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Original Research: Critical Care |

Ventilator-Associated Pneumonia During Weaning From Mechanical VentilationVentilator-Associated Pneumonia and Fluids: Role of Fluid Management FREE TO VIEW

Armand Mekontso Dessap, MD, PhD; Sandrine Katsahian, MD; Ferran Roche-Campo, MD, PhD; Hugo Varet, PhD; Achille Kouatchet, MD; Vinko Tomicic, MD; Gaetan Beduneau, MD; Romain Sonneville, MD, PhD; Samir Jaber, MD, PhD; Michael Darmon, MD, PhD; Diego Castanares-Zapatero, MD; Laurent Brochard, MD; Christian Brun-Buisson, MD
Author and Funding Information

From the Service de Réanimation Médicale (Drs Mekontso Dessap, Roche-Campo, and Brun-Buisson), and Unité de Recherche Clinique (Drs Katsahian and Varet), AP-HP, CHU Henri Mondor, Créteil, F-94010, France; Faculté de Médecine (Drs Mekontso Dessap and Brun-Buisson), Université Paris Est Créteil, Créteil, F-94010, France; INSERM (Drs Mekontso Dessap and Brun-Buisson), Unité U955, Créteil, F-94010, France; Servei de Medicina Intensiva (Dr Roche-Campo), Hospital de Sant Pau, Barcelona, Spain; Service de Réanimation Médicale (Dr Kouatchet), CHU d’Angers, Angers, France; Departamento de Paciente Crítico (Dr Tomicic), Clinica Alemana, Santiago de Chile, Chile; Service de Réanimation Médicale and UPRES-EA 3830 (Dr Beduneau), CHU de Rouen, Rouen, France; Service de Réanimation Médicale et des Maladies Infectieuses (Dr Sonneville), AP-HP, CHU Bichat-Claude Bernard, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France; Réanimation DAR B (Dr Jaber), CHU Saint Eloi, INSERM U1046, Montpellier, France; Service de Réanimation Médicale (Dr Darmon), AP-HP, CHU Saint Louis, Paris, France; Service de Soins Intensifs (Dr Castanares-Zapatero), Hôpital Universitaire Saint-Luc, Bruxelles, Belgium; Critical Care Department (Dr Brochard), St. Michael’s Hospital, Toronto, ON, Canada; and Interdepartmental Division of Critical Care Medicine (Dr Brochard), University of Toronto, Toronto, ON, Canada.

CORRESPONDENCE TO: Armand Mekontso Dessap, MD, PhD, Service de Réanimation Médicale, Centre Hospitalo-Universitaire Henri Mondor; 51, avenue du Mal de Lattre de Tassigny 94 010 Créteil Cedex, France; e-mail: armand.dessap@hmn.aphp.fr


FUNDING/SUPPORT: This project was funded by the French Ministry of Health research program (Programme Hospitalier de Recherche Clinique) [contract 05104]. Biosite France supplied the BNP assay devices and kits (Triage MeterPlus) for the study. Dräger provided the AWS-equipped ventilators for the study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(1):58-65. doi:10.1378/chest.13-2564
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BACKGROUND:  Pulmonary edema may alter alveolar bacterial clearance and infectivity. Manipulation of fluid balance aimed at reducing fluid overload may, therefore, influence ventilator-associated pneumonia (VAP) occurrence in intubated patients. The objective of the present study was to assess the impact of a depletive fluid-management strategy on ventilator-associated complication (VAC) and VAP occurrence during weaning from mechanical ventilation.

METHODS:  We used data from the B-type Natriuretic Peptide for the Fluid Management of Weaning (BMW) randomized controlled trial performed in nine ICUs across Europe and America. We compared the cumulative incidence of VAC and VAP between the biomarker-driven, depletive fluid-management group and the usual-care group during the 14 days following randomization, using specific competing-risk methods (the Fine and Gray model).

