Selfotel (Ross Bullock, M.D., Ph.D.). Selfotel was commercially developed by CIBA-GEIGY about 12 years ago, and it was the first glutamate antagonist to go into phase III trials. The drug went through a very extensive preclinical evaluation process, the kind of state-of-the-art drug evaluation process that a large company can bring to bear on a new compound. An important factor about this compound is that it is a competitive glutamate antagonist, and it binds to the same receptor site as glutamate. Most of Selfotel’s early evaluation was done using preinjury dosing paradigms in animal models. There were five animal studies related to TBI, which were well done and some of them are published.
When phase I volunteer studies were done, it was found that this compound had psychomimetic/psychoactive behavioral effects. This side effect limited testing of the compound particularly in alert, awake patients. For TBI higher doses were used, because the patients were in coma. The drug went on to later Phase II studies, through The American Brain Injury Consortium (ABIC). This was the first trial of Selfotel in the United States.
CIBA was feeling pressure in 1992-93 to get the compound into the marketplace, and consequently full analysis of the data from the phase II study was not completed before the phase III study began. They launched four, large, “state-of-the-art” phase III trials, with a tremendous amount of input from experts in academia. They aimed to enroll about 1,200 patients into each of two stroke trials and about 860 into two trials of severe TBI. All four trials were negative.
What did we learn from this experience? Some of the animal studies had shown spectacular neuroprotection. There had been a few negative studies in animal models, but the balance of information strongly favored an effect. In one phase II study (108 patients) there appeared to be an intracranial pressure (ICP)-lowering effect, exactly what you would want to see with this kind of compound. At the time that the phase III protocol was being designed, we obtained data on the amount of glutamate in tissue from microdialysis. Because of the long duration of glutamate exposure in the tissue, at least four days of treatment with the drug was proposed in human TBI.
Four concomitant trials in stroke and TBI were in progress, and the stroke trials began to show higher mortality rates in the Selfotel-treated group. CIBA closed all four trials. With further analyses, the excess mortality rates disappeared in the stroke trials. It is possible that CIBA shut down the TBI trials on the basis of incomplete information. CIBA then did a futility analysis, after unblinding all of the data, and found no efficacy for the drug in any of the trauma subgroups. What did emerge was a lower overall mortality rate for TBI, in a well-monitored trial with good data quality.
What can we say in retrospect about the Selfotel experience? Adequate brain pharmacokinetics was never done prior to the large phase III studies, during early clinical work-up, or in the animal studies. Adequate drug binding to the receptor in the presence of high glutamate concentrations was never shown, and the drug was not measured in brain. We know that in stroke and TBI, glutamate is present in very high concentrations. Perhaps the drug failed to bind the receptor competitively in this environment. In the future, pharmacokinetics should be done early and thoroughly; however, it is possible that this compound could make a difference in TBI or in high-risk cerebrovascular surgery. It appears a safe and effective drug, in pretreatment paradigms that had been done in animal models.
Cerestat (Ross Bullock, M.D.). Cerestat (CNS 1102) was the leading product of a small biotech company, Cambridge Neuroscience (CNS). Much of the data regarding this TBI trial is still confidential, and has never been released or published. Cerestat is a noncompetitive glutamate antagonist. It binds in the channel site of the glutamate receptor, that is, at the magnesium binding site, and only binds when the receptor is activated by high concentrations of glutamate, so-called use-dependency. Thus, the drug should not bind significantly unless glutamate was increased in the tissue; the more channels that were open, the more drug would bind, and thus “damp down the ionic storm.” The small size of the company and the relative lack of resources that could be put into development of the compound seemed to limit the amount of pre-clinical testing that was done.
The phase III protocol was designed with input from academia, including the European Brain Injury Consortium (EBIC); however, there were some points on which the sponsor had the last word. A 3-month GOS, which was at that time a departure from the norm, was the primary outcome measure. CNS enrolled 70 centers across Europe and the United States. Looking back at the data, over half of those centers enrolled fewer than five patients, a major factor in the outcome of the trial. A planned interim analysis at about 340 patients showed no benefit and no harmful effect. At the same time, the analysis of their stroke studies indicated lack of efficacy. To my knowledge, the final data analysis has not been published or presented. What can we learn from this trial? Large intercenter variability was probably enough to substantially degrade the quality of data.
CP 101-606 (Ross Bullock, M.D.). The most recently completed trial with a glutamate antagonist was by Pfizer with CP 101-606. A lot of information on this compound is currently under confidentiality, since there is ongoing data analysis. This compound was synthesized using techniques of molecular pharmacology and drug design. Molecular techniques were used to discover and clone receptors to which the compound could then be targeted. This is a “second generation” NMDA antagonist, and has fewer side effects than either Selfotel or Cerestat. Because the compound targets a specific subtype receptor (NR2B), it tends to have much cleaner pharmacology. The compound did not have any of the serotonergic effects that its predecessor, Eliprodil, had. The most interesting aspect of the compound is that it gets into brain tissue with apparently a fourfold higher concentration than seen in plasma. It achieves therapeutic concentrations quickly, and clears quickly when the infusion stops. Even at high concentrations, it produced no behavioral side effects in humans. At MCV, we used the compound in “open-label” phase II studies, and saw a potential beneficial effect and no bad side effects. The “phase IIb” trial is now completed, with 400 patients enrolled, and data analysis has been finished but not released. This seems to have been the best TBI trial to date in terms of protocol design, and development of the compound.
The mechanism of glutamate neurotoxicity is not disputed in neuroscience. These three compounds aimed at that mechanism have been highly effective in animal models, but have failed, in two of the three human trials. This is one of the biggest paradoxes that TBI researchers face. We must change the perceptions of industry and academia, if we want to persuade them to stay with this mechanism. Information from basic science presents many new fields to explore; however, in apoptosis, for example, there are no clinical drugs, the mechanisms are far less certain, and the contribution of apoptosis to TBI is not known and could be insignificant.
D-CPP-ene (Graham Teasdale, M.D.). The protocol for the Sandoz-sponsored study of the glutamate antagonist D-CPP-ene, is presented on the Lancet website. The data have been analyzed and reported in meetings. DCPP-ene was given twice a day for 5 days, and the recruitment time window was 12 h. The initial recruitment goal was 800 patients, but on statistical grounds the recruitment target was increased. The trial was completed when the new target was met, and 920 patients were recruited in less than 2 years in about 51 European centers. The population was well balanced for early severity and CT scan categories. The protocol did not allow inclusion into the study unless there was clear clinical evidence of brain damage on the CT scan. Only eight patients were lost to follow-up, four from each study group. Overall, the patients who received the active drug had a slightly worse outcome at 6 months than the placebo group. The difference was not statistically significant. This result, along with findings in other smaller studies that were not completed, reduced interest in development of either this agent, or other glutamate antagonists for treatment of severe head injury.
When a lack of benefit is found, it is necessary to ask if the dose of drug was appropriate. There was evidence that subjects received enough drug to affect brain function. Whether it was enough to affect the damage might be debated. Early in the study, we became aware that some patients showed abnormal involuntary movements of a choreoarthrotoid type, associated with hypertension. It was very likely that they were drug-related, and to manage the events would result in loss of blinding. There was a protocol change so that sedation and paralysis were continued for 12 h after the last study dosage. The incidence of abnormal movements then fell quite considerably. Drug treated patients took longer to come off the ventilator, longer to recover motor responsiveness, and longer to leave intensive care. Another question is if the timing of initiation of treatment appropriate? Only 4% in either placebo or treatment group began treatment within the first 4 h after injury. For those treated in the first 4 h, outcome was better in patients who received active drug. In comparing results across studies, there is a trend over time for fewer patients to receive treatment in that first 4-h “window.”
