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Original Article

Does ICP monitoring make a difference in neurocritical care?

Cremer, O. L.a

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European Journal of Anaesthesiology: February 2008 - Volume 25 - Issue - p 87-93
doi: 10.1017/S0265021507003237
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Abstract

Introduction

The attitude of doctors towards the benefits of monitoring equipment has often been guided by wishful thinking. Only few exceptions can be found in the literature. In obstetrics, intrapartum fetal monitoring has been investigated in retrospective as well as prospective randomized studies. It seems as if most of these studies have suggested that intrapartum fetal monitoring did not improve the neurological outcome of the babies [1,2]. In intensive care, the use of a pulmonary-artery catheter in high-risk surgical patients has not resulted in improved clinical outcome [3]. Part of the reason may have been that it proved very difficult to achieve the desired haemodynamic objectives, despite more aggressive treatment. Likewise, pulmonary-artery catheter-guided care in patients with acute lung injury has not improved survival or organ function, but it has been associated with more complications than standard care [4]. The case for intracranial pressure (ICP) monitoring may not be very different.

Indications for ICP monitoring vary from unit to unit and may include traumatic brain injury, anoxic-ischaemic brain injury, intracerebral and subarachnoid haemorrhage, hydrocephalus, or brain oedema after large strokes, hypoxic brain injury, central nervous system infections or fulminant hepatic failure. For none of these indications there is good evidence that incorporating data from ICP monitors into the management strategy improves outcome. A large cohort study in children with meningitis found that the use of ICP monitoring did not result in differences in hospital mortality but significantly increased both length of stay and hospital charges [5]. Recently, we reported similar findings in the setting of severe head injury [6]. This review will therefore critically examine data on the effectiveness of ICP-guided care in patients with traumatic brain injury.

Indications for ICP monitoring after traumatic brain injury

In the traumatic brain injury literature, the following indications for ICP monitoring are recognized: (1) patients with severe head injury, as defined by a Glasgow Coma Scale (GCS) score ≤8, with an abnormal head computed tomography (CT) scan; (2) patients with severe head injury (GCS score ≤8) with a normal head CT scan and who have two or more of the following characteristics: age >40 yr, systolic blood pressure <90 mmHg or motor posturing; (3) patients with moderate head injury (GCS score 9-12) and an abnormal head CT scan who are undergoing therapies for other injuries with a possible deleterious effect on ICP; and (4) patients following removal of intracranial mass lesions [7,8]. Although ICP monitoring has traditionally been advocated for all types of head injuries, the development of intracranial hypertension is less likely following diffuse axonal injury (without associated mass lesions), and a case has been made against its use in patients with such pathology [9].

How many centres use ICP monitoring?

Surveys of critical care management indicate that ICP monitors are currently used in approximately 75% of specialist neurosurgical centres in developed countries [10-12] and in 9-28% of non-specialist hospitals caring for head-injured patients [13,14]. The gold standard for assessing ICP is a catheter inserted into one of the lateral ventricles and connected to an external pressure transducer zeroed at the foramen of Monro (or, for clinical purposes, the ear). More commonly, however, an intraparenchymal probe will be used with a miniature strain gauge pressure sensor mounted at its tip. Despite the widespread use of ICP monitors, many clinicians seriously doubt whether routine monitoring improves outcome after severe traumatic brain injury and feel that a trial addressing this issue is warranted [11].

Does ICP monitoring have complications?

The reported incidence of bleeding complications following placement of ICP monitors depends largely on how well you look for intracranial haemorrhage. However, the reported incidences range from 0% to 15% in the literature [15,16]. Interestingly, in a recent study of 155 insertions with a 9.7% haemorrhage rate, complications occurred more frequently after ICP monitor placement in the operating theatre as compared to bedside procedures [17]. Although most haemorrhages seem to be small and probably unimportant, we do not know their long-term consequences. Furthermore, they may cause false readings of high ICP. The risk of infections increases over the monitored time and is in the range of 1.7-4% for intraparenchymal fibreoptic probes and 6-11% for ventricular catheters [18-21].

