- Email: [email protected]
Severe respiratory failure due to diffuse alveolar hemorrhage: Clinical characteristics and outcome of intensive care
Journal of Critical Care (2010) 25, 230–235
Severe respiratory failure due to diffuse alveolar hemorrhage: Clinical characteristics and outcome of intensive care Christian Rabe MD, MBA a,⁎,1 , Beate Appenrodt MD a,1 , Christian Hoff MD b , Santiago Ewig MD, FCCP b,c , Hans Ulrich Klehr MD a , Tilman Sauerbruch MD a , Georg Nickenig MD b , Selçuk Tasci MD b a
Medical ICU, Department of Internal Medicine I, University of Bonn, D-53105 Bonn, Germany Medical ICU, Department of Internal Medicine II, University of Bonn, D-53105 Bonn, Germany c Thoraxzentrum Ruhrgebiet, Kliniken für Pneumologie und Infektiologie, Herne und Bochum, D-44651 Herne, Germany b
Keywords: Diffuse alveolar hemorrhage; Mechanical ventilation; Outcome; Intensive care unit
Abstract Background: The aim of this study was to characterize patients and report outcome of diffuse alveolar hemorrhage (DAH) requiring intensive care unit support. Patients and Methods: Thirty-seven patients were identified. Clinical characteristics and outcome were determined by chart review. Results: Eighty-nine percent of patients presented with shortness of breath, 23% with cough, and 3% with hemoptysis. In 9% of patients, a diagnosis of DAH was suspected on admission. Diagnosis was confirmed by finding a progressively hemorrhagic bronchoalveolar lavage fluid in 89% and by a positive iron stain in 11% of patients. Vasculitis was causative in 19%, drug toxicity in 11%, thrombocytopenia in 27%, stem-cell transplantation in 5%, sepsis-associated lung injury in 22%, and unknown mechanisms in 16%. Thirty-two patients were mechanically ventilated, 4 received noninvasive ventilation, and 1 received supplemental oxygen therapy. Overall, 18 (49%) of 37 patients survived the intensive care unit stay. Survival was markedly different between patients with an immunologic/unknown etiology (82%) and patients with thrombocytopenia and/or sepsis (22%). Discussion: Diffuse alveolar hemorrhage should be considered in all patients with persistent pulmonary infiltrates. Both bronchoalveolar lavage fluid and iron stain are mandatory diagnostic means. Patients with an immunologic/idiopathic pathogenetic mechanism have a relatively good prognosis, whereas the outcome in individuals with DAH secondary to cancer therapy or sepsis is poor. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; ANCAs, antineutrophile cytoplasmic antibodies; BAL, bronchoalveolar lavage; DAH, diffuse alveolar hemorrhage; ICU, intensive care unit; MODS, multiorgan dysfunction score. 1 C.R. and B.A. contributed equally. ⁎ Corresponding author. Tel.: +49 228 28715507; fax: +49 228 28714698. E-mail address: [email protected] (C. Rabe).
0883-9441/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2009.04.009
Diffuse alveolar hemorrhage—characteristics and outcome
1. Introduction Diffuse alveolar hemorrhage (DAH) is a syndrome of heterogeneous etiology [1-7] characterized either by acute bleeding into the alveolar space or by insidious alveolar bleeding causing a slower deterioration in lung function. The underlying disease mechanism can be either a cellularly (“capillaritis”) or humorally mediated (eg, Goodpasture syndrome) disintegration of the alveolar-capillary barrier leading to entry of blood in the alveolar space. The precise mechanism varies with the underlying condition. Many “idiopathic” cases are probably caused by immunologic mechanisms [8]. The manifestations of this syndrome range from minor abnormalities noted only on sensitive imaging to a dramatic compromise of gas exchange necessitating prompt ventilatory support. The diagnosis of DAH is difficult, especially in patients with chronic bleeding, because signs of overt bleeding are absent. In this situation, diagnosis relies on the demonstration of iron-laden macrophages in bronchoalveolar lavage (BAL) fluid [2,9,10]. Patients who have DAH may easily be misdiagnosed as atypical pneumonia, and DAH can also imitate acute respiratory distress syndrome (ARDS) [11,12]. Because of the relative rarity of DAH, our knowledge on etiology and outcome of the more severe manifestations of this syndrome is limited. We report a series of patients with DAH seen in a specialized referral center who were treated on the intensive care unit (ICU). We only focused on critically ill patients with DAH.
2. Patients and methods 2.1. Data acquisition Our institution is an academic tertiary care center that receives most patients as referrals from other hospitals. Using computer-based searching for patients who had DAH and were treated on our ICU, we identified 37 patients who were treated between 2002 and 2004. Overall, 1286 ICU files were screened. Only the patients' first ICU admission was included in this study. Charts were reviewed retrospectively. All identified patients could be included in the study.
2.2. Diagnostic criteria/coding of data The diagnosis of DAH was made according to established criteria [9]. In brief, alveolar hemorrhage was diagnosed (1) in the absence of an identifiable respiratory tract infection, (2) in the presence of bilateral pulmonary infiltrates, and (3) when subsequent BAL aliquots were progressively more hemorrhagic or if the proportion of hemosiderin-laden macrophages was more than 20%. In all patients, routine microbiological analysis of tracheal secre-
231 tions and routine analysis of blood cultures were performed. In addition, all patients received BAL and cultures to exclude respiratory infection. The underlying illness was categorized as vasculitis (when there was either histological evidence of vasculitis, significant titers of cytoplasmic or perinuclear antineutrophile cytoplasmic antibodies [ANCAs], or high titer antidouble-stranded DNA antibodies in a patient with lupus) [13,14], drug-induced lung injury (when hemorrhage was associated with starting sirolimus [3 patients] or amiodarone [1 patient]) [15-17], cancer chemotherapy/thrombocytopenia associated (in the presence of these conditions and no sign of a primary thrombocytopenia), sepsis associated (in the presence of nonpulmonary sepsis), stem-cell transplant associated (in the context of stem-cell transplants) [18,19], or unknown (when no clear-cut cause could be found). The presence of respiratory symptoms on admission (dyspnea, cough, hemoptyses) was noted. The oxygenation index (arterial pO2/fraction of inspired oxygen) was calculated. For the patients receiving ventilatory support, the number of days on ventilation was noted.
