The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock

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1 Original Research CRITICAL CARE MEDICINE The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock Claire V. Murphy, PharmD; Garrett E. Schramm, PharmD; Joshua A. Doherty, BS; Richard M. Reichley, RPh; Ognjen Gajic, MD, FCCP; Bekele Afessa, MD, FCCP; Scott T. Micek, PharmD; and Marin H. Kollef, MD, FCCP Background: Recent studies have suggested that early goal-directed resuscitation of patients with septic shock and conservative fluid management of patients with acute lung injury (ALI) can improve outcomes. Because these may be seen as potentially conflicting practices, we set out to determine the influence of fluid management on the outcomes of patients with septic shock complicated by ALI. Methods: A retrospective analysis was performed at Barnes-Jewish Hospital (St. Louis, MO) and in the medical ICU of Mayo Medical Center (Rochester, MN). Patients hospitalized with septic shock were enrolled into the study if they met the American-European Consensus definition of ALI within 72 h of septic shock onset. Adequate initial fluid resuscitation (AIFR) was defined as the administration of an initial fluid bolus of > 20 ml/kg prior to and achievement of a central venous pressure of > 8 mm Hg within 6 h after the onset of therapy with vasopressors. Conservative late fluid management (CLFM) was defined as even-tonegative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset. Results: The study cohort was made up of 212 patients with ALI complicating septic shock. Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53 patients [56.6%] vs 27 of 35 [77.1%], respectively; p < 0.001). Conclusions: Both early and late fluid management of septic shock complicated by ALI can influence patient outcomes. (CHEST 2009; 136: ) Abbreviations: AIFR adequate initial fluid resuscitation; ALI acute lung injury; ANOVA analysis of variance; APACHE acute physiology and chronic health evaluation; BMI body mass index; CLFM conservative late fluid management; Fio 2 fraction of inspired oxygen; IQR interquartile range; ScvO 2 central venous oxygen saturation; SOFA sepsis-related organ failure assessment Despite advances in medical practice, severe sepsis and septic shock remain responsible for significant morbidity and mortality. 1,2 Early goaldirected cardiovascular resuscitation decreases mortality in patients with septic shock. 3 5 Acute lung injury (ALI) is a frequent complication of septic shock that is a risk factor for its occurrence. 6 Several studies 7 10 have demonstrated that conservative fluid management in patients with ALI can improve patient outcomes including reduced mortality and fewer days of mechanical ventilation. The most recent Surviving Sepsis Campaign 11 addressed the initial phase of fluid resuscitation in patients with septic shock, providing goals for resuscitation and a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion. The adoption of best practices for the management of septic shock and ALI should result in improved patient outcomes Therefore, we set out to perform a study with two main goals. The first goal was to determine the relationship of both adequate initial fluid resuscitation (AIFR) of patients with septic shock and conservative late fluid management (CLFM) of patients with ALI to hospital 102 Original Research

2 mortality. The second study goal was to establish whether AIFR and CLFM had additive effects on patient outcomes. Study Location and Patients Materials and Methods The study was conducted at the following two academic medical centers: Barnes-Jewish Hospital/Washington University Medical Center (1,300 beds) in St. Louis, MO, and the medical ICU of Mayo Medical Center (1,951 beds) in Rochester, MN. The study was approved by the institutional review boards of both institutions. Hospitalized patients with septic shock who had been admitted between January 1, 2005, and December 31, 2006 (to Barnes-Jewish Hospital), and between March 1, 2004, and April 1, 2007 (to Mayo Medical Center), requiring mechanical ventilation in an ICU for 24 h were eligible for this investigation. All patients had to meet the American-European Consensus definition of ALI within 72 h of the onset of septic shock. Patients were excluded if they had been hospitalized for 7 days after the onset of septic shock; had evidence of non sepsis-related cardiovascular compromise as defined by acute myocardial