Duane syndrome

Introduction: Lung transplantation is an acceptable treatment option for end-stage lung disease. Short-term survival has improved, but lung transplant recipients remain at high risk for a variety of complications that can necessitate care in an ICU. Little is known about the epidemiology, clinical outcomes, and risk factors for survival among lung transplant recipients admitted to the ICU.

Methods: All lung transplant recipients at a single institution discharged from the hospital after their transplant and subsequently admitted to the medical ICU (MICU) between March 1, 1999, and February 28, 2001, were included. Patients were followed until death or February 28, 2002. Demographic data collected included transplant type and date, APACHE (acute physiology and chronic health evaluation) III scores, last preadmission and best posttransplant FE[V.sub.1] in liters, admitting diagnosis, use of mechanical ventilation, and previous MICU admission.

Results: There were 51 patients admitted to the MICU during the study period (73 total admissions). Their demographic data, pretransplant diagnoses, and type of transplant were similar to those of the rest of Duke University Medical Center lung transplant patients. Fifty-three percent (27 of 51 patients) required mechanical ventilation during their first MICU admission. Thirty-seven percent (19 of 51 patients) died during their first MICU admission. Fifty-nine percent (16 of 27 patients) receiving mechanical ventilation died. Patients who died had lower FE[V.sub.1] to posttransplant best FE[V.sub.1] ratio prior to MICU admission, and also had higher APACHE III scores on MICU admission compared to survivors: FE[V.sub.1], 51.3 [+ or -] 21.9% (n = 14) vs 75.5 [+ or -] 20.4% (n = 30) [p = 0.001]; APACHE III score, 77.7 [+ or -] 21.4 (n = 19) vs 60.1 [+ or -] 16.5 (n = 32) [p = 0.002]. Survival rates by Kaplan-Meier analysis at 1 year and 2 years after initial MICU admission were 43.1% and 40.9%, respectively. The longest survivor is currently alive 1,087 days after initial MICU admission.

Conclusion: Admission to the MICU is common in lung transplant recipients. MICU care, including mechanical ventilation, is associated with a poor prognosis in lung transplant recipients, but is appropriate for selected patients with good allograft function.

Key words: ICU; lung transplantation; mechanical ventilation

Abbreviations: APACHE = acute physiology and chronic health evaluation; BMT = bone marrow transplant: BOS = bronchiolitis obiterans syndrome; CF = cystic fibrosis; IR = interquartile range; MICU = medical ICU: NS = not significant

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Lung transplantation has become an acceptable treatment option for many end-stage lung diseases, including COPD, cystic fibrosis (CF), idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, and others. Postoperative mortality has decreased due to improved surgical techniques and perioperative care, and approximately 90 to 95% of patients are discharged alive after their transplant operation. (1-2) The 5-year survival remains approximately 50%, and up to 75% of the surviving patients have obliterative bronchiolitis. (1)

Obliterative bronchiolitis is characterized by scar formation and fibrosis of the small airways? In clinical practice, FE[V.sub.1] is used as a surrogate marker of obliterative bronchiolitis. The term used for patients without histologic diagnosis is brochiolitis obliterans syndrome (BOS). (4) Patients with BOS have complicated medical problems leading to multiple hospital admissions Patients can be admitted to the medical ICU (MICU) and have extended lengths of stay resulting in significant mortality and morbidity. (5) The number of lung transplant patients that are admitted in the MICU is expected to increase, as there are more long-term survivors.

In the general population, there are clinical variables and scoring systems (APACHE [acute physiology and chronic health evaluation] and simplified acute physiology score are examples) that can predict the outcome of patients that are admitted to the MICU. (6,7) Information on outcomes of lung transplant recipients and possible predictors of their outcome could be useful to patients, their families, and their physicians. We performed a prospective study to describe patients who are admitted to the MICU after lung transplantation, to evaluate their outcomes, and to identify predictors of their outcomes.