RESULTS:  Among the 304 patients analyzed, 41 experienced VAP, including 27 (17.8%) in the usual-care group vs 14 (9.2%) in the interventional group (P = .03). From the Fine and Gray model, the probabilities of VAC and VAP occurrence were both significantly reduced with the interventional strategy while adjusting for weaning outcome as a competing event (subhazard ratios [25th-75th percentiles], 0.44 [0.22-0.87], P = .02 and 0.50 [0.25-0.96], P = .03, respectively).

CONCLUSIONS:  Using proper competing risk analyses, we found that a depletive fluid-management strategy, when initiating the weaning process, has the potential for lowering VAP risk in patients who are mechanically ventilated.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00473148; URL: www.clinicaltrials.gov

Figures in this Article

Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection in the ICU. Although there is debate about its impact on mortality,1,2 VAP is clearly associated with increased duration of mechanical ventilation, ICU and hospital stays, antibiotic consumption, and costs.3 The cumulative risk of developing VAP increases for the whole duration of mechanical ventilation.4 Many other risks factors for VAP have been described, including witnessed aspiration and exposure to paralytic agents.4

The concept of ventilator-associated complications (VACs) was recently proposed as a measure of respiratory deterioration in patients under mechanical ventilation.5 These complications, which are driven by atelectasis, pulmonary edema, and VAP, may overlap in some patients. VAP is a common complication of permeability pulmonary edema, with a prevalence ranging from 40% to 60% during moderate to severe ARDS.68 The association of pneumonia with hydrostatic pulmonary edema is also frequent.9 Pulmonary edema may predispose patients to pneumonia via several mechanisms that alter the alveolar microenvironment, including enhanced bacterial colonization and infectivity, decreased host bactericidal capacities, or both.10 A fluid-management strategy aimed at lowering lung fluid balance may, therefore, prove useful in amending both the risk of VAC and of VAP. We tested this hypothesis in the context of weaning from mechanical ventilation using data from the B-type Natriuretic Peptide for the Fluid Management of Weaning (BMW) study, which compared a biomarker-guided, depletive fluid-management strategy to usual care in patients who were in the ICU and mechanically ventilated. Since weaning outcome and VAP act as competing risks,4 we designed the present work with a competing-risk approach to properly estimate the effect of a depletive fluid-management strategy on VAP risk among patients enrolled in the BMW study.

Patients

This randomized controlled trial was conducted in nine ICUs in Europe and South America between May 2007 and July 2009. A detailed description of the BMW study design (NCT00473148) has been published previously with supplemental information on patients and methods.11 Inclusion criteria were those allowing early initiation of ventilator weaning: endotracheal mechanical ventilation for at least 24 h, transcutaneous oxygen saturation ≥ 90% with Fio2 ≤ 50% and positive end-expiratory pressure (PEEP) ≤ 8 cm H2O, hemodynamic stability during the past 12 h, sedation stopped or decreased over the past 48 h, stable neurologic status with Ramsay score ≤ 5, and body temperature > 36.0°C and < 39.0°C. Permanent noninclusion criteria were pregnancy or lactation, age < 18 years, known allergy to furosemide or sulfonamides, tracheostomy on inclusion, hepatic encephalopathy, cerebral edema, acute hydrocephalus, myasthenia gravis, acute idiopathic polyradiculoneuropathy, decision to withdraw life support, and prolonged cardiac arrest with a poor neurologic prognosis. Temporary noninclusion criteria were extubation scheduled on the same day; persistent, acute, right ventricular failure; renal insufficiency (defined as any of the following: need for renal replacement therapy, plasma urea level > 25 mmol/L, plasma creatinine level > 180 μmol/L, creatinine clearance < 30 mL/min, or > 25% increase in plasma creatinine over the past 24 h); injection of iodinated contrast agent in the past 6 h; blood sodium level > 150 mEq/L; blood potassium level < 3.5 mEq/L; or metabolic alkalosis with arterial pH > 7.50. When inclusion was delayed because of a temporary noninclusion criterion, enrollment could be performed after correction of the abnormal value. The protocol was approved by our institution’s local ethics committee (Comité de Protection des Personnes Ile-de-France IX, approval number 06-035), and informed consent was signed by the patient or a close relative. The primary end point was the time from randomization to successful extubation. Successful extubation was defined as the patient alive and without reintubation 72 h after extubation.11