infarction, cardiogenic shock, or a history of congestive heart failure with an ejection fraction 40%; had a requirement for extracorporeal membrane oxygenation or the use of a ventricular assist device; or developed septic shock at an outside hospital requiring vasopressor and fluid management prior to transfer. If a patient met the inclusion criteria on multiple occasions within the study period, only the first episode of septic shock complicated by ALI was reviewed. Study Design A retrospective cohort study was performed with hospital mortality as the primary outcome parameter. Secondary outcomes included ICU and hospital length of stay, duration of mechanical ventilation, total quantity of IV and enteral fluids administered, and the prescription of appropriate initial antimicrobial treatment. For the purposes of determining compliance with early goal-directed treatment guidelines and the timing of antibiotic administration, the time of septic shock onset was defined as the time that a vasopressor agent, either norepinephrine or dopamine, was first administered. All pertinent data were then collected relative to this time. From the Department of Pharmacy (Drs. Murphy and Micek), Barnes-Jewish Hospital, St. Louis, MO; Hospital Pharmacy Services (Dr. Schramm), and the Division of Pulmonary and Critical Care Medicine (Drs. Gajic and Afessa), Mayo Clinic, Rochester, MN; Medical Informatics (Mr. Doherty and Mr. Reichley), BJC Healthcare, St. Louis, MO; and the Division of Pulmonary and Critical Care Medicine (Dr. Kollef), Washington University School of Medicine, St. Louis, MO. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received November 19, 2008; revision accepted January 28, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/site/misc/reprints.xhtml). Correspondence to: Marin H. Kollef, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8052, St. Louis, MO 63110; mkollef@im.wustl.edu DOI: /chest Data Collection Patients with septic shock were identified electronically by International Classification of Diseases, ninth revision, codes for acute organ dysfunction and acute infection, and by an active order for a vasopressor through the pharmacy database at Barnes-Jewish Hospital or prospective surveillance at Mayo Medical Center. For the purpose of this study, septic shock was further limited to patients requiring vasopressor support for 1h. From this electronic list, patients with ALI were also identified using chest radiograph reports, Pao 2 /fraction of inspired oxygen (Fio 2 ) ratio, the requirement for mechanical ventilation, and medical record and available echocardiographic data indicating the absence of acute cardiac disease as the etiology for the pulmonary infiltrates. Data were collected retrospectively from automated patient medical records and pharmacy databases at both Barnes-Jewish Hospital and Mayo Medical Center by the investigators (C.V.M., G.E.S., J.A.D., R.M.R., and O.G.). Patient identifiers were removed from any aggregated data and were coded with a numbered assignment. A master list of the coding, which contained the number assignment and corresponding patient name, and the raw encoded data, was maintained in a password-locked folder on a password-protected computer. Pertinent demographic, laboratory, and clinical data were gathered and recorded on a structured data collection form, including age, gender, race, patient location at the time of septic shock and ALI onset, severity of illness based on the acute physiology and chronic health evaluation (APACHE) II score 19 and the sepsis-related organ failure assessment (SOFA) score, 20 comorbidities, site of the infection, and positive cultures with sensitivities. Patient-specific factors starting at the time of septic shock onset were also collected, including vital signs, hemodynamic measurements, and laboratory data. Information regarding the management of septic shock and ALI was recorded, including achievement of early goal-directed resuscitation, time to appropriate antimicrobial agent administration, steroid administration, mechanical ventilator settings, and daily fluid balances (including both IV and enteral fluid intake). Definitions Septic shock was defined as noted earlier by an International Classification of Diseases, ninth revision, code for acute organ dysfunction (eg, acute renal failure and respiratory failure) in the presence of an acute infection and by an active order for a vasopressor that was administered