Hemodynamic changes with initiation of veno-venous bypass in orthotopic liver transplant patients.

Removal of the liver to start the anhepatic stage of liver transplantation requires cross-clamping of the portal vein, inferior vena cava, and hepatic artery. Adverse effects occur from engorged splanchnic beds and decreased venous return. A veno-venous bypass from the inferior vena cava and portal vein to the axillary vein is used in an attempt to ameliorate these changes. The purpose of this study was to evaluate the effect of institution of veno-venous bypass on hemodynamics. Eight randomly selected adult patients undergoing orthotopic liver transplantation had general anesthesia induced with thiamylal and maintained with nitrous oxide and isoflurane. Cardiopulmonary data and arterial and mixed venous blood gases were measured prospectively using radial artery and pulmonary artery catheters. Measurements were taken under four conditions: (1) 10 minutes before bypass; (2) after partial bypass (vena cava to the axillary vein); (3) after partial bypass with portal vein clamping; and (4) after full bypass (vena cava and portal vein to the axillary vein). Statistically significant changes seen were a 22% decrease in cardiac output and a 47% increase in systemic vascular resistance (SVR). Bypass flow was lower than predicted. Venovenous bypass ameliorates, but does not fully prevent, the reduction of cardiac output and rise in SVR seen with initiation of the anhepatic stage. However, bypass does prevent the hypotension experienced during cross-clamping and for these reasons should be used routinely.

The effect of total parenteral nutrition and morphine on ventilation.

Total parenteral nutrition (TPN), specifically amino acid infusions, has been shown to increase the ventilatory response to inhaled CO2. The hypothesis tested was that morphine sulfate (known to depress ventilatory CO2 responsiveness) would diminish the augmented ventilatory CO2 response in patients receiving TPN. The influence of morphine on hyperoxic hypercapnic ventilatory response (assessed by the Read rebreathing technique) was therefore examined in four otherwise healthy subjects who were receiving TPN at home for long-standing nutritional support secondary to malabsorption syndrome (short-bowel syndrome), and in a control group of four healthy subjects who were not receiving TPN. The slope and intercept of the CO2 response was estimated by linear regression on the relationship between ventilation (VE) and end-tidal PCO2 (PETCO2). Administration of morphine in the non-TPN group elicited the expected decrease in the VE-PETCO2 slope. In contrast, morphine administration was associated with an increase in the VE-PETCO2 slope in the TPN group. While this investigation does not provide a direct indication of the mechanisms underlying the augmenting action of morphine on the ventilatory response to CO2 in subjects receiving TPN, it does suggest that patients on TPN who demonstrate no impairment of ventilatory control may be given normal doses of morphine sulphate (ie, as for pain control or preoperative medication) with no increased concern for an adverse ventilatory outcome.

Relationships among ventilation-perfusion distribution, multiple inert gas methodology and metabolic blood-gas tensions.

The retention equations upon which the Multiple Inert Gas Method is based are derived from basic principles using elementary algebra. It is shown that widely disparate distributions produce indistinguishable sets of retentions. The limits of resolution of perfused compartments in the VA/Q distribution obtainable by the use of the multiple inert gas method are explored mathematically, and determined to be at most shunt and two alveolar compartments ("tripartite" distribution). Every continuous distribution studied produced retentions indistinguishable from those of its unique "matching" tripartite distribution. When a distribution is minimally specified, it is unique. Any additional specification (increased resolution--more compartments) of the distribution results in the existence of an infinitude of possible distributions characterized by indistinguishable sets of retention values. No further increase in resolution results from the use of more tracers. When sets of retention values were extracted from published multiple inert gas method continuous distributions, and compared with the published "measured" retention sets, substantial differences were found. This illustrates the potential errors incurred in the practical, in vivo application of the multiple inert gas method. In preliminary studies, the tripartite distribution could be determined with at least comparable accuracy by blood-gas (oxygen, carbon dioxide) measurements.

Derivation of VA/Q distribution from blood-gas tensions.

Gas exchange was modelled by a Fortran program. Arterial blood-gas tensions have higher resolution than inert gas retentions in terms of distinguishing a single VA/Q compartment from a progressively broadening lognormal distribution. The maximum number of compartments determinable by arterial blood-gas tensions is three; VA/Q distributions containing more compartments are non-unique. Without utilizing 100% inspired oxygen, arterial blood-gas tensions cannot resolve the relative perfusion in shunt and low-VA/Q compartments, but the total perfusion in these compartments is determinable. The way in which the arterial blood-gas tensions vary with the variables of two and three-compartment distributions is described. Two- and three-compartment VA/Q distributions are derivable from either arterial blood-gas tensions or inert gas retentions.

