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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Treatment of Acute Hypoxemic Nonhypercapnic Respiratory Insufficiency With Continuous Positive Airway Pressure Delivered by a Face Mask: A Randomized Controlled Trial

Delclaux C, L'Her E, Alberti C, et al.

JAMA 2000;284(18):2352-2360. [abstract][full-text]

Reviewed by Caroline Davison, MB Bch, FRCA (UK), Children's Hospital, Boston.

Review posted December 20, 2000

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I. What is being studied?:

The study objective:

To compare the physiologic effects and the clinical efficacy of CPAP vs standard oxygen therapy in patients with acute hypoxemic, nonhypercapnic respiratory insufficiency.

The study design:

Prospective, multi-center, randomized controlled, unblinded study

The patients included:

123 consecutive adult patients who were admitted to 6 intensive care with:

1. acute respiratory insufficiency, defined as the PaO2/FIO2 ratio of 300 mm Hg or less after breathing oxygen at 10 L/min or more for 15 minutes
2. the presence of bilateral lung infiltrates on a posteroanterior chest radiograph
3. randomization within 3 hours after the criteria were first fulfilled

(n = 102 had ALI and n = 21 with pure cardiac disease, only patients with cardiac disease and a possible superimposed non-cardiac cause of respiratory failure, cardiac patients who didn't respond to therapy or patients with previously unknown cardiac disease were included.)

The patients excluded:

1. patients younger than 18 years
2. intubation was refused or contraindicated
3. history of COPD
4. acute respiratory acidosis (defined as a pH < 7.30 and a PaCO2 > 50 mm Hg)
5. systolic blood pressure less than 90 mm Hg under optimal therapy (fluid repletion)
6. ventricular arrhythmias
7. coma or seizures
8. life-threatening hypoxemia (defined as an SaO2 < 80% with an oxygen mask)
9. use of epinephrine or norepinephrine
10. inability to clear copious airway secretions

The interventions compared:

Oxygen therapy alone vs. face mask CPAP and oxygen therapy.

CPAP was given via a face mask utilizing a Vital Signs device and a spring loaded PEEP valve. Patients were started at a CPAP of 7.5 cm H2O and could be decreased to 5 cm H2O or increased to 10 cm H2O at the discretion of the clinician on clinical grounds, there were no criteria on which to base this change.

CPAP was given continuously for the first 6 to 12 hours and then intermittently depending on patient tolerance and ability to maintain a saturation greater then 90% on oxygen alone. CPAP was continued for a minimum of 6 hours per day until intubation, death or fulfillment of predetermined cessation criteria indicating improvement of their lung disease.

The goal in both treatment groups was to maintain saturations greater than 90%.

The outcomes evaluated:

Primary outcome

Endotracheal intubation

Secondary outcome measures

Improvement in PaO2/FIO2 ratio

Adverse events

Length of hospital stay

Mortality

Duration of ventilatory assistance

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. A computer generated randomization process was used to assign patients to their treatment groups. The randomization was stratified to ensure patients with underlying cardiac disease were equally distributed in both groups. It was also stratified based on the center.

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

Was followup complete?

Yes. 123 were registered and 123 were analyzed for the results.

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

Yes. Although 5 of the patients from the oxygen alone group received noninvasive ventilation and 2 patients, 1 patient from each group, were found after inclusion in the trial to meet exclusion criteria. However, excluding these patients or switching them to the other group had no significant effects on outcomes.

They were analyzed on an intention-to-treat basis.

Secondary questions:

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

No. It is impossible to blind patients and health care workers to the use of a CPAP mask.

The individuals who assessed the outcomes were blinded to the treatment; the article states they only had access to the medical charts.

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

Yes. The patients were similar for age, sex, PaO2/FiO2, Simplified Acute Physiology Score (SAPS) II, Logistic Organ Dysfunction score, and preexisting cardiac disease.

The SAPS and LOD scores were calculated without including the points for respiratory failure, as CPAP gives a score in itself.

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

Yes. Criteria for intubation were the same for each group, and included decreased alertness or major agitation requiring sedation, clinical signs of exhaustion, hemodynamic instability, cardiac arrest, or refractory hypoxemia (SaO2 < 85% with FIO2 of 100%).

All patients with suspected cardiac insufficiency received diuretics as required. Infectious causes were treated with antibiotics.

III. What were the results?

1. How large was the treatment effect?

Although there was an initial physiological and subjective improvement in the CPAP group after the first hour of treatment compared to the standard group there was no significant differences found between the 2 treatment groups for any of the clinical outcome variables studied.

However there were significantly more adverse events in the CPAP group; (18 [29%] vs. 6 [10%]; p = 0.01).

Adverse effects in the CPAP group included facial necrosis (2), gastric distension (1), cardiac arrest (4 vs. 0 in oxygen group; 3 of the arrests were at the time of intubation and 1 when the mask was removed), pneumothorax (1) and a stress ulcer (4).

Treatment with CPAP failed to reduce:

1. Endotracheal intubation rate (21 [34%] vs 24 [39%] in the standard therapy group; P = 0.53)
2. Hospital mortality (19 [31%] vs 18 [30%]; P = 0.89)
3. Median (5th-95th percentile) intensive care unit length of stay (6.5 [1-57] days vs 6.0 [1-36] days; P = 0.43)

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

This was a negative study which showed no benefit from face mask CPAP over oxygen therapy alone. In fact this study showed an increase in adverse events in the CPAP group.

It is possible that this study was underpowered to show a modest reduction in intubation rate. The size of the study group was chosen to show a difference in intubation rate from 40% to 15% and in fact the intubation rate in the CPAP group was 34%.

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

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

No pediatric patients were included in the study. However, face mask CPAP is a therapy which is utilized in pediatric intensive care. Previous studies have suggested that face mask CPAP is useful at lowering the intubation rates in hypercapnic ventilatory failure only, and as yet there is no evidence for its use in other forms of respiratory failure including cardiogenic pulmonary edema, neuromuscular failure and asthma (1). Despite the lack of evidence to support its use, CPAP continues to be used in these settings. This study in nonhypercapnic respiratory failure which shows no decrease in intubation rates and a significant increase in adverse events including cardiac arrest will make me examine the indications for CPAP in my own practice, and be aware of the risks.

2. Were all clinically important outcomes considered?

Yes. The authors looked at all relevant outcomes including endotracheal intubation, length of ventilatory support, mortality, morbidity, and length of hospital stay.

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

The results form this study would suggest that CPAP is not as innocuous a therapy as it may seem with significantly more adverse events occurring in the CPAP group (P = 0.01), including 4 cardiac arrests and 4 GI bleeds. As the authors suggest, it may be that these events represent the fact that CPAP allows an increased length of time spontaneously breathing prior to intubation and thus an increased period of physiological stress. Delaying the time to intubation may lead to the patient being more unstable than if CPAP had not been tried, although the survival curves do not seem to indicate that the CPAP patients "lasted longer" prior to intubation.

References:

1. Keenan S. Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure. JAMA 2000; 284: 2376-2378. [citation]
2. Keenan SP, Brake D. An Evidence Ð Based Approach to Noninvasive Ventilation in Acute Respiratory Failure. Crit Care Clin 1998; 14:359-372. [abstract]

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