Robert T. Blouin

Propofol Depresses the Hypoxic Ventilatory Response during Conscious Sedation and Isohypercapnia

BackgroundPropofol infusion at subanesthetic doses provides reliable conscious sedation. However, the ventilatory effects of sedative doses of propofol have not been established. The current study was conducted to determine the effects of propofol sedation on the hypoxic ventilatory response. MethodsEight healthy, male volunteers received 1 mg ± kg−1 propofol followed by a propofol infusion adjusted to maintain a constant, subanesthetic level of sedation. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: while keeping Petco2 constant (6 mmHg above prestudy baseline), the authors continuously recorded minute ventilation and tidal volume, as oxygen saturation (Spo2) decreased from 98 to 70%. Hypoxic response determinations were performed before and during propofol infusion, as well as 30 and 60 min after termination of the propofol Infusion. ResultsThe slope of the hypoxic ventilatory response curve (E vs. Spo2) decreased from 0.88 ± 0.15 to 0.17 ± 0.03 1 ± min−1 ± %Spo2−1 during propofol sedation (SE). Thirty minutes after discontinuation of the propofol infusion, slope returned to its prepropofol value. In addition, minute ventilation at Spo2 = 90% decreased during propofol sedation, from 16.1 ± 0.8 to 8.7 ± 0.4 1 ± min−1, accompanied by a similar decrease in tidal volume at Spo2 = 90%, from 1,099 ± 87 to 523 ± 21 ml. Thirty minutes after discontinuation of the propofol infusion, these variables also returned to their prepropofol values. ConclusionsThe authors concluded that propofol infusion for conscious sedation significantly decreases the slope and causes a downward shift of the hypoxic ventilatory response curve measured during isohypercapnia.

Effect of flumazenil on ventilatory drive during sedation with midazolam and alfentanil

Background Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine‐induced depression of ventilatory drive in the presence of an opioid. Methods Twelve healthy volunteers completed this randomized, double‐blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and “study drug” (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2–6 weeks later to receive the alternate study drug. Results Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/‐ 0.40 to 1.43 +/‐ 0.19 l [dot] min sup ‐1 [dot] mmHg sup ‐1 (x +/‐ SE, P < 0.05), and decreased the minute ventilation at PET CO2 = 50 mmHg (V with dotE 50) from 19.7 +/‐ 1.2 to 14.8 +/‐ 0.9 l [dot] min sup ‐1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/‐ 0.17 l [dot] min sup ‐1 [dot] mmHg sup ‐1 (P < 0.05) and 11.7 +/‐ 0.8 l [dot] min sup ‐1 (P <0.05), respectively. With addition of flumazenil, slope and V with dot sub E 50 increased to 1.47 +/‐ 0.37 l [dot] min sup ‐1 [dot] mmHg sup ‐1 (P < 0.05) and 16.4 +/‐ 2.0 l [dot] min sup ‐1 (P < 0.05); after placebo, the respective values of 1.02 +/‐ 0.19 l [dot] min sup ‐1 [dot] mmHg sup ‐1 and 12.5 +/‐ 1.2 l [dot] min sup ‐1 did not differ significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at PET CO2 = 46 +/‐ 1 mmHg, were affected similarly, with flumazenil showing a significant improvement compared to placebo. Conclusions Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

Time course of ventilatory depression following induction doses of propofol and thiopental

