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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Noninvasive ventilation in cardiogenic pulmonary edema: a multicenter randomized trial.

Nava S, Carbone G, DiBattista N, et al.

Am J Respir Crit Care Med. 2003 Dec 15;168(12):1432-7 [abstract]

Reviewed by Linda Thompson MD, Baylor College of Medicine, Texas Children's Hospital, Houston TX

Review posted October 14, 2004

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I. What is being studied?:

The study objective:

The authors aimed to assess the feasibility of initiating Noninvasive Pressure Support Ventilation (NPSV) outside of the ICU (for example, in the Emergency Room) and to evaluate differences in mortality and intubation rate in patients receiving Standard Treatment versus Standard Treatment with NPSV.

The study design:

Multicenter, randomized, prospective clinical trial

The patients included:

130 consecutive patients recruited from 5 emergency departments with acute cardiogenic pulmonary edema and:

1. Severe acute respiratory failure (Pa02 / Fi02 < 250),
2. Breathing oxygen < 10L / minute for at least 15 minutes,
3. Dyspnea of sudden onset with respiratory rate > 30 breaths / minute
4. Physical signs of pulmonary edema

The patients excluded:

1. Immediate need for endotracheal intubation
2. Severe sensorial impairment (Kelly score > 3)
3. Shock
4. Ventricular arrhythmias,
5. Sp02 < 80% despite supplemental O2
6. Acute MI requiring thrombolysis
7. Severe chronic renal failure
8. Pneumothorax

The interventions compared:

Standard medical treatment (continuous SpO2 and ECG monitoring, supplemental O2 by high flow facemask to maintain SpO2 > 90%, and protocolized administration of furosemide, morphine sulfate, and glyeryl trinitrate) vs. NPSV through a full face mask (and other protocolized medical management)

The outcomes evaluated:

The primary outcome is the need for endotracheal intubation as defined by criteria established by the authors:

1. Progressive or refractory hypoxemia (Sa02 < 85% with Fi02 of 1)
2. Cardiac or respiratory arrest
3. PaC02 increase > 5 mmHg in hypercapnic patients or at 50 mmHg for initially nonhypercapnic patients
4. Clinical signs of exhaustion
5. Inadequate clearance of secretions
6. Hemodynamic instability without response to fluids
7. Myocardial infarction necessitating thrombolysis in patients with risk factors
8. Massive GI bleeding

Secondary outcomes evaluated are in-hospital mortality, ABG values, respiratory rate, blood pressure, heart rate, dyspnea, duration of hospital stay, and cardiac enzymes.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

An independent statistician used random numbers to generate a block randomization schedule for each center. Randomization was stratified by presence/absence of hypercapnia (pC02 > 45 mm Hg) and by center using sealed, opaque envelopes.

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

Was followup complete?

The authors' intention was to follow patients until death or discharge. Note that Table 2 provides data for all 65 patients in each arm, but Table 3 provides reasons for intubation in only 11/13 NPSV patients who were intubated. No patients were lost in this study.

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

The authors used an intention-to-treat analysis, analyzing the patients in the group to which they were randomized. There is no mention of actual cross over of patients between groups.

Secondary questions:

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

Patients and health care workers were not blinded to the treatment. Patients receiving NPSV had a ventilator at bedside and were fitted with a mask designed for this ventilator. No attempt was made to conceal or camouflage the equipment.

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

Yes, the Standard Treatment and NPSV groups were very similar with regard to age and gender, initial ABG, initial hemodynamics, and medical history.

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

Yes. Aside from the experimental intervention, both groups received standard therapy of oxygen, Furosemide, Morphine, and Glyceryl Trinitrate dosed per guidelines from the authors (Table E4, Online Supplement)

III. What were the results?

1. How large was the treatment effect?

Pooled analysis

When dividing the patients simply into standard treatment and NPSV groups, there is no significant difference between the two groups in the need for endotracheal intubation or in hospital mortality.

	Standard Treatment	NPSV	ARR (95% CI)	NNT (95% CI)
Intubation	16/65 = 0.246	13/65 = 0.2	0.05 (-0.1, 0.2)	22 (5, infinity)
Death	9/65 = 0.138	6/65 = 0.092	0.05 (-0.06, 0.16)	22 (6, infinity)

Subgroup Analysis

If the groups are divided into subsets of hypercapnic and nonhypercapnic patients, the hypercapnic patients show a statistically significant decrease in intubations, and a small, but not statistically significant, decrease in mortality. A logistic regression analysis based on need for intubation and presence of hypercapnia did not show any statistically significant correlation, however.

