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 improves the oxygenation and ventilation of infants and children with acute, hypoxemic respiratory failure

Ream RS, Hauver JF, Lynch RE, Kountzman B, Gale GB, Mink RB.

Crit Care Med 1999;27:989-995. [abstract]

Reviewed by Ron Sanders Jr., MD, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Review posted November 17, 1999

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I. What is being studied?:

The study objective:

To look at "the dose response of low concentration inhaled nitric oxide (NO) on a heterogeneous population of children with severe lung disease to determine the optimal dose of drug and the characteristics of responders."

The study design:

Two phases. Phase I: A prospective dose-response trial. Phase II: A prospective randomized evaluation of a selected group (responders).

The patients included:

26 patients between 1 and 218 months of age (median of 31 months) with acute severe respiratory disease as defined by failure to maintain a PaO2/FIO2 ratio 160, while receiving a FIO2 0.5 and a PEEP 7 cm H2O.

The patients excluded:

Patients with chronic lung disease requiring mechanical ventilation, uncorrected heart disease, cardiac surgery within the last 30 days, or other clinical evidence of primary cardiac disease.

The interventions compared:

Part A: Each patient received stepwise increases in NO of 1, 5, 10 and 20 ppm to minimize the time required to achieve steady state levels.

Part B: Positive responders (15% increase in PaO2 over baseline) were randomized to either conventional therapy with inhaled NO or conventional therapy alone. Conventional therapy defined as adjustment of PEEP to maintain PaO2 55-60 torr while minimizing FiO2 < 0.6, allowing permissive hypercapnia, reducing PIP and keeping pH 7.28. The dose of nitric oxide used (treatment group) was determined by individual maximal response.

The outcomes evaluated:

The primary outcomes measured in the first phase were PaO2 and PaCO2. Secondary parameters of interest included PaO2/FIO2 ratios, oxygenation index (OI), mean systemic arterial pressure, heart rate, peak expiratory flow rate and mean airway resistance. The main outcomes measured in the second phase were ventilator days and survival.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, randomization of a selected group (responders to NO) to either conventional management with prolonged NO therapy or conventional management alone was performed by a random number table.

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

Was followup complete?

Yes. In regards to responders who numbered 16 out of the original 26.

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

Yes, the patients were analyzed to the groups that they were randomized to in a proper intention-to-treat analysis. However, all the patients in part B were eligible for "rescue therapy" if the attending determined that they were candidates for ECMO during this phase. Thus, 2 patients in the treatment group (iNO) met "rescue therapy" criteria and received ECMO, but both died. Four patients in the control group (conventional therapy) received iNO as "rescue therapy" and only one died. No patient in the control group went on to receive ECMO after receiving iNO as "rescue therapy."

Secondary questions:

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

No. The actual titration of NO was a key to the study. PICU personnel would be able to distinguish between both arms of the study performed on "responders."

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

Yes. Differences in gender, PaO2, PaCO2, PaO2/FIO2, OI and roentgenogram findings were not significant. The patients did exhibit a significant range in age (1 to 218 months) and time between intubation and iNO (4 to 353 hours).

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

Unknown. The investigators experimental intervention intended to monitor conventional management with only NO therapy being different. Each participant was provided rescue therapy with either NO therapy for control failures and ECMO for either group if necessary. However, no additional information is provided in regards to nutritional support, hemodynamic issues, interim infections (besides primary diagnoses), sedation characteristics, etc.

III. What were the results?

1. How large was the treatment effect?

The authors used an increase of PaO2 15% over baseline as a "positive" response to NO therapy. However, no substantial physiological evidence for this level is provided. Nevertheless, the investigators noticed that 16 of 26 (62%) of their patients had a "positive" response. In addition, they observed that the majority of "responders" (56%) experienced a "positive" effect on PaO2 at 1 PPM of inhaled NO to attain the target 15% rise in PaO2.

No significant patterns could be observed in regards to either mortality or ventilation-dependent days with NO therapy.

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

The authors conclude that iNO will significantly improve indexes of oxygenation and ventilation in most patients. However, it is not likely that the study had an adequate sample size to demonstrate a difference in clinical outcome with only 8 patients in each group.

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

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

Yes. The study was performed in expected PICU population.

2. Were all clinically important outcomes considered?

Almost. While the authors provided background on the experienced mortality rates of other institutional observations, no mortality data from their own unit was provided. Ventilator-dependent days and mortality rates of the nonresponders should have been provided.

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

In the context of acute respiratory failure, benefits leading to meaningful decrease in ventilator-dependent days and/or mortality remain to be elucidated. The use of NO in severe forms of respiratory disease (i.e., ARDS) could potentially lead to significant harms and costs through unintended free radical generation. (1) Nevertheless, beneficial effects of nitric oxide have been demonstrated in patients with ARDS secondary to pulmonary insults in randomized, blinded phase II trials. (2)

Furthermore, Demirakca et al. demonstrated that effective doses of NO are between 5 to 10 ppm in pediatric patients and 20 ppm in neonates (with persistent pulmonary hypertension of the newborn), but systemic complications and mortality were not studied. (3)

The contribution of Ream and his colleagues has been the identification of doses that are effective below 5 ppm which may be beneficial in regards to limiting side effects. These findings will facilitate larger controlled studies in evaluating optimal dosing as well as outcomes.

References

1. Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Amer J Resp Crit Care Med 1994; 149:538-51. [abstract]
2. Dellinger RP, Zimmerman JL, Taylor RW, et al. 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 [see comments]. Crit Care Med 1998; 26:15-23. [abstract] [PedsCCM EB Journal Club Review]
3. Demirakca S, Dotsch J, Knothe C, et al. Inhaled nitric oxide in neonatal and pediatric acute respiratory distress syndrome: dose response, prolonged inhalation, and weaning. Crit Care Med 1996; 24:1913-9. [abstract]

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