Paul A. Modica

Pro- and Anticonvulsant Effects of Anesthetics (Part I)

Many inhaled anesthetics and intravenous analgesics have been alleged to produce both proconvulsant and anticonvulsant activity in humans. The reasons for these contrasting actions on the CNS are poorly understood at the present time. However, biologic variability plays an important role in determining individual patients responses to anesthetic and analgesic drugs. In addition, variations in the responsiveness of inhibitory and excitatory neurons to the central depressant effects of these drugs could also explain these apparently conflicting data. Depending on the brain concentration, centrally active drugs may produce differing effects on the CNS inhibitory and excitatory neurotransmitter systems. The availability of increasingly powerful magnetic resonance imaging techniques to provide noninvasive information about tissue chemistry (e.g., neurotransmitters and citric acid cycle metabolites) and positron emission tomography to noninvasively evaluate CNS drug-receptor interactions should lead to a more in-depth understanding of the in vivo effects of anesthetics and analgesics on the CNS. In the second part of this review article, we discuss the pro- and anticonvulsant effects of the sedative-hypnotics, local anesthetics, and other anesthetic adjuvant drugs.

Intracranial pressure during induction of anaesthesia and tracheal intubation with etomidate-induced EEG burst suppression.

This study was designed to determine if induction of anaesthesia with etomidate titrated to an early EEG burst suppression pattern would produce minimal changes in cerebral perfusion pressure, and prevent increases in intracranial pressure (ICP) associated with tracheal intubation. Eight patients, 18–71 yr, with intracranial space-occupying lesions, were studied. In each patient ICP was monitored via a lateral ventriculostomy catheter placed preoperatively. In the operating room, an ECG, a radial arterial line, and a two-channel computerized EEG were placed. Control (awake) measurements of MAP (mmHg), ICP (mmHg), CPP(mmHg), heart rate (HR-bpm), EEG power(picowatts-pW), and spectral edge frequency (SEF, Hz) were obtained. Anaesthesia was induced with etomidate, 0.2 mg · kg−1 iv, followed immediately by an etomidate infusion, 20 mg · min−1, iv, and vecuronium 0.2 mg · kg−1 iv. When early burst suppression was achieved, the etomidate infusion was stopped and tracheal intubation performed. The etomidate dose (bolus plus infusion) required to reach burst suppression was 1.28 ± 0.11 mg · kg−1. Compared with awake control values (mean ± SE), the period from induction to burst suppression was associated with a 50% decrease in ICP (22 ± 1 vs 11 ± 1 mmHg, P < 0.01), but there were no changes in MAP, CPP, or HR. The decrease in ICP was maintained during the first 30 sec and the following 60 sec after intubation as MAP and HR remained unchanged. Our results suggest that when etomidate was administered to early burst suppression pattern on EEG, minimal changes in CPP occurred during induction of anaesthesia and a marked reduction in ICP was maintained following tracheal intubation.AbstractCette étude a été entreprise afin de déterminer si l’induction de l’anesthésie avec l’étomidate, dosé pour provoquer un début de suppression des ondes à l’EEG, produirait des changements minimes de la pression de la perfusion cérébrale, et préviendrait les augmentations de tension intrâcrdnienne (ICP) associées à l’intubation endotrachéale. Huit patients agés de 18 à 71 ans et avec une lésion intracrânienne expansive, ont été étudiés. Dans chaque cas, la tension intracrânienne, était surveillée à l’aide d’un cathéter inséré avant la chirugie à l’aide d’une ventriculostomie latérale. Après l’installation en salle d’opération d’un ECG, d’une ligne artérielle radiale et d’un EEG informatisé à deux canaux, des mesures de contrôle (à l’état d’éveil) de la tension artérielle moyenne (MAP) (mmHg), de la pression de la perfusion cérébrale (CPP) (mmHg), de la fréquence cardiaque (HR — bpm), de la puissance de l’EEG (picowatts-p W) et de la fréquence de l’extrémité du spectre («spectral edge») (SEF, Hz) était obtenues. L’anesthésie était induite avec l’étomidate à raison de 0,2 mg · kg−1 iv, suivie d’une perfusion d’étomidate à 20 mg · kg−1 iv.et de vécuronium à 0,2 mg · kg−1 iv. Lorsque la suppression des ondes de l’EEG était obtenue, la perfusion d’étomidate était cessée et on procédait à l’intubation endotrachéale. La dose d’étomidate (bolus et perfusion) requise pour supprimer les ondes à l’EEG était de 1,28 ± 0,11 mg · kg−1. Comparativement aux valeurs de contrôle à l’état d’éveil (moyenne ± SE), la période entre l’induction et la suppression des ondes de l’EEG était associée à une diminution de 50% de l’ICP (22 ± 1 vs 11 ± 1 mmHg, P < 0,01), mais il n’y avait aucun changement de MAP, CPP, ou HR. La diminution de l’ICP était maintenue pendant les 30 premières secondes, et une minute après l’intubation, alors que la MAP et le HR demeuraient inchangés. Nos résultats suggèrent que lorsque l’étomidate est administré et dosé jusqu’ à la suppression des ondes à l’EEG, des changements minimes dans la CPP apparaissent avec l’induction de l’anesthésie et une réduction marquée de l’ICP est maintenue suite à l’intubation trachéale.

