Sedation with Dexmedetomidine or Propofol Impairs Hypoxic Control of Breathing in Healthy Male Volunteers

Abstract

Background In contrast to general anesthetics such as propofol, dexmedetomidine when used for sedation has been put forward as a drug with minimal effects on respiration. To obtain a more comprehensive understanding of the regulation of breathing during sedation with dexmedetomidine, the authors compared ventilatory responses to hypoxia and hypercapnia during sedation with dexmedetomidine and propofol. Methods Eleven healthy male volunteers entered this randomized crossover study. Sedation was administered as an intravenous bolus followed by an infusion and monitored by Observer’s Assessment of Alertness/Sedation (OAA/S) scale, Richmond Agitation Sedation Scale, and Bispectral Index Score. Hypoxic and hypercapnic ventilatory responses were measured at rest, during sedation (OAA/S 2 to 4), and after recovery. Drug exposure was verified with concentration analysis in plasma. Results Ten subjects completed the study. The OAA/S at the sedation goal was 3 (3 to 4) (median [minimum to maximum]) for both drugs. Bispectral Index Score was 82 ± 8 and 75 ± 3, and the drug concentrations in plasma at the sedation target were 0.66 ± 0.14 ng/ml and 1.26 ± 0.36 μg/ml for dexmedetomidine and propofol, respectively. Compared with baseline, sedation reduced hypoxic ventilation to 59 and 53% and the hypercapnic ventilation to 82 and 86% for dexmedetomidine and propofol, respectively. In addition, some volunteers displayed upper airway obstruction and episodes of apnea during sedation. Conclusions Dexmedetomidine-induced sedation reduces ventilatory responses to hypoxia and hypercapnia to a similar extent as sedation with propofol. This finding implies that sedation with dexmedetomidine interacts with both peripheral and central control of breathing.

Dexmedetomidine’s inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation

“…In the current study we questioned whether clinically used anesthetic agents modulate upper airway responses by modulating cholinergic or C-fiber neural activity and/or have a direct relaxant effect on airway smooth muscle. Although these agents may also contribute to airway tone, or alter the hypercapnic ventilatory response [14] and hypoxic control of breathing [27] in vivo through central effects at the level of the brain or spinal cord, we utilized an ex vivo model in order to assess the peripheral airway effects of these agents. The primary findings were that dexmedetomidine was most potent at inhibiting cholinergic nerve activation, a peripheral parasympathetic neural pathway well appreciated to mediate reflex-induced bronchoconstriction via the release of acetylcholine.…”

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

“…Even at supratherapeutic plasma concentrations (up to 14.9 ng/mL) as studied by Ebert et al, when volunteers were unarousable, respiratory drive was unaffected, leading to only slight increases in carbon dioxide levels (3–4 mmHg) and respiratory rates. However, a recently published paper by Lodenius et al [73] does describe a significant reduction in respiratory response to hypercapnia and hypoxia in dexmedetomidine-sedated young healthy volunteers with mean plasma concentrations of around 0.66 ng/mL.…”

Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety

“…Dexmedetomidine does not impair the respiratory drive per se and seldom causes apnea. However, it has been shown to impair the respiratory responses to hypoxia and hypercapnia [2] and can cause hemodynamic effects such as hypertension, hypotension and bradycardia [1]. …”