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(Chest. 1999;115:397-402.)
© 1999 American College of Chest Physicians

The Higher Risk of Bleeding in Lung Transplant Recipients From Bronchoscopy Is Independent of Traditional Bleeding Risks*

Results of a Prospective Cohort Study

Gregory B. Diette, MD; Charles M. Wiener, MD, FCCP and Peter White, Jr., MD

* From the Johns Hopkins University School of Medicine, Baltimore, MD. Supported by a grant from the Johns Hopkins Bayview Physicians Association. Dr. Diette was supported by NHLBI (National Heart, Lung and Blood Institute) training grant number 2 T32 HL07534.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To determine whether recipients of lung transplants have a higher risk of bleeding from fiberoptic bronchoscopy (FOB) than other patients who undergo the procedure.

Design: Prospective cohort study.

Setting: Bronchoscopy services of Johns Hopkins Hospital, a tertiary referral center and Johns Hopkins Bayview Medical Center, a community hospital.

Patients: All adult patients (18 years) who underwent FOB between July 1, 1996 and June 30, 1997 by the full-time pulmonary medicine staff were included. A total of 720 procedures were performed, including 38 in lung transplant recipients.

Measurements: Bleeding was assessed by reviewing physician reports of bloody drainage after the procedure and whether the procedure was terminated early for bleeding. Patient reports of hemoptysis were assessed using questionnaires administered pre- and post-FOB. Predictor variables included patient demographics, bleeding parameters (platelets, prothrombin time, and activated partial thromboplastin time), immunosuppressive medications, aspirin use, use of transbronchial biopsy, and the time length of the procedure.

Results: Lung transplant recipients were significantly more likely to have used aspirin prior to FOB (18.4 vs 7.2%, p < 0.05) and to undergo transbronchial biopsy (64.9 vs 26.8%, p < 0.001). Lung transplant patients were more likely to have new or worsened hemoptysis (53.8 vs 24.6%, p < 0.001), to have > 25 mL of blood loss (44.5 vs 17.5%, p < 0.001) and to have the procedure terminated early for bleeding (5.4 vs 1.0%, p < 0.05). In multivariate analysis, predictors of new or worsened hemoptysis included lung transplant, longer procedure time, and older patient age. Independent predictors of greater blood loss included lung transplant, performance of transbronchial biopsy, longer procedure time, and older patient age.

Conclusions: Lung transplant recipients are at higher risk of bleeding from bronchoscopy than are other patients. This propensity to bleed is independent of coagulation parameters, platelet count, immunosuppressive medication use, aspirin use, or performance of transbronchial biopsy. The higher risk of bleeding should be considered when assessing the risks and benefits of bronchoscopy in lung transplant recipients.

Key Words: bleeding • fiberoptic bronchoscopy • lung transplantation • quality of care • transbronchial biopsy


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Fiberoptic bronchoscopy (FOB) is often performed in lung transplant recipients for investigation of suspected clinical pathology and, in asymptomatic patients, as a means of surveillance for rejection and subclinical infections.1 ,2 Anecdotal experience at Johns Hopkins has suggested that bleeding might be greater in lung transplant recipients than in other patients. Bleeding is a serious adverse event in FOB that can lead to airway and respiratory compromise and, in severe cases, mechanical ventilation or death. The risk of bleeding during bronchoscopy generally has been associated with uremia, thrombocytopenia, the immunocompromised state,3 the length of time of the procedure,4 and the performance of transbronchial biopsy (TBBx). Additional causes for increased bleeding in lung transplant recipients could include aspirin use in double-lung recipients, tissue hemorrhage resulting from lung rejection or infection, or from performing TBBx more frequently than in other patients. Previous studies of bronchoscopy in lung transplant recipients have been case series that have not included a comparison group that would allow the determination of whether the risk of bleeding is independent of other known risk factors. To investigate whether receipt of a transplanted lung allograft is independently associated with an increased risk of bleeding from fiberoptic bronchoscopy, we examined data from a prospective study of bronchoscopy outcomes.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This prospective cohort study of patients undergoing fiberoptic bronchoscopy was conducted at the Johns Hopkins Medical Institutions between July 1, 1996, and June 30, 1997. The overall goals of the study, called the Bronchoscopy Quality Improvement project (BRONCHQI), were to identify predictors of outcomes of fiberoptic bronchoscopy and to improve rates of adverse events, diagnostic success, patient comfort, and patient satisfaction. Data were collected from physicians, nurses, patients, and medical records. Physicians reported data on patient characteristics, indications for the procedures, details of the performance of the procedure, and outcomes of the procedure (including adverse events and final diagnosis). Nursing reports and medical record data were used to verify physician-reported outcomes, and patients were asked about symptoms, comfort, satisfaction, and adverse events.

Data collection by standardized physician reports began July 1, 1996, and a patient survey was introduced on September 4, 1996, to collect data on patient-reported symptoms following FOB. Eligible patients for the survey were all adults (>= 18 years of age) undergoing FOB by Pulmonary and Critical Care Medicine fellows-in-training with faculty supervision or performed alone by a full-time faculty member. The same attending physicians and fellows performed bronchoscopies, irrespective of whether or not patients were transplant recipients. Patients were considered ineligible to participate in the patient survey if they were: 1) mechanically ventilated, 2) non-English speaking, 3) had communication deficits that precluded answering questions, and 4) if they died within 48 h of the procedure. The local institutional Joint Commission on Clinical Investigation approved the study protocol.

Outcome Measurements
We examined three markers of bleeding that occurred during or following FOB. We examined the rates of patient self-reporting of increased or new hemoptysis following FOB, physician reporting of procedure-related bloody secretion volume, and physician reporting of early termination of the procedure for bleeding. The patient questionnaire was administered to patients just prior to starting FOB. Patients rated the symptoms for the prior 24-h period. They were asked to answer the same questions 48 h after the procedure, with regard to the 24-h period following the FOB. The questionnaire was either self-administered or administered by research staff in-person or by phone. A four-point response set was used to assess the frequency of coughing blood. Bloody secretion volume from the procedure was reported in milliliters of bloody secretions in the fluid trap at the end of the procedure. The quantity of bloody secretions in the suction trap was used as a surrogate for blood loss and represented a combination of blood, airways secretions, medications, and saline. Traps full of clear or mucoid secretions were reported as 0 mL. Early termination of the procedure for bleeding (ie, before all planned inspections or procedures were completed) was reported by physicians at the end of the procedure.

Predictor Variables
Data on potential predictors of bleeding outcomes collected from physician reports included patient age (years), gender, race (white, African-American, Asian, other), and co-morbid conditions (congestive heart failure, renal failure, liver failure, and cirrhosis). Bleeding parameters included prothrombin time (International Normalized Ratio), activated partial thromboplastin time (aPTT; in seconds), and platelet count (thousands) as well as aspirin use within 7 days and history of excess bleeding with prior surgery. Immunosuppressive medications included cyclosporine, azathioprine, and corticosteroids. Specific procedures performed were BAL, TBBx, needle aspiration or biopsy, brushing of proximal visualized lesions, brushing of distal lesions, mucosal biopsy, and airway inspection alone. Transbronchial biopsy was combined dichotomously (Yes or No) and continuously by number of biopsies. Procedure time length was reported in minutes from initial insertion of the bronchoscope into the patient until the final withdrawal of the instrument. Patient-reported factors included current weight and height. We hypothesized that height would be inversely related to the rate of bleeding. Shorter people have smaller diameter airways5 that could be more susceptible to the trauma of bronchoscope insertion.

Statistical Analysis
Baseline patient characteristics were examined by proportions of categorical or ordinal values. Several continuous variables were grouped for ease of interpretation or into categories of normality. Age was categorized as <= 35, 36 to 50, 51 to 65, and > 65 years; race as white vs nonwhite; patient height as <= 1.60, 1.61 to 1.70, 1.71 to 1.80, and > 1.80 m; and procedure time length as <= 15, 16 to 30, 31 to 45, and > 45 min. For comparison between normal and extremes of abnormality, platelets were categorized as < 50,000, 51,000 to 100,000, and > 100,000 (normal); PT as <= 1.1 (normal), 1.2 to 1.3, and > 1.3 International Normalized Ratio; and aPTT as <= 31 (normal), 32 to 45, and > 45 s.

Baseline characteristics of lung transplant recipients were compared with all other patients who underwent FOB by proportion of values of categorical and ordinal factors. Statistical significance was determined by using the {chi}2 test. Differences in the means of continuous variables were examined using the t test, with statistically significant results reported as p < 0.05.

To analyze predictors of patient-reported hemoptysis, we classified the symptom change dichotomously, so that we could test predictive models that distinguish patients with worsened hemoptysis from those who did not worsen. To analyze predictors of bloody secretion volume, bloody secretions were classified as a continuous variable. All factors that were statistically significant (p < 0.1) in bivariate analysis or that were believed by the investigators to be clinically important were examined in multivariate models. Logistic regression was used to examine predictors of worsened hemoptysis, and linear regression was used to examine milliliters of bloody secretions.6 All analyses were performed with STATA, version 5.0.7


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Between July 1, 1996, and June 30, 1997, 720 FOBs were performed. Data were reported by physicians in 697 cases (96.8%). During the period when the patient questionnaire was used, 608 FOBs were performed. Of these, 521 (85.7%) were in eligible patients, and, of the eligibles, 451 patients (86.6%) completed the forms before and after the procedure.

Patient Characteristics
Thirty-eight FOBs were performed in 15 patients who had received lung allografts. There were 8 single and 7 double lung recipients. The underlying medical conditions in the single lung transplant recipients included 6 with COPD, and 2 with interstitial pulmonary fibrosis, whereas the double lung recipients included 4 patients with cystic fibrosis, 1 with primary pulmonary hypertension, 1 with Eisenmenger syndrome, and one case of COPD from {alpha}1-antitrypsin deficiency. None of the bronchoscopies reported here were performed in the immediate postoperative period. The time interval post-transplant ranged from 2 weeks to 19 months. Indications for the FOBs (patients could have more than one indication) included surveillance for rejection (18), and evaluation of diffuse infiltrates (12), focal infiltrate (6), airway inspection (6), solitary nodule (1), and effusion (1).

Patient characteristics of transplant patients and all others are shown in Table 1 . Statistically significant differences were found between the two groups, with lung transplant recipients more likely to be white, of younger age, and to have used aspirin in the week prior to FOB. Lung transplant recipients were more likely to be male and to have normal values for platelets, PT, and aPTT, although these differences did not reach statistical significance. Only six patients overall (one lung transplant case) had a history of heavy bleeding with previous surgery. Immunosuppressive medication use was significantly more frequent in transplant patients, including cyclosporine, azathioprine, and corticosteroids (p < 0.001). Mean height was slightly greater in the lung transplant recipients (1.72 vs 1.63 m; data not significant).


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  		Table 1. Patient Characteristics

 
Procedures
Lung transplant recipients were more likely to have TBBx (64.9 vs 26.8%, p < 0.001) and BAL (83.8 vs 69.9%, difference not significant) performed and were less likely to have needle aspiration and biopsy (0.0 vs 18.3%, p < 0.01). No significant difference was found for the rate of mucosal biopsy. Procedure time was significantly longer in lung transplant recipients (mean 31.5 vs 24.7 min, p < 0.01), including cases where TBBx was performed (39.0 vs 32.6 min, p < 0.01). In lung transplant patients, 47.2% of procedures lasted longer than 30 min, whereas only 26.1% of all others lasted as long (p < 0.05). The number of transbronchial biopsies ranged from 0 to 16.

Outcomes
Lung transplant patients were more than twice as likely to report worsened hemoptysis (53.8 vs 24.6%, p < 0.001) (Fig 1 ), were five times more likely to have the procedure terminated prematurely for bleeding, and had double the volume of blood in the fluid traps from the procedure (mean, 28.1 vs 13.0 mL; p < 0.0001).



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  		Figure 1. Percent of patients by bleeding outcomes. p < 0.05 for all differences.

