Airway Examination and Airway Intervention
The most common reason for isolated airway examination was suspected atelectasis (Table 3). Retained secretions or blood was found upon bronchoscopy in the vast majority. The median duration from lung transplant to bronchoscopy for therapeutic aspiration was 6 months. The paO2/FiO2 ratio improved after 65% of procedures with geometric mean improvement of 30%. Chest imaging showed improved aeration after 41% procedures.
Airway evaluation for stenosis resulted in finding clinically significant abnormality not documented on earlier bronchoscopies, about one third of the time. These were suspected for hypercapneic respiratory failure and difficulty weaning off mechanical ventilation. Both anastomotic dehiscence were incidentally discovered during microbiological sampling for clinical sepsis/hypoxia associated with infiltrates on chest imaging. There was no evidence of pneumothorax on chest imaging. They were discovered at 6 weeks and 11 months. One patient needed airway stent, whereas the other was managed conservatively due to very small area of dehiscence. Bronchoscopy identified source of hemoptysis to tracheostomy site in 3/6 patients. Bronchoscopy was also used to secure endotracheal intubation (4 patients), including a patient with subglottic-stenosis and for selective lung intubation with hemoptysis in another.
Six patients (stenosis 4, dehiscence 2) with airway abnormalities required 12 interventional pulmonary procedures. A variety of airway ablation, dilation, stenting, and topical medication application (eg, mitomycin) procedures were performed with concurrent use of rigid bronchoscopy.
Ninety-nine microbiological specimens (79 BAL, 19 bronchial wash, and 1 protected brush specimen) were obtained through bronchoscopy, a median of 1 day (25th, 75th percentile: 0, 4 d) after MICU admission (Table 4). We obtained the BAL sample with instillation of three 20 mL aliquots of sterile normal saline from the abnormal-appearing area on chest imaging. Infiltrates on chest imaging and/or purulent respiratory secretions were present in all patients. Ninety-six percent patients received empiric antibiotics for a median of 3 days (1, 10 d) before bronchoscopy, covering gram-positive (91%), gram-negative (96%), atypical (50%), fungal (45%), and viral (42%) organisms. Isolated microorganisms are presented in Table 4.
Pseudomonas aeruginosa was the most commonly isolated of all organisms. Eighty percent of gram-negative bacilli (GNB) were isolated after 5 days (mean 36±43 d) of hospital stay. The GNB coverage of empiric antibiotics was inadequate in 50% (9/18) instances, mostly (n=8) due to antimicrobial resistance patterns. In most other instances, results were helpful in tailoring the antimicrobial regimen or duration. Gram-positive bacteria were covered by empiric antibiotics in the majority of cases, except when vancomycin-resistant enterococci were isolated and needed further tailoring of antibiotic therapy.
Cytomegalovirus (CMV) was the most commonly isolated virus, and was already being treated in 3/6 instances for viremia. Three of the 6 patients were CMV mismatch (donor+/recipient−). One patient with CMV pneumonitis had alveolar hemorrhage on BAL. Community-acquired respiratory viruses (CARV) isolated were treated (n=5) with specific antiviral therapy with or without intravenous immunoglobulin.
Among the fungi, Candida albicans was isolated on 6 occasions, and treated on 4 instances; the other cases were not felt to be contributing to the clinical presentation. Other species of Candida, Aspergillus, positive BAL Galactomannan testing, as well as “non-candida, non-cryptococcus yeast not identified further” also resulted in systemic treatment.
Overall, microbiological results from 35% bronchoscopies helped optimize regimen and/or duration of antibiotics. Fifty-eight isolates of pathologic microorganisms were found, and the empiric antibiotic therapy was inadequate for at least 25 of these instances either due to inadequate initial coverage or antibiotic resistance patterns (mostly GNBs).
On univariate analysis, MICU admission diagnosis of sepsis (OR=6.4, Fischer exact test), absolute WBC count on BAL (per 100 U increase), percent-neutrophil count on BAL fluid, and percent-neutrophil count on complete blood counts on bronchoscopy day (all P<0.05, Wilcoxon rank-sum test) were associated with subsequent isolation of pathogenic microorganism. On multivariate analysis, only MICU admission diagnosis of sepsis (OR=4.06; 95% CI, 1.12-14.68, P=0.033) and high WBC count in BAL (OR=1.08; 95% CI, 1.01-1.15, P=0.020) predicted subsequent isolation of pathogenic microorganism. For unclear reasons, hypoxia on MICU admission was inversely associated on univariate analysis, but this association was not observed in multivariate analysis (OR=0.69, Fischer exact test). Other independent variables tested included age, pretransplant diagnosis, single versus bilateral lung transplant, time since transplant, fever, respiratory failure, lung infiltrate, sputum characteristics, empiric antibiotic use, airway stents, degree of hypoxia (paO2/FiO2 and PEEP), immunosuppressive regimen, IgG level, and procalcitonin levels.
