Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the following effects of administration of inhaled nitric oxide to infants and children with congenital heart disease and pulmonary hypertension in the postoperative period:
1. mortality prior to hospital discharge
2. long‐term mortality
3. length of intensive care unit or hospital stay
4. neurologic disability
5. arterial oxygenation and, or, saturation
6. mean pulmonary arterial pressure (MPAP), mean arterial (systemic) pressure (MAP), and heart rate (HR)
Subgroup analysis will be done for the following to observe the effects of inhaled nitric oxide:
1. placebo versus use of conventional management
2. specific age groups (0 to 3 months, greater than 3 months to 6 months, greater than 6 months to 12 months, greater than 1 year)
3. specific concentrations of iNO and length of administration of therapy
To evaluate the potential toxicity, measured as maximum serum concentration of methaemoglobin, of iNO versus placebo and, or, conventional management;
Background
Nitric oxide is an omnipresent molecule produced throughout the human body with a diversity of physiologic actions. One of particular interest involves its role as a mediator of vasodilation. Within vascular endothelial cells, nitric oxide synthase acts to convert L‐arginine and oxygen into nitric oxide and L‐citrulline. Nitric oxide then diffuses into vascular smooth muscle where it binds to soluble guanylate cyclase to convert guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP then mediates vascular smooth muscle relaxation (Steudel 1999). Exogenous, or inhaled nitric oxide (iNO), has a similar mechanism of action on the pulmonary vascular bed. After initiating vascular smooth muscle relaxation, however, the molecule diffuses into the bloodstream where it binds with iron in haemoglobin to form methaemoglobin, and is inactivated (Steudel 1999). As a result of its inactivation, the molecule exerts no vasodilatory effect on the systemic circulation. It is the unique property of iNO as a selective pulmonary vasodilator that has led to the investigation of its use in a myriad of paediatric and adult diseases complicated by pulmonary hypertension (Nelin 1998).
While the efficacy of iNO has been extensively investigated and substantiated in the treatment of persistent pulmonary hypertension of the newborn,(Clark 2000; Kinsella 1992; NINOS 1997; Roberts 1992; Roberts 1997) the extreme vasoreactivity of the newborn pulmonary vasculature has raised the question of whether or not iNO would be an effective treatment for pulmonary hypertension in more diverse populations and clinical scenarios (Haworth 1984; Steudel 1999). For example, pulmonary hypertension may arise in patients with congenital heart disease characterized by pulmonary over circulation. The increased pulmonary flow can potentiate remodeling of the vascular bed resulting in a persistence of elevated pulmonary arterial pressures, accelerating the need for operative intervention, and complicating postoperative recovery (Atz 1997). Also, the use of cardiopulmonary bypass during surgical repair can contribute to elevated pulmonary arterial pressures through induction of hypoxaemia, production of microemboli, and excess production of endothelin and thromboxane (Atz 1997). These factors may result in acute elevations in pulmonary vascular resistance that can impede cardiac output and precipitate life‐threatening crises (Jones 1981; Wheller 1979). These events occur postoperatively in approximately 7% of patients with congenital heart disease with an associated mortality rate of about 29% (Bando 1996). As a result, researchers and clinicians have investigated the use of iNO in the postoperative management of congenital heart disease as a means of reducing pulmonary vascular resistance and averting such complications.
In 1994, Journois et al. studied 17 infants with congenital heart disease and critical postoperative pulmonary arterial hypertension unresponsive to conventional therapies. Initiation of 20 parts per million (ppm) of iNO resulted in a decrease in mean pulmonary arterial pressure in all patients without significant change in systemic arterial pressure (Journois 1994). Similar findings were published by Miller et al. in a case series of 10 infants with congenital heart disease who were administered low dose (2, 10, 20 ppm) iNO in the postoperative period. In those patients with a high ratio of pulmonary to systemic artery pressure, there was a significant reduction in mean pulmonary vascular resistance with a subsequent rise in cardiac output (Miller 1994). A 1995 case series by Beghetti et al. also demonstrated a reduction in pulmonary artery pressure and an increase in arterial oxygen saturation without significant alteration in systemic vascular resistance with the use of continuous iNO in the postoperative period (Beghetti 1995). Around the same time, Curran et al. demonstrated a minimal benefit of iNO in patients who had undergone atrioventricular canal repair, and a significant reduction in pulmonary artery pressure in those with pulmonary hypertension refractory to conventional therapies (Curran 1995). Also of note is that no significant toxicities were noted in any of these case series with the use of the new treatment modality. As a result of the findings described above, several investigators undertook randomized controlled trials to more effectively evaluate the use of iNO to treat pulmonary hypertension in the immediate postoperative period of paediatric patients with congenital heart disease. The following systematic review will evaluate the results of these trials.