Question: You said there were well-done animal studies that had never been published. Why aren’t they in the public domain? Why will investigators sign on to do such studies when they will not be published?
Answer: The majority are negative studies, and it is difficult to have a negative study published. Most such studies are contractual and reimbursed by the companies.
Question: Why do you make so much of the fact that Cerestat is a noncompetitive antagonist?
Answer: It is a critical issue pharmacologically. This characteristic confers important benefit to the compound for use in TBI, where glutamate is markedly elevated. We did not have enough information from pharmacologists in the beginning with Selfotel; for Cerestat, we did.
Question: Do you think there was any possibility of detecting a treatment effect in the Selfotel trial based on how the trial was done?
Answer: In animal studies, with pretreatment, Selfotel worked extremely well. But, human TBI trials are not a pretreatment paradigm. We rationalized the design on the basis that “40% of TBI patients deteriorate later, so we will focus on those people.” However, we did not see evidence of subgroup efficacy in those patients.
Comment: Graham, I would like to congratulate you on what I think is a good use of subgroup analysis. It is certainly legitimate to take a subgroup analyses and generate from that a hypothesis that goes into another trial; indeed, it would be a mistake for the trialists not to do that analysis.
Answer: The issue of starting treatment soon after injury was touched on earlier. This may be possible with an agent that either has been in widespread use, or there is clear evidence of its safety. Treatment could be started without prospective consent, with administration less than 4 h from injury. I do not think that we can expect to start treatment so quickly unless we are using waived consent.
Question: You provided some plasma levels for D-CPP-ene and said that you were convinced that this was an active brain plasma level. How do you know in a disease as complex as an injury what a sufficient plasma level is?
Comment: The plasma levels achieved in patients were comparable to the plasma levels achieved in animal models where efficacy was shown; also, abnormal movements were seen in patients, and a higher dose would have been inadvisable.
Question: Over the course of a trial, how does an investigator ensure that the centers adhere to the protocol? How do we make the variability of management as small as possible, so that it is not a major confounding factor for outcome?
Answer: The high protocol compliance in the EBIC study of D-CPP-ene was illustrated in the very small number of protocol violations that led to exclusion of a patient’s data. Of 900 patients, only five cases were protocol violations, there was 99% follow-up. I think that there is an “overconcern” about variations in management and how this might influence the results of a trial. Randomization within each center is a simple way to minimize the issue. Moreover, variations in management could be an advantage in enhancing the validity of the result. At an early stage, looking for proof of concept, it may be helpful to have a very uniform population, treated in “high-compliance centers.” In contrast, in the definitive study aimed to determine the merit of a treatment for general use, management variations must be accepted.
Steroids (Raj Narayan, M.D.). Steroids have been in common use in neurosurgery since the 1960s and were initially used to treat brain edema associated with brain tumors. The effect was usually dramatic, and there was no doubt that glucocorticoids had an important role in the management of these patients. Laboratory studies showed that steroids reduced free radical production and had a protective effect on the brain. Consequently, steroids became commonly used in the management of a variety of neurological conditions, including head injury. In 1976, Gobiet compared low-dose and high-dose dexamethasone in 93 severe head injury patients to a previous control group and reported a benefit in the high-dose group. In the same year, Faupel reported a favorable response on mortality using steroids in a prospective, double-blind trial of 95 patients; however, there was a significant increase in the number of vegetative survivors and no improvement in favorable outcome.
There were subsequently at least six studies of steroids in TBI that showed no clear beneficial effect on outcome or ICP. Gaab reported no significant improvement in a prospective, randomized, controlled trial of ultra high dose dexamethasone starting within 3 h of injury. Grumme reported a prospective, controlled, randomized, multicenter trial of 396 patients with the steroid triamcinalone. There was a trend towards better outcomes in steroid-treated patients, especially if they had a GCS of <8 and had a focal lesion on CT scan. This combination was seen in 93 patients; however, there was no statistically significant difference between the treatment and the placebo groups at discharge or at 1 year. The authors concluded that treatment with steroids was potentially helpful in a subgroup of patients with TBI.
Two additional studies related to steroids are presented in more detail later. Marshall reported on the results of a large trial of tirilazad mesylate in TBI. This drug was believed to be more potent than traditional steroid formulations, without the glucocorticoid side effects. No overall benefit on outcome was detected. In a meta-analysis of randomized controlled trials in acute TBI, Anderson reported no clear benefit, but stated that there was a possibility of a small effect. As a result, the group recommended that a larger trial of over 20,000 patients be conducted in order detect this effect.
In summary, the data available to date does not demonstrate a clear beneficial effect of steroids in severe acute TBI. It has been speculated that certain subgroups may benefit; however, this is not proven. The evidence-based Guidelines for the Management of Severe Traumatic Brain Injury state, “The use of steroids is not recommended for improving outcome or reducing ICP in patients with severe head injury.”
Tirilazad (Lawrence Marshall, M.D.). The Tirilazad database represents approximately 1,700 severe head injuries, internationally and from the United States. I am going to make a few comments about those studies: what was right and what was wrong. I am not going to comment on the pharmacology, because there are complex issues in the science of free radical scavenging that would require much more time. Country-specific differences, or differences in care, are a significant issue: the difference in mortality for contusions was dramatic between countries, and in the United States between centers. Intercenter variation, not explicable by GCS or CT scan, was responsible for 40% of the variation in the Tirilazad trial. Some differences could be explained by overhydration initially. Patients appeared “overresuscitated”—blood pressures were elevated, as were ICPs and treatment intensity levels (TILs). In patients with intracerebral hemorrhages, the ones who came in with lower GCS scores, higher lesion volumes, and were operated on early had better out-come than those patients who had smaller lesions initially, a higher GCS, but who then deteriorated. The mortality was half for the patients who were operated on early. Such regional differences in care are important when looking at results overall, and serve to emphasize the need to have a high level of protocol adherence. There is another lesson here. We need to think through what the target should be in our clinical trials. Results from the Tirilazad trial indicate that high ICP—whatever the cause of the elevation— needs to be a primary target.
An additional finding from the Tirilazad trial concerned the wide variety of patients included, and the necessity to assure that the treatment groups were well balanced. We had real imbalances in both the Selfotel and Tirilazad trials concerning frequencies of CT scans and the variety of different CT diagnoses that were made. We know that these areas are associated with different patterns of outcome. For example, the presence of traumatic SAH skews outcome. In the Tirilazad trial and in the Selfotel trial, we found that patients who had minimal intracranial pathology had an extremely low mortality (<5%), and almost 80% had a favorable outcome. The inclusion of many such patients is likely to “front-load” a trial, and make it more difficult to find efficacy of a treatment. In contrast, patients who have one lesion greater than 5 cc have less favorable outcome, with a mortality rate more than three times that of the patients with minimal pathology. How do we classify the patients? For the most part, we have used stratification of the GCS, but the CT scan correlates better with outcome, except at the very bottom of the scale. If we do use CT scans, then there has to be a centralized reader. In our experience in the United States, almost a third of the scans had been misinterpreted or miscoded using the Traumatic Coma Data Bank classification.
One positive, but still troubling, observation from the Selfotel trial was the extraordinary performance of patients in the placebo group on the GOS. Clinical care has improved dramatically over the last two decades. Are we fighting ourselves by sticking to a certain assessment of outcome? It is going to be difficult to do better than a mortality of 7% in patients with epidural hematomas, as occurred in the Selfotel trial. Patients in the placebo group are doing very well with diagnoses of subdural hematoma. A few years ago, we would have expected that they would do poorly and a new treatment would have room to move people up into better outcome categories. We need to measure outcome better than we presently do.
