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Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation

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      Abstract

      Dexmedetomidine (Precedex™) may be used as an alternative sedative in children, maintaining spontaneous breathing, and avoiding tracheal intubation in a non-intubated moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged ≥28 weeks' gestational age to <1 month postnatal received dose level 1 (0.1 μg/kg load; 0.05–0.2 μg/kg/h infusion); those aged 1 month to <17 years received dose level 2 (1 μg/kg load; 0.2–2.0 μg/kg/h infusion). Sedation efficacy was assessed and defined as adequate sedation for at least 80% of the time and successful completion of the procedure without the need for rescue medication. In all, 91 patients were enrolled (dose level 1, n = 1; dose level 2, n = 90); of these, 90 received treatment and 82 completed the study. Eight patients in dose level 2 discontinued treatment for the following reasons: early completion of diagnostic or therapeutic procedure ( n = 3); change in medical condition (need for intubation) requiring deeper level of sedation ( n = 2); adverse event (AE; hives and emesis), lack of efficacy, and physician decision (patient not sedated enough to complete procedure; n = 1 each). Sixty-seven patients experienced 147 TEAEs. The two most commonly reported AEs were respiratory depression (bradypnea; reported per protocol-defined criteria, based on absolute respiratory rate values for age or relative decrease of 30% from baseline) and hypotension. Four patients received glycopyrrolate for bradycardia and seven patients received intravenous fluids for hypotension. SpO 2 dropped by 10% in two patients, but resolved without need for manual ventilation. All other reported AEs were consistent with the known safety profile of dexmedetomidine. Two of the 78 patients in the efficacy-evaluable population met all sedation efficacy criteria. Dexmedetomidine was well-tolerated in pediatric patients undergoing procedure-type sedation.

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      The effects of increasing plasma concentrations of dexmedetomidine in humans.

      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.
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            Author and article information

            Affiliations
            1Pediatric Cardiac Anesthesiology, Duke Children's Hospital and Health Center Durham, NC, United States
            2Departments of Anesthesiology, Perioperative and Pain Medicine and Pediatrics, Stanford University School of Medicine Stanford, CA, United States
            3Department of Biostatistics, Pfizer Manila, Philippines
            4Department of Medical Affairs, Pfizer Collegeville, PA, United States
            5Department of Anesthesiology and Pain Medicine, Children's Health Medical Center, University of Texas Southwestern Medical Center Dallas, TX, United States
            6Outcomes Research Consortium Cleveland, OH, United States
            Author notes

            Edited by: Matitiahu Berkovitch, Assaf Harofeh Medical Center, Israel

            Reviewed by: Catherine M. T. Sherwin, University of Utah, United States; Saskia N. De Wildt, Radboud University Nijmegen, Netherlands

            *Correspondence: Edmund H. Jooste edmund.jooste@ 123456duke.edu

            This article was submitted to Obstetric and Pediatric Pharmacology, a section of the journal Frontiers in Pharmacology

            Contributors
            Journal
            Front Pharmacol
            Front Pharmacol
            Front. Pharmacol.
            Frontiers in Pharmacology
            Frontiers Media S.A.
            1663-9812
            11 August 2017
            2017
            : 8
            5554485
            10.3389/fphar.2017.00529
            Copyright © 2017 Jooste, Hammer, Reyes, Katkade and Szmuk.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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            Figures: 2, Tables: 5, Equations: 0, References: 30, Pages: 10, Words: 6990
            Categories
            Pharmacology
            Clinical Trial

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