June Journal Club

First JC of the new academic year with a STRONG showing by the interns! Some great burgers put together by our own residency director, and terrific conversation. Let's get to the articles.

1) "A Clinical Decision Rule for Cranial Computed Tomography in Minor Pediatric Head Trauma," Atabaki, SM, et. al. Archives of Pediatric and Adolescent Medicine. 162(5) May 2008

Yet another attempt to derive a reliable prediction rule for what kids bonked on the head need CT scans.

Design:
Prospective, observational study of a convenience sample of patients aged 0-21 years at 4 pediatric trauma centers. Patients were included if they had a closed head injury and a GCS greater than 13, and if the treating physician elected to obtain a head CT. Patients with intracranial injury (defined as subdural, epidural, subarachnoid, intrparenchymal or intraventricular hemorrhage, as well as contusion and cerebral edema) were identified and the study attempted to identify high risk clinical features. The secondary outcome measure was defined as the performance of any neurosurgical procedure.

Results:
1000 patients meeting the study criteria were enrolled. 65 (6.5%) of these had a positive finding on CT, and 6 of the 65 (9.2%, but only 0.6% of enrolled patients) required neurosurgical intervention.

The study identified eight features which were strongly associated with the presence of intracranial imaging(the primary outcome measure) through recursive partitioning. These are as follows:

1) GCS < class="blsp-spelling-error" id="SPELLING_ERROR_15">hematoma were also statistically associated with the primary outcome measure, but fell out on recursive partitioning.

Discussion points:
Overall, while this study raised some good points, the group did not feel it provided a reliable decision rule for pediatric head injury. One of the biggest flaws is in the number of patients. While 1000 patients were enrolled, there was a very low incidence of injury. Only 6.5% of the patients had an injury, and only 6 required neurosurgical intervention. This is a very small number of patients on which to base a decision rule.

Another flaw is the fact that only patients receiving CTs at the discretion of the treating physician were enrolled, raising the possibility of missing injuries in those not scanned. An alternative strategy would have been to CT all kids with minor CHI and use this population to define the decision rule.

The upshot:
We all agreed that deciding which kids to image is challenging, but that this study does not provide a reliable guide. While it did identify some important high risk features, especially age < 2 years, we do not feel comfortable relying on the decision rule.


2) "Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage," Mayer, SA, et. al. The New England Journal of Medicine. 358(20) May 15, 2008

An attempt to identify a useful treatment for the otherwise vexing problem of intracranial hemorrhage.

Design:
Randomized, placebo-controlled trial where patients with intracranial hemorrhage were given either placebo, 20 mcg/kg, or 80 mcg/kg of rFVIIa within 4 hours after the onset of the bleeding. 819 patients at 122 sites around he world were analyzed, The primary outcome measure was defined as severe disability or death as determined by the modified Rankin scale at 90 days. Other outcome measures were also identified, including rate of hemorrhage growth and occurrence of thromboembolic events.

Results:
No statistically significant difference was found in any of the primary outcome measures.

Death rates: 18% in 20 mcg/kg group; 21% in 80 mcg/kg group; 19% in placebo group.
Poor outcome (as defined by a Rankin score of 5 or 6) rates were as follows:
26% in the 20 mcg/kg group, 30% in the 80 mcg/kg group, and 24% in the placebo group.

There was a decrease in the rate of hemorrhage expansion in the 80 mcg/kg group which reached statistical significance, but this had no effect on the primary outcome measures. Additionally, there as a significant increase in the number of arterial thrombo-embolic events (MI and CVA) in this group, but the total number of these events was low.

Discussion points:
Unfortunately, the study did not demonstrate any meaningful clinical improvement in patient outcomes. While there was some effect on the size of the bleeding, this did not translate into any improvement in death rate or Rankin score. This points out an important difference between "disease oriented outcomes" and "patient oriented outcomes." The former refers to changes in disease parameters; in this case, the rate of increase in patients' bleeding. The later refers to factored that effect patient functional or symptomatic outcome; in this case mortality and poor neurologic outcome. Patent oriented outcomes are typically more clinically important than disease oriented outcomes when considering the value of an intervention.

Interestingly, the results of this study are at odds with the authors' previously published phase 2b study which showed an overall reduction in mortality of 38% in patients receiving rFVIIa. While the authors attempted to identify reasons for this difference, we did not believe that they adequately explained this. It is important to remember that phase 2 studies are safety trials, and should not necessarily be relied on to provide definitive outcome results.

The upshot:
Clearly, this study did not demonstrate a meaningful clinical benefit from the administration of rFVIIa to patients with intracranial hemorrhage. I suspect we will see more studies in the future, but for now the role of rFVIIa is unclear.