When discussing complications of ICP monitoring, however, we should also consider the possibility of false pressure readings, which may lead to unnecessary (or untimely) interventions. It is generally accepted that the intracranial compartment behaves as a unicameral space in which pressure is uniformly distributed, but this concept can be challenged. Clinically relevant craniospinal and suprainfratentorial gradients have long been recognized [22,23]. More recently, significant supratentorial pressure differences (>10 mmHg) and even completely incongruent ICP trends have been observed between hemispheres, in particular in patients with intracranial mass lesions [24,25]. Furthermore, mechanical complications, such as device dislocations and fibreoptic breakage or malfunction, occur in approximately 5% of monitored patients [26]. If unrecognized, these events too may lead to erroneous management decisions.

Do we know how to manage raised ICP?

Traditionally, the medical management of raised ICP is characterized by a stepwise approach [27]. The first step typically includes the use of analgesia and sedation, head of bed elevation, initial slight hyperventilation and cerebrospinal fluid drainage if indicated. The second step includes mannitol or hypertonic saline infusions and more aggressive hyperventilation (preferably with concomitant monitoring of jugular venous saturation). The third step includes rescue therapies such as high-dose barbiturate infusions and possibly decompressive craniectomy or hypothermia. Thus, interventions are traditionally chosen in the order of an increasing risk of complications.

Pathophysiological considerations are generally deemed less important for selecting any particular therapy. However, brain swelling after head trauma results from an increase in cell volume (cytotoxic oedema), interstitial fluid volume (vasogenic oedema), blood volume (vascular engorgement) or a combination of these factors. The distinction between these processes is important to treat intracranial hypertension rationally rather than empirically, but unfortunately the relative importance of each of these factors is difficult to ascertain and thus has been a matter of debate [28]. As a consequence, treatment protocols for severely head-injured patients differ widely. In any case, clinical experience teaches that it is often impossible to effectively and durably control ICP below 20 mmHg in many patients, despite aggressive therapy.

The most effective way to manage cerebral perfusion pressure (CPP) is even more uncertain. In the 1990s, based on the concept of the vasodilatory cascade, Rosner and colleagues [29] popularized the notion that CPP should be aggressively managed at levels above 70-90 mmHg, if necessary by using vasopressors. At the same time, however, the ‘Lund concept' urged for a reduction of microvascular hydrostatic pressures to minimize oedema formation, accepting CPPs as low as 50 mmHg in adults [30]. Following an update of the Brain Trauma Foundation guidelines in 2003, the consensus target value for CPP has been set at 60 mmHg [31]. Even so, the controversy described above exemplifies the frustrating lack of good evidence that is available to make rational treatment decisions in the setting of ICP-guided care.

Does ICP-guided care improve outcome?

To this date, there are no randomized controlled trials that have demonstrated the effectiveness of ICP-guided care in patients with severe head injuries. In the 1980s, several authors have argued in favour of ICP and/or CPP-targeted therapies for traumatic brain injury by comparing the mortality rates of 28-36% observed since the introduction of routine ICP monitoring in the 1980s, with a quoted 50% mortality rate observed in 1977 in three centres by Jennett and colleagues [32,33]. Others have compared outcomes between individuals who (during routine clinical practice) either did or did not receive an ICP monitor [18,34]. Obviously, confounding by indication is a major problem in this type of comparison. After adjustment for a limited number of available markers of injury severity, the effect estimate in these studies varied from improved to worsened outcome when ICP monitoring was used.

I am aware of only few studies that truly compared cohorts of head-injured patients who were exposed to different approaches to ICP monitoring and care. Gelpke and colleagues [35] found higher survival rates in centres with a more ‘conservative' management regimen compared with more ‘aggressive' treatment. Patel and colleagues [36] compared functional outcome between patients managed according to a contemporary ICP-guided protocol and historical controls from their own centre. They found an improved functional status, but not a reduced mortality, in a post hoc subgroup of the severest cases only. In other studies, outcome was compared between several trauma centres [37,38]. Each centre was characterized by a more or less ‘aggressive' approach to ICP- and CPP-targeted therapy, while centre ‘aggressiveness' was estimated from the observed frequency of ICP monitoring in the centres. However, in the study by Bulger and colleagues [37], centre classification was based on an average of <6 contributing patients per study hospital and the potential for misclassification of the determinant was thus considerable. Both studies found evidence of an association between more aggressive management and improved clinical outcome, but there is some inconsistency in the fact that both a reduced mortality without a difference in functional status in survivors and an improved functional survival without a decrease in the rate of death were reported. These studies relied retrospectively on medical records to retrieve the Glasgow Outcome Scale, and this may have caused significant misclassification of functional survival status.

