clinical investigations in critical care

Prospective Randomized Trial Comparing Pressure-Controlled Ventilation and Volume-Controlled Ventilation in ARDS*
Andre s Esteban, MD, PhD; Inmaculada Al a, MD; Federico Gordo, MD; Rau l de Pablo, MD; Jose Suarez, MD; Gumersindo Gonza lez, MD; and Jesu s Blanco, MD; for the Spanish Lung Failure Collaborative Group

Study objectives: To compare in-hospital mortality of patients with ARDS ventilated with either pressure-controlled ventilation (PCV) or volume-controlled ventilation (VCV) with a square-wave inspiratory flow. Design: Multicenter and randomized trial. Setting: Twelve medical-surgical ICUs located in tertiary-care hospitals. Patients: Seventy-nine patients having ARDS, as defined by the American-European Consensus Conference. Interventions: Patients were randomly assigned to be ventilated with either PCV (n 37) or VCV (n 42). In both instances, inspiratory plateau pressure was limited to < 35 cm H2O. Measurements and results: There were no significant differences among the studied groups at the moment of randomization, although there was a trend toward greater renal failure in patients assigned to VCV. Ventilatory settings and blood gases did not significantly differ over time between the two groups. Patients in the VCV group had both a significantly higher in-hospital mortality rate than those in the PCV group (78% vs 51%, respectively) and a higher number of extrapulmonary organ failures (median, 4 vs 2, respectively). The development of renal failure during the study period was also significantly more frequent among VCV patients (64% vs 32%, respectively). Multivariate analysis showed that factors independently associated with an increased mortality rate were the presence of two or more extrapulmonary organ failures (odds ratio [OR], 4.61; 95% confidence interval [CI], 1.38 to 15.40) and acute renal failure (OR, 3.96; 95% CI, 1.10 to 14.28) but not the ventilatory mode used. Conclusions: The increased number of extrapulmonary organ failures developed in patients of the VCV group was strongly associated with a higher mortality rate. The development of organ failures was probably not related to the ventilatory mode. (CHEST 2000; 117:1690 1696)
Key words: ARDS; mortality; pressure-controlled ventilation; volume-controlled ventilation Abbreviations: CI confidence interval; Fio2 fraction of inspired oxygen; I/E ratio of inspiration to expiration; OR odds ratio; PCV pressure-controlled ventilation; PEEP positive end-expiratory pressure; VCV volume-controlled ventilation; Vt tidal volume

is associated with mortality rates ranging A RDS from 40 to 70%. Clinical management of respi1

ratory failure in ARDS typically requires ventilatory assistance that is aimed at maintaining pulmonary function while the lung injury resolves. Mechanical ventilation, although life-sustaining, can be harmful

to the diseased lung, especially when high ventilatory volumes and pressures that cause lung overdistension are used.2,3 This observation led us to think that ventilatory strategies designed to avoid exposing the lung to high pressures or volumes might improve outcome. Consequently, it has been recommended