MATERIALS AND METHODS

A prospective cohort study was performed at Duke University Medical Center between March l, 1999, and February 28, 2001. All lung and heart-lung transplant recipients admitted to the MICU during this time period were followed up prospectively. Only patients who survived to discharge from their transplant operation were included. There were 151 patients at risk for admission to the MICU at the beginning of the study, and 214 patients at the end of the study. These numbers take into account new transplants and patients who died during the study period. All patients underwent transplantation at Duke University Medical Center. New lung and heart-lung transplant recipients are admitted to the surgical ICUs and surgical ward until they are discharged. Every transplant recipient surviving to discharge alter the transplant operation and requiring critical care is admitted to the MICU. Lung and heart-lung transplant recipients admitted to other hospitals in the area are transferred to Duke University Medical Center. In the rest of this article, the term lung transplant recipients will be used for brevity, but heart-lung transplant recipients are also included in the study.

Standardized surgical techniques were used for the operations, and these are described elsewhere. (8) All patients received postoperative immunosuppression with cyclosporin A or tacrolimus, azathioprine, or mycophenolate mofetil and corticosteroids. Some patients received induction immunosuppression with rabbit antithymocyte globulin as part of a clinical trial or if renal insufficiency developed in the early postoperative period. Since January 1999, patients received a monoclonal interleukin-2 receptor antibody (daclizumab) as part of their induction immunosuppression. Episodes of acute allograft rejection were treated with methylprednisolone, 500 mg/d for 3 days, followed by a 2-week oral prednisone taper. More detailed information on the immunosuppressive regimens and the antimicrobial prophylaxis after transplant have been described elsewhere. (9)

The following data were collected during the study: hospital and MICU admission and discharge dates, outcome of MICU and hospital admission (death vs survival), age, gender, pretransplant diagnosis, transplant type and date, APACHE III score on day 1 after admission to the MICU, last preadmission FE[V.sub.1] in liters, best posttransplant FE[V.sub.1] in liters, admitting diagnosis, use of mechanical ventilation during the MICU admission, and previous MICU admission. The first 24 h of admission to the MICU represented day 1. The rest of the days were counted accordingly. For patients surviving > 6 months, the presence of BOS was also collected. The standard definition of BOS was used. (4)

The first admission of each patient to the MICU was used for the analysis. Analyses of subsequent MICU admissions of each patient were not included because they were not completely independent from the original event (even if the cause was different, intrinsic patient characteristics remained the same). Descriptive statistics were used to characterize our patient sample. We used Student t test (or where appropriate, its nonparametric equivalent) or the [chi square] test for comparisons among the patients who died and the patients who survived their MICU and hospital admissions.

A logistic regression model was used in order to identify independent predictors of in-hospital death after MICU admission. Variables were chosen based on the univariate analysis. The variables tested were APACHE III day 1 score, occurrence of mechanical ventilation, and the ratio of the last to the best FE[V.sub.1] after transplant. Regression diagnostics were performed to determine the validity of the model.

The Kaplan-Meier method was used to estimate the survival of lung transplant recipients after admission to the MICU. The first admission for each patient was used for this analysis; p < 0.05 was considered significant during all statistical analyses. The actual p value is reported if it was < 0.100.

RESULTS

There were 51 of 214 patients (23.8%) admitted to the MICU (73 total admissions) during the study. Thirty-seven of 51 patients (72.5%) were admitted to the MICU once, 7 of 51 patients (13.7%) were admitted twice, 6 of 51 patients (11.8%) were admitted three times, and 1 of 51 patients (2.0%) were admitted four times. The most common admission diagnoses were respiratory failure (51 of 73 patients, 69.9%), sepsis (5 of 73 patients, 6.8%), pneumothorax, atrial fibrillation, high-risk bronchoscopy, pulmonary embolism, antibiotic desensitization, and cardiac arrest (2 of 73 patients, 2.7% each), and pulmonary edema, myocardial infarction, cerebral bleed, seizure, and GI bleeding (1 of 73 patients, 1.4% each). The causes for repeated admissions were similar to those of the first admission (respiratory failure, 16 of 21 patients, 76.2%; rest not reported). Forty-two of 73 admissions (57.5%) resulted in mechanical ventilation.

