Gerald L. Becker

Effects of aerosolized and/or intravenous lidocaine on hemodynamic responses to laryngoscopy and intubation in outpatients

A randomized, double-blind study was carried out on 40 unpremedicated, ASA I-II adult surgical outpatients to assess the effects of aerosolized lidocaine, intravenous lidocaine, both, orneither, on circulatory responses to laryngoscopy and intubation. Lidocaine (4 mg/kg) or saline was given by nebulizer in the holding area beginning at −15 minutes. The patient underwent a standarized induction of anesthesia that included IV curare (3 mg) and O2 by facemask at minute 2, followed by IV thiopental (5 mg/kg) and succinylcholine (1.5 mg/kg) at minute 5. Lidocaine (2 mg/kg) or saline was given by IV push at minute 4. Laryngoscopy was begun at 5 minutes and continued for 45 seconds before intubation. Heart rate and systolic, diastolic, and meanblood pressures were automatically recorded at 1-minute intervals from 0 to 11 minutes. The fourtreatment groups included: group 1, aerosolized and IV saline; group 2, aerosolized saline, IV lidocaine; group 3, aerosolized lidocaine, IV saline; and group 4, aerosolized and IV lidocaine. There were no differences among the four treatment groups (n = ten per group) in any of the fourhemodynamic variables before laryngoscopy and intubation. Within each group, after intubation all four hemodynamic variables increased significantly over the corresponding baseline values for that group. However, the maximum values attained after intubation did not differ significantly among the four treatment groups for any of the four hemodynamic variables, whether those maxima were expressed as absolute values or as a percentage of baseline. Having found no difference in the effects of aerosolized and/or intravenous lidocaine and saline placebo on hemodynamic response to laryngoscopy and intubation in adult surgical outpatients using a rigidly standardized protocol, it is recommended that such usage of lidocaine be abandoned.

Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.

Effectiveness of Triazolam, Diazepam, and Placebo as Preanesthetic Medications

Eighty-three ASA Physical Status 1-2 patients were orally premedicated with triazolam (0.125, 0.25, or 0.5 mg), diazepam (5, 10, or 15 mg), or placebo to evaluate the effectiveness of these drugs and doses in reducing preoperative anxiety, providing sedation, and producing amnesia. The drug treatments were administered in a randomized, double-blind manner. The results obtained with each drug (dose) group were compared against those of the placebo group as a control. Changes in anxiety at 60 min after drug administration were evaluated: 1) by a trained anesthesia nurse clinician using an analog scale, 2) by the patient using the same analog scale, and 3) by the patient with the Multiple Affect Adjective Check List (MAACL). Changes in sedation at 60 min were also evaluated by the patient and nurse clinician using an analog scale. Amnesia was assessed by postoperative recall of picture cards shown to the patient 1 h after receiving preanesthetic medication. There were no significant differences between any drug (dose) and placebo for changes in patient-evaluated anxiety or sedation on the analog scale. With the other measures of anxiety, only triazolam (0.5 mg) reduced anxiety more than did placebo on both the patient (MAACL) and the nurse (analog) scales. With the nurse (analog) measure of sedation, only the highest doses of triazolam and diazepam were more sedating than placebo. Triazolam (0.5 mg) was the only drug dose that produced significant amnesia. The authors conclude that drug effects on anxiety, sedation, or amnesia that are statistically significant versus placebo effect are seen at only the highest doses of triazolam (0.5 mg) and diazepam (15 mg).

Incidence of hypotension associated with epidural anesthesia using alkalinized and nonalkalinized lidocaine for cesarean section

: The onset of epidural anesthesia is accelerated by alkalinization of lidocaine with added epinephrine (LE). The possibility that decreases in systolic blood pressure (SBP) are also enhanced was studied in 21 patients having elective cesarean sections. Ten patients given LE + NaHCO3 (0.1 mEq/ml anesthetic solution) compared with 11 given LE alone had significantly (P less than 0.05) greater decreases in SBP (32% vs 19% from baseline values), as well as a greater rate of SBP decline to those minimum values (9%/min vs 3%/min, respectively). These differences were noted despite the fact that patients given LE + HCO3 received no less ephedrine and no more additional anesthetic than controls. Possible adverse effects of SBP reduction on uteroplacental blood flow suggest that caution be used in the use of alkalinized LE in obstetrical patients.