Objectives
To evaluate the following effects of administration of inhaled nitric oxide to infants and children with congenital heart disease and pulmonary hypertension in the postoperative period:
1. mortality prior to hospital discharge
2. long‐term mortality
3. length of intensive care unit or hospital stay
4. neurologic disability
5. arterial oxygenation and, or, saturation
6. mean pulmonary arterial pressure (MPAP), mean arterial (systemic) pressure (MAP), and heart rate (HR)
Subgroup analysis will be done for the following to observe the effects of inhaled nitric oxide:
1. placebo versus use of conventional management
2. specific age groups (0 to 3 months, greater than 3 months to 6 months, greater than 6 months to 12 months, greater than 1 year)
3. specific concentrations of iNO and length of administration of therapy
To evaluate the potential toxicity, measured as maximum serum concentration of methaemoglobin, of iNO versus placebo and, or, conventional management;
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) that compare use of inhaled nitric oxide with placebo or conventional management strategies (i.e. hyperventilation) and include at least one outcome of interest will be evaluated
Types of participants
Infants and children aged 1 day to 14 years with congenital heart disease requiring surgical repair and with subsequent evidence of pulmonary hypertension in the postoperative period will be included. No preterm neonates will be included in this analysis.
Types of interventions
The use of iNO in the postoperative period, given in various concentrations ranging from 1 to 80 parts per million (ppm) will be evaluated.
Placebo will be administered as nitrogen gas.
Therapy will be administered in the postoperative period to those identified with pulmonary hypertension. The initiation of iNO may take place in the operating room, recovery room, or patient room.
Timing of and criteria for evaluation of neurologic disability will be determined by those parameters defined in each trial
Pulmonary hypertension is diagnosed through the use of a pulmonary arterial catheter and defined as either a MPAP exceeding 50% of the MAP or a MPAP of greater than 25 millimetres of mercury
Conventional management will include hyperventilation to induce respiratory alkalosis, the use of sodium bicarbonate to induce metabolic alkalosis, use of intravenous inotropic and vasodilatory agents, and use of intravenous sedatives and neuromuscular blockades in an attempt to improve pulmonary blood flow.
Types of outcome measures
Primary:
-
Incidence of mortality prior to discharge;
-
Incidence of long‐term mortality;
-
Mean length of hospital stay;
-
Incidence of neurologic disability;
Secondary:
-
Change in mean pulmonary arterial pressure;
-
Change in arterial oxygen tension (PaO2);
-
Change in oxygen saturation;
-
Change in mean arterial pressure;
-
Change in heart rate;
-
Evaluation of methaemoglobin level as a determinant of potential toxicity (Methaemoglobin is formed by oxidation of the ferrous to the ferric state of haemoglobin to produce a compound which does not function as a carrier of oxygen. Levels of greater than 10% are considered toxic).
Search methods for identification of studies
We will search the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004), MEDLINE (January 1966 to July 1, 2004) and EMBASE (January 1980 to July 1, 2004). We will use filters to identify RCTs in MEDLINE (Dickersin 1994) and EMBASE (Lefebvre 1996). The searches will be limited to studies in humans. No language restrictions will be applied during the literature search or for trial inclusion. The reference lists of identified review articles and of all included studies will be searched in order to find other potentially eligible studies. Abstracts will be included. Reference lists from articles selected and from review articles, as well as conference abstracts, will be handsearched for relevant studies and all eligible studies will be retrieved in full. Personal communication with primary authors to identify unpublished data,when necessary, will be performed.
Strategy for Cochrane Central Register of Controlled Trials (CENTRAL)
#1 HEART DEFECTS CONGENITAL
#2 (congenital near heart)
#3 (heart near defect*)
#4 (heart near abnormal*)
#5 (#1 or #2 or #3 or #4)
#6 NITRIC OXIDE
#7 (nitric next oxide)
#8 ino
#9 (#6 or #7 or #8)
#10 (#5 and #9)
Strategy for MEDLINE (January 1966 to July 1, 2004)
1 exp Heart Defects, Congenital/
2 (congenital$ adj3 heart).tw.
3 (heart adj3 defect$).tw.
4 (heart adj3 abnormal$).tw.
5 or/1‐4
6 Nitric oxide/
7 nitric oxide.tw.
8 ino.tw.
9 or/6‐8
10 5 and 9
+ RCT filter terms.
