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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Long-Term Effects of Spontaneous Breathing During Ventilatory Support in Patients with Acute Lung Injury,

Putensen C, Zech S, Wrigge H, et al.

Am J Respir Crit Care Med 2001; 164:43-49. [abstract; full-text for subscribers]

Reviewed by Saraswati Kache, MD, Vatsala Kesavulu, MD, University of California Los Angeles

Review posted February 13, 2002

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I. What is being studied?:

The study objective:

The objectives of this study were two fold. First, the study measured the effects of partial ventilatory support, i.e. airway pressure release ventilation (APRV) with spontaneous breathing, on cardiorespiratory function in the first ten days following admission to the ICU for multiple trauma. Second, clinical outcomes were evaluated by comparing development of ARDS and acute lung injury, duration of ventilatory support, intubation, and ICU stay.

The study design:

It was a randomized, controlled, unblinded prospective study.

The patients included:

Thirty patients with multiple trauma requiring mechanical ventilation and having an injury severity score (ISS) of greater than 40 were included.

The patients excluded:

Patients with chronic lung or heart disease, bronchopleural fistula, or severe cerebral injury were not included in the study.

The interventions compared:

The conventional mode of pressure control time cycled ventilation (PCV) was compared to spontaneous breathing with airway pressure release ventilation (APRV). APRV differs from conventional ventilation because it ventilates by switching between two levels of high flow continuous airway pressure which allows spontaneous patient breathing during any portion of the ventilatory cycle.

After inclusion to the study, the patients had daily pressure-volume curves constructed under neuromuscular blockade which measured the lower inflection point (LIP) and the upper inflection point (UIP). After construction of a baseline PV curve, patients were then randomized either to the study group (APRV) or the control group (PCV). The control group was placed on a pressure control time cycled mode of mechanical ventilation (PCV) for the first 72 hours of the study with the PEEP 2 cm H2O above the LIP and the PIP set at a pressure below the UIP maintaining a tidal volume of less than 7ml/kg. After 72 hours, the patients were changed to spontaneous breathing with airway pressure release ventilation (APRV) and weaned off mechanical ventilation as tolerated (directed by a strict protocol). Patients in the PCV group were pharmacologically paralyzed to prevent spontaneous breathing during the first 72 hours. The study group was placed on APRV mode of ventilation from the start of the study and weaned off as tolerated (directed by the same protocol).

The outcomes evaluated:

Cardiorespiratory function, the amount of sedation required, and clinical outcomes were evaluated. The respiratory variables included pulmonary compliance, low and high airway pressures, spontaneous minute ventilation, and PaO2/FiO2 ratio. The cardiac variables included cardiac index, mean arterial pressure, pulmonary capillary wedge pressure, pulmonary arterial pressure, amount of norepinephrine and dobutamine required, oxygen delivery, and oxygen consumption. All cardiorespiratory variables were measured every 8 hours and averaged to produce a daily result. The amount of sufentanil and midazolam required to maintain adequate sedation were also evaluated. Finally, the clinical outcomes compared included the duration of ventilatory support, intubation, and ICU stay.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, but the method of randomization is not mentioned.

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

Was followup complete?

There is no comment in the paper suggesting that patients had to be withdrawn from the study for any particular reason. It is, therefore, presumed that all 30 patients included in the study remained in the study for the duration. All patients included in the study were followed until their discharge from the ICU. It is not stated whether any patients were extubated prior to 10 days - all their continuous data measurements are reported for a full ten days.

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

Yes. There was no cross-over of patients from one group to another.

Secondary questions:

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

The study was not blinded.

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

The demographic data between the two groups comparing age, gender, injury severity score, simplified acute physiologic score, patients with acute lung injury or acute respiratory distress syndrome, and the number of extrapulmonary organ systems in failure, were all found to be similar. There was also no statistically significant difference between the lower and upper inflection pressures at baseline or for the duration of the study between the two groups suggesting that the pulmonary compliance remained comparable.

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

The level of sedation required between the two groups in the first 72 hours was not comparable since the PCV group was paralyzed in order to prevent spontaneous respiration and, therefore, required a higher level of sedation. It appears the groups were otherwise treated equally, and the following interventions in particular were mentioned: dobutamine to maintain adequate cardiac index, norepinephrine to maintain systemic vascular resistance, dopamine if the patient became oliguric, packed red blood cell for a hemoglobin of 10 g/dl, and 5% albumin infusion if the albumin level dropped below 2.0 mg/dl.

