The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Low-Tidal-Volume Ventilation in the Acute Respiratory Distress Syndrome Atul Malhotra, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

A 55-year-old man who is 178 cm tall and weighs 95 kg is hospitalized with community-acquired pneumonia and progressively severe dyspnea. His arterial oxygen saturation while breathing 100% oxygen through a face mask is 76%; a chest radiograph shows diffuse alveolar infiltrates with air bronchograms. He is intubated and receives mechanical ventilation; ventilator settings include a tidal volume of 1000 ml, a positive end-expiratory pressure (PEEP) of 5 cm of water, and a fraction of inspired oxygen (FiO2) of 0.8. With these settings, peak airway pressure is 50 to 60 cm of water, plateau airway pressure is 38 cm of water, partial pressure of arterial oxygen is 120 mm Hg, partial pressure of carbon dioxide is 37 mm Hg, and arterial blood pH is 7.47. The diagnosis of the acute respiratory distress syndrome (ARDS) is made. An intensive care specialist evaluates the patient and recommends changing the current ventilator settings and implementing a low-tidal-volume ventilation strategy.

The Cl inic a l Probl e m Acute lung injury is defined by the American–European Consensus Conference as the acute onset of impaired gas exchange (the ratio of the partial pressure of arterial oxygen in millimeters of mercury to the FiO2 of 12 ml/kg quartile). In the multivariate analysis of the Spanish trial [19], the prone position was an independent risk factor associated with increased patient survival.

Conclusion During the last 15 years numerous studies consistently described the beneficial effects of the prone position on the lungs. Originating with marked improvement in oxygenation it has now become clear that the prone position can distribute ventilation, VILI and lung strains more homogeneously throughout the lungs. The mechanisms for this are not fully understood and include gravity, lung structure and other unknown factors. Therefore, the prone position can improve oxygenation without inducing and even by preventing lung overdistension/ hyperinflation. Hence, the prone position is a full component of a lung protective ventilatory strategy and a smart way to manage severe ARDS patients. The question is whether the prone position can be strongly recommended because a high level of clinical evidence is

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54 Respiratory system

lacking. Since patient outcome in ARDS regularly improves with the improvement in patient care and mechanical ventilation, it is now difficult for an intervention to prove its efficiency. Alternatively, even though turning prone is apparently simple with a low economical burden, its practice in daily intensive care unit life is still associated with some side effects, the incidence of which should be reduced by implementation of guidelines. Another RCT in the most severe ARDS patients, completed up to the required power, is mandatory, therefore, to clarify the impact of the prone position on outcome.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest

of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 67). 1

Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568–573.

2

Mure M, Martling CR, Lindahl SG. Dramatic effect on oxygenation in patients with severe acute lung insufficiency treated in the prone position. Crit Care Med 1997; 25:1539–1544.

3

Broccard AF, Shapiro RS, Schmitz LL, et al. Influence of prone position on the extent and distribution of lung injury in a high tidal volume oleic acid model of acute respiratory distress syndrome. Crit Care Med 1997; 25:16–27.

Gue´rin C, Gaillard S, Lemasson S, et al. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. JAMA 2004; 292:2379–2387. This is the largest RCT on the prone position to date. It did not show any change in mortality.

4


Vieillard-Baron A, Rabiller A, Chergui K, et al. Prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome. Intensive Care Med 2005; 31:220–226. Prospective physiologic study done in 11 severe ARDS patients showing suppression of expiratory flow limitation and increased alveolar ventilation with the prone position. This is the first study in humans indicating that the prone position reduced VALI.

5



8

Pelosi P, Tubiolo D, Mascheroni D, et al. Effects of the prone position on respiratory mechanics and gas exchange during acute lung injury. Am J Respir Crit Care Med 1998; 157:387–393.

9

Gainnier M, Michelet P, Thirion X, et al. Prone position and positive endexpiratory pressure in acute respiratory distress syndrome. Crit Care Med 2003; 31:2719–2726.

