Characteristics and Outcomes of Patients With Lung Transplantation Requiring Admission to the Medical ICU

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1 [ Original Research Critical Care ] Characteristics and Outcomes of Patients With Lung Transplantation Requiring Admission to the Medical ICU Amit Banga, MD, FCCP ; Debasis Sahoo, MD ; Charles R. Lane, MD ; Atul C. Mehta, MD, FCCP ; Olufemi Akindipe, MD ; Marie M. Budev, DO, MPH, FCCP ; Xiao-Feng Wang, PhD ; and Madhu Sasidhar, MD, FCCP BACKGROUND: There are few data on characteristics and outcomes among patients with lung transplantation (LT) requiring admission to the medical ICU (MICU) beyond the perioperative period. METHODS: We interrogated the registry database of all admissions to the MICU at Cleveland Clinic (a 53-bed closed unit) to identify patients with history of LT done. 30 days ago (n 5 101; mean age, years; 53 men, 48 women). We collected data regarding demographics, history of bronchiolitis obliterans syndrome, preadmission FEV 1, clinical and laboratory variables at admission, MICU course, length of stay, hospital survival, and 6-month survival. RESULTS: The most common indication for MICU admission was acute respiratory failure (n 5 51, 50.5%). Infections were most frequently responsible for respiratory failure, whereas acute rejection (cellular or humoral) was less likely (16%). Nearly one-fourth of the patients required hemodialysis (24.1%), and more than one-half required invasive mechanical ventilation (53.5%). Despite excellent hospital survival (88 of 101), 6-month survival was modest (56.4%). APACHE (Acute Physiology and Chronic Health Evaluation) III score at admission and single LT were independent predictors of hospital survival but did not predict outcome at 6 months. Functional status at discharge was the only independent predictor of 6-month survival (adjusted OR, 5.1; 95% CI, ; P 5.035). CONCLUSIONS: Acute rejection is an infrequent cause of decompensation among patients with LT requiring MICU admission. For patients admitted to the MICU, 6-month survival is modest. Functional status at the time of discharge is an independent predictor of survival at 6 months. CHEST 2014; 146(3): Manuscript received January 22, 2014; revision accepted April 21, 2014; originally published Online First May 5, ABBREVIATIONS: ACR 5 acute cellular rejection; APACHE 5 Acute Physiology and Chronic Health Evaluation; ARF 5 acute respiratory failure; LHI 5 lung hyperinflation; LT 5 lung transplantation; MICU 5 medical ICU; RRT 5 renal replacement therapy AFFILIATIONS: From the Respiratory Institute (Drs Banga, Sahoo, Lane, Mehta, Akindipe, Budev, and Sasidhar), and the Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute (Dr Wang), Cleveland Clinic Foundation, Cleveland, OH. This work was presented at Chest 2013, October 28, 2013, Chicago, IL, and was recognized with the Young Investigator Award. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Amit Banga, MD, FCCP, Respiratory Institute, 9500 Euclid Ave, A90, Cleveland Clinic Foundation, Cleveland OH 44195; amit.banga@gmail.com 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest Original Research [ 146 # 3 CHEST SEPTEMBER 2014 ]

2 Increasing numbers of lung transplantations (LTs) are being performed every year, 1 with. 3,500 patients undergoing LT in Furthermore, with advent of effective immunosuppressive regimens for graft preservation, patients with LT may be living longer. Yet, longterm survival remains poor when compared with other solid organ transplantation. 2 I t is reported that as many as 55% of patients will develop an episode of acute cellular rejection (ACR) or antibody-mediated rejection during the first year following transplantation. 3 Infection and/or rejection can result in respiratory decompensation, leading to the need for admission to medical ICUs (MICUs). Few data exist on the characteristics of such patients with LT who require MICU admission beyond their initial perioperative period. 4,5 Earlier studies on this subject have been small and have reported highly variable outcomes, 4-7 with only a single study describing variables that predict outcome in these patients. 