RESISTANCE TO ATRACURIUM-INDUCED NEUROMUSCULAR BLOCKADE IN PATIENTS WITH INTRACTABLE SEIZURE DISORDERS TREATED WITH ANTICONVULSANTS

Previous studies have demonstrated that, with the exception of atracurium, resistance to the neuromuscular blocking effects of various muscle relaxants develops in patients receiving anticonvulsant therapy. We studied the effects of 0.5 mg/kg IV atracurium in 53 neurosurgical patients: 21 nonepileptic patients receiving no anticonvulsant therapy (MED = 0); 14 epileptic patients treated with carbamaze-pinefor years (MED = 1); and 18 epileptic patients treated with carbamazepine plus either phenytoin or valproic acid for years (MED = 2). The evoked compound electromyo-gram of the adductor pollicis brevis was recorded, and results were analyzed using analysis of covariance, with weight and age as covariables. The onset time was not significantly different among the three groups. Times for recovery of baseline and train-of-four responses to stimuli were significantly shorter in the MED = 1 and MED = 2 groups than in control patients (MED = 0). The recovery index (time between 25% and 75% recovery of baseline electromyogram values) was progressively shorter in the three groups (MED = 0: 8.02 min; MED = 2: 5.93 min; MED = 2:1.96 min; P < 0.001). This study demonstrates that atracurium, when used on epileptic patients requiring long-term (that is, years of) anticonvulsant therapy, has a shorter duration of action than when used in nonepileptic patients.

Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy

This study was designed to determine whether patients receiving chronic anticonvulsant therapy demonstrate an altered requirement for fentanyl during anaesthesia. Sixty-one patients undergoing craniotomy were studied; 20 controls (MED = 0) who had never received anticonvulsants and 41 epileptics in whom therapeutic plasma concentrations of either one (MED = 1), two (MED = 2), or three (MED = 3) different anticonvulsants were documented. During anaesthesia with 60–70 per cent N2O in O2 and 0.2 per cent isoflurane, a maintenance dose (MD) of fentanyl was administered using a continuous variable-rate IV fentanyl infusion, supplemented by intermittent 50 μg IV boluses. In order to define the minimal dosage of fentanyl required, the MD was titrated according to increases or decreases in the heart rate and/or mean arterial pressure exceeding 15 per cent of baseline ward values. A progressively higher fentanyl MD was required in the epileptic patients (MED = 1 − 4.3 ± 0.5 μg · kg− 1 · hr− 1;MED = 2 − 5.4 ± 0.6; MED = 3 − 7.6 ± 0.6) compared with the control MD (MED = 0 − 2.6 ± 0.5) (P < 0.001). These findings indicate that there appears to be a dose- effect relationship between the number of anticonvulsants received and the maintenance dose of fentanyl required during balanced anaesthesia.RésuméLe but de cette étude est d’observer les effets du traitement anticonvulsant de longue durée sur la dose de fentanyl requise pendant l’anesthésie. Soixante et un malades pour chirurgie intracranienne ont été etudiés de façon prospective: 20 patients controle (MED = 0) qui n’ont jamais recus d’anticonvulsant et 41 épileptiques avec des niveaux plasmatiques thérapeutiques pour un (MED = 1), deux (MED = 2) ou trois (MED = 3) anticonvulsants. La maintenance de l’anesthésie était assurée avec 70 pour cent N2O- O2, 0,2 pour cent isoflurane et une perfusion intraveineuse à niveau variable de fentanyl supplementée par des bolus intermittents de 50 μg. De manière a définir le dosage minimum de fentanyl requis (sans tenir compte du traitement anticonvulsant), la dose de maintenance de fentanyl (MD = perfusion + bolus) était augmentée ou diminuée selon les variations du rythme cardiaque et ou de la pression artérielle moyenne, pour les maintenir dans des limites n’éxcèdant pas ± 15 pour cent de leurs valeurs preop obtenues dans le service. Une augmentation progressive de la MD de fentanyl a été requise chez les patients épileptiques des differents groupes (MED = 1 − 4,3 ± 0,5 μg · kg− 1 · hr− 1; MED = 2 − 5,4 ± 0,6; MED = 3 − 7,6 ± 0,6) quand comparé au groupe contrôle (MED = 0− 2,6 ± 0,5) (P < 0.001). Aucune différence significative entre le groupe contrôle et les patients épileptiques, ne fut notée concernant les differents critères d’émergence de l’anesthésie. Ces resultats semble indiquer qu’il existe une relation dose- effet entre le nombre d’anticonvulsants recus par les malades et la dose de maintenance de fentanyl requise pendant l’anesthésie générate « balancée ».

Propofol vs. thiopental-isoflurane for neurosurgical anesthesia: comparison of hemodynamics, CSF pressure, and recovery.

Sixty otherwise healthy patients with no clinical signs of intracranial hypertension who were undergoing elective intracranial surgery were randomly assigned to receive anesthesia with either thiopental, 3-6 mg/kg i.v., and isoflurane, 0.5-1.5% (group 1, N = 30) or propofol, 1-2.5 mg/kg i.v., and propofol infusion, 40-200 microg/kg/h (group 2, N = 30). Both groups received 50% nitrous oxide in O2 subsequent to dural opening. During induction, the changes in heart rate (HR), mean arterial pressure (MAP), cerebrospinal fluid pressure (CSFP), and cerebral perfusion pressure (CPP) were similar between the groups, except at 3 min when the findings (mean +/- SEM) for CPP (81 +/- 3.3 vs. 70.3 +/- 2.8 mm Hg, p <0.05) were significantly lower in group 2. At intubation, the highest level of MAP (103.1 +/- 3.3 vs. 88.9 +/- 2.7 mm Hg, p <0.05) was significantly greater in group 1. At pinhead-holder application, the highest values of HR (81.8 +/- 3 vs. 73.9 +/- 2.1 beats/min, p <0.05), MAP (112.2 +/- 3.6 vs. 98.3 +/- 3 mm Hg, p <0.05), CSFP (15.2 +/- 1.3 vs. 11.6 +/- 1.1 mm Hg, p <0.05), and CPP (97.0 +/- 3.9 vs. 86.7 +/- 3.3 mm Hg, p <0.05) were significantly greater in group 1. During early (20-30 min) recovery, group 2 had higher Glasgow Coma Scale scores and a greater percentage of patients in whom eye opening, response to commands, extubation, speech, and time/space orientation were present. In conclusion, when compared to thiopentalisoflurane for intracranial surgery, propofol produces similar HR, MAP, CSFP, and CPP responses during induction, adequate control of these responses during nociceptive stimulation, and faster recovery for cerebral function postoperatively.