2.3. Therapeutic protocols Intensive care unit care followed standardized written protocols. In brief, mean arterial pressure was adjusted to values of more than 65 mm Hg by fluids and/or vasopressors. Invasive hemodynamic monitoring (either by pulmonary artery catheter or by arterial waveform analysis; (PICCO; Pulsion Medical Instruments, Munich, Germany) was used in most patients. Hydrocortisone treatment was used in septic patients on vasopressors regardless of adrenal function testing. Protective mechanical ventilation with low tidal volumes as defined by the US ARDS network study [20] was used in all cases that fulfilled the ARDS criteria (bilateral infiltrates, oxygenation index b200, no left ventricular failure). The ventilation was carried out using either airway pressure release ventilation or biphasic positive airway pressure. Protective ventilation strategies were—in a nonevidencebased extrapolation—also used in ventilated patients not fulfilling the ARDS criteria. The patients were weaned from mechanical ventilation using continuous positive airway pressure ventilation with assisted spontaneous breathing, which was reduced before extubation. Intermittent hemodialysis or continuous veno-venous hemofiltration was administered as clinically indicated. Immunosuppressive therapy was administered as follows: Steroid pulses (100-500 mg/d) were used for 3 to 5 days and followed by an initial daily steroid dose of 70 to 100 mg, which was then tapered. Patients with ANCApositive vasculitis were treated with cyclophosphamide. The lupus patient and the patient with ANCA-negative vasculitis were treated with intravenous cyclophosphamide. The treatment was started immediately after diagnosis. Finely ground cyclophosphamide in a dosage of 100 to
232 150 mg was administered by nasogastric tube if patients were intubated. For vasculitis, intensive plasma exchange (every other day for at least 2 weeks) was used. Immunoglobulin was not given as vasculitis therapy but substituted when there was a serum immunoglobulin G less than 400 mg/dL. Thrombocyte transfusions (in 17 patients) and plasma transfusions (in 7 patients) were given as clinically indicated. Our transfusion trigger for thrombocytopenia is less than 20,000 thrombocytes/μL in septic and less than 10,000 thrombocytes/μL in nonseptic patients. Antifibrinolytics were used as adjunctive therapy in 3 patients. Activated factor VII was not used. The Acute Physiology and Chronic Health Evaluation (APACHE) II score [21] and the multiorgan dysfunction score (MODS) [22] were calculated on admission. Hospital survival was recorded.
C. Rabe et al. Table 1
Patient characteristics on ICU admission
Variable, unit (range) Age, y Creatinine, mg/dL Hemoglobin concentration, g/dL Prothrombin time, % control Platelet count, g/L Oxygenation index APACHE II score MODS Variable, n (%) Male sex Dyspnea Cough Hemoptysis DAH suspected at admission Diagnosis by hemorrhagic BAL fluid Diagnosis by iron stain
58 (27-79) 2.12 (0.54-6.3) 8.95 (5.5-14.1) 76 (12-130) 128.5 (2-634) 67 (40-211) 28 (16-36) 12 (7-21) 22/37 (60) 31/35 (89) 8/35 (23) 1/35 (3) 3/35 (9) 33/37 (89) 4/37 (11)
2.4. Statistical analysis Data are reported as median and range. The proportion of patients with a specific trait was reported for categorical data. Comparisons of continuous data between groups were performed using the Mann-Whitney U-test. Relationships between groups of nominal data were explored using the χ2 test, or if appropriate, the Fisher's exact test. An error level of less than 0.05 was considered statistically significant. To identify independent predictive factors for ICU death, logistic regression was performed. Because of the restricted number of patients, a conservative model design with ICU survival as the dependent and only 3 independent variables (oxygenation index, MODS, and the presence or absence of “classical” DAH) was used. We included all variables that were significant on univariate analysis. All calculations were carried out using Statview 5.01 and JMP 5.01 (both from SAS Institute, Cary, NC).
3. Results 3.1. Patients The characteristics of our cohort are presented in Table 1. Most patients from whom a history could be elicited presented with dyspnea. Although approximately a quarter of patients also reported cough, hemoptysis was only present in a single patient. Gas exchange was severely compromised in the cohort with a median (range) oxygenation index of 67 (40-211) mm Hg. All patients but 1 satisfied the ARDS criteria (oxygenation index b200 mm Hg, bilateral infiltrates, no evidence of left ventricular failure) on admission. The remaining patient satisfied acute lung injury criteria (oxygenation index b300 mm Hg, bilateral infiltrates, no evidence of left ventricular failure). The reason for ICU admission was hypoxemic lung failure in 30 (81%) of 37 patients. A
suspicion of pancreatitis was entertained in 1 patient, and 2 patients were admitted for hemodynamic instability. The preliminary diagnosis on ICU admission was “atypical pneumonia” in most patients. Only 3 patients were admitted with the correct diagnosis of DAH. We then diagnosed DAH by obtaining progressively bloody BAL aliquots in 89% of the patients. The iron stain contributed to the diagnosis in 11% of patients (by definition, those who presented without bloody BAL fluid). Of the 4 patients with positive iron stain, 2 had thrombocytopenia, 1 from sepsis and 1 from DAH due to unknown mechanisms. One of these 4 patients died. The median (range) hemoglobin concentration of 9 (5.5-14.1) g/dL was moderately decreased. Interestingly, creatinine concentration was normal (ie, b1.3 mg/dL) on admission in only 9 of 37 (24%) patients; median creatinine concentration was 2.12 mg/dL. Severity of illness scores were moderately increased in our cohort with a median APACHE II score of 28 and a median MODS of 12.
3.2. Causes of DAH The underlying diseases are summarized in Table 2. Only in a minority of DAH patients, one of the classical causes of DAH was present: drug toxicity and pulmonary vasculitis accounted for only 30% of all patients. In 54% of the patients, DAH was associated with chemotherapy, thrombocytopenia, and stem-cell transplant or occurred in the context of sepsis. In 16%, no definite cause could be found. These cases were designated as “unknown.” Chemotherapy and drug-related cases occurred between 0 to 45 days after drug/chemotherapy administration.