Transbronchial Biopsies (TBBX)
Eighteen patients underwent 20 TBBX 195±190 days posttransplant and 2.9±3.1 days after MICU admission. Hypoxemia and transplant-lung infiltrates on chest imaging were observed in all patients. Eighteen procedures were performed during mechanical ventilation support and fluoroscopy was available for 8 procedures. Diagnostic tissue to evaluate for ACR was not obtained during 5 procedures.
The most common histopathologic finding was acute lung injury (ALI)/inflammation (Fig. 1). ACR was discovered on 4 procedures [3 minimal (A1), 1 mild (A2)], all within the first posttransplant year. A2 rejection was felt to contribute to respiratory failure and was treated with pulsed corticosteroids. A1 was managed with augmented immunosuppression including steroids and calcineurin inhibitors. All C3D/C4D tests (n=12) were negative, 2 others were nondiagnostic. ALI was commonly associated with pneumonia. None of the hypothesized variables predicted finding ACR on TBBX on univariate analysis. These included pretransplant diagnosis, time since transplant, immunosuppression regimen, prior number of ACR, and BAL WBC count.
Survival and Length of Hospital Stay
Thirty-three inpatient deaths occurred among 76 LTRs during 93 hospitalizations (35.4% mortality). Two of the 3 patients transferred to hospice for terminal care had bronchiolitis obliterans syndrome. One other patient had squamous cell cancer of head and neck. When bronchoscopy was used for microbiological sampling, isolation of a microbiological agent did not impact (all P=NS, t test) the MICU (16±14 vs. 11±9) or hospital length-of-stay (31±26 vs. 53±45 d), or the survival of patient on hospital discharge (34% vs. 44%). These were also not different whether or not the empiric antibiotic adequately covered the isolated microorganism.
When discharged alive, 6 patients were transferred to long-term acute care facility for severe debility and 2 required inpatient physical rehabilitation.
Major Complications of Bronchoscopy
Hypoxia (n=4, 3%) and hypotension (n=4, 3%) of significant degree were the most common complications. Two of them required transient vasopressor support. Pneumothorax (n=1) and airway bleeding (n=1) were encountered after TBBX. Pneumothorax was observed after TBBX performed on mechanical ventilation support despite fluoroscopy use, and required chest tube placement. Airway bleeding was controlled with cold saline instillation. One patient suffered small airway tear during balloon dilation for bronchial stenosis, needing an airway stent. Two instances of supraventricular arrhythmia were noted, both in the same patient, which required electrical and chemical cardioversion. Both procedures were aborted. No deaths were directly attributable to bronchoscopy.