Patient Management

To standardize the weaning process, all patients were ventilated using a computer-driven, automated weaning system (AWS) (Evita Smart Care System; Dräger). Patients were assigned to one of two groups—B-type natriuretic peptide (BNP)-guided depletive fluid management or usual care based on clinical evaluation—via an independent, Internet-based, centralized block randomization with stratification on the center and underlying disease. A blood sample was collected each morning for a BNP assay in all randomized patients during the weaning phase. In the control group, the clinicians were blinded to the BNP assay results, and all treatments, including diuretics, were carried out according to usual care. In the interventional group, on days with a BNP level ≥ 200 pg/mL,12 fluid intake was restricted (baseline infusion ≤ 500 mL/24 h, parenteral nutrition ≤ 1,000 mL/24 h, no saline solutions apart from nutrition and drugs) and furosemide was administered (as IV bolus doses of 10-30 mg every 3 h, to achieve a target urine output of 4.5-9 mL/kg/3 h). During ventilation in both groups, the AWS gradually decreased the pressure support level while maintaining the patient within a zone of respiratory comfort, as previously described.13 When the AWS declared the patient “ready for separation,” extubation was performed as soon as possible (including during the night), provided the patient met the other criteria required for extubation, namely, transcutaneous oxygen saturation ≥ 90% with Fio2 ≤ 40% and PEEP ≤ 5 cm H2O, hemodynamic stability, Ramsay score ≤ 3 with continuous sedation stopped or minimal (analgesic medication could be continued), audible cough (spontaneously or during aspiration), need for fewer than three endotracheal suctionings during the last 4 h, and no scheduled procedure requiring sedation or scheduled surgery. Assist-control ventilation was resumed during ventilation using the AWS in case of respiratory worsening. VAP was assessed prospectively as preplanned in the protocol.11

The diagnosis of VAP was based on the following usual criteria: systemic signs of infection, new or worsening infiltrates on the chest roentgenogram, purulent tracheal secretions, and bacteriologic evidence of pulmonary parenchymal infection from distal airway sampling, preferably using a protected telescoping catheter or bronchoscopy and quantitative cultures (≥ 103 and 104 colony forming units/mL for protected telescoping catheter and BAL, respectively).3 VAP was diagnosed only in patients receiving invasive mechanical ventilation and VAP rates were assessed from the time of randomization to extubation; suggestive signs occurring after extubation were not considered. Radiographic screening was obtained daily unless considered futile by the attending intensivist. Radiographs were interpreted by staff radiologists, attending intensivists, or both as part of their daily clinical work. VAC was defined as the presence of at least one of the two following signs of worsening oxygenation: an increase ≥ 20% in minimum daily Fio2 values for ≥ 2 calendar days, or a ≥ 3 cm H2O increase in minimum daily PEEP values for ≥ 2 calendar days.5 Noninvasive ventilation was allowed after extubation if deemed necessary by the attending physician (based on predefined criteria).

Statistical Analysis

The data were analyzed using SPSS Base 13 (IBM) and R 2.15.2 (The R Foundation for Statistical Computing). Categorical variables were expressed as percentages, and continuous data were expressed as median (25th-75th percentiles) unless otherwise specified. We used the χ2 test or Fisher exact test to compare categorical variables between groups and the Mann-Whitney U test to compare continuous variables.

