Prophylactic milrinone for the prevention of low cardiac output syndrome and mortality in children undergoing surgery for congenital heart disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To review the effectiveness of the post‐operative use of milrinone in children having undergone surgery for congenital heart disease.
Background
With the technical and medical advances of the past few decades, approximately 85% of children with congenital heart disease now reach adulthood (Ermis 2011). Part of this improvement is due to the ability to operate on ever younger and smaller children (Warnes 2001). Those children suffering from the most severe forms of cardiac malformations need to undergo corrective or palliative surgery in their first year of life. For example, of the 12,495 procedures performed in 10,780 patients of all ages in Europe in 2009 which are registered in the European Association for Cardio‐Thoracic Surgery (EACTS) congenital database, 6717 procedures (53.8%) were done in 5777 (53.6%) neonates and infants (EACTS 2011). However, this comes at the cost of high risk of morbidity and mortality in the postoperative period as evidenced by the fact that 77.6% of deaths in the 30 days following surgery involved neonates and infants (333 out of 429 cases) (EACTS 2011).
Description of the condition
One important condition associated with increased morbidity and mortality is low cardiac output syndrome (LCOS). LCOS is thought to be due to a combination of the underlying heart disease, myocardial ischemia from aortic cross‐clamping, the residual effects of cardioplegia, and activation of inflammatory pathways from exposure of blood to foreign surfaces during cardiopulmonary bypass (Bailey 2004). It occurs in up to 25% of young children, even if there are no residual cardiac lesions after surgery (Bailey 2004) and typically occurs between six and 18 hours after surgery in a setting of elevated systemic and pulmonary vascular resistances, impaired myocardial function, and arrhythmias. LCOS is detected invasively or by signs of inadequate oxygen delivery to the organ systems, e.g. tachycardia, poor systemic perfusion, decreased urine output, elevated lactate, and reduced mixed venous oxygen saturation (Stocker 2006). If left untreated, LCOS can lead to cardiac arrest, the need for cardiopulmonary resuscitation or extracorporeal life support (Delmo Walter 2010), prolonged mechanical ventilation (Shi 2008), a prolonged intensive care stay and increased mortality (Baysal 2010).
Therefore, early detection and treatment or prevention of postoperative LCOS is paramount.
Cardiac output is regarded as low when the pumping capacity of the heart is insufficient to provide enough blood flow to satisfy the oxygen demand of the body tissues (Stocker 2006). In the adult intensive care setting, cardiac output can be measured directly by indicator dilution techniques like thermodilution (Lemson 2008), by Doppler echocardiography (Huntsman 1983), or by arterial pulse contour analysis (Tibby 2002; Kim 2006). A cardiac index of <2.2 l/min/m2 is considered low (Rao 1996; Hochman 1999). In children, especially in neonates and infants, it is usually not feasible to employ these techniques due to device sizes, shunts, and other characteristics of cardiovascular physiology (Teng 2011), as well as poor correlation with tissue oxygen delivery (Bohn 2011). With lack of a clear definition, different authors describe various parameters, which are often used as a compound measure. Such a composite parameter for LCOS may consist of several of the following findings:
‐ elevated blood lactate or rapid increase in blood lactate (Charpie 2000),
‐ decreased central venous oxygen saturation (Stocker 2006),
‐ increase in arterial to central venous oxygen saturation difference,
‐ decreased urine output (Stocker 2006),
‐ increased peripheral skin temperature to core body temperature difference,
‐ echocardiographic Doppler‐derived low cardiac index
‐ high inotrope requirement (Shore 2001).
The mainstays of treatment include catecholamines, calcium sensitizers, and phosphodiesterase inhibitors (usually milrinone) (Stocker 2006). It is very common for children after surgery for congenital heart disease to need catecholamines, vasopressin, calcium sensitizers, inhaled nitric oxide, or nitroprusside, or a combination of the above, in the immediate postoperative period for support of cardiac function.
