Robert M. Epstein

Photodegradation of sodium nitroprusside: biologic activity and cyanide release.

Because the belief that cyanide is released from nitroprusside in vivo recently was challenged, the authors performed a series of experiments that examined the conditions under which nitroprusside is degraded. These experiments include an examination of the release of cyanide and nitric oxide from nitroprusside in vitro, the release of cyanide in vivo, and a comparison of the biologic activity of intact and degraded nitroprusside. Nitroprusside in aqueous solution degraded when exposed to white or blue light but not to red light. While light at 20 μW·cm−2 produced 40% apparent photodegradation after 6 h exposure, while white light at 220 μW·cm−2 produced 100% apparent photodegradation after 2 h exposure. At 100% apparent photodegradation, 10% of the nitrosyl ligand was recovered as free nitric oxide, and 0.4% of the cyanide ligand was recovered as free cyanide. Following a 2-h infusion of light-protected nitroprusside in seven patients, cyanide concentrations ranged from 1.4 to 45.5 μM and 0.09 to 3.2 μM in blood and plasma, respectively. These values were not changed by exposing the samples to white light (220 μW·cm−2) for 4 h. Intact and photodegraded nitroprusside produced identical hypotensive responses in rats as would be expected, since the nitrosyl ligand was detected in solution following degradation, and it mediates this action. Cyanide was released from nitroprusside, both on its exposure to light in vitro and also in vivo. The latter was not an artifact of the assay for cyanide. Nitroprusside releases cyanide in vivo, and cyanide toxicity is a true complication of its use.

INFLUENCE OF THE CONCENTRATION EFFECT ON THE UPTAKE OF ANESTHETIC MIXTURES: THE SECOND GAS EFFECT.

The uptake of halothane given in constant concentration (1 per cent) was shown to be more rapid in a mixture with 70 per cent N2O than in one with 10 per cent N2O. This demonstrates that the uptake of a gas is influenced by the constituents of the mixture of which it is a component. Changes in the concentration of other components which are sufficient to produce a significant concentration effect will produce alterations of uptake rate of companion gases given in constant concentration (“second gas effect”). This acceleration of uptake was interpreted to be a result of additional inspiratory inflow secondary to the absorption of N2O at a higher concentration. This absorption produces the concentration effect on the rate of uptake of the N2O itself, also observed in this study. Second gas effects presumably occur as well for the other gases in the inspiratory mixture, including the usual respiratory gases.

The Renin–Angiotensin System during Controlled Hypotension with Sodium Nitroprusside

The role of the rennin–angiotensin system in blood pressure homeostasis during sodium nitroprusside (SNP) infusion in the rat was evaluated. Rats received infusions of SNP, 40 µg/kg/min, for one hour, and blood samples for renin determinations were drawn from the arterial cannula before and after infusion. Renin activity was measured by radioimmunoassay. At the termination of the SNP infusion, plasma renin activity had increased from 3.23 ± 1.53 to 13.25 ± 0.76 ng/ml/hr (P < 0.05). Control animals that received only vehicle showed no change in renin activity. When rats that had received SNP at 40 µg/kg/min for one hour were treated with a competitive inhibitor of angiotensin II (saralasin), there was a 7-torr decrease in blood pressure (P < 0.01). Control animals showed no hypotensive response to saralasin. The hypotensive response to the administration of SNP at 40 µg/kg/min in acutely nephrectomized rats exceeded that obtained in normal rats by 30 torr (P < 0.01). Enflurane anesthesia did not modify the renin response to SNP-induced hypotension. In conscious rats, larger doses of SNP (80 or 160 µg/kg/min) resulted in elevations of renin activity to 22.50 ± 0.90 and 19.84 ± 1.94 ng/ml/hr, respectively. When saralasin was infused into rats receiving 160 µg/kg/min, blood pressure decreased precipitously and the rats died. SNP-induced hypotension stimulates renin release and the subsequent production of angiotensin II helps maintain blood pressure.

