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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Effect of Mechanical Ventilation on Inflammatory Mediators in Patients with Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

Ranieri VM, Suter PM, Tortorella C, et al.

JAMA 1999; 282:54-61. [abstract; full-text for subscribers]

Reviewed by Saraswati Kache, MD and Rick Harrison, MD, UCLA, Los Angeles, CA

Review posted October 31, 2001

 

I. What is being studied?:

The study objective:

This study looked at the effects of mechanical ventilation on pulmonary and systemic cytokine response in patients with acute respiratory distress syndrome and if this response could be minimized by limiting ventilatory peak pressures and maximizing the number of alveoli recruited.

The study design:

Prospective randomized clinical trial in two adult ICU's in Europe.

The patients included:

Patients included in the study were 18 years or older and had ARDS as per the American-European consensus conference criteria which are as follows: acute onset of respiratory distress, PaO2/FiO2 < 200, bilateral infiltrates on chest X-ray, and < 18mm Hg of pulmonary capillary wedge pressure or no evidence of left heart failure.

The patients excluded:

The patients excluded from the study are as follows: 1) anticipated mechanical ventilation for less than 48 hours, 2) mechanically ventilated for greater than 8 hours prior to admission into study, 3) cardiogenic pulmonary edema, 4) history of tachyarrhythmias, unstable angina, or myocardial infarction within the last month, 5) preexisting chronic obstructive pulmonary disease, major chest wall abnormalities, chest tube with a persistent air leak, or abdominal distention, 6) pregnancy, 7) intracranial abnormality, 8) enrollment in another study.

The interventions compared:

All patients upon admission to the study had volume-pressure curves measured. This is a sigmoidal shaped curve in which the lower inflection (Pflex) point is believed to correspond to the pressure required to reopen collapsed lung and the upper inflection point (UIP) represents the pressure at which overdistention of some lung units occurs. There is a recent study, however, by Crotti et al.(1) that suggests in the acute lung injury model, recruitment occurs along the entire volume-pressure curve and is not related to the UIP or Pflex.

The patients were then randomized to either the control group or the lung protective strategy study group. The control group's ventilator strategy placed them on inspiratory pressures to maintain normal PaCO2 and utilized PEEP that maximized their oxygenation. Plateau airway pressure was limited to 35 cm H2O. The ventilator strategy used for the study group was to minimize the lung exposure to stress. This involved using a PEEP higher than the lower inflection point and the maximal inspiratory pressure lower than the upper inflection point or a tidal volume of 5-8 ml/kg when the UIP could not be determined on the volume-pressure curve. A PEEP of 15 cm H2O was utilized if the Pflex could not be determined.

The outcomes evaluated:

The patients had bronchoalveolar lavage fluid samples and blood samples collected at time 0, 24-30 hours and 36-40 hours after randomization. Inflammatory mediator levels were measured from these samples. In a post-hoc analysis, they computed the ventilator-free days and 28 day mortality between the two groups.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

The surrogate endpoint would be how the pulmonary and systemic inflammatory mediator levels are impacted by the ventilatory strategy. The clinical endpoint from this evaluation would be two fold. First, does impacting the patient's cytokine level impact the patient's risk of developing SIRS and MSOF. Second, does it effect the number of days on the ventilator, discharge time from the ICU and from the hospital, and mortality. This paper primarily addresses the surrogate endpoint and evaluated the clinical end point only very briefly. There are other papers however that do address this association between systemic cytokine levels and their overall impact on patient recovery. Meduri et al.(2) in 1995 showed that higher levels of cytokines at the onset of ARDS had a higher rate of mortality as compared to those patients with a lower level.

Slutsky and Tremblay (3) clearly state that lung injury can cause systemic inflammation by the spillover of inflammatory mediators into systemic circulation which in turn can initiate or propagate SIRS, and MSOF.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There have been studies which show steroids do decrease cytokine levels. Meduri et. al (4) demonstrated an improvement in target outcome with steroids. Their study showed that steroid use in the late phase of ARDS improved rate of extubation, decreased the rate of mortality, and improved the ALI and MODS score. There was no difference in the rate of infection between the placebo group and study group which received a steroid taper over the course of four weeks.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Amato et al. (5) noted that the lung protective strategy of high PEEP and low tidal volume improved the 28 day survival rate and rate of weaning from mechanical ventilation. It did not, however, improve rate of survival to hospital discharge. In a more recent paper, The Acute Respiratory Distress Syndrome Network did show an improvement in rate of mortality and ventilator free days amongst patients that had a low tidal volume ventilator strategy used to manage their ARDS. (6)

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The patients were assigned randomly to the control or study group by concealed allocation approach using opaque sealed envelopes.

