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

Prophylactic hyperventilation (PaCO₂ of 25 mm Hg or less) is not recommended.

Hyperventilation is recommended as a temporizing measure for the reduction of elevated intracranial pressure (ICP).

Hyperventilation should be avoided during the first 24hours after injury when cerebral blood flow (CBF) is often critically reduced.

If hyperventilation is used, jugular venous oxygen saturation (SjO₂) or brain tissue oxygen tension (PbrO₂) measurements are recommended to monitor oxygen delivery.

Aggressive hyperventilation (arterial PaCO₂ < 25 mm Hg) has been a cornerstone in the management of severe traumatic brain injury (TBI) for more than 20 years because it can cause a rapid reduction of ICP. Brain swelling and elevated ICP develop in 40% of patients with severe TBI, and high or uncontrolled ICP is one of the most common causes of death and neurologic disability after TBI. Therefore, the assumption has been made that hyperventilation benefits all patients with severe TBI. As recent as 1995, a survey found that hyperventilation was being used by 83% of U.S. trauma centers.

However, hyperventilation reduces ICP by causing cerebral vasoconstriction and a subsequent reduction in CBF. Research conducted over the past 20 years clearly demonstrates that CBF during the first day after injury is less than half that of normal individuals and that there is a risk of causing cerebral ischemia with aggressive hyperventilation. Histologic evidence of cerebral ischemia has been found in most victims of severe TBI who die. A randomized study found significantly poorer outcomes at 3 and 6 months when prophylactic hyperventilation was used, as compared to when it was not. Thus, limiting the use of hyperventilation following severe TBI may help improve neurologic recovery following injury, or at least avoid iatrogenic cerebral ischemia.

For this update, Medline was searched from 1996 through April of 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 23 potentially relevant studies, 2 were added to the existing tables and used as evidence for this question (Evidence Tables I, II, and III)

Three studies provide Class III evidence that CBF can be dangerously low soon after severe TBI (Evidence Table I). Two measured CBF with xenon-CT/CBF method during the first 5 days following severe TBI in a total of 67 patients. In one, CBF measurements obtained during the first 24 h after injury were less than 18 mL/100 g/min in 31.4% of patients. In the second, the mean CBF during the first few hours after injury was 27 mL/100g/min. The third study measured CBF with a thermodiffusion blood flow probe, again during the first 5 days post-injury, in 37 severe TBI patients. Twelve patients had a CBF less than 18 mL/100g/min up to 48 h post-injury.

Three Class III studies provide the evidence base for this topic (Evidence Table II). Results associating hyperventilation with SjO₂ and PbrO₂ values in a total of 102 patients are equivocal. One study showed no consistent positive or negative change in SjO₂ or PbrO₂ values. A second study associated hyperventilation with a reduction of PaCO₂ and subsequent decrease in SjO₂ from 73% to 67%, but the SjO₂ values never dropped below 55%. The third reported hyperventilation to be the second most common identifiable cause of jugular venous oxygen desaturation in a sample of 33 patients. Studies on regional CBF show significant variation in reduction in CBF following TBI. Two studies indicated lowest flows in brain tissue surrounding contusions or underlying subdural hematomas, and in patients with severe diffuse injuries. Similarly, a third found that CO2 vasoresponsivity was most abnormal in contusions and subdural hematomas. Considering that CO2 vasoresponsivity could range from almost absent to three times normal in these patients, there could be a dangerous reduction in CBF to brain tissue surrounding contusions or underlying subdural clots following hyperventilation. (Note only one of these three studies had adequate design and sample to be included as evidence.) Two studies, not included in the evidence base for this topic, associated hyperventilation-induced reduction in CBF with a significant increase in oxygen extraction fraction (OEF), but they did not find a significant relationship between hyperventilation and change in the cerebral metabolic rate of oxygen (CMRO2).

One Class II randomized controlled trial (RCT) of 113 patients (Evidence Table III) used a stratified, randomized design to compare outcomes of severe TBI patients provided normal ventilation (PaCO₂ 35 ± 2 mm Hg; n = 41; control group), hyperventilation (PaCO₂ 25 ± 2 mm Hg; n = 36), or hyperventilation with tromethamine (THAM; n = 36). One benefit of hyperventilation is considered to be minimization of cerebrospinal fluid (CSF) acidosis. However, the effect on CSF pH may not be sustained due to a loss of HCO3- buffer. THAM treatment was introduced to test the hypothesis that it would reverse the effects of the loss of buffer.

Patients were stratified based on the motor component of the Glasgow Coma Scale (GCS) score (1-3 and 4-5). The Glasgow Outcome Scale (GOS) score was used to assess patient outcomes at 3, 6, and 12 months. For patients with a motor GCS of 4-5, the 3- and 6-month GOS scores were significantly lower in the hyperventilated patients than in the control or THAM groups. However, the effect was not sustained at 12 months. Also, the effect was not observed in patients with the lower motor GCS, minimizing the sample size for the control, hyperventilation, and THAM groups to 21, 17, and 21, respectively. The absence of a power analysis renders uncertainty about the adequacy of the sample size. For these reasons, the recommendation that hyperventilation be avoided is Level II.

In the absence of trials that evaluate the direct effect of hyperventilation on patient outcomes, we have constructed a causal pathway to link hyperventilation with intermediate endpoints known to be associated with outcome. Independent of hyperventilation, CBF can drop dangerously low in the first hours following severe TBI. The introduction of hyperventilation could further decrease CBF, contributing to the likelihood of ischemia. The relationship between hyperventilation and metabolism, as well as cerebral oxygen extraction, is less clear. The one study that evaluated patient outcomes strongly suggests that hyperventilation be avoided for certain patient subgroups.

The causal link between hyperventilation and intermediate endpoints, and the subsequent relationship between those endpoints and patient outcomes, needs to be clearly specified. Further RCTs need to be conducted in the following areas:

• How does short-term hyperventilation affect outcome?
• The effect of moderate hyperventilation in specific subgroups of patients.
• Critical levels of PaCO₂/CBF and outcome.