 
Results of logistic regression analysis (Table 2 ) showed that odds of hemoptysis were more than three-fold greater in lung transplant recipients. Procedure time length was associated in dose-response fashion, with nearly eight times the odds of hemoptysis after procedures lasting more than 45 min compared with those of 15 min or less. Age also was significant, with odds of hemoptysis more than 2.5 times greater in patients older than 65 years, compared with those 35 and under. Transbronchial biopsy was not a significant, independent predictor of hemoptysis.


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  		Table 2. Results of Logistic Regression Analysis to Predict Worsened Hemoptysis*

 
In linear regression, lung transplant patients had greater blood loss (Table 3 ). Older age, longer procedures, and having a TBBx were also significant independent predictors. The model was not significantly different when TBBx number was considered. In both models, coagulation parameters, platelet count aspirin use, and immunosuppressive medication use were omitted from the final models because they were not statistically significant.


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  		Table 3. Results of Linear Regression to Predict Amount (in Milliliters) of Bloody Secretions*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates that lung transplant patients are more likely to bleed than are other types of patients during and after FOB. The propensity to bleed was not explained by bleeding parameters (PT, aPTT, platelet counts), aspirin use, or the performance of transbronchial lung biopsy. Bleeding is a potentially serious outcome of FOB, which can result in respiratory failure or death.8 This greater risk of bleeding should be considered in weighing the risks and benefits of the procedure in lung transplant recipients, especially in the case of surveillance, where the benefits have not been clearly established.

Previous reports on bleeding in lung transplant recipients have suggested that these patients have a higher risk of bleeding, but no studies have used concurrent "control" patients for comparison. Scott et al4 reported the results of 219 FOBs in which approximately 44% of patients had blood recovered by suctioning, including 12% of patients with greater than 100 mL of bleeding. In our study, blood was recovered in 72% of cases, but bleeding was greater than 100 mL in fewer than 3% of cases. Consistent with our study, Scott et al8 reported that the rate of bleeding was related to the duration of the procedure, although direct comparison with our study is not possible because the authors did not report these data. Scott et al8 reported experience with eight children recipients of heart-lung transplant who underwent 60 FOBs with transbronchial biopsies. Two cases of "clinically significant" hemorrhage were reported, including one death "directly attributed to hemorrhage" after TBBx. Root et al9 reported a 35% rate of new nodular opacities on postbiopsy radiographs in lung transplant recipients (compared with 8% in controls), which they stated were "almost certainly related to focal hemorrhage secondary to the biopsy itself." A low rate of "excessive bleeding" was reported by Trulock et al,1 although ascertainment of bleeding was limited to data available by retrospective chart review.

There have been previous reports of bleeding in lung transplant recipients in the perioperative period that has been attributed to activation of clotting and fibrinolysis by cardiopulmonary bypass.10 ,11 ,12 However, in the present study, all FOBs were performed well after any acute effects of cardiopulmonary bypass.

Possible explanations for increased bleeding in lung transplant recipients could include an increase in the likelihood of encountering already hemorrhagic or inflamed tissue (from infection, bronchiolitis obliterans, rejection) or local hemodynamic factors related to increased blood flow in the transplanted lungs. Denervated lungs could have a lesser tendency to retain airways fluids, which would make the amount of expectorated or suctioned blood greater, even without a greater tendency to bleed. Uremia cannot explain the bleeding rate, as we found no cases of bleeding in the six patients with renal failure in our study. Double lung transplant recipients are treated with aspirin at our center to prevent thrombosis; however, analysis showed that the risk of bleeding was independent of aspirin use.

Bleeding was greater in longer procedures whether or not biopsy forceps were used to obtain specimens. Longer procedure time might reflect a technically difficult procedure, a more aggressive sampling strategy, or differences in operator skill and experience. In some cases, the procedure could have been prolonged by attempts to control bleeding. These results suggest the need to further study and identify factors that lead to longer procedures, to determine whether these factors cause bleeding, and to modify such factors that cause longer procedures.

