Neonatal Intensive Care Drug Manual

There are no trials in neonates of clonidine as an adjunct to perioperative care. A systematic review in paediatric patients almost all over 1 year of age, found clonidine premedication 4 µg/kg may reduce postoperative pain in children. Side effects were minimal, but some of the studies used atropine prophylactically with the intention of preventing bradycardia and hypotension. [LOE I GOR C children] Infants enrolled in the trials were ≥1 year age. [10, 11]

Network meta-analysis of pharmacological treatments for NAS included buprenorphine, clonidine, diluted tincture of opium and clonidine, diluted tincture of opium, morphine, methadone, and phenobarbital. In network meta-analysis, clonidine had non-significant change in length of treatment (mean difference versus morphine –10.52 days [–24.05 to 2.92]), median rank 2 [6 to 1] and length of stay (days: mean difference versus morphine, –6.09 [–12.93 to 0.79], median rank 2 [7 to 1]. Rate of treatment failure was not reported. [12]

Three RCTs of clonidine in infants with NAS have used differing strategies. [7, 13, 14] Bada et al [7] in infants ≥35 weeks' gestation with NAS compared morphine 0.4 mg/kg/day versus clonidine 5 µg/kg/day divided into 8 doses as initial treatment of NAS. A 25% dose escalation every 24 hours was possible per protocol (maximum of 1 mg/kg per day for morphine and 12 µg/kg per day for clonidine). After control of symptoms, the dose was tapered by 10% every other day. Infants treated with clonidine (n = 16) versus morphine (n = 15) had decreased duration of treatment (median 39 days versus 28 days; P = .02), improved NNNS scores and lower height of arousal and excitability (P < .05). One-year motor, cognitive, and language scores did not differ between groups. Surran et al [14] in 64 infants compared morphine 0.32 to 0.8 mg/kg/day divided 3 hourly and clonidine 6 to 12 µg/kg/day divided 6 hourly according to NAS Score versus morphine sulfate 0.32 to 0.8 mg/kg/day divided 3 hourly and phenobarbital 6 to 12 mg/kg/day divided 8 hourly. Clonidine dose was weaned by halving daily dose every 24 hours for 2 steps then ceasing. Phenobarbital reduced duration of treatment 4.6 days, (95% CI: 0.3, 8.9; P=0.03). Two clonidine treated infants failed NMS-weaning attempts and were switched to phenobarbital whereas there were no failures occurred in the phenobarbital group. However, 3 (8.8%) infants in the phenobarbital group, manifested over sedation signs (poor feeds and mild respiratory depression) and serum phenobarbital measures were supratherapeutic (>40 mg/dL) and required dosage adjustment. There were no arrhythmias or abnormal BPs observed (hypo- or hypertension) in the clonidine group, no inpatient mortality and no infant was re-admitted to the hospital within 1 week post discharge. Agthe et al [13], in 80 infants with NAS treated with oral diluted tincture of opium, compared oral clonidine 1 µg/kg every 4 hours versus placebo. Median length of therapy was reduced in the clonidine group (11 versus 15 days), although 7 infants in the clonidine group required restarting opium after initial discontinuation. Clonidine reduced opioid use and rate of treatment failures (0% versus 12.5%). Hypertension, hypotension, bradycardia, or desaturations did not occur in either group. Three infants in the clonidine group died as a result of myocarditis, sudden infant death syndrome, and homicide, all after hospital discharge and before 6 months of age.

Conclusion: The optimal regimen to manage symptomatic NAS is unclear due to the low quality, small size and short-term outcomes considered in the published studies. [15]

For chronic hypertension, expert opinion suggested that drug therapy should be initiated mainly because sustained BP elevation may have renal, cardiac, and central nervous system effects [5, 16]. The ESCAPE Trial [17] of 385 children 3 to 18 years with chronic kidney disease (GFR 15-80 mL/minute/1.73 m²), hypertension was treated with ramipril 6 mg/ m²/day and patients were randomly assigned to intensified blood-pressure control (target 24-hour mean arterial pressure below the 50^th percentile) or conventional blood-pressure control (mean arterial pressure 50-95^th percentile) achieved by the addition of antihypertensive therapy that does not target the renin–angiotensin system. Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. [LOE II GOR B]

There are few case reports of clonidine use for neonatal hypertension [4, 18, 19]. One study of 11 infants and children with severe arterial hypertension associated with renal failure reported a single dose of clonidine 10 µg/kg infused over 4 hours, or an additional dose of 5 µg/kg resulted in a satisfactory response in 9 patients. [4]

Doses of clonidine for treatment of chronic hypertension in neonates [5] and paediatric patients [6] in expert reviews vary from 2–10 µg/kg/day in 3 or 4 divided doses, maximal 25 µg/kg/day.