Adnan I. Qureshi, MD, Professor of Neurology and Radiology
14 Clinical Trials in Intracerebral Hemorrhage
Alejandro A. Rabinstein, MD, Associate Professor of Neurologya, Consultantb aMayo Clinic College of Medicine,
bNeurological–Neurosurgical Intensive Care Unit, Saint Mary’s Hospital, Rochester, Minnesota, USA
Eelco F. M. Wijdicks, MD, Professor of Neurology and Chair Division of Critical Care Neurology, Mayo Clinic College of Medicine, and
Neurological–Neurosurgical Intensive Care Unit, Saint Mary’s Hospital , Rochester , Minnesota , USA
INTRODUCTION
Traditionally, the treatment of intracerebral hemorrhage (ICH) has been largely empirical.
However, this situation is rapidly changing due to the accumulation of data from rigorously conducted, randomized clinical trials that address old treatment quandaries and assess novel and promising therapeutic modalities. Evidence provided by these trials is likely to generate new standards of care for the management of patients with ICH.
Neurologists and neurosurgeons often share uncertainties when faced with patients with large intracerebral hematomas. Questions about appropriateness and timing of surgical inter-vention to evacuate the hematoma have been pervasive. Several randomized, controlled trials have addressed these questions, and their results offer valuable information to guide our decisions.
Medical treatment of patients with ICH remains mostly supportive, but ultraearly hemo-static therapy and the use of fi brinolytic drugs to accelerate the dissolution of intraventricular clots are strategies with great potential to improve the outcome of these patients. Confi rmation of favorable preliminary results from safety trials that tested these treatment modalities may transform the role of clinicians in the management of ICH after many years of therapeutic nihilism.
SURGICAL EVACUATION
The fi rst randomized trial assessing the value of surgical evacuation in patients with ICH was conducted by McKissock et al. in 1961 ( 1 ), before CT technology became available, an important limitation that implies that misdiagnosis at the time of enrollmentlikely resulted in the inclusion of patients without ICH. Actually, the authors recognized several misdiagnosed cases after ran-domization, reaching a known diagnostic error of 5%. The investigators randomized 180 patients to surgical evacuation (if the hematoma could be localized and was surgically accessible) or to conservative management. The results showed that patients in the surgical group had a 28%
increased mortality rate and worse overall functional outcome. The odds ratio (OR) for death or dependency was 2.0, with a 95% confi dence interval (CI) of 1.04 to 3.86.
Another study randomized 52 patients with ICH to surgery or medical treatment within 48 hr of symptom onset ( 2 ). Upon enrollment, patients were unconscious (but responsive to pain) or had severe hemiparesis or aphasia. Randomization was not well balanced because patients allocated to surgical treatment had larger hematomas and signifi cantly lower Glasgow Coma Scale (GCS) at entry. Both mortality and functional dependence were slightly higher among surgically treated patients. A small number of patients enrolled precluded subgroup analysis.
The authors logically concluded that spontaneous ICH should be treated conservatively.
Enrollment in a third trial was interrupted after only 21 patients had been randomized ( 3 ). The therapeutic arms were best medical treatment (including routine use of steroids and mannitol), best medical treatment plus ventriculostomy for intracranial pressure monitoring, and surgical evacuation (with attempts to standardize the procedure using a predefi ned
microsurgical technique). The trial was prematurely terminated because of the extremely poor outcome observed in both treatment groups. No differences among the groups were noticed, but the very small number of patients studied impeded any meaningful comparison.
In the only randomized trial that solely used endoscopic aspiration for clot evacuation, favorable results were reported with surgery ( 4 ). The investigators randomized 100 patients with symptomatic hematomas > 10 cc within 48 hr of symptom onset to partial endoscopic evacu-ation through a burr hole or medical treatment (including antifi brinolytic agents for 3 days).
At 6 months, mortality was signifi cantly lower, and functional outcome was improved in the surgically treated patients. Subgroup analysis showed that the benefi t afforded by surgery was restricted to patients younger than 60 years old who presented with lobar hematomas and were not stuporous at entry. The results of this trial have been questioned because outcome assess-ment was not blinded. However, this study remains the strongest evidence in favor of surgical treatment for spontaneous ICH.