*From the Hospital Universitario de Getafe (Drs. Esteban, Al a, and Gordo), Getafe, Spain; Hospital Pr ncipe de Asturias (Dr. de Pablo), Alcala de Henares, Spain; Hospital Severo Ochoa (Dr. Suarez), Legane s, Spain; Hospital Morales Meseguer (Dr. Gonza lez), Murcia, Spain; and Hospital del R o Ortega (Dr. Blanco), Valladolid, Spain.
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A complete list of the members of the Spanish Lung Failure Collaborative Group is located in the Appendix. Manuscript received August 12, 1999; revision accepted December 28, 1999. Correspondence to: Andre s Esteban, MD, PhD, Unidad de Cuidados Intensivos, Hospital Universitario de Getafe, Carretera de Toledo Km 12,5, Getafe 28905. Spain; e-mail: [email protected]
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that, under conditions in which lung overdistension is likely to occur, tidal volumes (Vts) and airway pressures should be limited, accepting the attendant increase in arterial carbon dioxide levels.4 Theoretically, pressure-limited ventilation can be equally provided by either pressure-targeted modes that limit airway pressure to preset levels or by volumecycled ventilation with tightly set pressure alarms and close monitoring of plateau pressure. Pressure-controlled ventilation (PCV) is a time-cycled mode in which approximately square waves of pressure are applied and released by means of a decelerating flow.5 The decelerating waveform results in a more laminar flow at the end of inspiration, resulting in a more even distribution of ventilation in patients who have markedly different resistance values from one region to the lung to another.6,7 A number of studies have demonstrated an improvement in oxygenation and pulmonary mechanics in patients with ARDS who were switched from volume-controlled ventilation (VCV) to PCV.8,9 For example, Davis et al9 prospectively crossed-over 25 patients with acute lung injury from VCV with square flow waveform to PCV and observed that VCV with square flow was associated with significantly lower Pao2 levels, higher inspiratory peak pressures, and lower mean airway pressures than PCV. Many years ago in an editorial, Marini and Kelsen10 emphasized the need for prospective controlled trials comparing PCV to conventional ventilation at fixed transalveolar pressures. Two years later, two prospective and randomized studies comparing PCV and VCV were published.11,12 Lessard et al11 compared, in nine patients with ARDS, PCV and VCV while keeping both the level of ventilation and end-expiratory alveolar pressure (ie, total positive end-expiratory pressure [PEEP]) constant, and no differences in respiratory mechanics, hemodynamics, or gas exchange parameters were observed. Rappaport et al12 prospectively compared early application of PCV and VCV in 27 patients with acute hypoxic respiratory failure and found that PCV was associated with a more rapid increase in static compliance and fewer days of mechanical ventilation in patients who survived and were extubated. No study has evaluated the effect of PCV on the morbidity and in-hospital mortality of ARDS patients. We undertook this study to determine whether hospital mortality of ARDS patients is influenced by the ventilatory mode used (PCV or VCV), when a strategy of mechanical ventilation limiting inspiratory pressure is implemented. Materials and Methods
Patients From February 1995 to January 1996, we enrolled patients at 12 ICUs in 12 tertiary-care hospitals. The study was approved by