3.3. Clinical course One patient did not need mechanical ventilation, 4 patients could be supported with noninvasive ventilation, and 32
Diffuse alveolar hemorrhage—characteristics and outcome Table 2
233 Table 4
Probable causes of DAH
Comparison of possible outcome factors
Probable cause
n (%)
Variable
Vasculitis SLE-associated DAH ANCA disease Other types of vasculitis Thrombocytopenia/Chemotherapy Stem-cell transplant Drug toxicity Sirolimus Other Sepsis Unknown origin
7 (19) 1 5 1 10 (27) 2 (5) 4 (11) 3 1 8 (22) 6 (16)
Age, y 56 (27-69) Creatinine, 2.01 (0.71-6.34) mg/dL Hemoglobin, 9.4 (5.5-14.1) g/dL 80 (29-130) Prothrombin time, % control Platelet count, 152 (11-459) g/L Oxygenation 87 (54-211) index APACHE II 21 (16-36) score MODS 11 (7-18) Male sex 9/18 14/18 Classical DAH a
SLE indicates systemic lupus erythematosus.
patients were intubated and invasively ventilated. Median (range) ventilation time was 9.5 (1-71) days in all ventilated patients; a median (range) time of 18 (3-67) days until weaning was completed in ICU survivors, and a median (range) ventilation time of 8 (1-71) days before death in those patients who died on the ICU. Using composite criteria (improvement of infiltrates on chest x-ray and increase of the oxygenation index to at least 200), DAH improved at least temporarily in 35 (94%) of 37 patients. Multiorgan failure developed in most of the patients who died. In 2 patients with multiorgan failure, therapy was discontinued after intracerebral bleeding. In 7 patients, hypoxemia (in the context of multiorgan failure) was noted as the immediate cause of death. In 29 (78%) of 37 patients, steroids (median [range] total dose, 1440 mg [100-7730 mg]) were used. There was no statistical difference in survival between patients treated with or without steroids (not significant, Fisher's exact test). Because renal function was already compromised in most patients on admission, it was not surprising that 14 patients became completely anuric. Renal replacement therapy was used as needed.
Table 3
Etiology and outcome of ICU treatment
Probable cause
Survival (%)
95% CI
Immunologic/unknown Vasculitis Drug toxicity Unknown Coagulation disorder/ thrombocytopenia Sepsis Thrombocytopenia/ Chemotherapy Stem-cell transplant Overall
14/17 7/7 3/4 4/6 4/18
(59%-94%) (65%-100%) (30%-95%) (30%-90%) (9%-45%)
CI indicates confidence interval.
(82) (100) (75) (67) (22)
2/8 (25) 2/10 (20)
(7%-59%) (6%-51%)
0/2 (0) 18/37 (49)
(0-66%) (33%-64%)
ICU survival
ICU deaths
Significance
62 (37-79) P = 0.23 2.5 (0.54-6.03) P = 1.0 8.9 (7.1-12)
P = 0.4
75 (12-104)
P = 0.12
28 (2-634)
P = 0.06
61 (40-135)
P = 0.049
29 (17-35)
P = 0.16
16 (8-21) 13/19 3/19
P = 0.02 P = 0.32 P b 0.0001
a Classical DAH: causes associated with pulmonary vasculitis/ capillaritis.
3.4. Survival Nineteen (51%) of 37 patients died during their hospital stay. Outcome differed by disease mechanism (Table 3): the patients with classical DAH, that is, DAH caused by immunologic mechanisms such as vasculitis and drug reactions or “idiopathic” cases. Conversely, most patients with DAH secondary to coagulopathy or thrombocytopenia, for example, in the context of chemotherapy or sepsis, died. There was no difference between age of patients with classical DAH (median [range] age, 55.8 [27-72] years) and “secondary” DAH (median [range] age, 61.5 [36-79] years; P = 0.42, U-test). Table 4 shows the effect of individual variables of organ function on ICU survival. Although both the oxygenation index and the MODS differed significantly between ICU survivors and patients who died on the ICU, the etiology of DAH showed the most pronounced differences between both patient groups.
Table 5 Results from logistic regression analysis for factors associated with clinical course of ICU patients with DAH Variable
Intercept Classical Oxygenation MODS
Estimate −3.26 −1.88 95% confidence −12.2 to −3.7 to interval 3.23 −0.68 Odds ratio 0.02 χ2 0.8 6.62 Probability Nχ2 0.37 0.01
0.03 −0.00 to 0.07 120 2.37 0.12
0.05 −0.32 to 0.5 2.0 0.07 0.8
234 When the parameters that differed significantly in univariate analysis between both groups (oxygenation index, MODS, etiology of DAH) were used as independent variables in a logistic regression analysis with ICU death as the outcome variable, the etiology of DAH was the only remaining variable in the model (Table 5).
4. Discussion We analyzed the etiology and outcome of severe course of DAH in critically ill patients on the ICU. Our study findings are not necessarily applicable to less severe manifestations of DAH. The main findings of our study were that (i) DAH is an unexpected diagnosis in most patients (ie, the diagnosis had not been considered before BAL analysis); (ii) hemoptysis is absent in most patients; (iii) most patients fulfill the ARDS criteria; (iv) iron stain is necessary for diagnosis in a substantial proportion of patients; (v) classical causes such as vasculitis or drug toxicity only account for one third of patients; and (vi) the prognosis is strikingly dependent on etiology with the survival in patients with classical DAH approaching 85%, whereas the survival of other patients is poor. Hemoptysis is regarded as the guiding clinical symptom in DAH [23,24,25]. Unfortunately, this symptom was absent in 97% of patients admitted to the ICU in our series. This explains that the diagnosis of DAH was entertained only in a small minority of patients in our series. Because the functional limitation of gas exchange in DAH is very prominent and bilateral pulmonary infiltrates in the absence of left ventricular failure are part of both syndromes, ARDS may be mistakenly diagnosed. In fact, some authors consider DAH as one of the “imitators” of ARDS [12]. One may, of course, argue that DAH with a profound functional limitation is ARDS, as the very definition of ARDS is met [25]. However, in clinical practice, it is still important to differentiate between DAH and ARDS of other etiology because many causes of DAH are readily reversible. In a cohort in which almost all patients fulfilled ARDS criteria, 18% mortality can be considered a relatively favorable outcome compared with 31% mortality in the US ARDS network study [20]. In a recent series of open lung biopsies in ARDS patients [11], DAH was diagnosed in 5 (9%) of 57 of cases. Although this may reflect selection bias as only a minority of ARDS patients undergo open lung biopsy, it is likely that large ARDS series include at least some DAH patients. The noninvasive criterion standard of diagnosis of DAH is the examination of BAL fluid [9]. Although this fluid was macroscopically bloody in most cases, iron stain [10] was necessary for a correct diagnosis in 11% of patients. Patients with DAH have a decreased hemoglobin concentration (median hemoglobin in our series, 9 g/dL).