Another variable that needs further discussion is traumatic subarachnoid hemorrhage (SAH). Using the grading system developed by Gabrielle Morris for SAH, we have seen that mortality varies from 13% to 44% among patients. Recording subarachnoid hemorrhage as “absent or present” is inadequate, and we more need data to help us develop a better classification of traumatic SAH.
To highlight the importance of balance within a trial, we need look no further than the experience with female patients in the Tirilazad trial. There was such a marked imbalance in the frequency of shock (4:1 for the Tirilazad group) that it masked our ability to analyze the data. Thus, given the relatively small number of women in the trial (incidence of severe TBI is lower in women than men), the data are meaningless. An additional observation from the Tirilazad trial, which also appears to be true in the Selfotel trial, is that the mortality rate for women is higher; but, in women who survive, cognitive outcome is better. We need to pay more attention to differences between men and women when we look at outcomes.
In our analysis of the Selfotel trial, we noted that the initial value of the ICP is a much more important predictor of outcome than cerebral perfusion pressure (CPP), as long as the CPP is at least 60 mm Hg. Neurological deterioration, which occurred in approximately 30% of patients, was usually associated with asymmetry of the pupils and increased the likelihood of death almost six-fold. These patients would likely benefit from a new treatment, and we should begin to concentrate our efforts in that select population. But, we must identify the patients early in the course of the injury. These results also suggest that treatments aimed at improving intracranial hypertension would be appropriate.
In summary, based on our previous experience with two large international trials and one large U.S. trial, we would recommend that one should exclude patients in the diffuse II category with lesions that are less than 5 cc in size. This criterion would lead somewhat surprisingly to a more equal distribution of patients with shock among treatment groups. Trial design should also take into account targeting elevated ICP: it kills 75% of the patients who die in the first week and contributes to many later deaths.
Question: When you say that we should make ICP the target, do you mean that it should be the primary outcome in clinical trials, or we should look into developing trials to treat intracranial pressure?
Answer: We suggested in the paper on the results of neurological worsening that it could certainly be a surrogate endpoint. It needs to be validated against a harder endpoint. I would say that if you do not see a change in ICP within a trial, you are not going to be able to show efficacy. These are the patients who ultimately go on to either have a poor outcome or die.
Comment: Another message from your study would be that one needs to see that the treatment lowers the initial ICP and the occurrence of worsening is lower in the treatment group; not that the treatment group does better for a given ICP. You can have a drug in which the treatment group had a lower ICP, but no better outcome, as was found in the phase II Selfotel studies. How soon was ICP measured in your study?
Answer: In the European Tirilazad trial, ICP was measured when the monitor was first put in, an average of 5.1 h from the time of injury. In fact, 70% of patients had it within 3.5 h. There is a trend in patients without surgical lesions that early aggressive attempts to reduce ICP favorably influences outcome. When patients went to the operating room earlier, the 6-month outcome in patients with intracerebral hemorrhage was dramatically better than in patients with delayed evacuation of hematomas—even though those patients were initially better clinically. To me, that is a hint that the ICP is critical, particularly in patients with an extraaxial lesion, but also in those with diffuse brain swelling. If one could treat high ICP earlier and more effectively, it should pay off both in terms of neurological deterioration, and with 6-month outcome.
Question: Your point is well taken that the assessment of the patient CT scans should be centralized; however, trials are getting larger and larger. Should they require central control and assessment of CT scans for the Corticosteroids Randomized After Significant Head Injury (CRASH) study with 20,000 patients? Also, you suggested several times that subarachnoid hemorrhage should be quantified. How can that be done in a huge trial?
Answer: Remember that CRASH focuses primarily on minor TBI, and only to some extent includes moderate and severe injuries. I think that for milder injuries, CT abnormalities may not need to play a role in the study. In severe injury, you can have variations in mortality rates of 6-10%, based on the CT diagnosis, if you have a large number of patients in the DI I or DI II categories. Either we limit a study to a targeted group of TBI patients, (remembering that the scan results change in 30% of the patients), or we include the entire spectrum. If we include all ranges of TBI, we need to make certain the treatment and control groups match.
PEG-SOD (Byron Young, M.D.). I am going to discuss the results of the PEG-Orgatine (PEG-SOD; superoxide dismutase) study. As you know, free radicals contribute to the generation of secondary injury. Before this study, there were a number of experimental models and clinical trials suggesting that free radical scavengers would improve the outcome from severe head injury. Probably Kontos and colleagues did the most important animal work in the early 1980s, and later Paul Muizelaar reported results of a phase II trial that suggested a benefit in head injury patients. Based on these and other studies a randomized, parallel, placebo-controlled, blinded, multicenter trial was done. The hypothesis was that PEG-Orgatine, which was a free radical scavenger, would prevent secondary injury and, therefore, improve the outcome from severe head injury. The trial was done in 29 centers in the United States, and there were 463 severely head-injured patients in the study. The patients received an intravenous dose of either placebo, 10,000 units, or 20,000 units of PEG-Orgatine within 8 h of injury. The primary endpoint was GOS at 3 months. Patients with GCS 3 were included in the trial, although some secondary analyses that eliminated results from these patients were done later. The planned secondary endpoints were mortality and the Disability Rating Scale (DRS). The distribution of patients receiving drug and placebo was as it should be. The bottom line of this trial was that there was no significant difference in neurological outcome (GOS, DRS) or mortality between the patients treated with PEG-Orgatine and those receiving placebo.
There were, however, better but not statistically significant outcomes in the patients who received 10,000 units/kg PEG-Orgatine compared to those who received the placebo or the 20,000 units/kg dose. At 3 months, there was an absolute difference of 7.9% improvement, and at 6 months, a 6% improvement using the dichotomized GOS (good recovery or moderately disabled vs. severely disabled, vegetative or dead).
What questions were raised by this study, and what have we learned? Why weren’t the statistics significant even though there was a measurable difference? Was there is a type 2 error? The study was designed to detect a difference of 14% with a 90% power. Was that adequate? The trial size and the treatment differences sought were based on a phase II trial. Did we miss a clinically significant difference between two arms of treatment? We would a new trial to detect a smaller, although important, treatment effect. What about standard care? There was good adherence to the protocol, but at the time we were not focused on the intercenter variations in routine treatment of TBI. That may be very important. The only statistically significant difference in this trial was that the patients treated with 10,000 units of PEG-Orgatine had a decreased incidence of acute respiratory distress syndrome (ARDS), but that did not seem to make a difference in mortality.
IGF-1/growth hormone (Byron Young, M.D.). We have just completed a single-institution, controlled trial in which we studied whether or not the administration of insulin-like growth factor (IGF)-1 and growth hormone and would improve neurological outcome and alter metabolic sequelae after severe head injury. IGF-1, which is produced in the liver, mediates the effects of growth hormone, and is important for organ growth. It stimulates glucose uptake, glycogen synthesis, net protein synthesis, amino acid transport, and DNA synthesis; and, it causes cellular proliferation both systemically and within the central nervous system. Patients who have a severe head injury are hypermetabolic. Their actual metabolic rate is about 40% more than their calculated metabolic rate, and they are in negative nitrogen balance. You can provide enough nutrition to give them a caloric positive balance, but nitrogen repletion alone will not result in positive nitrogen balance. By administering growth hormone (GH) and IGF-1 we wanted to push these patients to a positive nitrogen balance. We thought this might improve clinical outcome by reducing or preventing anabolism, and reducing infection, preventing secondary injury, and helping the reorganization of the central nervous system.