In 2005, we published a study in Critical Care Medicine in which we prospectively assessed long-term functional outcome after severe head injury in two Dutch hospitals that had very contrasting approaches to the management of these patients [6]. One centre provided supportive intensive care without ICP monitoring, whereas the other centre provided protocol-driven intensive care targeted to maintain ICP <20 mmHg and CPP >70 mmHg. In this study, we were unable to confirm even a trend towards improved functional survival in patients who were treated at the center which provided ICP-guided care (Fig. 1). However, compared with supportive intensive care without ICP monitoring, the ICP-guided treatment substantially prolonged length-of-stay parameters and resulted in a much more frequent use of sedatives, muscle relaxants, osmotic diuretic, vasopressors, fluid loading and hyperventilation, all of which have recognized neurological and systemic side-effects (Table 1). Although statistical uncertainty still allowed for a possible benefit of ICP-guided care, we were able to ascertain from our data that this potential benefit would be rather small, i.e. the number needed to monitor would be at least 16 patients in order to benefit one individual.

Figure 1.
Figure 1.:
Distribution of patients across the possible categories of the extended Glasgow Outcome Scale at 12-month follow-up. The odds ratio for a more favourable functional outcome following ICP-guided care was 0.95 (95% CI: 0.62-1.44).
Table 1
Table 1:
. Supportive vs. intracranial pressure (ICP)-guided treatments in head injury.

Does aggressive ICP-guided treatment carry risks?

There are several reasons as to why ICP-guided therapy need not necessarily result in improved outcome. First, aggressive objective-directed therapy fails to consistently control ICP below 20 mmHg in approximately one-fourth of patients [6]. Second, there is evidence that augmenting CPP does not significantly improve perfusion to ischaemic pericontusional tissue [39]. Third, it has been argued that the higher capillary hydrostatic pressures induced by augmenting CPP may promote cerebral oedema formation through a dysfunctional blood brain barrier [40]. Finally, there is an increasing awareness that an aggressive ICP- and CPP-targeted approach may result in cardiorespiratory complications. The Baylor group reported a fivefold increased incidence of adult respiratory distress syndrome with a treatment protocol targeted at maintaining CPP >70 mmHg [41]. In response to this finding, the Brain Trauma Foundation in 2003 issued an update of their guidelines for CPP management, lowering the recommended treatment threshold to 60 mmHg [31]. My group reported on the risk of cardiac complications following high-dose infusions of propofol and vasopressors in severely head-injured patients [42].

There are other potential complications related to the aggressive manipulation of systemic and cerebral physiological variables after head trauma. These adverse effects include iatrogenic cerebral ischaemia due to inappropriate hyperventilation, infectious pulmonary complications or neuromuscular dysfunction related to the use of metabolic suppression therapy, and metabolic disturbances or renal toxicity resulting from the administration of osmotic diuretics. Together, the iatrogenic consequences of aggressive ICP-guided treatment in the head injury population at large may offset a possible benefit of such therapy in specific subgroups of patients.

Why was a trial never done?

Over the past decades, numerous drugs with promising profiles in the laboratory have been evaluated for their neuroprotective effects in large randomized controlled trials and have failed to offer benefit to patients. In contrast, the effectiveness of basic treatment algorithms and physiological interventions that are routinely used in the management of head injury has not been evaluated at large [43]. Of the few studies that were done, perhaps the most valuable were those that have demonstrated adverse effects or lack of effectiveness of interventions that are commonly used, including hyperventilation, deliberate hypothermia and CPP augmentation [44-46]. This shows the importance of randomized controlled ‘management trials' (as opposed to drug trials) even for evaluation of long-standing clinical practices. Assessment of the effectiveness of ICP monitoring and targeted management of ICP and CPP should be no example.

