There are insufficient data to support a Level I recommendation for this topic.

Aggressive attempts to maintain cerebral perfusion pressure (CPP) above 70 mm Hg with fluids and pressors should be avoided because of the risk of adult respiratory distress syndrome (ARDS).

CPP of <50 mm Hg should be avoided.

The CPP value to target lies within the range of 50-70 mm Hg. Patients with intact pressure autoregulation tolerate higher CPP values.

Ancillary monitoring of cerebral parameters that include blood flow, oxygenation, or metabolism facilitates CPP management.

There is a substantial body of evidence that systemic hypotension independently increases the morbidity and mortality from TBI, both clinical and histological. CPP has been used as an index of the input pressure determining cerebral blood flow and therefore perfusion. CPP is defined as the MAP minus the ICP. It has long proven its value as a perfusion parameter in physiological studies. Its clinical use as a monitoring parameter burgeoned in the late 1980s in parallel with the concept that induced hypertension may improve outcome. Until this period, it was the practice to avoid systemic hypertension as it was felt to contribute to intracranial hypertension.

Rosner and Daughton proposed a management strategy based primarily on CPP management, stressing the maintenance of CPP at >70 mm Hg and often at much higher levels. This approach provided outcomes that were superior to an unadjusted control group from the Traumatic Coma Data Bank where ICP management was the primary therapeutic goal. Subsequently, CPP management became widely practiced, despite misgivings that the primary issue might be avoidance of cerebral hypotension rather than benefit from CPP elevation per se. The question of what is the optimal CPP to maintain after TBI remains unanswered.

For this update, Medline was searched from 1996 through April 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 48 potentially relevant studies, six were added to the existing table and used as evidence for this question (Evidence Table I).

This question suffers from lack of an adequate, generalizable definition of low CPP. The individual parameters of CPP (blood pressure and ICP) have been shown to be critically related to outcome from TBI. Systemic hypotension is highly associated with poor outcome. As well, elevated ICP predicts increased mortality and less recovery.

Low cerebral blood flow per se is associated with poor outcome. However, the reliability of CPP in this regard remains less well defined. When physiological indices (rather than clinical outcomes) are used as dependent variables, there is evidence that low CPP is associated with unfavorable physiological values. Within the range of autoregulation, low CPP is associated with increased ICP through compensatory vasodilation in response to decreased perfusion pressure.3,4 Looking at SjO₂ and transcranial Doppler pulsatility index values, Chan et al. found that these parameters appeared to stabilize at CPP values of 60-70 mm Hg, suggesting that this range might represent the lower end of cerebral pressure autoregulation. It has also been demonstrated that decreased CPP values associate with levels of brain tissue O2 saturation (PbrO₂) and jugular venous oxygen saturation that correlate with unfavorable outcomes, and that raising the CPP above 60 mm Hg may avoid cerebral O2 desaturation. Sahuquillo et al. studied PbO₂ values as a function of CPP in severe TBI patients and did not find that low PbO₂ values were predictable with low CPPs ranging from 48 to 70 mm Hg. They also found that raising CPP did not increase oxygen availability in the majority of cases. Cerebral microdialysis studies suggest that, although the normal brain may be more resistant to low CPP, the injured brain may show signs of ischemia if the CPP trends below 50 mm Hg, without significantly benefiting from various elevations above this threshold. These studies suggest that there is a physiologic threshold for CPP of 50-60 mm Hg, below which cerebral ischemia may occur.

When CPP per se is evaluated in terms of human clinical outcome, low CPP is frequently found to correlate with poor outcome. Clifton et al. retrospectively analyzed data on CPP within the dataset from 392 patients in the randomized controlled trial of therapeutic hypothermia for severe TBI. When they analyzed individual predictive variables separately, they found CPP of <60 mm Hg to be associated with an increased proportion of patients with poor outcome. They found similar associations for intracranial pressure >25 mm Hg, mean arterial pressure <70 mm Hg, and fluid balance lower than -594 mL. When these variables were combined into a stepwise logistic regression model, however, CPP fell out, although the other three variables remained within the group of most powerful variables in determining outcome.