Effects of isoflurane dose, duration of anoxia, and reoxygenation on isoflurane's preservation of energy balance in anoxic isolated hepatocytes

We investigated how the protection of energy status by isoflurane in isolated hepatocytes varied with isoflurane dose, duration of anoxia, and reoxygenation. Hepatocytes were isolated from fed rats and incubated in Krebs buffer under O2/CO2 or N2/CO2 (95/5) for 30 or 90 min, followed by 5 or 30 min of reoxygenation. From measurements of adenosine tri-, di-, and monophosphate (ATP, ADP, AMP) in the cells, energy charge (= [ATP + 1/2 ADP] / [ATP + ADP + AMP]) was calculated to reflect the balance between ATP supply and demand, and total adenine nucleotide (= ATP + ADP + AMP) to indicate the potential maximum ATP level. During 30 min of anoxia, energy charge and total adenine nucleotide steadily increased with isoflurane dose from 0 to 2 minimum alveolar anesthetic concentration, then decreased from 2 to 3 minimum alveolar anesthetic concentration. In short incubations (30–35 min) at 1 minimum alveolar anesthetic concentration isoflurane, there was a modest decrease in energy charge during anoxia, partially prevented by isoflurane and completely reversed by reoxygenation, and no decrease in total adenine nucleotide. In long incubations (90–120 min), there were large decreases in both energy charge and total adenine nucleotide during anoxia, with partial and no reversal by reoxygenation, respectively. Isoflurane partly prevented decreases in both energy charge and total adenine nucleotide during both anoxia and reoxygenation. We conclude that at doses in the clinical range, isoflurane partially protected isolated hepatocytes against decreases in both energy charge and total adenine nucleotide occurring either during short (reversible) or long (irreversible) anoxia. Other data from this study suggest that isoflurane may have protected in part by inhibiting AMP formation, an obligatory step in nucleotide degradation.

The effects of nitrous oxide on oxygen consumption by isolated cerebral cortex mitochondria.

The influence of N2O on O2 consumption by mitochondria isolated from the cerebral cortex of goats was examined in incubations preequilibrated with N2O-O2 or N2-O2. Rates of O2 consumption were measured polarographically in a closed system while adenosine triphosphate (ATP) formation was maximal (after addition of excess adenosine diphosphate (ADP), state 3 respiration) and then when it was at zero (after addition of excess oligomycin, state 4 respiration). Compared with 90% N2, 90% N2O produced no change in the rate of state 3 respiration; but an observed 9% decrease in the state 4 rate and an 11% increase in the state 3: state 4 ratio were statistically significant (P < 0.05). These differences were not seen with N2 and N2O at 70% rather than at 90%, or when succinate rather than pyruvate-malate was used as the respiratory substrate. We conclude the following: Unlike other inhalation anesthetics, N2O at comparable anesthetic concentrations does not inhibit mitochondrial electron transport or ATP formation coupled to it (oxidative phosphorylation). N2O does inhibit one or more other processes, as yet unidentified, which are energetically coupled to electron transport. The increased cerebral O2 consumption that accompanies N2O anesthesia cannot be attributed to a direct effect of N2O on mitochondrial respiration.

Cerebral mitochondrial respiration in diabetic and chronically hypoglycemic rats.

The respiratory function of cerebral mitochondria harvested from genetically diabetic (BB/W) and streptozotocin-diabetic rats deprived of insulin for 3-4 weeks was found to be unchanged from control values. Furthermore, insulin-deprived BB/W rats subjected to 30 min of insulin-induced hypoglycemic coma demonstrated a normal mitochondrial respiration following a 60 min period of glucose restitution, a finding consistent with earlier results in non-diabetic rats. However, in rats exposed to 1 week of moderate hypoglycemia (plasma glucose = 3.0 mumol.ml-1), both state 3 respiration and the respiratory control ratio (RCR) were reduced from control. In fact, when the chronic hypoglycemia was imposed following a 3-4 week period of diabetic hyperglycemia, the state 3 rate and RCR were found to be reduced to a greater degree than in chronically hypoglycemic, non-diabetic, previously normoglycemic rats. Finally, when 1 week of moderate hypoglycemia preceded a 30 min period of insulin-induced hypoglycemic coma, a disturbed pattern of mitochondrial respiration (i.e. increased state 4, decreased RCR) was found at 60 min of recovery following coma. These results indicate that chronic increases in glucose (and insulin deprivation) have no effect on cerebral mitochondrial respiratory function, whereas prolonged, albeit moderate, reductions in cerebral glucose supply result in perturbations in mitochondrial respiration. These results demonstrate the importance of an adequate glucose supply for normal mitochondrial activity.

Plasma laudanosine levels in patients given atracurium during liver transplantation.

