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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Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.

Taylor RW, Zimmerman JL, Dellinger RP, et al.

JAMA. 2004 Apr 7;291(13):1603-9 [abstract]

Reviewed by Renán Orellana MD, Baylor College of Medicine, Houston TX

Review posted February 27, 2005

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I. What is being studied?:

The study objective:

To evaluate the clinical efficacy of low-dose (5 ppm) inhaled nitric oxide (iNO) in patients with acute lung injury (ALI).

The study design:

Multicenter, randomized, triple-blinded, placebo-control study, conducted in multi-disciplinary ICU's of 46 academic, teaching, and community hospitals in the USA.

The patients included:

Adult, non-pregnant individuals from 46 hospitals with moderately to severe acute lung injury (ALI) (PAO2/ FIO2 < 250) developed in the preceding 72 hours of randomization, and due to cases other than sepsis, but resulting from at least one of the following: pneumonia, aspiration pneumonitis, toxic gas inhalation, pulmonary contusion, acute pancreatitis, massive blood transfusion, multiple trauma, surgery, fat emboli, post-partum ALI. Subjects were selected regardless of PEEP used in their management.

The patients excluded:

All patients with evidence of non-pulmonary system failure, sepsis induced ARDS, hypotension, high output failure, severe head injury, and immunocompromise were excluded from selection.

The interventions compared:

The effects of low-dose (5 ppm) inhaled NO versus placebo gas until ending the trial at 28 days, death, or adequate oxygenation achieved.

The outcomes evaluated:

The primary effectiveness endpoint was the duration of mechanical ventilation measured by the number of days patients were alive and not receiving assisted breathing, defined as 72 hours after extubation or the reduction of both pressure support and continuous positive airway pressure to 5 cm H2O or less in patients with tracheotomies. When death shortened the duration of mechanical ventilation, the numbers of days alive were measured from the time the patient was both alive and not receiving assisted breathing until the end of the 28 days.

Secondary endpoints were mortality, days patients were alive and meeting oxygenation criteria for extubation, and days patients were alive following a successful unassisted ventilation test.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. They received gas labeled only with patient code and study codes without designation of contents. The randomization occurred at the manufacturing plant, and utilized a concealed allocation of gas cylinders.

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

Was followup complete?

Yes. No patients were lost to follow-up or withdrew from the study. The followup was complete in all patients for the 28 days of the study for 193 patients assigned to placebo (22 with protocol violations) and 192 assigned to iNO (9 with protocol violations).

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

Yes. Analysis was by intention-to-treat (all patients randomized were analyzed).

Secondary questions:

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

Yes. The study was triple blinded (patients, clinicians, and investigators were blinded to treatment). The degree of blinding is a strength of this study.

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

Yes. There was no difference between placebo and treatment groups in patient baseline characteristics for demographics cause of ARDS, and pulmonary variables that described ventilatory support. There was a statistical difference in wedge pressure between the two groups (29 vs 31) however, it is extremely doubtful this difference was clinically important.

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

At least for mechanical ventilatory support, the participants agreed to use rather general guidelines for prioritizing support of patients with acute lung injury; however, no comment is made regarding how well these recommendations were followed. Practice variation in different institutions for the management of other systems is not specified and may have affected patient outcomes.

III. What were the results?

1. How large was the treatment effect?

This is a negative study when related to the primary and secondary endpoints. Inhaled NO did not affect the duration of mechanical ventilation, mortality, or the days alive without assisted breathing when compared to placebo (see below).

Outcome	Placebo (n=193)	iNO (n=193)	P value
Days alive without assisted breathing, mean (SD)	10.6 (9.8)	10.7 (9.7)	0.97
Mortality, N (%)	39 (20)	44 (23)	0.64

However, it appears that the group of patients that received iNO had an increased number of unspecified infections (34% vs. 21%) to which the authors do not discuss in details. This translates into a relative risk of 1.6 and an absolute risk increase of infection of 13%.

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

The authors report an increase number of infections, without further stratification of the source, in the iNO group.

	Infection	No Infection
iNO	66	126
Control	41	152
		95% CI
RRI:	0.618	[0.16-1.26]
ARI:	13%	[4-22%]
NNH:	7	[5-23]

It appears that for every 7 patients that receive iNO, one has a risk of developing an infection of some type. The confidence interval for the absolute risk increase ranges from 4% to 22%; that it does not cross zero implies statistical significance. The authors state that they found the infections not related to gas administration, but do not specify this further.

The authors also report an increase in respiratory system events in the control group. However, the confidence interval for the NNT is wide, which suggest that such events are not prevented by therapy, and they accept that it resulted from other clinical factors in the control group (see below).

	Respiratory events	No events
iNO	98	94
Control	118	75
		95% CI
RRI:	0.165	[0.0002-0.3]
ARI:	10.1%	[0.2-20%]
NNH:	9	[5-500]

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

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

Yes. Low-dose iNO does not improve mortality nor decreases ventilatory support in adult patients with ALI. This correlates with prior studies by the same group of investigators and others in adults and children (1,2). Using iNO in the setting of respiratory failure in adults can increase cost utilization without improving outcomes, and the existing evidence suggests that this applies to children as well. In pediatrics, it is recognized that there is a transient improvement in ventilation and reduction of FiO2, without improvement on mortality rates or the duration of mechanical ventilatory support (1,3,4).

2. Were all clinically important outcomes considered?

Yes. The clinically relevant outcomes of duration of ventilatory support and mortality were considered, as well as secondary endpoints such as days patients were alive and meeting oxygenation criteria for extubation and days patients were alive following a successful unassisted ventilation test.

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

No. The use of iNO in adult patients with ALI does not improve relevant outcomes, the treatment is costly, and there is an unexplained increase in the risk of infection in iNO treated adult patients.

References:

1. Sokol J, Jacobs SE, Bohn D: Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults (Cochrane Review). In: The Cochrane Library, Issue 2. Chichester, UK, Wiley, 2004 [abtract]
2. 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 Jan; 26(1):15-23. [abstract]
3. Fioretto JR, de Moraes MA, Bonatto RC, et al: Acute and sustained effects of early administration of inhaled nitric oxide to children with acute respiratory distress syndrome. Pediatr Crit Care Med 2004; 5:469Ð474 [abstract]
4. Marraro, G: Do we really need more confirmation on the usefulness of inhaled nitric oxide in children's acute respiratory distress syndrome? (Editorial) Pediatr Crit Care Med 2004 Sep; 5(5):496-7. [citation]

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