5 Furthermore, no study has reported outcomes after hospital discharge among these patients. The current study aims to describe the profile of patients with LT who require admission to MICU beyond 30 days after transplantation. We also report the incidence, risk factors, and outcomes of common complications, includ ing requirement of invasive ventilator support and renal failure requiring renal replacement therapy (RRT). Finally, we report outcomes at hospital discharge and at 6 months after MICU admission and describe predictors of those outcomes. Materials and Methods Study Site This is a single-center observational study conducted at the Cleveland Clinic, a tertiary care, high-volume center for LT. The MICU at the Cleveland Clinic Foundation is a 53-bed closed unit managed by boardcertified intensivists, with 24-h on-site coverage. Subject Selection Between July 2011 and July 2012, there were 3,129 admissions to the MICU. Among these, 101 LT recipients. 30 days from transplant surgery were included in the study (mean age, years; 53 men, 48 women). A large majority of these patients were admitted to the ICU after being discharged from the hospital after the LT surgery (90 of 101). Data Collection This study was approved by the Cleveland Clinic institutional review board (# ). Data collected included baseline demographics, reason for admission to the MICU, pulmonary function testing, organ failure in the ICU, and the need for RRT or mechanical ventilation. In addition, baseline immunosuppressive regimen, most recent preadmission lung function measures, and survival after discharge were collected. Although many patients were treated empirically for both infection and rejection, charts/discharge summaries were reviewed to identify the actual cause of decompensation. Charts were reviewed by two investigators independently (A. B. and D. S.), with concordance among 42 of 51 patients for the cause of acute respiratory failure (ARF). All nine discordant assessments were reconciled by the two investigators. Diagnosis of ACR was based upon presence of rejection seen on transbronchial biopsy (n 5 1) and/or presence of lymphocytic BAL with negative cultures and response to pulse steroids (n 5 1). Cause for respiratory failure was determined to be antibody-mediated rejection when patients had donor-specific antibodies and allograft dysfunction in absence of other causes and negative cultures (n 5 6). Presence of positive cultures from blood or body fluids with or without clinical signs of sepsis was considered to be consistent with infection as the cause for ARF. Among patients surviving to hospital discharge (n 5 88), functional status at discharge, as determined by the APACHE (Acute Physiology and Chronic Health Evaluation) registry assessments (patient classified as independent, partially dependent, or fully dependent as described in Table 1 ), discharge disposition, and outcome at 6 months were recorded. Outcome Variables Hospital mortality was analyzed as the primary outcome variable. In addition, several other variables were evaluated, including need of RRT, need of ventilator support, and 6-month outcome as secondary outcome variables. Statistical Analysis The study group was divided into two groups based upon the presence or absence of outcome variables. Categorical variables were compared using Pearson x 2 test, whereas continuous variables were compared using the two-sample independent t test. Along with the demographic parameters, variables significant at P,.1 on univariate analysis were identified as potential predictor variables and entered into a multivariate logistic regression model. Stepwise variable selection procedure was then performed to select a significant subset of predictors. For all outcome variables, regression equations were constructed with significant predictors, respectively. Survival analysis was done using Kaplan-Meier analysis. All analyses were performed by using the SPSS statistical package, version 17.0 for Windows (IBM). The level of statistical significance was set at P,.05 (two tailed). TABLE 1 ] De nition for Functional Status at Discharge as Determined by the APACHE Registry Assessments Functional Status Independent Partially dependent Fully dependent Definition The patient is discharged to home requiring no assistance in completing activities of daily living The patient is discharged to home, to a group home, or to a care facility and requires SOME assistance in completing the activities of daily living; the limitation or limitations requiring assistance may be physical or mental The patient is discharged to home or to a care facility and is unable to perform activities of daily living; must be cared for by others; the limitation or limitations requiring assistance may be physical or mental APACHE 5 Acute Physiology and Chronic Health Evaluation journal.publications.chestnet.org 591