Strategy for EMBASE (January 1980 to July 1, 2004)
1 exp Congenital Heart Disease/
2 (congenital$ adj3 heart).tw.
3 (heart adj3 defect$).tw.
4 (heart adj3 abnormal$).tw.
5 or/1‐4
6 Nitric oxide/
7 nitric oxide.tw.
8 ino.tw.
9 or/6‐8
10 5 and 9
11 random$.ti,ab.
12 factorial$.ti,ab.
13 (crossover$ or cross over$ or cross‐over$).ti,ab.
14 placebo$.ti,ab.
15 (double$ adj blind$).ti,ab.
16 (singl$ adj blind$).ti,ab.
17 assign$.ti,ab.
18 allocat$.ti,ab.
19 volunteer$.ti,ab.
20 Crossover Procedure/
21 Double Blind Procedure/
22 Randomized Controlled Trial/
23 Single Blind Procedure/
24 or/11‐23
25 exp animal/
26 nonhuman/
27 exp animal experiment/
28 or/25‐27
29 exp human/
30 28 not 29
31 24 not 30
32 10 and 31
Data collection and analysis
The standardized methods for conducting a systematic review as described by the Cochrane Collaboration in the Cochrane Reviewer's Handbook will be used (Alderson 2004).
Selection of studies
RCTs identified through electronic database and handsearching of journals will be read independently by two reviewers. Using inclusion and exclusion criteria defined above, a consensus will be reached between the reviewers as to which studies will be included in the review.
Quality assessment
The methodologic quality of each trial will be assessed by the reviewers following the guidelines described by the Cochrane Collaboration in the Cochrane Reviewer's Handbook (Alderson 2004). The following will be used as assessment criteria:
(1) method of randomization;
(2) allocation concealment;
(3) blinding of treatment;
(4) completeness of followup; and
(5) blinded outcome assessment.
Each reviewer will independently evaluate and rank the quality of each trial, with respect to allocation of concealment, as adequate (A), unclear (B), or inadequate (C). Major differences in methodological quality will be addressed by subgroup analysis. Conflicts in assessment will be resolved through discussion and, if necessary, through evaluation by a third party.
Data extraction
Data will be collected, through the use of a data extraction form, from each trial with respect to patient age, dose and duration of therapy (nitric oxide, placebo, conventional management), and outcome measurements which include incidence of mortality, followup assessment of neurodevelopmental outcome, length of hospital stay, in addition to mean pulmonary arterial pressure, heart rate, mean arterial pressure, arterial oxygen tension, oxygen saturation, and methaemoglobin level taken both at the initiation and termination of therapy.
Contacting trialists or authors
Authors of trials will be contacted by the reviewer, when necessary, to obtain raw data not presented in the trial but necessary for the analysis.
Data analysis
With respect to data analysis, the standardized methods of the Cochrane Neonatal Review Group will be employed (CNRG 2004). This includes, but is not limited to, considering which types of study design would be appropriate for the review and deciding how each will be addressed, determining the likely nature of outcome data (e.g. dichotomous, continuous etc), considering whether it is possible to specify in advance what treatment effect measures will be used, deciding how statistical heterogeneity will be identified, deciding whether random effects meta‐analyses, fixed effect meta‐analyses or both methods will be used, considering how clinical and methodological diversity (heterogeneity) will be assessed and whether (and how) these will be incorporated into the analysis strategy, deciding how quality of included studies will be assessed and addressed in the analysis, and deciding whether (and how) evidence of possible publication and, or, reporting biases will be sought.
For continuous data, a weighted mean difference with 95% confidence intervals will be calculated for each outcome described. For dichotomous data, relative risk, relative risk reduction, risk difference, and number needed to treat will be calculated when appropriate. A fixed effects model will also be used and a funnel plot analysis employed to identify and assess potential publication bias. Asymmetry in the funnel plot will be used as a marker for this type of bias. Testing for heterogeneity of treatment effect will be performed using a chi squared with two degrees of freedom. The I2 test will also be employed to measure the degree of inconsistency among results. Data will be considered highly suspicious if greater than 75% heterogeneity is identified. In this case, sensitivity analysis will be performed by excluding trials of lower methodological quality and reanalysing the data. Potential sources of heterogeneity among these studies include differential exposure intensity (i.e. dosing of iNO and length of treatment) and host factors (i.e. age, type of underlying cardiac disease) some of which will be addressed via subgroup analysis. Subgroups will be divided based on age (as described above in the "Objectives" section), concentration of iNO utilized, duration of iNO therapy, and by isolating and analysing those studies of highest methodological quality (i.e. omitting those studies without allocation concealment and reanalysing the data).