The baseline characteristics of the patients can be found in Table 1. Patients admitted to the MICU did not differ in their baseline characteristics (age, gender, pretransplant diagnosis, transplant operation) from the rest of the Duke University Medical Center lung transplant patients (age, 45.6 [+ or -] 14.0 years; gender, 50% male) [mean [+ or -] SD]. There were fewer patients with CF (9.8% vs 23.1%) and bilateral lung transplant recipients (37.3% vs 53.3%) in the group of patients admitted to the MICU compared to the patients who were not, but these differences did not reach statistical significance. The admission characteristics of the patients can also be found in Table 1. Patients were admitted to the MICU at all times after their transplant operation (median, 544 days; range, 23 to 2,593 days; interquartile range [IR], 200 to 1,117 days).

Thirteen of 51 patients (25.5%) died during their first admission to the MICU. Nineteen of 51 patients (87.8%) died in the hospital during the admission associated with a stay in the MICU for the first time (6 patients died in hospital after initial discharge from the MICU). Patients who died had higher APACHE III day I scores, lower last FE[V.sub.1] to best posttransplant FE[V.sub.1] ratio, were more likely to require mechanical ventilation, had more days on the ventilator, and had longer hospital and MICU stays. The characteristics of patients who died during the hospital stay associated with their first admission to the MICU vs the ones who were discharged alive can be seen in Table 2.

Thirty-eight of 51 patients (74.5%) had a BOS score available prior to MICU admission (26 of 38 patients or 68.4% had BOS). Eighty percent (12 of 15 patients) who died prior to discharge from the hospital had BOS, while only 60.9% (14 of 23 patients) who survived to discharge after admission to the MICU had BOS (p = not significant INS]). BOS rates in our cohort were higher compared to the total cohort of Duke University Medical Center lung transplant recipients (41.3%; p = 0.003). (10)

Overall, 11 of 27 patients (46.7%) requiring mechanical ventilation died in the MICU, while 16 of 27 patients (59.3%) died during the hospital stay associated with the MICU admission (5 patients died in hospital after discharge from the MICU). BOS scores were available in 20 of 27 patients (74.1%). Three of 5 patients (60%) without BOS died and 8 of 15 patients (53.3%) with BOS died during hospitalization (p = NS).

A logistic regression model was created in order to identify variables that independently predicted survival from the hospital for lung transplant recipients admitted to the MICU. The ratio of last FE[V.sub.1] to best posttransplant FE[V.sub.1] and the use of mechanical ventilation were independently associated with hospital survival. The odds ratios for hospital survival were 1.87 (95% confidence interval, 1.25 to 3.21) for every 10% increase in the FE[V.sub.1] ratio and 0.057 (95% confidence interval, 0.007 to 0.444) with the use of mechanical ventilation. APACHE III score did not independently predict outcome. The model was significant at p < 0.001, and it had a c score of 0.776, indicating a good fit for the data.

The median survival for a lung transplant recipient after admission to the MICU was 195 days (IR, 35 to 749). Thirty-two of 51 patients (62.7%) were discharged alive from the hospital. The survival curve of lung transplant recipients alter admission to the MICU can be seen in Figure 1. Despite the significant mortality rates associated with admission to the MICU, a high number of patients were discharged alive and were alive at last follow-up: 19 of 32 patients (59.4%) were alive at a median follow-up of 696 days (IR, 255 to 882). The median survival of the 13 of 32 patients (40.6%) who died was 195 days (IR, 77 to 839) after admission to the MICU. Observations were similar for patients who received mechanical ventilation: 7 of 11 patients (63.6%) were alive at a median follow-up of 713 days (IR, 297 to 990).

[FIGURE 1 OMITTED]

DISCUSSION

Admission to the MICU after lung transplantation is a common occurrence. It is frequently associated with the use of mechanical ventilation. The age, gender, pretransplant diagnoses, and transplant type of patients admitted to the MICU are similar to those of the general lung transplant population at our institution. MICU admission may occur at any point in their posttransplant course, with a wide range in our experience from 23 to 2,593 days after transplant. Respiratory failure was the most common reason for MICU admission, suggesting that lung problems remain the most common source of morbidity and mortality of lung transplant recipients. However, a variety of other causes were observed. Sepsis was the second most common reason for MICU admission. The prevalence of BOS was higher in the study group compared to the rest of the lung transplant recipients, but the effect of BOS severity was not evaluated in this study.