To improve our understanding of the respiratory pharmacology of intravenous induction agents, the authors compared the acute effects of intravenous (iv) propofol 2.5 mg.kg-1 and iv thiopental 4.0 mg.kg-1 on the ventilatory response to CO2 (VeRCO2) of eight healthy volunteers. The slope of VeRCO2 decreased from 1.75 +/- 0.23 to a minimum of 0.77 +/- 0.14 1.min-1.mmHg-1 (mean +/- standard error) 90 s after propofol; similarly, the slope of VeRCO2 decreased from 1.79 +/- 0.22 to a minimum of 0.78 +/- 0.23 l.min-1.mmHg-1 30 s after thiopental. For both drugs, the slope was less than control in the 0.5-5-min period after injection (P less than 0.05). The slope returned to baseline within 6 min after thiopental; in contrast, after propofol, the slope remained less than control for the entire 20-min follow-up period (P less than 0.05 at 6-10, 11-15, and 16-20 min after injection). Also, from 6-10, 11-15, and 16-20 min after injection, the slope was less after propofol than at corresponding times after thiopental (P less than 0.05). Recovery of consciousness was approximately 4 min slower after propofol than after thiopental; nonetheless, awareness scores returned to baseline within 14 min after both drugs. The authors conclude that propofol 2.5 mg.kg-1 iv produces longer-lasting depression of VeRCO2 than a 4.0 mg.kg-1 iv dose of thiopental; after propofol, ventilatory depression may persist despite apparently complete recovery of consciousness.

Sedative doses of propofol increase beta activity of the processed electroencephalogram

The effects of sedative infusions of propofol on the processed electroencephalograms (EEG) of eight healthy male volunteers were studied. EEG data for aperiodic analysis were collected during three 5-min periods: before propofol, during propofol infusion, and 30 min after termination of the infusion. After an initial dose of 1 mg/kg, subjects received a propofol infusion titrated to produce a standard level of conscious sedation. The infusion rate was 84 +/- 27 micrograms.kg-1 x min-1 (mean +/- SE) and plasma propofol levels were 2180 +/- 43 ng/mL. Total EEG power, defined as the sum of the squares of peak-to-peak amplitudes during each 5-s epoch, increased from 1350 +/- 295 microV2 x epoch-1 to 9675 +/- 2390 microV2 x epoch-1 during the propofol infusion (P < 0.05); it returned to 1445 +/- 145 microV2 x epoch-1 30 min after the infusion was discontinued (P < 0.05 vs the result during propofol). The change in total power was accompanied by a change in the distribution of power within the EEG spectrum, as the fraction of activity in the beta-band (12-35 Hz) increased during the infusion from 23% +/- 3% to 44% +/- 5% (P < 0.05). Thirty minutes after the infusion was terminated, the distribution of activity within the EEG spectrum had reverted to pre-propofol patterns. The similarity of EEG effects seen with sedative doses of propofol and benzodiazepines suggests that these drugs may share some neurochemical effects.

Diphenhydramine Enhances the Interaction of Hypercapnic and Hypoxic Ventilatory Drive

Background:Although diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids, there are no data regarding its effect on ventilatory control. We conducted the current study to evaluate the effects of diphenhydramine on hypercapnic and hypoxic ventilatory control in healthy volunteers. Methods:First, we measured the steady-state ventilatory response to carbon dioxide during hyperoxia with an end-tidal carbon dioxide tension of 46 or 54 mmHg (alternate subjects) in eight healthy volunteers. We then determined the hypoxic ventilatory response during isocapnic rebreathing at the same carbon dioxide tension. After a 10-min recovery period, we repeated the steady-state and hypoxic ventilatory response measurements at the other carbon dioxide tension (54 or 46 mmHg). Ten minutes after subjects received diphenhydramine 0.7 mg·kg-1 intravenously, we repeated this sequence of ventilatory measurements. Results:Under hyperoxic conditions (inspired oxygen fraction > 0.5) diphenhydramine did not affect the ventilatory resposnse to hypercapnia. Similarly, at an end-tidal carbon dioxide tension of 46 mmHg, neither the slope nor the position of the hypoxic ventilatory response curve changed significantly after diphenhydramine. However, at an end-tidal carbon dioxide tension of 54 mmHg, the slope of the hypoxic ventilatory response increased from 1.28 ± 0.33 to 2.13 ± 0.61 1·min-1 · %Spo2-1 (mean ± standard error), and &OV0312;E at an arterial hemoglobin oxygen saturation of 90% increased from 31.2 ± 3.1 to 43.1 ± 5.4 1·min-1). Conclusions:We conclude that although it did not affect the ventilatory response to carbon dioxide during hyperoxia or the ventilatory response to hypoxia at an end-tidal carbon dioxide tension of 46 mmHg diphenhydramine augmented the hypoxic response under conditions of hypercapnia in our young healthy volunteers. Although these findings may help to explain the apparent safety of diphenhydramine, they may not be applicable to debilitated patients or those who have received systemic or neuraxial ventilatory depressants.