Sympathetic Excitation during Nitrous Oxide—Halothane Anesthesia in the Cat

The effect of 70 per cent nitrous oxide on preganglionic sympathetic activity was studied by recording the compound action potential from the splanchnic nerve in the cat. Substitution of nitrous oxide for an equal concentration of nitrogen in the inspired mixture during steady-state halothane–nitrogen–oxygen anesthesia caused significant increases in splanchnic-nerve discharge and mean arterial pressure and a moderate increase in heart rate. When the carotid sinus and aortic baroreceptor nerves were sectioned, these responses were further accentuated and were accompanied by a 71 per cent incidence of cardiac arrhythmias. With continued halothane anesthesia, decerebration by transection of the brainstem at the midcollicular level completely suppressed the responses to nitrous oxide. Following the removal of halothane in decerebrate preparations, nitrous oxide acted as a depressant, producing marked decreases in heart rate in animals with intact baroreceptors and significant decreases in splanchnic-nerve activity in debuffered animals. These results indicate that the increase in sympathetic activity produced by nitrous oxide is neurally mediated and dependent on actions at suprapontine levels, the loci of which are undetermined. The study further suggests that the direct effect of nitrous oxide is depressant to vasomotor neurons at the brainstem or spinal level.

Captopril Reduces the Dose Requirement for Sodium Nitroprusside Induced Hypotension

The authors studied 12 patients who required deliberate hypotension for spinal fusion operations in order to investigate the efficacy of captopril for reducing dose requirement for sodium nitroprusside (SNP). Six patients, selected at random, were pretreated with captopril, 3 mg/kg po, and the remaining six patients served as controls. All patients received a similar anesthetic technique, consisting of thiopental 3 mg/kg, pancuronium 0.1 mg/kg, morphine 0.5 mg/kg, plus nitrous oxide 70% in oxygen. SNP was used to maintain mean arterial pressure (MAP) at 50–55 mmHg during deliberate hypotension lasting 140 · 13 minutes (mean · SE). Patients who received captopril required less SNP than untreated patients both early during hypotension (1.4 · 0.5 μg · kg−1 · min−1 vs. 4.8 · 0.8 μg·kg−1 · min−1, P < 0.05), as well as late during hypotension (2.2 · 0.2 μg · kg−1 · min−1 vs. 5.6 · 0.6 μg · kg−1 · min−1, P < 0.05). Whole blood cyanide was significantly lower in the patients pretreated with captopril than the untreated controls both early in the hypotensive period (2.7 · 0.6 μmol/1 vs. 13 · 4 μmol/1, P < 0.05) and also late in the hypotensive period (3.7 · 0.8 μmol/1 vs. 30 · 10 μmol/1, P < 0.05). MAP was reduced by captopril pre-treatment both following induction of anesthesia (64 · 4 mmHg captopril vs. 80 · 4 mmHg control, P < 0.05) and during surgery before deliberate hypotension (86 · 5 mmHg captopril vs. 100 · 4 control, P < 0.05). Cardiac output did not differ significantly between the groups, either awake or after anesthetic induction. The authors conclude that captopril pretreatment significantly reduces the dose of SNP required to produce deliberate hypotension and, therefore, reduces the potential for cyanide toxicity. No adverse hemodynamic consequences of combining captopril with thiopental, N2O, or morphine anesthesia were observed.

The electromyogram and the mechanical response of indirectly stimulated muscle in anesthetized man following curarization.

The electromyogram (EMG) and tension evoked by single and tetanic stimuli were studied during curarization in anesthetized subjects. d-Tubocurarine depressed both evoked twitch tension and EMG, but not identically. Before curarization posttetanic potentiation (PTP) was present on tension recordings but not on EMG recordings. Small amounts of tetanic fade were present on both tension and EMG recordings before curarization. On tension recordings PTP and fade increased significantly only during profound curarization, while on EMG recordings both increased at all levels of curarization. Electromyography is more sensitive than tension recordings in the investigation or monitoring of curarization.

