Failure of naloxone to reverse the nitrous oxide-induced depression of a brain stem reflex: an electrophysiologic and double-blind study in humans.

The effects of 33% nitrous oxide on the two components of the blink reflex were studied on seven healthy volunteers. The blink responses were elicited by a supraorbital nerve stimulation and recorded from the ipsilateral orbicularis oculi muscle. The intensity of stimulation was chosen at two to three times the reflex threshold in order to obtain stable suprathreshold reflex responses as well as a tolerable pain sensation reported by the volunteers. Nitrous oxide administration resulted in a potent depression of the two components of the blink reflex. This depressive effect was more marked upon the late (R2) nociceptive component (83%) than upon the early (R1) component (41%). Simultaneously, subjects reported either a decrease in pain sensation or an indifference toward the painful stimulus. None of these effects were reversed by a double-blind intravenous naloxone (1.4 mg) injection. The analgesic effect of nitrous oxide is a nonspecific depressant action on the transmission of the nociceptive messages in central nervous structures, independent of pain-suppressive endogenous morphine-like systems.

Ventilatory effects produced by the i.v. administration of incremental doses of thiopentone in the dog.

Ventilation, ventilatory pattern and ventilatory drive were studied in five dogs during the administration of increasing blood concentrations of thiopentone. Ventilation (VE, RR, VT) and blood-gas tensions (pHa, PaCO2, PaO2,) were measured. Ventilatory pattern (VT, TI, TE, Ttot) and ventilatory drive (VT/TI) and occlusion pressure) were analysed. Occlusions of the airway were performed at end-inspiration and at end-expiration. Thiopentone produced a biphasic action on respiratory rate, ranging from tachypnoea during light anaesthesia to a progressive slowing of respiration with deepening anaesthesia. The Hering-Breuer reflex did not seem to be modified by the level of anaesthesia, whereas the central mechanisms which modulate the duration of inspiration and of expiration, were perturbed.

beta-Endorphin plasma levels during neuromuscular blockade in unanesthetized cat.

Plasma concentrations of beta-endorphin were measured by radioimmunoassay in cats prepared chronically for sleep-waking polygraphic recordings and blood collection. beta-Endorphin (beta-END) levels were found to be stable in baseline conditions and were used as an index of stress. After habituation of each cat to experimental conditions in a veterinary pouch with head restraint, this partial restraint (45 min) or a short-lasting paralysis (30 min) induced by gallamine triethiodide did not significantly elevate plasma concentrations of beta-END. In contrast, hypoxia, ether-induced stress or tight immobilization of the limbs promoted a 7--8-fold increase in beta-END plasma levels. Sleep-waking patterns were not significantly different in restrained and paralyzed conditions. It is concluded that short-lasting paralysis induced in habituated animals by curarizing agents is not accompanied by a significant neuroendocrine response if all possible sources of pain are carefully avoided.

[Respiratory effects of increasing doses of alfathesin in the dog]. / Effets ventilatoires de débits croissants d'alfatésine chez le chien.

In 10 dogs the authors studied the effect of increasing doses of alfathesin on ventilation (VE, frequency, VT, blood gases), on the ventilatory pattern (TI, TE, TI/Ttot), on the neurological initiation of ventilation (VT/TI, occlusion pressure at 0.5 seconds), and on the Hering-Beurer reflex (duration of apnoea after occlusion of the airway at the end of inspiration). The results were compared with normal values taken from the literature. The correlation between the dose of alfathesin and the measured or calculated parameters was examined. Ventilation was stimulated by low doses of alfathesin, a stimulation, characterized by tachypnoea without change in tidal volume. Deepening of anaesthesia was accompanied by progressively increasing depression of respiration (diminution of VE, of frequency, of VT/TI and increase of PaCO2 and of the duration of apnoea). The mechanisms of the initial stimulation of ventilation and of respiratory depression are discussed. The authors conclude that the action of alfathesin on the central nervous system is biphasic, with stimulation during light anaesthesia followed by depression with associated depression of ventilation, despite increasing hypoxia and hypercapnia.

Effect of a new analeptic drug, almitrine, on fentanyl-induced respiratory depression and analgesia in man.

Five female patients received fentanyl 0.0066 mg kg-1 i.v. (group A); five other female patients received the same dose of fentanyl, followed immediately by almitrine 0.5 mg kg-1 i.v. (group B) and 20 minor gynaecological operations were performed under a combination of almitrine 0.5 mg kg-1 and fentanyl 0.0066 mg kg-1 (group C). In group A, fentanyl produced a marked and significant respiratory depression (P less than 0.001). In group B and C, almitrine antagonized the fentanyl-induced respiratory depression. Analgesia did not seem to be affected.

[Comparison of the effects of acute respiratory acidosis and acute metabolic acidosis on the jaw-opening reflex in the anesthetized dog]. / Comparaison des effets de l'acidose respiratoire aiguë et de l'acidose métabolique aiguë sur le réflexe d'ouverture de la gueule du chien anesthésie.

