The effect of neuroleptanalgesia (droperiodol-fentanyl) on motor potentials evoked by transcranial magnetic stimulation in the monkey.

Motor evoked potentials (MEPs) after transcranial magnetic stimulation (TMS) have been examined in 12 monkeys under neuroleptanalgesia (NLA). Compound muscle action potentials were recorded from abductor policis brevis (APB) and gastroncnemius (GN) muscles contralateral to the stimulation site. After obtaining baseline tracings during emergence from methohexitone, 10 mg/kg i.m., NLA was induced using droperiodol, 0.3 mg/kg i.v. followed by fentanyl, 0.006 mg/kg i.v. Sequential MEP recordings were obtained 10 min after i.v. droperiodol, 2, 8, and 16 min after i.v. fentanyl, and during recovery. Replicable TMS MEPs were consistently recorded under NLA. However, droperidol and fentanyl caused significant stimulation threshold elevation, amplitude depression, and latency delay compared to control values (p <0.01). Ten minutes after droperiodol administration, the APB-GN threshold, amplitude, and latency values (mean +/- SD) were 0.81 +/- 0.2-0.84 +/- 0.1 T (baseline 0.57 +/- 0.1-0.59 +/- 0.1 T), 3.4 +/- 2.1-4.0 +/- 2.5 mV (baseline 8.0 +/- 3.7-9.0 +/- 3.7 mV), and 15.8 +/- 1.3-21.1 +/- 1.2 ms (baseline 14.9 +/- 1.2-20.1 +/- 1.3 ms), respectively. Addition of fentanyl resulted in further response deterioration. Two minutes after fentanyl injection, the APB-GN threshold, amplitude, and latency values were 0.88 +/- 0.18-0.95 %% 0.15 T, 2.1 +/- 1.7-2.0 +/- 2.1 mV, and 16.0 +/- 1.4-21.9 +/- 1.3 ms, respectively. Subsequent MEPs revealed gradual response improvement but, in contrast to baseline, remained markedly altered (p <0.05). During the recovery period (53 +/- 6 min), the APB-GN threshold, amplitude, and latency measurements were 0.66 +/- 0.1-0.77 +/- 0.2 T, 4.4 +/- 3.1-4.2 +/- 2.9 mV, 15.5 %% 1.4-20.9 +/- 1.7 ms, respectively. We conclude that, in a primate model, NLA maintains measurable TMS MEPs. Nevertheless, droperiodol and fentanyl produce significant and prolonged response alterations. Knowledge of these changes, while administering NLA drugs intraoperatively, is essential to interpretation of MEP data.

A hypothetical model on the mechanism of anesthesia.

An hypothesis on the mechanism of action of general anesthetic agents is proposed. It is based on a potentiation of chloride influx due to the action of anesthetic agents on the GABA-receptor complex at the lipid-protein interface. This hypothesis accommodates various observations such as lipid solubility of anesthetic molecules, their lack of stringent structural requirement, pressure reversal of anesthetic action, and other neurochemical and neuropharmacological data.

A neurochemical hypothesis for halothane anesthesia.

We hypothesize that anesthetic agents exert their effects through an inhibition of oxidation of reduced nicotinamide adenine dinucleotide (NADH) in the synaptic regions of the brain. This inhibition could lead to gamma-amino-butyric acid (GABA) accumulation in the synaptic cleft and to hyperpolarization of the post-synaptic membrane. The resulting reduction in synaptic transmission then would manifest itself as the anesthetic state, reducing the work performed by the brain so that cerebral respiration is reduced and cerebral metabolite energy is conserved.

Inhibition of GABA metabolism in rat brain slices by halothane.