Lung transplant recipients admitted to the MICU requiring mechanical ventilation have significant morbidity and mortality. Less than half of the patients are discharged alive from the hospital. In comparison to other groups of medical patients receiving mechanical ventilation, survival of lung transplant recipients requiring mechanical ventilation in the MICU appears to be slightly worse, but the populations cannot be directly compared. (11,12)

Our findings are different from those of previous studies assessing the outcome of kidney and bone marrow transplant (BMT) recipients admitted to the ICUs. Renal transplant recipients are admitted less frequently than lung transplant recipients and have a high survival rate (1.4% of patients admitted; 2 of 19 patients admitted died). (13) Respiratory failure was the most common cause for MICU admission. (13) This finding is not surprising, since renal transplant recipients have fewer complications than lung transplant recipients, they require lower levels of immunosuppression, and they also have lower rates of chronic rejection. In contrast, BMT recipients who require mechanical ventilation have very poor outcomes. (14,15) BMT patients requiring mechanical ventilation frequently have severe sepsis in the context of impaired immunity and neutropenia, resulting in poor outcome. One study (13) assessed the rates of admission of liver transplant recipients to the ICU after they were discharged from their transplant operation. The rates of admission were more frequent and the outcomes were worse compared to renal transplant recipients, but the small numbers preclude definite conclusions (35% of patients admitted; 3 of 24 patients admitted died). (13) Respiratory failure was the most common reason for admission in this group as well. (13) Our results are not very different from those of another study assessing the outcome of lung transplant recipients admitted to the ICU. (5) In that group, the survival rate was similar to ours after admission to the MICU and the main reason for admission was respiratory failure. (5) However, unlike our study, the effect of preadmission lung function on survival was not assessed. In addition, no information on long-term survival was given.

In our cohort of patients, the most significant predictors of outcome were mechanical ventilation and the ratio of the last FE[V.sub.1] prior to MICU admission to the best posttransplant FE[V.sub.1]. Mechanical ventilation is performed on the sickest patients, and is a well-known risk factor for death after MICU admission in many patient populations. FE[V.sub.1] is the variable most commonly used to monitor lung transplant recipients, and it frequently identifies patients who have chronic rejection, especially after the early postoperative period. (3) In the early postoperative period, a low FE[V.sub.1] usually occurs because of significant infection, acute rejection, anastomotic complications, or nonimmune lung injury. (1) It is readily available in most cases. Therefore, the FE[V.sub.1] ratio and the use of mechanical ventilation can help define the prognosis of lung transplant recipients admitted to the MICU. Appropriate clinical judgment cannot be replaced by the variables noted. Larger numbers of patients are needed before a definite decision on their utility as predictors of outcome can be made. In addition, our current model will require validation in larger studies done in other institutions. Similar results were observed when only patients with BOS were included in the analysis, but because of the small number of patients the results did not reach statistical significance. APACHE III admission score did not predict outcome after multivariable analysis. The most likely explanation is the small number of patients in our sample.

Another interesting finding of our study was the good medium-term outcomes for hospital survivors, even for patients receiving mechanical ventilation. Our data suggest that lung transplant recipients can have very good medium-term survival, even after admission to the MICU, especially if the causes of the admission are potentially reversible.

In summary, our study provides information on the epidemiology and the outcomes of lung transplant recipients admitted to the MICU. Admissions to the MICU are associated with significant short-term morbidity and mortality. Lung function prior to admission and the use of mechanical ventilation were the major determinants of outcome. Survivors can have good outcomes > 1 year after the admission to the MICU. Further follow-up will provide information on the long-term outcome of these patients.

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* From the Toronto Lung Transplant Program (Dr. Hadjiliadis), Toronto, ON, Canada; and Duke Lung Transplant Program (Drs. Steele, Davis, and Palmer), Division of Pulmonary, and Critical Care Medicine (Dr. Govert), Duke University Medical Center, Durham, NC.

Study performed at Duke University Medical Center.

Manuscript received January 29, 2003; revision accepted September 4, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail permissions@chestnet.org).

Correspondence to: Denis Hadjiliadis MD, MHS, FCCP, Assistant Professor of Medicine, University of Toronto, clinical Associate, Division of Respirology, Toronto General Hospital, 200 Elizabeth St, Room 10-EN-N 240, Toronto, ON, M5G 2C4, Canada; e-mail: Denis.Hacjiliadis@utoronto.ca

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