Description of the intervention
In the adult population, phosphodiesterase type III inhibitors have been used extensively for congestive heart failure and in the postoperative management of patients undergoing coronary artery bypass grafting (Feneck 1992). In children undergoing congenital heart surgery, milrinone is thought to decrease the incidence of low cardiac output syndrome without an increase in adverse reactions (Hoffman 2003). Adverse effects have been described in terms of arrhythmias (Fleming 2008), hypotension (Jeon 2006), tachycardia (Paradisis 2009), hypokalemia, bronchospasm, headaches, thrombocytopenia (Ramamoorthy 1998), anemia, and elevated serum levels of liver enzymes (Sanofi Aventis 2010). In neonates treated with milrinone, intraventricular haemorrhage has been observed as well (Bassler 2006). Milrinone is administered intravenously, either as a bolus, or as a loading dose followed by continuous infusion, or by continuous infusion only. Bolus doses are given as 50 μg/kg of body weight (Bailey 1999). Typical loading doses range from 25 μg/kg (Hoffman 2003) to 250 μg/kg of body weight (Zuppa 2006). Continuous infusion rates vary between 0.2 μg/kg/min (Zuppa 2006) and 0.75 μg/kg/min (Hoffman 2003). The medication is started immediately or within several hours after separation from cardiopulmonary bypass, when surgical correction or palliation of the heart defect is completed. Usual infusion periods for continuous administration are up to 36 hours (Hoffman 2003) or even several days.
How the intervention might work
Milrinone is a phosphodiesterase type III inhibitor, exerting its pharmacologic action by increasing the intracellular cAMP concentration, which in turn has inotropic and lusitropic effects relating to intracellular calcium handling in cardiac myocytes (el Allaf 1984). In the peripheral and pulmonary vasculature, phosphodiesterase type III inhibitors act as vasodilators, thereby decreasing systemic and pulmonary vascular resistance (Alousi 1986; Stocker 2007).
Why it is important to do this review
In the paediatric age group, a large percentage of drugs are used off‐label, that is in ways that are not formally approved, depending largely on information from adult trials. In cardiovascular medicine especially, there is a great discrepancy between the availability of trial information from many large adult studies and systematic reviews/meta‐analyses, and very little knowledge about drug effects in children (Pasquali 2008). This is even more striking as cardiac defects constitute the most common type of separate congenital organ malformations, affecting more than one percent of newborns (Lindinger 2010).
The most common indication for milrinone in the paediatric age group is in children with congenital heart defects undergoing palliative or corrective surgery, in order to prevent or treat low cardiac output syndrome after cardiopulmonary bypass. As of July 6, 2011, the European Medicines Agency has issued a Paediatric Regulation assessment of milrinone, indicating the use of this substance for “the short‐term treatment (up to 35 hours) of severe congestive heart failure unresponsive to conventional maintenance therapy […], and for the short‐term treatment (up to 35 hours) of paediatric patients with acute heart failure, including low output states following cardiac surgery” (Anonymous 2011). Prophylactic use has not been approved by the European Medicines Agency.
The frequent use of milrinone warrants further investigation into its effects in children undergoing surgery for congenital heart disease. This review is an essential step to permit further relevant and ethical clinical trials in the paediatric population as needed, or to possibly prevent more children from being subjected to unnecessary trials, depending on its outcome.
Objectives
To review the effectiveness of the post‐operative use of milrinone in children having undergone surgery for congenital heart disease.
Methods
Criteria for considering studies for this review
Types of studies
Only randomized controlled trials are to be considered.
Types of participants
Children from birth to 12 years of age undergoing corrective or palliative heart surgery for congenital heart disease.
Types of interventions
Intervention: Prophylactic milrinone intravenous infusion alone or combined with other inotrope medications and/or vasopressin and/or calcium sensitizers and/or nitric oxide, started within 6 hours of surgery for congenital heart disease and irrespective of the administration protocol, provided that milrinone bolus doses are at least 25 μg/kg and continuous infusion rates are at least 0.2 μg/kg/min, and that milrinone is administered for a duration of at least 4 hours.
Comparative intervention: No milrinone infusion: a) or b)
(a) Placebo: Depending on the surgical intervention, children will rarely be weaned from cardiopulmonary bypass without inotropic medications. If any trials exist comparing milrinone with placebo, these will be included.