The concept of early surgery has been tested in a few small, randomized studies. One randomized 20 patients (over a 2-year period) with ICH volume > 10 cc, focal neurologic defi cit, and GCS > 4 at the time of enrollment to either surgical evacuation (craniotomy or stereotactic aspiration as decided by the case surgeon) or medical treatment ( 5 ). All patients were enrolled within 24 hr of symptom onset and underwent surgery within 3 hr of randomization. Median time from onset of symptoms to surgery was 8 hr and 35 min. Patients’ neurologic status at the time of randomization was better than in previous trials; median GCS was 13 (range, 11–14) in the surgical arm and 11 (range, 6–13) in the medical arm ( p = 0.06). At 3 months, a non-signifi cant but well-defi ned trend toward better outcome in the surgically treated patients was apparent on 3 different functional scales. Mortality was only minimally lower in the surgical group, but surgery afforded a signifi cant reduction in residual neurologic defi cits, as assessed by the National Institutes of Health stroke scale.
Although intuitively appealing, early surgery to prevent the consequences from hema-toma expansion has been formally evaluated with disappointing results. First, a single-center, pilot trial compared craniotomy within 12 hr of symptom onset versus best medical treatment ( 6 ). Inclusion criteria required hematoma volume ≥ 10 cc and presence of impairment of con-sciousness or severe hemiparesis. A total of 34 patients were randomized, and at 6 months, a trend toward lower mortality and better functional outcome was observed in the surgical group, although it is unclear if outcome assessment was blinded. Albeit modest, the benefi ts observed with early surgery in this pilot study reasonably led the investigators to postulate that shortening the time window to surgery could maximize the benefi t of the intervention. Thus, a subsequent trial enrolled patients for craniotomy and clot evacuation within 4 hr of symptom onset to compare them with the patients who had been randomized to the surgical and medical treatment arms within a 12-hr time window in the previous study ( 7 ). Median initial hema-toma volume was 40 cc (range, 23–84 cc), and median GCS was 12 (range, 6–15). The trial was prematurely terminated after only 11 patients had undergone surgery within 4 hr because of increased rate of rebleeding (40% compared with 12% among patients who underwent surgery between 4 and 12 hr) and mortality (36% vs. 18% in patients who went to surgery between 4 and 12 hr, including 3 of 4 patients who rebled). The investigators concluded that ultraearly craniotomy for hematoma evacuation cannot be recommended because it is complicated by rebleeding, most likely related to problems with homeostasis.
Several meta-analyses have attempted to systematically review the data of these prospec-tive randomized studies ( 8–13 ). The results should be interpreted with caution because of the marked heterogeneity of the original trials, which varied considerably in terms of diagnostic and inclusion criteria, surgical technique, outcome measures, and size of the population studied.
Older meta-analyses ( 8–10 ), including the fi rst 4 randomized trials ( 1–4 ), concluded that craniotomy showed a tendency to be detrimental. Pooled data from these trials ( n = 349 patients) shows a nonsignifi cant increase in the odds of death and dependency at 6 months for surgi-cal patients (OR: 1.23; 95% CI: 0.77–1.98). A subsequent meta-analysis ( 13 ) included the two more recent trials ( 5,6 ) as well as another previously overlooked Chinese study ( 14 ). When all trials ( n = 530 patients) were considered, the trend was still toward greater chance of death and dependency among patients undergoing surgery (OR: 1.20; 95% CI: 0.83–1.74). However, when the 2 trials with the most notable methodologic weaknesses were excluded, the results changed sensibly. The oldest study ( 1 ) was excluded because of the high diagnostic error rate as a result of the unavailability of CT at the time of the study and the uncertainty about the
number of patients allocated to surgery who actually underwent craniotomy. The Chinese study ( 14 ) was removed due to concerns about poorly balanced randomization, inclusion of cerebellar hematomas, and possible incorporation into the surgical group of patients who only underwent ventricular drainage. After these exclusions, the resulting meta-analysis ( n = 224) actually indi-cated a trend toward a reduction in the odds of death and dependency after surgery (OR: 0.63;
95% CI: 0.35–1.14).
These meta-analyses do not include the most recent trials. A randomized, multicenter trial compared stereotactic blood clot drainage after liquefaction with urokinase (instilled through a catheter into the hematoma every 6 hr for 2 days) with conservative treatment ( 15 ). Seventy patients were enrolled within 72 hr of ICH onset. No differences in mortality or severe disabil-ity between the treatment groups were observed. However, a signifi cant ICH volume reduction was achieved by neurosurgical intervention (10–20%; p < 0.05).
