Ventilatory Response to Hypoxia in Humans: Influences of Subanesthetic Desflurane

Background: At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia.

Methods: A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (VI) on (100 - SP O2). Values are mean +/-SE.

Results: Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45+/-0.071 *symbol* min *symbol* sup -1 *symbol* % sup -1 vs. 0.1 MAC desflurane: S = 0.43+/-0.09 1 *symbol* min sup -1 *symbol* % sup -1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74+/-0.091 *symbol* min sup -1 *symbol* %1 vs. 0.1 MAC desflurane: S = 0.53+/-0.06 1 *symbol* min sup -1 *symbol* % sup -1; P < 0.05).     

Effects of Alfentanil on the Ventilatory Response to Sustained Hypoxia

Background: The ventilatory response to acute hypoxia is biphasic, with an initial rapid increase followed by a slower decline. In humans, there is evidence that the magnitude of the decline in ventilation is proportional to the size of the initial increase. This study was done to define the role of exogenous opioids in the ventilatory decline seen with prolonged hypoxia.

Methods: Ten healthy persons were exposed to isocapnic hypoxia for 25 min, followed by 5 min of isocapnic normoxia and 5 min of isocapnic hypoxia. These conditions were repeated during a computer-controlled alfentanil infusion.

Results: Serum alfentanil levels were constant among the volunteers (38 +/- 12 ng/ml). Alfentanil decreased both the initial and second acute hypoxic responses (from 1.27 +/- 0.73 to 0.99 +/- 0.39 l [middle dot] min-1 [middle dot] %-1, P < 0.05; and from 0.99 +/- 0.70 to 0.41 +/- 0.29 l [middle dot] min-1 [middle dot] %-1, P < 0.05, respectively). The magnitude of the decrease in ventilation during the 25 min of hypoxia was not changed (10 +/- 3.3 l/min for control; 12.3 +/- 7.5 l/min for alfentanil).     

Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro-receptor agonist morphine.

Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup -1 [center dot] h sup -1) in 12 men and 12 women.

Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l [center dot] min sup -1 [center dot] mmHg sup -1 (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l [center dot] min sup -1 [center dot] mmHg sup -1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 to 0.5 +/- 0.4 l [center dot] min sup -1 [center dot] % sup -1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 vs. morphine = 0.9 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes.     

Accuracy of a Cerebral Oximeter in Healthy Volunteers under Conditions of Isocapnic Hypoxia

Background: A cerebral oximeter measures oxygen saturation of brain tissue noninvasively by near infrared spectroscopy. The accuracy of a commercially available oximeter was tested in healthy volunteers by precisely controlling end-tidal oxygen (PET O2) and carbon dioxide (PET CO2) tensions to alter global cerebral oxygen saturation.

Methods: In 30 healthy volunteers, dynamic end-tidal forcing was used to produce step changes in PET O2 resulting in arterial saturation ranging from [approximately] 70% to 100% under conditions of controlled normocapnia (each person's resting PET CO2) or hypercapnia (resting plus 7-10 mmHg). Blood arterial (SaO2) and jugular bulb venous (Sjv with bar O2) saturations during each PET O2 interval were determined by co-oximetry. The cerebral oximeter reading (rSO2) and an estimated jugular venous saturation (Sjv with bar O2), derived from a combination of SaO2 and rSO2, were compared with the measured Sjv with bar O2.

Results: The Sjv with bar O2 was significantly higher with hypercapnia than with normocapnia for the same SaO2. The rSO sub 2 and Sjv with bar O2 were both highly correlated with S sub jv with bar O2 for individual volunteers (mean r2 = 0.91 for each relation); however, the slopes and intercepts varied widely among volunteers. In three of them, the cerebral oximeter substantially underestimated the measured Sjv O2.     

Influence of Morphine Anaesthesia on the Endocrine-Metabolic Response to Open-Heart Surgery

Twelve patients scheduled for aortic valve replacement during extracorporal circulation were randomly allocated to either morphine anaesthesia or fluroxene anaesthesia. Morphine in a total dose of 4 mg/kg was administered before skin incision. At the start of extracorporal circulation all patients received 25 g glucose intravascularly. The endocrine-metabolic response to surgery, as expressed by changes in plasma ACTH, cortisol, insulin, growth hormone, cyclic adenosine-3',-5'-monophosphate (cyclic AMP), glucose, free fatty acids, blood b-hydroxybutyrate and cumulative nitrogen balance was measured before and during anaesthesia and surgery, and on the first five post-operative days. It was found that morphine anaesthesia blocked the increase in ACTH, cortisol, growth hormone, cyclic AMP, and glucose during surgery. However, after initiation of extracorporal circulation only ACTH, cortisol, and, to a lesser degree, the glucose and insulin response to glucose were lowered by morphine anaesthesia. From the first to the fifth days after operation no differences between the two groups could be demonstrated in any parameter. Cumulative nitrogen balance was similar in the two groups. It is concluded that morphine in large doses administered before skin incision inhibits the initial endocrine-metabolic response to open-heart surgery, but that the effect is short-lasting and without effect on overall postoperative protein catabolism.     