Based on studies with rat cerebral cortex slices, it was previously hypothesized that halothane anesthesia may result from increased GABA (gamma-aminobutyric acid) content in the synapses. Since GABA is an inhibitory neurotransmitter, such increases may cause a reduction in synaptic activity. The increase in GABA content could arise from several possible causes which are examined in this study using rat cerebral cortex slices as a model. The effects of halothane on uptake, release, and catabolism of GABA were determined. Uptake was studied by the amounts of radioactive GABA accumulated by the slices, and release studied by that discharged into the medium from slices preloaded with radioactive GABA. Catabolism was assessed by preloading the slices with radioactive GABA and then followed by measuring the amount of radioactivity found in unmetabolized GABA or in pooled GABA metabolites. Since CO2 was established as a major metabolite, it was subsequently used alone to measure the inhibition of GABA catabolism in the presence of varying amounts of halothane. Halothane (3 per cent) did not affect the high-affinity uptake or the release of GABA but did inhibit the catabolism of GABA. Using 14CO2 production as an index of catabolism, the inhibition of GABA catabolism by halothane was dose-related (8.79 per cent inhibition/per cent halothane). Such results support the hypothesis that halothane anesthesia may result at least in part from an inhibition of GABA catabolism which, in turn, causes increased GABA level in the synapse with resultant synaptic inhibition.

Effects of anesthetic agents on synaptosomal GABA disposal.

In brain slices, halothane was shown to inhibit the metabolic breakdown of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter. This inhibition leads to increased brain GABA content, presumably in the synaptic areas, and to the postulation that halothane anesthesia may arise from an enhanced synaptic inhibition due to this elevated GABA. The ability of many neurotropic agents to inhibit GABA breakdown was studied by assessing synaptosomal "GABA disposal". GABA disposal by intact synaptosomes, which simulate miniature synapses, measures the conversion of [1-14C]GABA to 14CO2 and includes the processes of uptake, release, and catabolism of GABA. The most potent inhibitor is chloroform, followed by halothane, enflurane, ether, and thiopental. Pentobarbital, ethanol, paraldehyde, and ketamine are weak inhibitors. Phenobarbital, morphine, and phenytoin are not inhibitory at pharmacologic concentrations. As a whole, anesthetic agents show particular inhibitory action on this metabolic process in this model system where the ID10 values (i.e., concentration of a drug necessary to produce 10 per cent inhibition of GABA disposal) correlate well with known pharmacologic potencies, ED50 values, or MACs. These observations support the possibility that anesthesia may be related to an inhibition of GABA disposal.

Inhibition of GABA metabolism in rat brain synaptosomes by midazolam (RO-21-3981).

Benzodiazepines are known to potentiate GABA (gamma aminobutyric acid) action in the brain. The effects of midazolam, a water-soluble benzodiazepine, on GABA disposal (14CO2 from [1-14C]GABA) and on the individual processes of GABA uptake, GABA release, and GABA-transaminase in the rat brain synaptosomal model system were studied. A 10 per cent inhibition of action was defined as ID10. Midazolam inhibited overall GABA disposal at ID10 = 13 micro M. The ID10 values for the three contributing process in the overall GABA disposal process are 580 micro M for GABA-transaminase activity, 96 micro M for GABA release, and 13 micro M for GABA uptake. The value for GABA release is probably not valid since it fell outside of the linear part of the regression line which was used for calculation. Therefore, GABA uptake inhibition appears to be responsible for the overall inhibition of GABA disposal. This value is consistent with the proposed hypothesis that anesthesia involves excess GABA in the synaptic area.

Inducing anesthesia with a GABA analog, THIP.

The authors have postulated previously that general anesthetic agents act via a potentiation of the inhibitory action of gamma-aminobutyric acid (GABA) at central synapses. If the hypothesis is true, GABA should induce anesthesia, however, GABA itself does not pass through the blood-brain barrier. A GABA analog was sought as a substitute to test the authors' hypothesis. A new bicyclic GABA analog, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) was selected because its properties are similar to GABA in vitro. THIP was found to induce anesthesia in rodents, and its behavior was compared with that of thiopental, ketamine, midazolam, and gamma-hydroxybutyrate. Complete loss of righting reflex occurred with doses of THIP and thiopental just under 100 mumol/kg, with ketamine and midazolam less than 50 mumol/kg and with gamma-hydroxybutyrate of more than 6,000 mumol/kg. Complete recovery from thiopental and ketamine occurred in less than 5 min, with midazolam recovery required about half an hour and with gamma-hydroxybutyrate and THIP it took about 1 1/2 h. THIP induced analgesia as well as sedation and loss of righting reflex. Recovery was complete, and no adverse effects were noted in these rodents.

Clinical use of etomidate for anesthesia induction: a preliminary report.