3 Results Baseline characteristics of the study group are presented in Table 2. Most patients were within 2 years of LT. The most common indication for admission to MICU was ARF (n 5 51). Most of these patients (33 of 51) were managed aggressively, with empirical treatment of both acute rejection (cellular and/or humoral) and infection, whereas workup was conducted to determine the cause of respiratory failure. Interestingly, acute rejection was infrequently determined as a cause of ARF ( Fig 1 ). The most common focus of infection was pneumonia (20 of 23); two patients had catheter-related blood stream infections, and one had urosepsis. Bacterial infections were most common (13 of 23) followed by fungal infections (six of 23), and Pseudomonas species were the most frequently isolated organisms (nine of 23). Need for RRT Patients on chronic dialysis before admission (n 5 10) to the MICU were excluded for this analysis (mean age, years; 50 men, 41 women). A significant number of patients needed RRT (n 5 22, 24.2%). Variables associated with need of RRT are presented in Table 3. On multivariate analysis, cystic fibrosis as the underlying diagnosis (adjusted OR, 2.9; 95% CI, ; P 5.018), history of diabetes (adjusted OR, 10.0; 95% CI, ; P 5.005), and APACHE III scores. 74 (adjusted OR, 25.7; 95% CI, ; P 5.031) were independent predictors of need for RRT. Serum creatinine or blood urea nitrogen levels at the time of admission to the MICU did not predict need for RRT. Patients needing RRT had a significantly longer ICU stay ( days vs days, P 5.025) and an increased risk of death (OR, 1.48; 95% CI, ; P,.001). Need for Ventilator Support A majority of patients required mechanical ventilation during the course of admission (n 5 54, 53.5%). The mean duration of ventilator support was days. Variables associated with need for ventilator support on univariate analysis are presented in Table 4. On multivariate analysis, acute physiology score was the only independent predictor of need of ventilator support (adjusted OR, 1.103; 95% CI, ; P 5.013). Hospital Survival The majority of patients survived to hospital discharge (n 5 88, 87.1%). Mean duration of ICU stay was 7 5 days, and hospital stay was days. Variables associated with hospital survival on univariate analysis are presented in Table 5. On multivariate analysis, history of single LT (adjusted OR, 4.56; 95% CI, ; P 5.025) and APACHE III score (adjusted OR, 1.04; 95% CI, ; P 5.002) were independent predictors of mortality. On receiver operating characteristic analysis, area under the curve for APACHE III as a predictor of survival was 74.4% (95% CI, 59%-89.9 %; P 5.005). Six-Month Outcome Overall 6-month survival was 56.4% (57 of 101). The causes of death for all 44 patients who died are shown in Figure 2. On univariate analysis, demographics, type or indication of transplant, duration since transplant, history of bronchiolitis obliterans syndrome (BOS) prior to admission, and pre-icu admission FEV 1 had no association with survival at 6 months. However, high APACHE III score at admission to the MICU (77 24 vs 61 24, P 5.003), longer ICU stay ( days vs days, P 5.048), and functional status at the time of discharge (survival, 54.9% for partially or fully dependent vs 75.7% for independent) were associated with 6-month outcome. There was no difference in survival among patients who were partially (55.9%) or fully dependent (52.9%). On multivariate analysis, functional status at the time of discharge emerged as the only independent predictor of survival at 6 months (adjusted OR, 5.1; 95% CI, ; P 5.035). Kaplan-Meier curve showed early separation of the survival curves for patients based on the functional status at discharge ( Fig 3 ). Although the 6-month survival appeared to remain better for patients with double LT (59.2%) as compared with single LT (50%), the difference was statistically not significant (0.35 by Kaplan Meier) Discussion Earlier studies reporting on the patients with LT needing MICU admission are compared in Table Patients included in the studies appear to have similar demographic profile as well as consistency in the indication for LT, which is reflective of uniform policies in candidate selection for LT. Despite idiopathic pulmonary fibrosis being the most common indication for transplantation in the post lung allocation score era, 8 the pool of patients with LT with COPD as the underlying diagnosis is still the largest. 9 This may explain the dominance of patients with COPD in the current and previously reported case series. ARF was the most common indication for MICU admission, which is similar to earlier reports. 4,5 However, ARF is a broad diagnostic category, and earlier reports have 592 Original Research [ 146 # 3 CHEST SEPTEMBER 2014 ]