C. Rabe et al. This does not seem to be reliable enough to differentiate them from ARDS, which often is also associated with anemia [26]. Ventilatory support is needed if patients are to survive their stay in the ICU: a median time of 18 days of ventilation in survivors translates into an enormous resource use expended to treat this disease. Most studies on DAH emphasize that it is immunologically mediated [9]. Vasculitis or drug reactions may lead to DAH. As our retrospective analysis of DAH on the ICU demonstrates, most of the severe cases of DAH today are not patients with classical DAH but patients who develop DAH in the context of significant comorbidities. However, our series is an unicentric series in a specialized referral center—it is likely that the proportion of pulmorenal patients and cancer cases is higher in our series than it would be in a nonselected patient population. It is not surprising that comorbidities, in particular malignant disease treated with chemotherapy or septic shock, lead to a markedly decreased survival in these patients with secondary DAH when compared with classical DAH. Although classical DAH can be easily treated with immunosuppressive regimens, the optimal therapy for DAH secondary to sepsis and cancer-related thrombocytopenia is undefined at the moment. Although a subset of patients with drug-induced or post–stem-cell transplant DAH may benefit from immunosuppression [1,2], we were frequently reluctant to use immunosuppression in patients with sepsis or in aplastic patients. Recent reports showed a beneficial effect of administration of recombinant activated factor VII [27,28] in DAH—the precise role for this promising treatment in patients with coagulation abnormalities needs to be defined. In view of the strikingly different outcome, it should be kept in mind that DAH is a heterogenous syndrome and not a disease entity by itself. It may therefore be useful to differentiate DAH—as we have done—in the classical and a thrombocytopenia/coagulopathy-related syndrome to better reflect outcome. A multicentric prospective descriptive series to eliminate selection bias and to identify prognostic predictors would be useful.
5. Conclusions In summary, DAH must be seriously considered in patients with pulmonary infiltrates. Both BAL and iron stain are necessary to make the diagnosis. Many patients do not experience the classical immunologic diseases that are associated with DAH but develop DAH in the context of serious comorbidities. Although immunosuppression leads to excellent results in immune-mediated cases, the optimal therapy for DAH secondary to major comorbidities remains to be defined.
Diffuse alveolar hemorrhage—characteristics and outcome
References [1] Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364-8. [2] Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:641-5. [3] Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir 2004;24:162-70. [4] Zandman-Goddard G, Ehrenfeld M, Levy Y, Tal S. Diffuse alveolar hemorrhage in systemic lupus erythematosus. Isr Med Assoc 2002;4: 470. [5] Zandman-Goddard G. Diffuse alveolar hemorrhage in autoimmune diseases. Isr Med Assoc 2002;4:461-2. [6] Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimusassociated interstitial pneumonitis in renal transplant patients. Transplantation 2001;72:787-90. [7] Collard HRSM. Diffuse alveolar hemorrhage. Clin Chest Med 2004; 25:583-92. [8] Hellmann MA, Gerhardt TM, Rabe C, Haas S, Sauerbruch T. Woitas RP Goodpasture's syndrome with massive pulmonary haemorrhage in the absence of circulating anti-GBM antibodies? Nephrol Dial Transplant 2006;21:526-9. [9] Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol 2001;13:12-7. [10] De Lassence A, Fleury-Feith J, Escudier E, Beaune J, Bernaudin JF, Cordonnier C. Alveolar hemorrhage. Diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med 1995; 151:157-63. [11] Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in ARDS. Chest 2004;125:197-202. [12] Schwarz MI, Albert RK. “Imitators” of the ARDS: implications for diagnosis and treatment. Chest 2004;125:1530-5. [13] Burkhardt O, Köhnlein T, Wrenger E, Lux A, Neumann KH, Welte T. Predicting outcome and survival in patients with Wegener's granulomatosis treated on the intensive care unit. Scand J Rheumatol 2007;36: 119-24. [14] Khan SA, Subla MR, Behl D, Specks U, Afessa B. Outcome of patients with small-vessel vasculitis admitted to a medical ICU. Chest 2007;131:972-6.
235 [15] Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant 2007;26:652-7. [16] Vlahakis NE, Rickman OB, Morgenthaler T. Sirolimus-associated diffuse alveolar hemorrhage. Mayo Clin Proc 2004;79:541-5. [17] Iskandar SB, Abi-Saleh B, Keith RL, Byrd Jr RP, Roy TM. Amiodaroneinduced alveolar hemorrhage. South Med J 2006;99:383-7. [18] Kretzschmar M, Steinke K, Steinbrich W. Diffuse alveolar hemorrhage (DAH): an underestimated pulmonary complication after hematopoietic stem cell transplantation. Schweiz Rundsch Med Prax 2005;94: 1267-9. [19] Gupta S, Jain A, Warneke CL, et al. Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2007;40:71-8. [20] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-8. [21] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13: 818-29. [22] Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995;23:1638-52. [23] Schwarz MI, Brown KK. Small vessel vasculitis of the lung. Thorax 2000;55:502-10. [24] Costabel U. Technic and method of broncho-alveolar lavage in interstitial lung diseases. Schweiz Med Wochenschr 1986;116: 1238-44. [25] Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-24. [26] Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191-8. [27] Henke D, Falk RJ, Gabriel DA. Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 2004; 140:493-4. [28] Heslet L, Nielsen JD, Levi M, Sengelov H, Johansson PI. Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 2006;10:R177.