By far, the largest randomized trial evaluating surgical evacuation in the management of ICH, the International Surgical Trial in Intracerebral Hemorrhage was an international (27 countries), multicenter (83 centers) study that enrolled 1033 patients to receive early surgery or initial conservative treatment. Eligible patients had confi rmed spontaneous supratentorial ICH that had arisen within the previous 72 hr, with a minimum hematoma diameter of 2 cm and GCS > 4. Patients randomized to the surgical arm underwent hematoma evacuation within the following 24 hr. The trial protocol did not include a standardized surgical technique; thus, the responsible surgeon chose the method used for evacuation in each case. Best medical treatment was similarly left to the discretion of the participating clinicians. Later surgical evacuation was allowed in patients initially treated conservatively, if it was deemed necessary due to neuro-logic deterioration. Outcome measures were death and functional disability at 6 months, as measured by several validated functional scales and using information obtained through struc-tured postal questionnaires. The investigators adopted a pragmatic prognosis-based outcome to evaluate functional end results; patient outcomes were categorized as good or poor upon randomization, and this classifi cation was considered to establish different outcome expecta-tions. Analysis of results was based on intention-to-treat.
In total, 503 patients were randomized to early surgery and 530 to conservative treatment.
Groups were well balanced for meaningful baseline variables. Median age was 62 years, and more than half of all patients were randomized within 20 hr of hematoma onset. Twenty per-cent of patients were comatose (GCS 5–8) upon enrollment. Hematomas were fairly equally distributed between lobar and ganglionic locations in both treatment groups. Median hematoma volume was 38 mL and comparable in both groups. Ninety-four percent of patients randomized to early surgery actually underwent evacuation. Median time between ictus and surgery was 30 hr, and between randomization and surgery, 5 hr. Meanwhile, 26% of patients randomized to initial conservative treatment eventually went to surgery due to neurologic deterioration after a median interval from ictus of 60 hr. Craniotomy was the procedure chosen for evacuation in 77% of surgical patients.
After excluding patients lost to follow-up or with insuffi cient follow-up information, the fi nal population analyzed consisted of 468 patients randomized to the surgical arm and 497 patients randomized to the conservative arm. Favorable functional outcome using the extended GCS occurred in 26% of patients who were randomized to early surgery and 24% of those randomized to initial conservative treatment (OR: 0.89; CI: 0.66–1.19; p = 0.41). Therefore, early surgery resulted in a nonsignifi cant absolute benefi t of 2.3% and a relative benefi t of 10%.
Similar results were observed with other functional scales. Mortality rates at 6 months did not differ much between treatment groups (36% vs. 37% for early surgery and initial conservative approach, respectively).
On subgroup analysis, the only remarkable fi nding was the greater likelihood of favorable outcome with early surgery among patients with superfi cial hematomas (i.e., located 1 cm or less from the cortical surface). For these patients, early surgery afforded an absolute benefi t of 8% over initial medical treatment ( p = 0.02). Conversely, patients with deep hematomas tended to fare better with conservative treatment. Craniotomy appeared to offer an advantage over other surgical techniques, but the difference was not signifi cant, and the number of patients treated with methods other than conventional craniotomy might have been too small to draw reliable conclusions. In the subpopulation of comatose patients, early surgery was actually asso-ciated with a trend toward increased risk of death or disability.
In conclusion, surgical evacuation cannot be advocated as standard treatment of choice for most patients with acute primary ICH. The role of surgery should probably be restricted to patients deteriorating because of mass effect. Nonetheless, future studies may defi ne a particular niche for specifi c surgical interventions targeted to well-defi ned subpopulations of patients.
The most important features of the randomized trials on surgical versus medical treat-ment of ICH are summarized in Table 1 .
Table 1 Summary of Published Randomized Trials Comparing Surgical and Medical Treatment for Patients with ICH
Trial Population
Surgical
technique Results
OR (95% CI) of death/
dependency McKissock
et al.
1961 (1)
n = 180
Clinical presentation/LP/
angio consistent with ICH No defi ned time limit
Craniotomy No signifi cant difference Death — S: 65%;
M: 51%
Poor outcome — S: 80%;
M: 66%
2.0 (1.0, 3.9)
Juvela et al.