4 TABLE 2 ] Characteristics of the Study Group Variable No. of Patients Mean SD Median (Range) Demographics Age, y (21-74) Sex Male 53 Female 48 Race White 90 Black 7 Hispanic 4 Source of admission Transfer from oor 66 Outside hospital or ED transfer 31 ED transfer 4 Type of transplant Single 30 Double 71 Underlying indication for transplant COPD 52 IPF 31 Cystic brosis 13 Others 5 Duration since transplant, mo (1-156) Preadmission FEV 1, % predicted (22-104) Preadmission diagnosis of BOS 22 Chronic dialysis Yes 10 No 91 Primary indication for admission to MICU Acute respiratory failure 51 Sepsis 9 Heart failure 8 GI bleed 7 Altered mental status 7 Renal failure, acute or acute on chronic 6 Others 13 Preadmission use of antimetabolites 25 (Continued) journal.publications.chestnet.org 593

5 TABLE 2 ] (continued) Variable No. of Patients Mean SD Median (Range) Preadmission use of CNI/mTORs (tacrolimus/cyclosporine/sirolimus) 70/30/4 Preadmission prednisone dose, mg (5-40) Outcomes Length of ICU stay, d (1-30) Length of hospital stay, d (3-50) Need of ventilator support 54 Need of renal replacement therapy (n 5 91) a 24 Hospital survival 88 Functional status at discharge, No. (%) Independent 37 (42) Partially dependent 34 (38.6) Fully dependent 17 (19.3) 6-mo survival 57 BOS 5 bronchiolitis obliterans syndrome; CNI 5 calcineurin inhibitor; IPF 5 idiopathic pulmonary fibrosis; MICU 5 medical ICU; mtor 5 mammalian target of rapamycin. a Ninety-one patients were analyzed for need of renal replacement therapy, as 10 patients on chronic dialysis were excluded for this analysis. not described underlying cause, specifically infection vs rejection, for ARF. Our analysis on the cause for ARF was based upon the review of charts/discharge summaries and provides some interesting insights. Acute rejection was infrequently seen in patients with ARF ( Fig 1 ), and nearly one-half of the patients with ARF had an infection. This is in consonance with an earlier study on transbronchial lung biopsies among patients undergoing LT on mechanical ventilation. 10 Figure 1 Pie chart showing causes for the acute respiratory failure among patients admitted with primary admission diagnosis of respiratory failure. AKI 5 acute kidney injury; CHF 5 congestive heart failure; PE 5 pulmonary embolism. Among 18 patients with biopsies, four had ACR, of which three were minimal (A1) and one was mild (A2). It appeared unlikely that minimal or mild ACR was responsible for causing ARF among any of these patients. Furthermore, these data are also consistent with the International Society for Heart and Lung Transplantation registry, where only 2% to 5% of deaths are reported to be directly related to acute rejection, whereas infections account for 20% to 40% of the deaths. 11 These data highlight the importance of carefully weighing the risks of high-dose corticosteroids, given the low incidence of ACR among these patients. Hospital mortality in the current series was lower than previously reported, 4-7 albeit similar to other solid organ transplant recipients, such as liver. 12,13 This is despite the incidence of ventilator support as well as the critical illness score (APACHE III) being similar or higher compared with earlier reports. Nonetheless, the difference may be partially attributed to heterogeneity among centers regarding policies pertaining to MICU admissions. 4-7 Also, general advances in critical care may also explain some of the differences, as the first two studies reported patient outcomes from. 10 years ago. 4,5 Fu r- thermore, the more recent reports by González-Castro et al 6 and Cohen et al 7 had small sample sizes, which were included over 10-year periods (n 5 28 over and n 5 40 over , respectively), which makes the comparison difficult with the current study, 594 Original Research [ 146 # 3 CHEST SEPTEMBER 2014 ]