Competing Risks Analysis

A competing risk is an event whose occurrence either precludes the occurrence of another event under examination or fundamentally alters the probability of occurrence of this other event.14 Because the risk of VAP increases cumulatively with duration of mechanical ventilation, weaning outcome is a competing risk for VAP occurrence and vice versa. Indeed, patients are no longer at risk for VAP after weaning; conversely, weaning may be prolonged because of VAP occurrence. In this context, standard survival methods (Kaplan-Meier method and Cox model) are inappropriate because they assume that censoring is noninformative,15 and specific competing-risk methods need to be considered. We, therefore, used a competing-risk model (cumulative incidence function of the Gray model)16,17 to properly estimate the effect of the depletive fluid-management strategy on VAP and VAC risks (up to day 14), while considering weaning outcome as a competing event. The strength of the association between each variable and the outcome was assessed using the subhazard ratio associated with the cumulative incidence function estimated using the cmprsk package developed by Gray in the R software.18 Two-sided P values < .05 were considered significant.

Main Outcomes

The 304 randomized patients (152 in each group) were similar at baseline regarding demographic and clinical characteristics (Table 1). The main results of the BMW study have been previously reported (Table 2).11 Compared with usual care, the interventional strategy was associated with a higher proportion of patients receiving diuretics (124 [81.6%] vs 108 [71.1%], P = .03), which were used in higher doses (average daily furosemide dose, 40 [9-78] mg/d vs 14 [0-40] mg/d; P < .0001), resulting in a significantly more-negative fluid balance (average daily fluid balance during weaning, −640 [−1,811 to 225] mL/d vs −37 [−731 to 586] mL/d; P < .0001) and a shorter duration of mechanical ventilation (time to successful extubation, 42.4 [20.8-107.5] h vs 58.6 [23.3-139.8] h; P = .03).

Table Graphic Jump Location
TABLE 1  ] Baseline Characteristics

Data given as No. (%) or median (interquartile range) unless otherwise indicated. LVD = left ventricular systolic dysfunction; PEEP = positive end-expiratory pressure; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment.

a 

Data were missing for 14 patients (six and eight cases in the usual-care group and in the interventional group, respectively).

b 

At admission or later during the ICU stay.

Table Graphic Jump Location
TABLE 2  ] Main Outcomes of the B-type Natriuretic Peptide for the Fluid Management of Weaning Study

IQR = interquartile range.

VAC and VAP

VAC occurred in 40 of the 304 patients (13.2%) during the 14 days following randomization: 27 patients (17.8%) in the usual-care group and 13 patients (8.6%) in the interventional group (P = .02). VAP occurred in 41 of the 304 patients (13.5%) during the 14 days following randomization: 27 patients (17.8%) in the usual-care group and 14 patients (9.2%) in the interventional group (P = .03). The agreement between VAP and VAC was fair (κ statistic = 0.33 ± 0.08, P < .01). Seventeen patients had VAP associated with VAC: 13 (8.6%) in the usual-care group and four (2.6%) in the interventional group (P = .03). VAP was diagnosed a median of 2 (1-3) days after randomization in the usual-care group and 2 (2-6) days after randomization in the interventional group, with the majority of VAPs occurring within 5 days from randomization in both groups (23 [85.2%] and 11 [78.6%], P = .59). The incidence density of VAP following randomization was 42 per 1,000 ventilator days and 24 per 1,000 ventilator days in the usual-care and intervention groups, respectively (P = .08).

The microbiologic diagnosis was based on quantitative cultures of BAL or protected telescoping catheter in 39 patients and semiquantitative tracheal aspirate cultures in two patients. Pathogens associated with VAP are listed in Table 3; bacteria in the Pseudomonadaceae were the most frequently isolated pathogens (44% of isolates). From the Fine and Gray model, the probability of successful extubation during the 14 days following randomization was significantly higher in the interventional arm while adjusting for VAP occurrence as a competing event (subhazard ratio, 1.32 [1.02-1.71]; P = .04) (Fig 1). Conversely, the probability of VAP occurrence was significantly reduced with the interventional strategy while adjusting for weaning outcome as a competing event (subhazard ratio, 0.50 [0.25-0.96]; P = .03) (Fig 1). The probability of VAC occurrence was also significantly reduced with the interventional strategy while adjusting for weaning outcome as a competing event (subhazard ratio, 0.44 [0.22-0.87]; P = .02). The weaning time, ICU length of stay, and hospital length of stay were significantly longer in patients with VAP as compared with those without, whereas no difference was found for ICU mortality or hospital mortality (Table 4).

