IN 1996, the Brain Trauma Foundation sponsored the development of guidelines for the management of severe traumatic brain injury (TBI). The method used for development of the guidelines was evidence based, and probably the most significant contribution of the guidelines has been to highlight the remarkable lack of class I evidence available for many current management practices. Recently, revisions to the guidelines were published, and little has been changed in the recommendations. 1From all of the aspects of management that were reviewed for the guidelines, the authors were only able to provide three standards based on class I evidence (randomized clinical trials) and only eight guidelines based on class II evidence (table 1). Furthermore, the randomized clinical trials that have supported the three guideline standards showed ineffectiveness of certain long-standing management practices (prophylactic hyperventilation, steroid administration, prophylactic anticonvulsants) rather than showing that any practices are beneficial.
One of the most controversial areas of TBI critical care that was highlighted in the review provided by the guidelines is the management of cerebral perfusion pressure (CPP). CPP is the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP). When pressure autoregulation is impaired and when CPP is below the lower limit of pressure autoregulation, cerebral blood flow (CBF) is dependent on CPP. It is important to emphasize that the controversial issue is not hypotension because overwhelming evidence from numerous clinical studies shows that hypotension has adverse consequences for the patient with TBI. Rather, the key controversial issues are what is the minimum level for CPP that is adequate for a brain-injured patient, and does increasing CPP beyond the level that provides adequate perfusion of the brain have an additional beneficial therapeutic effect or does it have a detrimental effect.
The traditional approach to treatment of the brain-injured patient has been to emphasize early surgical treatment of intracranial mass lesions, and meticulous critical care treatment of the patient to avoid causes of secondary injury to the brain and to minimize intracranial hypertension. This general critical care includes tracheal intubation to protect the airway, ventilatory support to prevent hypoxia and hypercarbia, sedation and analgesia, prevention of fever, maintenance fluids to provide normal intravascular volume and electrolytes, nutritional support, and prophylaxis for stress ulcer and for thromboembolism. The goal of this general care is to provide the optimal environment for the brain to recover and to minimize any factors, such as hypoxia, hypercarbia, hyponatremia, or fever, that may aggravate intracranial hypertension. ICP is monitored, and increases of ICP are treated using a stair-step approach, adding or subtracting therapies as needed based on response of ICP (fig. 1A). Usually, the therapies are added in an order that reflects the risk of complications associated with the use of the therapy. A typical protocol might start initially with cerebrospinal fluid (CSF) drainage and neuromuscular blocking agents. If additional treatment is required, osmotic agents are added. Barbiturate coma is reserved for intracranial hypertension refractory to these other treatments in a patient who is hemodynamically stable and who is potentially salvageable. The aim of all of these efforts is to control ICP.
Recently, however, several groups have advocated different overall strategies to the management of TBI. These approaches emphasize different aspects of the pathophysiology of TBI and are based on a favorable clinical experience by the individuals advocating the management protocol. None of these newly proposed approaches have been demonstrated to improve outcome after TBI over the traditional ICP management approach.