the institutional review board of each medical center, and informed consent was obtained from each patient or the patients next of kin. The criteria for enrollment were as follows: (1) one or more underlying disease processes that are known to be associated with ARDS (sepsis, shock, pneumonia, multiple transfusions, pulmonary contusion, multiple fractures, gastric aspiration, acute pancreatitis, near-drowning, etc); and (2) diagnostic criteria for ARDS, as defined in the American-European Consensus Conference13 (acute onset, bilateral chest radiographic infiltrates, pulmonary artery occlusion pressure 18 mm Hg or no evidence of left atrial hypertension, and Pao2/fraction of inspired oxygen [Fio2] ratio 200 mm Hg). Exclusion criteria were the following: age 18 years; pregnancy; head injury; coronary disease; enrollment in another interventional study; immunosuppression; burns; and the presence of any form of barotrauma (pneumothorax, pneumomediastinum, pneumoperitoneum, pneumopericardium, or subcutaneous emphysema). Intervention Patients were randomly assigned with the use of a random number table to receive either VCV or PCV. Patients were allocated to the two groups in a blinded fashion with the use of opaque, sealed, numbered envelopes, which were opened only when a patient fulfilled all of the inclusion criteria. Randomization was performed by permuted blocks according to the study center. VCV was always delivered with a square-wave inspiratory flow. For both groups, plateau inspiratory pressure was limited to 35 cm H2O. PEEP and Fio2 were titrated to maintain an oxygen saturation of 89 to 92% with the least Fio2 and a PEEP level never 5 cm H2O. Respiratory rate, ratio of inspiration to expiration (I/E), and either Vt in the VCV group or inspiratory pressure in the PCV group were adjusted in an attempt to maintain Paco2 at 35 to 45 mm Hg, but hypercapnia was accepted if this target could not be achieved with a plateau pressure 36 cm H2O. For both groups, adjustments of the I/E ratio were used at the discretion of the attending physician, with 3:1 being the maximal I/E ratio allowed. For both groups, IV sodium bicarbonate infusions were permitted if the arterial pH was 7.20. If the pH remained 7.20 despite bicarbonate sodium infusion, the Vt in the VCV group or the inspiratory pressure in the PCV group was increased until the pH reached 7.20. No study has specifically addressed the use of bicarbonate administration in acute respiratory acidosis. On the one hand, the CO2 generated from the buffering of protons by exogenous bicarbonate cannot be promptly excreted in the presence of reduced alveolar ventilation, so hypercapnia may be exacerbated. On the other hand, acidosis can blunt the myocardial and vascular responsiveness to catecholamines. It was thought that maintaining arterial pH at 7.20 theoretically might minimize any adverse circulatory changes associated with respiratory acidosis in the studied patients. Ventilatory data were recorded daily until successful extubation (defined as a period of 48 h without mechanical ventilation) or death. The following data were recorded each day: the best Pao2/Fio2 ratio, the highest Paco2 level, the lowest arterial pH, the highest plateau pressure, the maximal I/E, the highest Vt, the maximal respiratory rate, the appearance of any form of barotrauma (pneumothorax, pneumomediastinum, pneumoperitoneum, pneumopericardium, or subcutaneous emphysema), and the dose of sodium bicarbonate administered. Static compliance was measured once a day using a Vt of 10 mL/kg body weight and an inspiratory pause of 1.5 s. The development of multiple organ failure syndrome over the study period also was recorded. Organ failures were defined as follows: (1) renal failure, defined as a serum creatinine level
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 2.0 mg/dL or requirement for artificial renal support; (2) cardiovascular failure, defined as a pulmonary artery occlusion pressure of 18 mm Hg or a requirement for dopamine, dobutamine, or norepinephrine to maintain a mean arterial BP of 60 mm Hg or a cardiac index of 2.5 L/min/m2; (3) hepatic failure, defined as a total bilirubin level of 2.5 mg/dL and an elevation of transaminases or alkaline phosphatase to at least twice the upper limit of normal values; (4) coagulation failure, defined as a platelet count of 60,000/mm3 and an elevation of the partial thromboplastin time or the prothrombin to 1.5 times the control value; (5) CNS failure, defined as a score on the Glasgow coma scale of 10 in the absence of sedation; (6) GI failure, defined as upper digestive tract bleeding or ileus; and (7) metabolic failure, defined as an insulin requirement of 5 U/h. Outcome Measures The primary outcome was the in-hospital mortality rate. Secondary outcomes included the following: (1) in-ICU mortality rate; (2) the length of stay in the ICU and in the hospital; (3) the appearance of any form of barotrauma (pneumothorax, pneumomediastinum, pneumoperitoneum, pneumopericardium, or subcutaneous emphysema); and (4) the number of organ failures. Statistical Analysis Data are presented as mean and SD. An intention-to-treat analysis was used. A 2 test or Fishers Exact Test was used for comparisons of categorical variables. Continuous variables were compared with a Mann-Whitney U test. Kaplan-Meier survival curves were compared using the log-rank test. A p value of 0.05 was considered to indicate statistical significance.

Table 1Baseline Demographic and Clinical Characteristics of the Study Groups*

Characteristics Age, yr Female SAPS II score on admission Duration of mechanical ventilation before entry, d Lung injury score Pao2/Fio2 Static compliance, mL/cm H2O Patients without organ failures Extrapulmonary organ failures, No. Cardiovascular failure Renal failure Liver failure Coagulation failure Digestive failure Metabolic failure CNS failure VCV (n 42) 59 16 12 (29) 42 17 33 2.9 0.5 131 48 30 10 6 (14) 2.4 1.2 31 (74) 12 (28) 8 (19) 13 (31) 11 (26) 3 (7) 7 (17) PCV (n 37) 56 17 13 (35) 39 14 44 2.8 0.6 126 47 31 14 7 (19) 2.1 1.2 23 (62) 5 (13) 9 (24) 10 (27) 10 (27) 2 (5) 5 (13) p Value 0.48 0.70 0.71 0.30

0.46 0.63 0.72 0.58 0.38 0.38 0.06 0.77 0.89 0.86 0.34 0.23

*Values given as mean SD or No. of patients (%), unless otherwise indicated. SAPS simplified acute physiology score.