Juul et al. retrospectively analyzed the data on ICP and CPP within the dataset of 427 patients in the international, multicenter, randomized, double-blind trial of the N-methyl-D-aspartate antagonist Selfotel. They found that a CPP of <60 mm Hg was associated with worse outcome, however this relationship is confounded by high ICP which independently associates with poor outcome.

Andrews et al. prospectively studied 124 severe TBI patients for the purpose of determining predictive variables. They employed on-line collection of physiologic variables, which allowed them to detect and grade a number of secondary insults, including low CPP. Using decision tree analysis, they found that CPP was predictive of outcome when insults were severe and, in common with systemic hypotensive insults of moderate or severe intensity, was more predictive of outcome than ICP. Systemic hypotension per se was consistently important as a predictor of unfavorable outcome in all analyses.

These studies support CPP as a valuable monitoring parameter in managing patients with severe TBI. They suggest that there is a critical threshold for CPP that, in aggregate, appears to lie between 50 and 60 mm Hg. They do not support substituting CPP for monitoring and management of either of its constituent parameters (MAP and ICP).

Early proponents of CPP management reported improved outcomes for severe TBI patients whose CPPs were higher during their treatment course. McGraw developed a model using retrospective data analysis that proposed that patients with a CPP of >80 mm Hg had better outcomes than those with a lower CPP. The same group subsequently reported a 100% mortality for patients for whom ≥33% of their CPP course was <60 mm Hg. Both of these studies, however, were retrospective data analyses without risk adjustment on patients managed using ICP-targeted therapy.

Rosner and Daughton prospectively studied 34 patients managed with CPP of >70 mm Hg. When they compared their outcomes to those from the Traumatic Coma Data Bank, they described an increase in good or moderately impaired outcomes and a decrease in mortality, which they attributed to the elevation of CPP. However, there was no adjustment for differences between the two populations. One subsequent analysis suggested that the outcome differences disappeared if there was adjustment for the incidence of in-ICU hypotension (presumably rare in patients undergoing CPP elevation).

With respect to ICP or intracranial hypertension, elevating CPP by up to 30 mm Hg does not appear to be associated with intracranial hypertension in patients with patently intact pressure autoregulation. In patients with impaired autoregulation, the ICP response to such CPP elevation is less predictable, sometimes slightly decreasing, while others see mostly a small elevation, albeit some patients demonstrate more profound ICP responses. In these papers, MAP elevation was generally initiated at CPP values of >60 mm Hg. Increased intracranial hemorrhage has not been generally reported as a complication, even in reports where CPP was greatly augmented.

Subsequent reports call into question whether there is any marginal gain by maintaining the CPP at an elevated level. Robertson et al. reported a randomized controlled trial of CPP therapy versus ICP therapy. In the CPP therapy group, CPP was kept at >70 mm Hg; in the ICP therapy group, CPP was kept at >50 mm Hg, and ICP was specifically kept at ≤20 mm Hg. They found no significant difference in outcome between the two groups. However, the risk of ARDS was five times greater among patients in the CPP-targeted group and associated with a more frequent use of epinephrine and a higher dose of dopamine. One perceived benefit of the CPP-based protocol was fewer episodes of jugular venous desaturation, which logistic regression modeling suggested was attributed to less hyperventilation in the CPP group. They also noted, however, that the expected influence on outcome of such desaturations was probably minimized because all episodes in both groups were rapidly corrected.

In their analysis of the data from the international, multicenter, randomized, double-blind Selfotel trial, Juul et al. did not find a benefit of maintaining CPP greater than 60 mm Hg.

