defined time above a given value,20 whereas others have used a more loosely defined duration.21 One commonly quoted threshold determination report normalized time above a set threshold by dividing it by the total duration of monitoring.10 Another approach was used in a randomized barbiturate trial where the duration was linked to the degree of ICP elevation.22 Finally, more recently, an entirely different approach has been used involving the examination of the area under the ICP curve over given time intervals.23–25 The upshot is that an impressive number of definitions of an event of intracranial hypertension have been used, without one having been shown to be physiologically superior. This leaves in question not only the definition of a threshold value but also the definition of intracranial hypertension dose. It is also important to examine the data that have been used in the studies underlying our understanding of ICP. Recent studies have used automated high-resolution systems, which greatly expand our analytic capabilities. In general, however, most
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Figure 1. Contrast between a list (incomplete) of pathophysiological processes involved in sTBI and current, commonly used treatment modalities. In addition, some of the toxicities associated with these treatments are illustrated.
studies have used intermittent measurement, most commonly at a frequency of 1 hour. The most widespread approach has been to request that the nurse record end-hour ICP. However, it is clinically much more frequent that nurses record an hourly value that they think reflects the previous hour. Alternatively, they may use various summary measures provided by vendor display units. Once such variability is examined openly, the lack of standardization is concerning. Further magnifying the problem is that the method of recording is not specified in the majority of published ICP studies. As such, in most reports, the precise definition of the data on which we are basing our analyses is unknown. In summary, ICP research has been remarkably nonrigorous to date, casting our scientific foundation into question. We are still far from a complete scientific understanding of how ICP reflects the spectrum of injury-induced pathophysiology in a given patient, at a given time, by a specific type of TBI. CPP monitoring and management A similar skepticism can be profitably applied to our current concepts of CPP. When CPP became popularized in the 1980s and 1990s, the initial response was to push the target thresholds quite high to, for example, 80–90 mmHg. An RCT of ICP-based versus CPP-based management tempered this initial response by showing that the benefits of CPP-based treatment to the injured brain were eliminated as a result of systemic toxicity of treatments when the
CPP threshold was greater than 70 mmHg.26 This not only throttled back the eagerness to elevate CPP, but also again illustrated the systemic toxicity of brain-specific treatments. The hallmark paper supporting CPP-based management was by Rosner et al.,27 a prospective observational study of 747 patients collected during the late 1980s. They compared the outcome of patients treated with elevated CPP to a control group derived from the Traumatic Coma Data Bank and showed that CPP-directed treatment was associated with lower mortality and improved recovery, which was interpreted as strong support for this treatment approach. However, the effects of CPP treatment are not simple. There is a large body of data establishing that one of the strongest predictors of poor outcome from sTBI is systemic hypotension, particularly during the early stages following injury.28–30 It is notable that the maintenance of MAP at an elevated threshold has the indirect but potentially important consequence of making it less likely that early swings in blood pressure should reflect systemic hypotension. Therefore, the question becomes whether the influence of CPP is simply that of avoiding hypotension or if there is an added benefit to higher values. When a comparison group that did not have CPP management, but also did not have in-hospital episodes of hypotension, is extracted from the Traumatic Coma Data Bank, a comparison of the outcomes of this cohort to Rosner’s CPP-based management group reveals an elimination of any differences (Fig. 2).31
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Figure 2. Comparison of reported outcomes of sTBI patients treated with aggressive CPP-based therapy27 (n = 158) versus two groups from the Trauma Coma Data Bank (TCDB), neither of which were treated according to CPP. One group was unselected (TCDB, n = 746)3 and the other consisted of a subset of TCDB patients who did not have in-hospital hypotension (systolic blood pressure (SBP) < 90 mmHg; TCDB, no late hypotension; n = 337).31 Reproduced, with permission, from Chesnut et al.31
