Efficacy of α2-Agonists for Sedation in Pediatric Critical Care

Hayden, John; Breatnach, Cormac; Doherty, Dermot; Healy, Martina; Howlett, Moninne; Gallagher, Paul; Cousins, Gráinne

doi:10.1097/pcc.0000000000000599

Cited by 58 publications

(44 citation statements)

References 27 publications

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“…However, in recent years an increase of studies about the use of alpha-agonists has been seen, as shown in the systematic review published in the literature recently [15]. The data are very heterogeneous, which prevents getting good conclusions.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Clonidine: A Useful and Safety Sedation for Critically Ill Children

Carme¹,

David²,

Sergio³

et al. 2017

Int J Pediatr Res

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Aim: To determine usefulness and safety of intravenous infusion of clonidine in critically-ill children.Methods: Prospective, single-centre observational study from January 2013 to December 2014. PICU of Hospital Sant Joan Déu.Results: 73 patients were enrolled. Median age 7.9 months. Reasons for admission: Respiratory failure (42.5%) and post-cardiac surgery (30.1%). Median PICU length of stay: 14 days. 72 patients were intubated. The median days of clonidine use was 4. Reason for choosing clonidine: To improve prior sedation. We found no major adverse effects but some asymptomatic bradycardia. Conclusions:Clonidine seems to be a good alternative for sedation in critically-ill children. KeywordsClonidine, Sedation, Critically-ill child Opioids and benzodiazepines are the most frequently administered, but long-term use of these drugs is associated with tolerance and withdrawal, suppression of respiratory drive with prolonged ventilation, constipation, and delayed enteric feeding [2,3].Clonidine is a mixed alpha-1 and alpha-2 adrenoceptor agonist with a predominant alpha-2 action [4]. It has a sedative effect mediated by binding to post-synaptic alpha-2 receptors in the pontine locus ceruleus, reducing noradrenergic output and thereby facilitating the firing of inhibitory neurones, mainly, the gamma-aminobutyric acid system. Clonidine has an analgesic action through binding to alpha-2 receptors in the dorsal horn and supra-spinal sites and thereby reduce the release of P substance [1,5,6]. It also causes peripheral vasodilatation and a decrease in systolic blood pressure, heart rate and cardiac output by decreasing sympathetic nervous system activity. Clonidine has varying degrees of affinity for other cellular components called Nonadrenergic Imidazoline Binding Sites (NAIBS). It seems that the hypotensive effect of clonidine would owe more to their affinity for one type of NAIBS, called I1 receptors [7].As clonidine is lipid soluble, it penetrates the bloodbrain barrier to reach the hypothalamus and medulla [5]. It does not require transformation in to another substance prior to its action and about 20-40% is bound to protein. 50% of the drug is metabolized in the liver to inactive metabolites which are excreted in the urine

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Section: Discussionmentioning

confidence: 99%

Intravenous Clonidine: A Useful and Safety Sedation for Critically Ill Children

Carme¹,

David²,

Sergio³

et al. 2017

Int J Pediatr Res

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“…The α 2 agonists have been of intense interest in the pediatric critical care literature as sedative agents . An alternative mechanism of action to opioids and benzodiazepines makes them attractive to clinicians.…”

Section: Introductionmentioning

confidence: 99%

“…Bioavailability of orally administered clonidine formulations has been estimated to be approximately 55% in children . Pediatric‐derived information to date, on both α 2 agonists, has been scarce with limited evidence of efficacy on sedation outcomes …”

Section: Introductionmentioning

confidence: 99%

Optimizing clonidine dosage for sedation in mechanically ventilated children: A pharmacokinetic simulation study