We were interested to note that TBBx was a significant independent predictor of suctioned blood but not of hemoptysis. In a previous analysis, we showed that hemoptysis was more likely to worsen after proximal airways manipulation (mucosal biopsy 49%; transbronchial needle aspiration, 44%) than after TBBx (35%). This finding suggests that, although there can be a high volume of blood suctioned from a patient after TBBx, less is expectorated by the patient from the lower airway source.13

Finally, this study demonstrates the feasibility and value of an ongoing quality improvement initiative. A goal of the project has been to identify risk factors for adverse events. The data from this study can be used to inform our decision making about the risks and benefits of FOB by providing better estimates of bleeding risks in lung transplant recipients, and to improve clinical outcomes of FOB through improved patient selection.


   Acknowledgements
 
The authors thank Drs. Jonathan Samet and Albert Wu for comments and suggestions on earlier versions of the manuscript and thank Sherrie Otterbein, RN, and Heather Murphy, MLA, for their diligence and hard work in many operational aspects of this study. We are grateful for the assistance with data collection by the nurses and technicians at the Johns Hopkins Hospital and Johns Hopkins Bayview endoscopy and radiology suites.


   Footnotes
 
Correspondence to: Gregory Diette, MD, MHS, Blalock 910, 600 N Wolfe St., Baltimore, MD 21287; e-mail: gdiette@welchlink. welch.jhu.edu

Abbreviations: aPTT = activated partial thromboplastin time; BRONCHQI = bronchoscopy quality improvement project; FOB = fiberoptic bronchoscopy; PT = prothrombin time; TBBx = transbronchial biopsy

Received for publication February 9, 1998. Accepted for publication August 4, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Trulock, EP, Ettinger, NA, Brunt, EM, et al (1992) The role of transbronchial lung biopsy in the treatment of lung transplant recipients: an analysis of 200 consecutive procedures. Chest 102,1049-1054[Abstract/Free Full Text]
  2. Guilinger, RA, Paradis, IL, Dauber, JH, et al (1995) The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients. Am J Respir Crit Care Med 152,2037-2043[Abstract]
  3. Fulkerson, WJ (1984) Current concepts: fiberoptic bronchoscopy. N Engl J Med 311,511-515[ISI][Medline]
  4. Scott, JP, Fradet, G, Smyth, RL, et al (1991) Prospective study of transbronchial biopsies in the management of heart-lung and single lung transplant patients. J Heart Lung Transplant 10,626-637[ISI][Medline]
  5. Thurlbeck, WM, Haines, JR (1975) Bronchial dimensions and stature. Am Rev Respir Dis 112,142-144[ISI][Medline]
  6. Harrell, FE, Lee, KL, Mark, DB (1996) Tutorial in biostatistics multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 15,361-387[CrossRef][ISI][Medline]
  7. STATA, version 5.0. Stata Corporation, College Station, TX
  8. Scott, JP, Higenbottam, TW, Smyth, RL, et al (1990) Transbronchial biopsies in children after heart-lung transplantation. Pediatrics 86,698-702[Abstract/Free Full Text]
  9. Root, JD, Molina, PL, Anderson, DJ, et al (1992) Pulmonary nodular opacities after transbronchial biopsy in patients with lung transplants. Radiology 184,435-436[Abstract/Free Full Text]
  10. Gu, YJ, de Haan, J, Brenken, UP, et al (1996) Clotting and fibrinolytic disturbance during lung transplantation: effect of low-dose aprotinin. J Thorac Cardiovasc Surg 112,599-606[Abstract/Free Full Text]
  11. Jaquiss, RD, Huddleston, CB, Spray, TL (1995) Use of aprotinin in pediatric lung transplantation. J Heart Lung Transplant 14,302-307[ISI][Medline]
  12. Royston, D (1993) Aprotinin therapy in heart and heart-lung transplantation. J Heart Lung Transplant 12,S19-S25[ISI][Medline]
  13. Diette, G, White, P, Jenckes, M, et al (1998) Patient reported symptoms from fiberoptic bronchoscopy [abstract]. Am J Respir Crit Care Med 157,A222



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