The suggestion, therefore, is that the major influence of CPP management may simply be the avoidance of cerebral ischemia, which is a threshold effect, without implying marginal benefits from further elevation. This is consistent with the study by Downard et al. that looked at mean CPP over the first 48 posttraumatic hours in a cohort of pediatric TBI patients.32 They found that, although mortality was 100% for those patients whose mean 48-h CPP was less than 40 mmHg, there was no difference associated with serial increases in mean CPP above that value. This again suggests that a large part of the benefit of CPP-based management results simply from the avoidance of transient cerebral hypoperfusion related to systemic hypotension. In light of the demonstrated systemic toxicity of routinely maintaining CPP at values greater than 70 mmHg,26 the relevance of the concept of primum non nocere to understanding the benefit of CPP management is well illustrated. Similarly to ICP concepts, our current approach to CPP management appears much less secure than commonly thought. Finally, differences in the level at which the MAP is zeroed for CPP calculation render the use of treatment thresholds sensitive to measurement inconsistencies on the order of 10 mmHg. Given the reported wide clinical variability in setting the zero point, and the rarity with which the technique used is reported in studies cited in developing CPP treat-
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ment guidelines,33 the solution to this discrepancy does not readily appear in the current literature.34 Cerebral pressure autoregulation following sTBI Another aspect worthy of critical analysis is the concept that cerebral pressure autoregulation is disrupted in the majority of sTBI patients. The normal brain closely regulates cerebral blood flow (CBF) over a wide range of CPPs (Fig. 3). Between the low end of approximately 50 mmHg and a less welldefined upper end of approximately 150 mmHg, CBF is maintained fairly constant because of reflex cerebral vasoconstriction in response to CPP elevation. Below approximately 50 mmHg, the vessels are maximally dilated, and there is no reserve, which means that CBF falls as CPP decreases further. In this range, the risk of ischemia rises as CPP decreases. (What occurs above 150 mmHg is less well defined and not really relevant to this discussion.) Critically, over the zone of active pressure autoregulation, the brain “takes care of itself ” with respect to matching CPP to its needs. The instance of disrupted autoregulation occurs when the cerebral vasoconstriction response to elevated CPP is lost. This creates a pressure—a passive system in which CBF is directly proportional to CPP. The vessels serially dilate as CPP increases,
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Figure 3. Intact and disrupted cerebral pressure autoregulation. The solid line represents intact pressure autoregulation, where CBF is maintained over the CPP range from 50 to 150 mmHg by active vasoconstriction, failing outside of these values. The dashed line represents completely disrupted autoregulation, where CBF is pressure passive (directly dependent on CPP), and cerebral blood volume and ICP increases in parallel with CPP. The illustrations at the top represent cross-sectional vascular profiles for both conditions.
which means that cerebral blood volume increases, thereby driving up ICP. In this case, there is no zone in which “the brain takes care of itself.” Elevating the CPP improves CBF and makes it less likely that metabolic needs will be unmet, but also results in elevated ICP, which may itself impede perfusion or result in cerebral herniation. Low CPPs will be associated with low CBF and a much higher risk of ischemia. Therefore, the status of cerebral pressure autoregulation is a critical determinant of how CPP should be manipulated following sTBI. As noted above, it is commonly thought that pressure autoregulation is frequently disrupted following sTBI. Sviri et al. reported that cerebral pressure autoregulation was disrupted in 83% of patients during postinjury days 3–5 and in 54% of patients during postinjury days 9–11;35 this has serious implications for treatment, as discussed above. However, further understanding of the different components of cerebral pressure autoregulation, and examination of the methods used to measure autoregulation in such reports, may lead to a differ-
ent conclusion. Dynamic cerebral pressure autoregulation is the rapid, transient ability of the vessel caliber to respond to changes in blood pressure. The rapidity of this response can be measured by inflating and then quickly deflating large blood pressure cuffs on the thighs of patients, while concomitantly measuring the flow velocity of the middle cerebral arteries using transcranial doppler. When the cuffs are deflated, there is a transient drop in blood pressure, followed by a rapid recovery. If one convolutes the rapidity of the recovery of the transcranial doppler flow velocity against the blood pressure response, one can determine the status of dynamic pressure autoregulation in a quantitative manner. This status can range from hyperreactive through hyporeactive, all the way to absent. Static cerebral pressure autoregulation, as previously discussed, is measured over the course of minutes or more and reflects the overall capacity of the vessels to maintain CBF over variable CPP values. One method of testing this is to iatrogenically alter the CPP and measure the CBF response
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Figure 4. Status of static and dynamic pressure autoregulation in 83 sTBI patients measured within 48 h of trauma, showing that they are not equally disrupted following trauma.36 Note the absence of the group “intact dynamic, disrupted static,” which is consistent with dynamic autoregulation being the mechanism of static autoregulation.