A nonlinear model for the uptake and distribution of halothane in man.

An analog computer simulation of the uptake and distribution of halothane in man which incorporates the effect of halothane on cardiac output is presented. The computed partial pressures in each tissue compartment in response to a constant inspired partial pressure of 1.0 per cent atm are given. A theoretical derivation of the inspired partial pressure necessary to achieve instantaneously a constant anesthetic depth is also included. Based on this information, a program for the induction of halothane anesthesia in man utilizing a nonrebreathing anesthesia circuit is developed. With a maximum inspired partial pressure of 4.0 per cent atm, this program achieves a partial pressure of 0.75 per cent atm in the well perfused tissues in six minutes without overshoot, and will maintain this partial pressure indefinitely. Comparing the nonlinear model with a linear model having fixed cardiac output, the authors have shown that the difference between these two models is insignificant for the first five minutes; however, the effect of the nonlinearity is to elevate the partial pressures in the well-perfused tissues and the lung by 6 per cent after one hour of anesthesia with an inspired partial pressure of 1.0 per cent atm.

Halothane Mimics Oxygen in Oxygen Microelectrodes

The effects of halothane and enflurane on the polarographic measurement of oxygen with five platinum and three gold microelectrodes were examined. Oxygen microelectrodes were calibrated in saline solution equilibrated with either nitrogen (N2) or air, then either halothane, 1.0 per cent, or enflurane, 2.0 per cent, was added to the gas mixture. For each electrode, polarographic curves were determined during exposure to five equilibrating gas mixtures: N2, air, N2 plus halothane, air plus halothane, and N2 plus enflurane. Halothane variably increased the current produced (and therefore the estimated oxygen tension) at all polarizing voltages in saline solution equilibrated with either N2 or air. The effect was present in both conical platinum electrodes and recessed-tip gold electrodes and was not prevented by membrane coatings of polystyrol, Rhoplex or collodion. Enflurane did not alter the polarographic measurement of oxygen. It is concluded that tissue oxygen tension measurements, made with these microelectrodes and membranes, may be unreliable in the presence of halothane.

RESPIRATORY FACTORS IN THE UPTAKE AND EXCRETION OF ANESTHETICS.

: We have considered some of the ways in which respiration can affect the gas exchange process. The simplest relationships are purely physical and relate to the speed with which the lung and tissues can be filled or emptied. More complex relationships involve a consideration of the interplay between blood and gas in the lung and the effects of gas exchange on respiratory volumes themselves. Finally, some examples of the importance of physiologic alteration produced by, and producing respiratory shifts during, gas uptake processes were presented briefly. The detailed interpretation of gas exchange phenomena demands more quantitative information of this sort, concerning not only the respiratory but the circulatory and tissue level variations affecting uptake during anesthesia. Nevertheless, understanding of the principles and application of such data as are available can go far toward removing the handicaps of empirical practice from the day-to-day administration of anesthetic agents to human beings.

The Uptake of Ethylene in Man

Uptake of 1 per cent ethylene was studied in eight healthy, awake, unpremedicated adults. End-expiratory concentrations of ethylene were measured by gas chromatography, and CO2 by infrared analysis. In all subjects, end-tidal concentration of ethylene was at least 95 per cent of equilibrium at the end of five minutes, 97 per cent by 10 minutes and 99 per cent at the end of 20 minutes. Studies were terminated at 30 minutes because of inability to detect differences between inspired and expired ethylene concentrations. It was unlikely that total body saturation had occurred in that time. Ordinate-derivative analysis of the individual experimental curves yielded two exponentials of the general form ae−kt. Neither exponential could be related to a specific body compartment. Comparison of two separate studies done on the same subject, measuring “wet” end-tidal samples in one and “dry” samples in the other, showed no essential differences between the two uptake curves, indicating that the diluting effect of pulmonary water vapor on the dry inspired gas mixture could be ignored.