1989 (2)
n = 52
Unconscious and/or severe hemiparesis/
dysphasia S within 48 hr
Craniotomy No signifi cant difference Death — S: 46%;
M: 38%
Poor outcome — S: 98%;
M: 66%
4.39 (0.8, 23.6)
Auer et al.
1989 (4)
n = 100
ICH > 10 cc; altered consciousness Ictus within < 48 hr
Endoscopic aspiration
S signifi cantly better Death — S: 42%;
M: 70%
Poor outcome — S: 58%;
M: 74%
0.46 (0.2, 1.0)
Batjer et al.
1990 (3)
n = 21
Putaminal ICH > 3 cm Altered consciousness or hemiparesis Ictus within < 24 hr
Craniotomy No signifi cant difference Death — S: 50%;
M: 85%
Poor outcome — S: 75%;
M: 85%
0.55 (0.1, 4.9)
Morgenstern et al.
1998 (6)
n = 31
ICH > 9 cc, lobar or extending out of thalamus, GCS 5–15 Ictus within 12 hr
Craniotomy No signifi cant difference Death — S: 24%;
M: 18%
Poor outcome — S: 69%;
M: 50%
0.46 (0.1, 1.9)
Zuccarello et al.
1990 (5)
n = 20
ICH > 10 cc; GCS > 4, (+) neuro defi cit
Ictus within 12 hr
Craniotomy/
stereotactic aspiration
No signifi cant difference Death — S: 22%;
M: 27%
Poor outcome — S: 44%;
M: 64%
0.48 (0.1, 2.7)
Teernstra et al.
2003 (15)
n = 70 ICH > 10 cc;
GEM 2–10 Ictus within 72 hr
Urokinase installation and stereotactic drainage
No signifi cant difference Death — S: 56%;
M: 59%
Poor outcome — S: 75%;
M: 76%
0.52 (1.2, 2.3)
STICH 2005 (16)
n =1033 ICH > 2 cm;
GCS > 4 Ictus within 72 hr Surgery within 24 hr of enrollment
At the surgeon’s discretion (78% craniotomy)
No signifi cant difference Death — S: 36%
M: 37%
Poor outcome — S: 74%;
M: 76%
0.89 (0.7, 1.2)
Abbreviations: CI, confi dence interval; ICH, intracerebral hemorrhage; LP, lumbar puncture; M, medical; OR, odds ratio; S, surgery; GCS, Glasgow Coma Scale; GEM, Glasgow Eye Motor Scale; STICH, Surgical Trial in Intracerebral Hemorrhage; lctus, symptom onset.
MEDICAL TREATMENT Early Hemostatic Therapy
The use of hemostatic agents designed to arrest ongoing hemorrhage in the hyperacute setting constitutes one of the most promising interventions to improve the outcome of patients with ICH (17). In that, hematoma expansion is most common in the fi rst few hours after bleeding onset, the effectiveness of this treatment depends on its very early administration. Hemostatic agents may theoretically increase the risk of thrombotic complications. Therefore, the results of a recently conducted Phase 2 trial, which proved the feasibility and safety of this therapeutic strategy, are of great importance ( 18,19 ). The information yielded from the trial has already become available for the use of activated recombinant factor VII (rFVIIa), which is a genetically altered agent resembling a natural clotting factor.
This randomized, double-blinded, placebo-controlled, dose-escalation trial tested the use of 6 different doses of rFVIIa versus placebo in 47 patients with ICH within 3 hr of ictus onset ( 18 ).
Mean age of participants was 61 ± 15 years, median GCS was 14, and mean ICH volume was 21 ± 24 mL (range, 1–151 mL). ICH was ganglionic in 72% of cases, and intraventricular exten-sion was present in 45%. Treatment was initiated after a median interval of 181 min (range, 120–265 min) from hematoma onset. ICH growth was documented in 17% at 1 hr and 19% at 24 hr. No differences were observed in hematoma growth or functional outcome among the treatment groups, but the study was not powered to assess effi cacy. Twelve serious adverse events occurred, including 5 deaths; all fatalities were primarily caused by the ICH itself. No relationship was detected between the frequency, type, or severity of side effects and rFVIIa dose.
Six adverse events were considered possibly related to treatment, but only two were potentially severe (popliteal deep venous thrombosis in the acute phase in one case and T-wave inversion at 24 hr without elevation of creatinine kinase isoenzyme MB (CK-MB) level in the other).