Table Graphic Jump Location
TABLE 3  ] Microorganisms Responsible for Ventilator-Associated Pneumonia During Weaning

Data are given as No. (% of pathogens).

a 

Including two cases of mixed oropharyngeal flora in the usual-care group and three cases in the interventional group.

Figure Jump LinkFigure 1  Cumulative incidence function of successful extubation (bold lines) and VAP (dotted lines) during the first 14 d following randomization in patients managed according to the interventional fluid-management strategy (red) or according to usual care (black). BNP = B-type natriuretic peptide; VAP = ventilator-associated pneumonia.Grahic Jump Location
Table Graphic Jump Location
TABLE 4  ] Main Outcomes of Patients With or Without VAP During Weaning

Data are given as median (IQR) unless otherwise indicated. VAP = ventilator-associated pneumonia. See Table 2 legend for expansion of other abbreviation.

a 

Patients still in ICU or in hospital at last follow-up (day 60) were attributed a 60-d length of stay in ICU or hospital, respectively.

b 

Mortality analyses are unadjusted for differences in acuity or mortality risk.

Previous studies of goal-directed fluid management in critically ill patients who are mechanically ventilated have shown beneficial respiratory effects of interventions aimed at lowering fluid balance.1922 However, none of these studies reported on VAP rate. To our knowledge, the present study is the first to assess the effect of fluid management on VAP occurrence in patients on ventilation in the ICU. Using competing risks analysis, we found that a depletive fluid-management strategy was associated with a significant reduction of VAP cumulative incidence, while adjusting for extubation outcome as a competing risk.

When recording complications during the 14 days following randomization in the BMW study, we found significantly lower rates of VAC and VAP in the depletive fluid-management group as compared with usual care. The clinical significance of this observation was not straightforward, with several possible explanations and a potential ascertainment bias. First, worsening respiratory symptoms due to pulmonary edema may have been mistaken for VAP in some patients. However, the strict criteria used to diagnose pneumonia limited this possibility. Second, the earlier separation from the ventilator achieved with the depletive fluid-management strategy decreased the risk exposure to VAP. Although the daily hazard rate of VAP has been shown to decrease after day 5, its cumulative risk increases over time throughout the entire duration of mechanical ventilation.4 Therefore, weaning outcome and VAP act as competing risks. Specific statistical tools based on cumulative incidence estimates have been developed to analyze data suffering from competing risks.16,17 These approaches have been previously used in ICU studies to evaluate nonfatal end points or even mortality associated with intercurrent events.15,23,24 Applying this methodology to data from the BMW randomized controlled trial, we found that a depletive fluid-management strategy was associated with lower cumulative incidences of VAC and VAP while controlling for successful extubation as a competing risk. The incidence density of VAP, which is the number of observed events divided by population-time at risk, is misleading if competing risks are present, which is the case of this study.25

Several factors may confer an advantage to a depletive fluid-management strategy over the usual clinical approach in reducing the incidence of VAP. First, the edematous lung may be more susceptible to bacterial infection. Studies in rodents have shown impaired, in vivo, intrapulmonary bacterial inactivation in animals with pulmonary edema.26 Crystalloid infusion has been shown to markedly depress lung bacterial clearance of Staphylococcus aureus and Klebsiella pneumoniae in animals.10 The degree of impairment of lung bacterial clearance by intraalveolar fluid may, however, vary from one pathogen to another.27 Second, pulmonary edema may exert a direct effect on bacterial colonization and infectivity. Pathogens in the Pseudomonadaceae account for the predominant cause of late-onset VAP3 and represented 44% of isolated species in our study. Because these organisms are particularly well adapted to wet or damp conditions,28,29 their virulence and infectivity may be enhanced in the context of “wet lungs.” There is currently no practical guide to fluid management in guidelines for VAP prevention.30 Whether incorporating a depletive fluid-management strategy into a bundle of preventive measures may favorably alter patients’ outcomes needs further research.

