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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Aminophylline for the prevention of apnea during prostaglandin E1 infusion.

Lim DS, Kulik TJ, Kim DW, Charpie JR, Crowley DC, Maher KO.

Pediatrics. 2003 Jul;112(1 Pt 1):e27-9. [abstract]

Reviewed by Plato Alexander MD, Duke Children's Hospital, Durham NC

Review posted November 4, 2005

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I. What is being studied?:

The study objective:

To determine if aminophylline can be used to prevent apnea and intubation for apnea in neonates who are on prostaglandin E1 (PGE1) therapy for congenital heart disease.

The study design:

Single-center, placebo-controlled, prospective, double-blinded study

The patients included:

42 newborn infants with known or suspected ductal-dependent congenital heart lesions were enrolled. All patients were started on 0.01 mcg/kg/min of PGE1, and increased on an hourly interval to 0.03 mcg/kg/min or higher if clinically indicated.

The patients excluded:

Infants were excluded if they had prior initiation of PGE1, were transported from an outside facility, were already intubated or were thought to have impending cardiovascular collapse. 44 consents were obtained; however, 1 infant was excluded for intubation at birth. Another was inadvertently started on PGE1 therapy before being started on the study drug.

The interventions compared:

Patients were randomized to receive either aminophylline or placebo. The aminophylline arm consisted of a 6mg/kg iv bolus, followed by a 2 mg/kg iv dose every 8 hours for 72 hours. Serum aminophylline levels were followed in both arms, and a target drug level was set in the range between 6 and 12 mcg/mL.

The study drug was administered before or during initiation of PGE1 therapy.

The outcomes evaluated:

The primary outcome was intubation for apnea. Apnea was defined as no respiratory effort for >15 seconds, or no respiratory effort for > 10 seconds with associated bradycardia. Patients were intubated if they had apnea, recurrent apnea or hemodynamic instability. This is a clinical definition of course, and may have an element of subjectivity in its application.

The secondary outcome was apnea, i.e., acute cessation of breathing with associated hypoxia and bradycardia.

It should be noted that some may consider this definition of apnea to be too inclusive; more traditional definitions of apnea specify a minimum duration of 20 seconds or greater.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were prospectively randomized in a double-blinded fashion to receiver either aminophylline or placebo.

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

Was followup complete?

The study drug was discontinued at 72 hours after the first drug administration. A previous review of apneic events associated with PGE1 at the study institution found that all occurred within the first 48 hours of drug initiation.

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

Yes. There were no crossovers between study groups.

Secondary questions:

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

Yes. However, aminophylline can cause irritability in infants, and health workers may have detected this clinical finding (although this is not substantiated in the study). Aminophylline-induced tachycardia may also unblind the clinicians to the treatment assignment. The authors do not report the heart rates of the study infants.

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

The demographic data indicates that there were no statistically significant differences between the two groups in terms of birth weight, gestational age or hematocrit. They were also similar in their need for preoperative inotropic support, lowest arterial pH, antibiotic therapy, irritability, length of hospitalization, and survival to discharge. While there were no statistically significant differences in terms of cardiac diagnosis, there did appear to be a trend towards a skewed distribution of the fetal diagnoses of single ventricle (treatment group 9 vs. placebo group 16) and coarctation (treatment group 5 vs. placebo group 0).

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

Yes, probably. Since this was a heterogeneous group of patients, all management apart from the study drug and PGE infusions could not be standardized.

III. What were the results?

1. How large was the treatment effect?

Primary outcome: Intubation for apnea:

6 of the patients in the placebo group and none of the patients in the treatment group required intubation for apnea (P = 0.02)

	Quotient	Percentage	95% Confidence Interval
Intubation Event Rate for Placebo (ERp)	6/21	29%	(N/A)
Intubation Event Rate for Aminophylline (ERa)	0/21	0%	(N/A)
Relative Risk Reduction RRR = (ERp - ERa)/ERp	(29-0)/29	100%	[44.5-100]
Absolute Risk Reduction ARR = ERp - ERa	29-0	29%	[8.2-28.6]
Number Needed to Treat = 1/ARR	1/0.28	4 patients for 72 hours	[3.5-12.23]

6 of the patients in the placebo group and none of the patients in the treatment group required intubation for apnea (P = 0.02).

Secondary outcome: Study results for apnea:

11 patients in the control group and 2 patients in the treatment group developed apnea (P = 0.006)

	Quotient	Percentage	95% Confidence Interval
Apnea Event Rate for Placebo (ERp)	11/21	52%	(N/A)
Apnea Event Rate for Aminophylline (ERa)	2/21	9%	(N/A)
Relative Risk Reduction RRR = (ERp - ERa)/ERp	(52-9)/52	83%	[40.2-95.2]
Absolute Risk Reduction ARR = ERp - ERa	52-9	43%	[15.6-56.3]
Number Needed to Treat = 1/ARR	1/0.43	2 patients for 72 hours	[1.8-6.4]

When outcomes were stratified based on whether or not sedation was administered, statistical significance was lost.

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

The confidence intervals for all outcome measures were quite wide, likely due to the small numbers of patients.

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

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

These results can be applied to term neonates with ductal-dependent heart lesions who are born in-house. This assumes that they are not in imminent cardiovascular collapse and that they are on continuous cardiorespiratory monitoring.

All patients remained in-house and were not transported out of the facility. Therefore, the study does not address the safety or efficacy of using aminophylline to avoid prophylactic intubation for patients who will be transported while on PGE.

2. Were all clinically important outcomes considered?

Aminophylline has a known side effect of tachycardia, a potentially significant complication for a child with a congenital heart lesion. While patients were monitored for arrhythmias, heart rate trends were not reported in the study. This outcome would be of interest.

Other pertinent outcomes measurements such as length of stay and survival to discharge are needed to help discriminate whether this intervention has lasting benefit for these patients.

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

There are known significant side effects of aminophylline, some of which include fever, irritability, seizure, and dysrhythmias. Furthermore, drug monitoring is essential for patients so treated.

As indicated above, the definition of apnea was very inclusive, i.e. no respiratory effort for > 15 seconds. Therefore, events that met criteria here may not have satisfied other more traditional definitions of apnea. It is not clear how the use of a stricter definition of apnea would have changed their reported outcomes.

Despite these and the other above-mentioned concerns, the authors have presented data that indicate this treatment intervention is worthwhile - at least in the short term - for the stable, term neonate who is not in need of immediate transport. The physiologic, as well as financial, costs of an intubation that can be avoided (or delayed until the operating room) are likely more severe than the potential costs and harms of properly administered aminophylline therapy. The vast majority of these patients will be intubated for a surgical procedure in the first week or so life regardless. It remains to be demonstrated whether long-term outcomes are affected by this intervention.

Finally, many clinicians prefer to avoid intubating a preoperative patient for as long as possible. The rationale for this is that an intubated neonate frequently requires more sedation than one who is not intubated. Furthermore, the benefits of negative pressure ventilation on left-sided heart function and output, as well as on lung function, have been well documented in various texts. In contradistinction to negative pressure ventilation, positive pressure ventilation may hamper right-sided heart function, and can decrease venous return and preload to the heart. For this reason, a patient who has been intubated for apnea may require more inotropic support than a patient with similar physiology, but who has not needed intubation for drug-induced apnea.

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