Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged. Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.

Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery.