clinical investigations in critical care

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1 clinical investigations in critical care Outcome of Patients Requiring Medical ICU Admission Following Bone Marrow Transplantation* Harold L. Paz,.\I.D.,.\I.S., F.C.C.P. ; Pamela Crilley, D.O;.\lartlw \Veinar, R.N., M.S.; and Isadore Brodsky,.\I.D. Despite encouraging results seen following bone marrow transplantation (BMT), it has been observed that once these patients become critically ill and require medical intensive care unit (MICU) admission, the chances of survival are poor. We hypothesized that while mechanical ventilation would be an important predictor for death in the MICU, those patients not requiring mechanical ventilation could be successfully discharged from the MICU. The records of 36 patients with 43 admissions to the MICU following BMT were analyzed. Of these admissions, 33 (76. 7 percent) patients had allogeneic and 1 (23.3 percent) had autologous transplants, respectively. Overall, 14 (32.6 percent) of the admissions resulted in a satisfactory discharge from the MICU. There was no significant difference in the survival rates between those patients undergoing allogeneic or autologous transplantations, II (33.3 percent) vs 3 (3. percent), respectively. Twenty-seven (62.8 percent) of the admissions resulted in mechanical ventilation and were performed in 2 (66.7 percent) patients with allogeneic BMTs and 7 (7. percent) patients with autologous BMTs, which was not significantly different. The survival rate for those requiring mechanical ventilation was significantly less ver the past two decades, bone marrow transplantation (BMT) has become accepted as a standard treatment modality in adults with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), lymphoma, and certain solid tumors.' Prior to BMT, patients receive conditioning regimens that include myeloablative chemotherapy often accompanied by total-body irradiation. 2 For at least 2 weeks after BMT, patients will experience profound leukocytopenia and thrombocytopenia. 1 This and the additional use of immunosuppressive therapy place these patients at increased risk for numerous complications, *From the Division of Aller!,'}; Critical Cart. and Pulmonary Medicine, Departments of Medicine and Neoplastic Disease. Hahnemann University, Philadelphia. Presented in part at the annual meeting, American Thoracic Societv, Miami, Mav 17, Manust:ript receivet!'july 31, 1992; revision accepted February Reprint ret{ut's fs: Dr. Ill::, Hahnemm111 Urlit:ersity,.\fail Stop.3, Broad t..- Vrru, Philadelphia 1912 than for those not mechanically ventilated during their MICU stay, I (3.7 percent) vs 13 (81.3 percent), respectively (p<o.ooi). Those patients who did not survive their MICU stay had a significantly higher mean APACHE II score of 21.2±4.7 than the survivors' score of 15.8±3.8 (p<o.ooi). The average length of stay for the survivors was days, which was significantly less than the 17.8±24. days for those patients not surviving (p<o.ooi). These data indicate that admission to the MICU may result in a beneficial outcome for critically ill patients with BMTs, but for those requiring mechanical ventilation due to respiratory failure, the chances of survival are poor. This information may be useful for providing patients with BMTs and their families with realistic estimates of prognosis prior to transfer to the MICU and mechanical ventilation. (Chest 1993; 14:527-31) AA =aplastic anemia; ALL= acute lymphocytic leukemia; AML=acute myeloid leukemia; BMT=bone marrow transplantation; CML =chronic myelogenous leukemia; GVHD = graft-vs-host disease; MICU =medical ICU; MOF =multiple organ failure including opportunistic infections, bleeding, and graft \ s-host disease (GVHD). 2 Pulmonary complications have been observed in 4 to 6 percent of patients with BMTs. 1 These include interstitial pneumonitis in up to 4 percent of allogeneic BMT recipients, bacterial, viral, and fungal pneumonias, cardiogenic and noncardiogenic pulmonary edema, bronchiolitis obliterans, and alveolar hemorrhage syndrome. 2 4 With these severe acute complications, it has been estimated that 3 to 4 percent of BMT recipients require treatment in an ICU..s- The outcome of patients with BMTs with respiratory failure generally has been poor, with a 3 percent survival at 6 months in one series. N Earlier work has focused specifically on these patients' respiratory failure or on mixed medical and postoperative surgical patients admitted to critical care units. We report our experience with patients with BMTs with and without respiratory failure requiring mechanical ventilation admitted to a medical intensive care unit (MICU). CHEST I 14 I 2 I AUGUST,