Hayden

Bardol

Doherty

et al. 2019

Pediatric Anesthesia

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Background Clonidine is in widespread off‐label use as a sedative in mechanically ventilated children, despite limited evidence of efficacy. A variety of dosage regimens have been utilized in clinical practice and in research studies. Within these studies, clonidine has inconsistently shown useful sedation properties. One of the reasons attributed to the inconsistent signs of efficacy is suboptimal clonidine dosing. Aims This study aims to propose a target plasma concentration and simulate clonidine pharmacokinetics (PK) in a cohort of mechanically ventilated children to evaluate the adequacy of clonidine dosage regimens used in clinical practice and research studies. Methods A literature search was undertaken to identify a clonidine pharmaockinetic‐pharmacodynamics (PKPD) model, from which a target concentration for sedation was defined. Using a previously published PK model, the projected plasma concentrations of 692 mechanically ventilated children (demographics taken from a recent study) were generated. Doses from recently published clinical studies were investigated. Adequacy of each regimen to attain therapeutic clonidine plasma concentrations was assessed. Results A target plasma concentration of above 2 µg/L was proposed. Nine dosage regimens (four intravenous boluses, four intravenous infusions, and one nasogastric route boluses) were evaluated ranging from 1 µg/kg eight hourly intravenous boluses to a regimen up to 3 µg/kg/hr continuous intravenous infusion. Regimens with a loading dose of 2 µg/kg followed by variable continuous infusion of up to 2 µg/kg/hr titrated according to sedation score appear most suitable. Doses should be halved in neonates. Conclusion The variety of dosage regimens in the previous studies of clonidine along with difficulties in the conduct of interventional studies may have contributed to the lack of efficacy data to support its use. Simulations of clonidine plasma concentrations based on known population pharmacokinetic parameters suggest a loading dose followed by higher than current practice maintenance dose infusion is required to achieve adequate steady‐state concentrations early in treatment. Further PKPD studies will aid in the determination of the optimal clonidine dosage regimen.

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“…One recent systematic review on the efficacy of alpha-2 agonists for sedation in the pediatric critically ill population included three RCTs using clonidine, but did not pool estimates. They concluded that robust evidence was lacking for the use of clonidine as a sedative in the pediatric critically ill population [14]. A Cochrane meta-analysis that assessed the efficacy of alpha-2 agonists on the quality of sedation in ventilated critically ill patients did not include any studies on clonidine [15].…”

Section: Introductionmentioning

confidence: 99%

Clonidine for sedation in the critically ill: a systematic review and meta-analysis

et al. 2017

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BackgroundThis systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical ventilation.MethodsWe performed a comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane trial registry. We identified RCTs that compared clonidine to any non-clonidine regimen in critically ill patients, excluding neonates, requiring mechanical ventilation. The GRADE method was used to assess certainty of evidence.ResultsWe included eight RCTs (n = 642 patients). In seven of the trials clonidine was used for adjunctive rather than stand-alone sedation. There was no difference in the duration of mechanical ventilation (mean difference (MD) 0.05 days, 95% confidence interval (CI) = -0.65 to 0.75, I 2 = 86%, moderate certainty), ICU mortality (relative risk (RR) 0.98, 95% CI = 0.51 to 1.90, I 2 = 0%, low certainty), or ICU length of stay (MD 0.04 days, 95% CI = -0.46 to 0.53, I 2 = 16%, moderate certainty), with clonidine. There was a significant reduction in the total dose of narcotics (standard mean difference (SMD) -0.26, 95% CI = -0.50 to -0.02, I 2 = 0%, moderate certainty) with clonidine use. Clonidine was associated with increased incidence of clinically significant hypotension (RR 3.11, 95% CI = 1.64 to 5.87, I 2 = 0%, moderate certainty).ConclusionsUntil further RCTs are performed, data remains insufficient to support the routine use of clonidine as a sedative in the mechanically ventilated population. Clonidine may act as a narcotic-sparing agent, albeit with an increased risk of clinically significant hypotension.

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Efficacy of α2-Agonists for Sedation in Pediatric Critical Care

Cited by 58 publications

References 27 publications

Intravenous Clonidine: A Useful and Safety Sedation for Critically Ill Children

Intravenous Clonidine: A Useful and Safety Sedation for Critically Ill Children

Optimizing clonidine dosage for sedation in mechanically ventilated children: A pharmacokinetic simulation study

Clonidine for sedation in the critically ill: a systematic review and meta-analysis

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