Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome Marcelo Britto Passos Amato, M.D., Carmen Silvia Valente Barbas, M.D., Denise Machado Medeiros, M.D., Ricardo Borges Magaldi, M.D., Guilherme Paula Schettino, M.D., Geraldo Lorenzi-Filho, M.D., Ronaldo Adib Kairalla, M.D., Daniel Deheinzelin, M.D., Carlos Munoz, M.D., Roselaine Oliveira, M.D., Teresa Yae Takagaki, M.D., and Carlos Roberto Ribeiro Carvalho, M.D. N Engl J Med 1998; 338:347-354 DOI: 10.1056/NEJM80602.

Methods We randomly assigned 53 patients with early acute respiratory distress syndrome (including 28 described previously), all of whom were receiving identical hemodynamic and general support, to conventional or protective mechanical ventilation. Ahon Bata Sa Lansangan Programme. Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure (PEEP) for acceptable oxygenation, with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels (35 to 38 mm Hg).

Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure–volume curve, a tidal volume of less than 6 ml per kilogram, driving pressures of less than 20 cm of water above the PEEP value, permissive hypercapnia, and preferential use of pressure-limited ventilatory modes. Results After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P. Mechanical ventilation can damage the lungs. Lesions at the alveolar–capillary interface, alterations in permeability, and edema have repeatedly been shown to occur in animals subjected to adverse patterns of mechanical ventilation. In clinical practice, however, the “mechanical stretch” caused by conventional ventilation has been found to be detrimental in only a few uncontrolled studies.

Large variations in the susceptibility of individual animal species and the apparent success of mechanical ventilation based on a strategy of using the lowest positive end-expiratory pressure (PEEP) that results in acceptable oxygenation suggest that the devastating effects observed in animals cannot be easily extrapolated to humans. We recently demonstrated that mechanical lung protection can be provided in patients with the acute respiratory distress syndrome, resulting in better pulmonary function and higher rates of weaning from the ventilator. Briefly, lung protection was based on a strategy of maintaining low inspiratory driving pressures (. Stabilizing Procedures and Randomization After enrollment, all patients underwent a standardized regimen of ventilatory–hemodynamic procedures for at least 30 minutes (control period), during which time their initial clinical condition was evaluated and stabilized. General Ventilatory Support Protective or conventional mechanical ventilation was rigorously maintained until the patient was extubated or died. Each patient was connected to a closed system for aspirating tracheal secretions; the patient remained connected to the ventilator during aspiration, minimizing temporary drops in airway pressure.

In both groups, the target partial pressure of arterial oxygen was 80 mm Hg, and the PEEP level was never set below 5 cm of water, even during weaning from the ventilator. The weaning procedure was the same in the two groups: a gradual decrease in the level of pressure support. Patients received ventilation exclusively through endotracheal tubes. Conventional Approach We sought to maintain an arterial carbon dioxide level of 35 to 38 mm Hg, independent of airway pressures, and an inspiratory oxygen fraction of less than 0.6 with adequate systemic oxygen delivery. To optimize this compromise, we used a stepwise algorithm for PEEP increments. Other ventilatory settings were as follows: tidal volume, 12 ml per kilogram (volume-cycled assisted or controlled ventilation); square-wave inspiratory flow rate, 50 to 80 liters per minute (adjusted to avoid auto-PEEP, or abnormal gas trapping leading to an elevated end-respiratory pressure); inspiratory pause, 0.4 second; and backup respiratory rate, 10 to 24 cycles per minute (depending on the value for arterial carbon dioxide). In addition to the administration of sedative drugs to keep the patients comfortable, additional doses of sedatives were given to prevent patient-triggered respiratory rates higher than 24 cycles per minute or arterial carbon dioxide values lower than 25 mm Hg.