No cases of consumption coagulopathy, systemic embolism, or excessive cerebral edema caus-ing neurologic deterioration were reported. The authors reasonably concluded that this small Phase 2 trial did not raise major safety concerns and that a larger trial was justifi ed to confi rm the safety and evaluate the effectiveness of rFVIIa in the treatment of acute ICH.
Another Phase 2B (19), dose-ranging, proof-of-concept trial randomized 399 patients with primary ICH (confi rmed by CT scan) within 3 hr after onset of symptoms to receive rFVIIa 40 µg/kg body weight (BW; 108 patients), 80 µg/kg BW (92 patients), 160 µg/kg BW (103 patients), or placebo (96 patients) ( 18 ). Patients were excluded if they had a GCS > 6, history of coagulopathy or recent use of oral anticoagulants, or any history of thrombotic or vaso-occlusive disease.
Treatment was started within 1 hr of obtaining the CT scan and administered in a double-blinded fashion. The primary outcome measure was the percentage change in the hematoma volume at 24 hr. Clinical outcomes were assessed at 90 days using various validated scales.
Analysis followed the intention-to-treat principle. Baseline characteristics were similar in all groups, although the degree of acute blood pressure elevation was not reported. Location of the hematoma was deep in more than 80% of cases, and median GCS was 14. Mean hematoma volume at baseline was 27 mL (range, 0.4–153 mL). Mean time from symptom onset to initiation of treatment was 167 ± 32 min.
Increase in hematoma volume was lower in the rFVIIa arms than in the placebo group ( p = 0.01 for the difference between placebo and the combined rFVIIa groups), and the difference was more pronounced with the higher doses of rFVIIa. Mean percentage increase from baseline was 29% with placebo, versus 16%, 14%, and 11% with the 3 escalating doses, respectively.
This refl ected absolute volume differences of 3.3, 4.5, and 5.8 mL in the 3 treatment doses.
Benefi t was greater when therapy was initiated within 3 hr of symptom onset. Total lesion volume [ICH + intraventricular hemorrhage (IVH) + edema] was also signifi cantly reduced in the treatment groups; the estimated mean total volume reduction at 72 hr was 11 mL for the combined treatment groups. Mortality at 3 months was 29% in the placebo group versus 18%
in the treatment groups combined ( p = 0.02; relative risk reduction 5 38%; Fig. 1 ). Functional outcome was also signifi cantly better in patients who received rFVIIa; a 16% absolute reduc-tion in the number of patients with modifi ed Rankin score of 4 to 6 at 90 days was associated with the use of rFVIIa. In terms of functional outcome, the best dose was 80 µg/kg BW. Severe arterial thromboembolic events were signifi cantly more frequent among patients treated with rFVIIa (5% vs. 0% with placebo; p = 0.01), including 2 cases of ischemic stroke that were fatal and 5 more that were disabling. Rates of venous thromboembolic events did not differ between
groups. Only 2% of the serious thromboembolic events were considered possibly or probably related to the drug.
In summary, this trial showed that early infusion of rFVIIa can ameliorate ICH growth, with a resulting favorable impact on functional outcome. However, it did not dispel concerns that the treatment might increase the risk of serious arterial vascular events. The investigators concluded that further research is still needed to identify the best candidates for the safe use of this hemostatic treatment, as well as the ideal dose and optimal time window for its admin-istration. The cost of the drug is high—up to $12 per patient—but may be offset by reduced hospital stay and rehabilitation time.
Intraventricular Thrombolysis
IVH is a poor prognostic factor in patients with ICH ( 20,21 ), and a large volume of IVH is predictive of mortality and unfavorable functional outcome ( 22 ). Although external ventricular drainage is effective in treating obstructive hydrocephalus, it has never been proven to accelerate resolu-tion of the intraventricular clot. Furthermore, obstrucresolu-tion of the ventriculostomy catheter by the clot is a relatively frequent problem. Therefore, the use of thrombolytic drugs to hasten the removal of intraventricular blood is based on a solid rationale. The safety and effi cacy of this strategy has been successfully tested in case series and cohort studies ( 23,24 ).