Selective Shunting During Carotid Endarterectomy Based on Two-Channel Computerized Electroencephalographic/Compressed Spectral Array Analysis

The reliability of selective shunting based on computerized electroencephalographic (EEG) monitoring has not been addressed. In this study, 103 carotid endarterectomies were performed with selective shunting based on a two-channel computerized EEG monitor that processed the on-line, raw electroencephalogram (EEG) to produce a compressed spectral array (CSA). Ischemic EEG events were identified by amplitude attenuation of the raw EEG and/or loss of high-frequency activity on the CSA. Fourteen patients (13.6%) received a bypass shunt, and postoperative neurological examinations showed 97 patients (94.2%) to be intact. A correlation between total (cumulative) ischemic EEG time and the postoperative neurological exam was demonstrated (P less than 0.0001). Six postoperative deficits (5.8%) occurred, five in patients whose computerized EEGs demonstrated an ischemic EEG event late during carotid clamping, when it was no longer possible to place a shunt. The sixth deficit was found in a patient whose EEG did not demonstrate any patient whose EEG did not demonstrate any signs of cerebral ischemia. Five of these six new deficits resolved within 12 hours, and only one persisted for 72 hours, when the patient died of a pulmonary embolism (cerebral infarction and mortality rate of 1%). These results appear to demonstrate that two-channel monitoring of both the CSA and the unprocessed (raw) EEG simultaneously can be used as a reliable indicator of whether a bypass shunt is required during carotid cross-clamping in all patients, regardless of their preoperative neurological history or angiographic findings.

Accelerated recovery from pipecuronium in patients treated with chronic anticonvulsant therapy

STUDY OBJECTIVE To determine whether chronic anticonvulsant therapy affects recovery time from pipecuronium. DESIGN Open-labeled, controlled study. SETTING Inpatient neurosurgical service at a university medical center. PATIENTS ASA physical status II and III patients within 30% of their ideal body weight and without significant history of ethanol abuse or renal or hepatic disease. Nineteen patients were admitted into the study and were divided into three groups based on the number of anticonvulsant medications (MED) they were taking: MED = 0, control group (6 patients); MED = 1, one anticonvulsant (6 patients); MED = 2, two or more anticonvulsants (7 patients). INTERVENTIONS Intravenous (IV) administration of pipecuronium 80 micrograms/kg with general anesthesia after thiopental sodium 4 to 6 mg/kg IV, maintained with 70% nitrous oxide in oxygen, 0.2% to 0.3% end-tidal isoflurane, and fentanyl. MEASUREMENTS AND MAIN RESULTS The evoked compound electromyogram (ECEMG) of the adductor pollicis brevis muscle was measured after stimulation of the ulnar nerve by train-of-four (TOF) supramaximal impulses at 2 Hz repeated every 20 seconds. Measurements include T-1% (ECEMG signal at 25%, 50%, and 75% of baseline), TR% (TOF ratio), and recovery index (RI). Patients administered chronic anticonvulsant therapy recovered more rapidly from pipecuronium than untreated patients. For instance, time to 25% recovery of baseline (T-1 25%) was 123 +/- 13 minutes for MED = 0, 91 +/- 7 minutes for MED = 1, and 58 +/- 5 minutes for MED = 2 (p < 0.05). TOF recovery to 20% (TR 20%) and RI were similarly affected. CONCLUSIONS Patients treated with chronic anticonvulsant therapy recovered from pipecuronium more rapidly than unmedicated patients. Furthermore, there seemed to be a dose-effect relationship between the number of anticonvulsants received and a decreased time to recovery from pipercuronium neuromuscular blockade.