Etomidate (0.3 mg/kg) and thiopental (4 mg/kg) were administered IV for induction of general anesthesia, comparing heart rate, blood pressure, respiration, and side effects. No significant difference between the drugs was found in the circulatory parameters, but respiration was more depressed by thiopental. A high incidence of the side effects of myoclonia and pain on injection was seen with etomidate. The incidence of side effects was not affected by speed of injection or type of premedication. Mechanisms to reduce the incidence of side effects are needed for etomidate to become a useful induction agent.

Effects of anesthesia on intermediary metabolism.

Major inhalational anesthetics cause inhibition in the electron transport chain in the region of Complex I resulting in decreased oxygen utilization, inhibition of metabolism of NAD-linked substrates, but not of succinate, inhibition of mitochondrial calcium uptake, and depression of synaptic transmission because of postulated changes in ACh sensitivity or GABA inhibition. Many cellular metabolic effects in CNS and other tissues are secondary to the above. Many metabolic changes noted with anesthetics occur subsequent to activation of the sympathetic nervous system either directly by the anesthetic or by surgical stimulation in the presence of light anesthesia. Many important studies remain to be done.

Trimethaphan-induced hypotension: effect on renal function.

This study was designed to evaluate the effects of trimethaphan-induced hypotension on renal function in healthy young patients undergoing maxillofacial surgery. Anaesthesia was induced with thiopentone and was maintained with halothane 1.5-2.0 per cent in oxygen. Each patient served as his own control, and data were analyzed using the paired t-test. Trimethaphan was infused at a rate of 45-52 microgram.kg-1.min-1 for an average hypotensive period of 53 +/- 4 (mean +/- SEM) minutes to reduce the mean arterial pressure (MAP) to 49 +/- 2 torr. Endogenous creatinine clearance, urinary Po2, sodium reabsorption rate (Tna), and serum and urine osmolalities were determined before, during and after arterial hypotension with trimethaphan. Urine flow averaged 2.9 +/- 1 ml/min during the period of hypotension. Endogenous creatinine clearance and Tna were significantly decreased (p less than 0.05) in the hypotensive period. These values returned to normal levels within one hour upon discontinuation of trimethaphan and restoration of blood pressure. We found no statistical difference in urine Po2, and serum and urine osmolalities during control, hypotensive and recovery periods. These results suggest that medullary renal tissue oxygenation, an index of tissue viability, may have remained adequate despite a significant reduction in endogenous creatinine clearance during the hypotensive period. Furthermore, it appears that the effect of trimethaphan-induced hypotension on renal function is similar to the sodium nitroprusside-induced hypotension in man which we have reported previously.

Effects of hyperosmotic mannitol infusion on hemodynamics of dog kidney.

This study evaluated the effect of systemic infusion of hypertonic mannitol on renal hemodynamics (aortic pressure [P]-renal blood flow [RBF] relationship, glomerular filtration rate [GFR], and effective renal plasma flow [ERPF]) during 50% reduction of left kidney blood flow. Conditioned mongrel dogs anesthetized with halothane were hydrated by continuous infusion of lactated Ringer's solution containing creatinine to measure GFR and p-aminohippurate (PAH), to measure ERPF. The left kidney was exposed and two hydraulic occluders were placed, one around the aorta just above the renal arteries and the other around the left renal artery. Experimental design consisted of measuring P near the left renal artery, RBF by electromagnetic flowmeter, and ERPF and GFR by clearance methods in both kidneys in response to stepwise reduction in the aortic pressure by aortic occlusion before and after 50% reduction in the left kidney blood flow. The P-RBF relationship, GFR, and ERPF thus obtained were compared with those obtained during systemic intravenous infusion of 20% mannitol for a period of 1 h. We found that 1) a transient increase occurred in RBF with step reduction of P from 80 to 60 mm Hg under control conditions; 2) reducing the RBF by 50% changed the shape of the P-RBF relationship from a convex to the P axis to a linear form with a marked shift toward the P axis; 3) infusion of mannitol, during reduced RBF, caused a significant shift of the P-RBF curve toward the RBF axis and returned the linear P-RBF relationship toward normal, but had no effect on altered yield pressure; and 4) infusion of hypertonic mannitol had slightly increased GFR and ERPF in the right (unconstricted) kidney. However, hypertonic mannitol significantly increased GFR and ERPF values in the left (constricted) kidney suggesting a beneficial effect of mannitol on ischemic kidney. The results are consistent with the hypothesis that infusion of hypertonic mannitol to ischemic kidney increases RBF, presumably by decreasing the intrarenal vascular resistance. We speculate that this compensatory response may be mediated either 1) by stimulating the release of a vasodilator substance (e.g., prostaglandins), or 2) by washing out interstitial sodium, thereby reducing the sensitivity of the renal vasculature to ischemia-induced stimulation of renin-angiotensin system.