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

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Yes. The control group had 19 patients and the study group had 18 patients. Initially, 44 patients were enrolled: seven patients were withdrawn from the trial for the following reasons: increase in the initial number of organ failures (1 in each group), need for higher doses of norepinephrine (1 in each group), high risk of death (1 in the study group), and weaning from mechanical ventilation (1 in each group). All patients withdrawn met previously established criteria for protocol withdrawal. One other point of interest is that some of the cytokine measurements included only 10 - 15 patients rather than all 18 or 19 patients assigned to that group because measurements were not available for all subjects.

Yes. Patients were compared within their assigned group for the entry time vs. at time 36 - 40 hours out. There was no crossover of patients from one group to another.

Secondary questions:

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

It is unclear if the patients were blinded to the treatment, but they were sedated for the duration of the study. It would appear the attending physicians were not blinded to the study, but they were not involved in the protocol. The technicians measuring the blood and bronchoalveolar lavage fluid samples were blinded to the ventilator strategy used.

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

Yes. The demographic data of gender and age was comparable between the two groups. The reasons for development of ARDS was also similar between the two groups and included pneumonia, sepsis, multiple trauma, acute pancreatitis, abdominal aneurysm rupture, and drug overdose. The measurements of lung injury which included PaO2/FiO2 ratio, acute physiology and chronic health evaluation II score, lung injury score, lower inflection point, and upper inflection point on the volume-pressure curve were also comparable between the groups.

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

It is unclear since the remainder of the patient management was left up to the discretion of the attending physicians who were not involved in the protocol. One would presume it would be similar between the two groups, however, since the attending physicians would maintain the standard of care in all other aspects of the patient care.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

There was a statistically significant difference in the levels of most inflammatory mediators measured in the BALF and the plasma. The cytokine levels at the time of entry were compared to the levels at 36-40 hours later; this showed a significant increase in the cytokine levels in the control group and significant decrease in the lung protective group. The inflammatory mediators measured included TNF-alpha receptors, IL-1 receptors, PMN %, IL-1beta levels, TNF-alpha levels, IL-8 levels, and IL-6 levels.

The post hoc analysis demonstrated an improvement of ventilator free days; 12 days in the experimental group vs. 4 in the control group. No confidence intervals were given for the mediator values or the clinical outcomes, so precision can not be determined. The duration of the effect on mediator levels cannot be determined beyond the 40 hours studied.

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

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

The paper has some very convincing data that a high PEEP low tidal volume ventilator management strategy is very effective in reducing inflammatory mediator release in patients with ARDS. Other studies since have shown that this protective mode of ventilation does translate into lower mortality rates and a greater number of ventilator free days. Although all such studies have been done in adults, these findings, I believe, are quite applicable to the pediatric population since the basic pathophysiology for ARDS remains unchanged for the two age groups.

2. Were all clinically important outcomes considered?

This study was not intended to evaluate clinical outcomes and those that were presented were done as a post hoc analysis. For the purposes of this study, the patients were only followed for 40 hours out after entry. The authors do suggest, though, that the patients randomized to the lung protective strategy did remain on that strategy until weaned from mechanical ventilation. The ad hoc results show an increase in ventilator free days, but no significant improvement in mortality at 28 days.

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

The likely treatment benefits from an immediate management perspective include decreased FiO2 requirement which decreases oxygen toxicity for the patient. There is also a decrease in both pulmonary and systemic inflammatory mediators and therefore potentially decreasing the risk of developing SIRS and MSOF. The patients also seem to wean off of mechanical ventilation faster when placed on the high PEEP low tidal volume strategy. Indeed, from the NIH trial we know that this strategy is clinically efficacious; this current study lends a possible scientific mechanism to the improved outcomes seen with such a strategy.

The one potential harm appears that the patients in the study group had a significantly higher PaCO2 which would obviously cause some amount of acidosis. Although the PaCO2 in the study group was statistically higher (46.9), this seems a clinically acceptable number for a patient with ARDS. It is also worth noting that reasons for withdrawal from the study were similar between the two groups with the exception of one patient that was withdrawn from the study group for high risk of death. I think although this paper was not intended to be a clinical outcomes evaluation, the data from this and other papers would suggest that the possible benefits do outweigh the potential harms of the lung protective strategy.

References

1. Crotti S, et. Al. Recruitment and Derecruitment during Acute Respiratory Failure. Am J Resp Crit Care Med 2001; 164(1): 131-140. [abstract]
2. Meduri GU, et al. Persistent elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS. Chest. 1995; 107(4): 1062-1073.[abstract]
3. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med. 1998;157:1721-5. [citation only]
4. Meduri GU, et. al. Effect of Prolonged Methylprednisolone therapy in unresolving acute respiratory distress syndrome: A randomized controlled trial. JAMA 1998; 280: 159-165.[abstract]
5. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998 Feb 5;338(6):347-54.[abstract]
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]

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