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Hippocampal N-methyl-D-aspartate receptors (NMDARs) are thought to be involved in the regulation of memory formation and learning. Investigation of NMDAR function during experimental conditions known to be associated with impaired cognition in vivo may provide new insights into the role of NMDARs in learning and memory. Specifically, the mechanism whereby high concentrations of L-phenylalanine (L-Phe) during phenylketonuria (>1.2 mM) cause mental retardation remains unknown. Therefore, the effects of L-Phe on NMDA-activated currents (I(NMDA)) were studied in cultured hippocampal neurons from newborn rats using the patch-clamp technique. L-Phe specifically and reversibly attenuated I(NMDA) in a concentration-dependent manner (IC(50) = 1.71 +/- 0.24 mM). In contrast, L-tyrosine (L-Tyr), an amino acid synthesized from L-Phe in normal subjects, did not significantly change I(NMDA). Although the L-Phe-I(NMDA) concentration-response relationship was independent of the concentration of NMDA, it was shifted rightward by increasing the concentration of glycine. Consistent with an effect of L-Phe on the NMDAR glycine-binding site, L-Phe (1 mM) did not attenuate I(NMDA) in the presence of D-alanine (10 microM). Furthermore, L-Phe significantly attenuated neither glutamate-activated current in the presence of MK-801, nor current activated by AMPA. The finding that L-Phe inhibits specifically NMDAR current in hippocampal neurons by competing for the glycine-binding site suggests a role for impaired NMDAR function in the development of mental retardation during phenylketonuria and accordingly an important role for NMDARs in memory formation and learning.

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P0.001, n=16) and 69+/-7% (P0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.

Although nitrous oxide (N2O) should theoretically increase the severity of venous air embolism (VAE), data confirming this hazard in clinical situations are not available. The effect of 50% N2O on the incidence and severity of VAE and on the emergence time from anesthesia was evaluated in 300 neurosurgical patients operated upon while in the sitting position. Of these, 110 patients underwent craniectomy for posterior fossa pathology and 190 patients underwent cervical spine surgery (CSS). Patients were randomized to receive either 50% N2O in oxygen (O2) (N2O group) or O2 (no-N2O group) as part of an isoflurane-fentanyl-based anesthetic. In patients in the N2O group, N2O administration was discontinued immediately upon Doppler-detection of VAE and was reinstituted in not less than 30 min after resolution of the episode. The incidence of Doppler-detected VAE was significantly greater in the craniectomy group than the CSS group (43% vs. 7%, respectively; P less than 0.001). N2O had no effect on the incidence of VAE or the severity of VAE as judged by the magnitude of the reduction in blood pressure during hemodynamically significant episodes of VAE, the volume of gas aspirated from the right atrial catheter during episodes of VAE, or the magnitude of the decrease in end-tidal carbon dioxide tension during episodes of VAE. Hemodynamically significant episodes of VAE (i.e., episodes associated with a reduction in systolic blood pressure of greater than or equal to 15 mmHg) occurred in 17 of the 61 patients experiencing VAE (28%) and was not different between the N2O and no-N2O groups. Similarly, hemodynamically significant episodes of VAE (n = 18) accounted for 15% of all episodes of VAE (n = 118) and was not different between the N2O and no-N2O groups. Emergence time was not significantly different between the N2O and no-N2O groups, with mean times of 2 +/- 6 and 3 +/- 7 min (+/- SD), respectively. Emergence time was significantly longer in the craniectomy group than in the CSS group (5 vs. 1 min, respectively; P less than 0.001). Within the craniectomy group, the incidence of Doppler-detected VAE was significantly less in patients with previous surgery at the operative site (21%) compared to patients without previous surgery at the operative site (47%). Postoperatively, no complications could be related to the use of N2O or directly attributed to the occurrence of VAE.(ABSTRACT TRUNCATED AT 400 WORDS)

