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Randomized, prospective trial of oxygen, continuous positive airway pressure, and bilevel positive airway pressure by face mask in acute cardiogenic pulmonary edema.

Park M, Sangean MC, de S Volpe M, et al.

Crit Care Med. 2004 Dec;32(12):2407-15. [abstract]

Reviewed by Jason Kane MD, Medical College of Wisconsin, Milwaukee WI

Review posted May 6, 2005

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I. What is being studied?:

The study objective:

To compare the effects of oxygen versus continuous positive airway pressure (CPAP) versus bilevel positive airway pressure (bilevel-PAP) on the rate of endotracheal intubation in patients with acute cardiogenic pulmonary edema.

The study design:

A prospective, randomized, controlled trial performed at a single center in Sao Paulo, Brazil between January 1999 and August 2000.

The patients included:

Patients ≥ 16 years old, acute onset of severe respiratory distress (respiratory rate ≥ 25 breaths per minute), associated tachycardia and diaphoresis, and findings of pulmonary congestion on physical exam and chest radiograph who presented to an Emergency Department.

The patients excluded:

Patients with impaired level of consciousness at presentation; intractable vomiting; acute myocardial infarction with persistent ST segment elevation; systolic blood pressure < 90 mm Hg at presentation; decompensated pulmonary disease such as pulmonary embolism, chronic obstructive pulmonary disease, pneumonia, or pneumothorax.

The interventions compared:

Patients were randomized to receive either oxygen therapy alone by Venturi mask, oxygen with CPAP, or oxygen with bilevel-PAP. Patients were randomized after medical screening including arterial blood pressure, electrocardiogram, peripheral oximetry, and initiation of standard medical therapy including oxygen delivery by Venturi mask with FIO2 of 0.5, and sublingual administration of isosorbide dinitrate. Ventilatory support algorithms were employed in all three treatment groups and primary target was to maintain SpO2 at ≥ 90%.

The outcomes evaluated:

Primary endpoint was endotracheal intubation rate with secondary endpoints of in-hospital mortality and survival at 15 and 60 days.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomized with sealed envelopes using a 3:3:3 assignment scheme and then ventilatory support was applied according to randomization.

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

Was followup complete?

Yes. 400 patients were eligible for enrollment. 316 failed to meet inclusion criteria. 83 patients were ultimately enrolled. Only 3 patients were excluded from the eventual analysis.

One patient was excluded from the oxygen therapy group due to myocardial infarction with persistent ST segment elevation. Two patients were excluded from the bilevel-PAP group due to presence of decompensated COPD and pneumonia. 80 patients were included in the statistical analysis.

The study was stopped during the second interim analysis after 80 patients had been studied because of a significant difference in endotracheal intubation rates.

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

Yes, there were no cross-overs between groups.

Secondary questions:

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

No. No one was blinded to treatment modality. Endotracheal intubation was performed according to the judgment of the medical staff on duty without input from the researchers.

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

No. Baseline characteristics were similar among groups with respect to age, gender, APACHE II score, etiology of pulmonary edema, time until medical support initiated, presence of chest pain, blood urea nitrogen level, and creatinine level. However, more patients in the oxygen group had previous myocardial infarctions compared to the bilevel-PAP group (p < 0.05). This may have affected the outcome of patients randomized to this group. Also, patients in the bilevel-PAP and CPAP groups had more previous events of cardiogenic pulmonary edema compared to the oxygen group (p < 0.05).

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

Yes. There is mention of other aspects of patient care including medications and doses administered (Isosorbide dinitrate, morphine, furosemide, nitroprusside, nitroglycerin) and procedures performed within 12 hours (surgical myocardial revascularization, angioplasty, cardiac valvular surgery); none was statistically different between groups.

The investigators indicate that the investigator on call was only responsible for implementation of respiratory support, whereas the medical staff was responsible for other medical interventions including the decision about endotracheal intubation. This at minimum allows for the possibility of other interventions that were not included in the study results.