Results Seventy-nine patients with ARDS were enrolled in the study, 42 in the VCV group and 37 in the PCV group. There were no significant differences between the studied groups regarding clinical characteristics and risk factors for ARDS at the moment of randomization (Tables 1, 2), although a trend toward a higher rate of acute renal failure was observed in patients of the VCV group (Table 1), and there was also a tendency toward a higher percentage of patients with shock as a risk factor for ARDS in the VCV group than in the PCV group (52% vs 38%, respectively; p 0.19). The values of ventilatory parameters on days 1, 4, 7, 14, and 21 are presented in Table 3, and those of parameters for arterial blood gases are presented in Table 4. As expected by the study design, ventilatory settings did not differ significantly over time between the two groups. Oxygenation was not different over the study period in patients ventilated with PCV as compared with patients ventilated with VCV. The main outcomes are summarized in Table 5. Patients in the VCV group had significantly higher in-hospital mortality rates than patients in the PCV group (78% vs 51%, respectively; 95% confidence interval [CI] for the difference between the groups,
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4.3 to 50.1%). Survival curves for both groups are shown in Figure 1. Most fatalities resulted from multiple organ failure or shock (PCV group, 68%; VCV group, 71%), but four patients in the PCV group and five patients in the VCV group died from intractable respiratory failure. There were no significant differences between the two groups for the incidence of barotrauma, the duration of mechanical ventilation, the length of stay in the ICU, or the length of stay in the hospital (Table 5). However, the number of organ failures was significantly higher in patients of the VCV group. We identified the variables predicting mortality in the univariate analysis, and, thereafter, stepwise

Table 2Distribution of Risk Factors for ARDS*

Risk Factors Sepsis Shock Pneumonia Multiple transfusions Pulmonary contusion Multiple fractures Gastric aspiration Acute pancreatitis Near-drowning Other *Values given as No. of patients. VCV (n 42) 23 22 18 4 3 4 4 1 2 PCV (n 37) 19 14 17 3 3 5 4 4 1

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Table 3Ventilatory Parameters During the Study Period*

Day 1 Parameters Plateau pressure, cm H2O Vt, mL/kg Respiratory rate, breaths/min Fio2, % Total PEEP, cm H2O Tinsp/Ttot, % VCV 32 (5) 8.3 (2.5) 19 (6) 0.79 (0.21) 12 (4) 0.68 (0.33) PCV 33 (6) 8.0 (1.9) 19 (4) 0.73 (0.21) 11 (4) 0.87 (0.45) VCV 32 (6) 8.3 (2.4) 20 (6) .73 (0.21) 11 (4) 0.74 (0.40) Day 4 PCV 33 (7) 8.2 (2.6) 19 (4) 0.75 (0.23) 11 (4) 0.81 (0.42) VCV 34 (7) 8.3 (2.6) 20 (6) 0.70 (0.23) 12 (5) 0.81 (0.55) Day 7 PCV 34 (8) 8.1 (2.4) 19 (5) 0.66 (0.22) 10 (4) .81 (0.50) VCV 32 (7) 7.8 (2.3) 22 (7) 0.73 (0.24) 11 (4) 0.88 (0.66) Day 14 PCV 36 (9) 7.2 (2.2) 20 (84) 0.70 (0.24) 12 (6) 0.78 (0.51) VCV 33 (11) 8.1 (2.3) 20 (6) 0.57 (0.20) 8 (3) 0.81 (0.73) Day 21 PCV 31 (5) 7.8 (3.1) 20 (6) 0.50 (0.07) 7 (3) 0.60 (0.22)

*Values given as mean (SD). Tinsp/Ttot ratio of inspiratory time to total respiratory time. p 0.05.

multiple logistic regression analysis was performed to estimate the independent effect of each variable on mortality after controlling for the other variables. The variables associated with a significantly higher mortality rates in the univariate analysis were the following: age, 65 years (odds ratio [OR], 1.57; 95% CI, 1.13 to 2.17); simplified acute physiology II score on admission, 40 (OR, 1.63; 95% CI, 1.15 to 2.32); number of extrapulmonary organ failures, 2 (OR, 2.31; 95% CI, 1.38 to 3.85); acute renal failure (OR, 2.01; 95% CI, 1.38 to 2.92); cardiovascular failure (OR, 1.76; 95% CI, 0.98 to 3.17); coagulation failure (OR, 1.36; 95% CI, 0.99 to 1.86); and VCV (OR, 1.53; 95% CI, 1.08 to 2.17). Only the following two factors were independently associated with an increased mortality rate: the presence of two or more extrapulmonary organ failures over the study period (OR, 4.61; 95% CI, 1.38 to 15.40); and acute renal failure (OR, 3.96; 95% CI, 1.10 to 14.28). Discussion The main finding of this study was that, in patients with ARDS who require mechanical ventilation, the way in which mechanical ventilation is provided to deliberately reduce the inspiratory plateau pressure, by

