Intraoperative Hypothermia For Aneurysm Surgery Trial Research Articles

Abstract W P80: Predictors of Cognitive Status in Post-Aneurysm Surgery Patients

Introduction: Patients who undergo surgical treatment for ruptured intracranial aneurysms may have a different risk profile for a spectrum of cognitive impairment based upon characteristics at presentation of their subarachnoid hemorrhage. Methods: The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is a multi-center, prospective, randomized clinical trial investigation of whether induced hypothermia during surgical treatment for subarachnoid hemorrhage resulted in improved outcomes. Cognitive status was defined by raw Mini-Mental Status Examination (MMSE) cutoff scores. A normal cognition was defined as a MMSE score of 28 or greater. Mildly impaired patients were defined as a score of 24-27, and severely impaired patients were defined as those with a score of less than 24. Age was analyzed by five-year age groups, with the exception of patients 30 or younger and patients 75 and older. Ordinal logistic regression was utilized to determine the final predictors. Results: Of the 1,000 patients who were followed for cognitive testing, 61 died and 21 were medically untestable. Five patients refused testing and tests were not administered to 30 patients. A total of 883 patients completed the MMSE at 3 months post-surgery. Based on the raw MMSE scores, the median score for the severely impaired patients was 20 (IQR: 16-22), 26 (IQR: 25-27) for mildly impaired patients, and 29 (IQR: 29-30) for cognitively normal patients. Gender, and race were found to be statistically significant (p<.05) predictors after controlling for age and education. Baseline Rankin Score and the occurrence of a leakage or rupture during surgery were also predictive of cognitive status. The World Federation of Neurosurgical Societies Score, the Fisher’s SAH Score, and aneurysm size and location were not found to be statistically significant. Conclusion: Patients with surgical treatment for subarachnoid hemorrhage share several demographic risk factors associated with cognitive changes in the general public, but have additional neurological risk factors associated with SAH and aneurysm procedures.

Bayesian methods to determine performance differences and to quantify variability among centers in multi-center trials: the IHAST trial

BackgroundTo quantify the variability among centers and to identify centers whose performance are potentially outside of normal variability in the primary outcome and to propose a guideline that they are outliers.MethodsNovel statistical methodology using a Bayesian hierarchical model is used. Bayesian methods for estimation and outlier detection are applied assuming an additive random center effect on the log odds of response: centers are similar but different (exchangeable). The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is used as an example. Analyses were adjusted for treatment, age, gender, aneurysm location, World Federation of Neurological Surgeons scale, Fisher score and baseline NIH stroke scale scores. Adjustments for differences in center characteristics were also examined. Graphical and numerical summaries of the between-center standard deviation (sd) and variability, as well as the identification of potential outliers are implemented.ResultsIn the IHAST, the center-to-center variation in the log odds of favorable outcome at each center is consistent with a normal distribution with posterior sd of 0.538 (95% credible interval: 0.397 to 0.726) after adjusting for the effects of important covariates. Outcome differences among centers show no outlying centers. Four potential outlying centers were identified but did not meet the proposed guideline for declaring them as outlying. Center characteristics (number of subjects enrolled from the center, geographical location, learning over time, nitrous oxide, and temporary clipping use) did not predict outcome, but subject and disease characteristics did.ConclusionsBayesian hierarchical methods allow for determination of whether outcomes from a specific center differ from others and whether specific clinical practices predict outcome, even when some centers/subgroups have relatively small sample sizes. In the IHAST no outlying centers were found. The estimated variability between centers was moderately large.

Acute postoperative neurological deterioration associated with surgery for ruptured intracranial aneurysm: incidence, predictors, and outcomes.