The particulars of the study were as follows. The primary endpoint was improvement in nitrogen retention. We also wanted to determine whether this could be done safely: in the literature there are reports of adverse effects, primarily from lowering glucose. The patients in the study had GCS scores 4-10. We started the IGF-1/GH within 72 h of injury, and we used traditional recommendations for nutritional support. There was no difference in the demographics between the control and IGF/GH groups.
We were able to demonstrate that we could achieve sustained positive nitrogen balance in patients with severe head injury; however, this made no difference in the outcomes measured. There is no difference in the DRS. We also did quite a battery of neuropsychological tests, and there were no significant difference between groups at any time throughout the trial. We followed these patients for 24 months. There were more infections in the patients who were treated than in the control group (not significant). The conclusion of this study is that IGF1/GH blunts the metabolic sequelae of TBI, but does not improve the neurological outcome, and may increase the risk of infection. After we finished the study, we compared the pulmonary complications in our patients with the ABIC database and it appeared that the patients that received IGF-1 and GH showed a reduction in the incidence of ARDS.
At the start of the trial Genentech provided the IGF-1. In the middle of the trial there was a corporate restructuring, and they decided to no longer supply the IGF-1. After about 6 months of conversation with our university lawyers, Genentech reconsidered. About 6 months after that, the European trials with GH and IGF-1 were stopped for safety reasons. Even though we saw no safety problems, our study was also stopped. Did the early end of the trial affect its outcome?
Comment: We have a huge discrepancy among TBI trials. On one hand is the small PEG-SOD study showing a 60% better outcome at 6 months, possibly an 80% better outcome at an earlier time point, for a drug that is given in one dose and is completely safe. On the other hand, sits the CRASH trial, designed to include 10,000 patients treated with high-dose steroids, for which no efficacy has been shown before and where there are well-known side effects. Surely PEG-SOD is the better drug for a mega-trial. Focus such a trial on the emergency room with a single dose given as early as possible, when free radicals are known to be active.
Comment: There has been expectation that one study will answer everything—a so-called mega-study. Isn’t this a bit of an illusion? There is a strong desire to examine a trial that is negative on its primary, protocol-specified outcome measure, in order to find a positive “subgroup.” People are looking at subgroups retrospectively and saying, “Well, here is where the action is. Let’s do a large trial looking at this.” It is treacherous to do that.
Nimodipine (Graham Teasdale, M.D.). Studies of Nimodipine in head injury began in 1987. At that time, there was a low level of interest in pharmacological treatment of TBI, apart from trials of steroids with varying doses in smallish numbers of patients. There was clear evidence that Nimodipine was beneficial in spontaneous subarachnoid hemorrhage, reducing the incidence of infarction and ischemia and improving outcome.
Two studies were done in relatively unselected head injury populations: HIT-1, involving five British centers and Helsinki, and then HIT-2, with about 12 centers in different parts of Europe. These studies showed a 4% absolute improvement and 8% relative improvement for favorable outcome, which was not significant. Both of these involved a 7-day treatment with Nimodipine. In HIT-1, 20% of patients were recruited and treatment started within 4 h of injury. HIT-2 was started while HIT-1 was still going on; however, in this second trial, the proportion of subjects entered in less than 4 h fell to 10% of those recruited, and the relative difference for favorable outcome dropped to 2%. Although these results were disappointing, the recognition of the drug’s effect in spontaneous subarachnoid hemorrhage, along with evidence from the Traumatic Coma Databank on the importance of SAH in head injury, prompted examination of the HIT-2 data to see what was going on. This analysis showed overall greater mortality in patients graded as having traumatic SAH on the CT scan, but outcome was better (8% improvement) in patients treated with Nimodipine.
This finding stimulated two activities: a further retrospective analysis of the HIT-1 database and a new prospective study. The study of the HIT-1 database indicated that traumatic SAH patients did slightly worse with Nimodipine than placebo. In contrast, a clinical study (HIT-3) involving 123 patients with CT scan evidence of SAH, admitted to 12 centers in Germany, showed a difference in the rate of favorable outcome for Nimodipine-treated patients. In a meta-analysis of these studies, there was a “just-significant” improvement in mortality and disability in Nimodipine treated-patients. HIT-3 had some limitations. For example, on review of the 123 patients admitted, 20% were found not to have subarachnoid hemorrhage. Although the overview resulted in Nimodipine being registered for the treatment of traumatic SAH in some countries, it has not been widely accepted as a standard treatment. A dialogue between clinicians and Bayer prompted the company to do a further prospective study, HIT-4. Results are not available at the time of this report.
This sequence of studies illustrate how an interesting subgroup can emerge from trials, and be evaluated retrospectively and prospectively. In the end, through Bayer sticking with the area for 12-13 years, a definitive answer will be obtained.
Question: It is my understanding that before the Nimodipine trials, there was not a single published preclinical study in any animal model of head injury. I was wondering how the company could possibly have convinced themselves to launch a large-scale clinical trial with no preclinical data available?
Answer: It was firmly established in the 1970s that ischemia is a major component of brain damage after head injury. Demonstration that Nimodipine had a good effect in models of ischemia seemed to be sufficient to move to patient studies. At that stage showing a good effect in a model of ischemia seemed to be sufficient to jump to patients with either spontaneous SAH or head injury. It was not just the company that was convinced, but the investigators as well. We were correct for spontaneous bleeding; the position in head injury remains to be defined.
Bradycor (Anthony Marmarou, Ph.D.). There had been a number of animal studies using bradykinin antagonists that dealt predominantly with brain swelling. It was on the basis of these preclinical studies that SmithKline Beecham elected to use intracranial pressure as the primary endpoint in the Bradycor trial. A prospective, randomized trial was designed, and began in 39 centers in the United States with coordination by the American Brain Injury Consortium (ABIC). After 139 patients were accrued, the company placed the trial on clinical hold. The hold was based on new animal work using a second batch of the drug conducted during the course of the trial. The first batch of the drug was made in the United States, and this was the one that we were using in the trial. The second batch was formulated in Europe, and samples from this batch were tested in rats by a contract laboratory. In a study with 12 animals, all of the rats died. This event was startling to us because we had observed no safety concerns with our patients in the trial, and our preclinical data had been clean. We (ABIC and the clinical centers) continued to hold, but presumed that this issue would be resolved by additional studies; however, the trial was stopped and the blinded randomization was broken. Therefore, I can only report the data that we had available at that time; the numbers will be small in the various groups.
There were no significant differences between control and treatment groups in any of the adverse event categories. The study groups were balanced with regard to the intracranial hypertension, cerebral hemorrhage, and in all other factors.. With regard to the primary endpoint (the percent time ICP. 20 mm Hg), there was a trend for reduction of ICP with Bradycor, although not significant. Looking at the entire intent-to-treat population, there was certainly variability in ICP, but a trend toward better control with treatment. With regard to outcome, we saw a reduction in mortality in the drug group. Analyzing the dichotomized GOS at 3 months, we saw close to a 10% improvement. This trend was seen at 6 months with a difference in favorable outcome between placebo and drug, but again not significant considering the small number of patients. Interestingly, we observed an improvement (not significant) in neuropsychological indices in the drug-treated group at 3 and 6 months. It is important to note the cooperation by SmithKline Beecham in assisting us in proceeding toward publication of a so-called negative trial.