Impaired secretion clearance among LTRs is related to the presence of anastomosis, mucosal ischemia, decreased ciliary beat frequency,8,9 loss of innervation with impaired cough,10 and/or immunosuppression.11 It can persist beyond the first posttransplant year.11,12 The improvement in oxygenation and chest imaging with therapeutic aspiration observed is comparable with prior studies among other populations.13 Among non-LTRs, bronchoscopy is suggested for patients remaining symptomatic after 24 hours of aggressive chest physiotherapy.14,15 Albuterol can enhance mucociliary clearance among LTRs.11
Our rates of airway complications were lower than prior studies (7.8% vs. 8.3% to 20%), partly because of our stringent study outcomes criteria.16–18 Prior publications from our institution have described management approaches for airway complications.19–21 Use of airway stents for significant stenosis among LTRs can improve FEV1,18 symptoms, and achieve permanent patency among the vast majority.16 Patients in our study were transferred to lower level-of-care between 1 and 8 days after the initial airway intervention. Early liberation from mechanical ventilation and change in the level-of-care after airway intervention has been reported for benign and malignant central airway obstruction.22
Pneumonia is the most common infection after lung and heart-lung transplantation.23–25 When clinically suspected, microbiological sampling by bronchoscopy modified antimicrobial management in about 35% cases in our study, mostly related to isolation of resistant gram-negative bacteria, non-CMV respiratory viruses, and fungi. Mattner et al23 described P. aeruginosa, Staphylococcus aureus, and other GNB as the most common pathogens for pneumonia among heart and heart-lung recipients routinely admitted to ICU between 2 and 250 days posttransplant. Similar spectrum has been described among noncritically ill LTRs during clinically indicated bronchoscopies.24–28
CMV was the most common virus isolated in our study. Before availability of effective oral antiviral prophylaxis, CMV pneumonitis was reported in 4% to 10% and CMV infection (isolation of CMV in BAL) in over 20% of clinically indicated bronchoscopies among noncritically ill LTRs.26,27 Lower rates of infection in our study (1% pneumonitis, 6% infection) likely reflects use of prophylactic valganciclovir in at-risk patients.29,30
The spectrum of CARV in our study was conspicuous by the absence of rhinovirus and coronavirus, commonly isolated during surveillance bronchoscopies.31–34
We routinely give prophylaxis with inhaled amphotericin B (early postoperatively) and oral itraconazole with close monitoring of levels. When Aspergillus was isolated, there was no clinical evidence of dissemination in our study.35,36 C. albicans was the most commonly isolated fungus in our study, and treated with systemic agents due to concerns for the health of surgical anastomosis.37 Mortality and hospital length-of-stay in the group where a specific microorganism was isolated was not different compared with other patients. Nearly all patients received empiric antibiotic therapy and it is plausible that only the resistant microbes were isolated. MICU admission diagnosis of sepsis/hypotension with suspected pneumonia, and elevated WBC count in BAL/bronchial washings may predict subsequent isolation of pathogen.
ALI is a nonspecific finding, and may be seen with infections and antibody-mediated rejection. Overall, we found 20% yield of TBBX with minimal-mild (A1-A2) ACR, all within the first-year posttransplantation. A prior study38 reported overall 37% diagnostic yield of performing TBBX, with 11% ACR. The higher yield in this study was driven by finding of 26% infections. The diagnostic utility of clinically indicated TBBX among noncritically ill adult and pediatric LTRs has been reported in the range 26% to 65%26,27 and 54%,39 respectively. Diagnoses range from ACR, lymphocytic bronchiolitis, and infection.
TBBX when compared with surgical lung biopsy (gold standard) among critically ill, mechanically ventilated LTRs carries poor sensitivity to diagnose ACR (53% sensitivity), especially grade ≥A2a (36%).40 It also tends to underestimate the grade of ACR. At our institution, we obtain TBBX from 2 different lobes on the same side, collecting 6 to 8 pieces of tissue. This may improve the sensitivity of TBBX for detecting ACR. When on mechanical ventilation, TBBX are performed by experienced bronchoscopists. We allow for adequate sedation to minimize patient discomfort and movement, reduce PEEP below 5 and preferably to 0, whenever tolerated. To minimize airway bleeding after TBBX, we wedge the bronchoscope in position for 4 minutes. Fluoroscopic guidance is not available in our ICU, but may be used when the patient is transferred to bronchoscopy suite (40% TBBX).
As finding of ACR on TBBX is specific, any grade of ACR noted should be treated with augmented immunosuppression. Because of low sensitivity of TBBX, it cannot rule out ACR and should be treated as such when clinically suspected.
Hypoxia and hypotension were the most common complications. There were no associated fatalities. Pneumothorax was noted on 1 occasion (5.5%) despite fluoroscopy use in mechanically ventilated patient. Prior studies among mechanically ventilated LTRs have reported rates between 2.3% and 6.5%.38,40 Lower pneumothorax rates among mechanically ventilated LTRs compared with non-LTRs (6.6% to 23%)38,41–44 may be related to pleural adhesions among LTRs, differences in experience, techniques, and/or facilities at lung transplant programs. Rates of pneumothorax among nonmechanically ventilated LTRs are lower (1.5%).27
Strengths of Our Study
This is the first study to comprehensively evaluate the utility of all bronchoscopic procedures among critically ill LTRs. Our data comprises all bronchoscopies serially performed over the 3-year duration and thereby reflects usual practices in MICU from a high-volume lung transplant center. It can provide an insight into expected outcomes from bedside bronchoscopy and aid clinical decision making.