Atracurium, a nondepolarizing muscle relaxant, does not depend on the liver for clearance, but its principal metabolite, laudanosine, is eliminated primarily by the liver and is potentially neurotoxic. We measured atracurium and laudanosine levels in 15 adult patients during the three stages of liver transplantation to assess the effect of major impairment of liver function. Atracurium was given in a bolus dose of 0.5 mg/kg followed by continuous infusion at a rate adjusted to maintain 95–99% of total neuromuscular block, as judged by train of four response to facial nerve stimulation. Atracurium levels remained constant at 1.4--1.8 μg/mL during the 180-min preanhepatic and 75-min anhepatic stages but decreased to a mean of 1.0 μg/mL by the end of the 180-min postanhepatic stage. In contrast, laudanosine levels increased during each stage, being 0.40 ± 0.18, 0.50 ± 0.22, and 0.43 ± 0.16 μg/mL after the preanhepatic, anhepatic, and postanhepatic stages, respectively. The highest individual value recorded was 1.02 μg/mL. We conclude that, despite increases in laudanosine levels during each stage of liver transplantation in patients receiving atracurium, those levels are only about one-tenth of the maximum values previously reported in humans.

Fentanyl intermittent bolus technique for anesthesia in infants and children undergoing cardiac surgery

The use of fentanyl by an incremental intravenous (IV) bolus technique was evaluated in eight pediatric patients (ages 4 months to 5 years, ASA III-IV) undergoing corrective surgery for congenital heart defects. Anesthesia was induced with 5 to 10 micrograms/kg of fentanyl. Additional boluses of comparable size were given intermittently thereafter, in order that a total dose of 100 micrograms/kg was achieved just before instituting cardiopulmonary bypass (CPB). Heart rate, systolic blood pressure, various measures of anesthetic depth, and plasma fentanyl levels measured by radioimmunoassay were compared at various points during anesthesia, surgery, and recovery. Decreases in heart rate were observed at the time of sternal incision and at 30 minutes thereafter, when doses of fentanyl were near-maximal. No changes from baseline in systolic blood pressure or in anesthetic depth occurred at any of the intervals studied. The plasma concentration of fentanyl was 30 +/- 8 ng/mL just after completion of the fentanyl administration, immediately before CPB. With onset of CPB, the fentanyl level fell to 13 +/- 9 ng/mL, a statistically significant difference from the baseline value. No further change occurred over the additional 231 +/- 74 minutes in the operating room. The fentanyl concentration was 10 +/- 4 ng/mL upon entry into the recovery room. It is concluded that administration of fentanyl in small, intermittent IV boluses, with dosing completed before the onset of CPB, produces satisfactory plasma levels, anesthesia, and hemodynamic stability in children undergoing corrective surgery for congenital cardiac defects.

Effects of nonvolatile agents on oxygen demand and energy status in isolated hepatocytes

The role of hepatic energy deficits in the pathogenesis of anesthetic hepatotoxicity is suggested by the involvement of hypoxia in various animal models and by the ability of anesthetics to inhibit mitochondrial oxidations. We have been studying anesthetic effects on hepatocellular energy metabolism using suspensions of intact hepatocytes freshly isolated from phenobarbital-treated or untreated rats (+PB or PB cells, respectively), an experimental system that is metabolically complete yet also biochemically homogeneous and accessible. In the present work, diazepam, lidocaine, thiopental, and enflurane, as well as the combination of thiopental and enflurane, were studied at concentrations similar to those achieved in vivo. Thiopental increased cellular oxygen consumption rate (VO2) in both +PB and - PB cells significantly, as did aminopyrine, a test substrate for PB-inducible cytochrome P450 activity. Diazepam increased VO2 only in +PB cells, as did enflurane, whereas lidocaine did not increase VO2 in either +PB or -PB cells. The combination of thiopental and enflurane significantly decreased VO2 in -PB cells but increased it in + PB cells. The higher VO2 in +PB cells compared to -PB cells, seen with all drugs tested (except lidocaine), was eliminated by prior addition of the P450 inhibitor metyra-pone.Starting from steady states of oxygen metabolism, with VO7 offset by O2 supply from an overlying gas phase and PO2 stabilized at 24 mm Hg, aminopyrine significantly lowered extracellular PO2, increased lactate production, and decreased high energy phosphate levels within 10 minutes. These changes in energy status were limited to +PB cells and were largely prevented by running incubations at higher PO2 levels (>20 mm Hg throughout), suggesting that hypoxia due to P450-mediated VO2increased had been mainly responsible. On the other hand, in contrast to either drug alone, the combination of thiopental and enflurane produced statistically significant hepatocellular energy impairment that was seen even in -PB cells; this impairment could not be reversed at higher Pu2, a finding that is consistent with direct inhibition of the mitochondrial respiratory chain. These results support the possibility that with increases in oxygen demand (P450 induction), decreases in oxygen supply (hypoxia), and/or other agents present with interacting effects on oxygen-supported metabolism, drugs and doses that are considered safe during anesthesia might nonetheless promote hepatocellular energy deficits as a result of hypoxic or nonhypoxic mechanisms.