Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Prevention of secondary ischemic insults after severe head injury

Robertson CS, Valadka AB, Hannay HJ, et al.

Crit Care Med. 1999;27:2086-95. [abstract]

Reviewed by Jeanette R. M. White, Children's National Medical Center, Washington, DC

Review posted March 4, 2001

I. What is being studied?:

The authors study two different strategies designed to minimize secondary brain injury occurring in the severely head injured trauma patient. In the CBF targeted management strategy, the investigators maintain CPP by elevating mean arterial pressures to supranormal values. In the group receiving the ICP targeted management strategy, the investigators maintained CPP by decreasing intracranial pressure using significant hyperventilation, a strategy which may compromise cerebral blood flow.

The study objective:

These authors propose three hypotheses:

1. A cerebral blood flow (CBF) targeted management strategy will reduce the frequency of jugular venous desaturation
2. CBF-targeted management will decrease the frequency of refractory intracranial hypertension
3. CBF- targeted management will improve long term outcome

The study design:

Prospective, uncontrolled, time-randomized therapeutic trial. The authors note the impracticality of randomizing individual patients within a single ICU to separate treatment protocols. Therefore, they chose to randomize "time-periods" rather than patients. The investigators divided the year into three parts, to correspond to the rotations of the neurosurgical residents. Within each four-month block, a single treatment approach was randomly assigned to occur during each two-month interval. The authors do not describe any crossover between therapeutic regimens.

The patients included:

The eligibility criteria for the trial included the following:

1. coma (motor Glasgow Coma Scale score [GCS] of 5 at admission or deteriorated to motor GCS of 5 within 48 hrs after injury);
2. coma must have been caused by head injury;
3. age 15 yrs;
4. admission within 12 hrs of injury

The patients excluded:

Patients with either:

1. GCS 3 with fixed and dilated pupils after resuscitation;
2. contraindication to placement of jugular bulb catheter; and/or
3. severe associated systemic injury.

The interventions compared:

The authors outline two separate treatment protocols in Table 1 in the paper. In brief, the major differences between the two protocols were the treatment goals for MAP, CPP, and PaCO2 (in response to acute elevations in ICP). In the ICP-targeted protocol, MAP was kept 70 mm; however, if SBP went higher than 160 mm Hg, subjects were treated with antihypertensive agents. CPP was kept at 50 mm Hg. Acute increases in ICP were treated primarily by hyperventilating the patient to a PaCO2 of 25-30 torr; investigators also used CSF drainage, paralysis, and mannitol for ICP control.

In the CBF-targeted protocol, MAP was kept elevated at 90 mm Hg and CPP was kept 70 mm Hg. These patients received significant fluid resuscitation or inotropic support to achieve these blood pressure goals( whereas the ICP-targeted group received only maintenance fluids). ICP control was achieved using CSF drainage, paralysis, and mannitol; hyperventilation was not used to treat acute episodes of intracranial hypertension.

In both protocols, catheters measuring MAP, ICP, and CPP were all calibrated at the same level.

The outcomes evaluated:

The primary outcome variable was the frequency of jugular venous desaturation events (SjvO2 of < 50% for > 10 mins ). The SjvO2 was measured using a catheter ultrasonographically placed in the dominant jugular vein. The tip was placed in the jugular bulb, and this was confirmed using skull x-ray. Calibration occurred every 8 to 12 hours; all desaturation events recorded on the monitor were confirmed with a blood sample from the catheter.

Secondary outcome variables included:

1. frequency of refractory intracranial hypertensive events ( ICP of > 25 mm Hg) which were unresponsive to conventional treatment, required barbiturate coma, or resulted in death
2. 3- and 6-month Glasgow Outcome Score and Disability Rating Scale

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

No. The surrogate endpoint was the measurement of the frequency and duration of episodes of jugular venous desaturation, as well as the duration of time that it was below a predetermined critical threshold (< 50%). These jugular venous desaturation events were a proxy measure of secondary cerebral ischemia occurring post-injury. The ischemic events were, in turn, hypothesized to be associated with long term neurological outcome. However, the strength of this relationship is not clear. We know from work performed by the authors and others that SjvO2 is a homogenous measure of global cerebrovenous oxygenation saturation. Changes in SjvO2 may reflect changes in any of the multiple factors that contribute to cereral oxygen delivery or utilization. In a previous study (reference #9 in the paper), this group prospectively monitored jugular venous desaturation events in brain injured patients. They found that patients with more frequent drops in SjvO2 were more likely to have poor neurological outcome. However, we cannot determine from the study whether the frequency of jugular venous desaturation events is an independent predictor of outcome, nor can we state with surety that it is a better predictor than the clinical evidence we routinely collect (CO2, MAP, PaO2 etc).