What have we learned? Firstly, considering the favorable effect upon GOS, it is possible to include patients with GCS 3 and one reactive pupil. This trial shows that, even though there is devastating injury as evidenced by the low GCS group with one reactive pupil, some patients do show measurable improvement. With regard to interim analysis, we believe that guidelines for breaking the blind should be firmly established. In this case, the 100% rodent mortality using the second batch of drug could not be reproduced. This was confirmed by a second contract laboratory. It was thought that the rats were hyperthermic as a result of a heating lamp used during the testing, but no further work was done to assess the true safety of the second batch of drug. The investigators involved in this trial had no voice in the decision to break the blind and stop the trial. We believe that we owe it to our patients, to complete a trial whenever possible, and to reach a scientific conclusion.
One lesson is to do as much as possible before the trial starts. Stopping rules (safety, futility) should be stated clearly and agreed to at the outset. The manufacturing process and drug supply should be in place prior to entering patients.
Dexanabinol (Nachshon Knoller, M.D., and Anat Biegon, Ph.D.). Dexanabinol is a novel synthetic chemical analog of the active component of marijuana. It was designed as a mirror image of the naturally occurring compound, so it is not recognized by the cannabinoid receptors in the brain that mediate the intoxicating effect of marijuana. Preclinical studies demonstrated that Dexanabinol is a noncompetitive inhibitor of the NMDA receptor, a free radical scavenger and antioxidant, and an inhibitor of the pro-inflammatory cytokine TNF alpha. Dexanabinol inhibits breakdown of the blood-brain barrier, edema formation, and neurological deficit in a closed head injury in rats with a therapeutic window of 6 h. It has also been shown to be efficacious in models of axonal crush injury to optic nerve, and in focal and global ischemia. Following completion of a phase I safety evaluation in healthy volunteers, work started on the design of the study protocol in severe head trauma. Several phase II and phase III trials of neuroprotective agents have been already completed or ongoing (PEG-SOD, hypothermia, Tirilazad) or were on hold (Selfotel) at that point in time, such that lessons learned from these trials could be incorporated into the design of the Dexanabinol protocol. Two major design principles were implemented based on the analysis of pre-clinical data and data from previous trials so as to increase the likelihood of detecting a drug effect: (1) tighten inclusion/exclusion criteria and (2) follow the lead from preclinical studies.
Criteria were chosen to exclude patients with a high likelihood of extreme outcome (death or good recovery) regardless of treatment. To achieve this end, patients with enrollment GCS 4-8 were included unless both pupils were fully dilated and fixed. The latter subgroup was excluded due to extremely poor prognosis. Evidence of intracranial pathology was required (CT category 2 or above) but patients with pure epidural hematomas were excluded since this subgroup has an extremely good post-surgical prognosis. Finally, due to the potent antiedema effect of the drug in animal models, there was a strong emphasis on monitoring ICP (a measure of the brain edema) in this study such that only patients requiring ICP monitoring were enrolled.
Treatment parameters (time to treatment, dose, and duration) were kept as close as possible to those established as safe and efficacious in relevant preclinical models. Thus, Dexanabinol was delivered within 6 h of injury (window of efficacy established in closed head injury and axonal crush models). The doses were derived from comparative pharmacokinetics in animal studies where effective doses in rats (2-5 mg/kg) produced peak plasma levels of ~2-5 mg/mL, and in the phase I trial. Plasma levels in this range were obtained in volunteers and patients at doses of 48-200 mg/subject, so this was the dose range chosen for the patient study. The drug was administered only once, since repeated administration in the animal models did not appear to provide additional benefits. In fact, the best treatment paradigm in rats consisted of one injection within an hour of injury and a second injection after 6 h (additional treatments at 12 and 24 h, and 3, 7, or 10 days showed no further benefit). Since an hour after injury was not considered a realistic treatment time to expect within the framework of a clinical trial, a single injection within 6 h was chosen.
The study was not powered for efficacy; rather the expectation was to derive safety data and some indicators for efficacy through influence on surrogate markers such as ICP and early recovery. The phase II trial of Dexanabinol in severe head trauma took place in all six neurosurgical units in Israel between 1996 and 1999. The study was a multi-center, randomized, double-masked phase II b trial of a single dose of Dexanabinol intravenous solution with a placebo control. A total of 101 patients were randomized to receive a 48-, 150-, or 200-mg dose of Dexanabinol, or an appropriate volume of vehicle. The primary outcome (safety) measures were ICP, cardiovascular function, and clinical outcome/adverse events. Secondary outcome (safety) measures were dichotomized GOS, GOAT, and DRS.
The study patients had the demographic profile expected for TBI: mostly young (mean age, 30 years), mostly males (80%), victims of motor vehicle accidents (70%). There were no statistically significant differences in important risk factors (GCS, CT, age) between the drug and placebo groups. Dexanabinol was shown to be safe and well tolerated in the dose range tested, as expected from the preclinical and phase I data. The drug did not change the adverse event profile, such that the observed adverse events and their relative frequency were those characteristic of the severe TBI population. There were decreases in the incidence of fever, hypotension and mortality, although the differences did not reach statistical significance. Significant effects of the drug were seen on ICP. The drug appeared to prevent the increase of ICP over the first 2-3 days postinjury, such that mean ICP values (which were initially similar in the drug and placebo groups) rose above 15 mm Hg in the placebo group and remained consistently below 15 mm Hg in the Dexanabinol group. The percentage of time ICP was above 25 mm Hg was decreased in the Dexanabinol treated groups at all doses, and the effect was statistically significant from the second day. This stabilizing effect of Dexanabinol on ICP was achieved without lowering systolic blood pressure; conversely, the percentage of time systolic blood pressure fell below 90 mm Hg was reduced in the Dexanabinol-treated patients.
Examination of the distribution of patients among the various GOS categories over time results in several expected and some unexpected observations. The trend towards lower mortality and higher percentage of patients in the “favorable” outcome categories, observed in recent clinical trials, continues in this study, such that mortality is below 20% and a more than 65% of patients achieve favorable outcome without treatment. Thus, dichotomized GOS used in the traditional way produces a ceiling effect, which makes it hard to show a drug effect. Although, as expected, there were no significant effects of treatment on 6-month GOS; trends towards better outcome in the Dexanabinol-treated patients were stronger in the more severely injured subgroups (GCS 4-6, CT. 2) and at the earlier time points (1 and 3 months). In fact, the percentage of patients achieving good recovery after 1 month was significantly increased in the Dexanabinol-treated group. Statistically significant differences in favor of the drug were found on the GOAT. GOAT scores were persistently better in the Dexanabinol-treated patients throughout the follow-up period.
These lessons should promote discussion of the design of future phase III studies in relation to patient selection as well as outcome measures. Excluding patients without CT evidence of severe parenchymal damage, or those above GCS 8 might increase the likelihood of a significant effect of treatment. Alternatively, one may consider the inclusion of patients with GCS 3 and one fixed dilated pupil. In terms of outcome criteria, it appears that a 10% difference in favorable outcome on the dichotomized GOS should be replaced by another, more innovative statistical analysis, which better, reflects the reality of current outcome distribution in severe TBI. We should also consider other endpoints with clinical importance, such as ICP/CPP management, evolution in CT pathology, shorter hospitalization, shorter ICU stay, and early recovery. From the clinical perspective as well as in terms of cost effectiveness and reduction of suffering for patients and families, a drug that facilitates ICP management, shortens ICU and hospital stays, and promotes achievement of the good recovery category after 1 month instead of 6 months, is a very good drug indeed.