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Yuvraj Movie Free Download 3gp. Protective Approach The protective approach was intended to prevent alveolar collapse and overdistention, regardless of arterial carbon dioxide levels, and to maintain an “open lung” independently of hemodynamic conditions. The tidal volume was maintained at a level lower than 6 ml per kilogram, with a respiratory rate of less than 30 cycles per minute, even during pressure support. Permissive hypercapnia and continuous infusions of fentanyl and diazepam were used to prevent discomfort and signs of increased respiratory drive. Initial arterial carbon dioxide levels of up to 80 mm Hg were allowed, and slow intravenous sodium bicarbonate infusions (1] and pressure-support ventilation, both generating constant airway pressure during inspiration) or combined modes (volume-ensured pressure-support ventilation, in which a constant inspiratory pressure is targeted at the same time that a minimal tidal volume is guaranteed ) were used, according to a stepwise algorithm. PEEP was preset at 2 cm of water above P FLEX.

When auto-PEEP (defined as the difference between alveolar pressures at end expiration and airway pressures) was present, the total PEEP (external PEEP plus auto-PEEP) was considered and adjusted to equal P FLEX plus 2 cm of water. Finally, if a sharp P FLEX could not be determined on the pressure–volume curve, an empirical total-PEEP value of 16 cm of water was used. Recruiting maneuvers — aimed at reaerating alveolar units requiring very high opening pressures — were frequently used, especially after inadvertent disconnections from the ventilator. Continuous positive airway pressures of 35 to 40 cm of water were applied for 40 seconds, followed by a careful return to previous PEEP levels.

Finally, pressure-controlled inverse-ratio ventilation was used whenever the inspiratory oxygen fraction was higher than 0.5, in order to decrease minute-volume requirements. General Support All patients were monitored with the Swan–Ganz catheter, and a stepwise algorithm for hemodynamic optimization was used. Measurements of plasma lactate and mixed venous saturation were used to correct imbalances between oxygen transport and demand.

The pulmonary-artery wedge pressure never exceeded 15 mm Hg. Procedures for nutritional support, treatment of infections, and renal dialysis (when needed) were the same in both groups. Corticosteroids were given only to patients with Pneumocystis carinii pneumonia. No patients received immunotherapy. The protocol for sedation was the same for both groups, with only two sedatives prescribed (fentanyl and diazepam) and only one neuromuscular paralyzing drug (pancuronium). Although larger doses (up to 9 mg per day) were used in the protective-ventilation group, continuous infusions of fentanyl were used in both groups to keep the patients comfortable.

All patients received ranitidine (50 mg intravenously every eight hours) as prophylaxis against bleeding. Statistical Analysis The primary end point was survival at 28 days. The effect of the protective approach was analyzed with a Cox proportional-hazards model, with the base-line adjusted APACHE II score (adjusted risk of death) included as a covariate. After the first block of 28 patients had been enrolled, a beneficial effect of the protective approach on pulmonary function became evident, and we were concerned about the possibility of subjecting the patients to an unnecessary continuation of the protocol. Therefore, we performed an interim analysis after each new block of five patients. We estimated that a maximal sample of 58 patients was required, assuming a type I error of 5 percent, a statistical power of 85 percent, and a survival rate in the protective-ventilation group that would be 2.4 times that in the conventional-ventilation group, according to our initial results. To counterbalance the increased chance of prematurely stopping the study because of a type I error, we used the conservative correction for multiplicity proposed by Peto et al.

And Geller and Pocock, with a nominal significance level of. Results The study was stopped during the fifth interim analysis, after 53 patients had been enrolled, because of a significant survival difference between the groups ( Table 2 Study Outcomes According to the Intention-to-Treat Analysis. And Table 3 Base-Line Factors Influencing the Relative Risk of Death at 28 Days. And Figure 1 Actuarial 28-Day Survival among 53 Patients with the Acute Respiratory Distress Syndrome Assigned to Protective or Conventional Mechanical Ventilation. The data are based on an intention-to-treat analysis.

The P value indicates the effect of ventilatory treatment as estimated by the Cox regression model, with the risk of death associated with the adjusted base-line score on APACHE II included as a covariate. After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P48 hours), four patients in the protective-ventilation group died before hospital discharge: one from massive hemothorax with arterial rupture during attempts at central venous cannulation (on day 7), one from diffuse gastrointestinal bleeding (on day 23), one from intracerebral nocardiosis with brain edema (on day 11), and one from a new episode of nosocomial pneumonia followed by refractory septic shock (on day 68). Except for the episode of arterial rupture, no iatrogenic event related to central lines occurred after study entry. The values for the respiratory variables measured during the first week of the study are shown in Table 4 Respiratory Values during the First Week of Mechanical Ventilation.. The objectives of ventilatory support were achieved in 48 of the 53 patients. Although the mean respiratory values suggest good adherence to the protocol, there were minor protocol violations in the care of four patients in the protective-ventilation group and one patient in the conventional-ventilation group.

