Carol A. Hirshman, M.D., Editor
Society of Neurosurgical Anesthesia and Critical Care. San Francisco, California, October 14, 1994.
The 22nd annual meeting of the Society of Neurosurgical Anesthesia and Critical Care (SNACC) was held at the Parc 55 Hotel, San Francisco, California, on October 14, 1994. Among the topics discussed were the design and implementation of clinical trials in the neurosciences, current concepts in the management of seizures, and the use of either regional or general anesthetic techniques for carotid endarterectomy surgery. A poster discussion session highlighted controversies concerning the action of nitric oxide in the central nervous system, the role of hypothermia in brain protection, and the use of motor evoked potential monitoring to prevent iatrogenic injury during spine surgery.
Harold P. Adams, Jr., M.D., Professor of Neurology at the University of Iowa College of Medicine (Iowa City), spoke on “The Trials of Clinical Trials.” Adams has been involved as the principal investigator for several multicenter clinical trials that have attempted to measure efficacy of various experimental pharmacologic interventions in acute stroke patients. His account of the many pitfalls ahead of an inexperienced researcher was enlightening. As the Janssen Distinguished Lecturer, Adams suggested that, before a randomized clinical trial of a new therapy for acute ischemic stroke is undertaken, there must be strong evidence from experimental and pilot clinical studies of a reasonable chance for success. In addition, the intervention must have widespread clinical applicability. Issues of safety and possible efficacy are best addressed by pilot clinical studies, and data from the pilot studies determines the best regimen for dosage and duration of treatment. Pilot studies should be followed by multicenter randomized trials. Unfortunately, in the past, several small pilot studies have led to conclusions that a particular intervention was not effective; yet the small number of patients in the study did not permit a statistical analysis with either valid positive or valid negative conclusions.
Concerning the design of large, multicenter randomized clinical trials. Adams stated that the biggest danger to success is the urge to make the project too elaborate. Researchers must resist the temptation to create an exceedingly complex trial or to add spinoff projects. Often the basic hypothesis is not logically stated. Adams advises investigators to keep the protocol treatment regimen, timing of patient assessments, and data collection forms as clear as possible. An operations manual is helpful. Many trials have been weakened by use of excessive time-consuming baseline tests, as well as the addition of therapies to the investigational drug. Clinical trials are exhaustive in Adams' view, because they are truly a trial of the scientific method being applied to the art and inexact science of patient care.
After Adams' lecture, David S. Warner, M.D., (Durham, North Carolina) discussed the use of randomized clinical trials in neuroanesthesia. He finds a lack of large-scale, randomized multicenter trials in the field and suspects that an individual center is unable to collect enough of one type of patient to pursue a large outcome study. He is hopeful that a recently initiated study on the use of intraoperative hypothermia might pave the way for cooperative, multi- institutional, clinical trials of neuroanesthetic techniques and interventions ultimately designed to improve patient care.
In his remarks, Warner referred to a presentation by Rosemary A. Craen, M.B.B.S., (London, Ontario) of data from a survey of 41 North American centers where cerebral aneurysm surgery is performed. In discussing specific brain protective measures, 71% of the 65 responding neuroanesthesiologists used some level of induced hypothermia. Fifty percent use 33–34 degrees Celsius, 29% use greater than 34 degrees Celsius, and 16% use less than 34 degrees Celsius. Twenty-six percent used mild hypothermia in every patient. Warner is concerned that intraoperative hypothermia for cerebral protection has never been studied in a prospective, randomized, double-blind multicenter trial, and it is worrisome that nine neuroanesthesiologists in eight P.S. centers believe it is unethical to conduct a controlled study with normothermia.
Gregory D. Cascino, M.D., (Rochester, Minnesota) delivered an invited lecture, “Current Concepts in the Management of Seizures.” Much of Cascino's address dealt with complex partial seizures, a common seizure type in patients with partial epilepsy. Most of these seizures emanate from the temporal lobe; however, they may be extratemporal in origin. Carbamazepine and phenytoin are the antiepileptic drugs of choice in the management of complex partial seizures. Cascino is concerned that polypharmacy and the use of cognitively impairing antiepileptic drugs may cause patients to lose confidence in medication, reducing compliance and further impairing the quality of life for the patient with epilepsy. He views epilepsy surgery as an important alternative for the patient with intractable partial seizures.