SNX-111 (J. Paul Muizelaar, M.D.). Good preclinical studies are essential for a good clinical trial. We need to understand the mechanism of action of the drug. There should be improved outcome in experimental animals. For most of the trials that were designed before the trial of Dexanabinol or SNX111, that was really not the case. What preclinical data existed about SNX111? An important finding in studies of stroke mechanisms was that this drug was effective if given 24 h after transient forebrain ischemia. This long “window of opportunity” was one of the attractive features of the drug. In addition the effect appeared long lasting, and was still present on day 28 after injury. So, before the TBI trial was started, we determined what the time window for the drug was. In preclinical work, we chose a dose of 4 mg/kg and gave that to animals 15 min before the injury, and 15 min, or 1 h, 2 h, 4 h, 6 h, or 10 h after injury. We looked, not at outcome, but at a very specific measure of metabolic (mitochondrial) function in the brain. We found that this drug works very well if given 2-4 h after the injury. Then we looked at mitochondrial function, efficiency and found again that the drug given later was actually more effective than when given right after the injury. Next, we looked at different doses, and these doses were then always given 4 h after injury. In addition to 4 mg/kg, we also looked at 0.5 mg/kg and 1.0 mg/kg; 1.0 mg/kg was still fairly effective, but 0.5 mg/kg was not. So on the basis of these data, and after testing pharmacokinetics in animals and in human volunteers, a dose was chosen for this particular drug. We also felt that this drug in this dose could be successful in TBI because the time window allows a later administration. One important finding from our preliminary experiments was that by targeting mitochondrial function, we were able to get a dose and time window using only 39 animals. For behavioral outcomes, we would have needed 114 experiments.
The trial was designed in 1995 with standard inclusion criteria for severe closed head injury. The only thing I feel we did a little bit differently was to use a decision tree published by Choi. The decision analysis combined parameters for patient outcome. We used this particular decision tree to derive strata in the trial for predicting those patients likely to have a good outcome. We predicted good progress in patients with bilateral pupillary responses, under 40 years old (y/o), and GCS > 4; or a unilateral pupillary response and <30 y/o; or a motor score of 5 and <25 y/o. Other patients were considered in a poor prognostic stratum.
What have we learned from this trial? The trial was suspended when it was found that mortality in the patients receiving the drug was higher than in the patients who were receiving placebo, and the company has not yet released the full data. A summary of what we know follows. We entered 160 patients before the trial ended. The strata for expected good outcome and expected bad outcome were approximately equal in the treatment groups. There were 40 patients treated with placebo who were expected to have a poor outcome, and 40 treated with drug who were expected to have a poor outcome; the same figures for patients with an expected favorable outcome. The mortality for the SNX arm was almost 25%, while for the placebo arm it was 15%. It was very disappointing, because we thought that we finally had a drug that could be given a long time after the initial injury. At the start, we knew that the drug caused hypotension; so, the design stated that treatment was never given if patients did not have a normal CVP, and if dopamine and/or phenyl-epinephrine were not already hanging as an infusion.
From this trial, we can see what very aggressive fluid management will do. I think I never saw better preclinical data with any drug; but the animals were not as severely injured as many of our patients. Perhaps that contributed to the disappointing outcome.
Anticonvulsants (Nancy Temkin, Ph.D.). The University of Washington has conducted three acute trials in epilepsy after traumatic brain injury: Dilantin, 1983-1989, Valproate 1990-1997, and, currently, magnesium sulfate. Briefly, the Dilantin study was a randomized, double-blind, parallel group study; 404 patients were entered, treatment was initiated within 24 h, and 24% of the subjects were lost during the 2-year follow-up. The primary goal of the study was to see if Dilantin prevented epileptogenesis. We found that the drug prevented seizures in the first week after head trauma, but, even though treatment continued for 1 year, there was no effect on late seizures either during the treatment period or after treatment was stopped. We found that phenytoin had substantial medical and neurobehavioral side effects, especially early on, in the more severely injured cases. The second study used a similar design to see if Valproate had an antiepileptogenic effect. We examined two durations of Valproate therapy, 1 month and 6 months, with follow-up continued to 2 years. Of 400 patients entered, about 15% were lost to follow-up. Conclusions were that Valproate showed no benefit over phenytoin for early seizures, and neither drug prevented late seizures. There were essentially no adverse neuropsychological effects in the Valproate groups; however, there was a trend towards higher mortality, the cause of which we were never able to determine. Our current study examines magnesium sulfate: randomized, double-blind, parallel group, placebo-controlled, about 400 patients. The treatment is initiated within 8 h, and the duration of treatment is 5 days. We are looking at 6-month follow-up rather than 2 years, using a composite endpoint. In addition to antiepileptogenesis, the study will evaluate survival and, primarily, neurobehavioral outcome.
If you have two studies, one with 100 patients targeted to the mechanism of a drug, and another study with 200 patients, but in 100 patients the drug is not appropriate and has no effect, then you will have the same power for both of these studies. If more than half the patients who are unaffected, the effect on the power will be more extreme. As much as possible, you want to know what a drug is supposed to do, and how to identify patients for whom that drug might be useful. In our Dilantin and Valproate studies, we were looking at effect on seizures, so we used patients who were at high risk for developing seizures. In the magnesium sulfate study, the drug effect is likely very broad, so the inclusion criteria are much less stringent than in the two seizure studies.
Comment: There are a couple of issues surrounding use of anticonvulsants to keep in mind. The first is a pharmacokinetics issue. Those of us who were involved in the Tirilazad trials learned a very difficult lesson, and that is that drugs like phenytoin, and even phenobarbital, stimulate liver enzymes and enhance the metabolism of drugs like Tirilazad. The second issue has to do with the potential impact of depressant-type agents. Anticonvulsants are depressant agents and may affect brain plasticity and recovery after trauma. Animal work has shown that administration of stimulants during a critical phase after injury facilitates behavioral recovery, and administration of depressants blunts that recovery. Wholesale, continuous use of anticonvulsants in “neurocritical” patients, has to be looked at very carefully. These trials are very important.
Comment: One has to ask if a particular outcome is an appropriate measure of the function that you would like to improve. What is the clinical utility of a particular outcome? Another issue concerns use of composite scores. While they may be appropriate, one has to ask, “What is the clinical interpretation of composites? What does such outcome mean?”
Cerebral perfusion pressure (Claudia Robertson, M.D.). The purpose of this study was to determine if a management protocol could be developed to reduce the incidence of the most common causes of secondary insults, particularly hypotension and hypocapnia, after severe TBI. The first hypothesis was that the treatment protocol, coined the “CBF-targeted” protocol, would reduce the incidence of secondary ischemic insults. The second hypothesis was that if the CBF-targeted protocol successfully reduced ischemic insults, the incidence of refractory intracranial hypertension would be reduced, and the third hypothesis was that neurological outcome would be improved.
Two management protocols were compared in a prospective, randomized, single-institution clinical trial. This information is summarized in . The control protocol was called the “ICP-targeted protocol.” This control protocol consisted of a traditional TBI management strategy, where the primary goal of the treatment was to reduce ICP. The treatment or CBF-targeted protocol was designed to improve cerebral perfusion and prevent secondary ischemic insults. There were four major differences in the two treatment protocols. The first difference was in the end-points for fluid administration. In the ICP-targeted group, maintenance fluids were given. In the CBF-targeted group, fluids were given to maintain a normal central venous pressure or pulmonary wedge pressure. The second difference was the goal for mean blood pressure, at least 70 mm Hg in the ICP-targeted group and at least 90 mm Hg in the CBF-targeted group. The third difference was the goal for cerebral perfusion pressure, at least 50 mm Hg in the ICP-targeted group and at least 70 mm Hg in the CBF-targeted group. The final difference was in the use of hyperventilation. Although hyperventilation was not used in any patient as a routine, the ICP-targeted protocol allowed use of hyperventilation as a treatment of intracranial hypertension. The CBF-targeted protocol did not use hyperventilation, because, although it lowers ICP, it does so at the expense of reducing cerebral perfusion.