Postoperative Ventilatory Response to Carbon Dioxide Following Neurolept Anaesthesia

In order to investigate the duration of respiratory depression following neurolept anaesthesia, 21 patients who had hemilaminectomia performed were subjected to ventilation-carbon dioxide response tests by a rebreathing method in the post-operative period. Up to 3 1/2 h after start of anaesthesia all patients had a decreased ventilatory response to carbon dioxide. After this period some patients showed a normal respiratory response, while others remained depressed for up to 6 h, the period for which the investigation lasted. Most patients in the depressed group were premedicated with pethidine. We conclude that additional narcotics are contraindicated for a period of 3 1/2 h following the start of neurolept anaesthesia for surgical procedures lasting 1-2 h, while clinical control is still necessary before administration of additional narcotics within 6 h, especially if narcotics have been used as premedication.     

The Pulmonary Vasoconstrictor Response to Hypoxia during Enflurane Anesthesia

Previous investigations have shown that diethyl ether, halothane and methoxflurane inhibit the vasoconstrictor response to hypoxia in isolated rat lungs. A damping effect of diethyl ether and halothane has been observed in the human lung as well. In the intact dog lung, however, other workers have recently denied any effect of halothane and enflurane on this vasoconstrictor mechanism. These findings challenged us to investigate the effect of enflurane on the vasoconstrictor response to hypoxia in isolated rat lungs. We found that enflurane administered via the airways reduced the response in proportion to the end-tidal concentration of enflurane, as determined by mass spectrometry.     

The Circulatory Response to Specific Ventilatory Patterns Using a Tidal Volume Ventilator

The circulatory response to different ventilatory patterns during artificial ventilation was examined in 17 sternotomized piglets. A constant CO2-tension level was maintained in all investigations by reference to analyses of the end-tidal infra-red CO2 fraction and arterial CO2-tension. The greatest variation in mean values for end-tidal CO2-tension was 0.2 kPa. Total compliance and lung compliance were lower at a ventilator volume/pressure quotient of 20 compared to those at 80 ml/kPa, and at f = 30 compared to f = 11 cycles/min. Higher cardiac output, lower pulmonary vascular resistance and systemic vascular resistance were measured at f = 11 (inspiration 20%) than at f = 30 (inspiration 50%). An increase in inspiration time by about 100% at the lower ventilatory frequency (f = 11) resulted in a significant but uncompensated decrease in cardiac output and stroke volume. These results demonstrate the value of a rapid insufflation in order to give longer expiration time per minute for the benefit of the venous return and cardiac output.     

The Influence of Arterial Carbon Dioxide Tension on the Cerebrovascular Response to Arterial Hypoxia and to Haemodilution

Cerebral blood flow (CBF) measurements and blood gas analyses were performed on anaesthetized and artifically ventilated dogs during arterial hypoxia or haemodilution in different ranges of arterial carbon dioxide tension. Arterial hypoxia as well as haemodilution produced a flow increase in all ranges of ventilation. However, this flow increase was elicited at a cerebrovenous oxygen tension which rose with the arterial carbon dioxide tension, but which tended to be maintained by the flow increase during continued decrease of the arterial oxygen content. On the assumption that the cerebrovenous oxygen tension reflects the oxygen tension of the brain tissue, it is suggested that the arterial carbon dioxide tension influences the ability of the brain tissue to maintain the aerobic metabolism during reduced tissue oxygen tension. This means that tissue hypoxia, in the sense of utilisation of anaerobic metabolism, occurs at a tissue oxygen tension which is lower the lower the arterial carbon dioxide tension is.     

Effects of Pain and Audiovisual Stimulation on the Opioid-induced Depression of the Hypoxic Ventilatory Response

Background: Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported.

Methods: Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion.

Results: The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 [mu]g [middle dot] kg-1 [middle dot] min-1. Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l [middle dot] min-1 [middle dot] sat-1 with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil.     

Contribution of Peripheral Chemoreception to the Depression of the Hypoxic Ventilatory Response during Halothane Anesthesia in Cats

Background: 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.

Methods: Cats were anesthetized with pentobarbital sodium and [Greek small letter 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%.

Results: 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, 0.8%.     