III. What were the results?

1. How large was the treatment effect?

The primary outcome measured was the rate of endotracheal intubation. During the first 24 hours after randomization CPAP and bilevel-PAP groups each had lower rates of intubation with 7% (2 in each group of 27 patients) compared to the oxygen group of 42% (11 of 26). Although not presented in the results, confidence intervals can be calculated from data provided in the article. (1)

Outcome	Oxygen Only	CPAP	Bi-PAP	P value
Intubation	42 %	7 %	7 %	0.001
Hospital Mortality	23 %	4 %	7 %	0.061

	Intubation	No Intubation
Oxygen (n=26)	11	15
Either CPAP or BIPAP (n=54)	4	50
		95% Confidence Interval
Absolute Risk Reduction	35%	15-55%
Relative Risk Reduction	83%	50-94%
NNT	3	2 to 7

	In-hospital Mortality	Alive at Discharge
Oxygen (n=26)	6	20
Either CPAP or BIPAP (n=54)	3	51
		95% Confidence Interval
Absolute Risk Reduction	18%	0.2-35%
Relative Risk Reduction	76%	11-94%
NNT	6	3-47

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

The number of patients needed to treat with CPAP or bilevel-PAP in order to prevent 1 intubation was 3. The 95% confidence interval suggests that the actual number of patients ranges anywhere between 2 and 7. The question of whether CPAP is more effective than bilevel-PAP remains unanswered in that the trial was insufficiently powered to demonstrate a difference between the CPAP and bilevel-PAP groups. The use of either CPAP or bilevel-PAP was associated with a significant reduction in intubation rates among patients. The study was stopped after the second interim analysis because of a significant difference in intubation rates between the groups.

Fifteen-day mortality was higher in the oxygen group, but this difference did not persist at hospital discharge. A decrease in hospital mortality was seen in the CPAP and Bi-PAP groups compared to the oxygen group, but the decrease was not statistically significant by chi square analysis. Of note, however, the lower limits of the 95% confidence intervals for the absolute risk reduction do not cross zero and the absolute risk reduction of in-hospital mortality could be as high as 35%. At minimum, there was a strong trend towards lower in-hospital mortality in patients who received CPAP or bilevel-PAP compared to oxygen therapy alone.

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

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

Maybe. This study included adult patients only. No pediatric patients were included in the trial. Although there are physiologic and anatomic differences between pediatric and adult patients, it is possible that the results of this study could be applied to pediatric cardiac patients with acute cardiogenic pulmonary edema. Adult patients are also more likely to cooperate with non-invasive ventilation compared to infants or young children. Using CPAP or bilevel-PAP appears to be a low risk intervention that may have significant benefit in preventing of intubation.

2. Were all clinically important outcomes considered?

Yes. The clinically relevant outcomes of intubation, duration of hospitalization, procedures performed, and complication rates were considered. Secondary outcomes of interim and in-hospital mortality were also measured. However, this study does not address whether CPAP is more or less effective than bilevel-PAP in the prevention of intubation in patients with cardiogenic pulmonary edema.

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

Yes. One previously published trial of non-invasive ventilation revealed concerns over safety. Mehta et al compared CPAP to bilevel-PAP but the study was stopped due to high incidence of myocardial infarction in the bilevel-PAP group.(2) A second trial by Masip et al compared bilevel-PAP to oxygen alone.(3) In that study there were no adverse effects associated with bilevel-PAP. In the present study there were no significant differences in adverse events associated with either CPAP or bilevel-PAP compared to oxygen therapy alone. Given the risks and complications associated with intubation and mechanical ventilation, the benefit of non-invasive ventilation in patients with cardiogenic pulmonary edema outweighs risks that were originally identified, but have not been reproduced in later studies.

References:

1. Newcombe RG. Interval estimation for the difference between independent proportions: Comparison of eleven methods. Statistics in Medicine. 1998. 17:873-890. [abstract]
2. Mehta S, Jay GD, Woodlard RH, et al. Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med. 1997. 25:620-628. [abstract]
3. Masip J, Betbese AJ, Paez J, et al. Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: A randomized trial. Lancet. 2000. 356:2126-2132. [abstract]

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