A few effects of carbon dioxide on pain threshold and acid-base balance are known. The purpose of this study was to investigate specifically the variations of analgesia in relation to hypercapnia during general anaesthesia and the respective roles played by carbon dioxide and [H+]. The nociceptive jaw opening reflex was studied on five beagle dogs anaesthetized with alfathesin administered at constant rate under acute hypercapnic conditions and acute metabolic acidosis. Acute hypercapnia did not decrease the jaw opening reflex significantly until a level was reached where PaCO2 values modified blood [H+] (pH) significantly (10 +/- 1.04 kPa corresponding to [H+] 91.5 +/- 13.24 nmol/l (pH 7.04 +/- 0.06) p less than 0.05)). At [H+] 176.2 +/- 42.77 nmol/l (pH 6.7 +/- 0.13) (p less than 0.01) the reflex was only 9.3 +/- 3.9 per cent (p less than 0.001) of its initial value. The infusion of decinormal solution of HCl during constant capnia caused an abrupt drop of the reflex. There was a correlation between reflex and metabolic acidosis (p less than 0.05). The authors conclude that modification of the jaw opening reflex occurs with extreme values of arterial [H+] incompatible with safe anaesthesia and they discuss the mechanisms involved.

[Comparative study of the effects of diazepam and fentanyl on the blink reflex threshold in the normal, conscious human (preliminary study)]. / Etude comparée du diazépam et du fentanyl sur les seuils du réflexe de clignement chez l'homme normal éveillé (étude préliminaire).

The search in man for experimental techniques suitable for study of the neurospecificity of anaesthetic drugs led us to use the blink reflex. Thirteen female volunteers undergoing gynaecological surgery received as a double-blind basis either 0.2 mg/kg of diazepam (7 cases) or 3 X 10(-1) mg/kg of fentanyl (6 cases) intravenously. The thresholds of the two components of the reflex R1 + R2, of respectively tactile and painful natures, were sought before and for three minutes after the injection of the drugs. The threshold of R2 rose to four times its initial value (P less than 0.001) after diazepam, whilst R1 remained unchanged. Fentanyl was not associated with any change in the thresholds. Study of the blink reflex may be used to dissociate and analyse the effects of two drugs on precise nervous functions. The nature of these functions and of their controls are discussed.

[Effect of different FiO2 on the ventilatory action of almitrine in the anesthetized dog. Preliminary study]. / Effet de différents niveaux de FiO2 sur l'action ventilatoire de l'almitrine chez le chien anesthésié. Etude préliminaire.

The effects of progressively increasing hyperoxia from 0.22 to 1 on the ventilatory action of a ventilatory analeptic with a peripheral action, almitrine, were studied in six dogs under deep anaesthesia by Alfatesine administered at a constant flow rate. At FiO2 = o.22, almitrine partially corrected hypoventilation. From FiO2 o.30 to FiO2 0.50, initial hypoventilation was unaltered. At FiO2 = 1, it was worsened. This preliminary study will need to be completed by examination of the interference almitrine-FiO2 at different levels of anaesthesia and of respiratory depression, by study of the effects of different levels of FiO2 on the respiratory depression caused by Alfatesine and by study of the effects of the sudden administration of pure oxygen.

[Competitive study of the effects of naloxone and of almitrine on fentanyl analgesia in the anesthetized dog: effects on the muzzle opening reflex and blood gases]. / Etude comparative des actions de la naloxone et de l'almitrine sur l'analglésie au fentanyl du chien anesthésié. Effets sur le réflexe d'ouverture de la gueule et les gaz du sang.

UNLABELLED: The search for a technique making it possible to dissociate the analgesia and ventilatory depression of central analgesics led to a comparison of the effects of naloxone, a specific morphinomimetic antagonist, with almitrine, a ventilatory stimulant with a peripheral action, on muzzle opening reflex and blood gases. Five male dogs (Beagles, aged one year), anaesthetised with Alfetesine were treated separately with the two drugs used alone and after fentanyl analgesia (injection of fractionnated doses up to the threshold of apnoea). The association of the two drugs was also tested in tyhe dog after analgesia. The parameters studied were muzzle opening reflex, as an indication of analgesia, and blood gases, and were observed for 45 minutes, including 15 minutes control. RESULTS: 1 - The intravenous injection of 1,2 mg of naloxone had the effect of increasing the surface area of muscle potentials with a maximum of 7 per cent (p 0.001) at the 15 th minute. By contrast, no significant change in blood gases was seen. In the same dogs given fentanyl analgesia, naloxone not only reversed respiratory depression but had a stimulatory effect on MOR reaching 7 per cent (p 0.001) at the 30 th minute. 2 - The effects of 1 mg.kg-1 of almitrine were characterised by a fall in MOR for a period equal to that of the study and a minimum of 7.8 per cent (p 0.001) at the 20 th minute. At the same time, marked ventilatory stimulation was seen. PO2 rose by 22.7 per cent (p 0.02) at the 5 th minute. PCO2 fell during the 30 minutes studied with a minimum of 39.6 per cent (p 0.01) at the 20 th minute. Almitrine did not antagonise the depression of MOR caused by fentanyl but reversed the respiratory depression of the analgesic, increasing PO2 by 26 per cent (p 0.01) and decreasing PCO2 by 25.7 per cent (p 0.01). 3 - The combination of both drugs cancelled out the abolition of the reflex by fentanyl then facilitated it up to 24.7 per cent (p 0.001) in comparison with the animal not receiving any analgesic. By contrast, the ventilatory action of almitrine was not potentialised by naloxone. In view of these data, and in the absence of any emergency, the choice of naloxone as an antagonist of ventilatory depression of central analgesics should not be preferential in order to avoid the rebound effect.