In the patient in the conventional-ventilation group, a tidal volume of 7 ml per kilogram was inadvertently used for 12 hours. Among the violations in the protective-ventilation group, there was an inadvertent use of a tidal volume higher than 7 ml per kilogram during a period of eight hours, a PEEP prematurely reduced in disregard of the protocol, use of antibiotics in disregard of the protocol, and a previous pneumothorax detected during a careful review of radiographs. The exclusion of these five patients from the analysis of mortality had little effect on the mortality rate associated with the protective-ventilation approach (relative risk of death, 0.14 [95 percent confidence interval, 0.05 to 0.38], as compared with 0.19 [95 percent confidence interval, 0.08 to 0.47]).

The protective-ventilation approach had significant benefits with regard to oxygenation and lung compliance. Shows the results of univariate and multivariate analyses of mortality at 28 days according to base-line factors (data collected during the control period before randomization). The APACHE II scores and the ventilatory treatment were the only significant factors. These were the two covariates that had been included a priori in the final multivariate Cox regression model. Discussion We found that in a group of patients with severe acute respiratory distress syndrome, the protective approach to mechanical ventilation improved the survival rate at 28 days and the weaning rate but not the rate of survival to hospital discharge.

The incidence of barotrauma was significantly lower in the protective-ventilation group than in the conventional-ventilation group, despite the use of higher PEEP levels and higher mean airway pressures. The complexity of the procedures in this study precluded the use of a protocol in which the investigators were unaware of the treatment assignments.

Nevertheless, we believe that the stringent algorithms used for infectious problems, hemodynamic values, nutrition, sedation, dialysis, and general care were sufficient to minimize additional bias due to differences in the management of nonrespiratory problems. We demonstrated in a previous analysis that we were able to accomplish the planned hemodynamic goals in most patients in both groups. Finally, it is difficult to ascribe the better outcome in the protective-ventilation group to uncontrolled or unrecognized factors, since our staff was much more used to the conventional approach.

In fact, a greater number of fatal iatrogenic accidents occurred in the protective-ventilation group than in the conventional-ventilation group. Considering the small size of the study, the conservative nature of Bonferroni's statistical adjustment, and the severity of base-line disease in the patients (which was responsible for many of the late deaths), the failure to detect a significant difference in survival to hospital discharge was not surprising. Despite the use of an appropriate rule for early termination of the study during all interim analyses, the estimates of relative risk shown in may be imprecise. The corrections proposed for multiple sequential analysis can properly control the overall type I error, but they cannot prevent associated distortions of the magnitude of the treatment effect caused by early termination or the small sample. Since the effect of the protective-ventilation strategy on survival was observed in the context of many concomitant maneuvers (permissive hypercapnia, lower peak and driving pressures, higher PEEP, a tidal volume of less than 6 ml per kilogram, and so forth), we performed a pooled “retrospective” analysis to determine the key combination of ventilatory variables responsible for the ventilatory treatment effect on mortality at 28 days (data not shown).

When the treatment assignment was removed from the Cox mortality model, there were three significant prognostic factors: the APACHE II score, the mean PEEP used during the first 36 hours (with a protective effect indicated by a coefficient of -0.15), and the driving pressures (P PLAT-PEEP) during the first 36 hours (with a deleterious effect of high driving pressures indicated by a coefficient of 0.06). All other respiratory variables were of secondary importance. Higher PEEP values (preferentially above the P FLEX value) and lower driving pressures were independently associated with better survival. High initial PEEP values appeared to be beneficial, even when the P PLAT value increased, as long as the driving pressure did not change disproportionately.