Naloxone and the ventilatory response to exercise in man.

Endogenous opiate peptides are known to exert a depressant action on ventilation (VE), and their plasma levels have been shown to be elevated during a variety of exercise protocols. We investigated whether they might modulate the control of the hyperpnea of short-term constant-load (CLE) and incremental (IE) cycle-ergometer exercise. Four healthy subjects performed CLE tests at ca. 80% of the anaerobic threshold (theta an) for 5 min following a period of unloaded pedaling, and IE tests (10 or 20 W min-1) to the limit of tolerance. Normal saline (3 ml) or the opiate antagonist naloxone (1.2 mg in 3 ml) were administered intravenously prior to each test. Naloxone elicited no discernible effect on VE, alveolar gas tensions, or heart rate throughout the entire range of work rates; neither were theta an nor the maximum work rate affected. It is concluded that, for short-term exercise ranging in intensity from moderate to severe, the role played by endogenous opiate peptides in the control of the exercise hyperpnea appears to be negligible in man.

Total hip arthroplasty. An investigation of factors related to postoperative urinary retention.

The predisposing factors to urinary retention in patients undergoing hip arthroplasty were investigated by a review of the charts of 272 patients. Age, sex, surgeon, choice and duration of anesthesia, volume of fluid replacement, and use of postoperative intramuscular narcotics did not correlate significantly with urinary retention. However, urinary retention increased from 24% to 62% with the use of epidural morphine for postoperative pain management.

Tourniquet-induced hypertension.

The anaesthetic records of 600 patients undergoing lower limb surgery were reviewed to determine the frequency of intraoperative arterial hypertension (defined as a 30% incision). The overall frequency of hypertension during operation in 500 patients to whom a tourniquet was applied during surgery was 11%. The probability of hypertension was increased if the patient was elderly, had cardiac enlargement shown by x-ray or e.c.g., or had nitrous oxide and narcotic anaesthesia. Pre-existing hypertension, increased serum creatinine concentration, anaemia, or treatment with antihypertensives, diuretics, or steroids were not strongly associated with intraoperative hypertension. A control group of 100 patients undergoing hip surgery without application of a tourniquet exhibited hypertension in 1% of cases.

Potency, duration of action and pA2 in man of intravenous naloxone measured by reversal of morphine-depressed respiration.

Placebo and morphine (5 and 10 mg) alone and in combination with naloxone (0.2, 0.4 and 0.8 mg) were administered i.v. to six volunteers. Respiratory responses curves obtained by the rebreathing method were obtained before and 15, 30, 45, 60, 90, 120, 180 and 240 min after the drug infusions. At each time, morphine dose-effect curves, alone and with naloxone, were constructed. Dose ratios and thus the apparent pA2 of these drugs were determined from these curves. The pA2 ia a measure of the affinity of an antagonist for its receptor. The peak effects of both morphine and naloxone occurred at 0.5 hr. Morphine effect showed no significant fall up to 4 hr after infusion. The duration of naloxone appears to be dose-related, statistically significant up to approximately 1.5 hr. The apparent pA2 at each time was calculated by three methods; these values were used, in turn, to calculate the pA2 by a time-dependent method. The apparent pA2 and T1/2 of naloxone in man were determined to be approximately 8.37 and 0.32 hr, respectively. A clinical measure of naloxone potency, the cA2, is proposed.

Respiratory depression of intravenous hydroxyzine in man: potency, duration, and lack of reversal by naloxone.

The effects of intravenous hydroxyzine and hydroxyzine with naloxone on respiration were determined in man. Drug effect was expressed as the shift in the 20-L intercept of the respiratory response curve measured by a rebreathing technique. The time-effect curve of hydroxyzine was found to be the same for hydroxyzine alone and in combination with naloxone, but significantly different from placebo or naloxone alone. The duration of respiratory depression in man resulting from hydroxyzine, 100 mg IV, is greater than 3 hours. Our data did not support the hypothesis that the respiratory depressant and recently discovered antinociceptive effects of hydroxyzine result from endorphin release or are mediated by opiate receptors.

Relative potencies and durations of action with respect to respiratory depression of intravenous meperidine, fentanyl and alphaprodine in man.