Comparison of the Major Differences in the ICP-Targeted (Control) and CBF-Targeted (Experimental) Protocols
The inclusion criteria were adults ($15 years), who were admitted within 12 h of a severe TBI and who had a motor component of the GCS of 5 or less on admission. Exclusion criteria included only brain death, contraindication to placement of a jugular bulb catheter, or severe associated systemic injuries.
The primary outcome measure for the trial was the incidence of secondary insults, indicated by the occurrence of jugular venous desaturation. The secondary outcome measures were the incidence of refractory intracranial hypertension, and neurological outcome measured by the 6-month GOS and the DRS. The sample size of 182 was chosen to give an adequate power to detect a 50% reduction in the incidence of jugular venous desaturation. This sample size would also detect a reduction in the incidence of intracranial hypertension from 27% to 12%, and an increase in the number of favorable outcomes (good recovery/moderate disability) from 35% to 54%. It was recognized that this number of patients would only detect a very large effect on neurological outcome; however, this is the improvement in outcome that has been observed in clinical series with this type of management protocol.
The patients were randomly assigned to treatment by time blocks. Each 4-month rotation of neurosurgeons through the ICU was divided into 2-month treatment blocks. The treatment protocol was randomly assigned for each of the 2-month treatment blocks, and all patients admitted to the hospital were treated by the assigned protocol for that 2-month block. In this manner, each physician group had experience with both treatment regimens, but the order of this experience was random.
The study required eight 4-month blocks of time to enroll the required number of patients. A total of 89 patients were enrolled in the ICP-targeted treatment months, and 100 patients were enrolled in the CBF-targeted months. Because this randomization scheme does not completely protect against bias, the patients who were admitted but not enrolled in the study during the time period of the study were compared to the study group. The only differences were those that would be expected because of the exclusion criteria for the study. The excluded patients had a lower initial GCS, a higher frequency of abnormal pupils, a higher frequency of gunshot wounds as the cause of the injury, and a higher frequency of prehospital hypoxia and hypotension. The characteristics of the patients enrolled in the two treatment groups were also compared. There were no significant differences in any measure of demographic characteristics or initial injury severity.
The CBF-targeted protocol, was very successful in preventing secondary ischemic insults. The number of patients who had one or more episodes of jugular venous desaturation was reduced from 51% to 30%, and the length of time that jugular venous saturation was decreased was significantly reduced. This improvement occurred primarily in secondary ischemic insults caused by hypotension and hypocapnia, which were the two aspects of treatment emphasized by the CBF-targeted protocol. The reduction in ischemic insults occurred with the CBF-targeted protocol throughout the entire study, that is, it was not physician-dependent and it did not depend on which protocol was assigned first to each physician group. In addition, the treatment protocol remained a significant predictor of the occurrence of secondary ischemic insults, even when logistic regression analysis was used to adjust for injury severity. In the final best-fit logistic model, the ICP-targeted protocol was associated with a 2.4-fold increased risk of an ischemic insult.
The CBF-targeted protocol, however, did not reduce the incidence of intracranial hypertension. The mean ICP, the duration of time that the ICP was elevated, the percent of patients with refractory intracranial hypertension, and the number of patients who died of intracranial hypertension were similar in the two treatment groups. The CBF-targeted protocol, did not significantly improve neurological outcome either. It must be remembered that the study was not powered to detect anything but a very large improvement in outcome. However, the trend was for a higher morality rate, and a lower percentage of patients with a favorable outcome in the CBF-targeted protocol. Because of this apparent paradox, where a marked reduction in secondary ischemic insults did not result in an improvement in neurological outcome, potential complications of the CBF-targeted protocol, which might have confounded the ultimate outcome, were examined.
Three complications were possible from the treatment required to maintain an elevated CPP. A higher blood pressure could cause delayed or recurrent intracranial hematomas. Higher fluid intake and prolonged use of pressor agents could result in pulmonary edema, and high doses of pressors could be associated with renal failure. Any one of these complications could have offset any beneficial effect of reducing secondary insults. Two complications were easy to eliminate: there was only one case of acute renal failure, and there was no difference in the incidence of either recurrent or delayed intracranial hematoma between the two protocols. The incidence of ARDS, however, was five times higher in the CBF-targeted protocol group than in the ICP-targeted group (15% vs. 3%, respectively). The aspects of treatment that were related to the development of ARDS included the following: a greater intake of fluid, a more positive fluid balance, a higher central venous pressure and pulmonary wedge pressure, and more prolonged use of pressors (both dopamine and epinephrine). Finally, the outcome in the patients who developed ARDS was significantly worse. Seventy-one percent of the patients who developed ARDS remained vegetative or died of their injury by 6 months postinjury.
To summarize, the CBF-targeted treatment significantly reduced the incidence of secondary ischemic insults, from 51% to 30%, but this reduction in ischemia did not improve neurological outcome. There may be several explanations for these findings. First the sample size was not large enough to detect a realistic difference in outcome. Second, because jugular venous desaturation was treated in both groups when it did occur, this minimized any adverse effect on outcome. Finally, the beneficial effects of reducing secondary ischemic insults may have been offset by systemic complications, especially ARDS.
The lessons that can be learned from the experiences of this study include the following: (1) Management trials can be done in TBI patients. There are many management issues that exist in neurocritical care, and it is only through systematic controlled studies that issues such as this can be sorted out. (2) The current recommendation of keeping all TBI patients at a CPP of at least 70 mm Hg needs to be reconsidered in light of the significant complications that were observed in this study and the lack of benefit on overall outcome.
Question: Given your findings, how would you change your management?
Answer: This study suggests that we need to individualize treatment. It does not make sense to maintain all patients at an elevated CPP, when perhaps only a few patients really need that level. In doing so, all patients are put at risk of the complications, while only a few receive benefits. As a routine now, we maintain patients with a CPP of at least 60 mm Hg, which is adequate for most patients. However, if some measures, such regional CBF or SjvO2 or brain tissue pO2, suggest that perfusion is inadequate with a CPP of 60 mm Hg, then we try to raise CPP. This puts only patients with potential to benefit at risk of complications.
Comment: I think that CPP is a red herring, and we are trying to increase a “parameter” that does not really exist. We need to consider that pulmonary failure potentially exacerbates the brain swelling, and we need to rethink the whole notion of the CPP calculation. We need to protect the brain against ischemia, which you have argued very well. An alternative explanation for your data is that we need to direct therapy more quickly, vigorously, and intelligently against ICP. What we are really looking at early on is cytotoxic edema and not diffuse intravascular swelling. How would you go after that?
Answer: Your points are well taken, and I would add some strength to what you have said. We did not change the incidence of ischemia associated with intracranial hypertension. We did not design our treatment of ICP-related events any differently in the two treatment protocols. And the results could suggest that ICP-related ischemic events are much more important than those associated with hypotension or hypocapnia. How to treat is a much more difficult question. I presume that this type of edema is from the primary injury, which will require a different treatment strategy.
Comment: One point stares me in the face from your data: You have effectively treated secondary insults, which we have all been targeting for so many years, but the primary insult overshadows that treatment. How do we define the mechanisms for the primary insult?
Question: Some of us have advocated utilizing two different compounds in treating acute head injury. From your management standpoint has anybody ever thought about the possibility of combining a particular compound or therapeutic agent with a management style that could dictate what sort of patient should be a candidate for a particular treatment?