The strong protective effect associated with a high PEEP value is consistent with recent experimental data, and the benefit seems to be more pronounced than the deleterious effect of high distending pressures. Had we not used high PEEP levels (>P FLEX), the results might have been very different, with the isolated reduction in P PLAT potentially causing reabsorption atelectasis, loss of alveolar surface, and hypoxemia in some patients. Recent evidence suggests that the minimization of ventilator-induced lung injury may have important systemic benefits, decreasing the release of proinflammatory mediators, the dissemination of infections, and possible complications related to air embolism. In addition to preventing progressive respiratory failure, the protective-ventilation approach may be associated with these mechanisms. Despite the use of higher PEEP values (up to 24 cm of water) and higher mean airway pressures, there was a lower incidence of barotrauma in the protective-ventilation group. The protective-ventilation approach may thus not only improve pulmonary function and oxygenation but also reduce clinically apparent alveolar damage.

Another study suggested a protective effect of PEEP against clinical barotrauma. The paucity of data in favor of this concept may be explained by the correlation normally found between PEEP and peak pressures. In our study, however, the use of high PEEP levels did not necessarily result in high peak or plateau pressures. References • 1 Snyder JV, Froese A.

Respirator lung. In: Snyder JV, Pinsky MR, eds. Oxygen transport in the critically ill. Chicago: Year Book Medical Publishers, 1987:358-73. • 2 Marini JJ. Ventilation of the acute respiratory distress syndrome: looking for Mr.

Anesthesiology 1994;80:972-975 • 3 Fu Z, Costello ML, Tsukimoto K, et al. High lung volume increases stress failure in pulmonary capillaries. J Appl Physiol 1992;73:123-133 • 4 Carlton DP, Cummings JJ, Scheerer RG, Poulain FR, Bland RD. Lung overexpansion increases pulmonary microvascular protein permeability in young lambs. J Appl Physiol 1990;69:577-583 • 5 Parker JC, Hernandez LA, Longenecker GL, Peevy K, Johnson W.

Lung edema caused by high peak inspiratory pressures in dogs: role of increased microvascular filtration pressure and permeability. Am Rev Respir Dis 1990;142:321-328 • 6 Tsuno K, Prato P, Kolobow T. Acute lung injury from mechanical ventilation at moderately high airway pressures. J Appl Physiol 1990;69:956-961 • 7 Dreyfuss D, Saumon G. Role of tidal volume, FRC, and end-inspiratory volume in the development of pulmonary edema following mechanical ventilation.

Am Rev Respir Dis 1993;148:1194-1203 • 8 Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990;16:372-377 • 9 Hickling KG, Walsh J, Henderson S, Jackson R. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med 19-1578 • 10 Gattinoni L, Pesenti A, Mascheroni D, et al.

Low-frequency positive-pressure ventilation with extracorporeal CO 2 removal in severe acute respiratory failure. JAMA 1986;256:881-886 • 11 Lee PC, Helsmoortel CM, Cohn SM, Fink MP. Are low tidal volumes safe? Chest 1990;97:430-434 • 12 Mathieu-Costello O, Willford DC, Fu Z, Garden RM, West JB. Pulmonary capillaries are more resistant to stress failure in dogs than in rabbits. J Appl Physiol 1995;79:908-917 • 13 Albert RK.

Least PEEP: primum non nocere. Chest 1985;87:2-4 • 14 Petty TL. The use, abuse, and mystique of positive end-expiratory pressure.

Am Rev Respir Dis 1988;138:475-478 • 15 Amato MBP, Barbas CSV, Medeiros DM, et al. Beneficial effects of the “open lung approach“ with low distending pressures in acute respiratory distress syndrome: a prospective randomized study on mechanical ventilation. Am J Respir Crit Care Med 1995;152:1835-1846 • 16 Carvalho CRR, Barbas CSV, Medeiros DM, et al. Temporal hemodynamic effects of permissive hypercapnia associated with ideal PEEP in ARDS. Am J Respir Crit Care Med 1997;156:1458-1466 • 17 Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome.

Am Rev Respir Dis 1988;138:720-723[Erratum, Rev Respir Dis 1989;139:1065.] • 18 Teboul JL, Besbes M.

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