These initial favorable results were confi rmed in a Phase 2, multicenter, prospective, con-trolled trial, in which 12 patients with IVH requiring ventriculostomy were randomized to receive intraventricular injections of urokinase (25,000 IU) or saline solution. Injections were adminis-tered every 12 hr starting at between 12 and 24 hr after bleeding onset. They were continued until the ventriculostomy catheter was removed following prespecifi ed criteria (i.e., clamping of catheter for 24 hr without elevation of intracranial pressure above 15 mmHg). IVH volumes were measured on daily CT scans by examiners blinded to treatment assignment. Unfortu-nately, enrollment had to be stopped when the manufacturer withdrew urokinase from the market. Patients in the urokinase group received a mean of 7.7 injections (range, 4–11 doses).
Clot resolution was signifi cantly faster in patients treated with urokinase ( p = 0.02). After adjust-ment for baseline differences in gender distribution—which was necessary because faster IVH resolution was also associated with females—a reduction of 3.8 days in the intraventricular clot half-life was observed (i.e., time required for a 50% decrement in the initial volume of the clot).
Mean duration of external ventricular drainage tended to be reduced in patients treated with urokinase (170 hr vs. 208 hr in the placebo group). No signifi cant differences in adverse events between groups were observed, and no cases of expansion of ICH or IVH were reported.
A larger ( n = 48) Phase 2 trial using recombinant tissue plasminogen activator (rtPA) has also offered encouraging results ( 25 ). Infusion of rtPA strongly accelerated IVH resolution, and treated patients showed improved levels of consciousness more rapidly and tended to have better functional outcomes. Although symptomatic hemorrhages were more common in the rtPA Figure 1 Survival at 90 days according to study group. Mor tality was reduced by approx imately 35% in each rFVIIa group, as compared to placebo group (p = 0.10 by the log-rank test, comparing all 4 groups; p = 0.02 by the chi-square test for the comparison of the three rFVIIa groups combined with pla-cebo). Source: From Ref. 19.
group, this difference was not signifi cant. In addition, nonhemorrhagic complications occurred more frequently in the placebo group. The results of this study justify the conduction of a Phase 3 trial to establish the role of intraventricular thrombolysis in daily practice.
Treatment of Edema
Edema is responsible for complications from mass effect and may further worsen cerebral blood fl ow in areas already affected by hypoperfusion. Both cytotoxic and vasogenic edema occur after ICH, and their amelioration was the target of controlled trials that tested the effi cacy of glycerol and corticosteroids.
Dexamethasone was tested in two randomized, controlled trials. Tellez and Bauer enrolled 40 patients with a clinical diagnosis of nontraumatic ICH and impaired consciousness to receive dexamethasone (19 patients) or placebo (21 patients) ( 2 6). Treatment was started within 48 hr of the ictus, and patients on the active treatment group received a total of 120 mg of dexamethasone over 10 days. Diagnosis was based on history, physical examination, and the fi nding of more than 200 erythrocytes/mL of cerebrospinal fl uid. The mortality was very high in both groups (89% with dexamethasone and 76% with placebo) and uniform among patients presenting with deep stupor or coma, who were treated with corticosteroids. Over-all functional outcome upon discharge from the hospital was similarly poor in both groups.
Two patients treated with steroids developed episodes of gastrointestinal hemorrhage, versus none in the control group. Limitations of this study included its low population size, lack of confi rmation of ICH by brain imaging, and partial blinding (only the last 23 patients were double blinded).
A larger and more scientifi cally rigorous trial evaluating the effects of dexamethasone in primary supratentorial ICH was subsequently conducted in Thailand ( 27 ). This double-blinded, controlled trial randomized patients within 48 hr of the ictus. Diagnosis of ICH was confi rmed by CT scan. Patients in the dexamethasone group were scheduled to receive a total of 150 mg of the drug over 9 days. Ninety-three patients were enrolled before the trial was prematurely terminated due to an excess of adverse events among patients treated with the corticosteroid.
Groups were well balanced at baseline in terms of age, comorbid conditions, ICH location, and severity of initial clinical presentation. The only notable difference was a larger mean hema-toma volume among patients assigned to receive dexamethasone than among those in the control group (72 vs. 59 mL). Neither mortality nor functional recovery after 21 days was dif-ferent between groups. However, the rate of complications and possible adverse effects was signifi cantly greater in the dexamethasone group, mainly due to the increased frequency of persistent hyperglycemia and infections.