One novel strategy, called CPP management, has been advocated by Rosner et al. 2This approach is based on a physiologic concept called the vasodilatory cascade, diagrammed in figure 1B. According to this hypothesis, a reduction in CPP—either a decrease in arterial blood pressure, an increase in ICP, or both—stimulates the cerebral vessels to dilate in an attempt to maintain CBF. This is the normal pressure autoregulatory response to a decrease in CPP. Because the increase in cerebral blood volume that accompanies the vasodilation further reduces CPP by increasing ICP, this sets up a cycle that leads to ever reducing CPP. An increase in arterial blood pressure under this circumstance has been observed to break the cycle and reduce ICP. A detailed description of this approach is given in a recent report of a clinical series. 2In this series of 158 patients admitted with Glasgow Coma Scale score less than 7, mortality was only 29%, and 59% achieved a good recovery or moderate disability by 6 months postinjury. This approach has been widely adapted, and there was believed to be sufficient value in this practice that it was included in the 1996 Head Injury Guidelines and has continued to be recommended in the 2000 Head Injury Guidelines as a treatment option (supported by class III evidence and expert opinion). 1,3
Another recent approach, called the Lund therapy, emphasizes reduction in microvascular pressures to minimize edema formation in the brain (fig. 1C). The goals of this approach are to preserve a normal colloid osmotic pressure (infusion of albumin and erythrocytes), to reduce capillary hydrostatic pressures by reducing systemic blood pressures (metoprolol and clonidine), and to reduce cerebral blood volume by vasoconstricting precapillary resistance vessels (low-dose thiopental and dihydroergotamine). Treatments that would favor increasing transcapillary filtration of fluid are avoided, including cerebrospinal fluid drainage, high-dose (to burst suppression) barbiturates, osmotic diuretics, and high CPP. Decompressive craniectomy, which can also increase edema formation, is reserved as a last resort. A detailed description of this approach is given in two recent publications, including a report of a clinical series in which mortality was 8% and in which 80% of patients recovered with a Glasgow Outcome Scale of good recovery or moderate disability by 6 months postinjury after institution of these measures. 4,5
A final approach has been to try to match the treatment to the underlying pathophysiology. With this approach, it is emphasized that traumatic brain injury is heterogeneous, and each individual patient has a predominant pathophysiologic pattern. In addition, it recognizes that the pathophysiology of traumatic brain injury evolves over time, and treatment that is appropriate in the first few hours after injury may not necessarily be optimal 2 or 3 days after injury. Miller et al. 6proposed that treatment of intracranial hypertension was more successful if the treatment was targeted at the underlying cause, i.e. , hypnotic–sedative agents for vascular causes of intracranial hypertension and osmotic agents for edema causes of intracranial hypertension. With regard to management of CPP, this approach reserves the treatment of increasing CPP for the patient who demonstrates a need for this higher CPP to adequately perfuse the brain. This approach most closely follows general critical care principles that emphasize optimizing each individual patient’s physiologic status.
A summary of the similarities and differences in the details of management with these various approaches is given in table 2. All of the approaches have some physiologic basis for their use. However, except for the strategy of individualizing treatment, each approach focuses on only one or two aspects of what is a complex problem. The final outcome of the patient at 6 months after a severe traumatic brain injury sums the age and the underlying genetic and physiologic makeup of the individual, the severity of the primary injury, and the events that occur during prehospital care, emergency room resuscitation, surgical treatment of the injury, early hospital care in the intensive care unit, later hospital care on the wards, and rehabilitation. Although acute care after TBI is usually available regardless of financial resources, extensive rehabilitation is often dependent on insurance issues, so socioeconomic factors may also play a role in the final outcome. No study has shown superiority of any one of the approaches on the overall outcome of the TBI patient.
The definition of what characteristic defines an adequate CPP varies with the management approach. Advocates of the Lund therapy consider the minimum CPP that does not result in cerebral ischemia to be optimal. This group argues that a high CPP only serves to increase edema in the injured brain. Advocates of the Rosner CPP approach, in contrast, argue that CPP should be kept above the lower limit of autoregulation. Above this threshold, changes in CPP do not alter cerebral perfusion because the brain is able to compensate adequately for the pressure changes. It is sometimes argued that the brain “knows” what CBF is appropriate as long as CPP is kept within the autoregulatory range. However, there are two flaws in this approach. First, pressure autoregulation is not the primary regulatory mechanism that normally couples CBF to metabolic requirements. 7It does not logically follow that keeping CPP in the autoregulatory range will necessarily provide an adequate perfusion of the brain. Second, the Rosner CPP approach assumes that pressure autoregulation is intact but that the lower limit of autoregulation is just shifted to a higher CPP. More recent studies using dynamic testing of pressure autoregulation have suggested that pressure autoregulation is not an all-or-none phenomenon but rather can present with various degrees of impairment. 8
In an attempt to define a minimal threshold for CPP after TBI, a number of clinical studies have examined the relation between CPP and CBF or between CPP and a measure of cerebral oxygenation, either jugular venous oxygen saturation (Sjvo2) or, more recently, brain tissue Po2. In a prospective study of 21 patients with severe TBI, increasing CPP from 32 ± 2 to 67 ± 4 mmHg improved brain tissue partial pressure of oxygen (Po2) by62%. 9Increasing CPP above 68 mmHg did not result in an additional improvement in brain tissue Po2. Below a CPP of 60 mmHg, Bruzzone et al. 10found a significant relation between CPP and brain tissue Po2. Between a CPP of 60 and 130 mmHg, another investigator found no relation between Sjvo2and CPP. 11Chan et al. 12found no relation between Sjvo2and CPP above 70 mmHg, whereas Sjvo2decreased with CPP below 70 mmHg.