over the ensuing minutes, using either CT perfusion or transcranial doppler. If elevating the CPP is not associated with a change in CBF, cerebral static pressure autoregulation is interpreted as intact. If, in contrast, elevating the CPP results in an elevation of CBF, this implies that cerebral pressure autoregulation is dysfunctional over that range of CPP. When static and dynamic cerebral pressure autoregulation are measured within the same patient, it has been demonstrated that dynamic autoregulation may be disrupted without necessarily being associated with abnormal static autoregulation. A study by Peterson and Chesnut suggested that dynamic autoregulation was abnormal in 88% of sTBI patients but that static autoregulation remained relatively intact in 60% (Fig. 4).36 Therefore, it is important to determine whether static or dynamic pressure autoregulation is being measured when planning the treatment of a given patient. When looking carefully at the study by Sviri et al., the thigh cuff method was used to measure pressure autoregulation, implying that their results pertain to dynamic pressure autoregulation and should not be interpreted as implying concomitant disruption of static pressure autoregulation. Peterson et al. suggests that the frequency of static pressure autoregulation disruption is much lower, implying that, in the majority of sTBI patients, merely keeping the CPP within the zone will allow the brain to manage its own CBF through static pressure autoregulation. This greatly simplifies management and implies that exuberant CPP elevation is not required. In the significantly smaller group of patients in which static
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pressure autoregulation specifically is found to be disrupted, assiduous CPP management on the basis of multimodality monitoring will be required in order to balance the risk of ischemia against treatment toxicity. Clearly, however, the commonly held concept that cerebral pressure autoregulation is disrupted in the vast majority of sTBI patients requires reconsideration in a similar fashion to that suggested for ICP and CPP. Caveat This highly skeptical presentation of a neurotrauma dystopia is not meant to imply that our present concepts are unfounded or incorrect, that current management approaches are ineffective, or that we should immediately radically alter our treatments for sTBI. The progress that has been made over the past four decades in decreasing the morbidity and mortality from this disease stands on its own and many of the treatments used (such as surgical evacuation of acute intracranial hematomas) will certainly remain critical despite their lack of RCT support. Nevertheless, unexpected recent study results37–39 prompt a skeptical review of current concepts and consideration of the possibility that modified or alternative approaches may provide equal or superior benefit. One such approach is the concept of targeting interventions and treatment thresholds at subgroups of sTBI patients on the basis of multimodality monitoring using refined analytic methods. It is intended that the skepticism contained in this analysis should strengthen many current concepts by attempting to highlight areas where
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incomplete assumptions may have mislead clinicians. Most of the current practices will likely survive such re-analysis and be stronger as a result of it. However, new concepts can only be built if there is confidence in the foundation, and nothing destroys confidence like follow-up. Summary Therefore, cerebral pressure autoregulation, ICP, and CPP should currently be viewed as inadequately defined and requiring more work. The importance of such skepticism is illustrated historically by the total reversal of the fortunes of steroid use, maintaining low MAPs following injury, and restricting fluid resuscitation following sTBI. All of these once popular and dogmatically supported concepts have fallen by the wayside. Our current, reoriented approach can be characterized as seeking normovolemia, normothermia, maintaining normal partial pressure of carbon dioxide (PaCO2 ) and partial pressure of oxygen (PaO2 ), euglycemia, promoting adequate nutrition, titrating CPP and ICP thresholds to individual patients, and minimizing iatrogenic injury. An obvious theme here is that of maintaining a normal milieu internal, where the injured brain may recover, in contradistinction to our frequently misguided exuberance toward overtreatment. It must be recalled that none of our current treatment modalities for sTBI are conditiones sine quibus non for recovery. Therefore, the use of individual agents, as well as the targeting of specific or rigorous treatment thresholds, must be judiciously balanced against the potential for iatrogenic injury. Until we have much improved data on how to tailor therapy and target treatments for individual cases, the risk of overtreating patients in search of poorly supported goals must be taken to heart. It is recognized that this article is extremely skeptical, but it is offered to suggest that a logical analysis of many of our current concepts readily invalidates any tendencies toward being dogmatic and illustrates the need for further research. It will be important to delineate how to tailor therapies to individual patients using multimodality monitoring in order to optimize the risk–benefit ratio of treatment in individual cases.40 Conflicts of interest The author declares no conflicts of interest.
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19. Saul, T.G. & T.B. Ducker. 1982. Intracranial pressure monitoring in patients with severe head injury. Am. Surg. 48: 477–480. 20. Cooper, D.J. et al. 2011. Decompressive craniectomy in diffuse traumatic brain injury. N. Engl. J. Med. 364: 1493–1502. 21. Hutchinson, P.J. et al. 2006. Decompressive craniectomy in traumatic brain injury: the randomized multicenter RESCUEicp study. Acta Neurochir. Suppl. 96: 17–20. 22. Eisenberg, H.M. et al. 1988. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J. Neurosurg. 69: 15–23. 23. Kahraman, S. et al. 2010. Heart rate and pulse pressure variability are associated with intractable intracranial hypertension after severe traumatic brain injury. J. Neurosurg. Anesthesiol. 22: 296–302. 24. Lazaridis, C. et al. 2014. Patient-specific thresholds of intracranial pressure in severe traumatic brain injury. J. Neurosurg. 120: 893–900. 25. Vik, A. et al. 2008. Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury. J. Neurosurg. 109: 678–684. 26. Robertson, C.S. et al. 1999. Prevention of secondary ischemic insults after severe head injury. Crit. Care Med. 27: 2086– 2095. 27. Rosner, M.J., S.D. Rosner & A.H. Johnson. 1995. Cerebral perfusion pressure: management protocol and clinical results. J. Neurosurg. 83: 949–962. 28. Bullock, R. et al. 2000. Guidelines for the management and prognosis of severe head injury—hypotension. J. Neurotrauma 17: 591–595. 29. Chesnut, R.M. et al. 1993. The role of secondary brain injury in determining outcome from severe head injury. J. Trauma 34: 216–222.