Volume expansion of intravascular air by nitrous oxide (N2O) may improve the sensitivity of monitors used to detect venous air embolism (VAE) and/or exacerbate hemodynamic changes following VAE. The purpose of this study was to determine if the administration of N2O alters the sensitivity (i.e., threshold of detection) of monitors used to detect VAE or the hemodynamic consequences of VAE. Twenty-one dogs were monitored for VAE with precordial Doppler ultrasound, transesophageal echocardiography (TEE), changes in end-tidal carbon dioxide tension (ETCO2), and changes in pulmonary artery pressure (PAP). Venous air was infused at rates between 0.005 and 0.4 ml.kg-1.min-1 during 1 MAC (total anesthetic level) of isoflurane with and without 50% N2O (group 1, n = 7) or isoflurane with and without 75% N2O (group 2, n = 7). The mean quantity of infused air necessary to elicit a positive response in both the presence and absence of N2O was calculated for each monitor. Positive responses were defined as follows: unmistakable audible change in frequency on Doppler ultrasound, visualization of densities consistent with air bubbles in the right cardiac chambers or outflow tract on TEE, a decrease in ETCO2 greater than or equal to 2 mmHg, and an increase in mean PAP greater than or equal to 3 mmHg. In group 3 (n = 7), venous air was infused at rates between 0.1 and 0.8 ml.kg-1.min-1 during 1 MAC (total anesthetic level) of isoflurane with and without 50% N2O. In group 3, N2O administration was discontinued immediately upon Doppler detection of VAE and air infusion continued until mean arterial pressure (MAP) decreased by 10 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective, stratified, randomized clinical trial of the safety and efficacy of four general anesthetic agents (enflurane, fentanyl, halothane, and isoflurane) was conducted in 17,201 patients (study population). Patients were studied before, during, and after anesthesia for up to 7 days. Nineteen patients died (0.11%), and in seven of these (0.04%) the anesthetic may have been a contributing factor. The rates of death, myocardial infarction, and stroke in the study population were so low (less than 0.15%) that no conclusions regarding the relative rates of these outcomes among the four anesthetic agents could be reached. The rates of 16 of 66 types of adverse outcomes in the study population were significantly different among the four study agents. Most of these outcomes were minor. However, severe ventricular arrhythmia (P less than 10(-6)) was more common with halothane, severe hypertension (P less than 10(-6)) and severe bronchospasm (P = 0.028) were more common with fentanyl, and severe tachycardia (P = 0.001) was more common with isoflurane. Recovery from anesthesia during the first 30 min was slowest in those patients who received halothane (P less than or equal to 0.001). In addition, patients who received fentanyl experienced less pain during the first hour in the recovery room (P less than 10(-6)). In conclusion, clinically important differences do exist for some outcomes among the four study agents.

Despite the pathophysiological and therapeutic significance of the negative dromotropic effect of adenosine, its underlying ionic mechanism, and specifically the role of the adenosine-activated K(+) current (I(K,ADO)) is not experimentally defined. Therefore, we studied the contribution of I(K,ADO) to the negative dromotropic effect of adenosine.Effects of adenosine on single atrioventricular nodal and left atrial myocytes from rabbits were studied using the whole cell configuration of the patch clamp technique. Complementary experiments were done in rabbit and guinea pig isolated hearts instrumented to measure the atrium-to-His bundle interval.In contrast to its effect in atrial myocytes, Ba(2+) selectively and completely blocked I(K,ADO) at membrane potentials from -70 to 0 mV in atrioventricular nodal myocytes and abolished the adenosine-induced leftward shift of the reversal membrane potential. Ba(2+) alone did not significantly prolong the A-H interval, but markedly attenuated the A-H interval prolongation caused by adenosine. In guinea pig heart, EC(50) values ( pD(2) +/- SEM) for adenosine-induced atrium-to-His bundle interval prolongation were 3.3 micromol/L (5.48 +/- 0.04) and 13.2 micromol/L (4.88 +/- 0.05, P0.001) in the absence and presence of Ba(2+), respectively. Despite species-dependent differences in sensitivities to adenosine (guinea pigrabbit), the relative contribution of adenosine-activated K(+) current to the atrium-to-His bundle interval prolongation was nearly identical. In guinea pig hearts it ranged from 37.8 % (P = 0.013) to 72.5 % (P0.001) at 2 to 6 micromol/L adenosine, respectively.I(K,ADO) contributes significantly to the negative dromotropic effect of adenosine, but predominantly at relatively high concentrations of the nucleoside.