The Effect of Flumazenil on Midazolam-induced Depression of the Ventilatory Response to Hypoxia during Isohypercarbia

BackgroundWhile flumazenil reverses benzodiazepine-induced sedation, its ability to antagonize the ventilatory depressant effects of benzodiazepines has not been fully established. A randomized, double-blind study was conducted to determine whether flumazenil effectively reverses midazolam-induced depression of the hypoxic ventilatory response. MethodsTwelve healthy male volunteers received intravenous midazolam 0.12 ± 0.01 mg·kg-1 followed by either flumazenil 1.0 mg or placebo. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: as SpO2 decreased to 70%, &OV0312;E and tidal volume were continuously recorded. Hypoxic response determinations were performed before and after midazolam, as well as 3, 30, 60, 120, and 180 min after flumazenil or placebo. ResultsAfter midazolam, the slope of the hypoxic ventilatory response curve (&OV0312;E vs. SpO2) decreased to 0.59 ± 0.05 (&OV0398; ± SE) times its premidazolam baseline; likewise, at SpO2 = 90%, minute ventilation (&OV0312;E90) and tidal volume (TV90) decreased to 0.70 ± 0.04 and 0.62 ± 0.03 times baseline, respectively. Three minutes after flumazenil, the slope increased to 1.10 ± 0.13 times baseline (P < 0.05 vs. postmidazolam), while following placebo, it was only 0.81 ± 0.09 times baseline (P = NS vs. postmidazolam, P < 0.05 between treatments). &OV0312;E90 and TV90, after flumazenil, increased to 1.45 ± 0.15 and 1.27 ± 0.09 times baseline, respectively (P < 0.05 vs. postmidazolam); these increases were significantly greater than the corresponding changes observed after placebo (P < 0.05 between treatments). ConclusionsIt was concluded that, after sedation with midazolam, flumazenil causes a greater Increase in hypoxic ventilatory response during isohypercarbic conditions than does placebo, and may, therefore, be useful in the treatment of midazolam-induced ventilatory depression.

Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Background Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined. Methods The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] [almost equal to] 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels [almost equal to] 10 ng/ml) before and after diphenhydramine 0.7 mg/kg. Results The slope of the ventilatory response to carbon dioxide decreased from 1.08 +/- 0.38 to 0.79 +/- 0.36 l [middle dot] min-1 [middle dot] mmHg-1 (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17 +/- 0.28 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). The minute ventilation (VE) at PETCO2 [almost equal to] 46 mmHg (VE 46) decreased from 12.1 +/- 3.7 to 9.7 +/- 3.6 l/min (P < 0.05) and the VE at 54 mmHg (V (E) 54) decreased from 21.3 +/- 4.8 to 16.6 +/- 4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, VE 46 did not change significantly, remaining lower than baseline at 9.9 +/- 2.9 l/min (P < 0.05), whereas VE 54 increased significantly to 20.5 +/- 3.0 l/min. During hypoxia, VE at Sp O2 = 90% (VE 90) decreased from 30.5 +/- 9.7 to 23.1 +/- 6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE 90 to 27.2 +/- 9.2 l/min was not significant (P = 0.06). Conclusions Diphenhydramine counteracts the alfentanil-induced decrease in the slope of the ventilatory response to carbon dioxide. However, at PET (CO)2 = 46 mmHg, it does not significantly alter the alfentanil-induced shift in the carbon dioxide response curve. In addition, diphenhydramine does not exacerbate the opioid-induced depression of the hypoxic ventilatory response during moderate hypercarbia.