Lesions that may be amenable to surgery are identified through the use of neuroimaging. Magnetic resonance imaging (MRI) is a reliable and accurate indicator of the common pathologic findings that underlie a partial seizure disorder. The use of MRI to identify an epileptogenic lesion affects the selection of patients for epileptic surgery and may alter the diagnostic evaluation and operative strategy. Surgical ablative therapy is successful in patients with lesional epileptic syndromes, and neurocognitive outcome can be predicted from hippocampal volume studies performed with MRI technology. MRI is a reasonable initial “screening” procedure in selected patients with intractable partial epilepsy who might be considered for presurgical evaluation. After Cascino's presentation, Ian A. Herrick, M.D., (London, Ontario) reviewed the current database on anesthetic induced seizures.
The final session of the meeting featured a debate on “Monitoring during Carotid Endarterectomy—the Awake Patient vs. the Asleep Patient.” With Ira J. Rampil, M.D., (San Francisco, California) as moderator, Thomas J. Losasso, M.D., (Rochester, Minnesota) and John A. Youngberg, M.D., (New Orleans, Louisiana) presented arguments for the asleep versus the awake patient. Losasso maintained that carotid endarterectomy surgery, even in elderly patients, can be undertaken safely with minimal neurologic morbidity when monitoring such as a 16- channel electroencephalogram and cerebral blood flow studies are used to evaluate cerebral perfusion and determine the necessity of shunt placement during cross-clamping. While acknowledging that no definitive study had been performed to demonstrate the superiority of maintaining a patient awake with regional anesthesia versus placing a patient under general anesthesia for carotid endarterectomy. Youngberg presented evidence that at his institution (Tulane), it was more cost-effective to proceed under regional anesthesia. A lively and informative discussion ensued.
The topics of both hypothermia and hyperthermia as they relate to neurosurgical care were popular among presenters at the SNACC meeting. R. Klementavicius, M.D., (Pittsburgh, Pennsylvania) followed up on a study presented at last year's meeting for which he and his colleagues found that hypothermia depresses basal cerebral metabolic rate for oxygen (CMRO2) more than active CMRO2in a rat model. Data from this year's study allow them to prove the hypothesis that the Q10 for active and basal CMRO2differs and that active CMRO2is less sensitive to the effects of hypothermia than is basal CMRO2in their model. Applying the use of hypothermia to patients, S. Black, M.D. and associates, (Gainesville, Florida) compared temperature measurements made from the brain, tympanic membrane, and esophagus during craniotomy. The data demonstrated that, in each patient, the brain temperature was consistently lower than esophageal or tympanic membrane temperature. During craniotomy in humans, brain temperature is lower than the more commonly measured parameters in animal studies with a closed cranium. It is hypothesized that small decreases or increases in temperature may lead to differing degrees of cerebral protection, and small variations may be clinically important. G. Ihra, M.D. and colleagues, (Vienna, Austria) evaluated transesophageal echocardiographic data in neurosurgical patients undergoing mild hypothermia (esophageal temperature to 32 degrees Celsius). Recording left ventricular segmental wall motion and left ventricular long axis views to examine apical contraction as well as cardiac isoenzymes, this group failed to observe systolic wall motion abnormalities indicative of myocardial ischemia in their group of 26 patients. Their data support the hypothesis that myocardial ischemia in hypothermic patients is more likely caused by shivering during rewarming than hypothermia. In a companion study reported by A. Bacher, M.D., from the same institution, body temperature reductions from 35.5 degrees Celsius to 32 degrees Celsius in anesthetized, paralyzed, and mechanically ventilated patients caused no untoward effects on total body oxygenation or metabolism.