The effect of esmolol on fetal heart rate (FHR) after maternal administration has not been reported previously. We describe the use of esmolol in a 22-week pregnant woman undergoing resection of a cerebellar arteriovenous malformation and its effect on FHR

In patients undergoing neurosurgical procedures at high risk for venous air embolism (VAE), the presence of a right-to-left shunt adds an additional risk for paradoxical air embolism (PAE). Although this is a rare complication, it can have devastating results. The most common form of right-to-left shunt is a patient foramen ovale (PFO), which can be detected by contrast echocardiography. This study evaluates the efficacy of preoperative precordial and intraoperative transesophageal echocardiography (TEE) to detect right-to-left shunting in patients undergoing neurosurgical procedures while in the sitting position. In 101 patients precordial contrast echocardiography was performed prior to surgery. The Valsalva maneuver was utilized as a provocative maneuver to facilitate demonstration of right-to-left shunting. Fifty-one of these patients also had intraoperative TEE monitoring. Right-to-left shunting was demonstrated in only six of the 101 patients examined. Of these, four were detected by TEE. This is less than the expected incidence based on the known incidence of PFO in the general population. The usefulness of preoperative ECHO as a screening test for PFO in patients undergoing neurosurgical procedures is limited, but when a PFO is found, valuable information is acquired to help manage these patients.

Desflurane, a new volatile anesthetic, produces cerebral vasodilation. The purpose of this study was to compare the effects of 1 MAC desflurane with those of isoflurane on cerebrospinal fluid pressure (CSFP) in patients with supratentorial mass lesions and a mass effect on computerized tomography (CT scan). Twenty adult patients undergoing craniotomy for removal of supratentorial mass lesions were studied. Ten patients received desflurane and 10 patients received isoflurane. Prior to induction of anesthesia, a radial artery catheter was inserted and a 19-G needle was inserted into the lumbar subarachnoid space to measure CSFP. Baseline arterial blood gases and CSFP were measured with the patient awake and unmedicated. Anesthesia was induced with thiopental (6-9 mg/kg) and muscle relaxation achieved with vecuronium (0.2 mg/kg). The lungs of all patients were hyperventilated to achieve an arterial CO2 tension of 24-28 mmHg. Anesthesia was maintained with 1 MAC volatile anesthetic, either 7.0% desflurane or 1.2% isoflurane in an air:O2 mixture to maintain an inspired O2 fraction (FIO2) of 0.50. Patients were not administered any other anesthetic until the dura was incised. Mean arterial pressure was kept within 20% of the patient's mean ward values with the use of esmolol or phenylephrine. CSFP, mean arterial pressure, end-tidal CO2 concentration (PETCO2), hemoglobin O2 saturation, and cerebral perfusion pressure were recorded with the patient awake, immediately postinduction with thiopental, postintubation, after institution of the volatile anesthetic, and every 5 min until the dura was incised. There was no difference in the mean (+/- SD) awake CSFP between the desflurane (11 +/- 4 mmHg) and the isoflurane (10 +/- 2 mmHg) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

✓ Because of a suspicion that intraoperative penicillin antibiotics might be causing early postoperative seizures in craniotomy patients, a deliberate effort was initiated in 1987 to avoid these agents in favor of nonpenicillin antibiotics. This permitted a retrospective comparison of the incidence of early postoperative seizures in craniotomy patients who did and who did not receive intraoperative penicillins. Records of patients treated between July 1, 1984, and July 1, 1985, and between July 1, 1987, and July 1, 1988, were reviewed, for a total of 1316 procedures. There were no seizures in the 323 patients who underwent suboccipital craniectomy. However, among the 993 patients receiving supratentorial procedures there were 30 with seizures within the first 6 hours postoperatively, 19 of which were generalized seizures. The incidence of early seizures was 4.7% (20 cases) of the 427 patients given penicillins and only 1.8% (10 cases) of the 566 not given penicillins (p < 0.01). Since patients undergoing surgery for intractable seizures have a high incidence of early postoperative seizures (11 of 92 in this series, or 12%), creation of a subgroup eliminated these from consideration but did not alter the relationship of penicillins to early seizures (p < 0.02). The authors conclude that intraoperative (and early postoperative) penicillin antibiotic administration should be avoided, if possible, in patients undergoing craniotomy for supratentorial pathology.

A prospective randomized clinical trial of enflurane, fentanyl, halothane, and isoflurane is described. The 17,201 patients were stratified into two groups (preanesthetic medication and no preanesthetic medication) and were randomized to one of four study agents: enflurane, fentanyl, halothane, and isoflurane. Fifteen university-affiliated hospitals in the United States and Canada participated. All patients were first assessed preoperatively. Data were collected during anesthesia, in the immediate recovery period, and for up to 7 days after anesthesia/surgery. The mean age of the patients was 43 yr, the mean height 167 cm, and the mean weight 68 kg. Sixty-five percent of patients were female. In this study 90.7% of patients were classified as ASA Physical Status 1 or 2, and 34.7% of patients smoked. It is concluded that pooling of data across institutions was valid and does allow determination of the efficacy and relative safety of the four study agents.

