Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study

Miller OI, Tang SF, Keech A, Pigott NB, Beller E, Celermajer DS.

Lancet 2000;356:1464-1469. [abstract]

Reviewed by Kshama Daphtary, MD and Kathleen Meert, MD, Children's Hospital of Michigan.

Review posted January 15, 2001

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I. What is being studied?:

The study objective:

To determine whether the administration of inhaled nitric oxide immediately after corrective heart surgery prevents pulmonary hypertensive crises (PHTC) in infants with congenital heart disease and history of preoperative pulmonary hypertension.

The study design:

Prospective, double-blind, randomized placebo-controlled study.

The patients included:

Infants with congenital heart lesions that were suitable for corrective heart surgery, with high pulmonary flow, pressure, or both, and with objective evidence of pulmonary hypertension at the immediate preoperative assessment, were eligible for the study. Suitable heart lesions included non-restrictive ventricular septal defect, complete atrioventricular septal defect, truncus arteriosus, and total anomalous pulmonary venous return. Pulmonary hypertension was defined as a mean pulmonary artery pressure higher than 25 mm Hg or, when estimated by echocardiography, pulmonary artery pressure more than half the systemic artery pressure.

One hundred twenty four of 130 eligible patients were randomized prior to surgery. Parental consent could not be obtained for the other 6 patients.

The patients excluded:

No patients were excluded except those for whom parental consent could not be obtained.

The interventions compared:

Nitric oxide (10 ppm) was compared to a nitrogen placebo. Study gases were administered by continuous inhalation that began immediately after surgery and stopped just before extubation. Study gases were delivered to the first 40 patients via a simple calibrated flow meter and mixing chamber, and were monitored by a commercially available electrochemical device. Subsequent patients received study gas via an integrated dosing, delivery, and analysis system. When the infants were eligible for extubation, the flow of the study gas was reduced by 20% each hour, aiming for discontinuation of the study gas after 4 hours. If major PHTC occurred, the weaning process was suspended for an hour. Instability after three successive attempts to wean led to a 12-hour pause. The maximum duration of study gas administration was set at 7 days.

The outcomes evaluated:

1. Primary outcome: Number of PHTC
2. Main secondary outcome: Time until objective criteria for extubation were met

PHTC were defined as episodes in which the pulmonary/systemic artery pressure ratio was > 0.75. Episodes were classified as major if there was a fall in the systemic artery pressure > 20%, a fall in the transcutaneous oxygen saturation to < 90%, or both. Episodes were classified as minor if the systemic artery pressure and transcutaneous oxygen saturation remained stable.

Predefined criteria for extubation were as follows: hemodynamic stability (an absence of major PHTC during the previous 6 hours, hourly urine output > 0.5 mL/kg, no acidosis, mean systemic artery pressure within age-related normal values); and satisfactory gas exchange (partial pressure of carbon dioxide < 6.0 kPa, and of oxygen > 13.3 kPa, and spontaneously breathing an inspired oxygen fraction < 0.40 at a mechanical ventilation rate of < 8 breaths per minute).

Other secondary outcomes were:

1. Use of open-label nitric oxide (10 ppm) as rescue gas for persistent or recurrent major PHTC, associated with clinical deterioration and unresponsive to conventional treatment
2. Time required for weaning from the study gas, and the total time on study gas
3. Proportion of patients still ventilated at the end of the 7 day study period
4. Duration of intubation
5. Time to discharge from the intensive care unit
6. Number of deaths, and deaths from PHTC

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomized prior to surgery using a computer-based algorithm. Randomization was stratified based on the presence or absence of Down's syndrome.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, all randomized patients were followed for the duration of their intensive care stay and were included in the analysis. The time period during which mortality was assessed is not clearly stated. One patient died 42 days postoperatively but it is unknown whether all patients were followed for this duration.

Were patients analyzed in the groups to which they were randomized?

Yes, patients were analyzed in the groups to which they were randomized. Sixty-three patients were randomized to the nitric oxide group and 61 patients to the placebo group.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes, patients, health workers and study personnel were "blind" to treatment. Nitric oxide and nitrogen were provided in identical coded cylinders. The displays on the gas monitors were masked with locked opaque covers. A non-clinical investigator supervised randomization and preparation of the gas cylinders and set up gas delivery and the monitoring circuit for each patient.