Antioxidants Reverse Reduction of the Human Hypoxic Ventilatory Response by Subanesthetic Isoflurane

Background: In subanesthetic concentrations, volatile anesthetics reduce the acute hypoxic response (AHR), presumably by a direct action on the carotid bodies but by an unknown molecular mechanism. To examine a possible involvement of reactive oxygen species or changes in redox state in this inhibiting effect, the authors studied the effect of antioxidants on the isoflurane-induced reduction of the AHR in humans.

Methods: In 10 volunteers, the authors studied the effect of antioxidants (intravenous ascorbic acid and oral [alpha]-tocopherol) on the reduction by isoflurane (0.12% end-tidal concentration) of the AHR on a 3-min isocapnic hypoxic stimulus (hemoglobin oxygen saturation 86 +/- 4%). All subjects participated in three separate sessions in which the effects of the antioxidants (session 1), placebo (session 2), and sham isoflurane plus antioxidants (session 3) were tested on the (sham) isoflurane-induced effect on the AHR.

Results: Isoflurane reduced the acute hypoxic response from 0.82 +/- 0.41 l [middle dot] min-1 [middle dot] %-1 to 0.49 +/- 0.23 l [middle dot] min-1 [middle dot] %-1 and from 0.89 +/- 0.43 l [middle dot] min-1 [middle dot] %-1 to 0.48 +/- 0.28 l [middle dot] min-1 [middle dot] %-1 in sessions 1 and 2, respectively (mean +/- SD; P < 0.05 vs. control). This reduction of the AHR was completely reversed by antioxidants (AHR = 0.76 +/- 0.39 l [middle dot] min-1 [middle dot] %-1; not significantly different from control, session 1) but not by placebo in session 2 (AHR = 0.50 +/- 0.30 l [middle dot] min-1 [middle dot] %-1; P < 005 vs. control). Sham isoflurane or antioxidants per se had no effect on the hypoxic response.     

Intrathecal Morphine Reduces the Visceromotor Response to Acute Uterine Cervical Distension in an Estrogen-independent Manner

Background: Acute uterine cervical distension (UCD) forms the basis for obstetric and some gynecologic pain. Systemic morphine inhibits the visceromotor response to UCD in rats by an action in the central nervous system, but the effect of morphine is blocked by exposure to estrogen. The purpose of the present study was to determine whether this estrogen blockade of the action of morphine reflects a spinal mechanism.

Methods: Virgin Sprague-Dawley rats received estrogen or placebo treatment for 1 week after ovariectomy. Rats were then anesthetized, and the electromyographic response in the rectus abdominis muscle to UCD was recorded in the absence and presence of cumulative dosing with intrathecal morphine.

Results: Estrogen treatment did not alter the stimulus- response relationship between UCD and reflex muscle contraction. Intrathecal morphine reduced the visceromotor reflex response to UCD in a dose-dependent manner that was unaffected by estrogen treatment.     

Early Response in Central Hemodynamics to High Doses of Sufentanil or Morphine in Dogs

The hemodynamk effects of high doses of sufentanil, a newly synthetized highly potent analgesic, were investigated in dogs. This study compared the early (30 min) cardiovascular effects of sufentanil 0.01 mg^- kg^-1 and morphine 4 mg^-kg^-1. Sufentanil caused a moderate and insignificant decrease in mean arterial pressure (MAP). A 30% decrease in cardiac index (CI) was almost outbalanced by an increased systemic vascular resistance (SVRI). The lowering of CI was due to a more than 50% decrease in heart rate (HR) which was partly compensated for by a greater stroke volume index (SVI). In the first 5 min after morphine injection, MAP fell significantly to about 50 mmHg (below 50% of the control value). CI was reduced to about 50% of the control value because of significant decreases in both SVI and HR. The calculated SVRI was unchanged alter morphine. Within 30 min some of the initially changed parameters had returned to control levels. Central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) increased immediately after sufentanil, but decreased alter morphine. With time, both parameters returned towards control values. Peak left ventricular dP/dt decreased by about 25–50% after both analgesics. The rate-pressure products (RPP) were significantly decreased to less than one half of the control values after both analgesics. Mixed venous oxygen tension (Pv?o₂), oxygen transport and oxygen consumption were significantly lowered in the sufentanil group, whereas immediate decreases after morphine were followed by gradual increases towards control values. We conclude that the use of high doses of sufentanil in dogs is safe. Apart from initial, transient changes, a stable cardiovascular stale characterizes the high-dose sufentanil anesthesia, while morphine causes fluctuations in several hemodynamic parameters. Compared to morphine anesthesia, sufentanil anesthesia appears to be an attractive alternative which deserves further evaluation in humans.