Our study has some limitations. First, we recorded VAP episodes occurring during weaning from mechanical ventilation, which started after a median of 5 days following intubation. Therefore, we could not assess the effect of fluid-balance management on early-onset VAP. Second, the generalizability of our study (ie, its external validity) may be limited by the specific inclusion and exclusion criteria used in the BMW trial, especially the exclusion of patients with renal failure because of the influence of renal function on BNP levels. Third, we could not control for implementation of VAP preventive measures in both groups, but the study was randomized. Fourth, the overall rate of VAP was relatively high in our study; this may be explained by the inclusion of the majority of patients in the first week of mechanical ventilation and the high proportion of patients with ARDS, a subgroup at very high risk of such complication.3,6,7 Last, although we used a standard and commonly accepted research definition for VAP, based on a combination of clinical criteria and microbiologic confirmation, this characterization is still prone to both false positives and false negatives.

In conclusion, using a competing risks analysis, we found that a biomarker-driven, depletive-fluid strategy decreases the cumulative incidence of VAP during the weaning period, which may have contributed to reducing its duration. This finding may encourage innovative strategies aimed at preventing VAP in patients in the ICU.

Author contributions: A. M. D. served as principal author, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. A. M. D., L. B., and C. B.-B. contributed to study concept and design; A. M. D., F. R.-C., A. K., V. T., G. B., R. S., S. J., M. D., and D. C.-Z. contributed to patient recruitment; A. M. D., F. R.-C., A. K., V. T., G. B., R. S., S. J., M. D., and D. C.-Z. contributed to data collection; A. M. D., S. K., H. V., L. B., and C. B.-B. contributed to data analysis and interpretation; A. M. D., S. K., L. B., and C. B.-B. contributed to the drafting of the manuscript; and A. M. D., S. K., F. R.-C., H. V., A. K., V. T., G. B., R. S., S. J., M. D., D. C.-Z., L. B., and C. B.-B. contributed to the review, revision, and approval of the final version.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Brochard has been a consultant for Dräger, and his research laboratory has received research grants from Covidien, General Electric, Dräger, and Vygon. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The study sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

AWS

automated weaning system

BMW

B-type Natriuretic Peptide for the Fluid Management of Weaning

BNP

B-type natriuretic peptide

PEEP

positive end-expiratory pressure

VAC

ventilator-associated complication

VAP

ventilator-associated pneumonia

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Figures

Figure Jump LinkFigure 1  Cumulative incidence function of successful extubation (bold lines) and VAP (dotted lines) during the first 14 d following randomization in patients managed according to the interventional fluid-management strategy (red) or according to usual care (black). BNP = B-type natriuretic peptide; VAP = ventilator-associated pneumonia.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Baseline Characteristics

Data given as No. (%) or median (interquartile range) unless otherwise indicated. LVD = left ventricular systolic dysfunction; PEEP = positive end-expiratory pressure; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment.

a 

Data were missing for 14 patients (six and eight cases in the usual-care group and in the interventional group, respectively).

b 

At admission or later during the ICU stay.

Table Graphic Jump Location
TABLE 2  ] Main Outcomes of the B-type Natriuretic Peptide for the Fluid Management of Weaning Study

IQR = interquartile range.

Table Graphic Jump Location
TABLE 3  ] Microorganisms Responsible for Ventilator-Associated Pneumonia During Weaning

Data are given as No. (% of pathogens).

a 

Including two cases of mixed oropharyngeal flora in the usual-care group and three cases in the interventional group.

Table Graphic Jump Location
TABLE 4  ] Main Outcomes of Patients With or Without VAP During Weaning

Data are given as median (IQR) unless otherwise indicated. VAP = ventilator-associated pneumonia. See Table 2 legend for expansion of other abbreviation.

a 

Patients still in ICU or in hospital at last follow-up (day 60) were attributed a 60-d length of stay in ICU or hospital, respectively.

b 

Mortality analyses are unadjusted for differences in acuity or mortality risk.

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