10 Gattinoni L, Vaggineli F, Carlesso E, et al. Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome. Crit Care Med 2003; 31:2727–2733. 11 Rouby JJ, Lu Q, Goldstein I. Selecting the right level of positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 165:1182–1186. 12 Rouby JJ, Puybasset L, Nieszkowska A, Lu Q. Acute respiratory distress syndrome: lessons from computed tomography of the whole lung. Crit Care Med 2003; 31:S285–S295. 13 Rouby JJ, Puybasset L, Cluzel P, et al. Regional distribution of gas and tissue in acute respiratory distress syndrome. II: Physiological correlations and definition of an ARDS Severity Score. CT Scan ARDS Study Group. Intensive Care Med 2000; 26:1046–1056. 14 Johansson MJ, Wiklund A, Flatebo T, et al. Positive end-expiratory pressure
affects regional distribution of ventilation differently in supine and prone sheep. Crit Care Med 2004; 32:2039–2044. Comprehensive description of regional distribution of ventilation using two highresolution methods (technegas and fluorescent microspheres). 15 Mentzelopoulos SD, Roussos C, Zakynthinos E. Prone position reduces lung

stress and strain in severe acute respiratory distress syndrome. Eur Respir J 2005; 25:534–544. In this very well designed and carefully performed study, the authors measured lung stress as the transpulmonary plateau pressure and lung strain as tidal volume/ EELV ratio and found both of them were reduced with the prone position. 16 Valenza F, Guglielmi M, Mafioletti M, et al. Prone position delays the progres

sion of ventilator-induced lung injury in rats: does lung strain distribution play a role? Crit Care Med 2005; 33:361–367. Study done in 30 rats, 15 in the prone position and 15 in the supine position. VILI induced by high tidal volume. Very smart design. CT scan assessment. 17 Reignier J, Thenoz-Jost N, Fiancette M, et al. Early enteral nutrition in mechanically ventilated patients in the prone position. Crit Care Med 2004; 32:94–99.

6

Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149:1327–1334.

18 Bein T, Sabel K, Scherer A, et al. Comparison of incomplete (1358) and complete (1808) prone position in patients with acute respiratory distress syndrome: results from a prospective randomised trial. Anaesthesist 2004; 53:1053–1060.

7

Koutsoukou A, Armaganidis A, Stavrakaki-Kallergi C, et al. Expiratory flow limitation and intrinsic positive end-expiratory pressure at zero positive endexpiratory pressure in patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161:1590–1596.

19 Mancebo J, Rialp G, Fernandez R, et al. Randomized multicenter trial in ARDS: supine versus prone position [abstract]. Intensive Care Med 2003; 29:S64.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Intensive Care Med (2005) 31:227–235 DOI 10.1007/s00134-004-2506-z

John L. Moran Andrew D. Bersten Patricia J. Solomon

Received: 11 December 2003 Accepted: 30 December 2004 Published online: 28 January 2005
Springer-Verlag 2005

Electronic Supplementary Material Electronic supplementary material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/ 10.1007/s00134-004-2506-z.. J. L. Moran ()) Department of Intensive Care Medicine, Queen Elizabeth Hospital, 28 Woodville Road, 5011 Woodville, SA, Australia e-mail: [email protected] Tel.: +61-08-82226463 Fax: +61-08-82226045 A. D. Bersten Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, SA, Australia P. J. Solomon School of Mathematical Sciences, University of Adelaide, Adelaide, SA, Australia

ORIGINAL

Meta-analysis of controlled trials of ventilator therapy in acute lung injury and acute respiratory distress syndrome: an alternative perspective

Abstract Objective: The role of protective ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is controversial. Evidence was sought from published randomised trials for a consistent treatment effect of protective ventilation and any covariate modification. Design: Meta-analysis of protective ventilation trials in ALI/ ARDS and meta-regression of covariates on treatment effect (log odds ratio), with respect to 28-day mortality. Heterogeneity impact on the meta-analysis was assessed by the H statistic (substantial impact, >1.5) and graphical analysis. Five trials with a total of 1,202 patients were considered. Measurements and results: Average 28-day mortality was 0.40 in the treatment group (protective ventilation, n=605) vs. 0.46 in the control group (control ventilation, n=597). The treatment effect (odds ratio) was: fixed-effects, 0.71 (95% CI 0.56–0.91, p=0.006; heterogeneity, p=0.06) and random effects: 0.80