Computerized electroencephalographic monitoring and selective shunting: influence on intraoperative administration of phenylephrine and myocardial infarction after general anesthesia for carotid endarterectomy.

During carotid endarterectomy (CEA), phenylephrine infusions are commonly used to induce hypertension during carotid clamping in an attempt to increase collateral cerebral blood flow and prevent cerebral ischemia. Although this practice appears to increase the incidence of intraoperative myocardial ischemia during CEA when general anesthesia is employed, whether the limited use of phenylephrine infusions in specific instances of cerebral ischemia, as shown on an electro-encephalogram, results in low perioperative rates of both myocardial infarction (MI) and cerebral infarction remains unclear. We studied 171 CEAs done under general anesthesia performed with selective shunting based on the identification of cerebral ischemia by a two-channel computerized electroencephalographic monitor. The use of a phenylephrine infusion was restricted to the following instances of cerebral ischemia: 1) ischemia associated with hypotension that did not resolve within 2 minutes of decreases in anesthetic administration and treatment with fluid and/or colloid; 2) ischemia poorly or slowly responsive to shunt placement, accompanied by either hypo- or normotension; and 3) ischemia poorly or slowly responsive to removal of the carotid clamp, accompanied by either hypo- or normotension. Two non-Q wave MIs (1.2%) occurred, both nonfatal. There were two cerebral infarctions (1.2%) and three deaths not related to MI (1.8%). Based on these findings, in order to decrease the incidence of both MI and cerebral infarction after general anesthesia for CEA, we recommend the restrictive use of phenylephrine-induced hypertension for specific instances of slowly or poorly reversible cerebral ischemia, as shown on the electroencephalogram.

A comparison of computerized EEG with internal carotid artery stump pressure for detection of ischemia during carotid endarterectomy.

Summary Previous investigations appear to indicate that an ischemic EEG is not observed during carotid cross-clamping when the stump pressure is ≥60 mm Hg. In this report of 124 carotid endarterectomies (CEA) performed with selective shunting based on computerized EEG (CEEG), we compared the CEEG and this previously established critical stump pressure level of 60 mm Hg as methods of detecting cerebral ischemia during carotid clamping. A significant association between stump pressure and CEEG findings during clamping existed (p <0.05). Only 1 of 44 patients with a stump pressure ≥60 mm Hg received a shunt based on CEEG signs of cerebral ischemia. However, 62 of the remaining 80 patients did not receive a shunt and awoke neurologically intact despite a stump pressure <60 mm Hg. A highly significant association between the postoperative neurologic exam and the CEEG findings during carotid clamping was demonstrated (p <0.001). In contrast, for stump pressure, a correlation with the neurologic exam was not found. Compared to CEEG, these results appear to indicate that a critical stump pressure of 60 mm Hg is a sensitive but not specific indicator for the placement of a shunt selectively during CEA. The combined use of these two monitors should lead to reliable shunt selection, especially when stump pressure is <60 mm Hg.

Effect of Propofol on Cerebro-Spinal Fluid Pressure in Patients with and without Intracranial Hypertension

Propofol has been shown to be a suitable agent for neuroanesthesia [2]. It decreases cerebral oxygen consumption (CMRO2) and cerebral blood flow (CBF), and increases cerebral vascular resistance [4]. Intracranial pressure (ICP) decreases as a result of the effects of propofol on cerebral hemodynamics [2]. In this study [2], baseline ICP of the 23 patients before propofol ranged from 6 to 32 mmHg. Accordingly, the present study was designed to evaluate and to quantify prospectively the cerebrospinal fluid pressure (CSFP) decreasing effect of propofol in patients with and without intracranial hypertension (ICH) to determine whether their ICP reacts in the same way to propofol and to the same degree in both groups.