PaC02 > 45	Standard Treatment	NPSV	ARR (95% CI)	NNT (95% CI)
Intubation	9 / 31 = 0.29	2 / 33 = 0.06	0.23 (0.05, 0.41)	4 (2, 19)
Death	5 / 31 = 0.16	1 / 33 = 0.03	0.13 (-0.01, 0.27)	8 (4, infinity)
PaC02 < 45	Standard Treatment	NPSV	ARI (95% CI)	NNH (95% CI)
Intubation	7 / 34 = 0.21	11 / 32 = 0.34	0.13 (-0.08, 0.34)	8 (3, infinity)
Death	4 / 34 = 0.12	5 / 32 = 0.15	0.03 (-0.13. 0.19)	33 (5, infinity)

Secondary outcomes

The physiologic variables recorded by the authors showed statistically significant improvement in the NPSV group at one or more time points, though these are of doubtful clinical significance. Likely clinically significant is the improvement in Borg Scale (1) at several time points in the NPSV group. Assuming that "Borg Scale" refers to the Modified Borg Scale with a range of 0-10 (a bedside scale to evaluate the patient's subjective feeling of dyspnea), the decreases in Borg's dyspnea scores shown by the NPSV patient group are clinically significant. For example, a decrease in score from 4 to 2 indicates an improvement from "somewhat severe" dyspnea to "slight breathlessness."

Significantly higher PaO2/FiO2 ratios were observed among the patients assigned to NPSV during the first three hours of therapy. The difference in PaO2/FiO2 ratios between the two groups in this time period was in the range of 40-50 mm Hg. Significantly lower PaCO2 levels were also observed in the NPSV group over the first hour of therapy, but the differences were in the range of 4-5 mm Hg, which may not be clinically important.

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

When looking at the combined patient group (nonhyper- and hypercapnic), the upper 95% Confidence Interval suggests a potential absolute risk reduction of death of 20%. Looking at the group with PaC02 > 45, however, NPSV could potentially provide an Absolute Risk Reduction of death as high as 40%. In nonhypercapnic patients, there could potentially be an Absolute Risk Increase death of 34%.

In other words, the study results, due to small numbers of patients included, were not very precise. The only result where the 95% CI do not cross zero for an ARR is for intubation among hypercapnic patients. NPSV could reduce the absolute rate of intubations anywhere from 5 to 41%, with 95% confidence.

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

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

The majority of the patients in the study had co-morbidities not seen in the pediatric population (chronic bronchitis and previous myocardial infarction) and 15-20% of patients had acute myocardial infarction as a precipitating cause of the edema. Not only is the patient group older than the pediatric age, but many were ill with diseases not found commonly in pediatrics so the findings must be applied with caution to the pediatric population. That being said, with cardiogenic pulmonary edema decidedly less common in pediatrics than in adults it is unlikely that this topic will be addressed soon in the pediatric population. Outside of the relief of dyspnea, there is little evidence in the paper to persuade pediatric intensivists to apply NPSV in our patients with cardiogenic edema. The authors may have excluded an important benefit, however, in patients with PaC02 > 45. The 95% Confidence Intervals show that there may be an important reduction in intubations with NPSV in this group. It would be premature to exclude NPSV in this group, and further investigation of the topic is warranted.

2. Were all clinically important outcomes considered?

The authors included all clinically important outcomes in their analysis.

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

The harms evaluated, increased hospital stay, acute myocardial infarction, infectious and noninfectious complications, were not increased in the NPSV group. There was, however, a significant number of patients with skin lesions from the face mask, including erythema in 14 patients, ulceration in 9 patients, and necrosis in 4 patients. Given that there is no significant improvement in primary outcomes for patients with NPSV and little clinical benefit with regard to secondary outcomes, it does not seem reasonable to subject patients to potentially disfiguring skin lesions. It is possible that the risk of skin lesions could be decreased by increased staff experience in the use of NPSV or by use of alternative patient-ventilator interfaces.

The authors made no attempt to analyze cost of the different treatment arms. Potential costs, however, include staffing the ED and "step-down" units with individuals skilled in the management of NPSV and the costs of acquiring ventilators capable of providing NPSV, as well as other necessary equipment.

References

1. Kendrick KR, Usefulness of the Modified 0-10 Borg Scale in assessing the degree of dyspnea in patients with COPD and asthma. J Emerg Nurs. 2000 Jun; 26 (3): 216-22. [abstract]

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