decreasing either Vt on VCV or inspiratory pressure on PCV, does not independently influence mortality. We also have found that the mortality of ARDS patients is strongly associated with the development of multiple organ failure, with especially those patients with acute renal failure having a very poor prognosis. Although the survival rate of ARDS patients may have improved,14 it still remains at a level of 50% and mainly depends on the severity of the underlying disease and the accompanying organ dysfunction.1,1518 In-hospital mortality rates in our patients of the VCV group seem to be extremely high despite studies that have reported similar rates. For example, the study by Amato et al19 showed a mortality rate of 71% in the conventional ventilation group, and the study by Brochard et al20 showed a mortality rate around 70% in patients in the pressure-limitation group who developed secondary multiple organ failure. The increased mortality rate in patients of the VCV group as compared with patients of the PCV group was explained as being the result of both the number of extrapulmonary organ failures and the incidence of acute renal failure, the values for which were significantly higher in those VCV patients. There are a number of possible explanations for the increased incidence of multiple organ failure

Table 4 Arterial Blood Gases and Compliance During the Study Period*
Day 1 Characteristics Pao2/Fio2, mm Hg Paco2, mm Hg Arterial pH Compliance, mL/cm H2O VCV 128 (45) 51 (15) 7.31 (0.10) 29 (9) PCV 147 (59) 52 (16) 7.31 (0.11) 31 (13) VCV 141 (65) 52 (14) 7.34 (0.10) 30 (11) Day 4 PCV 137 (53) 49 (10) 7.36 (0.09) 32 (14) VCV 150 (67) 54 (13) 7.35 (0.10) 28 (11) Day 7 PCV 163 (93) 51 (16) 7.36 (0.10) 35 (15) VCV 183 (79) 50 (16) 7.36 (0.10) 31 (13) Day 14 PCV 146 (53) 58 (23) 7.35 (0.06) 28 (11) VCV 202 (100) 56 (16) 7.35 (0.09) 28 (12) Day 21 PCV 217 (65) 53 (18) 7.41 (0.05) 28 (12)

*Values given as mean (SD). CHEST / 117 / 6 / JUNE, 2000

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Table 5Main Outcomes*

Outcomes In-ICU mortality In-hospital mortality Barotrauma ICU length of stay, d Hospital length of stay, d Extrapulmonary organ failures, No. Cardiovascular failure Renal failure Liver failure Coagulation failure Digestive failure Metabolic failure CNS failure VCV (n 42) PCV (n 37) 29 (69) 33 (78) 4 (9) 25 19 30 24 3.7 1.8 33 (78) 27 (64) 18 (43) 22 (52) 16 (38) 7 (17) 7 (17) 18 (49) 19 (51) 6 (16) 21 15 27 20 2.6 1.5 25 (67) 12 (32) 9 (24) 12 (32) 11 (30) 4 (16) 6 (16) p Value 0.11 0.02 0.18 0.46 0.84 0.005 0.39 0.009 0.13 0.12 0.59 0.20 0.24

*Values given as mean SD or No. of patients (%), unless otherwise indicated.

syndrome and acute renal failure in the VCV group. First, it is quite likely that patients at risk for renal dysfunction were mainly distributed in the VCV group. Whenever a randomized study is performed, it is reasonable to assume that the randomization process equally distributes risk factors for morbidity and mortality among patients of the studied groups. However, this did not completely work out in our study since a trend toward a higher percentage of patients with either acute renal failure or with shock as a risk factor for ARDS was observed at enrollment in the VCV group. On the other hand, the increase in the relative risk for acute renal failure among patients in the VCV group as compared with those in the PCV group was similar before and after the exposure to VCV (relative risk at the moment of