Introduction The recently reported trial of “low” (6 ml/kg predicted body weight) tidal volume ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by the ARDS Network [1] in 2000 appears to have established the efficacy of this ventilatory strategy although initial concerns were expressed in correspondence regarding the “unconventionally high plateau pressures in the group treated with traditional tidal volumes” [2]. The

(95% CI 0.49–1.31, p=0.37). Heterogeneity impact (H statistic=1.50) was adjudged as modest. The treatment effect was significant and (a) favoured protective ventilation for a tidal volume less than 7.7 ml/kg predicted (treatment group) and a mean plateau pressure of 30 cmH2O or higher (control group) but was not influenced by plateau pressure 21– 30 cmH2O (treatment group) and (b) depended upon plateau pressure difference greater than 5–7 cmH2O between protective ventilation and standard ventilation. Conclusions: Overall treatment effect estimate favoured protective ventilation but did not achieve statistical significance. Protective ventilation depended upon threshold levels of tidal volume, plateau pressure, and plateau pressure difference. Keywords Meta-analysis · Acute lung injury · Acute respiratory distress syndrome · Heterogeneity · Meta-regression · Plateau pressure

smaller difference in plateau pressures between treatment arms had already been advanced in the accompanying editorial [3] to the ARDS Network publication as a potential reason for the failure to demonstrate a treatment effect in three previous trials [4, 5, 6] of lung protective ventilation. Similarly, an editorial in early 2002 reviewing what was “best for ARDS management” concluded that, “These studies do not tell us whether ARDS patients should be ventilated with a tidal volume of 6 ml/kg body weight or simply only less than 12 ml/kg” [7].

228

Table 1 Patient outcomes, demographics and treatment variables (mean values) (N/A not available)

Protective ventilation Dead Alive Mortality: 28 day Age (years) Women (%) APACHE II score, baseline Mechanical tidal volume (ml/kg-predicted) Plateau pressure (cmH2O): day 1 Plateau pressure (cmH2O): days 1–7 Standard ventilation Dead Alive Mortality: 28 day Age (years) Women (%) APACHE II score, baseline Mechanical tidal volume (ml/kg-predicted) Plateau pressure (cmH2O): day 1 Plateau pressure (cmH2O): days 1–7 a b c

Brochard et al. [4]

Stewart et al. [6]

Amato et al. [9]

Brower et al. [5]

ARDSNet [1]

22 36 0.38 57 0.43 18 7.8

30 30 0.50a 59 0.22 22.4 8.1

11 18 0.38 33 N/A 24 7.3c

13 13 0.50a 49.8 0.58 22.65 7.3

108 324 0.25 51 0.4 21.5 6.3

25.7

22.3

30.1

27

25

25.2

21.5

27

24.9b

25.7

18 40 0.31 56.5 0.43 17 11.3

28 32 0.47a 58 0.38 21.5 12.2

17 7 0.71 36 N/A 24 14.2

12 14 0.46 46.9 0.31 24.15 10.2

150 279 0.35 52 0.41 22.5 11.7

31.7

26.8

36.8

31

33

31.7

27.97

37.3

30.6b

34.7

Hospital mortality Days 1–5 Averaged over first 7 days

Against this background, two more recent papers have added to the debate on protective ventilation; a metaanalysis [8] of the five randomised controlled trials of this intervention [1, 4, 5, 6, 9] and a health policy report detailing the institutional responses to the controversies over “How best to ventilate” [10]. Considerable retort has followed this meta-analysis: an editorial [11], correspondence from the original ARDS Network [12] trial authors and exchanges over the detail of both the meta-analysis and the trials. The purpose of the present analysis is to contribute to the “continued scrutiny” [13] of the trials above, an endeavour parallel to that of the recent review by Petrucci and Iacovelli [14]. First, we departed from the approach of Eichacker et al. [8] who grouped the trials into beneficial/non-beneficial based upon heterogeneity and thus did not consider the implications of a pooled estimate of the efficacy of protective ventilation. Second, and contingent upon this pooled estimate, we investigated the underlying cause(s) of the heterogeneity using meta-regression [15]. Rather than the existence of heterogeneity precluding the finding of covariate modification of the pooled estimate [16, 17], the “primary value of metaanalysis is in the search for predictors of between-study heterogeneity” [18] and serves also to formalise the attempt by Eichacker et al. [8] to relate plateau pressure and mortality. Devoid of a pooled estimate, there is limited

ability to examine those variables which may have determined heterogeneity [11]. Third, we highlight the question of the cause of the observed treatment effect in the two “positive” trials [1, 9]: an increase in control mortality as a consequence of high plateau pressures or decrease in treatment arm mortality due to low plateau pressures. Some debate has occurred over the propriety of the increment of mechanical tidal volume in the treatment arm of the ARDS Network trial [19]; this question is not directly canvassed; rather the comment by Senn [20] is noted: “Clinical trials are not and never will be representative of general medical practice”.