Severe respiratory failure due to diffuse alveolar hemorrhage: Clinical characteristics and outcome of intensive care Christian Rabe MD, MBA a,⁎,1 , Beate Appenrodt MD a,1 , Christian Hoff MD b , Santiago Ewig MD, FCCP b,c , Hans Ulrich Klehr MD a , Tilman Sauerbruch MD a , Georg Nickenig MD b , Selçuk Tasci MD b a
Medical ICU, Department of Internal Medicine I, University of Bonn, D-53105 Bonn, Germany Medical ICU, Department of Internal Medicine II, University of Bonn, D-53105 Bonn, Germany c Thoraxzentrum Ruhrgebiet, Kliniken für Pneumologie und Infektiologie, Herne und Bochum, D-44651 Herne, Germany b
Keywords: Diffuse alveolar hemorrhage; Mechanical ventilation; Outcome; Intensive care unit
Abstract Background: The aim of this study was to characterize patients and report outcome of diffuse alveolar hemorrhage (DAH) requiring intensive care unit support. Patients and Methods: Thirty-seven patients were identified. Clinical characteristics and outcome were determined by chart review. Results: Eighty-nine percent of patients presented with shortness of breath, 23% with cough, and 3% with hemoptysis. In 9% of patients, a diagnosis of DAH was suspected on admission. Diagnosis was confirmed by finding a progressively hemorrhagic bronchoalveolar lavage fluid in 89% and by a positive iron stain in 11% of patients. Vasculitis was causative in 19%, drug toxicity in 11%, thrombocytopenia in 27%, stem-cell transplantation in 5%, sepsis-associated lung injury in 22%, and unknown mechanisms in 16%. Thirty-two patients were mechanically ventilated, 4 received noninvasive ventilation, and 1 received supplemental oxygen therapy. Overall, 18 (49%) of 37 patients survived the intensive care unit stay. Survival was markedly different between patients with an immunologic/unknown etiology (82%) and patients with thrombocytopenia and/or sepsis (22%). Discussion: Diffuse alveolar hemorrhage should be considered in all patients with persistent pulmonary infiltrates. Both bronchoalveolar lavage fluid and iron stain are mandatory diagnostic means. Patients with an immunologic/idiopathic pathogenetic mechanism have a relatively good prognosis, whereas the outcome in individuals with DAH secondary to cancer therapy or sepsis is poor. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; ANCAs, antineutrophile cytoplasmic antibodies; BAL, bronchoalveolar lavage; DAH, diffuse alveolar hemorrhage; ICU, intensive care unit; MODS, multiorgan dysfunction score. 1 C.R. and B.A. contributed equally. ⁎ Corresponding author. Tel.: +49 228 28715507; fax: +49 228 28714698. E-mail address: [email protected] (C. Rabe).
0883-9441/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2009.04.009
Diffuse alveolar hemorrhage—characteristics and outcome
1. Introduction Diffuse alveolar hemorrhage (DAH) is a syndrome of heterogeneous etiology [1-7] characterized either by acute bleeding into the alveolar space or by insidious alveolar bleeding causing a slower deterioration in lung function. The underlying disease mechanism can be either a cellularly (“capillaritis”) or humorally mediated (eg, Goodpasture syndrome) disintegration of the alveolar-capillary barrier leading to entry of blood in the alveolar space. The precise mechanism varies with the underlying condition. Many “idiopathic” cases are probably caused by immunologic mechanisms [8]. The manifestations of this syndrome range from minor abnormalities noted only on sensitive imaging to a dramatic compromise of gas exchange necessitating prompt ventilatory support. The diagnosis of DAH is difficult, especially in patients with chronic bleeding, because signs of overt bleeding are absent. In this situation, diagnosis relies on the demonstration of iron-laden macrophages in bronchoalveolar lavage (BAL) fluid [2,9,10]. Patients who have DAH may easily be misdiagnosed as atypical pneumonia, and DAH can also imitate acute respiratory distress syndrome (ARDS) [11,12]. Because of the relative rarity of DAH, our knowledge on etiology and outcome of the more severe manifestations of this syndrome is limited. We report a series of patients with DAH seen in a specialized referral center who were treated on the intensive care unit (ICU). We only focused on critically ill patients with DAH.
2. Patients and methods 2.1. Data acquisition Our institution is an academic tertiary care center that receives most patients as referrals from other hospitals. Using computer-based searching for patients who had DAH and were treated on our ICU, we identified 37 patients who were treated between 2002 and 2004. Overall, 1286 ICU files were screened. Only the patients' first ICU admission was included in this study. Charts were reviewed retrospectively. All identified patients could be included in the study.
2.2. Diagnostic criteria/coding of data The diagnosis of DAH was made according to established criteria [9]. In brief, alveolar hemorrhage was diagnosed (1) in the absence of an identifiable respiratory tract infection, (2) in the presence of bilateral pulmonary infiltrates, and (3) when subsequent BAL aliquots were progressively more hemorrhagic or if the proportion of hemosiderin-laden macrophages was more than 20%. In all patients, routine microbiological analysis of tracheal secre-
231 tions and routine analysis of blood cultures were performed. In addition, all patients received BAL and cultures to exclude respiratory infection. The underlying illness was categorized as vasculitis (when there was either histological evidence of vasculitis, significant titers of cytoplasmic or perinuclear antineutrophile cytoplasmic antibodies [ANCAs], or high titer antidouble-stranded DNA antibodies in a patient with lupus) [13,14], drug-induced lung injury (when hemorrhage was associated with starting sirolimus [3 patients] or amiodarone [1 patient]) [15-17], cancer chemotherapy/thrombocytopenia associated (in the presence of these conditions and no sign of a primary thrombocytopenia), sepsis associated (in the presence of nonpulmonary sepsis), stem-cell transplant associated (in the context of stem-cell transplants) [18,19], or unknown (when no clear-cut cause could be found). The presence of respiratory symptoms on admission (dyspnea, cough, hemoptyses) was noted. The oxygenation index (arterial pO2/fraction of inspired oxygen) was calculated. For the patients receiving ventilatory support, the number of days on ventilation was noted.