(b) Other inotrope medications and/or vasopressin and/or calcium sensitizers and/or nitric oxide/nitroprusside alone: Inotropes (usually catecholamines) such as epinephrine, norepinephrine, dopamine, or dobutamine, may be used in combination with vasopressin and/or with calcium sensitizers such as levosimendan and/or combined with inhaled nitric oxide/ intravenous nitroprusside.
These combination regimens will be regarded as eligible comparators, as long as they do not contain milrinone. Studies using medication regimens which contain other phosphodiesterase type III inhibitors (amrinone, inamrinone, enoximone, piroximone, pimobendane, imazodan, sulmazole, isomazole, flosequinan, indolidan, carbazeran, quazinone, adibendan, pelrinone, olprinone, siguazodan, cilostamide, cilostazol, zardaverine, alifedrine, lixazinone) will also be excluded.
Types of outcome measures
Primary outcomes
a) Total mortality within 30 days
b) Time to death (censored after three months)
c) Low cardiac output syndrome defined as two or more of the following:
‐ blood lactate > 3 mmol/l (27 mg/dl) or increase in blood lactate of at least 2 mmol/l (18 mg/dl) from baseline,
‐ central venous oxygen saturation <50% in biventricular physiology without shunts,
‐ increase in arterial to central venous oxygen saturation difference by at least 20% from baseline,
‐ urine output < 1 ml/kg/h,
‐ peripheral skin temperature to core body temperature difference of > 7°C,
‐ cardiac index as determined by Doppler echocardiography of < 2.2 l/min/m2.
Secondary outcomes
Secondary: Length of intensive care stay, length of hospital stay, duration of mechanical ventilation, inotrope score, number of patients requiring mechanical circulatory support (e.g. ECMO, pulsatile assist devices) or cardiac transplantation.
Safety outcomes: Number/proportion of adverse events. Adverse events include
‐ arrhythmias (number/proportion),
‐ tachycardia (number/proportion of patients with heart rate above heart rate appropriate for age or body surface area),
‐ hypotension (number/proportion of patients with blood pressures below blood pressure appropriate for age or body surface area),
‐ intraventricular haemorrhage (number/proportion),
‐ hypokalemia (number/proportion),
‐ bronchospasm (number/proportion),
‐ thrombocytopenia (number/proportion of patients with platelet count <50/nl or with a drop in platelet count of >100% from baseline prior to administration of milrinone),
‐ elevated serum levels of liver enzymes (number/proportion of patients with serum enzymatic activities more than two‐fold the age‐appropriate normal values),
‐ left ventricular ejection fraction <50% or left ventricular fraction of shortening <28% as assessed by biplane or M‐mode echocardiography.
Search methods for identification of studies
Electronic searches
We will search the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, EMBASE, and Web of Science. No language restrictions will be applied.
Clinical trial registries ( www.clinicaltrials.gov, Current Controlled Trials, and the eleven Primary Registries in the WHO Registry Network) will be consulted for trials that are completed or nearing completion but have not been published yet.
The proposed search strategy to be used to search MEDLINE (OVID), using the Cochrane sensitivity‐maximising RCT filter, (Lefebvre, 2011), can be found in Appendix 1
Searching other resources
Reference lists of published studies will be hand searched for further trials. Also, general reviews and overviews will be scanned for relevant citations. We are going to contact authors of published trials and expert colleagues from scientific medical societies (e.g. Deutsche Gesellschaft für Pädiatrische Kardiologie, Association for European Paediatric Cardiology, American Academy of Pediatrics Section on Cardiology and Cardiac Surgery, American Heart Association Council on Cardiovascular Disease in the Young) to find out about possible unpublished data. We will also ask the manufacturer (Sanofi Aventis) to provide us with information about any additional trials.
Data collection and analysis
Data analysis will be carried out using RevMan 5.1 software.
Selection of studies
Only randomized controlled trials will be selected for analysis. Study selection will be documented according to the PRISMA statement format (Moher 2009).