for 1 h. The onset of septic shock was defined as the time of vasopressor initiation. The definition for ALI for this investigation 21 was based on the American-European Consensus definition and defined as bilateral infiltrates on the chest radiograph, acute onset of respiratory failure requiring mechanical ventilation, Pao 2 /Fio 2 ratio 300 mm Hg, and a pulmonary artery occlusion pressure 18 mm Hg, or no evidence of left atrial hypertension. Pulmonary artery catheters were not routinely used, and the assessment of left atrial hypertension was at the discretion of the treating clinician. The etiology of ALI was deemed to be septic shock if the patient met the criteria for ALI within 72 h of the onset of septic shock. 11 The APACHE II and SOFA scores were calculated from clinical data available from the first 24-h period surrounding the onset of septic shock. Obesity was defined as a body mass index (BMI) 40 kg/m 2. Appropriate empiric antimicrobial therapy was defined as antimicrobial agents administered within 24 h of the onset of septic shock that were active against the pathogen associated with septic shock, based on susceptibility testing. 22 AIFR was defined as the administration of an initial fluid bolus of 20 ml/kg prior to vasopressor therapy initiation and the achievement of a central CHEST / 136 / 1/ JULY,

3 venous pressure of 8 mm Hg within 6 h after vasopressor therapy initiation. 11 CLFM was defined as even-to-negative fluid balance on at least 2 consecutive days during the first 7 days after septic shock onset. Statistical Analysis The primary data analysis compared hospital survivors to hospital nonsurvivors. Continuous data were reported as the mean SD for parametric data and the median with interquartile ranges (IQRs) for nonparametric data. The Student t test was used when comparing parametric data, and the Mann-Whitney U test was employed to analyze nonparametric data. Categorical data were expressed as frequency distributions, and the 2 test was used to determine whether differences existed between groups. After univariate analysis, stepwise multivariable logistic regression was undertaken to determine the independent risk factors for hospital mortality. Risk factors significant at the 0.20 level in the univariate analysis were included in the models. The values are reported as adjusted odds ratios and corresponding 95% confidence intervals. Analysis of variance (ANOVA) for repeated measures was used for pairwise comparisons of fluid balance between groups (survivors and nonsurvivors) and between time points within each group. All tests were two-tailed, and a p value 0.05 was determined to represent statistical significance. Analyses were performed using a statistical software package (SPSS, version for Windows; SPSS, Inc; Chicago, IL). Patients Results Of the 212 patients included in the study, 125 (59%) survived and 87 (41%) died during hospitalization. Echocardiograms were employed in 82% of the patients (174 of 212 patients) to exclude the presence of pulmonary hypertension. Hospital nonsurvivors were statistically more likely to be medical ICU patients, had a lower incidence of obesity, and were more likely to have been admitted to the hospital from a health-care setting (Table 1). Hospital nonsurvivors were also more severely ill at baseline compared to survivors, as indicated by higher mean APACHE II and mean SOFA scores. Process-of-Care Variables Table 2 outlines the process-of-care variables for survivors and nonsurvivors. Survivors received a larger median fluid volume within the 6-h window of septic shock onset (3,500 ml [IQR, 1,825 to 6,000] vs 3,000 ml [IQR, 1,000 to 4,500], respectively; p 0.076). Survivors were also more likely to have central venous pressure measured (92.0% vs 70.1%, respectively; p 0.001) and to have a documented central venous pressure 8 mm Hg (79.2% vs 54.0%, respectively; p 0.001) within the 6-h window of septic shock onset. There was no difference in central venous oxygen saturation (ScvO 2 ) measurement or attainment of an ScvO 2 of 70%. Variables Table 1 Baseline Characteristics Survivors (n 125) Nonsurvivors (n 87) p Value Age, yr Male gender 62 (49.6) 47 (54.0) Race White 94 (75.2) 65 (74.7) African-American 26 (20.8) 17 (19.5) Other 5 (4.0) 5 (5.7) BMI 40 kg/m 2 23 (18.4) 6 (6.9) Charlson comorbidity score Coexisting conditions Coronary artery 24 (19.2) 16 (18.4) disease COPD 30 (24.0) 21 (24.1) Cirrhosis 15 (12.0) 14 (16.1) Chronic kidney 18 (14.4) 19 (21.8) disease Long-term 2 (1.6) 5 (5.7) hemodialysis Diabetes 46 (36.8) 22 (25.3) Active malignancy 14 (11.2) 12 (13.8) HIV positive 1 (0.8) 3 (3.4) Solid organ transplant 13 (10.4) 9 (10.3) Other 23 (18.4) 17 (19.5) immunosuppression Location prior to ICU admission Home 81 (64.8) 43 (49.4) Extended-care facility/ 8 (6.4) 19 (21.8) nursing home Hospital 36 (28.8) 25 (28.7) Medical ICU 72 (57.6) 62 (71.3) APACHE II score SOFA score Respiratory variables Tidal volume, ml/kg IBW Pao 2 /Fio 2 ratio PEEP Neuromuscular blockade 28 (22.4) 16 (18.4) Values are expressed as the mean SD or No. (%), unless otherwise indicated. IBW ideal body weight; PEEP positive end-expiratory pressure. Those patients who received colloids (albumin or hetastarch) or packed RBCs as part of their fluid resuscitation were noted to have a statistically higher rate of hospital death. Figure 1 depicts the average daily fluid balance between nonsurvivors and survivors from the onset of septic shock through hospital day 7. Significant differences in average fluid balance for both groups were observed when compared to the previous 24-h time frame (days 2 to 5). When average daily fluid balances were compared, there were statistically significant differences on days 3 to 7 after the onset of septic shock for nonsurvivors and survivors. Figure 2 shows a similar pattern when 104 Original Research

4 Table 2 Process of Care Variables Variables Survivors (n 125) Nonsurvivors (n 87) p Value Initial IV fluid resuscitation Volume within6hofseptic shock onset ml 3,500 (1,825 6,000) 3,000 (1,000 4,500) ml/kg 45.5 ( ) 42.9 ( ) CVP measured 115 (92.0) 61 (70.1) AIFR 99 (79.2) 47 (54.0) ScvO 2 measured 57 (45.6) 34 (39.1) ScvO 2 70% 40 (32.0) 30 (34.5) Colloids administered 59 (47.2) 53 (60.9) PRBCs administered 87 (69.6) 71 (81.6) Vasopressor and inotrope usage Norepinephrine 117 (93.6) 86 (98.9) Dopamine 20 (16.0) 18 (20.7) Phenylephrine 17 (13.6) 5 (5.7) Vasopressin 38 (30.4) 22 (25.3) Epinephrine 1 (0.8) 3 (3.4) Dobutamine 8 (6.4) 11 (12.6) Requiring vasopressor support at day 7 11 (8.8) 25 (28.7) after septic shock onset Late fluid management Cumulative 7-day fluid balance, ml 8,062 (2,412 13,833) 13,694 (7,113 20,249) CLFM 91 (72.8) 30 (34.5) ICU fluid balance, ml 8,037 (2,487 13,575) 19,335 (9,765 27,274) Hospital fluid balance, ml 6,603 ( ,026) 22,231 (11,643 30,682) Appropriate initial antimicrobial therapy in 43 (70.5) 24 (61.5) patients with positive cultures Corticosteroids 70 (56.0) 50 (57.5) Drotrecogin alfa activated 9 (7.2) 7 (8.0) Values are expressed as the median (IQR) or No. (%), unless otherwise indicated. CVP central venous pressure; PRBC packed RBC. average cumulative fluid balances were compared to the previous time frames and between study groups. In comparison to nonsurvivors, survivors had lower cumulative fluid balances for days 3 to 7. There were no significant differences for vasopressor selection between the two groups; however, those patients who required vasopressor support at day 7 after septic shock onset had higher mortality rates. The majority of patients received norepinephrine and had low rates of dobutamine usage (Table 2). The median vasopressor infusion duration for nonsurvivors was double that of survivors (4 days [IQR, 2 to 6.5 days] vs 2 days [IQR, 1 to 3.5 days, respectively; p 0.001). Outcomes and Multivariate Analysis Patients achieving AIFR had a lower hospital mortality compared to those not achieving AIFR (47 of 146 patients [32.2%] vs 40 of 66 patients [60.6%], respectively; p 0.001). Patients achieving CLFM also had a lower hospital mortality compared to those not achieving CLFM (30 of 121 patients [24.8%] vs 57 of 91 patients [62.6%], respectively; p 0.001). Hospital mortality was lowest for those patients achieving both AIFR and CLFM and was higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53 patients [56.6%] vs 27 of 35 patients [77.1%], respectively; p 0.001) [Fig 3]. Multivariate analysis identified not achieving either AIFR or CLFM, duration of vasopressor administration, increasing Charlson comorbidity score, increasing APACHE II score, renal replacement therapy, and colloid administration as independent risk factors for hospital mortality (Table 3). Discussion Our study demonstrated that both early and late fluid management of septic shock complicated by ALI may influence patient outcomes. We found that achievement of AIFR and CLFM was associated with statistically greater rates of hospital survival. Our data also suggest that there may be an additive effect of these fluid management strategies on patient outcomes. Patients whose management attained both AIFR and CLFM had the lowest risk of hospital mortality, whereas patients who achieved only one of these goals had intermediate hospital CHEST / 136 / 1/ JULY,