2.3. Therapeutic protocols Intensive care unit care followed standardized written protocols. In brief, mean arterial pressure was adjusted to values of more than 65 mm Hg by fluids and/or vasopressors. Invasive hemodynamic monitoring (either by pulmonary artery catheter or by arterial waveform analysis; (PICCO; Pulsion Medical Instruments, Munich, Germany) was used in most patients. Hydrocortisone treatment was used in septic patients on vasopressors regardless of adrenal function testing. Protective mechanical ventilation with low tidal volumes as defined by the US ARDS network study [20] was used in all cases that fulfilled the ARDS criteria (bilateral infiltrates, oxygenation index b200, no left ventricular failure). The ventilation was carried out using either airway pressure release ventilation or biphasic positive airway pressure. Protective ventilation strategies were—in a nonevidencebased extrapolation—also used in ventilated patients not fulfilling the ARDS criteria. The patients were weaned from mechanical ventilation using continuous positive airway pressure ventilation with assisted spontaneous breathing, which was reduced before extubation. Intermittent hemodialysis or continuous veno-venous hemofiltration was administered as clinically indicated. Immunosuppressive therapy was administered as follows: Steroid pulses (100-500 mg/d) were used for 3 to 5 days and followed by an initial daily steroid dose of 70 to 100 mg, which was then tapered. Patients with ANCApositive vasculitis were treated with cyclophosphamide. The lupus patient and the patient with ANCA-negative vasculitis were treated with intravenous cyclophosphamide. The treatment was started immediately after diagnosis. Finely ground cyclophosphamide in a dosage of 100 to
232 150 mg was administered by nasogastric tube if patients were intubated. For vasculitis, intensive plasma exchange (every other day for at least 2 weeks) was used. Immunoglobulin was not given as vasculitis therapy but substituted when there was a serum immunoglobulin G less than 400 mg/dL. Thrombocyte transfusions (in 17 patients) and plasma transfusions (in 7 patients) were given as clinically indicated. Our transfusion trigger for thrombocytopenia is less than 20,000 thrombocytes/μL in septic and less than 10,000 thrombocytes/μL in nonseptic patients. Antifibrinolytics were used as adjunctive therapy in 3 patients. Activated factor VII was not used. The Acute Physiology and Chronic Health Evaluation (APACHE) II score [21] and the multiorgan dysfunction score (MODS) [22] were calculated on admission. Hospital survival was recorded.
C. Rabe et al. Table 1
Patient characteristics on ICU admission
Variable, unit (range) Age, y Creatinine, mg/dL Hemoglobin concentration, g/dL Prothrombin time, % control Platelet count, g/L Oxygenation index APACHE II score MODS Variable, n (%) Male sex Dyspnea Cough Hemoptysis DAH suspected at admission Diagnosis by hemorrhagic BAL fluid Diagnosis by iron stain
58 (27-79) 2.12 (0.54-6.3) 8.95 (5.5-14.1) 76 (12-130) 128.5 (2-634) 67 (40-211) 28 (16-36) 12 (7-21) 22/37 (60) 31/35 (89) 8/35 (23) 1/35 (3) 3/35 (9) 33/37 (89) 4/37 (11)
2.4. Statistical analysis Data are reported as median and range. The proportion of patients with a specific trait was reported for categorical data. Comparisons of continuous data between groups were performed using the Mann-Whitney U-test. Relationships between groups of nominal data were explored using the χ2 test, or if appropriate, the Fisher's exact test. An error level of less than 0.05 was considered statistically significant. To identify independent predictive factors for ICU death, logistic regression was performed. Because of the restricted number of patients, a conservative model design with ICU survival as the dependent and only 3 independent variables (oxygenation index, MODS, and the presence or absence of “classical” DAH) was used. We included all variables that were significant on univariate analysis. All calculations were carried out using Statview 5.01 and JMP 5.01 (both from SAS Institute, Cary, NC).
3. Results 3.1. Patients The characteristics of our cohort are presented in Table 1. Most patients from whom a history could be elicited presented with dyspnea. Although approximately a quarter of patients also reported cough, hemoptysis was only present in a single patient. Gas exchange was severely compromised in the cohort with a median (range) oxygenation index of 67 (40-211) mm Hg. All patients but 1 satisfied the ARDS criteria (oxygenation index b200 mm Hg, bilateral infiltrates, no evidence of left ventricular failure) on admission. The remaining patient satisfied acute lung injury criteria (oxygenation index b300 mm Hg, bilateral infiltrates, no evidence of left ventricular failure). The reason for ICU admission was hypoxemic lung failure in 30 (81%) of 37 patients. A
suspicion of pancreatitis was entertained in 1 patient, and 2 patients were admitted for hemodynamic instability. The preliminary diagnosis on ICU admission was “atypical pneumonia” in most patients. Only 3 patients were admitted with the correct diagnosis of DAH. We then diagnosed DAH by obtaining progressively bloody BAL aliquots in 89% of the patients. The iron stain contributed to the diagnosis in 11% of patients (by definition, those who presented without bloody BAL fluid). Of the 4 patients with positive iron stain, 2 had thrombocytopenia, 1 from sepsis and 1 from DAH due to unknown mechanisms. One of these 4 patients died. The median (range) hemoglobin concentration of 9 (5.5-14.1) g/dL was moderately decreased. Interestingly, creatinine concentration was normal (ie, b1.3 mg/dL) on admission in only 9 of 37 (24%) patients; median creatinine concentration was 2.12 mg/dL. Severity of illness scores were moderately increased in our cohort with a median APACHE II score of 28 and a median MODS of 12.
3.2. Causes of DAH The underlying diseases are summarized in Table 2. Only in a minority of DAH patients, one of the classical causes of DAH was present: drug toxicity and pulmonary vasculitis accounted for only 30% of all patients. In 54% of the patients, DAH was associated with chemotherapy, thrombocytopenia, and stem-cell transplant or occurred in the context of sepsis. In 16%, no definite cause could be found. These cases were designated as “unknown.” Chemotherapy and drug-related cases occurred between 0 to 45 days after drug/chemotherapy administration.
