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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Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.

Brower RG, Shanholtz CB, Fessler HE, et al.

Crit Care Med 1999;27:1492-8. [abstract]

Reviewed by Priya Prabhakaran, MD, University of Alabama, Birmingham, Alabama

Review posted October 13, 2000

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I. What is being studied?:

The study objective:

This study was designed to evaluate the possible efficacy and safety of a mechanical ventilation strategy with small tidal volumes to reduce stretch induced lung injury in patients with ARDS.

The study design:

Prospective randomized controlled clinical trial.

The patients included:

Patients who fulfilled the following criteria in the same 24 hour period were enrolled

• PaO2/FiO2 < 200 torr
• Bilateral alveolar or interstitial infiltrates not due to atelectasis or effusions
• No suspicion of congestive heart failure or PAWP < 18 torr
• On positive pressure ventilation via an endotracheal tube

A total of 52 patients were enrolled from medical, surgical and oncologic ICU's in 4 hospitals. No data is available about the total number of eligible patients,

The patients excluded:

The following were reasons for excluding eligible patients

• Age < 18 years
• Pregnancy
• Acute CNS disease for which hypercapnia would be contraindicated
• Severe chronic obstructive or restrictive lung disease
• Anticipated life expectancy from co-morbid conditions < 3 months
• Hb SS or SC disease
• Lobectomy or pneumonectomy in the current hospitalization

The interventions compared:

Patients in the Small Tidal Volume (STV) group were ventilated with tidal volumes (Vt) of 6-8 ml/kg keeping Pplat < 30 cms H20. Patients in the traditional tidal volume group (TTV) group were ventilated with Vt of 10-12 ml/kg keeping Pplat < 45-55 cm H2O. The minimum Vt in both groups was 5 ml /kg. The ventilator rate was less than or equal to 30 bpm and was adjusted to keep the PaCO2 between 30 and 45 torr if possible. Similar combinations of FiO2 and PEEP were permitted in both groups to achieve target PaO2 of 55-75 torr and SpO2 of 86-94%.

The outcomes evaluated:

Effects on pulmonary gas exchange were studied by comparing levels of PEEP and FiO2 required to achieve similar levels of oxygenation. Effects of STV on patient agitation/dyspnea were assessed by comparing requirements for sedatives/ muscle relaxants. Daily fluid intakes and requirements for pressors were used to study the effects of STV on hemodynamics.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, randomization was stratified by ICU, with equal numbers of patients in each treatment group in variable sized blocks.

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

Was followup complete?

Yes

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

Yes, there was no cross over between the two groups.

Secondary questions:

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

Due to the complex nature of the interventions being compared, health care personnel and study personnel were not "blind" to treatment. However, all members of the study team and clinical staff were masked to the study group assignment sequence and block size.

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

The patients in the STV group had a slightly higher APACHE score (mean of 90.6) versus 84.6 in the TTV group. Although the LIS was similar in both groups, patients in the STV group had a lower mean PaO2/FiO2 (129 versus 151) than those in the TTV group. Pneumonia, sepsis and aspiration were the commonest causes of ARDS in both groups. AIDS, s/p BMT and cancer were the co-morbid conditions in both groups - there were twice as many patients s/p BMT in the STV group as compared to the TTV group (4 versus 2). Although these differences appear small, (and were not statistically significant) they could affect the results of a trial with low number of patients as this one.

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

Ventilator management was similar in both groups, although weaning was not standardized. Acid base status was also managed similarly in both groups with administration of bicarbonate being mandated for pH < 7.2, and permissible for 7.3-7.2. The target for PaCO2 was 30-45 torr without exceeding an IMV rate of 30 bpm. No data has been presented with regards to other aspects of overall management which may have impacted on the outcomes evaluated - some of these include antibiotic use, diuretic therapy, nutrition and transfusion therapy. This data is probably even more important, given that this was a multicenter trial.

III. What were the results?

1. How large was the treatment effect?

In view of the fact that 33% of patients either died or achieved spontaneous ventilation within 5 days of being enrolled in the study, requirements for supplemental oxygen, PEEP, sedatives and muscle relaxants were compared between the two groups through day 5.