The use of glycerol was assessed in one double-blinded, randomized, placebo-controlled trial that enrolled 120 patients with ICH onset within the previous 24 hr ( 28 ). Active treatment consisted of 500 mL of 10% glycerol in a physiologic saline solution admin istered intravenously over 4 hr for 6 consecutive days. Groups were adequately balanced in terms of clinical severity at presentation (most patients had GCS = 12–15), concomitant illnesses, and hematoma volume (mean = 28–32 mL). Functional outcome at 6 months was not affected by treatment assignment.
No subgroup of patients was shown to benefi t from receiving glycerol. Hemolysis was the only side effect noticed to be more common in the glycerol-treated patients, but the resulting anemia most often was not clinically meaningful.
Therefore, these trials indicate that the routine use of corticosteroids or glycerol has no role in cases of ICH. Other osmotic agents, including mannitol and hypertonic saline (the two most commonly used in United States), have not been formally tested in random-ized, controlled trials. In light of the absence of data supporting their effi cacy and the lack of benefi t observed with glycerol, the use of these agents should be reserved for cases with documented or highly suspected intracranial hypertension or signs of impending herniation ( 29 ).
Acute Reduction of Blood Pressure
No randomized, controlled trials sought to identify the ideal target for acute blood pressure reduction after spontaneous ICH. Current guidelines for the management of this condition recommend keeping the mean arterial pressure below 130 mmHg in patients with history of
hypertension but recognize the lack of solid scientifi c grounds for this advice by rating the level of evidence as V (i.e., data from anecdotal case series) ( 29 ).
The rationale for this rather conservative approach lies in the hypothesis that an area of penumbra typically surrounds intraparenchymal hematomas. Reduced cerebral perfusion in the perihematoma region has been demonstrated by various tech niques ( 30–32 ). However, the existence of an area of true penumbra has been questioned by data obtained from experimental models ( 33,34 ) and human studies using positron-emission technology ( 35,36 ). It is possible that the hypoperfusion observed around the hematoma does not produce tissue ischemia, but might be the result of regional metabolic depression after the hemorrhage. Meanwhile, hema-toma enlargement has been repeatedly noticed to be associated with more elevated blood pres-sures ( 37,38 ). Aggressive early blood-pressure reduction has been successfully tested in a small preliminary study ( 39 ). A randomized, controlled trial to evaluate the effects of this approach in a large population of patients with acute primary ICH appears to be the next logical and necessary step.
FUTURE TRIALS
The trials discussed in this chapter indicate that emergent, targeted medical interventions have the potential to greatly improve the outcome of some patients with ICH. However, more research is needed before any of these novel therapies will be ready for introduction in daily clinical practice. A recent National Institute of Neurological Disorders and Stroke ICH work-shop identifi ed priorities for clinical research ( Table 2 ) ( 16 ). It is hoped that additional trials that test optimized protocols of early hemostasis with rFVIIa, and intraventricular thrombolysis with rtPA, will offer robust data to support their approval for clinical application. Infusion of rFVIIa should also be evaluated for the treatment of ICH induced by excessive anticoagulation.
Techniques of minimally invasive surgery in combination with local infusion of a thrombolytic drug deserve further exploration. New studies that test the role of surgery exclusively on patients with superfi cial hematomas are justifi ed. Prompt administration of neuroprotectants to limit neuronal death is an option that must continue to be studied regardless of the disap-pointing results so far observed in patients with ischemic infarction. The value of aggressive reduction of blood pressure as soon as ICH is diagnosed should also be formally investigated.
It is only reasonable to expect that these clinical trials will hold the key to providing a better outlook for future patients with ICH.
Table 2 Priorities for Clinical Research in ICH Medical priorities
Blood-pressure management Treatment of hyperglycemia Normalization of body temperature Prophylactic use of antiepileptic agents Safety of prophylactic anticoagulants
Reversal of antithrombotic- and fi brinolytic-induced ICH Evaluation of hemostatic agents in coagulopathy-associated ICH Surgical priorities
Mechanical clot removal devices Surgical targeting
Perioperative imaging
Local delivery of protective restorative agents Regional hypothermia
Intracavitary microdialysis for markers of ongoing injury Polymer-based sustained release technology
Delayed restorative surgical procedures Delayed implantation of bionic interfaces Abbreviation: ICH, intracerebral hemorrhage.
Source: From Ref. 16.