Depression Of Hypoxic Ventilatory Response Research Articles

A Novel Molecule with Peripheral Opioid Properties: The Effects on Hypercarbic and Hypoxic Ventilation at Steady-State Compared with Morphine and Placebo

Frakefamide (FF), is a new peripherally acting mu-opioid receptor agonist. The aim of this double-blind, randomized, double-dummy, four-way, crossover study was to investigate FF effects on hypercarbic and hypoxic ventilation at steady-state after a 6-h infusion. We compared the effect with 2 clinical doses of morphine (M-small and M-large) and placebo in 12 healthy men. The subjects received 1.22 mg/kg of FF, 0.44 mg/kg of M-large, and 0.11 mg/kg of M-small. Sodium chloride 9 mg/mL was used as placebo. Ventilation was studied by pneumotachography and in-line capnography. There were no ventilatory effects caused by FF or placebo. As expected, large doses of morphine influenced both hypercarbic and hypoxic ventilatory responses. We conclude that there were no signs of central respiratory depression caused by FF after 6 h of constant infusion, which supports a peripheral action of the compound. However, morphine caused a dose-dependent central depression during the hypercarbic ventilatory response and a mild depression of hypoxic ventilatory response.

Contribution of peripheral chemoreception to the depression of the hypoxic ventilatory response during halothane anesthesia in cats.

The effects of inhalational anesthetics on the hypoxic ventilatory response are complex. This study was designed to determine the contribution of peripheral chemoreception to the depression of hypoxic ventilatory response seen with halothane anesthesia. Cats were anesthetized with pentobarbital sodium and alpha-chloralose and artificially ventilated. Respiratory output was evaluated by phasic inspiratory activity of the phrenic nerve. In 12 cats, this activity was measured during inhalation of an hypoxic gas mixture with halothane, 0, 0.1, and 0.8%, with intact or denervated carotid bodies. In 10 cats, a carotid body was isolated from the systemic circulation and perfused with hypoxic Krebs-Ringer solution equilibrated with halothane, 0, 0.1, and 0.8%. The hypoxic ventilatory response was depressed in a dose-dependent manner during halothane anesthesia. In carotid body perfusion studies, the response was significantly depressed only with halothane, 0.80%. The hypoxic ventilatory response is depressed by a high dose of halothane through a peripheral effect at the carotid body.

Efficacy of Methylnaltrexone Versus Naloxone for Reversal of Morphine-Induced Depression of Hypoxic Ventilatory Response

Methylnaltrexone (MNTX) is a quaternary derivative of naltrexone. It does not cross the blood-brain barrier and, thus, it reverses peripherally mediated effects of morphine without blocking its centrally located analgesic effects. The effects of MNTX on morphine-induced depression of hypoxic ventilatory response are unknown. We evaluated the efficacy of MNTX, compared with naloxone, in reversing this effect. On three sessions separated by a week, 10 healthy male volunteers received morphine, 0.125 mg/kg, as a bolus at 20 min after completing a control hypoxic ventilatory challenge. At 60 min, naloxone, 5 micrograms/kg, MNTX, 0.3 mg/kg, or placebo was administered in a randomized double-blind order. Four isocapnic hypoxic ventilatory challenges were conducted: 0 min (control), 40 min (postmorphine), and 80 and 120 min (postreversal) and the hypoxic respiratory responses were recorded. Morphine administration was associated with a significant depression in hypoxic responses: The slope of the response (L/min/Spo2) and the predicted ventilation at 80% O2 saturation (VE80) (L/min) decreased significantly in the three sessions (P < 0.05). Naloxone injection reversed the respiratory depression at 80 min (85% of the control value of the slope and 89% of VE80), whereas MNTX and placebo did not. At 120 min, the slope (69%) and VE80 (80%) after naloxone administration were not significantly different from control. MNTX slope (69%) was not statistically different from the control, whereas VE80 (70%) was still depressed (P < 0.05). Placebo slope and VE80, at 120 min, remained lower than the control (P < 0.05). These data show that MNTX is not as effective as naloxone for reversal of morphine-mediated depression of respiration during acute hypoxia.