3.3. Clinical course One patient did not need mechanical ventilation, 4 patients could be supported with noninvasive ventilation, and 32
Diffuse alveolar hemorrhage—characteristics and outcome Table 2
233 Table 4
Probable causes of DAH
Comparison of possible outcome factors
Probable cause
n (%)
Variable
Vasculitis SLE-associated DAH ANCA disease Other types of vasculitis Thrombocytopenia/Chemotherapy Stem-cell transplant Drug toxicity Sirolimus Other Sepsis Unknown origin
7 (19) 1 5 1 10 (27) 2 (5) 4 (11) 3 1 8 (22) 6 (16)
Age, y 56 (27-69) Creatinine, 2.01 (0.71-6.34) mg/dL Hemoglobin, 9.4 (5.5-14.1) g/dL 80 (29-130) Prothrombin time, % control Platelet count, 152 (11-459) g/L Oxygenation 87 (54-211) index APACHE II 21 (16-36) score MODS 11 (7-18) Male sex 9/18 14/18 Classical DAH a
SLE indicates systemic lupus erythematosus.
patients were intubated and invasively ventilated. Median (range) ventilation time was 9.5 (1-71) days in all ventilated patients; a median (range) time of 18 (3-67) days until weaning was completed in ICU survivors, and a median (range) ventilation time of 8 (1-71) days before death in those patients who died on the ICU. Using composite criteria (improvement of infiltrates on chest x-ray and increase of the oxygenation index to at least 200), DAH improved at least temporarily in 35 (94%) of 37 patients. Multiorgan failure developed in most of the patients who died. In 2 patients with multiorgan failure, therapy was discontinued after intracerebral bleeding. In 7 patients, hypoxemia (in the context of multiorgan failure) was noted as the immediate cause of death. In 29 (78%) of 37 patients, steroids (median [range] total dose, 1440 mg [100-7730 mg]) were used. There was no statistical difference in survival between patients treated with or without steroids (not significant, Fisher's exact test). Because renal function was already compromised in most patients on admission, it was not surprising that 14 patients became completely anuric. Renal replacement therapy was used as needed.
Table 3
Etiology and outcome of ICU treatment
Probable cause
Survival (%)
95% CI
Immunologic/unknown Vasculitis Drug toxicity Unknown Coagulation disorder/ thrombocytopenia Sepsis Thrombocytopenia/ Chemotherapy Stem-cell transplant Overall
14/17 7/7 3/4 4/6 4/18
(59%-94%) (65%-100%) (30%-95%) (30%-90%) (9%-45%)
CI indicates confidence interval.
(82) (100) (75) (67) (22)
2/8 (25) 2/10 (20)
(7%-59%) (6%-51%)
0/2 (0) 18/37 (49)
(0-66%) (33%-64%)
ICU survival
ICU deaths
Significance
62 (37-79) P = 0.23 2.5 (0.54-6.03) P = 1.0 8.9 (7.1-12)
P = 0.4
75 (12-104)
P = 0.12
28 (2-634)
P = 0.06
61 (40-135)
P = 0.049
29 (17-35)
P = 0.16
16 (8-21) 13/19 3/19
P = 0.02 P = 0.32 P b 0.0001
a Classical DAH: causes associated with pulmonary vasculitis/ capillaritis.
3.4. Survival Nineteen (51%) of 37 patients died during their hospital stay. Outcome differed by disease mechanism (Table 3): the patients with classical DAH, that is, DAH caused by immunologic mechanisms such as vasculitis and drug reactions or “idiopathic” cases. Conversely, most patients with DAH secondary to coagulopathy or thrombocytopenia, for example, in the context of chemotherapy or sepsis, died. There was no difference between age of patients with classical DAH (median [range] age, 55.8 [27-72] years) and “secondary” DAH (median [range] age, 61.5 [36-79] years; P = 0.42, U-test). Table 4 shows the effect of individual variables of organ function on ICU survival. Although both the oxygenation index and the MODS differed significantly between ICU survivors and patients who died on the ICU, the etiology of DAH showed the most pronounced differences between both patient groups.
Table 5 Results from logistic regression analysis for factors associated with clinical course of ICU patients with DAH Variable
Intercept Classical Oxygenation MODS
Estimate −3.26 −1.88 95% confidence −12.2 to −3.7 to interval 3.23 −0.68 Odds ratio 0.02 χ2 0.8 6.62 Probability Nχ2 0.37 0.01
0.03 −0.00 to 0.07 120 2.37 0.12
0.05 −0.32 to 0.5 2.0 0.07 0.8
234 When the parameters that differed significantly in univariate analysis between both groups (oxygenation index, MODS, etiology of DAH) were used as independent variables in a logistic regression analysis with ICU death as the outcome variable, the etiology of DAH was the only remaining variable in the model (Table 5).
4. Discussion We analyzed the etiology and outcome of severe course of DAH in critically ill patients on the ICU. Our study findings are not necessarily applicable to less severe manifestations of DAH. The main findings of our study were that (i) DAH is an unexpected diagnosis in most patients (ie, the diagnosis had not been considered before BAL analysis); (ii) hemoptysis is absent in most patients; (iii) most patients fulfill the ARDS criteria; (iv) iron stain is necessary for diagnosis in a substantial proportion of patients; (v) classical causes such as vasculitis or drug toxicity only account for one third of patients; and (vi) the prognosis is strikingly dependent on etiology with the survival in patients with classical DAH approaching 85%, whereas the survival of other patients is poor. Hemoptysis is regarded as the guiding clinical symptom in DAH [23,24,25]. Unfortunately, this symptom was absent in 97% of patients admitted to the ICU in our series. This explains that the diagnosis of DAH was entertained only in a small minority of patients in our series. Because the functional limitation of gas exchange in DAH is very prominent and bilateral pulmonary infiltrates in the absence of left ventricular failure are part of both syndromes, ARDS may be mistakenly diagnosed. In fact, some authors consider DAH as one of the “imitators” of ARDS [12]. One may, of course, argue that DAH with a profound functional limitation is ARDS, as the very definition of ARDS is met [25]. However, in clinical practice, it is still important to differentiate between DAH and ARDS of other etiology because many causes of DAH are readily reversible. In a cohort in which almost all patients fulfilled ARDS criteria, 18% mortality can be considered a relatively favorable outcome compared with 31% mortality in the US ARDS network study [20]. In a recent series of open lung biopsies in ARDS patients [11], DAH was diagnosed in 5 (9%) of 57 of cases. Although this may reflect selection bias as only a minority of ARDS patients undergo open lung biopsy, it is likely that large ARDS series include at least some DAH patients. The noninvasive criterion standard of diagnosis of DAH is the examination of BAL fluid [9]. Although this fluid was macroscopically bloody in most cases, iron stain [10] was necessary for a correct diagnosis in 11% of patients. Patients with DAH have a decreased hemoglobin concentration (median hemoglobin in our series, 9 g/dL).