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There are no trials demonstrating improvement in long-term outcome as a result of reduction of the rate of jugular venous desaturation events, regardless of the methods by which this reduction is achieved.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There are no trials demonstrating improvement in long-term outcome as a result of reduction of the rate of jugular venous desaturation events using a CBF targeted approach.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

No. Patients were not individually randomized to a particular treatment protocol, because simultaneous execution of two distinct treatment protocols within the ICU was felt to be too difficult. Thus, time periods were randomized. Within each 4 month block of a neurosurgical resident's rotation, each protocol was randomized to occur during one of two eight-week blocks. Thus, patients' characteristics were theoretically randomly distributed; however, caretakers were not masked to the treatment protocol.

To evaluate for resultant selection bias, the investigators recorded all patients excluded from the trial during each protocol's time period to be certain that specific patient subgroups weren't being systematically excluded from any protocol. They found that the proportion of patients randomized during the ICP block was not significantly different than the proportion randomized during the CBF block (p = .707); thus, patients weren't more likely to have been treated according to a certain protocol as a result of the admitting physician's bias.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Of the 319 patients who met the definition for severe head injury, 189 were included in the study. Of the 130 patients excluded, 124 met exclusion criteria (90 had a GCS of 3 with fixed and dilated pupils, 19 had a rapidly improving motor score, 2 had contraindication to placement of a jugular bulb catheter, and 13 had severe systemic injury). The remaining 6 patients were excluded for "miscellaneous reasons". If we presume that these six patients were not included for failure to consent to the protocol, then these investigators had a remarkable rate (189/195 = 97%) of enrollment!

Data from all patients included in the study were presented with regards to acute care. Long-term follow-up was described, but the patient capture rate is confusing. The investigators report neurological outcomes at 3 month for 91 patients in the CBF group, and 81 patients in the ICP group. The disposition of the remainder of the cohort is not clear; presumably they are lost to follow-up. At six months, there were 83 patients in the CBF group, and 71 patients in the ICP group.

Yes - crossover of therapy was not reported. However, there was some deviation from protocol if patients required treatment for a SjvO2 desaturation event. Both groups were treated using the same algorithm in response to low SjvO2. However, this algorithm included increasing the PaCO2 to 30-35 torr, or augmenting CPP, even if the patient was in the ICP targeted group.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No. Investigators were, for the most part, not masked to treatment protocols. Since this study required therapeutic intervention, bedside caretakers were necessarily aware of the patient's treatment assignment. However, investigators responsible for the post-injury follow-up and assignment of DRS were masked to treatment group assignment.

4. Were the groups similar at the start of the trial?

The groups were balanced with regards to demographic characteristics and injury severity variables, such as GCS, prehospital hypoxia and/or hypotension, and other factors, with the exception of a slight increase in the number of women (20% vs.10%, p = 0.048) and a slight increase in the number of patients with gunshot wounds (11% vs. 4%, p = 0.058) in the ICP targeted group (see table 2 in the paper).

5. Aside from the experimental intervention, were the groups treated equally?

Treatment groups were treated equally with regard to their intracranial injury. Baseline management was protocolized such that both groups were sedated with morphine, ventilated to maintain PaCO2 between 35-40 torr and PaO2 > 100 torr, and kept normothermic with antipyretics. In response to an episode of intracranial hypertension, both groups received vecuronium, mannitol, and CSF drainage. However, subjects in the ICP targeted protocol were hyperventilated to a PaCO2 of 25-30 torr in response to intracranial hypertension, whereas those in the CBF targeted protocol did not receive hyperventilation. Blood pressure management also varied between the two protocols: patients in the ICP targeted protocol were treated with Labetol for systolic hypertension > 160 mm Hg, whereas no therapy was given in the CBF group. Hypotension was treated with volume, dopamine, and/or phenylephrine in the ICP group if MAP was < 70 mm Hg whereas these same therapies were instituted for MAP < 90 mm Hg in the CBF group.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

The investigators performed power calculations for their primary outcome and subsequently enrolled enough patients to detect a large (50%) reduction in Sj O2 desaturation occurrence. The patients in the CBF protocol vs. ICP protocol had a significantly lower incidence of jugular venous desaturation episodes (30% vs. 50.6%; chi-square = 7.81, p = .006), with an absolute risk reduction of 20.6% (95% CI:6.9% - 34.3%). The relative risk of a jugular venous desaturation event for patients in the CBF protocol was 0.59; the relative risk reduction was 41% (95% CI:14%-59%). The patients in the CBF protocol also had a shorter duration of each desaturation episode (0.81 +/- 0.27 hrs/event vs. 1.52 +/- 0.54 hrs/event,p < .001). Using logistic regression analysis, investigators found a significant (2.4-fold higher) increase in adjusted risk of jugular venous desaturation for patients in the ICP-targeted group after adjustment for duration of monitoring, day one motor score, presence of a mass lesion on CT scan, and pupillary reactivity on day one (OR 2.36 +/- 0.81, p = 0.012).