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30. Miller, J.D. & D.P. Becker. 1982. Secondary insults to the injured brain. J. R. Coll. Surg. (Edinburgh). 27: 292–298. 31. Chesnut, R.M. 1996. Avoidance of hypotension: the Conditio Sine Qua Non of successful severe head injury management. J. Trauma 42: S45–S52. 32. Downard, C. et al. 2000. Relationship of cerebral perfusion pressure and survival in pediatric brain-injured patients. J. Trauma 49: 654–658; discussion 658–659. 33. Bratton, S.L. et al. 2007. Guidelines for the management of severe traumatic brain injury. J. Neurotrauma 24: S1–S106. 34. Rao, V. et al. 2013. Confusion with cerebral perfusion pressure in a literature review of current guidelines and survey of clinical practise. Scand. J. Trauma Resusc. Emerg. Med. 21: 78. 35. Sviri, G.E. et al. 2009. Time course for autoregulation recovery following severe traumatic brain injury. J. Neurosurg. 111: 695–700. 36. Peterson, E. & R.M. Chesnut. 2009. Static autoregulation is intact in majority of patients with severe traumatic brain injury. J. Trauma 67: 944–949. 37. Chesnut, R.M. et al. 2012. A trial of intracranial-pressure monitoring in traumatic brain injury. N. Engl. J. Med. 367: 2471–2481. 38. Cremer, O.L. et al. 2005. Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit. Care Med. 33: 2207–2213. 39. Shafi, S. et al. 2008. Intracranial pressure monitoring in brain-injured patients is associated with worsening of survival. J. Trauma 64: 335–340. 40. Chesnut, R.M. 2015. A conceptual approach to managing severe traumatic brain injury in a time of uncertainty. Ann. N.Y. Acad. Sci. 1345: 99–107.
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Qatar Clinical Neuroscience Conference
What is wrong with the tenets underpinning current management of severe traumatic brain injury? Randall M. Chesnut Departments of Neurological Surgery and Orthopaedics and Sports Medicine, Harborview Medical Center, School of Medicine, and School of Global Health, University of Washington, Seattle, Washington Address for correspondence: Randall M. Chesnut, M.D., F.C.C.M., F.A.C.S., Department of Neurological Surgery, Harborview Medical Center, Mailstop 359766, 325 Ninth Ave., Seattle, Washington 98104-2499. [email protected]
The results of a recent randomized controlled trial comparing intracranial pressure (ICP) monitor–based treatment of severe traumatic brain injury (sTBI) to management without ICP monitoring prompt this skeptical reconsideration of the scientific foundation underlying current sTBI management. Much of current practice arises from research performed under conditions that are no longer relevant today. The definition of an episode of intracranial hypertension is incomplete, and the application of a fixed, universal ICP treatment threshold is poorly founded. Although intracranial hypertension is a valid indicator of disease severity, it remains to be demonstrated that lowering ICP improves outcome. Furthermore, sTBI has not been categorized on the basis of underlying pathophysiology despite the current capability to do so. Similar concerns also apply to manipulation of cerebral perfusion with respect to maintaining universal thresholds for contrived variables rather than tailoring treatment to monitored processes. As such, there is a failure to either optimize management approaches or minimize associated treatment risks for individual sTBI patients. The clinical and research TBI communities need to reassess many of the sTBI management concepts that are currently considered well established. Keywords: traumatic brain injury; intracranial pressure; intracranial hypertension; cerebral perfusion pressure; cerebral pressure autoregulation; neurological critical care
Introduction The purpose of this article is to present an alternative and skeptical look at many of the tenets that are held fundamental in the management of severe traumatic brain injury (sTBI), starting with intracranial pressure (ICP). Many clinicians and researchers have recently had their clinical opinions shaken by the publication of a randomized controlled trial (RCT) that suggested that guideline-based, ICP monitor– driven management did not produce outcomes superior to those achieved through aggressive treatment based on serial imaging and clinical examination without ICP monitoring.1 Although the ICP monitor–based approach produced satisfactory outcomes with significantly greater efficiency, the fact that the outcomes were not improved with monitoring was surprising and disappointing. Why did the most commonly recommended ICP monitor–
based treatment approach not produce the expected superiority in recovery? ICP monitoring and management Regarding the evolution of the current status of sTBI management, sTBI was essentially divided into two categories in the 1950s and early 1960s. The first category was treatable brain injury, consisting of patients with intracranial mass lesions amenable to surgical evacuation. The other, larger group was essentially untreatable because it did not include surgical pathology. Indeed, those patients with surgical options were shifted into the latter group following surgery. Other than basic support, the recovery became similar to a natural history study. Subsequently, primarily driven by the emergence of ICP monitoring, the treatable and untreatable sTBI cohorts were merged into a single category (i.e., doi: 10.1111/nyas.12482
