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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Tidal Volume Reduction for Prevention of Ventilator-induced Lung Injury in Acute Respiratory Distress Syndrome.

Brochard L, Roudot-Thoraval F, Roupie E et al.

Am J Respir Crit Care Med 1998; 158: 1831-1838. [abstract] [full-text for subscribers]

Reviewed by Graham Tse, MD, University of California - Los Angeles

Review posted November 16, 1999

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I. What is being studied?:

The study objective:

The study objective: To compare the effects of pressure limited versus "conventional" ventilation on mortality in ARDS patients.

The study design:

The study was a multicenter, randomized, nonblinded, prospective trial

The patients included:

The study specifically looked at patients with ARDS and no other organ failure at entry and included 116 adults in the intensive care units of 25 hospitals in seven countries. The exact entry criteria were:

• above 17 years old and below 76 years old
• diffuse bilateral infiltrates on chest x-ray
• arterial hypoxemia requiring mechanical ventilation
• use of FiO2 of 0.50 or greater for at least 24 hours
• lung injury score above 2.5 for less then 72 hrs

The patients excluded:

Patients were excluded for any of the following reasons:

• history of left heart failure
• evidence of cardiogenic edema
• PCWP of greater then or equal to 18 mmHg
• severe organ failure other than the lung
• need for high levels of vasopressor agents
• presence of pre-existing chronic disease
• a moribund state
• major chest wall abnormalities
• chest tube and persistent air leak
• bone marrow transplant
• presence of AIDS
• intracranial hypertension
• head injury with obtundation (decrease in Glasgow Coma Scale by at least two points)

The interventions compared:

Standard Group:

• Assist Control Ventilation - Volume Limited
• Tidal Volume 10 ml/kg up to 15 ml/kg
• Respiratory rate adjusted to keep PaCO2 38-42 mmHg
• Peak Inspiratory Pressure to 60 cm H2O
• i:e ratio not greater then 1

Pressure Limitation Group:

• Assist Control Ventilation - Volume Limited
• End-inspiratory plateau pressure at or below 25 cm H2O
• Tidal Volume < 10 ml/kg but no less than 6 ml/kg or 300 ml
• No recommendation on respiratory rate

PEEP was determined before randomization using a "PEEP trial". There was no protocol or recommendations for weaning of the ventilator.

The outcomes evaluated:

Primary outcome was sixty day mortality. Secondary outcomes evaluated were:

• incidence of pneumothorax require chest tube placement
• incidence of secondary organ system failure
• duration of mechanical ventilation
• length of stay in intensive care unit
• number of ventilator free days up to day 60

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was done after stratification to three groups was performed (multiple trauma, immunosuppressive therapy, others). Randomization was done by the sealed envelope method. The stratification was undertaken to "ensure that causes of ARDS that are likely to influence mortality would be equally distributed between the two arms of the study." Any other causes of ARDS which could influence mortality were not stratified before randomization.

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

Was followup complete?

There is no specific mention of adequacy of follow-up.

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

Yes, this was implied though not directly specified. The authors examined case report forms to ensure the protocols were followed. They indicated satisfaction in response to the question: "in the case of pressures and volumes that were not in the range dictated by the arm of the study, was it due to a safety limit imposed by the protocol?" This seems to indicate that no patient crossed over to the other group.

Secondary questions:

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

No. No attempts were made to blind anyone.

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

Yes. There were no statistically significant differences found in any of several variables examined between the groups at inclusion into the study. Specifically the investigators evaluated:

• age
• Apache II scores (1) on admission and inclusion
• SAPS II (2) scores on admission and inclusion
• previous duration of mechanical ventilation
• lung injury score
• PaO2/FiO2
• multiple trauma (%)
• immunosuppression (%)

The possibility exists that other factors which may have had an effect on outcome were not examined nor compared between the two groups.

