Drug use patterns for the prevention of paediatric low cardiac output syndrome in Europe.

Dear Editor,

Low cardiac output syndrome (LCOS) affects approximately 25% of children undergoing open heart surgery (OHS) and is associated with increased morbidity and mortality [1]. Evidence for preventive drug therapy for LCOS is derived primarily from the PRIMACORP study [1], which reported a reduction in LCOS risk after administration of high-dose milrinone, using a bolus of 75 μg/kg, followed by a maintenance infusion of 0.75 μg kg−1 min−1 over 35 h. Low-dose milrinone (25 μg/kg bolus and 0.25 μg kg−1 min−1 infusion) was not more effective than placebo. Other drugs may be also used but are not supported by safety and efficacy data [2, 3]. Data on drug use for LCOS prevention in children with OHS is not available for Europe. Therefore, the aim of this study was to characterise hospital practices related to preventive drug therapy for LCOS in children undergoing OHS as a basis for improving the standard of care in this setting.

A Web-based questionnaire was developed to survey 125 specialised hospitals from 36 European countries between January and August 2009. It included 15 questions allocated to 4 sections: prescribing resources and LCOS treatment (data not shown), LCOS prevention, and participant characteristics and comments. The questions on LCOS prevention enquired about the target patient group (all, at risk, none) and mode of drug administration, which was not further stratified. The hospitals were notified by email; of those, 90 hospitals from 31 countries responded (72.0% response rate). Respondents included clinicians (98.9%) and pharmacists (1.1%), specialising primarily in paediatric intensive care, anaesthesiology, cardiology, and cardiothoracic surgery. Nearly all respondents (94.4%) had at least 5 years of experience in caring for children undergoing OHS.

Most European hospitals (70 out of 90) reported preventive drug therapy for LCOS, from which the majority (57 hospitals) selectively targeted patients at risk. However, the drug use was highly variable. In total, 24 different drug regimens were reported, including 17 drugs from 7 therapeutic drug classes. Overall, 70.7% of the drug regimen reports included milrinone, making this the most commonly used drug. Dopamine, dobutamine, epinephrine, and levosimendan were reported significantly less often (Table 1). The dosage and duration of drug administration differed substantially among hospitals.

Table 1

Summary characteristics of the drugs commonly reported for LCOS prevention

Druga	Frequency of drug use			Drug administration
	N	%	95% CI	Bolusb (μg/kg)	Maintenance infusionb (μg kg–1 min–1)	Durationb (h)
Milrinone	53	70.7	59.6–79.8	50 (20–300)	0.5 (0.2–1.5)	39 (6–168)
Dopamine	14	18.7	11.5–28.9	–c	5 (0–15)	36 (8–72)
Dobutamine	12	16	9.4–25.9	7d (6–8)	5 (2–14)	36 (6–48)
Epinephrine	12	16	9.4–25.9	1 (1–1)	0.065 (0.003–0.3)	9 (6–12)
Levosimendan	12	16	9.4–25.9	12 (12–12)	0.15 (0.1–0.2)	24 (24–48)
Methylprednisolone	4	5.3	2.1–12.9	25e (10–35)	–	–

The analysis was based on 75 drug regimens reported from 69 hospitals. Two hospitals provided three different drug regimens and another two hospitals provided two drug regimens based on the clinical condition of the patient and the type of open heart surgery. One hospital did not fill in the information on drug dosing

aOnly 6 out of 17 drugs were reported more than twice and are listed in the table. The following drugs were reported once or twice: alprostadil, bosentan, calcium, enoximone, glyceryl trinitrate, inhaled nitric oxide, norepinephrine, phenoxybenzamine, phenylephrine, nitroprusside, and thiopental

bData are median with range in parenthesis

cNot reported

dBolus dose in μg kg−1 min−1

eBolus dose in mg/kg

The results of this survey present the current pattern of drug use for LCOS prevention in children with OHS across Europe, which is characterised by a marked variability. In addition, the dose of milrinone appears to be lower than that supported by PRIMACORP. Although our survey shows that milrinone is the most frequently used drug in Europe, neither the dosing nor the duration of drug administration coincide with those demonstrating efficacy in PRIMACORP (Table 1). Reasons for the reduced dose of milrinone may be attributable to concerns about potential side effects, especially hypotension [4], and the role of age-specific pharmacokinetic differences in the elimination of milrinone [5]. Nonetheless, these factors cannot explain the generally lower dose of milrinone used across all paediatric age groups, which needs to be addressed in future clinical research.

In summary, preventive drug therapy for LCOS in children undergoing OHS is highly variable across Europe, and the data available to support current hospital practices are insufficient. Given the importance of balancing benefits and risks with preventive drug therapy, this survey emphasises the need for further studies that will substantiate effective and safe LCOS prevention.