A Randomized, Prospective, Double-Blinded Study of Physostigmine to Prevent Sedation-Induced Ventilatory Arrhythmias.

BACKGROUND: Physostigmine, a centrally acting acetylcholinesterase inhibitor, is most commonly used by anesthesiologists in the postanesthetic setting to reverse confusion caused by central anticholinergic medication effects. It has also been proposed as a treatment for sleep-disordered breathing. We investigated whether physostigmine was effective in decreasing the frequency of ventilatory arrhythmias produced during moderate sedation with midazolam and remifentanil during the conditions of breathing room air or 2 L/min nasal O2. METHODS: Ten healthy male volunteers participated in this randomized, double-blind control trial of physostigmine (0.24 µg·kg·min) versus placebo. Moderate sedation was achieved with infusions of midazolam and remifentanil and monitored with full and processed electroencephalogram. Analgesia was quantified with subjective pain score to thermal stimulation. Ventilatory arrhythmias, as measured by the sedation apnea-hypopnea index (S-AHI), were scored as the number of apneas and hypopneas during two 1-hour periods on room air or 2 L/min nasal O2. RESULTS: All subjects tolerated the sedation and physostigmine without significant adverse effects. Sedation during placebo infusion resulted in clinically significant (S-AHI > 15) ventilatory arrhythmias in 5 conditions in 3 subjects (2 on room air and then O2, and 1 on O2 only). Physostigmine did not significantly (P > 0.46) reduce the total number of ventilatory arrhythmias on either room air or O2 (13.4 ± 18.8 events/h [mean ± SEM], 95% confidence interval [CI] = -9.9 to 62.7; and 6.2 ± 8.0, 95% CI = -3.1 to 28.7, respectively). Physostigmine did reduce the S-AHI in all 5 instances of clinically significant ventilatory arrhythmias (S-AHI decreased by 67.0 ± 22.2; CI = 29.2-111.7; P = 0.04). CONCLUSIONS: Physostigmine does not appear to be useful as a pretreatment to prevent ventilatory arrhythmias during moderate sedation. However, it may be useful as a treatment for clinically significant ventilatory arrhythmias during moderate sedation.

Validation of a measurement to predict upper airway collapsibility during sedation for colonoscopy.

Techniques to quantify the effects of sedation on upper airway collapsibility have been used as research tools in the laboratory and operating room. However, they have not been used previously in the usual clinical practice environment of colonoscopy sedation. The propensity for upper airway collapsibility, quantified as the critical pharyngeal pressure (P(crit)), was hypothesized to correlate with the need for clinical intervention to maintain ventilation. Twenty patients scheduled for colonoscopy with sedation were prospectively recruited to undergo measurement of upper airway collapsibility using negative airway pressure (NAP) provocation with a minimum pressure of -18 cmH(2)O. The P(crit) was the negative pressure that collapses the airway, either directly or by extrapolation from the pressure-flow relationship. An exponential transformation was applied to the P(crit) data for statistical analysis. A clinical intervention score (CIS) was used to quantify required interventions by the sedation nurse. The measurement of the P(crit) during sedation was significantly larger (less negative) than both the baseline ("awake") (P = 0.0029) and late recovery (P = 0.01) values. The CIS was not predicted by the transformed baseline or sedated P(crit) with or without including demographics associated with sleep apnea syndrome. Although the NAP technique showed the expected changes with sedation in this clinical situation, we did not find that it predicted the need for clinical intervention during endoscopy. Our study was not large enough to test for subpopulations in which the test might be predictive; further studies of these particular groups are needed to determine the clinical utility of the NAP measurement.

The role of the carotid bodies in the counter-regulatory response to hypoglycemia.