5 Figure 1. Mean ( SE) daily fluid balance (in milliliters) for days 1 through 7 following the onset of septic shock. Nonsurvivors are depicted by squares, and survivors by circles. * p 0.05 pairwise compared between survivors and nonsurvivors (ANOVA for repeated measures); p 0.05 compared with the previous time point (ANOVA for repeated measures). mortality, and those achieving neither had the greatest risk of hospital mortality. Septic shock and ALI are disease states requiring timely and directed interventions. 6,11 Appropriate fluid management of septic shock appears to be an important determinant of patient outcomes. 3 5 Unfortunately, despite the recommendations of the Surviving Sepsis Campaign, there appears to be variation in the management of this important parameter. Gao et al 13 studied 101 patients with severe sepsis initially evaluated outside of a critical care unit. They found that only 52% of these patients were treated in compliance with their 6-h sepsis bundle. When they compared mortality rates for patients receiving care based on the 6-h bundle, the noncompliant group had a significantly greater hospital mortality rate (49% vs 23%, respectively; p 0.01) despite similar severities of illness for the two groups. Fluid management in patients with ALI also appears to be an important determinant of hospital mortality. Sakr et al 8 showed that patients with ARDS who survived their ICU stay achieved a net negative fluid balance compared to nonsurvivors. A positive mean fluid balance was also shown to be an independent predictor of ICU mortality in their investigation. Simmons et al 23 found similar results in their study of fluid balance in ARDS; Humphrey et al 24 demonstrated that patients with ARDS who achieved goal-directed fluid removal had a statistically greater hospital survival compared to those not attaining this therapeutic end point. Wiedemann et al 7 performed a large multicenter study to determine whether conservative fluid management in ARDS patients impacted survival. Although they demonstrated no difference in hospital mortality, patients assigned to the conservative fluid management group had more ventilator-free and ICU-free days during their hospital stay compared to patients in the liberal fluid management group. It is important to note that many of our patients were treated before these study results were available. Additionally, we required that patients achieve the negative fluid balance goals in order to be classified as attaining CLFM, whereas in the study by Wiedemann et al 7 it was the application of the process and not necessarily achieving the fluid management goals that separated their study groups. This difference may explain the lack of mortality benefit in this earlier study. The studies examining fluid balance in septic shock and ALI patients individually, as well as our 106 Original Research

6 Figure 2. Mean ( SE) cumulative daily fluid balance (in milliliters) for days 1 through 7 following the onset of septic shock. Nonsurvivors are depicted by squares, and survivors by circles. * p 0.05 pairwise compared between survivors and nonsurvivors (ANOVA for repeated measures); p 0.05 compared with the previous time point (ANOVA for repeated measures). data assessing fluid management in patients with both syndromes, suggest that improvements in patient survival can be attained if patients improve to the point where optimal fluid management practices are able to be applied. The standardization of evidence-based practices in the care of critically ill patients with septic shock has become accepted as the optimal method for their management. 11 By standardizing care, clinicians ensure that necessary procedures and therapies are carried out in a timely manner. They also allow practice changes to be more accurately monitored in terms of their impact on patient outcomes. The management of septic shock easily lends itself to standardization because of the importance of achieving early goal-directed resuscitation and administration of appropriate antimicrobial treatment. 