Research news and notes

1. Should we use recombinant activated factor VII for acute intracerebral hemorrhage? 

Factor VII (rFVIIa) has been used for rapid reversal of coagulopathy in neurosurgical patients [5] and for the prevention of the expansion of intracerebral hemorrhage [4]. A new study published May 15, 2008, in the New England Journal of Medicine [3] sought to confirm their previous work that demonstrated reduced growth of intracerebral hematoma and improved survival and functional benefit [4]. They randomly assigned 841 patients with intracerebral hemorrhage to placebo or 2 different doses of rFVIIa (20 or 80 μg). The drug was given within 4 hours of the onset of stroke symptoms. The higher dose group displayed a significant reduction in growth of the volume of the hemorrhage, but the overall mortality and morbidity were not significantly different. This result is in contradiction to the previous study. Why were the results different? Which study should we believe?

The authors observed that a substantial area of edema surrounds the hematoma, and the total lesion volume, including edema, was not significantly different at 72 hours among the groups. Some patients appeared to benefit more than others. (On a post hoc analysis, the patients younger than 70, who had less than 60-mL of hematoma at baseline, less than 5 mL of blood in the ventricles, and were treated within 2.5 hours, had significantly lower odds of poor outcome.) In addition, the patient populations turned out not to be balanced. The most conspicuous imbalance—29% of the placebo group had intraventricular hemorrhage, compared to 41% of the high dose rFVIIa group. Intraventricular hemorrhage is an independent risk factor for poor outcome, resistant to the effects of rFVIIa. Another explanation was also offered: the outcome of the placebo group was better in the new study. This may have been chance or may have reflected real improvements in care for these patients. The bar may have been raised for any additional improvements in outcomes.

The lack of efficacy may also have been an artifact of the kind of outcome measures that were used (Glasgow outcome score, National Institutes of Health Stroke Scale). These tests are well-known measures, but are best at detecting mortality and serious disability. Subtler, albeit still functionally significant deficits may go unnoticed. Detailed neuropsychological evaluations are expensive but worth it. An intervention that can save a few IQ points can be very useful, even if the Rankin score has not changed.

What should we do now? When, if at all, should we administer rFVIIa? There is no clear answer. The authors proposed further study in a limited subgroup of patients at higher risk of rebleeding. I think that it is reasonable to suspect that rFVIIa may still help patients without intraventricular hemorrhage presenting soon after the onset of symptoms in whom the hematoma is still small. Institutions where a neurosurgeon is not readily available or the intensive care facility is suboptimal may have a worse outcome at baseline. There, rFVIIa may be more useful.

2. Routine screening for methicillin-resistant Staphylococcus aureus—is it useful? 

For some time now, we have been routinely testing all patients admitted to our Neurosurgical Intensive Care Unit for the presence of methicillin-resistant Staphylococcus aureus (MRSA). The logic behind the policy is solid—early identification and isolation of patients carrying these bacteria can reduce a nosocomial MRSA infection spread. In addition, proper surgical prophylaxis can be chosen for these patients. To determine if early MRSA detection changes nosocomial MRSA infection rates, Harbarth et al [2] studied 21 754 consecutive surgical patients at a Swiss-teaching hospital, comparing incidence of nosocomial MRSA infection between patients who had rapid screening on admission and those who did not. All patients received standard infection control measures. Among 12 participating wards, half were assigned to screening and half to a control group for 9 months, and then the assignments were switched for another 9 months. The infections studied included rates of nosocomial acquisition of MRSA, and most importantly, MRSA surgical site infection. Screening identified 515 MRSA-positive patients (5.1% of the population). The MRSA infection rate was very similar in both groups as follows: 1.11 per 1000 patient days in the intervention period and 0.91 per 1000 patient days in the control period.

This apparent lack of efficacy of the screening policy raises important questions. Is the effort and expense justified? The authors suggested that the combination of high prevalence of MRSA in the screened population and the low incidence of infection at their institution made finding a significant benefit to screening more difficult. They also cited many instances where emergency surgery precluded timely screening or left no time to wait for the results of the screening. On occasion, surgeons were reluctant to administer vancomycin. In a real-life study, the expense and effort expended on a screening program was not justified. Good general infection control and prevention practices were probably far more important. Universal screening should not be instituted without a careful analysis of the local epidemiology, existing patient population, and physician practices. Institutions who already have an MRSA screening policy should reevaluate the cost and benefit. Epidemiologic interventions that make sense in one situation or for one institution do not necessarily apply everywhere.

3. Is a revolution about to happen in radiation therapy? 

Radiation therapy is limited by the damage it causes to normal tissue. In the April 11, 2008, issue of Science, Burdelya at al [1] report an experiment in mice that uses a novel paradigm for protection of tissues against the effects of radiation. The authors recognized that apoptosis is a major mechanism by which cell loss occurs in tissues damaged by radiation. Moreover, they knew about an antiapoptotic mechanism that some tumor cells exhibit—constitutive activation of the nuclear factor κB (NF-κB) pathway. To minimize the side effects of the nuclear factor activation, the authors chose to activate the receptor that activates NF-κB in gut cells: toll-like receptor 5 (TLR 5). They chose gut cells as the protective intervention target because these cells are highly sensitive to radiation. The bacterial protein flagellin can directly activate TLR 5. However, administering a whole bacterial protein can induce an immune response. Therefore, the authors tested a variety of flagellin derivatives designed to resemble the active domain of flagellin. The derivatives were produced in Escherichia coli as a recombinant protein. One of the derivatives, the polypeptide CBLB502, was the most potent NF-κB activator.

In the central experiments of the project, a single dose of CBLB502 before a lethal dose of whole body irradiation, protected mice from both the gastrointestinal and hematopoietic radiation damage and improved their survival. Similar, albeit lesser protection was seen when CBLB502 was injected after irradiation. The drug, maybe thanks to its selectivity for particular normal tissues, did not confer any protection on tumors in mouse models. Next, 19 rhesus macaques were subjected to irradiation after a single injection of CBLB502 (11 animals) or placebo (8 animals). The 40-day survival rate in the treated animals increased from 25% to 64%. Finally, the authors tested whether the drug can increase the risk of radiation-induced cancer. The model was a mouse strain that regularly develops radiation-induced tumors. CBLB502 did not increase the rate of cancer appearance after radiation or change the survival of the animals.

This is a very impressive article that summarizes multiple experiments, each of which is worthy of notice on its own merit. The authors addressed all the key concerns. The efficacy of the drug in both mice and rhesus monkeys indicates that it is likely to be effective in humans. An increase in the therapeutic index and efficacy of radiation therapy can be revolutionary. The logical approach of the authors to drug design is also very promising. Rather than finding an agent that has a beneficial activity by serendipity, they used a logical sequence of experiments to find the optimal agent. Using the same method, it should be possible to design radioprotective drugs for additional tissues.