Background Inhibition of adenosine metabolism offers a unique approach to harness the cardioprotective properties of adenosine in a site- and event-specific manner. Benzodiazepines inhibit adenosine metabolism by blocking nucleoside transporter. Therefore, the authors studied the binding affinities of structurally different benzodiazepines to nucleoside transporter and benzodiazepine-induced potentiation of A1-adenosine (negative dromotropy) and A2A-adenosine (coronary vasodilation) receptor-mediated effects. Methods In membranes from porcine striatum and guinea pig ventricle, competition binding assays to displace [3H]nitrobenzylmercaptopurine riboside ([3H]NBMPR) from nucleoside transporter were performed using alprazolam, chlorodiazepoxide, diazepam, flurazepam, and midazolam. The augmentation by the most potent benzodiazepine of A1- and A2A-adenosine receptor-mediated responses, elicited by exogenous administration of adenosine or brief periods of global hypoxia, was subsequently studied in guinea pig Langendorff-perfused hearts. Results All benzodiazepines completely displaced [3H]NBMPR in a concentration-dependent manner with Hill coefficients not significantly different from unity in both striatal and ventricular membranes. Midazolam was the most potent inhibitor of nucleoside transporter (ventricle:pKi = 5.22+/-0.41, Ki = 6 microM). In isolated hearts, midazolam (5, 10, 20 microM) significantly augmented coronary flow in a concentration-dependent manner in the presence of adenosine (30 nM), an effect reversed by ZM 241385, a selective A2A-receptor antagonist. In contrast, midazolam did not increase the effect of adenosine (30 nM) on atrioventricular conduction. Similarly, midazolam potentiated A2A- but not A1-receptor-mediated effects of endogenous adenosine released during hypoxia. Conclusions Structurally distinct benzodiazepines inhibit nucleoside transporter to different degrees. Midazolam selectively augments A2A- but not A1-receptor-mediated effects of adenosine by inhibiting nucleoside transporter.

Airway management in patients with craniofacial trauma presents the anesthesiologist with several complex problems. Not only are these patients often in acute respiratory distress, but also disruption of normal anatomic relationships in the head and neck can make placement of artificial airways, laryngoscopy, and tracheal intubation both technically difficult and hazardous. We present a case in which insertion of a nasopharyngeal airway in a patient with head and neck injury may have contributed to further damage to the central nervous system

The postoperative course of patients emerging from general anesthesia after intracranial surgery is frequently complicated by hypertension. This study examined the comparative efficacy of esmolol and labetalol in treating increases in blood pressure during emergence and recovery from anesthesia after intracranial surgery. Both esmolol and labetalol were equally effective in controlling systolic blood pressure on emergence and in the recovery room in patients undergoing intracranial surgery. However, decreases in heart rate were significantly more frequent in the immediate postoperative period in patients given labetalol. An increase in blood pressure after intracranial surgery appears to be a transitory phenomenon adequately treated with a short-acting antihypertensive agent such as esmolol.

The cerebral metabolic and vascular effects of isoflurane (Forane) were investigated in six unmedicated ventilated dogs. At the MAC of this anesthetic (1.4 per cent, end-expired) there was a 23 per cent decrease in the rate of cerebral oxygen consumption (CMRO2) (compared with values at end-expired concentrations of

Controversy continues to surround the use of the sitting position for neurosurgical procedures. This retrospective review of 579 posterior fossa craniectomies performed over a 4-yr period from 1981 through 1984 examines outcome following these procedures performed with the patients in either the sitting (n = 333) or horizontal (supine, prone, lateral, park bench) (n = 246) position. Multiple preoperative, intraoperative, and postoperative variables were analyzed. Venous air embolism occurred significantly more often in patients in the sitting position (45% versus 12%). However, no morbidity or mortality was attributed to venous air embolism. The incidence of hypotension with positioning was not different by position (19% in the sitting patients and 24% in the horizontal patients). Average blood replacement was significantly lower in the sitting patients (359 ml versus 507 ml), and the incidence of transfusion of greater than two units of blood was significantly higher in the horizontal patients (13% versus 3%). Postoperative cranial nerve function was significantly better in patients in the sitting group as compared to those in the horizontal group. The incidence of perioperative cardiopulmonary complications was not different between groups. These outcome data suggest that there are potential advantages and disadvantages of both the sitting and horizontal positions without supporting a significantly increased morbidity or mortality associated with either position.