C. Rabe et al. This does not seem to be reliable enough to differentiate them from ARDS, which often is also associated with anemia [26]. Ventilatory support is needed if patients are to survive their stay in the ICU: a median time of 18 days of ventilation in survivors translates into an enormous resource use expended to treat this disease. Most studies on DAH emphasize that it is immunologically mediated [9]. Vasculitis or drug reactions may lead to DAH. As our retrospective analysis of DAH on the ICU demonstrates, most of the severe cases of DAH today are not patients with classical DAH but patients who develop DAH in the context of significant comorbidities. However, our series is an unicentric series in a specialized referral center—it is likely that the proportion of pulmorenal patients and cancer cases is higher in our series than it would be in a nonselected patient population. It is not surprising that comorbidities, in particular malignant disease treated with chemotherapy or septic shock, lead to a markedly decreased survival in these patients with secondary DAH when compared with classical DAH. Although classical DAH can be easily treated with immunosuppressive regimens, the optimal therapy for DAH secondary to sepsis and cancer-related thrombocytopenia is undefined at the moment. Although a subset of patients with drug-induced or post–stem-cell transplant DAH may benefit from immunosuppression [1,2], we were frequently reluctant to use immunosuppression in patients with sepsis or in aplastic patients. Recent reports showed a beneficial effect of administration of recombinant activated factor VII [27,28] in DAH—the precise role for this promising treatment in patients with coagulation abnormalities needs to be defined. In view of the strikingly different outcome, it should be kept in mind that DAH is a heterogenous syndrome and not a disease entity by itself. It may therefore be useful to differentiate DAH—as we have done—in the classical and a thrombocytopenia/coagulopathy-related syndrome to better reflect outcome. A multicentric prospective descriptive series to eliminate selection bias and to identify prognostic predictors would be useful.
5. Conclusions In summary, DAH must be seriously considered in patients with pulmonary infiltrates. Both BAL and iron stain are necessary to make the diagnosis. Many patients do not experience the classical immunologic diseases that are associated with DAH but develop DAH in the context of serious comorbidities. Although immunosuppression leads to excellent results in immune-mediated cases, the optimal therapy for DAH secondary to major comorbidities remains to be defined.
Diffuse alveolar hemorrhage—characteristics and outcome
References [1] Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364-8. [2] Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:641-5. [3] Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir 2004;24:162-70. [4] Zandman-Goddard G, Ehrenfeld M, Levy Y, Tal S. Diffuse alveolar hemorrhage in systemic lupus erythematosus. Isr Med Assoc 2002;4: 470. [5] Zandman-Goddard G. Diffuse alveolar hemorrhage in autoimmune diseases. Isr Med Assoc 2002;4:461-2. [6] Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimusassociated interstitial pneumonitis in renal transplant patients. Transplantation 2001;72:787-90. [7] Collard HRSM. Diffuse alveolar hemorrhage. Clin Chest Med 2004; 25:583-92. [8] Hellmann MA, Gerhardt TM, Rabe C, Haas S, Sauerbruch T. Woitas RP Goodpasture's syndrome with massive pulmonary haemorrhage in the absence of circulating anti-GBM antibodies? Nephrol Dial Transplant 2006;21:526-9. [9] Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol 2001;13:12-7. [10] De Lassence A, Fleury-Feith J, Escudier E, Beaune J, Bernaudin JF, Cordonnier C. Alveolar hemorrhage. Diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med 1995; 151:157-63. [11] Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in ARDS. Chest 2004;125:197-202. [12] Schwarz MI, Albert RK. “Imitators” of the ARDS: implications for diagnosis and treatment. Chest 2004;125:1530-5. [13] Burkhardt O, Köhnlein T, Wrenger E, Lux A, Neumann KH, Welte T. Predicting outcome and survival in patients with Wegener's granulomatosis treated on the intensive care unit. Scand J Rheumatol 2007;36: 119-24. [14] Khan SA, Subla MR, Behl D, Specks U, Afessa B. Outcome of patients with small-vessel vasculitis admitted to a medical ICU. Chest 2007;131:972-6.
235 [15] Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant 2007;26:652-7. [16] Vlahakis NE, Rickman OB, Morgenthaler T. Sirolimus-associated diffuse alveolar hemorrhage. Mayo Clin Proc 2004;79:541-5. [17] Iskandar SB, Abi-Saleh B, Keith RL, Byrd Jr RP, Roy TM. Amiodaroneinduced alveolar hemorrhage. South Med J 2006;99:383-7. [18] Kretzschmar M, Steinke K, Steinbrich W. Diffuse alveolar hemorrhage (DAH): an underestimated pulmonary complication after hematopoietic stem cell transplantation. Schweiz Rundsch Med Prax 2005;94: 1267-9. [19] Gupta S, Jain A, Warneke CL, et al. Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2007;40:71-8. [20] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-8. [21] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13: 818-29. [22] Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995;23:1638-52. [23] Schwarz MI, Brown KK. Small vessel vasculitis of the lung. Thorax 2000;55:502-10. [24] Costabel U. Technic and method of broncho-alveolar lavage in interstitial lung diseases. Schweiz Med Wochenschr 1986;116: 1238-44. [25] Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-24. [26] Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191-8. [27] Henke D, Falk RJ, Gabriel DA. Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 2004; 140:493-4. [28] Heslet L, Nielsen JD, Levi M, Sengelov H, Johansson PI. Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 2006;10:R177.