Induced enzyme release from synaptosomes by halothane.

GABA-transaminase has been found to be released from rat brain synaptosomes by halothane in a dose-related manner. The releases of both GABA-transaminase and succinic semialdehyde dehydrogenase were increased with time. The release of other enzymes (creatine kinase, glutamate decarboxylase, aspartate transaminase, lactate dehydrogenase, and malate dehydrogenase) was less in magnitude and not related to the duration of incubation. Such observations suggested a specific event in the halothane-induced release of GABA-catabolizing enzymes. A suggestion linking mode of anesthetic action to a mitochondrial effect of volatile anesthetics was made.

Halothane acts as a partial agonist of the alpha6 beta2 gamma2S GABA(A)receptor.

Whole-cell patch clamp recording was performed on human embryonic kidney 293 cells stably transfected with rat cDNAs for the alpha6, beta2, and gamma2S subunits of the GABA(A) receptor. The volatile anesthetic halothane directly activated a current in the absence of the ligand gamma-aminobutyric acid (GABA). Both the current amplitude and the rate of desensitization increased in a dose-dependent manner with an EC50 of 1.0+/-0.2 mM and a Hill coefficient (nh) of 1.5+/-0.1. The EC50 and nh for GABA to activate the receptor were 1.0+/-0.3 microM and 1.4+/-0.2, respectively. The peak amplitude of the halothane-activated current was about 4% of the maximal GABA response, which was not changed when the concentration of Ca2+ in the external solution was decreased from 2 mM to 0.2 mM. The reversal potential of both halothane- and GABA-activated currents changed with the external Cl- concentration as predicted by the Nernst equation for chloride ions. The halothane- and GABA-activated currents were blocked by both the noncompetitive GABA(A) receptor antagonist picrotoxin and the competitive GABA(A) receptor antagonist bicuculline. Schild plots revealed that the K(i)s for bicuculline to competitively antagonize the currents activated by halothane and GABA are similar (0.69 and 0.72 microM, respectively). These results indicate that halothane activates the alpha6 beta2 gamma2S GABA(A) receptor to induce a current similar to the GABA-induced current.

Postdural puncture headache in patients with chronic pain.

The incidence of headache after dural puncture in patients being treated for chronic pain was studied prospectively. Dural punctures were performed in 142 patients and headache developed in 13 (9.2%). Four of 32 patients (12.5%) who underwent diagnostic differential spinal and nine of 110 patients (8.2%) given intrathecal steroid injection developed headache. There was a 10.7% incidence of headache when a 22-gauge needle was used as compared to 5% with a 25-gauge needle. This difference was not statistically significant. The incidence decreased with increasing age. The incidence of postdural puncture headache in chronic pain patients does not differ significantly from that previously reported for surgical patients. All patients who developed headache responded to treatment which consisted of intravenous and oral fluids, analgesics, bed rest, and, if necessary, epidural blood patch.

Relationship between past academic performance and results of specialty in-training examinations.

In this study, the authors review the records of 63 graduates of Northwestern University Medical School who were residents in its graduate medical education programs of anesthesia and orthopedic surgery. They examine the relationship among college grades, medical school performance, and the results of assessment by annual, nationwide, medical specialty in-training examinations. For the anesthesia group, the best predictors of in-training examination performance were the Medical College Admission Test (MCAT) Verbal Ability score, the college grade-point average for nonscience subjects, and the MCAT Science, General Information, and Quantitative Ability scores. For the orthopedic group, the best predictors were the MCAT Verbal Ability score, the college grade-point average in nonscience subjects, the MCAT Science score, and the National Board of Medical Examiners Part I and Part II examination scores. The previous academic records for the 63 residents contained little to presage results in the in-training examination. The correlation obtained between nonscience college subjects and the in-training examination results was negative.