Transcutaneous oxygen tension (Ptco2) and transcutaneous carbon dioxide tension (Ftcco2) were monitored in 60 patients undergoing neurosurgical procedures. Twenty-six patients were in the sitting position and underwent routine monitoring for air embolism. Seventeen episodes of air embolism were diag

A prospective, randomized study was performed in 87 patients to compare the safety, efficacy and dose requirements of two sedation techniques for stereotactic headframe application. Sedation administration and headframe application averaged 30 min. Fifty patients weighing 76 +/- 13 kg (mean +/- SD) received mean doses of 154 micrograms fentanyl plus 5.5 mg droperidol i.v. (FD group). An additional 37 patients weighing 76 +/- 19 kg received mean doses of 127 micrograms fentanyl plus 6.7 mg Valium (diazepam; FV group). Both treatments provided excellent hemodynamic stability and a low incidence of adverse side effects while providing adequate analgesia and sedation. The incidence of anesthetist-assessed patient anxiety and discomfort was more favorable in the FD group.

We reviewed the results of intraoperative monitoring of short-latency cortical evoked potentials in 81 patients who underwent surgical procedures of the cervical spine. Of these patients, 43 had (1) baseline somatosensory evoked potentials from stimulation of the upper and lower extremities, (2) intraoperative monitoring for at least 3 hours, and (3) absence of an intrinsic lesion of the spinal cord. Major reductions in amplitude of the ulnar and tibial cortical evoked potentials occurred shortly after induction of anesthesia in 12% of patients. Latencies gradually increased during the operation as the concentration of volatile anesthetic agents increased. In patients with preoperative evidence of cervical cord damage, the cortical responses showed more fluctuations and could be lost without major changes in the concentration of the anesthetic agent or surgical manipulation. In one patient, intraoperative monitoring of the cervical cord function prevented a postoperative neurologic deficit. Ulnar and tibial cortical evoked potentials were successfully monitored throughout operation in all patients in whom baseline scalp responses could be obtained, but careful monitoring of anesthetic effect is necessary for proper interpretation.

The effect of isoflurane on cerebrospinal fluid pressure (CSFP) was determined in 20 patients undergoing craniotomy for intracranial supratentorial neoplasm or hepatoma. In 15 of these patients, following endotracheal intubation, hyperventilation sufficient to result in PaCO2 25-30 torr was begun simultaneously with the introduction of 1 per cent isoflurane. In the remaining five patients ventilation was equivalent, but normocapnia was maintained by adding CO2 to the inspired gases. In the hypocapnic patients CSFPs did not increase above awake values (range 5-45 torr) following isoflurane administration. In the normocapnic patients (CSFPs consistently increased. In three of these five patients the increases were precipitous, but were corrected rapidly by establishment of hypocapnia. The authors conclude that the known cerebral vasodilator properties of isoflurance can be countered effectively by hypocapnia. Furthermore, unlike the situation with halothane, it is not necessary to establish hypocapnia prior to introducing isoflurane in order to avoid CSFP increases.

The sensitivities of current monitoring methods for detection of air embolism were compared in eight anesthetized dogs. Air was infused at controlled rates of 0.001 and 0.005 ml X kg-1 X min-1 for 1 min; 0.01, 0.05, 0.1, 0.2, and 0.4 ml X kg-1 X min-1 for 6 min; and 5 ml X kg-1 bolus injection. Based on the mean quantity of air infused to elicit a positive response, the monitors could be placed into three significantly different sensitivity groups. Transesophageal echocardiography (TEE) and precordial Doppler ultrasound were the most sensitive monitoring methods detecting 0.19 and 0.24 ml X kg-1 of air, respectively. TEE detected air during six infusions in which the Doppler failed to do so. The next most sensitive group of monitoring methods included pulmonary artery pressure (PAP), end-tidal CO2 (PETCO2), arterial oxygen tension (PaO2), and transcutaneous oxygen tension (PtcO2). The mean quantity of air infused to elicit a positive response in this group of monitors ranged from 0.61 to 0.76 ml X kg-1. The response of PtcO2, PaO2, PETCO2, and PAP equally reflected the quantity of air infused. The least-sensitive group of methods included arterial and transcutaneous carbon dioxide tension and systemic arterial blood pressure. These data indicate that TEE is more sensitive than Doppler ultrasound and that PAP, PETCO2, and PtcO2 are equally sensitive in detecting venous air embolism in the dog.