While most studies presented at the meeting dealt with hypothermia. C. T. Wass, M.D. and colleagues, from the Mayo Clinic, (Rochester, Minnesota) were awarded the Omeda Pharmaceutical Products Division New Investigator Award for their study on hyperthermia. Twenty- one dogs were divided into three groups: a control group 37.0 plus/minus 0.3 degrees Celsius, a mildly hyperthermic group 38.0 plus/minus 0.3 degrees Celsius, and a moderately hyperthermic group 39.0 plus/minus 0.3 degrees Celsius. Complete cerebral ischemia of 12.5 min duration was produced in each animal using a compression technique. Temperatures were maintained at a target value beginning 20 min before ischemia and afterwards for 1 h. Later, temperatures were returned to 37 degrees Celsius in all dogs. After recovery from anesthesia, neurologic assessment was performed by a blinded observer at 24, 48, and 72 h postischemia using a 100-point scoring scale. In addition, each dog's brain was subsequently examined and scored by a neuropathologist. When compared to control dogs, both mildly and moderately hyperthermic dogs had significantly worse neurologic function scores and histopathology scores. There was also a significant correlation between neurologic function and histopathology scores. This study demonstrated that small clinically relevant increases in temperature result in significant worsening of postischemic neurologic function and cerebral histopathology in this model.
Remifentanil is an investigational micro-opioid agonist cleared via nonspecific esterases, resulting in an extremely short duration of action. Because rapid clearance permits quick emergence from anesthesia, this drug may be useful: timely postoperative assessment of neurosurgical patients is important. B. Hindman, M.D., (Iowa City, Iowa) reported on remifentanil's effect on cerebral dynamics. Adult patients undergoing elective supratemorial craniotomy constituted this study group. After the induction of anesthesia with thiopental, with maintenance by 60%, N2O in oxygen and isoflurane and the use of vecuronium for tracheal intubation, an epidural intracranial pressure (ICP) transducer was placed. When baseline values were obtained, patients received one of three study medications: placebo, 10 or 20 micro gram/kg alfentanil, or remifentanil, 0.5 or 1.0 micro gram/kg. Hemodynamics and ICP were recorded at the end of a 1-min infusion of the study drug and for 10 min thereafter. Data analysis indicated no significant ICP differences within groups or among groups following this study drug administration. Because mean arterial pressure decreased significantly after the administration of the larger doses of alfentanil or remifentanil compared to placebo, cerebral perfusion pressure decreased significantly as well. In all groups, however, mean arterial pressure and cerebral perfusion pressure were similar to baseline values 10 min after completion of the infusion. The authors concluded that remifentanil was unlikely to have major or unique clinical effects on intracranial pressure, and decreases in cerebral perfusion pressure are the result of remifentanil's effect on systemic hemodynamics. W. Andrew Kofke, M.D., (Pittsburgh, Pennsylvania) presented data that fentanyl given in large doses produces limbic system brain damage in rats. Additional studies presented by this investigator used a model of cerebral ischemia caused by bilateral carotid occlusion for 12 min. which allowed him to demonstrate that high-dose fentanyl (80 micro gram/kg) with a maintenance infusion of 32 micro gram *symbol* kg sup - 1 *symbol* min sup -1 produced epileptiform activity on the electroencephalogram. Ischemia also produced lesions in the cerebral cortices, amygdala, hippocampus, thalamus, hypothalamus, mid-brain, and olfactory bulb. Kofke and colleagues believed that fentanyl use in their model could exacerbate incomplete brain ischemia in the rats. A preliminary study from this same group using positron emission tomography (PET) imaging in three nonhuman primates demonstrated that fentanyl selectively activates the limbic system structures and causes bilateral activation of the temporal lobes as well.
The use of propofol is increasingly common in neuroanesthesia B. F. Matta, M.B.F.R.C.A., and colleagues (University of Washington, Seattle, Washington) studied the effects of propofol-induced electroencephalogram suppression on cerebral carbon dioxide reactivity and blood flow autoregulation. Propofol-induced electrical silence on the electroencephalogram was demonstrated in ten patients undergoing anesthesia for nonneurosurgical procedures. Autoregulation was characterized by using a phenylephrine infusion to increase mean arterial pressure while cerebral blood flow velocity was recorded with a transcranial Doppler probe through a temporal window Carbon dioxide reactivity was tested by varying PaCO2between 30 and 50 mmHg and simultaneously recording cerebral blood flow velocity. The authors demonstrated that cerebral carbon dioxide reactivity and blood flow autoregulation remain intact during propofol-induced electrical silence of the electroencephalogram. In an additional study reported by the same group of investigators, it was apparent that, when nitrous oxide was added during anesthesia for patients who had a propofol-induced electrical silence on their electroencephalogram, nitrous oxide increased cerebral blood flow velocity approximately 20% as measured by transcranial Doppler, although there was no apparent increase in cerebral metabolism/blood flow ratio. This suggests that the increase in cerebral blood flow may be the result of cerebral stimulation.