Subarachnoid hemorrhage (SAH) results in significant morbidity and mortality, even among patients who reach medical attention in good neurological condition. Many patients have neurological decline in the perioperative period, which contributes to long-term outcomes. The focus of this study is to characterize the incidence of, characteristics predictive of, and outcomes associated with acute postoperative neurological deterioration in patients undergoing surgery for ruptured intracranial aneurysm. The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) was a multicenter randomized clinical trial that enrolled 1001 patients and assesssed the efficacy of hypothermia as neuroprotection during surgery to secure a ruptured intracranial aneurysm. All patients had a radiographically confirmed SAH, were classified as World Federation of Neurosurgical Societies (WFNS) Grade I-III immediately prior to surgery, and underwent surgery to secure the ruptured aneurysm within 14 days of SAH. Neurological assessment with the National Institutes of Health Stroke Scale (NIHSS) was performed preoperatively, at 24 and 72 hours postoperatively, and at time of discharge. The primary outcome variable was a dichotomized scoring based on an IHAST version of the Glasgow Outcome Scale (GOS) in which a score of 1 represents a good outcome and a score > 1 a poor outcome, as assessed at 90-days' follow-up. Data from IHAST were analyzed for occurrence of a postoperative neurological deterioration. Preoperative and intraoperative variables were assessed for associations with occurrence of postoperative neurological deterioration. Differences in baseline, intraoperative, and postoperative variables and in outcomes between patients with and without postoperative neurological deterioration were compared with Fisher exact tests. The Wilcoxon rank-sum test was used to compare variables reported as means. Multiple logistic regression was used to adjust for covariates associated with occurrence of postoperative deficit. Acute postoperative neurological deterioration was observed in 42.6% of the patients. New focal motor deficit accounted for 65% of postoperative neurological deterioration, while 60% was accounted for using the NIHSS total score change and 51% by Glasgow Coma Scale score change. Factors significantly associated with occurrence of postoperative neurological deterioration included: age, Fisher grade on admission, occurrence of a procedure prior to aneurysm surgery (ventriculostomy), timing of surgery, systolic blood pressure during surgery, ST segment depression during surgery, history of abnormality in cardiac valve function, use of intentional hypotension during surgery, duration of anterior cerebral artery occlusion, intraoperative blood loss, and difficulty of aneurysm exposure. Of the 426 patients with postoperative neurological deterioration at 24 hours after surgery, only 46.2% had a good outcome (GOS score of 1) at 3 months, while 77.7% of those without postoperative neurological deterioration at 24 hours had a good outcome (p < 0.05). Neurological injury incurred perioperatively or in the acute postoperative period accounts for a large percentage of poor outcomes in patients with good admission WFNS grades undergoing surgery for aneurysmal SAH. Avoiding surgical factors associated with postoperative neurological deterioration and directing investigative efforts at developing improved neuroprotection for use in aneurysm surgery may significantly improve long-term neurological outcomes in patients with SAH.

Variation of patient characteristics, management, and outcome with timing of surgery for aneurysmal subarachnoid hemorrhage.

The past 30 years have seen a shift in the timing of surgery for aneurysmal subarachnoid hemorrhage (SAH). Earlier practices of delayed surgery that were intended to avoid less favorable surgical conditions have been replaced by a trend toward early surgery to minimize the risks associated with rebleeding and vasospasm. Yet, a consensus as to the optimal timing of surgery has not been reached. The authors hypothesized that earlier surgery, performed using contemporary neurosurgical and neuroanesthesia techniques, would be associated with better outcomes when using contemporary management practices, and sought to define the optimal time interval between SAH and surgery. Data collected as part of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) were analyzed to investigate the relationship between timing of surgery and outcome at 3 months post-SAH. The IHAST enrolled 1001 patients in 30 neurosurgical centers between February 2000 and April 2003. All patients had a radiographically confirmed SAH, were World Federation of Neurosurgical Societies Grades I-III at the time of surgery, and underwent surgical clipping of the presumed culprit aneurysm within 14 days of the date of hemorrhage. Patients were seen at 90-day follow-up visits. The primary outcome variable was a Glasgow Outcome Scale score of 1 (good outcome). Intergroup differences in baseline, intraoperative, and postoperative variables were compared using the Fisher exact tests. Variables reported as means were compared with ANOVA. Multiple logistic regression was used for multivariate analysis, adjusting for covariates. A p value of less than 0.05 was considered to be significant. Patients who underwent surgery on Days 1 or 2 (early) or Days 7-14 (late) (Day 0 = date of SAH) fared better than patients who underwent surgery on Days 3-6 (intermediate). Specifically, the worst outcomes were observed in patients who underwent surgery on Days 3 and 4. Patients who had hydrocephalus or Fisher Grade 3 or 4 on admission head CT scans had better outcomes with early surgery than with intermediate or late surgery. Early surgery, in good-grade patients within 48 hours of SAH, is associated with better outcomes than surgery performed in the 3- to 6-day posthemorrhage interval. Surgical treatment for aneurysmal SAH may be more hazardous during the 3- to 6-day interval, but this should be weighed against the risk of rebleeding.