Answer: I think that the individualization of treatment for a particular patient’s injury is a way to approach the problems that we are seeing. We used a very specific definition of ischemia; that is, a global ischemic insult sufficient to reduce the SjvO2 below 50%. I think that is good evidence that the brain is being hypoperfused. Whether it is actually ischemic or not is another question.
Question: Your previous studies have shown that patients who have few desaturations do much better. Have you not shown here that you can potentially improve neurological outcome, but overall outcome depends on the systemic complications? Therefore, should you try to find a way to eliminate the systemic complications, rather than concluding that improving the perfusion did not improve neurological outcome?
Answer: We would agree that reducing secondary ischemic insults is a good thing to do. However, trying to maintain all patients at an artificially elevated CPP may not be the best way to approach this because of systemic complications associated with this preventative treatment. One alternative that can be applied right now is to only elevate CPP in those patients who really need a higher CPP to adequately perfuse their brain.
National acute brain injury study: hypothermia (Guy L. Clifton, M.D.). For the recent hypothermia trial, our primary question was: Does early induction of hypothermia to 33°C for 48 h improve outcome with low toxicity? It did not.
The trial was set to detect a 10% shift in dichotomized GOS. That is Good Recovery/Moderate Disability versus Severe Disability/Vegetative/Dead. The inclusion/exclusion criteria were as usual for most trials in TBI: no gunshot wounds, randomization within 6 h of injury, exclusion of major multiple trauma. There were 11 U.S. centers in the trial at different times. Four centers randomized a total of 33 patients before they were dropped from the trial for various reasons, and two other centers came into the study rather late; therefore, five centers randomized 88% of the patients. From the very start of the trial, we paid serious attention to early cooling and complication rates. Our goal was to reach a core body temperature of 33°C by 8 h after injury. Temperature and hypothermia-related complications were reported to the Performance/Safety Monitoring Board on a regular basis. We saw no significant demographic differences between the two treatment groups (hypothermia vs. normothermia), so our randomization was effective. Within the hypothermia group, eight patients did not reach target temperature. In the normothermia group, the mean temperature in the first 96 h was 37°C. The hypothermia patients were cooled to reach 33°C by 8.4 6 3h after injury. Randomization was at 4.3 h after injury. Patients remained hypothermic for 48 h and were re-warmed very slowly over 18-24 h. From pilot work we knew that this slow rewarming was very important.
Overall, there were differences in management of the two study groups for only two areas. One difference was that hypothermia patients received more fluids, with a mean fluid balance of 3 L positive over 96 h. Normothermia patients were about 1.6 L positive. That difference was significant. Hypothermia patients also received vasopressors for about 80% of their total hours in the first 96 h, and normothermia patients 69% of those first hours.
There was a concern expressed during peer review of the grant application that this was an unblinded trial, and everybody wanted it to work; the personnel who most wanted it to work would manage the hypothermia patients differently in some way. So we evaluated treatment intensity using a standard scoring system to quantify the number and intensity of interventions. It was the same in the hypothermia and normothermia groups. Despite the use of hypothermia, there was no evidence that one group was managed more vigorously. We targeted a CPP of .70 mm Hg based on the best information available before the trial. In the first 96 h in ICU, 97% of the patients had a CPP under 70 mm Hg at some point, so virtually everybody experienced an episode for some period. About 40% of the patients had a CPP under 50 mm Hg at some point. The “percent hours under 50 mm Hg” was small (about 2% of hours); the “percent hours under 70 mm Hg” were about 10% of the hours monitored. So, while patients did drop under 50 mm Hg, they did not stay there long.
Our data show that there are critical management thresholds which adversely affect outcome if they occur at all: CPP, 60 mm Hg, ICP. 25 mm Hg, and MAP, 70 mm Hg. The incidences of these critical thresholds were the same in both treatment groups.
We saw a difference between the incidence (time) of ICP. 30 for the hypothermia and normothermia groups, and it was a big difference, about 25%. We found a decrease in the numbers of patients with ICP. 30 mm Hg and .40 mm Hg in the hypothermia group. It seems that hypothermia reduced the incidence of high ICP.
The mean arterial pressures (MAPs) were not different between the groups; but, considering the occurrence of MAP, 70 mm Hg, there were more of these patients in the hypothermia group. The MAP reduction was offset by the significant ICP reduction, so that if you look at the hourly occurrences of CPP, 50 mm Hg, you do not see a difference between the groups. Overall, there was a slight but statistically significant increase in complications in the hypothermia group. There was no treatment effect in terms of the primary hypothesis: 56.9% of patients had poor outcomes in the hypothermia group, 56% in the normothermia group. The mortality rate was 28% with hypothermia and 27% with normothermia.
We looked at the effect of hypothermia on GCS subgroups, age subgroups, presence of operative hematomas, subarachnoid hemorrhage, time to target temperature, and admission temperature. An effect of hypothermia was seen in older patients and in patients who were hypothermic on admission. We found that in the patients over 45 years old, there was an 89% poor outcome in the hypothermia group, and a 69% poor outcome in the normothermia group. This difference was highly significant. The cause of this outcome was an increase in medical complications; there were statistically significant increases in bleeding, sepsis, and pneumonia in the hypothermia group over 45 years of age.
Over 20% of patients were hypothermic (≤35°C) on admission, and the mean temperature over the first 8 h for this group was about 33.7°C. The mean admission temperature for the rest of the patients was about 36.2°C. The patients who came in hypothermic and who were randomized to normothermia warmed very slowly over 16-18 h after admission. Patients hypothermic on admission who were randomized to hypothermia had 61% poor outcome; “hypothermia-on-admission” patients randomized to normothermia had about a 78% poor outcome. This difference is significant.
The overall treatment effects for the five largest centers are summarized: Houston had a 5% positive (15%) effect for hypothermia; Sacramento, 24%; Pittsburgh, 114%; St. Louis, 214%; and Indianapolis, 220%. There were significant differences in CPP management among centers; however, we cannot detect a correlation with treatment effect. It appears that differences in baseline variables among centers in numbers of older patients and/or patients who were hypothermic on admission caused this effect. My conclusion is that patients over 45 years old should not be cooled. In addition, I think we missed the treatment window.
Question: If you sort out the subset that was GCS 5-8, comparable to the phase II Pittsburgh study by Marion, did that stand up with a significant effect?
Answer: No. We found a 7% treatment effect in the GCS 5-8 patients; Marion reported a 38% treatment effect. In his study, he actively rewarmed patients who were hypothermic on admission over a period of approximately 6 h. In the laboratory, rapid re-warming worsens outcome. In our phase III study, we allowed patients to rewarm spontaneously. In Marion’s phase II normothermia treatment group, there was a 66% poor outcome for the GCS 5-8 patients. Our phase III trial showed a 52% poor outcome for this group. There had been an unexpectedly bad result in normothermia patients the earlier Pittsburgh study. Dr. Marion and I think that the discrepancy may relate to active rewarming of the patients. In addition, I think the effect seen at Pittsburgh in our phase III trial may have been due to an increased number (36%) of patients who were hypothermic on admission.
Comment: In stroke patients who were rewarmed over 24 h the fatality rate was directly related to increased ICP. If patients are rewarmed over 48 h, there is none of the elevated ICP. Frankly, I think that a problem in your phase III trial was that the treatment groups were not well matched.
Answer: Fewer older patients in the hypothermia group in combination with admission hypothermia would maximize the probability of a treatment effect in any center.
Comment: Perhaps hypothermia should be viewed as a potential measure to buy time for the introduction of other therapies (e.g., drugs), rather than as a primary treatment.