The sensitivity and specificity of eight homologous channel pairs in a 16-channel electroencephalogram system to detect ischemia during carotid endarterectomy was determined in a study using 50 consecutive patients who underwent carotid endarterectomy with an isoflurane-based anesthetic and 16-channel electroencephalogram monitoring. R. M. Kraft, M.D., (Rochester, Minnesota) found that certain channel pair combinations provided 100% sensitivity and specificity to detect ischemia:Equation 1. These investigators determined that electroencephalogram channels are most sensitive to ischemia when they cover the middle cerebral artery distribution, and clamp-related electroencephalogram changes of ischemia can be detected with 100% sensitivity and specificity using two electroencephalogram channels per cerebral hemisphere. As shown in the table, acceptable channel pair combinations provide frontal parietal plus frontal temporal coverage correlating with the superior and inferior M2 branches of the middle cerebral artery, respectively.
T. S. Mayberg, M.D., (Seattle, Washington) and colleagues studied the issue of whether hyperoxia during acute hyperventilation would improve oxygen delivery to the cerebral circulation. They monitored cerebral oxygen content and used a continuous jugular venous bulb catheter to study and calculate cerebral oxygen content in patients undergoing various neurologic procedures when arterial hyperoxia PaO2greater than 200 mmHg was introduced. The investigators found that hyperoxia, during acute hyperventilation in the anesthetized patient, improves oxygen delivery to the cerebral circulation as measured by higher cerebral venous oxygen content and saturation. C. Melot, M.D., (Brussels, Belgium) used a thermodilution catheter within the internal jugular bulb to measure cerebral blood flow with a continuous thermodilution technique. In seven patients, cerebral blood flow measurements with the thermodilution catheter were compared with cerebral blood flow measurements using the Kety-Schmidt method and nitrous oxide. Good agreement was obtained between the two techniques.
M. Mahla, M.D., (Gainesville, Florida) and colleagues reported on the use of somatosensory evoked potential (SSEP) monitoring during aneurysm surgery. Two hundred seventy-seven patients were studied, and the effects of interventions when somatosensory evoked potential amplitude decreased by 50% were recorded. For anterior circulation aneurysms, neurologic outcome was better when the SSEPs returned to normal than when the SSEP abnormality persisted. If an SSEP abnormality of any type occurred with posterior circulation aneurysms, new neurologic deficits were likely in their group of patients. E. W. Lang (San Diego, California) presented data on motor evoked potentials recording during spinal surgery in 40 patients. Using a technique of partial neuromuscular blockade, nonrecoverable motor evoked potential loss correlated with neurologic deficit. Whereas the San Diego group used etomidate for their anesthetic technique, T. Sloan, M.D., (San Antonio, Texas) presented experimental data using cynomologous monkeys that indicated that propofol demonstrates a dose-related depression of transcranial electric and magnetic motor evoked potentials. Additionally, Sloan presented data that both isoflurane and desflurane produced similar degrees of depression of motor evoked potentials in adult baboons studied at their institution.
Abstracts of the scientific papers presented and poster presentations are published in the Journal of Neurosurgical Anesthesiology. Volume 6, No. 4, 1994. The next meeting of the Society of Neurosurgical Anesthesia and Critical Care is scheduled for October 20, 1995, in Atlanta, Georgia.
Patricia H. Petrozza, M.D., Associate Professor of Anesthesia; Head, Section on Neuroanesthesia, The Bowman Gray School of Medicine of Wake Forest University, Medical Center Boulevard; Winston Salem, North Carolina 27157–1009.