Other studies have examined the relation between different thresholds for CPP and outcome from TBI. The concept for these studies is that if a CPP of 60 or 70 mmHg is a critical value below which additional damage may occur to the injured brain, there should be a significant relation between the length of time that CPP is below this critical threshold and the neurologic outcome of the patient. Clearly, this type of study can only show an association and does not prove that the relation is that of cause and effect. Using the physiologic data collected by the Traumatic Coma Data Bank, Marmarou et al. 13examined the length of time that ICP, MAP, and CPP were beyond several different threshold levels and found that for MAP and CPP, the thresholds of 80 and 60 mmHg, respectively, were the most closely related to outcome. Struchen et al. 14studied 184 patients with severe head injury and found significant relations between the length of time that ICP, MAP, and CPP were beyond the thresholds of 25, 80, and 60 mmHg, respectively, and neurologic outcome measured by both the Glasgow Outcome Scale and the Disability Rating Scale. In both of these studies, the predictive value of the physiologic variables did not seem to be simply a measure of severity of injury, because the relation to outcome remained significant when the models were adjusted for demographic characteristics that indicate severity of injury, such as initial Glasgow Coma Scale score, type of injury, and age. In children, the critical threshold for CPP may be lower. A mean CPP below 40 mmHg has been associated with certain fatality in pediatric TBI, but above 40 mmHg, higher levels for the average CPP do not seem to be correlated with a better outcome. 15
Based on the available information, it is probably most correct to conclude that after TBI, an adequate CPP is necessary, but not sufficient to guarantee that CBF is adequate. The available clinical studies suggest that a CPP of 60 mmHg provides an adequate perfusion pressure for the majority of adult TBI patients, based on measures of global CBF and cerebral oxygenation.
The Rosner CPP approach argues that it is sometimes necessary to increase CPP higher than 70–80 mmHg to keep CPP in the autoregulatory range. In fact, the average CPP in their clinical series (Glasgow Coma Scale score 7 group) was 85 ± 12 mmHg (ICP 27 ± 12 and MAP 111 ± 14). The Lund approach argues that a high CPP only induces additional edema formation and aggravates intracranial hypertension. It is not possible to directly compare these two clinical series, which both report excellent outcomes with these different approaches to management of CPP. There are likely many differences in the overall population of patients included in the two studies, which confound the effect of the management strategy.
One randomized clinical trial has examined the consequences, both beneficial and adverse, of different levels of CPP. 16This trial compared a CBF-targeted strategy (CPP was kept > 70 mmHg) to a conventional ICP-targeted strategy (CPP was kept > 50 mmHg) in the initial management of acute TBI. The CBF-targeted treatment decreased the duration of time that CPP was less than 60 mmHg from a median of 13 h to 4 h (P = 0.008). The CBF-targeted treatment reduced the incidence of secondary ischemic events by approximately 50% (P < 0.001). However, this treatment strategy also increased the incidence of acute respiratory distress syndrome fivefold and did not improve long-term neurologic outcome. The interpretation of this study favored by the authors is that the beneficial effect from the CBF-targeted management of reducing secondary ischemic insults was offset by complications associated with maintaining blood pressure at an increased level.
Much more work is needed to answer this controversial question definitively. However, it is clear from the work that has been done to date that neurologic critical care issues such as this can and must be systematically studied in randomized clinical trials. Additional uncontrolled clinical series will never provide a convincing answer. In addition, because the only randomized trial that has compared the consequences of targeting different levels of CPP failed to show a long-term benefit and, in fact, showed a clear detrimental effect (increased incidence of acute respiratory distress syndrome) with a CPP goal of greater than 70 mmHg, there is no compelling reason to increase CPP beyond that required to adequately perfuse the brain. It seems likely that a CPP of 60 mmHg provides adequate perfusion for most TBI patients. Higher CPP levels should probably be reserved for those TBI patients who demonstrate a specific indication for induced hypertension, such as regional or global ischemia. This recommendation differs from that of the 2000 Head Injury Guidelines but is better supported by the available literature.