25 Similar arguments 6,10,11,26 have been made to standardize the treatment of ARDS/ ALI, given the complexity of this syndrome and emerging evidence that specific practices are associated with improved patient outcomes. Although there are expenses associated with implementing treatment bundles for complex disorders like septic shock and ALI, a cost analysis by Shorr et al 27 suggests that optimizing the care of patients with septic shock will reduce overall hospital costs. Our study has several important limitations. First, it was performed within two large teaching hospitals, so the results may not be generalizable to other types of institutions. However, the results are consistent with those demonstrated by other investigations, 3 5,7 10 suggesting that these findings are more generalizable. Second, the retrospective study design limits our ability to determine a causal relationship between the fluid management strategies examined and the outcomes we evaluated. Despite the large odds ratios, AIFR and CLFM may simply represent markers of disease severity and not determinants of outcome. Third, because this was not a randomized clinical trial we cannot distinguish between provider actions and severity of illness. For example, we cannot exclude the presence of potential interaction between fluid therapy for septic shock and CLFM. Patients with more persistent shock requiring therapy with vasopressors, and thus more likely to die, were unlikely to achieve negative fluid balance (ie, CLFM). Fourth, we had few patients treated with drotrecogin alfa activated and thus could not assess the effect of this therapy on patient outcomes. Fifth, it is important to note that in our study, AIFR specifically refers to the initial fluid bolus administered and corresponded to the positive fluid balance CHEST / 136 / 1/ JULY,

7 Figure 3. Hospital mortality according to whether or not patients achieved AIFR, CLFM, both, or neither. reported by Rivers et al 3 in the first 6hoftheir early goal-directed therapy strategy. However, it is important to note that other therapies such as the optimization of myocardial contractility and oxygen delivery to tissues, manipulated by nonfluid approaches, likely influenced patient outcomes as well. Another potential limitation of our study, as well as of other analyses of shock resuscitation, is defining the timing of fluid resuscitation. Several studies have suggested that the prevention of tissue injury and inflammation requires adequate fluid resuscitation within 2 to 3 h and not 6 h after shock onset. Table 3 Multivariate Analyses of Independent Risk Factors for Hospital Mortality Variables Adjusted OR 95% CI p Value APACHE II score, 1-point increments Charlson comorbidity score, point increments Renal replacement therapy Colloid administration AIFR not achieved Duration of vasopressors, day increments CLFM not achieved Other covariates not in the table had a p value 0.5, including BMI 40 kg/m 2, patient location prior to ICU admission, medical ICU patients, and transfusion of packed RBCs (p Hosmer- Lemeshow goodness-of-fit test ). CI confidence interval; OR odds ratio. Therefore, our definition of AIFR may not have been specific enough to differentiate between patients achieving a beneficial effect from their initial fluid resuscitation and those who did not. We also included patients from two different hospitals with different but overlapping enrollment periods. However, one of the authors (G.E.S.) worked at both hospitals, and examination of the individual hospital data showed the trends for both AIFR and CLFM to be in the same direction as for the combined cohort, suggesting that similar fluid resuscitation protocols were followed at both sites. Finally, our study results may not be applicable to patients with extremes of illness because we excluded patients who did not survive 24 h and those hospitalized for 7 days. This was done purposely to evaluate a more homogeneous patient population. In summary, the fluid management of patients with septic shock complicated by ALI appears to be an important determinant of hospital mortality. Both early goal-directed fluid resuscitation and CLFM seem to be independent aspects of fluid management that affect patient outcomes. References 1 Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence outcome and associated costs of care. Crit Care Med 2001; 29: Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through N Engl J Med 2003; 348: Original Research

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