Figure 1. The Kaplan-Meier curves of the probability of survival over time between patients in the PCV group (dashed line) and patients in the VCV group (solid line). p 0.19 for the log-rank test.
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randomization, 112%; and relative risk after entry into the study, 128%). Second, CO2 has known vasoactive properties that might impair renal blood flow leading to renal failure,21 but Paco2 values did not differ significantly over time between the two study groups. Third, VCV caused the impairment of renal function by initiating a systemic inflammatory response. Mechanical ventilation has been shown to have significant effects on the levels of inflammatory cells and soluble mediators in the lung and might play a pivotal role in the pathogenesis of the systemic inflammatory response that leads to multiple organ failure syndrome.22,23 The hypothesis that VCV induced a more severe systemic inflammatory response than PCV seems as appealing as it is unlikely since the ventilatory strategy used for patients of the VCV group was equally injurious, in terms of endinspiratory volume and pressure, as that used for patients of the PCV group. The only difference between the two studied ventilatory modes was the inspiratory flow waveform profile, and, at the moment, we are unaware of any study showing that the inspiratory flow waveform profile is a major determinant of ventilator-induced lung injury. Finally, the fact that prospective studies comparing conventional ventilatory strategies with a less injurious (protective) strategy have reported similar numbers of organ failures in the study groups,20,24 leads us to think that there is not a causal effect between the way in which mechanical ventilation is delivered and the development of multiple organ failure syndrome. Respiratory failure directly accounts for 20% of deaths in patients with ARDS in several studies.15,2527 We have found similar results and have also showed that refractory hypoxemia is as frequent in patients ventilated with PCV as in those ventilated with VCV. Davis et al9 reported more improved oxygenation with PCV than with VCV when Vt, inspiratory time, and PEEP were held constant and that this finding was thought to be due to an increase in mean airway pressure. However, other authors have demonstrated that oxygenation does not improve, or even deteriorates slightly, when PCV has been compared with VCV, despite a higher mean airway pressure with PCV.11,28 Our data agree with those of Lessard et al11 and Mancebo et al28 that relatively minor differences in gas-exchange efficiency are expected between different patterns of ventilation when peak and mean alveolar pressures are matched at a similar level of minute ventilation and when sufficient end-expiratory alveolar pressures are used. Since multiple organ failure syndrome remains the primary cause of death in ARDS patients, the preClinical Investigations in Critical Care

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vention of that condition should be a first priority in improving outcome. Randomized studies have demonstrated that ventilatory strategies aimed at avoiding alveolar overdistension by limiting peak alveolar pressure do not have a beneficial effect on the mortality rates of ARDS patients.20,23 The lack of efficacy of the PCV and VCV strategies on the mortality rates of ARDS patients might be regarded as reasonable by taking into account that a decrease in the number of organ failures could not be achieved in patients of the limited ventilation group as compared with patients of the conventional ventilation group. Decreasing the mortality rates of ARDS patients will be feasible only by limiting both the inflammatory response and the development of multiple organ failure syndrome. Therefore, further studies are needed to clarify the role of mechanical ventilation in the initiation and propagation of the systemic inflammatory response before new ventilatory strategies aimed at reduce ventilator-induced lung injury are tested in clinical trials.

Appendix
Members of the Spanish Lung Failure Collaborative Group are: Juan A. Gomez-Rub , MD, PhD (Hospital Virgen de la Arrixaca, Murcia); Santiago Mac as, MD (Hospital General de Segovia, Segovia); Ana I. Ezpeleta, MD, PhD (Hospital General de Alicante, Alicante); Anselmo Gil, MD (Hospital del S.A.S., Jerez de la Frontera); Alfonso Bonet, MD (Hospital Dr. Josep Trueta, Girona); Demetrio Carriedo, MD (Hospital Virgen Blanca, Leo n); Jose M. Allegue, MD (Hospital Nuestra Sen ora del Rosell, Cartagena); Jose A. Cambronero, MD (Hospital Pr ncipe de Asturias, Alcala de Henares); Susana Temprano, MD (Hospital Severo Ochoa, Legane s); Dolores Rodriguez, MD (Hospital Morales Meseguer, Murcia); Pedro Enriquez, MD (Hospital del R o Ortega, Valladolid); Virginia Pujalte (Hospital Virgen de la Arrixaca, Murcia); Victor Sagredo, MD (Hospital General de Segovia, Segovia); Bernabe Alvarez, MD (Hospital General de Alicante, Alicante); Francisco Carrizosa, MD (Hospital del S.A.S., Jerez de la Fontera); Isabel Rodriguez (Hospital Dr. Josep Trueta, Girona); Daniel Fontaneda, MD (Hospital Virgen Blanca, Leo n); and Eugenio Palazo n, MD (Hospital General, Murcia).

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