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

Not clearly defined or stated. Treatment other than those parameters limited by the study were left up to the individual attending physicians. It is mentioned that the two groups had similar usage and duration of sedation, paralysis, and nitric oxide use, but the study did not define how each was to be used or in what situations. There is the possibility that significant differences in treatment between the two groups occurred (aside from the study parameters). No mention was made of the enrollment numbers from each of the 25 participating hospitals. The number of patients from each hospital may have varied greatly, and management differences between the participating sites may have had an effect on the study results.

III. What were the results?

1. How large was the treatment effect?

The two groups had significant differences in tidal volumes and plateau pressures at days 1, 2, 7, 14.

		Plateau Pressure Limitation	Standard Treatment
Tidal Volume (ml/kg)	Day 1	7.1 ± 1.3	10.3 ± 1.7
	Day 2	7.07 ± 1.3	10.5 ± 1.8
	Day 7	7.37 ± 1.3	10.7 ± 1.8
	Day 14	7.6 ± 1.8	9.9 ± 2.1
Plateau Pressure (cm H2O)	Day 1	25.7 ± 5.0	31.7 ± 6.6
	Day 2	25.4 ± 5.4	31.3 ± 6.5
	Day 7	24.5 ± 5.7	30.5 ± 9.4
	Day 14	24.5 ± 5.8	33.6 ± 11.7

The two groups did achieve the desired ventilatory parameters. Specifically, the standard treatment group received tidal volumes of 10 ml/kg or greater, while the pressure limited group maintained plateau pressures at or below 25 cm H2O and tidal volumes less then 10 ml/kg. There were no differences between the two groups over time in FiO2, PEEP, or PaO2/FiO2.

No significant difference in mortality at 60 days could be observed between the two groups (46.6% in the pressure limitation group versus 37.9% in the standard treatment group, p=0.38). The study was stopped after interim analysis of the first 100 patients showed that pressure limitation would not achieve a beneficial effect within the planned frame of the study. The study was designed to detect a reduction in mortality from 50% to 30% with an alpha error of 5% and a beta error of 10%, this would have required 240 patients. As well, there was no significant difference found in any of the other outcome variables studied (i.e. multiple organ failure, pneumothorax, duration of mechanical ventilation, etc.)

This failure to show a statistically significant difference may be attributable to the fact that the standard (control) group did not receive extremely high volume or pressure settings. The standard group had median tidal volumes below 11ml/kg and median plateau pressures below 34 cm H2O. These plateau pressures did not exceed those delineated by the American-European consensus conference on ARDS (3) (30-40 cm H2O). Even though the two groups had statistically significant different tidal volumes and plateau pressures, it is possible that both groups received ventilatory support below the levels required to cause clinically appreciable ventilator induced pulmonary or alveolar trauma.

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

Not applicable

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

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

No. The study found no significant differences in the outcome variables between the two groups. There was no significant difference in mortality, incidence of multiple organ failure, pneumothorax, duration of mechanical ventilation, number of ventilator free days at day 60, duration of ventilation for survivors, or length of stay in the ICU for survivors. We cannot conclude that modifying our ventilator management to that of the pressure limitation group would be of any benefit to our patients. The study design also made any results not directly applicable to the pediatric population.

2. Were all clinically important outcomes considered?

The study did not look at any factors or outcomes beyond 60 days. Other outcomes which could have been examined include patients surviving to hospital discharge, long term O2 requirements, and long term pulmonary function tests.

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

Not applicable as no treatment benefit was found.

References

1. Knaus WA et al. Apache II: A severity of disease classification system. Crit Care Med 1985;13: 818-829. [abstract]
2. Le Gall J, Lemeshow S, Saulnier F. A New Simplified Acute Physiology Score (SAPS II) Based on a European/ North American Multicenter Study. JAMA 1993;270:2957-2963. [abstract]
3. Artigas A et al. The American-European Consensus Conference on ARDS, Part 2. Ventilatory, Pharmacologic, Supportive Therapy, Study Design Strategies and Issues Related to Recovery and Remodeling. Intensive Care Med 1998;24:378-398. [abstract]

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