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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Intravenous Almitrine Combined with Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome

Gallart L, Lu Q, Puybasset L, et al.

Am J Respir Crit Care Med 1998; 158:1770-1777. [abstract] [full-text for subscribers]

Reviewed by Steven Cray MBBS FRCA, Birmingham Children's Hospital, UK

Review posted November 11, 1999

I. What is being studied?:

The study objective:

To examine, in patients with early adult respiratory distress syndrome (ARDS), the effects of almitrine, inhaled nitric oxide (iNO) and their combination on systemic oxygenation. The authors also investigated the dose-response of almitrine combined with nitric oxide and potential adverse effects of these agents.

Almitrine acts as a selective pulmonary vasoconstrictor (1) and stimulates peripheral chemoreceptors. It was used in some European countries in the 1980's in patients with hypoxemia secondary to chronic obstructive pulmonary disease. In the present study, the authors hypothesis was that the combination of almitrine and nitric oxide would produce pulmonary vasoconstriction in poorly ventilated areas of the lung and vasodilatation in well ventilated areas, leading to improved systemic oxygenation.

The study design:

Prospective non-randomized interventional study. There was no control group. Patients served as their own controls with before-after comparisons. The order of the intervention was not randomized within patients.

The patients included:

48 consecutive mechanically ventilated adult patients (age 56+/-14 yrs) with ARDS for < 72hrs according to the following criteria: (1) extensive bilateral pulmonary infiltrates, (2) PaO2/FiO2 < 150 without PEEP.

The patients excluded:

Patients with left ventricular dysfunction (pulmonary artery occlusion pressure > 18 mmHg, left ventricular ejection fraction < 50% by transesophageal echocardiography).

The interventions compared:

All patients were ventilated with 10cm PEEP and a minute volume necessary to maintain PaCO2 between 40 to 50 mmHg and peak airway pressure below 35 cm H2O for 24 hrs. FiO2 was set to 1.0. They then received iNO 5 ppm for 15 min, intravenous almitrine 4 mcg/kg/min for 1 hr and finally iNO 5 ppm combined with IV almitrine 4 mcg/kg/min for 15 min. On the next day, dose response to almitrine 2, 4 and 16 mcg/kg/min with and without iNO 5 ppm was studied in 30 patients.

After the study period, those patients deemed to have responded to iNO, almitrine or their combination were continued on that therapy until SaO2 was 90% with FiO2 0.4.

The outcomes evaluated:

Primary outcome measure:

Change in PaO2 after iNO, almitrine or their combination.

Secondary outcome measures:

Changes in hemodynamic and respiratory measurements:

Mean systemic and pulmonary arterial pressures

Cardiac index

Heart rate

Pulmonary shunt fraction

Mixed venous oxygen saturation

Alveolar dead space to tidal volume ratio

Pulmonary vascular resistance

Oxygen delivery and consumption

Plasma lactate concentrations during administration of almitrine 16 mcg/kg/min

Plasma almitrine concentrations during administration of varying doses of almitrine.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

No. The present study used the surrogate end point of an increase in PaO2 rather the clinically important end points of death or serious morbidity. Patients with ARDS frequently have multi-system disease and it is unusual that intractable hypoxemia is the direct cause of death. However, high inspired oxygen concentrations and high airway pressures may contribute to the development of long term pulmonary morbidity.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

In general, randomized controlled trials of various ventilation strategies (as an example of a different "drug" or intervention class) in patients with ARDS have not shown consistent correlations between improvements in PaO2 and mortality or morbidity.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Trials of nitric oxide in ARDS in adults have demonstrated short term improvements in oxygenation in some patients, but when nitric oxide was compared with placebo gas in a randomized controlled trial (2), there was no difference in morbidity or mortality between the two groups.

III. What were the results?

1. How large, precise, and lasting was the treatment effect?

PaO2 increased from 140+/-10 (mean +/- SEM) at baseline to 215+/-13 after iNO 5 ppm, 242+/-15 after almitrine 4 mcg/kg/min and 310+/-15 after iNO 5 ppm combined with almitrine 4 mcg/kg/min. Although each treatment caused significant improvements over baseline, and there appeared to be an additive effect between iNO and almitrine, no synergistic effect was demonstrated.

Defining a positive response to treatment as a >20% increase in PaO2 from baseline, 69% of patients responded to iNO and almitrine, 15% to iNO, but not to almitrine, 12% to almitrine, but not to iNO and 4% to neither drug.

The dose-response element of the study demonstrated that almitrine infusion rates between 2 and 4 mcg/kg/min were associated with a substantial increase in mean PaO2/FiO2 from baseline, with a much smaller additional increase in PaO2/FiO2 at an almitrine infusion rate of 16 mcg/kg/min.

Although the authors state that the mortality of patients entered in the study was 52%, no details are given of cause of death. Further, they do not give information about the subsequent course of those patients who continued to receive iNO, almitrine or the combination after the study period.

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

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

No. This study only involved adult patients. The effects of nitric oxide and almitrine on oxygenation cannot necessarily be extrapolated to children.

2. Were all clinically important outcomes considered?

No. This study only evaluated short term changes in oxygenation and other physiological parameters. ARDS is frequently part of multiple organ failure syndrome and improvements in PaO2 may have little effect on final outcome. The important outcomes of death or long term respiratory function were not addressed by this study.

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

Unclear. The present data show an impressive short-term increase in PaO2 after nitric oxide and almitrine, however there is no indication of whether this is sustained or whether it has any impact upon survival in ARDS. Potentially harmful adverse effects of almitrine which are not properly addressed by this paper include those on lactate metabolism and hepatic function [3], right ventricular strain secondary to increased pulmonary artery pressures and peripheral neuropathy with long term use.

A major problem with this paper is that nothing is randomized. Patients with ARDS frequently improve over time. How can we be sure that they were not just improving over time? It would have been better to show a dose-response relationship by putting the doses in a random order.

A randomized controlled trial of nitric oxide and almitrine in ARDS is justified to determine whether the impressive short term physiological effects of these agents translates into improved survival.

References

1. Melot C, Dechamps P, Hallemans R, Decroly P, Mols P. Enhancement of hypoxic pulmonary vasoconstriction by low dose almitrine bismesylate in normal humans. Am Rev Respir Dis 1989;139(1):111-9. [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. Crit Care Med 1998;26(1):15-23 [abstract] [PedsCCM EBJC Review]
3. B'chir A, Mebazaa A, Losser MR, Romieu M, Payen D. Intravenous almitrine bismesylate reversibly induces lactic acidosis and hepatic dysfunction in patients with acute lung injury. Anesthesiology 1998; 89(4):823-30. [abstract]

    

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