Weaknesses of Our Study
First, this study is a retrospective cohort design without a control group. Therefore we cannot compare the performance of FB with other techniques; for example, BAL versus noninvasive microbiological sampling. Early bronchoscopy may also reduce the drive for alternative noninvasive techniques. The benefits and risks of bronchoscopy versus other diagnostic and therapeutic techniques will need to be validated in future comparative studies.
Second, for microbiological sampling, the actual timing of empiric antibiotic administration (before/after bronchoscopy) could not be ascertained for all patients. Therefore we recorded antibiotics administered until the date of bronchoscopy and this may have introduced bias. However, reanalyzing the data with antibiotics administered till the day before bronchoscopy did not change our results.
Third, this study reflects practices in a high-volume lung transplant center. Although most lung transplant centers are well-equipped hospitals, availability, practices, and threshold for performing testing such as FB would likely be different in different settings.
Use of bedside bronchoscopy modified patient management in one third of airway evaluation and microbiological sampling procedures. The yield of performing transbronchial biopsy was modest. No fatalities were attributed to performing bronchoscopy among critically ill LTRs. Further studies are warranted to evaluate performance of bronchoscopy compared with less-invasive diagnostic tests, especially for microbiological sampling.
1. Pietrantoni C, Minai OA, Yu NC, et al..Respiratory failure and sepsis are the major causes of ICU admissions and mortality in survivors of lung transplants.Chest.2003;123:504–509.
2. Cohen J, Singer P, Raviv Y, et al..Outcome of lung transplant recipients requiring readmission to the intensive care unit.J Heart Lung Transplant.2011;30:54.
3. Gonzalez-Castro A, Suberviola B, Llorca J, et al..Prognosis factors in lung transplant recipients readmitted to the intensive care unit.Transplant Proc.2007;39:2420.
4. Hadjiliadis D, Steele MP, Govert JA, et al..Outcome of lung transplant patients admitted to the medical ICU.Chest.2004;125:1040.
5. Levine SM, Angel LF.The patient who has undergone lung transplantation: Implications for respiratory care.Respir Care.2006;51:392.
6. Guerreiro da Cunha Fragoso E, Goncalves JM.Role of fiberoptic bronchoscopy in intensive care unit: current practice.J Bronchology Interv Pulmonol.2011;18:69.
7. Jolliet P, Chevrolet JC.Bronchoscopy in the intensive care unit.Intensive Care Med.1992;18:160.
8. Veale D, Glasper PN, Gascoigne A, et al..Ciliary beat frequency in transplanted lungs.Thorax.1993;48:629.
9. Read RC, Shankar S, Rutman A, et al..Ciliary beat frequency and structure of recipient and donor epithelia following lung transplantation.Eur Respir J.1991;4:796.
10. Duarte AG, Terminella L, Smith JT, et al..Restoration of cough reflex in lung transplant recipients.Chest.2008;134:310.
11. Laube BL, Karmazyn YJ, Orens JB, et al..Albuterol improves impaired mucociliary clearance after lung transplantation.J Heart Lung Transplant.2007;26:138.
12. Herve P, Silbert D, Cerrina J, et al..Impairment of bronchial mucociliary clearance in long-term survivors of heart/lung and double-lung transplantation. The Paris-Sud Lung Transplant Group.Chest.1993;103:59.
13. Kreider ME, Lipson DA.Bronchoscopy for atelectasis in the ICU: a case report and review of the literature.Chest.2003;124:344.
14. Marini JJ, Pierson DJ, Hudson LD.Acute lobar atelectasis: a prospective comparison of fiberoptic bronchoscopy and respiratory therapy.Am Rev Respir Dis.1979;119:971.
15. Jelic S, Cunningham JA, Factor P.Clinical review: airway hygiene in the intensive care unit.Crit Care.2008;12:209.
16. Thistlethwaite PA, Yung G, Kemp A, et al..Airway stenoses after lung transplantation: incidence, management, and outcome.J Thorac Cardiovasc Surg.2008;136:1569.
17. Moreno P, Alvarez A, Algar FJ, et al..Incidence, management and clinical outcomes of patients with airway complications following lung transplantation.Eur J Cardiothorac Surg.2008;34:1198.
18. Fernandez-Bussy S, Majid A, Caviedes I, et al..Treatment of airway complications following lung transplantation.Arch Bronconeumol.2011;47:128.