Data extraction and management
Data will be independently extracted by two authors (B.B. and B.S.) according to a pre‐defined protocol and using the same data extraction work sheet. Incongruities will be settled by discussion with the third author (G.R.).
If quality assessment of data reveals shortcomings of the publications identified, for example lack of mentioning of methods for allocation concealment in randomized trials, authors will be contacted and asked to provide further information in order to obtain as complete a data set as possible concerning each individual study.
Assessment of risk of bias in included studies
Risk of bias tables will be used to list possible concerns over the potential for bias of each individual study, evaluating sequence generation, allocation sequence concealment, blinding of participants, personnel, and outcome assessors, incomplete outcome data, selective outcome reporting, and other potential sources of bias, according to "The Cochrane Collaboration’s tool for assessing risk of bias" (Higgins 2011).
Measures of treatment effect
For total mortality within 30 days, relative risk with 95% confidence interval will be used as an effect measure (as for other binary outcomes). Data will be pooled using a random effects model.
For time to death, the effect measure will be the log hazard ratio with its standard error. If the hazard ratio or its standard error are not directly reported, it will be derived from other reported information as possible (Tierney 2007).
For evaluation of time to extubation (duration of mechanical ventilation), hazard ratios will be calculated according to the Cox model, if available.
For continuous variables (e.g. if mean and standard deviation of the duration of mechanical ventilation are available instead of hazard ratios), the weighted mean difference (WMD) with 95% confidence interval will be used.
Data will be illustrated using forest plots. Heterogeneity between studies will be assessed using Cochran’s Q and I2 according to Higgins and Thompson (Higgins 2002; Higgins 2011).
Unit of analysis issues
The following outcomes could be reported in repeated measurements of individual study participants at different time intervals following surgery: number of events of low cardiac output syndrome, number of patients requiring mechanical circulatory support, inotrope score.
For the numbers of LCOS and mechanical circulatory support, respectively, the incidence at any time within 30 days after surgery will be considered relevant. For the inotrope score, the maximum value reported within 30 days after surgery will be used for meta‐analysis.
Dealing with missing data
Study authors will be contacted and asked to supply additional information in case of missing data.
Assessment of heterogeneity
Heterogeneity between studies will be assessed using Cochran’s Q and I2 statistic. If I2 > 50%, a subgroup analysis will be performed between patients with biventricular surgical repair of a congenital heart defect versus patients after univentricular palliation of a congenital heart defect.
Assessment of reporting biases
If protocols of eligible studies are available, then outcomes in the protocols and published reports will be compared. Additional information will be obtained from study authors if necessary. Funnel plots will be applied to assess reporting bias, if the number of studies allows (Harbord 2006). If reporting bias is suspected, results will be adjusted for in an additional sensitivity analysis (Schwarzer 2010; Rücker 2011).
Data synthesis
Binary outcomes (LCOS yes/no, 30‐day mortality) will be assessed with relative risk as an effect measure. Data will be pooled using a random effects model. For evaluation of time to extubation, hazard ratios (Cox) will be calculated, if available. For continuous variables, the weighted mean difference (WMD) will be used. Data will be illustrated using forest plots.
Subgroup analysis and investigation of heterogeneity
With the small numbers of children studied in clinical trials, and owing to the fact that most surgical interventions for congenital heart disease are nowadays carried out in the first year of life, age‐based subgroup analysis will be confined to two age groups: infants < 1 year of age, and children and adolescents from 1 to 12 years of age.
The infant group will comprise subjects undergoing complicated palliative and corrective operations, necessitating long cardiopulmonary bypass times with concomitant long periods of cardioplegia, and with a high risk of morbidity and mortality. On the other hand, in the group of children ≥ 1 year old, there is a higher proportion of less complicated and lengthy procedures, which leads to an a priori lower morbidity and mortality risk.
Furthermore, two subgroups are defined based on cardiovascular physiology: 1) children with biventricular surgical repair of a congenital heart defect versus 2) children after univentricular palliation of a congenital heart defect.
Sensitivity analysis
We expect to find studies with different levels of risk of bias. In that case, analysis will be repeated excluding studies with a high risk of bias.