There was no significant difference in the mean slopes of PEEP and FiO2 versus time between the two groups after adjusting for the effects of age APACHE scores, LIS and cause of ARDS. Age alone had a significant positive predictive value for PEEP requirements.

There was no significant difference in the mean daily fluid intakes and mean number of vasopressors used per patient ventilator day between the TTV and STV groups.

The mean proportion of ventilator days on which a muscle relaxant was used and the mean pancuronium equivalent doses used were similar.

The mean number of sedative classes per patient ventilator day and the mean diazepam equivalent doses used were not different.

58% of patients achieved spontaneous ventilation in both groups. There was no difference in the duration of mechanical ventilation or the duration of weaning to extubation between the two groups. Of the patients who achieved Reversal of Respiratory Failure (RRF), the mean number of days (± s.d.) on the ventilator was 11.9 (± 1.9) and 11.3 (± 2.2) in the TTV and STV groups respectively. The mean number of days from the onset of weaning (FiO2 < 0.5, PEEP < 5 ) to RRF was 5.2 (± 1.1) and 5.1(± 1 ) in the TTV and STV groups respectively.

The mortality prior to hospital discharge was 46% in the TTV group versus 50% in the STV group. This was not significant after adjusting for the effects of age, APACHE scores, LIS, type of ICU and cause of ARDS. The RR of mortality for patients in the STV group was 1.08.

The ARR for mortality was -4%.

There was one barotrauma event in either group.

This study did show that STV ventilation does not adversely affect gas exchange or patient comfort.

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

The 95% CI for the RR of 1.08 are 0.57 and -2.1, which is not very precise.

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

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

Unclear, since the study was conducted on adult patients and was inconclusive. There could be several potential reasons why the authors failed to demonstrate a beneficial effect of STV ventilation in this trial. First, there was only a very modest difference in Vt and Pplat between the groups. A difference between the groups may have been demonstrated if enrollment had been restricted to patients with very low respiratory system compliance, i.e. more severe disease. The Oxygenation index (OI) may have been a better criterion to enroll patients than the PaO2/FiO2 alone. The fact that the trial was small and insufficiently powered to detect moderate differences between treatment groups, combined with the fact that the patients enrolled were not very sick may also explain the negative results of this study. The slightly higher APACHE scores, lower PaO2/FiO2 ratios and higher requirements for PEEP in the treatment group may have been sufficient to obscure any real treatment effect in this small study. Further, it is possible that this study showed no benefit of STV ventilation because the levels of PEEP used to support oxygenation were lower , (and similar in both groups) than those recommended to prevent ventilator associated lung injury secondary to cyclic opening and closing of airways and alveoli.

It follows therefore that STV ventilation could have modest beneficial effects on lung injury. Since this, and other trials have shown it's safety, it might be helpful in caring for my patients.

2. Were all clinically important outcomes considered?

Yes, all important outcomes including time to extubation, percent achieving spontaneous ventilation, and mortality before discharge were considered. It may have been helpful to include data about other organ dysfunction which could possibly be secondary to the effect of hypercapnia in the STV group. Information about how many of the patients in either group still required supplemental oxygen, and for how long would also be useful.

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

Possibly. Although no positive treatment effects were demonstrated in this trial, it appears to be safe and STV ventilation and compensated hypercapnia may reduce lung injury. A subsequent large multicenter trial has shown a reduction in mortality with this strategy.(6).

References

1. Hickling KG, Walsh J, Henderson S, et al. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med 1994;22:1568-1578. [abstract]
2. Muscedere JG, Mullen JBM, Gan K, et al. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149:1327-1334. [abstract]
3. Tuxen DV. Permissive hypercapnic ventilation. Am J Respir Crit Care Med 1994;150:870-874. [citation]
4. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a Ventilation Strategy to Prevent Barotrauma in Patients at High Risk for Acute Respiratory Distress Syndrome. N Engl J Med 1998;338:355-361. [abstract] [PedsCCM EBJC Review]
5. Amato MBP, Barbas CSV, Medeiros DM, et al.Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome. N Engl J Med 1998;338:347-354. [abstract] [PedsCCM EBJC Review]
6. Acute Respiratory Distress Syndrome Network. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med 2000; 342: 1301-1308. [abstract] [PedsCCM EBJC Review]

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