6 TABLE 3 ] Variables Associated With Need of Renal Replacement Therapy on Univariate Analysis Variable Need of Renal Replacement Therapy Yes (n 5 22) No (n 5 69) OR (95% CI) P Value Age, mean SD, y Sex, actual No. of patients Male 9 41 Female ( ).15 Race, actual No. of patients White Black 2 4 Hispanic History of diabetes mellitus, a % ( ).007 b History of cystic brosis, a % ,.001 b Serum bilirubin, mean SD, mg/dl b Acute physiology scores, mean SD b APACHE III score, mean SD b OR (95% CI) provided where applicable. APACHE 5 Acute Physiology and Chronic Health Evaluation. a Proportion of patients in the respective group. b Statistically significant. which included all patients over 1 year. This is one of the strengths of the current analysis, as the study group was homogenous regarding institutional protocols for admission and management that make the results more reliable and generalizable in comparison with earlier studies. APACHE III score at admission to the unit and single LT emerged as independent predictors of hospital mortality. APACHE III score appears to reliably reflect severity of acute physiologic derangement in this subgroup and thereby predict outcomes. Interestingly, preadmission variables related to graft function, such as TABLE 4 ] Variables Associated With Need of Ventilator Support on Univariate Analysis Need of Ventilator Support Variable Yes (n 554) No (n 547) OR (95% CI) P Value Age, mean SD, y Sex, actual No. of patients Male Female ( ).55 Race, actual No. of patients White Black 3 4 Hispanic Heart rate, mean SD, per min a F IO 2, mean SD, % a APACHE, acute physiology score, mean SD ,.001 a APACHE III score, mean SD a APACHE III score. 74, b % ( ),.001 OR (95% CI) provided where applicable. See Table 3 legend for expansion of abbreviation. a Statistically significant. b Proportion of patients in the respective group. journal.publications.chestnet.org 595

7 TABLE 5 ] Variables Associated With Hospital Survival After Admission to MICU on Univariate Analysis Variable Yes Hospital Survival No OR (95% CI) P Value Age, mean SD, y Sex, actual No. of patients Male 45 8 Female ( ).56 Race, actual No. of patients White Black 6 1 Hispanic APACHE, acute physiology score, mean SD a APACHE III score, mean SD a Respiratory rate, mean SD, per min a WBC count, mean SD, /dl a Type of transplant, actual No. of patients Single 23 7 Bilateral ( ).04 a OR (95% CI) provided where applicable. See Table 2 and 3 legends for expansion of abbreviations. a Statistically significant. the most recent FEV 1 and history of BOS, did not predict outcomes. An independent association of single LT with hospital mortality may reflect relatively poor reserve among these patients. This association was independent of demographics and underlying diagnosis, which may have otherwise explained the association, but it is possible that this is driven by factors considered in selecting candidates for single LT, which are not reflected in the multivariate analysis. Furthermore, this Figure 2 Pie chart showing cause of death among nonsurvivors (n 5 44). Number of deaths during index admission was 13; another 31 patients died during the ensuing 6 mo. BOS 5 bronchiolitis obliterans syndrome. association may also be related to the challenges during mechanical ventilation. Irrespective of the underlying cause, patients with single LT have a fairly unique situation of two lungs with completely different pulmonary mechanics and physiology. This may not be a major issue with spontaneous negative pressure-driven breathing but may pose challenges with positive pressure ventilation. One of the well-known complications seen as an effect of this is the native lung hyperinflation (LHI) seen after single LT for emphysema. 14 There is evidence linking development of native LHI to poor outcomes in the postoperative period after transplant. 15,16 In the study by Anglès et al, 16 duration of mechanical ventilation (22 days vs 3 days), ICU stay (36 days vs 6 days), and mortality (67% vs 20%) trended to be higher among patients with LHI. This phenomenon might come into play again during the episodes of decompensation necessitating ventilator support among patients with COPD with single LT beyond the perioperative period. Despite lower hospital mortality in comparison with earlier reports for the index episode of MICU admission, outcome at 6 months remains modest. A significant number of patients get readmitted to the hospital, and overall mortality is. 40% at 6 months. It was 596 Original Research [ 146 # 3 CHEST SEPTEMBER 2014 ]