Fentanyl, 0.7 and 1.4 microgram/kg, alphaprodine, 0.135 and 0.270 mg/kg meperidine, 0.564 and 1.127 mg/kg, and placebo were administered intravenously over 2.6 min by infusion to five healthy adult males. The crossover study was of incomplete Latin square design with at least 1 week between administrations of each study drug. The subjects breathed from a mixing chamber the gas composition of which was servo-controlled so as to produce CO2 ramps in the end-tidal gases. Each experiment was composed of: 1) control CO2 ramps, 2) a 25-min isocarbic run during which the drug was infused and 3) CO2 ramps at half-hour intervals for 3 hr postinfusion. The 20-liter intercept (the PETCO2 at which ventilation was 20 liters/min) was used as the measure of respiratory drive; the change in 20-liter intercept measured drug effect. The potency ratios at peak effect were: fentanyl/meperidine, 679; alphaprodine/meperidine, 3.68; fentanyl/alphaprodine, 179. With the area under the time-effect curves, the potency ratios of mean effect were: fentanyl/meperidine, 45c; alphaprodine/meperidine, 3.00; fentanyl/alphaprodine, 141. Thus, both fentanyl and alphaprodine are shorter-acting than meperidine, and fentanyl is shorter-acting than alphaprodine. The time-effect curves were fitted to linear and mono- and bi-exponential models. The time constants were compatible with the above relative durations of action.

Effect of hypercapnia on hypoxic ventilatory drive in carotid body-resected man.

Steplike end-tidal hypoxic drives (PETCO2 = 53 Torr) lasting for 5 min were generated in a group of normal subjects and a group of carotid body-resected subjects when end-tidal CO2 was maintained constant under eucapnic (PETCO2 = 39 Torr) and hypercapnic (PETCO2 = 49 Torr) conditions. The hypoxic ventilatory response of the normal subjects was prompt and significant in eucapnia and was enhanced in the hypercapnic state, evidencing CO2-O2 interaction. In contrast, the carotid body-resected subjects did not respond to eucapnic hypoxia but did demonstrate a small but significant ventilatory response to hypoxia against the hypercapnic background. This suggests that the aortic bodies in man may contribute a small component of the hypoxic ventilatory drive under hypercapnic conditions, although the possibility of neuromalike ending regeneration cannot be excluded.

Biophysical mechanisms of anesthetic action: historical perspective and review of current concepts.

The large number and diversity of anesthetic agents were evident to investigators 80 years ago, and suggested a physicochemical theory of anesthesia. Meyer and Overton were the first to offer a quantitative relationship between a physicochemical property and potency of anesthetic agents. They also focused attention on the lipid phase as the site of anesthetic action. Ferguson realized that the concentration of an agent at its site of action bears a generally unknown relation to the concentration in the external phase. However, at equilibrium the activity of an agent is the same in every phase, motivating Ferguson to suggest that activities rather than concentrations be used as indices of dosage. The critical-volume theory resulted from modification of the Meyer-Overton theory to include the molal volume of the anesthetic. The allowance for molal volume resulted initially from an attempt further to regularize the experimental data. The concept of a critical-volume fraction of anesthetic being necessary for narcosis was discussed in most detail by Mullins. Subsequently, the concept of the effect of the anesthetic has changed from filling of free space to expansion and fluidization of the membrane. The ability of pressure to cause excitant phenomena and antagonize anesthetics is predictable from the critical-volume theory and is therefore highly significant evidence. K. W. Miller and associates are perhaps most prominent in the recent quantification and formalization of the critical-volume theory and HPNS. The existence of a separate convulsant site(s) is suggested by the demonstration of significantly different compressibilities associated with anesthesia and convulsions. Work corroborating a separate convulsant site involved measurement of the partial molal volumes of a series of related convulsant and anesthetic ethers and calculation of each compound's solubility parameter. Multiple convulsant sites may exist, and these two methods may not have accessed the same site. Understanding the anesthetic-convulsant duality will have important practical application to deepwater diving, and may well offer important insight into the neurophysiologic and electrophysiologic effects of anesthetics. The application of ESR and NMR allows investigation at the molecular level of effects of anesthetics on biological and model membranes. Magnetic resonance techniques have generally supported the concept of membrane fluidization by anesthetics. Some investigators have recently attempted to displace the focus of attention from the lipid phase. However, the evidence is clearly against the aqueous-phase theory of Pauling and S.L. Miller. The microtubule theory of Allison and Nunn has not accumulated supporting evidence comparable to the lipid theories. Contradictory evidence makes any evaluation of this theory speculative. Additionally, the interspecies and intracellular variability of microtubules raises questions of the relevance of many studies...

Respiratory effects of lorazepam, pentobarbital, and pentazocine.

The respiratory effects of a new benzodiazepine, lorazepam, were compared to those of pentobarbital and pentazocine. Pentobarbital, 50 and 150 mg, produced respiratory depression, as did pentazocine, 30 mg intramuscularly. Lorazepam at 1.33 and 4 mg intramuscularly produced none.