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treatable sTBI), where there was a treatment strategy applicable to all patients. The advent of ICP monitoring was associated with, and attributed to, an approximately 50% decrease in the mortality, and an associated decrease in morbidity, from sTBI.2–4 However, it is necessary to examine such attribution more closely. The adoption of ICP monitoring had many influences. As noted above, it integrated all sTBI into the treatable category. It also invoked medical management of ICP and all of its ramifications. On a wider scale, the involvement of neurocritical care in an intensive care unit (ICU) setting pari passu included intensive care management of systemic variables, ranging from oxygenation and ventilation through infectious disease and nutrition. Over the same time course of the adoption of ICP monitoring, numerous developments were occurring in the areas of prehospital care, emergency department management, trauma surgery, and rehabilitation, and one of the most important developments in TBI treatment was becoming readily available—computed tomography (CT) imaging. Therefore, although the improvement in sTBI outcome tends to be attributed to ICP monitoring, the proper attribution is to an amalgamation of all of the above. Differentiating the contribution of any one element to this change requires an RCT. However, the only published RCT to date did not show the expected association of improved outcome with ICP monitor–based treatment, suggesting that ICP monitoring is not independently responsible for many of the beneficial changes attributed to it. To a great extent, the current concept of ICP has become oversimplified. Succinctly put, it can be summarized as “less than 20 mmHg is good and greater than 20 mmHg is bad.” That such a gross oversimplification closely resembles commonly held dogma is concerning. The evolution of current ICP treatment is largely based on practice and research from the late 1960s through the early 1990s, as exemplified in publications from the Traumatic Coma Databank.3,5–13 It is notable, however, that during this period there was concern that elevated systolic blood pressure drove intracranial hypertension and therefore much effort was directed toward “keeping the patient dry” and minimizing fluid resuscitation. Such under-resuscitation resulted in the routine maintenance of mean arterial pressures (MAPs) at approximately 70 mmHg. The MAP interacts with the
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lower breakpoint of cerebral pressure autoregulation, which is approximately 50 mmHg, according to the cerebral perfusion pressure (CPP) calculation CPP = MAP – ICP. This means that, when MAPs are maintained around 70 mmHg and CPPs below 50 mmHg bring increased risk of ischemia, ICPs greater than 20 mmHg will risk cerebral hypoperfusion. Under current management schemes, however, MAP is managed to keep the CPP greater than 60 mmHg. As a result, sTBI patients tend to have MAPs closer to 90 mmHg. In addition, modern ICU sedative management of sTBI patients frequently involves agents, such as propofol or dexmedatomidine, that lower the cerebral metabolic rate, therefore decreasing the ischemic risks of CPPs below 50 mmHg. Under current management, the necessity of maintaining an ICP less than 20 mmHg for the purposes of avoiding cerebral ischemia is greatly lessened. It must be remembered that ICP is an epiphenomenon, reflecting a large variety of nonexclusive underlying pathophysiological processes. There are many pathways to an ICP of 30 mmHg. Differentiating these pathways requires the use of different tests and monitors, and managing them requires different treatments. It is unlikely that our current approach of treating all sTBI patients in a similar fashion is consistent with such concepts. The ICP threshold of 20 mmHg is highly deserving of questioning. Despite conducting several thorough literature searches, the author of this article was unable to determine the origin of the adoption of this ICP threshold into sTBI management. The use of a single value is not trivial. Is it actually expected that the same threshold be used for all injuries? Should the diffusely swollen brain be treated at the same threshold as the brain following evacuation of a subdural hematoma? Should a 15-year-old patient have the same threshold as a 60-year-old patient? In addition, is it reasonable to believe that the ICP threshold is constant over the duration of treatment, not varying with recovery time and serial management? With respect to the interaction of duration and threshold, is an ICP greater than 20 mmHg for 10 min the same as an ICP greater than 30 mmHg for 2 minutes? Although maintenance of CPP is critical, maintaining a target value does not require an absolute threshold of ICP. Frank and open examination of the underpinnings of such current management concepts adds further weight
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to the idea that we have vastly oversimplified the understanding and management of ICP. With respect to the ICP treatment threshold, it must be remembered that modern studies that have attempted to determine the critical threshold have used data derived from patients who were concomitantly being treated using a particular threshold value.10,14–17 For obvious reasons, there have been no natural history studies. Unfortunately, there have been no sufficiently powered, randomized investigations of the effects of using different ICP treatment thresholds on outcome. Therefore, although many studies have supported 20–25 mmHg as a relevant threshold, they have been confounded by the above factors to the extent of not being definitive. These difficulties are reflected in the analysis of a recent paper that suggests that the response to ICP management predicts outcome from sTBI.18 This paper retrospectively reviewed 388 patients who received an ICP monitor, and the definition of intracranial hypertension was an ICP > 25 mmHg for 1 h or more. These patients received at least one treatment for ICP over the first 3 days and were examined for 2-week survival. It was found that the 2-week mortality rate was significantly improved in those patients who responded to ICP management. In addition, a regression analysis toward determining the predictors of 2-week mortality found that a positive response to ICP treatment was independently predictive. The authors concluded that lowering ICP improves outcome. Unfortunately, the definitions used in this paper make such a result almost self-fulfilling; the definition of intracranial hypertension involved a fairly mild dose of elevated ICP, which put a large collection of patients into the group requiring treatment. The responders group included only those patients who had 0 h of ICP > 25 mmHg following treatment, while the rest were placed into the nonresponders group, as were those patients dying within 3 days posttreatment. The result of such definitions is that almost any patient with a TBI of any degree of severity would be categorized into the nonresponders group. On closer analysis, therefore, this paper most likely examined the association of the severity of injury with outcome and does not provide strong evidence that a response to ICP management per se is anything other than an indicator of TBI severity. This paper illustrates not only the tenuousness of the belief that managing ICP strongly influences outcome, but also 76