2 Table!-Patient CharacterVtic8 Survivors Nonsurvivors Variable (n=12) (n=24) Age, yr Mean±SD 34.4± ± 11.7 Sex Male 4 15 Female 8 9 Underlying disease ALL 4 AML 7 7 CML 1 5 Lyu;phoma 3 7 AA 1 S m a l llung - ccancer e ~ 1 Disease state Remission 9 19 Relapse 3 5 Type of transplant Autologous 3 5 Allogeneic 9 19 Conditioning regimen Bu/Cy Bu/Cy3 2 Bu/Cy Bu/CyNJl BCNUNfl16/cis-platinum 1 CytrBI History of GVHD Positive 3 14 Negative 9 1 *ALL=acute lymphocytic leukemia; AML=acute myelogenous leukemia; CM L =chronic myelogenous leukemia; AA =aplastic anemia; GVHD = graft-vs-host disease; Bu =busulfan; Cy =cyclophosphamide; BCN U =carmustine; Vfl16 =etoposide; TBI =total body irradiation. For all variables p = NS. METHODS A registry of all patients admitted to the M1CU between March 3, 1984 and March 26, 1991 was reviewed for patients who were status post-bmt. The medical records of 36 patients with a total of 43 admissions to the MICU were reviewed who underwent either allogeneic or autologous BMT. Variables that were studied included age, sex, underlying disease, remission status, type of transplant, conditioning regimen, and history ofgvhd. The date and indication for admission to MICU were noted along with the need for mechanical ventilation, duration of mechanical ventilation, and overall length of stay. An APACHE II (acute physiology and chronic health evaluation) score was determined for the day of admission to the MICU. In the case of a patient with more than one admission to the MICU separated by at least 48 h, each was calculated as a separate admission. Statistical analysis was performed using Students t test, and the Mann-Whitney rank-sum test. A p value of less than.5 was considered significant. RESULTS There were 229 BMTs performed at our institution (129 allogen"eic transplants and 1 autologous transplants) between March 3, 1984 and March 26, During this period 36 of these patients (15.7 percent) had 43 admissions to the MICU. The admission data for these patients in terms of outcome are summarized in Table 1. There was no statistically significant difference in age between the survivors and nonsurvivors, 34.4 years vs 37.6 years of age, respectively. Of these patients, 19 were male and 17 were female. The indications for BMT included acute myeloid leukemia in 14, lymphoma in 1, chronic myelogenous leukemia in 6, acute lymphocytic leukemia in 4, aplastic anemia in 1, and small-cell carcinoma of the lung in 1. There was no statistically significant difference in outcome with regard to the patients indication for BMT. A larger percentage of nonsurvivors had disease in remission, but this trend was not statistically different. Similarly, there was no statistically significant difference in outcome between the 28 patients who had allogeneic transplants and the 8 patients who had autologous transplants. Furthermore, we did not determine a difference in outcome with regard to a patient's conditioning regimen. Of those patients with GVHD, 82 percent did not survive, but this difference was not statistically different when compared with those without GVHD. Table 2 summarizes the reason for admission to the MICU. The most frequent admitting diagnosis was respiratory failure (58 percent), followed by septic shock (23 percent), cardiogenic shock (12 percent), gastrointestinal tract bleeding (5 percent), and seizure disorder (2 percent). There was no significant differ- Table 2-Admiuiona to the Medicallntenaioe Care Unit Variable Survivors (n= 12) Nonsurvivors (n=24) p Value Diagnosis Cardiogenic shock GI bleeding Respiratory failure Sepsis syndrome/shock Seizure disorder Intubation Positive Negative Length of stay, days APACHE II score, mean ± ± ± ±4.7 NS :s.ool :s.1 :s Outcome al MICU Adrnleaion after Bone Marrow 1iBn1p1anta11on (Paz et e/)

3 ence in outcome based on any of the admitting diagnoses. There were 28 patients (12.2 percent) who required mechanical ventilation after BMT. This group made up 65.1 percent of the patients with BMTs admitted to the MICU. Neither age nor disease state was a significant risk factor for mechanical ventilation. Mechanical ventilation for respiratory failure was a highly significant predictor of outcome for these patients, with only one patient (3.8 percent) successfully discharged from the MICU (p:5.1). For patients who were not mechanically ventilated, 13 of 15 (81.3 percent) admissions resulted in a satisfactory discharge from the MICU (p:5.1). Mechanical ventilation was performed in 2 patients with allogeneic BMTs and 7 patients with autologous BMTs, which was not significantly different. There were 5 of 25 MICU admissions for respiratory insufficiency that did not result in mechanical ventilation. All five of these patients were successfully discharged from the MICU. Multiple organ failure (MOF) developed after MICU admission in 3 of the 12 (25 percent) surviving patients and 2 of the 24 (83 percent) nonsurvivors (p:5.1). Of the three surviving patients with evidence of MOF, only one required mechanical ventilation for respiratory failure. Those patients who did not survive their MICU stay had a significantly higher mean APACHE II score of 21.2±4.7 than the survivors' score of 15.8 ± 3.8 (p:5.1). Similarly, mechanically ventilated patients had a higher APACHE II score (21.3 ± 4.1) than nonmechanically ventilated patients (16.4 ± 5.2, p:5.2). The average length of MICU stay (Fig 1) was 18.2 ± 24.8 days for those requiring mechanical ventilation and was significantly less for those not requiring mechanical ventilation, 6.