A randomized controlled trial of ICP-guided therapy has been proposed in the past by the centres that comprised the Traumatic Coma Data Bank but was not funded by the National Institutes of Health. Furthermore, the ethical basis of such a study has been questioned [47]. The enthusiasm to embark on such a study of a technique that is considered indispensable by many experts in the field may be even more limited now. Nonetheless, given the fact that aggressive ICP-guided care may be associated with increased lengths of stay, conceivable costs and possible adverse events, whereas outcome benefits are doubtful, I think a trial is still in demand. This view was shared by a majority of Canadian neurosurgeons in 2000 [11]. However, such a trial would pose several complicated design issues.

Methodological challenges relate particularly to the heterogeneity within the head injury population and a general lack of statistical power to detect small but clinically relevant differences in outcome. First, heterogeneity in a study sample adds ‘noise' to the data and reduces the chance of detecting a true treatment effect. In the case of traumatic brain injury, this pertains both to a wide range of pathologies associated with head trauma and to large variations in baseline prognostic factors between patients. In order to be successful, future trials will therefore need to be targeted on subgroups of patients with a specific pathology and an intermediate prognosis [48]. Second, most (failed) drug trials to date have aimed to demonstrate a 10% absolute improvement in favourable outcome in patients with severe head injury [49]. Such a treatment effect may be considered overoptimistic and unrealistic in relation to the heterogeneous patient population. In addition, statistical power has frequently been sacrificed by using a binary outcome, most often the dichotomized Glasgow Outcome Scale. Merging outcome categories, only to facilitate data analysis, is a waste of valuable information. As an alternative, it has been proposed to use more sophisticated analysis tools, such as ordinal logistic regression models, or differentiate the point of dichotomization of the outcome according to the patient's baseline risk [48-50].

There are many other problems related to the design of ‘management trials' for severe traumatic brain injury, including poor feasibility of individual patient randomization (randomization according to assigned time blocks may be an alternative), blinding of treatment allocation, prevention of protocol violations and treatment crossovers, and acceptance of the reference therapy by ‘believers' in a particular therapeutic concept. Nonetheless, a trial of ICP-guided care vs. supportive care for severe head injury is necessary and should be attempted, provided that a strong and sustained multidisciplinary effort can be acquired in a multi-centre setting.

Conclusion

With the present state of knowledge, one should be extremely cautious to recommend any one particular way of physiological management of severe traumatic brain injury over another. However, it is important to consider that there is large heterogeneity within the head trauma population, and that it is therefore possible that many commonly used interventions that are aimed to reduce intracranial hypertension are ineffective, unnecessary or even harmful for some patients at certain times. Without any doubt, ICP monitoring will be helpful in several situations. However, its benefits in the head trauma population at large may well be much smaller than its enthusiasts would concede to. Data from our observational study support the notion that at least 16 patients would need to be monitored in order to benefit one individual. This result would be attainable at the expense of greatly prolonged lengths of stay in the neurocritical care unit, conceivable costs and possibly increased complications. Against this background, I contend that there is sufficient clinical equipoise to conduct a prospective randomized controlled trial that is adequately powered to compare ICP-guided management with supportive critical care without ICP monitoring in patients with severe traumatic brain injury. However, the realization of such a trial is likely to be problematic for a number of reasons, not least of which the firmly held biases of many clinicians.

Conflict of interest: The author has no financial interests related to the subject matter.