4. Were the groups similar at the start of the trial?

Both groups were similar with respect to age, baseline pulmonary and systemic artery pressures, pulmonary and systemic vascular resistance indices, sex, and proportion of patients with Down's syndrome. Although there were no statistically significant differences between the groups, the nitric oxide group appears to have a greater proportion of patients with ventricular septal defect (46% vs 31%), and lower proportion with truncus arteriosus (13% vs 21%) and total anomalous pulmonary venous drainage (9% vs 18%) compared to the placebo group. The lack of significance was likely due to the small numbers involved.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. Surgery and anesthesia were done in a way routine for the authors' institution. Both groups were managed according to the same protocols for routine postoperative care and pulmonary hypertension with instability. These protocols included sedation, ventilation, and use of inotropic and vasodilator agents. Persistent or recurrent major PHTC, associated with clinical deterioration unresponsive to maximum conventional treatment, was treated with open-label inhaled nitric oxide (10 ppm) as rescue gas in addition to study gas. The attending physician decided the duration of rescue therapy. This rescue therapy did not compromise the treatment group assignment or masking; control patients who received rescue therapy were therefore not considered crossovers.

III. What were the results?

1. How large was the treatment effect?

	Nitric oxide group (n = 63)	Placebo group (N = 61)
Number of PHTC per patient	4 (0-12)*	7 (1-19)
Time to eligibility for extubation (hours)	80 (38-121)*	112 (63-164)
Time required for weaning from study gas (hours)	4 (4-5)	4 (4-4)
Total time on study gas (hours)	87 (43-125)*	117 (67-168)
Duration of intubation (hours)	117 (70-173)	140 (86-214)
Time to discharge from ICU	138 (89-192)	162 (96-222)
Number requiring rescue gas	2	5
Number of patients ventilated at day 7	6*	16
Number of deaths	5	3
Number of deaths from PHTC	1	1

Data represent the median and interquartile range, or the number in each category. Statistically significant differences between treatment groups are denoted by an asterisk (*).

The nitric oxide group had an ARR (absolute risk reduction) for requiring rescue gas of 5%, RR (relative risk) of 38.7%, RRR (relative risk reduction) of 61.3% and NNT (number needed to treat) of 20. The nitric oxide group had an ARR for being ventilated at day 7 of 16.7%, RR of 36.5%, RRR of 63.5%, and NNT of 5.9. The nitric oxide group had an ARR for mortality of Ð3% (ARI- absolute risk increase- of 3%), RR of 161%, RRR of Ð61% (RRI of 61%), and NNT of Ð33 (NNH- number needed to harm- of 33).

2. How precise was the estimate of the treatment effect?

Confidence intervals for ARR

	ARR	95% CI
Number requiring rescue gas	5%	-3% to 13%
Number of patients ventilated at day 7	16.7%	3.5% to 30%
Number of deaths	-3%	-11.6% to 5.6%

Confidence intervals for RR

	RR	95% CI
Number of PHTC per patient (non-adjusted)	66%	59-74%
Number of PHTC per patient (adjusted for dispersion)	65%	43-99%
Number requiring rescue gas	38.7%	7.8%-192%
Number of patients ventilated at day 7	36.5%	15.3% to 86.9%
Number of deaths	161%	40% to 640%

Confidence intervals for RRR

	RRR	95% CI
Number requiring rescue gas	61.3%	-92% to 92%
Number of patients ventilated at day 7	63.5%	13.1% to 84.7%
Number of deaths	-61%	-540% to 60%

Confidence intervals for NNT

	NNT	95% CI
Number requiring rescue gas	20	8 to infinity
Number of patients ventilated at day 7	5.9	3.3 to 28.6
Number of deaths	33 (number needed to harm)	9 to infinity

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Yes. The study included infants with congenital heart disease who were at high risk for developing PHTC in the postoperative period. The study population appeared similar to our patients undergoing congenital heart surgery as well.

2. Were all clinically important outcomes considered?

Yes, all clinically important outcomes were considered.

3. Are the likely treatment benefits worth the potential harms and costs?

No. The routine postoperative administration of inhaled nitric oxide in infants with congenital heart disease and a history of preoperative pulmonary hypertension cannot be recommended from this study. Inhaled nitric oxide decreased the number of PHTC but did not reduce the duration of intubation or length of stay in the ICU. More infants in the nitric oxide group died, although the deaths were not directly attributable to nitric oxide use. Nitric oxide gas is expensive. Since nitric oxide, when used as a preventative therapy, has not been shown to reduce mortality or length of stay, its routine use is not warranted.

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