demonstrates the difficulties of carrying out such research. If the pathophysiological events thought to underlie sTBI are closely examined with respect to the treatments that are currently used to manage intracranial hypertension, none of the treatments specifically address pathophysiological processes (Fig. 1). Their use is phenomenologically based on their influence on intracranial hypertension, meaning that they are focused on avoiding secondary insults rather than treating primary brain injury. Although this is very important and has resulted in remarkable improvement in recovery from sTBI, it also implies that none of these treatments are absolutely necessary in the treatment of sTBI in general. Therefore, the concept of primum non nocere must be kept in mind when choosing treatment modalities, and in attempting to improve recovery, avoiding overtreatment is important. One fundamental problem relates to a method of defining an event of intracranial hypertension. As noted above, the most common method is to define it as any reading above a set threshold.4,15,18,19 The speciousness of this definition is suggested by the likelihood that any given non-sTBI individual will exceed such a threshold several times per day during the course of routine daily activities and will not require treatment or suffer related untoward consequences. Some studies have used a closely defined time above a given value,20 whereas others have used a more loosely defined duration.21 One commonly quoted threshold determination report normalized time above a set threshold by dividing it by the total duration of monitoring.10 Another approach was used in a randomized barbiturate trial where the duration was linked to the degree of ICP elevation.22 Finally, more recently, an entirely different approach has been used involving the examination of the area under the ICP curve over given time intervals.23–25 The upshot is that an impressive number of definitions of an event of intracranial hypertension have been used, without one having been shown to be physiologically superior. This leaves in question not only the definition of a threshold value but also the definition of intracranial hypertension dose. It is also important to examine the data that have been used in the studies underlying our understanding of ICP. Recent studies have used automated high-resolution systems, which greatly expand our analytic capabilities. In general, however, most
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Figure 1. Contrast between a list (incomplete) of pathophysiological processes involved in sTBI and current, commonly used treatment modalities. In addition, some of the toxicities associated with these treatments are illustrated.
studies have used intermittent measurement, most commonly at a frequency of 1 hour. The most widespread approach has been to request that the nurse record end-hour ICP. However, it is clinically much more frequent that nurses record an hourly value that they think reflects the previous hour. Alternatively, they may use various summary measures provided by vendor display units. Once such variability is examined openly, the lack of standardization is concerning. Further magnifying the problem is that the method of recording is not specified in the majority of published ICP studies. As such, in most reports, the precise definition of the data on which we are basing our analyses is unknown. In summary, ICP research has been remarkably nonrigorous to date, casting our scientific foundation into question. We are still far from a complete scientific understanding of how ICP reflects the spectrum of injury-induced pathophysiology in a given patient, at a given time, by a specific type of TBI. CPP monitoring and management A similar skepticism can be profitably applied to our current concepts of CPP. When CPP became popularized in the 1980s and 1990s, the initial response was to push the target thresholds quite high to, for example, 80–90 mmHg. An RCT of ICP-based versus CPP-based management tempered this initial response by showing that the benefits of CPP-based treatment to the injured brain were eliminated as a result of systemic toxicity of treatments when the
CPP threshold was greater than 70 mmHg.26 This not only throttled back the eagerness to elevate CPP, but also again illustrated the systemic toxicity of brain-specific treatments. The hallmark paper supporting CPP-based management was by Rosner et al.,27 a prospective observational study of 747 patients collected during the late 1980s. They compared the outcome of patients treated with elevated CPP to a control group derived from the Traumatic Coma Data Bank and showed that CPP-directed treatment was associated with lower mortality and improved recovery, which was interpreted as strong support for this treatment approach. However, the effects of CPP treatment are not simple. There is a large body of data establishing that one of the strongest predictors of poor outcome from sTBI is systemic hypotension, particularly during the early stages following injury.28–30 It is notable that the maintenance of MAP at an elevated threshold has the indirect but potentially important consequence of making it less likely that early swings in blood pressure should reflect systemic hypotension. Therefore, the question becomes whether the influence of CPP is simply that of avoiding hypotension or if there is an added benefit to higher values. When a comparison group that did not have CPP management, but also did not have in-hospital episodes of hypotension, is extracted from the Traumatic Coma Data Bank, a comparison of the outcomes of this cohort to Rosner’s CPP-based management group reveals an elimination of any differences (Fig. 2).31