References

1. Freeman R. Intrapartum fetal monitoring - a disappointing story. N Engl J Med 1990; 322: 624-626.
2. Natale R, Dodman N. Birth can be a hazardous journey: electronic fetal monitoring does not help. J Obstet Gynaecol Can 2003; 25: 1007-1009.
3. Sandham JD, Hull RD, Brant RF et al.. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003; 348: 5-14.
4. Wheeler AP, Bernard GR, Thompson BT et al.. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354: 2213-2224.
5. Odetola FO, Tilford JM, Davis MM. Variation in the use of intracranial-pressure monitoring and mortality in critically ill children with meningitis in the United States. Pediatrics 2006; 117: 1893-1900.
6. Cremer OL, Van Dijk GW, van Wensen E et al.. Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med 2005; 33: 2207-2213.
7. Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Indications for intracranial pressure monitoring. J Neurotrauma 2000; 17: 479-491.
8. Narayan RK, Kishore PR, Becker DP et al.. Intracranial pressure: to monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg 1982; 56: 650-659.
9. Lee TT, Galarza M, Villanueva PA. Diffuse axonal injury (DAI) is not associated with elevated intracranial pressure (ICP). Acta Neurochir 1998; 140: 41-46.
10. Wilkins IA, Menon DK, Matta BF. Management of comatose head-injured patients: are we getting any better? Anaesthesia 2001; 56: 350-352.
11. Sahjpaul R, Girotti M. Intracranial pressure monitoring in severe traumatic brain injury - results of a Canadian survey. Can J Neurol Sci 2000; 27: 143-147.
12. Kornecki A, Constantini S, Adani LB et al.. Survey of critical care management of severe traumatic head injury in Israel. Childs Nerv Syst 2002; 18: 375-379.
13. McKeating EG, Andrews PJ, Tocher JI, Menon DK. The intensive care of severe head injury: a survey of non-neurosurgical centres in the United Kingdom. Br J Neurosurg 1998; 12: 7-14.
14. Shigemori M, Tokutomi T. Result of nationwide survey of the management of severe head injury in Japan. Neurol Res 2002; 24: 41-44.
15. Martinez-Manas RM, Santamarta D, de Campos JM, Ferrer E. Camino intracranial pressure monitor: prospective study of accuracy and complications. J Neurol Neurosurg Psychiatry 2000; 69: 82-86.
16. Blaha M, Lazar D, Winn RH, Ghatan S. Hemorrhagic complications of intracranial pressure monitors in children. Pediatr Neurosurg 2003; 39: 27-31.
17. Blaha M, Lazar D. Traumatic brain injury and haemorrhagic complications after intracranial pressure monitoring. J Neurol Neurosurg Psychiatry 2005; 76: 147.
18. Stocchetti N, Penny KI, Dearden M et al.. Intensive care management of head-injured patients in Europe: a survey from the European brain injury consortium. Intensive Care Med 2001; 27: 400-406.
19. Bekar A, Goren S, Korfali E, Aksoy K, Boyaci S. Complications of brain tissue pressure monitoring with a fiberoptic device. Neurosurg Rev 1998; 21: 254-259.
20. Aucoin PJ, Kotilainen HR, Gantz NM et al.. Intracranial pressure monitors. Epidemiologic study of risk factors and infections. Am J Med 1986; 80: 369-376.
21. Mayhall CG, Archer NH, Lamb VA et al.. Ventriculostomy-related infections. A prospective epidemiologic study. N Engl J Med 1984; 310: 553-559.
22. Crockard HA, Hanlon K, Ganz E, Duda EE. Intracranial pressure gradients in a patient with a thalamic tumor. Surg Neurol 1976; 5: 151-155.
23. Miller JD, Peeler DF, Pattisapu J, Parent AD. Supratentorial pressures. Part I: differential intracranial pressures. Neurol Res 1987; 9: 193-197.
24. Mindermann T, Reinhardt H, Gratzl O. Significant lateralisation of supratentorial ICP after blunt head trauma. Acta Neurochir (Wien) 1992; 116: 60-61.
25. Sahuquillo J, Poca MA, Arribas M, Garnacho A, Rubio E. Interhemispheric supratentorial intracranial pressure gradients in head-injured patients: are they clinically important? J Neurosurg 1999; 90: 16-26.