There is a growing body of clinical evidence that elevating the CPP above the threshold for ischemia may not be beneficial and may indeed have detrimental cerebral and systemic effects. Cruz et al. reported a prospectively collected dataset with one group of patients managed based on jugular venous saturation and CPP, and another group managed under a CPP-based protocol, targeting a CPP of >70 mm Hg. The patients were characterized by having CT evidence of diffuse swelling either on admission or following craniotomy for clot evacuation. The patients were well matched in terms of demographic and injury variables. However, there was no adjustment for other confounding variables (e.g., no adjustment was done to control for specific management variables that covaried with the two treatment philosophies). Mortality in the cohort managed according to jugular venous saturation was 9% versus 30% in the CPP group. This study strongly suggests that CPP-based therapy may not be optimal in all patient groups and that it should be possible to match management strategies to patient characteristics.

Howells et al. compared two separate prospective databases of severe TBI patients managed via two differing philosophies allowed quantitative comparison of outcomes using ICP-guided protocols versus CPP-guided protocols. Their general results supported using CPP as an important index in directing targeted therapy. They noted that a CPP of >60 mm Hg appeared to be too high in some patients. They reported that CPP-based management appeared more efficacious in patients with more intact autoregulation. Patients with less intact autoregulation, however, appeared to do less well if their CPP exceeded 60 mm Hg.

Steiner et al. used an on-line method of measuring cerebral pressure autoregulation and estimated the CPP at which autoregulation appeared most robust in 60% of their patient group. The more closely the mean CPP at which individual patients were maintained approximated the CPP at which their autoregulation was optimal, the more likely that patient was to have a favorable outcome. In addition to the hazard of too low CPP, they specifically stated that maintaining the CPP at levels that are too high may have a negative influence on outcome.

There also appear to be serious detrimental systemic effects of elevating CPP. Analyzing data from their randomized controlled trial (RCT) on ICP-based management versus CPP-based management, Contant et al. reported a highly significant association (fivefold increase in risk) between CPP-based therapy and ARDS. Associated medical maneuvers included increased administration of epinephrine and dopamine. Patients who developed ARDS had a higher average ICP and received more treatment to manage intracranial hypertension. They were 2.5 times more likely to develop refractory intracranial hypertension and this group was two times more likely to be vegetative or dead at 6-month followup. In this trial, it was felt that any potential benefits of a focus on elevating CPP was obviated by such systemic complications.

It is important to differentiate physiologic thresholds representing potential injury from clinical thresholds to treat. Much of the definition of the former can come from simple physiologic monitoring; the latter requires clinical evidence from controlled trials using outcome as their dependant variable. With respect to CPP, it appears that the critical threshold for ischemia generally lies in the realm of 50-60 mm Hg and can be further delineated in individual patients by ancillary monitoring.

At this time, it is not possible to posit an optimal level of CPP to target to improve outcome in terms of avoiding clinical episodes of ischemia and minimizing the cerebral vascular contributions to ICP instability. It is becoming increasingly apparent that elevating the CPP via pressors and volume expansion is associated with serious systemic toxicity, may be incongruent with frequently encountered intracranial conditions, and is not clearly associated with any benefit in terms of general outcome. Based on a purely pragmatic analysis of the randomized, controlled hypothermia trial, Clifton et al. noted that a CPP target threshold should be set approximately 10 mm Hg above what is determined to be a critical threshold in order to avoid dips below the critical level. In combination with the studies presented above, this would suggest a general threshold in the realm of 60 mm Hg, with further fine-tuning in individual patients based on monitoring of cerebral oxygenation and metabolism and assessment of the status of pressure autoregulation. Such fine-tuning would be indicated in patients not readily responding to basic treatment or with systemic contraindications to increased CPP manipulation. Routinely using pressors and volume expansion to maintain CPP at >70 mm Hg is not supported based on systemic complications.

Minimally invasive, efficient, and accurate methods of determining and following the relationships between CPP and autoregulation and between CPP and ischemia in individual patients are needed. There is a need for randomized trials of the influence on outcome of basing optimal CPP on ischemia monitoring (e.g., jugular venous saturation or PtiO2) or on the quantitative indices of pressure autoregulation.