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Figure 2. Comparison of reported outcomes of sTBI patients treated with aggressive CPP-based therapy27 (n = 158) versus two groups from the Trauma Coma Data Bank (TCDB), neither of which were treated according to CPP. One group was unselected (TCDB, n = 746)3 and the other consisted of a subset of TCDB patients who did not have in-hospital hypotension (systolic blood pressure (SBP) < 90 mmHg; TCDB, no late hypotension; n = 337).31 Reproduced, with permission, from Chesnut et al.31
The suggestion, therefore, is that the major influence of CPP management may simply be the avoidance of cerebral ischemia, which is a threshold effect, without implying marginal benefits from further elevation. This is consistent with the study by Downard et al. that looked at mean CPP over the first 48 posttraumatic hours in a cohort of pediatric TBI patients.32 They found that, although mortality was 100% for those patients whose mean 48-h CPP was less than 40 mmHg, there was no difference associated with serial increases in mean CPP above that value. This again suggests that a large part of the benefit of CPP-based management results simply from the avoidance of transient cerebral hypoperfusion related to systemic hypotension. In light of the demonstrated systemic toxicity of routinely maintaining CPP at values greater than 70 mmHg,26 the relevance of the concept of primum non nocere to understanding the benefit of CPP management is well illustrated. Similarly to ICP concepts, our current approach to CPP management appears much less secure than commonly thought. Finally, differences in the level at which the MAP is zeroed for CPP calculation render the use of treatment thresholds sensitive to measurement inconsistencies on the order of 10 mmHg. Given the reported wide clinical variability in setting the zero point, and the rarity with which the technique used is reported in studies cited in developing CPP treat-
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ment guidelines,33 the solution to this discrepancy does not readily appear in the current literature.34 Cerebral pressure autoregulation following sTBI Another aspect worthy of critical analysis is the concept that cerebral pressure autoregulation is disrupted in the majority of sTBI patients. The normal brain closely regulates cerebral blood flow (CBF) over a wide range of CPPs (Fig. 3). Between the low end of approximately 50 mmHg and a less welldefined upper end of approximately 150 mmHg, CBF is maintained fairly constant because of reflex cerebral vasoconstriction in response to CPP elevation. Below approximately 50 mmHg, the vessels are maximally dilated, and there is no reserve, which means that CBF falls as CPP decreases further. In this range, the risk of ischemia rises as CPP decreases. (What occurs above 150 mmHg is less well defined and not really relevant to this discussion.) Critically, over the zone of active pressure autoregulation, the brain “takes care of itself ” with respect to matching CPP to its needs. The instance of disrupted autoregulation occurs when the cerebral vasoconstriction response to elevated CPP is lost. This creates a pressure—a passive system in which CBF is directly proportional to CPP. The vessels serially dilate as CPP increases,
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Figure 3. Intact and disrupted cerebral pressure autoregulation. The solid line represents intact pressure autoregulation, where CBF is maintained over the CPP range from 50 to 150 mmHg by active vasoconstriction, failing outside of these values. The dashed line represents completely disrupted autoregulation, where CBF is pressure passive (directly dependent on CPP), and cerebral blood volume and ICP increases in parallel with CPP. The illustrations at the top represent cross-sectional vascular profiles for both conditions.
which means that cerebral blood volume increases, thereby driving up ICP. In this case, there is no zone in which “the brain takes care of itself.” Elevating the CPP improves CBF and makes it less likely that metabolic needs will be unmet, but also results in elevated ICP, which may itself impede perfusion or result in cerebral herniation. Low CPPs will be associated with low CBF and a much higher risk of ischemia. Therefore, the status of cerebral pressure autoregulation is a critical determinant of how CPP should be manipulated following sTBI. As noted above, it is commonly thought that pressure autoregulation is frequently disrupted following sTBI. Sviri et al. reported that cerebral pressure autoregulation was disrupted in 83% of patients during postinjury days 3–5 and in 54% of patients during postinjury days 9–11;35 this has serious implications for treatment, as discussed above. However, further understanding of the different components of cerebral pressure autoregulation, and examination of the methods used to measure autoregulation in such reports, may lead to a differ-
ent conclusion. Dynamic cerebral pressure autoregulation is the rapid, transient ability of the vessel caliber to respond to changes in blood pressure. The rapidity of this response can be measured by inflating and then quickly deflating large blood pressure cuffs on the thighs of patients, while concomitantly measuring the flow velocity of the middle cerebral arteries using transcranial doppler. When the cuffs are deflated, there is a transient drop in blood pressure, followed by a rapid recovery. If one convolutes the rapidity of the recovery of the transcranial doppler flow velocity against the blood pressure response, one can determine the status of dynamic pressure autoregulation in a quantitative manner. This status can range from hyperreactive through hyporeactive, all the way to absent. Static cerebral pressure autoregulation, as previously discussed, is measured over the course of minutes or more and reflects the overall capacity of the vessels to maintain CBF over variable CPP values. One method of testing this is to iatrogenically alter the CPP and measure the CBF response
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Figure 4. Status of static and dynamic pressure autoregulation in 83 sTBI patients measured within 48 h of trauma, showing that they are not equally disrupted following trauma.36 Note the absence of the group “intact dynamic, disrupted static,” which is consistent with dynamic autoregulation being the mechanism of static autoregulation.