Methods The study population comprised the five trials [1, 4, 5, 6, 9] identified above [8] using protective ventilation in ALI/ARDS. The outcome end-point was 28-day mortality except for the Brower et al. [5] and Stewart et al. trials [6], where hospital mortality was used. Data for 28-day outcomes in both the Multicenter Trial group on Tidal Volume Reduction in ARDS (trial report, 60 day outcome [4]) and the ARDS Network Trial (trial report, 180 day outcome [1]) were supplied on request to the study authors. The relationship between Acute Physiology and Chronic Health Evaluation (APACHE) versions III and II scores was deemed to be: APACHE III score=4.48+3.259 APACHE II score (R2=0.81, P=0.0001). This was based upon a sample of 73,000 patients from the Aus-

229

Fig. 1 Mortality outcome: Forrest plot, random effect estimates. Horizontal axis Odds ratio; vertical axis individual trials; vertical solid line line of null effect; vertical dashed line pooled estimate; horizontal lines 95% CI of point estimates indicated as solid squares, the size of which reflects the weight (% weight column) accorded the study in the analysis

tralian and New Zealand Intensive Care Society (ANZICS) database, as recently reported [21]. Table 1 presents patients’ outcomes and demographic characteristics (age, gender, APACHE II score at study entry) for each arm of the trials. Overall the trials included 1,202 patients: 605 receiving protective ventilation and 597 control ventilation. Mean age was 50 years in both arms, 41% were women in the treatment arm and 38% in controls, and mean APACHE II score was 21.7 in the treatment arm and 21.8 in control. For individual trials values for mean mechanical tidal volume in milliliters per predicted kilogram, after the definitions of the ARDS Network [1], were derived from: the two trials in which tidal volume was prescribed according to these definitions [1, 5], estimates made by the ARDS Network [1] authors for two trials [4, 6], and calculated from values reported in the original meta-analysis [8] according to the estimated ratio, measured body weight=1.2 predicted weight [19], for the remaining trial [9]. Estimated average plateau pressures over day 1 and days 1–7 of ARDS were obtained from the same trial reports; in the Amato et al. trial [9] day 1 values were those over the first 36 h; in the Brower et al. trial [5] values for day 1 were derived from the graphic and values, as reported in the paper, for days 1–5 only were used. The range of mechanical tidal volumes was 6.3–8.1 ml/kg-predicted in the treatment arm and 10.2–14.2 ml/kg-predicted in controls. The range of plateau pressures was 21–30 cmH2O in the treatment arm and 27–37 cmH2O in controls. The analytic strategy was: (a) Initial determination of the pooled treatment effect (fixed effects) as odds ratio [OR, treatment arm (protective ventilation) vs. control (control ventilation)] using the “metan” routine [22] and Stata statistical software (version 8.2, 2003, Stata, College Station, Tex., USA). Dependent upon evaluation of heterogeneity (see a, below), random effects estimates were also determined. Cumulative meta-analytic estimates, whereby the cumulative estimate up to and including each individual trial, were also graphically displayed [23]; trial year-date was determined as being that of actual trial termination in the respective published reports. (b) Assessment of heterogeneity: the extent of heterogeneity was assessed by the Q statistic, the Breslow-Day and Zelen exact test of homogeneity of ORs (StatXact 4 for Windows release 4.0.1, Cytel Software, CambridgeMass., USA). The (p value) level at which heterogeneity should be diagnosed is unclear, given that the Q statistic has low power, and Fleiss has recommended a value of at least 0.1 [24]. The impact of heterogeneity upon (the pooled estimates of) the meta-analysis was assessed using the H and I 2

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