Hypoxic ventilatory response in cats lightly anesthetized with ketamine: effects of halothane and sevoflurane in low concentrations.

The effect of low concentration sevoflurane and halothane on the ventilatory response to isocapnic hypoxia was studied in sixteen cats. The cats were divided into two groups, sevoflurane group and halothane group, of eight subjects each. As parameters of the hypoxic ventilatory response, A value [the slope of the hyperbolic curve, V(E) = V(0) + A/(Pa(O)(2)-32)] and ratio of V(50) (the minute volume obtained from the hyperbolic equation when Pa(O)(2) = 50 mmHg) to V(0) were studied. These two parameters were examined at three states, sedative state with ketamine as the control, ketamine plus 0.1 MAC inhalation anesthetic, and ketamine plus 0.5 MAC inhalation anesthetic. In the sevoflurane group, the A values were 4789 +/- 1518, 2187 +/- 1214, 1730 +/- 880 (mean +/- SE. ml.min(-1).mmHg) at the control state, 0.1 MAC and 0.5 MAC, respectively. In the halothane group, the A values were 6411 +/- 2368, 2529 +/- 842 and 2372 +/- 545, respectively. The ratios of V(50) to V(0) were 1.32 +/- 0.09, 1.22 +/- 0.09, 1.25 +/- 0.08 in the sevoflurane group, 1.47 +/- 0.18, 1.32 +/- 0.11, 1.54 +/- 0.18 in the halothane group, respectively. The A value at 0.1 MAC of the halothane group was less than the control value significantly. This proved that even low concentration halothane depressed the hypoxic ventilatory responses. The depression of hypoxic ventilatory response could cause postanesthetic hypoventilation. On the other hand, we could not find significant depression on the hypoxic ventilatory response in the sevoflurane group, but we should notice that variances of the hypoxic ventilatory response were large.

Depression of hypoxic ventilatory response in humans by somatostatin.

In nine normal subjects we measured the ventilatory response to isocapnic hypoxia with and without an intravenous infusion of 1 mg of somatostatin. Arterial O2 saturation was rapidly lowered to 80 +/- 2% in 2 min and maintained for 30 min. During control experiments, ventilation increased immediately (3-5 min) and then declined so that at 25 min of hypoxia ventilation was little above that in room air. Somatostatin was associated with a small decrease in ventilation while the subjects breathed room air. With hypoxia there was no immediate increase in ventilation for the group as a whole, although an increase was observed in one subject. With somatostatin, after 25 min of hypoxia, mean ventilation was lower than at any other time in the study; as hypoxia was discontinued ventilation increased slightly. Somatostatin causes profound depression of the ventilatory response to hypoxia by a mechanism that is not known but may be central. With somatostatin hypoxia of 25-min duration tends to depress ventilation.

Depression of hypoxic ventilatory response by nitrous oxide.

Ventilatory responses to CO2 and hypoxia were measured in four normal volunteers breathing 30-50 per cent N2O with and without added inspiratory resistance. CO2 response was measured by a steady-state technique, hypoxic response by a non-steady-state progressive technique. Added inspiratory resistance depressed ventilatory responses to both CO2 and hypoxia. N2O had no effect on CO2 response either with or without resistance. N2O depressed the ventilatory response to hypoxia without added resistance and further depressed the response measured with added resistance. It is thought that this was probably the result of selective depression of peripheral chemoceptor function by N2O.

Effect of diazepam on ventilatory responses.

To investigate the effects of diazepam on ventilatroy control, hypoxic and hypercapnic ventilatory responses were studied in 8 normal subjects before and after 10 mg of intramuscular diazepam. There was no significant change in either resting minute ventilation or resting end-tidal CO2 tension, but depression of hypoxic ventilatory response was observed 15 (60% of control) and 30 min (53% of control) after diazepam (p less than 0.05). No significant depression of hypercapnic ventilatory response was noted 70 to 130 min after diazepam. In view of the depression of hypoxic ventilatory response by diazepam in normal subjects, adverse responses along these lines should be considered in patients with impaired ventilatory function, such as chronic airways obstruction, and in those encountering acute hypoxemia.