This Month in Anesthesiology

749The goal of in-flight medical assistance is to stabilize the patient and advise the crew as to a diagnosis and treatment.659Breathing hydrogen sulfide induces a “suspended animation-like” state.627Consequences of opioid-induced sleep inhibition are important concerns in postoperative patients.596Iribarren et al . used data obtained from a randomized, double-blind, placebo-controlled study to explore the possible links between genotype and efficacy of tranexamic acid (TA) administered before and after cardiopulmonary bypass surgery. The original 50 study patients (the study had been halted due to a higher rate of excessive bleeding in the placebo group) had been classified according to plasminogen activator inhibitor-1 (PAI-1) genotype. The authors' secondary analysis from this trial revealed that in patients not receiving TA, those with the 5G/5G genotype had significantly higher chest tube blood loss and transfusion requirements compared with other patients. 5G/5G homozygotes who received TA showed the greatest blood-sparing benefit.703Ilfeld et al. compared a 4-day ambulatory continuous femoral nerve block (cFNB) to overnight cFNB in patients who had undergone tricompartment total knee arthroplasty. Compared with those receiving overnight cFNB, patients in the group receiving four days of perineural ropivacaine (via a portable infusion pump) showed a 53% decrease in the time required to reach three important discharge criteria: adequate analgesia, independence from intravenous analgesics, and ambulation of at least 30 m.634Statins appear to confer greater cardiovascular benefits in diabetic patients. To further elucidate this observed benefit, Gu et al . designed experiments to investigate whether simvastatin improves the beneficial effects of ischemic preconditioning during hyperglycemia in dogs subjected to coronary artery occlusion and reperfusion. Simvastatin restored the cardioprotective effects of ischemic preconditioning during hyperglycemia via nitric oxide–mediated signaling. The results suggest that enhanced cardioprotective signaling could be a mechanism for statin-induced decreases in perioperative cardiovascular risk.568In this issue, McGregor et al . report on their post hoc analysis of data from the large multicenter Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST). In the IHAST, anesthesia was dictated by a limited-options protocol and the decision about using nitrous oxide was left to individual anesthesiologists. Of the 1,000 patients for whom data were available, 373 had received nitrous oxide. According to various instruments used in the IHAST to assess neurologic and neuropsychological outcomes, intraoperative use of nitrous oxide was not associated with delayed ischemic neurologic deficits, long-term neurologic deficits, or neuropsychological deficits. See the accompanying Editorial View on page 553 559This article has been selected for the Anesthesiology CME Program. See the accompanying Editorial View on page 551 .

Timing of Neuropsychological Outcome Measures in Patients With Subarachnoid Hemorrhage

See related article, pages 1864–1872. Aneurysmal subarachnoid hemorrhage (SAH) accounts for up to 5% of all strokes and changes the lives of ≈30 000 people in the United States each year.1 The majority of patients experiencing SAH are young (mean age of presentation 55 years) and their average case fatality is 51%.2,3 About half of survivors are left with significant long-term cognitive dysfunction. Such cognitive impairment can also be seen in patients defined as having good neurological recovery by the Glasgow Outcome Scale. Despite these well-known facts, the available literature in the English language has important limitations. Such limitations include relatively small sample sizes, lack of follow-up beyond a 3-month period in many reports, and variations of timing of neurosychological assessments within and between studies. To bridge these gaps, …

Recovery of Cognitive Function After Surgery for Aneurysmal Subarachnoid Hemorrhage

Abnormalities in neurocognitive function are common after surgery for aneurysmal subarachnoid hemorrhage, even among patients with good functional outcomes. The time course of neurocognitive recovery, along with the long-term effects of mild intraoperative hypothermia (33 degrees C) and aneurysm location, is unknown. We determined these in a subset of subarachnoid hemorrhage patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST). We performed a longitudinal, multicenter, prospective, blinded study of adult IHAST patients with a Glasgow Outcome Score=1 or 2 (independent function), 3 months postsurgery and a matched control group (n=45). Subjects were tested with a 5-test cognitive function battery and standard neurological evaluations at 3, 9 and 15 months postsurgery. The primary outcome measure was a composite score on cognitive test performance. There were 303 IHAST patients available for inclusion: 218 eligible, 185 enrolled (89 hypothermic, 96 normothermic). Significant cognitive improvement was noted from 3 to 9 (P<0.001) and 3 to 15 (P<0.001) months in both hypothermic and normothermic groups, even after adjusting for practice effects observed in the control group. No significant change was identified between 9 and 15 months. Neither mild hypothermia nor aneurysm location (anterior communicating artery versus others) had a significant effect on recovery over time or frequency of cognitive impairment. Compared with control group, the frequency of cognitive impairment (Z score <-1.96) in all patients at 3, 9 and 15 months was 36%, 26% and 23%, respectively. In this population, cognitive improvement continued beyond 3 months, with a plateau between 9 and 15 months. This was not affected by the use of intraoperative hypothermia or anatomical location of aneurysm.

Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST)

New neurologic deficits may occur after intracranial vascular surgery, even in the absence of overt complications. Consequently, several efforts have emerged in an attempt to protect the brain intraoperatively. Systemic hypothermia is one such protective adjunct that was first reported in the 1950's. Although this technique was essentially abandoned in the decades that followed, interest returned after mild hypothermia was shown to improve outcomes in experimental models of cerebral ischemia. Hypothermia has since been implemented in the treatment of head trauma, stroke, and cardiac arrest. The benefit of hypothermia during neurovascular surgery, however, remains controversial. Dr. Michael Todd and colleagues recently completed their Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) and presented their results at the Society for Neuroanesthesia and Critical Care (October 2004, Las Vegas, NV). A full scale report is expected to be published in the New England Journal of Medicine sometime in 2005. In this large, prospective, international, multicenter, and blinded study, 1001 patients presenting with aneurysmal subarachnoid hemorrhage (aSAH) in good clinical grade (WFNS score of I, II, or III) were randomized to either intraoperative hypothermia (target temperature 33 degrees Celsius, using surface cooling techniques) or normothermia (target temperature 36.5 degrees Celsius) during aneurysm surgery. Exclusion criteria included a pre-hemorrhage Rankin Disability Score greater than 1, body mass index >35kg/m2, cold-related disorders, or endotracheal intubation at the time of enrollment. Outcome was assessed at 90 days postoperatively, primarily using the Glasgow Outcome Score (GOS). No significant differences in outcome measures was found between groups and, as a result, the authors concluded that intraoperative hypothermia does not improve neurologic outcome following craniotomy for intracranial aneurysm surgery. Furthermore, there was a suggestion that postoperative bacteremia may be more common in the hypothermic group, even though there was no difference in pneumonia, UTI, meningitis, or wound infection rate. Based on these findings, there appears to be minimal, if any, benefit to intraoperative hypothermia during aneurysm surgery. These results appear robust, considering the study design, sample size, cohort similarities, adjudicated outcomes, protocol compliance, and near-perfect follow-up. There are limitations to this investigation, however, that must be taken into account when interpreting the authors' findings. First, subgroup analysis of the data suggests a beneficial effect of intraoperative hypothermia when this technique is used in males and patients undergoing late surgery (8-14 days after initial aSAH). While these are secondary calculations without patient randomization and small sample sizes, future studies are warranted for clarification. Secondly, GOS, although widely used and universally accepted, is a relatively crude measurement of clinical outcome that may not detect subtle cognitive changes. This issue will be resolved once the outcomes from this trial's neuropsychiatric examinations are released. Furthermore, the findings of this investigation do not apply to all aSAH patients, as only those in good clinical grade were included. Closer inspection of the results reveals intraoperative hypothermia led to absolute and relative improvements in GOS 1 of 3.2% and 5.0%, respectively. This study, however, was only designed to identify absolute and relative improvements in GOS 1 of 10.0% and 15.0%, respectively. Thus, even with 1000 patients enrolled, this investigation may have been underpowered to detect the benefit of intraoperative hypothermia. To address this issue, future trials would ideally examine the effects of intraoperative hypothermia exclusively in patients with temporary clips placed for various durations, as hypothermia is intended to prolong cerebral tolerance during ischemic episodes. It is difficult, however, to endorse another expanded randomized trial, as the downside of mild intraoperative hypothermia appears trivial given the data on bleeding and cardiovascular instability from IHAST. Perhaps a more likely outcome is that surgeons will increasingly employ hypothermia in a selective manner in those cases in which prolonged ischemia is anticipated. The problem with such an approach is knowing exactly who is going to have a problem before it happens. While experience has shown that larger lesions, especially those with intraluminal thrombus or calcification, are more likely to require longer ischemia times, even the most straight-forward lesion can surprise. Without definitive data regarding the benefit of intraoperative hypothermia during aneurysm surgery, the use of this technique will continue to be determined by clinical judgment, individual case circumstances, and surgeon preference. RICARDO J. KOMOTAR, MD JESS E. JONES, BA E. SANDER CONNOLLY, JR., MD TECHNICAL & CLINICALRESEARCH