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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury.

Dahlem P, van Aalderen WMC, de Neef M, Dijkgraaf MGW, Bos AP.

Crit Care Med 2004; 32:1055-1060. [abstract]

Reviewed by Ayse Akcan Arikan MD, Baylor College of Medicine, Department of Pediatrics, Critical Care Section, Texas Children's Hospital

Review posted December 16, 2004

---

I. What is being studied?:

The study objective:

To determine whether aerosolized prostacyclin will acutely improve oxygenation in children with acute lung injury (ALI).

The study design:

Single center, prospective, randomized, crossover double blind study

The patients included:

14 patients (out of 15 eligible admitted between 1999-2002) who met criteria for ALI (acute onset respiratory failure, P/F ratio ≤ 300 torr (in two consecutive measurements at least 8 hours apart), no clinical signs of atrial hypertension [if left heart failure was suspected on a clinical basis, this was confirmed or not by an echocardiogram] and presence of bilateral infiltrates on CXR) were randomized after the first 24 hours in the ICU

The patients excluded:

1. Left heart dysfunction (mitral regurgitation and/or enlarged left atrium) and/or a shortening fraction < 30%.
2. patients intubated with small endotracheal tubes (ETT < 3.5 cm)
3. patients with thrombocytopenia, bleeding diatheses or coagulopathy, intracranial hemorrhage, congenital heart disease, or acute renal failure
4. patients who had a poor prognosis with a high probability of death or withdrawal in the next 24 hours

The interventions compared:

Inhalational administration of nebulized dose-escalating prostacyclin was compared within each patient to nebulized saline.

There were two groups in crossover design. Group 1 (designated as the placebo group) received 5 incremental doses of prostacyclin followed by saline. Group 2 received the treatments in reverse order, that is, five doses of saline were followed by the 5 incremental doses of prostacyclin.

The outcomes evaluated:

Primary outcome: Improvement in oxygenation index (OI) immediately after the nebulized treatment was the main outcome variable. OI is a measurement of oxygenation on mechanical ventilation, OI= mean airway pressure x 100 x fraction of inspired oxygen(FiO2)/ PaO2

Secondary outcomes:

1. Hemodynamic variables (heart rate, mean arterial pressure) aiming to detect spillover of the aerosolized medication into the systemic circulation.
2. Changes in ventilator settings (FiO2, tidal volume, mean airway pressure, PEEP, PIP) and arterial blood gas variables were also recorded and compared between the two groups.
3. In 9 of the 14 patients, flow/volume loops on the ventilator screen were inspected by investigators before and after each nebulization to detect the presence of flow limitation

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the patients were randomized to treatment groups by sequentially numbered envelopes "following a crossover randomization procedure described by Altman" (1)

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

Was followup complete?

Yes, all fourteen patients were accounted for at the end. The data was collected immediately, so there was no follow-up needed.

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

Yes, there was no cross-over between group assignment, but this was designed as a cross-over study; both groups got drug and placebo.

Secondary questions:

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

Yes, the medications were prepared by the pharmacy in identical vials so as to blind the investigators and the caregivers.

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

Unclear. Although the authors provide us with demographic information about the study participants, these data do not include group assignments. However, it appears that the patients in Group 2 had significantly higher OI's throughout the trial. The reason for this difference is uncertain, perhaps initial saline nebulization worsened oxygenation further in this group of patients. It also seems that Group 2 has fewer patients with secondary lung injury compared to Group 1.

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

Unclear. Ventilator adjustments as required by the changing patient status were done by the attending physicians. However, since there were no detectable differences between the two groups regarding ventilator settings and blood gas measurements, we can assume that the two groups were treated similarly regarding ventilatory management. Apart from this, we do not have further data regarding the details of patient care management (e.g. fluid regimen used, pressor/inotrope requirement, etc). Since each patient was his own control, the real question is whether the patient's care was different while receiving placebo vs. drug. Since it was a blinded study, hopefully there was no difference.

III. What were the results?

1. How large was the treatment effect?

(To correct for the multiple comparisons made (five different dosages of study medication), the authors chose p< 0.01 to be statistically significant. )

Primary outcome: Of the different dosages used, prostacyclin improved oxygenation index values over saline placebo by 26% at 30 ng/kg/min. At this dose, there were eight children who showed a 20% improvement in OI in response to prostacyclin. The NNT was 1.8. If these data were correct, we would have to treat 1.8 children with aerosolized prostacylin at 30 ng/kg/min to see a 20% improvement in oxygenation in one child.