Of particular interest was that the CBF targeted group experienced a reduction in frequency and duration of episodes of jugular venous desaturation caused by hypotension and hypocapnia . Patients had fewer desaturation events due to hypotension (8 vs. 27 events) and due to hypocapnia (10 vs. 23 events) in the CBF directed group. There was no difference in the number jugular venous desaturation episodes caused by intracranial hypertension (16 vs. 15 events), hypoxia ( 3 vs. 6 events), anemia (0 vs. 2 events) or seizure (2 vs. 0 events) in the CBF treated group.

The number of patients who had severe intracranial hypertension was similar in the two treatment groups, 22 (24.7%) patients in the ICP-targeted group compared with 26 (26%) patients in the CBF-targeted group. Thirteen (14.6%) patients in the ICP-targeted group died of intracranial hypertension, whereas 12 (12%) patients in the CBF-targeted group died of refractory intracranial hypertension.

Neurologic outcome was assessed at 3 and 6 months post-injury using the Glasgow Outcome Score and the Disability Rating Scale. The authors did not capture all patients in these follow-ups, for unclear reasons. Of the patients they did assess, there was no difference in the proportion of patients having a favorable recovery (with only mild to moderate disability) in the CBF vs. ICP-targeted protocols at three months (37.0% vs. 31.9%) or at 6 months (39.8% vs. 49.3%).

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Not immediately. The study demonstrates an important concept: "secondary ischemic insults after severe head injury can be prevented with a targeted management protocol"; namely, focused attention on maintenance of adequate MAP results in fewer cerebrovenous desaturation events. However, as with so many similar studies, the presence of multiple confounding factors makes it difficult to determine whether the intervention improves ultimate outcome.

In addition, the results must be applied with care to pediatric patients. We cannot directly translate the parameters used in the study protocol to the pediatric population: a target MAP > 90 mm Hg may not be appropriate for an infant, for example. In fact, since little is known about either the cerebral blood flow requirements or the autoregulatory capacity of the injured child's brain, we cannot merely "extrapolate downward" the target physiologic variables used in this study.

2. Were all clinically important outcomes considered?

Many important outcomes were considered. Both acute clinical and monitored (ICP elevations, jugular venous desaturations) endpoints were measured as were relevant long-term outcome scores. Certainly, many other outcomes could have been evaluated. For example, the investigators chose to evaluate jugular venous desaturation as their measurement of brain ischemia, yet they acknowledge the possible utility of a local measure of ischemia, such as brain tissue monitoring. However, the authors state their reasoning for their choices very succinctly and their outcome measures appear appropriate for their stated goals.

3. Are the likely treatment benefits worth the potential harms and costs?

The investigators acknowledged the potential harms of hypertensive therapy and actively sought these complications in their patients. They found no increased risk for development of new or worsened intracranial hemorrhage in patients who had CBF- directed therapy, nor were these patients at a higher risk for renal failure. However, the CBF-directed therapy group did have a significantly higher incidence of pulmonary complications (15% vs. 3.3%, p = 0.007). As a result, being in the ICP targeted group afforded a relative risk for ARDS of 22%. Patients in this group had an absolute risk reduction of 12% (95% CI 3-20%) and relative risk reduction of 78% (29% - 93%).Patients in the CBF targeted group received significantly higher fluid volumes and had higher central venous pressures, which raises some question as to the etiology of their pulmonary compromise (i.e., did these patients meet the standard criteria for ARDS or were they in fact experiencing hydrostatic pulmonary edema, cardiac failure, or neurogenic pulmonary edema made worse by the higher hydrostatic pressure?)

For the reasons outlined above, it appears that the CBF protocol is not ready for immediate clinical application, at least not as performed in this study. While it is encouraging that CBF targeted therapy decreases the number of jugular venous desaturations, it is not clear from this or other studies whether the treatment method can actually affect long term clinical outcome. In addition, it must be recognized that CBF-directed therapy as performed was associated with a nearly five times higher risk of pulmonary complications ("ARDS"), probably due to the increased fluid administration required to maintain blood pressures at a supranormal level. Therefore, until a more fluid-sensitive regimen is developed to optimize CBF to targets appropriate for the injured child, the CBF-directed protocol cannot be universally adopted.

References

1. Clinical calculator at: http://www.healthcare.ubc.ca/calc/clinsig.html
2. Cruz, J. Cerebral Oxygenation: Jugular Bulb Oximetry In: Tobin, MJ, editor Principles and Practice of Intensive Care Monitoring. New York:McGraw-Hill, 1998, pp.1011-1017.

 

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