26. Gelabert-Gonzalez M, Ginesta-Galan V, Sernamito-Garcia R et al.. The Camino intracranial pressure device in clinical practice. Assessment in a 1000 cases. Acta Neurochir (Wien) 2006; 148: 435-441.
27. Vincent JL, Berre J. Primer on medical management of severe brain injury. Crit Care Med 2005; 33: 1392-1399.
28. Unterberg AW, Stover J, Kress B, Kiening KL. Edema and brain trauma. Neuroscience 2004; 129: 1021-1029.
29. Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol and clinical results. J Neurosurg 1995; 83: 949-962.
30. Eker C, Asgeirsson B, Grände PO, Schalen W, Nordström CH. Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation. Crit Care Med 1998; 26: 1881-1886.
31. Brain Trauma Foundation. Update notice 5-1-2003. Guidelines for the management of severe traumatic brain injury: cerebral perfusion pressure. Available at: http://www2.braintrauma.org/guidelines/. Accessed: 11-1-2006.
32. Brain Trauma Foundation, 2000. Management and prognosis of severe traumatic brain injury. Available at: http://www2.braintrauma.org/guidelines/. Accessed: 11-1-2006.
33. Jennett B, Teasdale G, Galbraith S et al.. Severe head injuries in three countries. J Neurol Neurosurg Psychiatry 1977; 40: 291-298.
34. Lane PL, Skoretz TG, Doig G, Girotti MJ. Intracranial pressure monitoring and outcomes after traumatic brain injury. Can J Surg 2000; 43: 442-448.
35. Gelpke GJ, Braakman R, Habbema JD, Hilden J. Comparison of outcome in two series of patients with severe head injuries. J Neurosurg 1983; 59: 745-750.
36. Patel HC, Menon DK, Tebbs S et al.. Specialist neurocritical care and outcome from head injury. Intensive Care Med 2002; 28: 547-553.
37. Bulger EM, Nathens AB, Rivara FP et al.. Management of severe head injury: institutional variations in care and effect on outcome. Crit Care Med 2002; 30: 1870-1876.
38. Murray LS, Teasdale GM, Murray GD et al.. Head injuries in four British neurosurgical centres. Br J Neurosurg 1999; 13: 564-569.
39. Steiner LA, Coles JP, Johnston AJ et al.. Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cerebral perfusion pressure. J Cereb Blood Flow Metab 2003; 23: 1371-1377.
40. Grände PO, Asgeirsson B, Nordström CH. Physiologic principles for volume regulation of a tissue enclosed in a rigid shell with application to the injured brain. J Trauma 1997; 42: 23-31.
41. Contant CF, Valadka AB, Gopinath SP, Hannay HJ, Robertson CS. Adult respiratory distress syndrome: a complication of induced hypertension after severe head injury. J Neurosurg 2001; 95: 560-568.
42. Cremer OL, Moons KG, Bouman EA et al.. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001; 357: 117-118.
43. Roberts I, Schierhout G, Alderson P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998; 65: 729-733.
44. Muizelaar JP, Marmarou A, Ward JD et al.. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991; 75: 731-739.
45. Clifton GL, Miller ER, Choi SC et al.. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001; 344: 556-563.
46. Robertson CS, Valadka AB, Hannay HJ et al.. Prevention of secondary ischemic insults after severe head injury. Crit Care Med 1999; 27: 2086-2095.
47. Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe head injury. J Neurotrauma 1996; 13: 641-734.
48. Doppenberg EM, Choi SC, Bullock R. Clinical trials in traumatic brain injury: lessons for the future. J Neurosurg Anesthesiol 2004; 16: 87-94.
49. Maas AI, Marmarou A, Murray GD, Steyerberg EW. Clinical trials in traumatic brain injury: current problems and future solutions. Acta Neurochir Suppl 2004; 89: 113-118.
50. Cremer OL, Moons KG, Van Dijk GW, van Balen P, Kalkman CJ. Prognosis following severe head injury: development and validation of a model for prediction of death, disability, and functional recovery. J Trauma 2006; 61: 1484-1491.
Keywords:

HEAD INJURY; INTRACRANIAL PRESSURE MONITORING; BLOOD PRESSURE, intracerebral; OUTCOME

© 2008 European Society of Anaesthesiology