Although there was a trend toward improvement in OI at doses of 20, 40 and 50 ng/kg/min, the differences did not reach statistical significance perhaps due to the small sample size of this study.

It is not clear why the improvement in OI was only notable with a single does of prostacyclin, and only in Group 2. All the OI changes in Group 1 appear minimal, ranging from means of Ð0.1 (a miniscule worsening with treatment) to 0.6, while Group 2's improvements in OI at different dosages range from 1.3 to 6. It may be due to Group 2's OI's being higher throughout the study (with more room for improvement). It appears that patients given 5 doses of nebulized saline first may have been made much worse, and then demonstrated some improvement with prostacyclin. There was very little improvement in oxygenation in patients given prostacyclin first. It is possible that patients who received prostacyclin first continued to experience beneficial effects even after receiving saline nebulization, possibly secondary to on-going drug effect. The patients in Group 2 seem to respond to escalating doses of prostacyclin, with a plateau at 30 ng/kg/dose.

Secondary outcomes: No changes were observed in heart rate, mean arterial blood pressure, ventilation, F/V curves, and respiratory variables (Paw, FiO2, arterial pH) during the study.

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

We might have to treat as few as 1.2 and as many as 3.2 cases to see a 20% improvement in OI in one patient. I am not sure that the small number of patients allows a true precision analysis.

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

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

Perhaps. The results of this trial should be interpreted carefully. Even though the study population seems to be a good mix of patients typical of a tertiary pediatric ICU, the sample size is very small. In addition, the major outcome variable was very acute improvement after administration of the selective pulmonary vasodilator, namely the investigators measured the OI directly after aerosol delivery. It is unclear whether this short-term improvement in oxygenation will be sustainable. It must be pointed out however, that several studies have found inhaled prostacyclin to be equally efficacious to inhaled nitric oxide (iNO) (2, 3). Therefore, inhaled prostacyclin can be an alternative selective pulmonary vasodilator especially for those selected ICUs not equipped for iNO administration.

If we choose to look at this study as a phase I study of prostacyclin use in kids, prostacyclin appears to be quite safe. At the dosages used, there were no hemodynamic changes observed. There are no bleeding incidents reported, and in 9 of 14 patients in the study group, there were no changes in airway reactivity according to F/V curves. The efficacy data might provide a justification for the next phase.

2. Were all clinically important outcomes considered?

No, the authors chose to focus on improvement in oxygenation as their major outcome variable. However, multiple studies in adults done with other selective pulmonary vasodilators (e.g., iNO) have demonstrated that improvement in oxygenation does not always translate into improvement in long-term outcome such as decreased morbidity/mortality or shorter ICU stay (4-6). The authors correctly point out that other clinically relevant outcomes such as change in duration of ICU and hospital stay and cost savings need to be studied. However, given the relatively low incidence of acute lung injury in the pediatric population, these outcomes would be better investigated with larger multi-center trials.

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

There were no adverse effects demonstrated with inhaled prostacyclin administration . The lower cost and the simple administration as nebulization directly into the ventilator tubing make prostacyclin an attractive option. However, what remains to be determined is whether a maneuver such as selective pulmonary vasodilatation (with iNO or prostacyclin) aimed at improving oxygenation in the short term will actually improve long-term clinically important outcomes.

References:

1. Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos AP: Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Crit Care Med 2004, 32(4):1055-1060. [abstract]
2. Van Heerden PV, Blythe D, Webb SA: Inhaled aerosolized prostacyclin and nitric oxide as selective pulmonary vasodilators in ARDS--a pilot study. Anaesth Intensive Care 1996, 24(5):564-568. [abstract]
3. Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W: Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 1996, 153(3):991-996. [abstract]
4. Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K, Jr., Kelly KM, Smith TC, Small RJ: Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004, 291(13):1603-1609. [abstract]
5. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K, Jr., Hyers TM, Papadakos P: Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998, 26(1):15-23. [abstract]
6. Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Charbonneau M, Blaise G: Should we treat acute respiratory distress syndrome with inhaled nitric oxide? Lancet 1997, 350(9071):111-112. [citation]

Comments

Back to the EB Journal Club Index