over the ensuing minutes, using either CT perfusion or transcranial doppler. If elevating the CPP is not associated with a change in CBF, cerebral static pressure autoregulation is interpreted as intact. If, in contrast, elevating the CPP results in an elevation of CBF, this implies that cerebral pressure autoregulation is dysfunctional over that range of CPP. When static and dynamic cerebral pressure autoregulation are measured within the same patient, it has been demonstrated that dynamic autoregulation may be disrupted without necessarily being associated with abnormal static autoregulation. A study by Peterson and Chesnut suggested that dynamic autoregulation was abnormal in 88% of sTBI patients but that static autoregulation remained relatively intact in 60% (Fig. 4).36 Therefore, it is important to determine whether static or dynamic pressure autoregulation is being measured when planning the treatment of a given patient. When looking carefully at the study by Sviri et al., the thigh cuff method was used to measure pressure autoregulation, implying that their results pertain to dynamic pressure autoregulation and should not be interpreted as implying concomitant disruption of static pressure autoregulation. Peterson et al. suggests that the frequency of static pressure autoregulation disruption is much lower, implying that, in the majority of sTBI patients, merely keeping the CPP within the zone will allow the brain to manage its own CBF through static pressure autoregulation. This greatly simplifies management and implies that exuberant CPP elevation is not required. In the significantly smaller group of patients in which static
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pressure autoregulation specifically is found to be disrupted, assiduous CPP management on the basis of multimodality monitoring will be required in order to balance the risk of ischemia against treatment toxicity. Clearly, however, the commonly held concept that cerebral pressure autoregulation is disrupted in the vast majority of sTBI patients requires reconsideration in a similar fashion to that suggested for ICP and CPP. Caveat This highly skeptical presentation of a neurotrauma dystopia is not meant to imply that our present concepts are unfounded or incorrect, that current management approaches are ineffective, or that we should immediately radically alter our treatments for sTBI. The progress that has been made over the past four decades in decreasing the morbidity and mortality from this disease stands on its own and many of the treatments used (such as surgical evacuation of acute intracranial hematomas) will certainly remain critical despite their lack of RCT support. Nevertheless, unexpected recent study results37–39 prompt a skeptical review of current concepts and consideration of the possibility that modified or alternative approaches may provide equal or superior benefit. One such approach is the concept of targeting interventions and treatment thresholds at subgroups of sTBI patients on the basis of multimodality monitoring using refined analytic methods. It is intended that the skepticism contained in this analysis should strengthen many current concepts by attempting to highlight areas where
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incomplete assumptions may have mislead clinicians. Most of the current practices will likely survive such re-analysis and be stronger as a result of it. However, new concepts can only be built if there is confidence in the foundation, and nothing destroys confidence like follow-up. Summary Therefore, cerebral pressure autoregulation, ICP, and CPP should currently be viewed as inadequately defined and requiring more work. The importance of such skepticism is illustrated historically by the total reversal of the fortunes of steroid use, maintaining low MAPs following injury, and restricting fluid resuscitation following sTBI. All of these once popular and dogmatically supported concepts have fallen by the wayside. Our current, reoriented approach can be characterized as seeking normovolemia, normothermia, maintaining normal partial pressure of carbon dioxide (PaCO2 ) and partial pressure of oxygen (PaO2 ), euglycemia, promoting adequate nutrition, titrating CPP and ICP thresholds to individual patients, and minimizing iatrogenic injury. An obvious theme here is that of maintaining a normal milieu internal, where the injured brain may recover, in contradistinction to our frequently misguided exuberance toward overtreatment. It must be recalled that none of our current treatment modalities for sTBI are conditiones sine quibus non for recovery. Therefore, the use of individual agents, as well as the targeting of specific or rigorous treatment thresholds, must be judiciously balanced against the potential for iatrogenic injury. Until we have much improved data on how to tailor therapy and target treatments for individual cases, the risk of overtreating patients in search of poorly supported goals must be taken to heart. It is recognized that this article is extremely skeptical, but it is offered to suggest that a logical analysis of many of our current concepts readily invalidates any tendencies toward being dogmatic and illustrates the need for further research. It will be important to delineate how to tailor therapies to individual patients using multimodality monitoring in order to optimize the risk–benefit ratio of treatment in individual cases.40 Conflicts of interest The author declares no conflicts of interest.
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