1. Standards. There are insufficient data to support treatment standards for this topic.

2. Guidelines. A cerebral perfusion pressure (CPP) >40 mm Hg in children with traumatic brain injury (TBI) should be maintained.

3. Options. A CPP between 40 and 65 mm Hg probably represents an agerelated continuum for the optimal treatment threshold. There may be exceptions to this range in some infants and neonates.

   Advanced cerebral physiologic monitoring may be useful to define the optimal CPP in individual instances.

   Hypotension should be avoided.

4. Indications from Adult Guidelines. The adult guidelines1 stated there were insufficient data to support either a treatment standard or guideline. Under Options, it stated, "Cerebral perfusion pressure (CPP) should be maintained at a minimum of 70 mm Hg."1

Global or regional cerebral ischemia is an important secondary insult to the acutely injured brain. Grossly, the CPP - defined as the mean arterial pressure minus the intracranial pressure (ICP) - defines the pressure gradient driving cerebral blood flow (CBF), which, in turn, is related to metabolic delivery of essential substrates. The posttraumatic brain has a significant incidence of vasospasm that may increase the cerebral vascular resistance and decrease the CPP, producing ischemia. With the use of continuous monitoring capabilities including invasive blood pressure and ICP equipment, the CPP could be manipulated in an attempt to avoid both regional and global ischemia.

We searched Medline and Healthstar from 1966 to 2001 by using the search strategy for this question (see Appendix A) and supplemented the results with literature recommended by peers or identified from reference lists. Of 53 potentially relevant studies, five were used as evidence for this question (Table 1).

There is abundant evidence that CBF declines following TBI and may frequently reach the ischemic threshold for brain tissue2-6. Regional CBF may be even more reduced in the vicinity of intracranial hematomas and contusions7, 8. There is much debate on how best to measure CBF and at what threshold there is actual tissue ischemia. Cerebral perfusion pressure is relatively easy to measure and appears to correlate well with CBF when measured. A low CPP is highly correlated with poor outcome, but there is less evidence that manipulating the CPP can change eventual neurologic outcome in both adults and children.

There is little quality evidence for the role of CPP in pediatric patients. The comprehensive literature search for this guideline only found one class II study and no class I studies.

A retrospective cohort, class II study collected data on all pediatric TBI patients presenting to both level I pediatric trauma centers in Oregon who received an ICP monitor (118 patients, Glasgow Coma Scale [GCS] 6 ± 3, age 7.4 ± 4.6 yrs). By logistic regression methods, the authors found mortality rate significantly associated with a mean CPP <40 mm Hg (p < .01) and mean ICP >20 mm Hg (p < .001). Mean arterial pressure <70 mm Hg (their definition of "hypotension") was not statistically independently associated with death. They also found no incremental reduction of mortality rate or improved 3-month Glasgow Outcome Scale score associated with mean increases of CPP >40 mm Hg. However, only 60% of patients had documented follow-up at 3 months9.

Barzilay et al.10 studied 56 consecutive admissions to their pediatric intensive care unit (PICU) with coma from TBI, central nervous system infections (five cases), and miscellaneous etiologies (ten cases) for at least 6 hrs before admission. Mean arterial pressure and CPP were treated in an uncontrolled fashion, and patients were followed until hospital discharge only. Comparison of survivors and nonsurvivors showed results in Table 2. The difference in minimum CPP is significant at p < .001.

Elias-Jones et al.11 studied 39 consecutive PICU admissions for TBI with an initial GCS ranging from 3 to 11 and an age range of 2 months to 13 yrs (average age 7.8 yrs) who had multiple interventions for ICP >20 mm Hg or CPP <50 mm Hg. They showed that all but one survivor (of total 30) had CPP >40 mm Hg, and CPP was <40 mm Hg in seven of nine fatalities (p < .00002, Fisher's exact test). The interventions included hypothermia to 32°C and hyperventilation to a PaCO₂ of 3.0 -3.5 kPa for all patients. Severe hypocapnia was associated with a worse outcome.

Another retrospective case series of 24 consecutive admissions to a PICU of patients with a GCS <8, average age 6.3 yrs, with ten patients between 1 and 5 yrs of age, showed that all survivors had CPP>50 mm Hg (p < .005, Fisher's exact test)12.

Sharples et al.13, 14 studied a convenience sample of 17 pediatric patients (2-16 yrs old, average age 7 yrs) with TBI and GCS 3-8 by measuring continuous mean arterial pressures and ICPs and calculating CBF and cerebral vascular resistance by using the nitrous oxide method. The authors found cerebral vascular resistance was proportional to CPP (Pearson r = .32, p = .0003) and the relationship was even closer in those patients deemed to have a "good" outcome (i.e., near-normal neurologic function).

Key Elements from the Adult Guidelines Relevant to Pediatric TBI

A large randomized controlled trial of 189 patients with severe TBI (15% with a gunshot wound) compared ICP-targeted therapy with CBF-targeted therapy that resulted in a CPP >50 mm Hg in the first group and a CPP >70 mm Hg in the second. It showed no difference in 3- or 6-month Glasgow Outcome Scale score, but there was an increased risk of adult respiratory distress syndrome in the second group15. Another large prospective study of 353 severe TBI patients, with 178 receiving continuous monitoring and management of cerebral oxygen extraction in addition to management of CPP, showed that the additional intervention was associated with better neurologic outcome at 6 months16. A retrospective study by Changaris et al.17 in 136 adult patients showed that all patients with a CPP <60 mm Hg on the second day of injury died and more patients with a CPP >80 mm Hg had a better outcome. Another retrospective study of 221 patients followed for a year after TBI also showed better outcomes including mortality rate (p < .001) if CPP >80 mm Hg18. Multiple prospective studies evaluating interventions such as hypothermia, barbiturate coma, and controlling jugular venous oxygen content used CPP >70 mm Hg as a target without directly evaluating this variable alone19-23. Two studies looked at the relationship of artificially raising the mean arterial pressure in TBI patients with inotropes, and these studies found that this intervention had little effect on the ICP, thereby raising CPP and CBF. The studies were too small to find an effect on ultimate outcome24, 25. Another small study (n = 21) showed that an increase of CPP from an average of 32 to 67 mm Hg significantly improved brain tissue PO2 but that further increases did not improve this variable26.

A CPP <40 mm Hg is consistently associated with increased mortality, independent of age. It is unclear whether this value represents a minimal threshold or whether the optimal CPP may be above this in children (e.g., 50-65 mm Hg), based on available data. There are likely to be age-related differences in optimal CPP goals that are indiscernible due to small numbers in these pediatric studies. No study demonstrates that active maintenance of CPP above any target threshold in pediatric TBI is responsible for improved mortality or morbidity.

Controlled, prospective, randomized studies in children are needed to determine optimal CPP levels in various pediatric age groups and mechanisms of injury. The relative importance of ICP and CPP-targeted therapies needs to be assessed by using age-appropriate longterm (>1 yr) functional outcomes.