19. Santacruz JF, Mehta AC.Airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis.Proc Am Thorac Soc.2009;6:79.
20. Murthy SC, Gildea TR, Machuzak MS.Anastomotic airway complications after lung transplantation.Curr Opin Organ Transplant.2010;15:582.
21. Mughal MM, Gildea TR, Murthy S, et al..Short-term deployment of self-expanding metallic stents facilitates healing of bronchial dehiscence.Am J Respir Crit Care Med.2005;172:768.
22. Colt HG, Harrell JH.Therapeutic rigid bronchoscopy allows level of care changes in patients with acute respiratory failure from central airways obstruction.Chest.1997;112:202.
23. Mattner F, Fischer S, Weissbrodt H, et al..Post-operative nosocomial infections after lung and heart transplantation.J Heart Lung Transplant.2007;26:241.
24. Maurer JR, Tullis DE, Grossman RF, et al..Infectious complications following isolated lung transplantation.Chest.1992;101:1056.
25. Kramer MR, Marshall SE, Starnes VA, et al..Infectious complications in heart-lung transplantation. Analysis of 200 episodes.Arch Intern Med.1993;153:2010.
26. Chan CC, Abi-Saleh WJ, Arroliga AC, et al..Diagnostic yield and therapeutic impact of flexible bronchoscopy in lung transplant recipients.J Heart Lung Transplant.1996;15:196.
27. Hopkins PM, Aboyoun CL, Chhajed PN, et al..Prospective analysis of 1235 transbronchial lung biopsies in lung transplant recipients.J Heart Lung Transplant.2002;21:1062.
28. Kovats Z, Sutto Z, Murakozy G, et al..Airway pathogens during the first year after lung transplantation: a single-center experience.Transplant Proc.2011;43:1290.
29. Finlen Copeland CA, Davis WA, Snyder LD, et al..Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: a single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial.J Heart Lung Transplant.2011;30:990.
30. Sun HY, Wagener MM, Singh N.Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review.Am J Transplant.2008;8:2111.
31. Kumar D, Husain S, Chen MH, et al..A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients.Transplantation.2010;89:1028.
32. Milstone AP, Brumble LM, Barnes J, et al..A single-season prospective study of respiratory viral infections in lung transplant recipients.Eur Respir J.2006;28:131.
33. Soccal PM, Aubert JD, Bridevaux PO, et al..Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients.Clin Infect Dis.2010;51:163.
34. Gottlieb J, Schulz TF, Welte T, et al..Community-acquired respiratory viral infections in lung transplant recipients: a single season cohort study.Transplantation.2009;87:1530.
35. Hibberd PL, Rubin RH.Clinical aspects of fungal infection in organ transplant recipients.Clin Infect Dis.1994;19suppl 1S33.
36. Pinney MF, Rosenberg AF, Hampp C, et al..Invasive fungal infections in lung transplant recipients not receiving routine systemic antifungal prophylaxis: 12-year experience at a university lung transplant center.Pharmacotherapy.2011;31:537.
37. Hadjiliadis D, Howell DN, Davis RD, et al..Anastomotic infections in lung transplant recipients.Ann Transplant.2000;5:13.
38. O’Brien JD, Ettinger NA, Shevlin D, et al..Safety and yield of transbronchial biopsy in mechanically ventilated patients.Crit Care Med.1997;25:440.
39. Greene CL, Reemtsen B, Polimenakos A, et al..Role of clinically indicated transbronchial lung biopsies in the management of pediatric post-lung transplant patients.Ann Thorac Surg.2008;86:198.
40. Burns KE, Johnson BA, Iacono AT.Diagnostic properties of transbronchial biopsy in lung transplant recipients who require mechanical ventilation.J Heart Lung Transplant.2003;22:267.
41. Papin TA, Grum CM, Weg JG.Transbronchial biopsy during mechanical ventilation.Chest.1986;89:168.
42. Pincus PS, Kallenbach JM, Hurwitz MD, et al..Transbronchial biopsy during mechanical ventilation.Crit Care Med.1987;15:1136.
43. Turner JS, Willcox PA, Hayhurst MD, et al..Fiberoptic bronchoscopy in the intensive care unit—a prospective study of 147 procedures in 107 patients.Crit Care Med.1994;22:259.
44. Bulpa PA, Dive AM, Mertens L, et al..Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients.Eur Respir J.2003;21:489.
Keywords:© 2014 by Lippincott Williams & Wilkins.
lung transplantation; bronchoscopy; critical care medicine; opportunistic infections