Although controversial, animal and tissue studies indicate that carotid bodies are sensitive to changes in glucose as well as in oxygen, thereby functioning as metabolic sensors. This study was designed to test the hypothesis that carotid bodies in humans participate in the counter-regulatory response to insulin-induced hypoglycemia.Dopamine and hyperoxia were used to suppress the carotid bodies' responsiveness in 16 normal subjects. Insulin and glucose infusions were used to clamp the plasma glucose in a step-wise decrease to 2.5,mmol/l over 4 hours while counter-regulatory hormones were measured.The hypoglycemic trajectories were similar under all three interventions (dopa-mine, hyperoxia and control), but the total glucose infused was significantly larger for hyperoxia than for dopamine. Cortisol and epinephrine both showed the expected increase with hypoglycemia, but there was no difference among interventions. Glucagon and norepinephrine levels were increased by dopamine, but only the normalized increase in glucagon was lower with dopamine and hyperoxia than control.The decrease in total glucose required for the dopamine experiments was most likely due to the higher baseline glucagon and norepinephrine levels. Hyperoxia did require more infused glucose, indicating some increased insulin sensitivity, but it was not clearly due to a decrease in cortisol or epinephrine responses. Thus, we did not find direct evidence of the carotid bodies' role in glucose homeostasis in humans.

The effects of hypo- and hyperglycaemia on the hypoxic ventilatory response in humans.

Animal and tissue studies have indicated that the carotid bodies are sensitive to glucose concentrations within the physiological range. This glucose sensitivity may modulate the ventilatory response to hypoxia, with hyperglycaemia suppressing the hypoxic response and hypoglycaemia stimulating it. This study was designed to determine whether hypo- and hyperglycaemia modulate the hypoxic ventilatory response in humans. In 11 normal research participants, glucose levels were clamped at 2.8 and 11.2 mmol l(-1) for 30 min. At the start and end of each clamp, blood was drawn for hormone measurement and the isocapnic hypoxic ventilatory response was measured. Because generation of reactive oxygen species may be a common pathway for the interaction between glucose and oxygen levels, the experiments were repeated with and without pretreatment for 1 week with vitamins C and E. Hypoglycaemia caused an increase in the counter-regulatory hormones, a 54% increase in isocapnic ventilation, and a 108% increase in the hypoxic ventilatory response. By contrast, hyperglycaemia resulted in small but significant increases in both ventilation and the hypoxic ventilatory response. Antioxidant vitamin pretreatment altered neither response. In conclusion, the stimulant effect of hypoglycaemia on the hypoxic ventilatory response is consistent with a direct effect on the carotid body, but an indirect effect through the activation of the counter-regulatory response cannot be excluded. The mechanisms behind the mild stimulating effect of hyperglycaemia remain to be elucidated.

Differences between midazolam and propofol sedation on upper airway collapsibility using dynamic negative airway pressure.

BACKGROUND: Upper airway obstruction (UAO) during sedation can often cause clinically significant adverse events. Direct comparison of different drugs' propensities for UAO may improve selection of appropriate sedating agents. The authors used the application of negative airway pressure to determine the pressure that causes UAO in healthy subjects sedated with midazolam or propofol infusions. METHODS: Twenty subjects (12 male and 8 female) completed the study. After achieving equivalent levels of sedation, the subjects' ventilation, end-tidal gases, respiratory inductance plethysmographic signals, and Bispectral Index values were monitored for 5 min. Negative airway pressure was then applied via a facemask in steps of 3 cm H(2)O from -3 to -18 cm H(2)O. UAO was assessed by cessation of inspiratory airflow and asynchrony between abdomen and chest respiratory inductance plethysmographic signals. RESULTS: Equivalent levels of sedation were achieved with both drugs with average (+/- SD) Bispectral Index levels of 75 +/- 5. Resting ventilation was mildly reduced without any changes in end-tidal pressure of carbon dioxide. There was no difference between the drugs in the negative pressure resulting in UAO. Five female subjects and one male subject with midazolam and four female subjects and one male subject with propofol did not show any UAO even at -18 cm H(2)O. Compared with males, female subjects required more negative pressures to cause UAO with midazolam (P = 0.02) but not with propofol (P = 0.1). CONCLUSIONS: At the mild to moderate level of sedation studied, midazolam and propofol sedation resulted in the same propensity for UAO. In this homogeneous group of healthy subjects, there was a considerable range of negative pressures required to cause UAO. The specific factors responsible for the maintenance of the upper airway during sedation remain to be elucidated.