III. What were the results?

1. How large was the treatment effect?

The study showed that the APRV group had significant improvement in cardiorespiratory function, reduced amount of sedation required, and decreased duration of mechanical ventilation and intensive care compared to the PCV group. From a pulmonary standpoint, the following factors were found to be significantly improved in the APRV group. The peak airway pressure was lower, compliance was higher, spontaneous minute ventilation was higher, and the PaO2/FiO2 ratio was higher in the study group. Specifically, the peak airway pressure was lower only by 2-5 cm H2O between the two groups. The spontaneous minute ventilation was approximately 1 L/min higher, and the compliance was about 10 cc/cm H2O higher in the APRV group.

From a cardiac standpoint, the cardiac index was higher by 1 L/min/m2 and oxygen delivery was also higher by approximately 100 cc/min/m2 in the study group. The inotropic support required was lower in the APRV group by approximately half throughout the ten day study period. The pulmonary capillary wedge pressure, PA pressure, and mean arterial pressure remained comparable between the two groups.

The data on duration of ventilatory support, intubation, and ICU stay is shown below. By the design of the study, the APRV group had a distinct advantage in these outcomes, since the PCV group was maintained on controlled ventilation for the first three days by design. The APRV group could have had a "head start" towards weaning off support.

	APRV	PCV	P value
Length of vent support (days)	15 ± 2	21 ± 2	0.032
Length of intubation (days)	18 ± 2	25 ± 2	0.011
Length of ICU stay (days)	23 ± 2	30 ± 2	0.032

The levels of sufentanil and midazolam required were lower among the APRV patients as would be expected since these patients were maintained at a lower level of sedation. It is not clear if the observed improvement in cardiorespiratory function in the study group is secondary to the mode of ventilation or a decreased level of sedation and sedative medications. The authors themselves concede that this difference could not be clearly distinguished.

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

It is difficult to offer a precision factor for the treatment effect since the clinical outcomes evaluated are duration of ventilatory support, duration of intubation, and duration of ICU stay rather than a specific yes or no outcome. All three of these outcomes did have a statistically significant difference (with a p value < 0.05) between the control group and the experimental group. As for other outcomes, there was a significant decrease in the risk of developing ARDS, but a significant increase in the risk of developing acute lung injury (ALI) by being placed on the APRV mode of ventilation. The relative risk reduction of developing ARDS in the study group was 73% with a 95% confidence interval of 22%, 91%.

The proposed mechanism by which persistent spontaneous breathing improved ventilation, and therefore improved gas exchange, is by allowing diaphragmatic contraction to oppose alveolar compression in dependent lung regions. Decreased atelectatic lung regions would explain the decreased risk of developing ARDS in the APRV group. However, ALI and ARDS represent different ends of the spectrum of the same disease process. The study group patients manifested signs of lung injury with a higher incidence of ALI, whereas the control group had a higher incidence of ARDS.

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

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

I believe this study shows a significant improvement in the patient's cardiorespiratory function if allowed to breathe spontaneously. It is unclear if the observed improvements are secondary to the mode of ventilation or decreased sedation. Regardless of the reason, patients overall do better with some amount of spontaneous ventilation while being mechanically ventilated. In pediatric patients, however, maintaining appropriate levels of sedation is more challenging. Although in theory allowing spontaneous ventilation by maintaining lower levels of sedation is ideal, I believe it would be more difficult in the pediatric population, in particular the younger patients.

2. Were all clinically important outcomes considered?

The clinical outcomes evaluated by the study which showed a significant improvement in the APRV group over the PCV group were length of ventilator support required, the length of intubation, and length of ICU stay. There was no improvement in the number of survivors, however, between the two groups. Of course with the small size of the study, finding a difference in mortality would be very unlikely.

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

The one significant cost to be considered in providing the APRV mode of ventilation is acquiring a ventilator that delivers this mode. (The ventilator used in the study was the Evita from Drager, Lubeck, Germany.) Otherwise, there appear to be no significant harms to using the APRV mode of ventilation since it allows the patient to receive accepted standards of care. The only significant difference is that the patient is allowed to maintain spontaneous respirations. I would submit that the treatment benefits of improved cardiorespiratory function along with increased ventilator free days in the face of non-existent harm is a worthwhile treatment modality presuming that one has access to a ventilator that allows for this mode.

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