8 Figure 3 Kaplan-Meier survival curves based on the functional status (independent vs partially or fully dependent). Curves show early separation, and difference in survival remained significant at 6 mo ( P on multivariate logistic regression analysis ). surprising that none of the preadmission measures of graft function predicted outcome at 6 months. However, functional status appeared to be a strong predictor of 6-month outcome. Although this has not been reported before, functional status is well-recognized as a pretransplant predictor of outcome among patients being considered for LT Moreover, functional status has also been identified as an independent risk factor for TABLE 6 ] Comparison of the Current Study With Earlier Studies Among Patients With LT Requiring MICU Admission Variable Pietrantoni et al 4 /2003 Hadjiliadis et al 5 /2004 González-Castro et al 6 /2007 Cohen et al 7 /2011 Current Study Study design Retrospective Prospective Retrospective Retrospective Prospective (registry based) Study period, y 4 ( ) 3 ( ) 10 ( ) 10 ( ) 1 ( ) No. of patients Mean age, y Sex, male (female) 29 (17) 27 (24) 23 (5) 22 (18) 53 (48) Most common underlying transplant indication Most common indication for ICU admission Need of ventilator support, % Duration of ventilator, d Duration of ICU stay, d Mean APACHE III score COPD/IPF COPD IPF, COPD COPD/IPF ARF ARF Sepsis Sepsis ARF (median) (median) Mortality, % Independent predictors of hospital outcome Ratio of last FEV 1 to best posttransplant FEV 1, need of MV Type of transplant and APACHE III score ARF 5 acute respiratory failure; LT 5 lung transplantation; MV 5 mechanical ventilation. See Table 2 and 3 legends for expansion of other abbreviations. journal.publications.chestnet.org 597

9 hospital readmissions. 20,21 Whether interventions aimed at improving the functional status before discharge would lead to improved outcomes needs to be studied. Nevertheless, it may be useful to evaluate the functional status of patients for their discharge readiness as well as planning postdischarge care. The current analysis has several limitations. Despite the MICU admission-related variables collected as part of a registry database, a significant portion of the data were obtained via chart review. This must be considered when interpreting the data on cause for ARF. Patients did not undergo a workup for rejection and/or infection in a protocolized fashion, which could have resulted in some misclassification. This is especially true for ACR, as several patients were empirically treated for acute rejection, and bronchoscopy was only done for a small number of patients (10 of 51). Nevertheless, the adjudication for the cause had the benefit of hindsight and was based upon a comprehensive chart review including assessment of response to therapeutic modalities, with a high concordance rate between the two investigators who conducted the reviews. Being an observational study, causality cannot be determined. Furthermore, a relatively small sample size and the observational nature of the study also make associations prone to effect by hidden confounders. It is concluded that ICU and hospital outcomes among patients with LT requiring admission to MICU may be improving, but these patients are at high risk of readmission and death during the 6 months after the index episode. Measures of premorbid graft function have limited usefulness in predicting outcomes. Severity of acute illness as determined by the APACHE III score and presence of single LT are useful prognostic markers for hospital survival, although the outcomes at 6 months are similar for single and double LT. Functional status at the time of discharge appears to predict outcomes at 6 months after the MICU admission. Acknowledgments Author contributions: A. B. had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. A. B. contributed to study design, acquisition of the data, data management and analysis, and preparation of the manuscript; D. S. contributed to acquisition of the data, data management and analysis, and preparation of the manuscript; C. R. L., A. C. M., O. A., and M. M. B. contributed to preparation of the manuscript; X.-F. W. contributed to statistical analysis and preparation of the manuscript; and M. S. contributed to study design, acquisition of the data, data management and analysis, and preparation of the manuscript. Financial/nonfinancial disclosures: Th e authors have reported to CHEST the following conflicts of interest: Dr Budev has worked on the Speakers Bureau for Boehringer Ingelheim GmbH (Spiriva), Pfizer Inc, and Eisai Inc. Drs Banga, Sahoo, Lane, Mehta, Akindipe, Wang, and Sasidhar have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. References 1. Christie JD, Edwards LB, Kucheryavaya AY, et al ; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report J Heart Lung Transplant ;31(10): Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant ;11(6): Martinu T, Howell DN, Palmer SM. 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