±5. days (p:5.1). The average length of MICU stay for the survivors was 4.4 ± 3. days, which was significantly less than the 17.8±24. days for those patients not surviving (p:5.1). There was no statistical correlation be- tween length of MICU stay and APACHE II score. DISCUSSION We conclude that while the mortality rate for patients requiring mechanical ventilation after BMT is more than 96 percent for those patients without significant respiratory failure, tliere is a reasonable chance of MICU survival. Overall, 16 percent of patients required admission to the MICU after BMT. This figure varied from others reported in the literature; for example, Afessa and colleagues 5 found that 24 percent of patients at their institution required ICU care after BMT. Other series have reported that 3 to 4 percent of patients with BMTs required ICU admission.& 1 It is unlikely that the patients studied had a lower premorbid risk to account for this difference.8 The lower rate of MICU admission at our institution may be due to the impact of the controlled environmental oncology unit, which is an intermediate care unit with laminar air flow; this unit can care for patients with increased levels of acuity. Since most patients with BMTs at our institution are referred locally, it is unlikely that their posttransplant critical care took place at other institutions and was not recorded. The overall mortality rate for nonsurgical patients with BMTs admitted to the ICU has been reported to be 87 percent to 96 percent. 5 6 While overall the survival rate was much higher in our study with 33 percent of patients surviving their MICU stay, the outcome for patients requiring mechanical ventilation was similar to that in other series.lhi Denardo and colleagues 6 reported that only one of 4 (2.5 percent) mechanically ventilated patients with BMT with respiratory failure survived hospitalization and that individual died after 1 months. In a second series, the overall survival after mechanical ventilation was 7 percent. 5 Similarly, Crawford and Petersen 8 found that 348 of 1,482 (23 percent) marrow recipients required mechanical ventilation with only four patients (3 percent) surviving for more than 6 months after LENGTH OF STAY 1 2 ml SURVIVORS NONINTUBATED NONSURVIVORS INTUBATED DAYS FIGURE 1. Length of stay in days in the MICU for survivors (n = 14) compared with nonsurvivors (n = 29) and intubated (n = 27) compared with nonintubated (n = 16) patients. Asterisk= p:so.ool; two asterisks= p:so.ol. CHEST I 14 I 2 I AUGUST

4 intubation. We did not find significant differences in patient characteristics between survivors and nonsurvivors with regard to age, sex, indication for BMT, conditioning regimen, and history of GVHD, as did an earlier report. 5 In addition, there were no differences with regard to conditioning regimen, disease state, type of transplant, and MICU admitting diagnosis. Unlike the study by Crawford and Petersen, 8 we did not identify age or disease state as risk factors for mechanical ventilation. In contrast to the study by Afessa and colleagues, 5 we did find that there was a significant difference in APACHE II scores between survivors and nonsurvivors at the time of admission. In that report, there were no differences in APACHE II even when surgical patients were not included. While these results support the use of prognostic scoring systems in the ICU setting, it should be noted that mechanical ventilation alone similarly predicted outcome Y The only two nonmechanically ventilated patients who died in the MICU had APACHE II scores of 16 and 17, which were similar to the survivors. While both APACHE II score and length of stay were significantly different with respect to survivors and nonsurvivors, there was no significant correlation between these two variables. The lack of a statistical relationship may be due to the population size. Of significance is the finding that the nonsurvivor group had the longest average length of stay in the MICU. While clearly related to prognostic score at the time of admission, the development of MOF during MICU hospitalization was also an important predictor of death. A number of studies have demonstrated a relationship between MOF and death in the ICU Of the 24 nonsurvivors, all but 4 developed MOF during their MICU stay. All three of the patients who developed MOF on their first MICU admission and survived were later readmitted to the MICU and died. Of note, in a larger series, a small number of patients were identified who survived ICU admission after developing MOF along with requiring mechanical ventilation. 8 Given these findings, important predictors of outcome in the MICU include the presence of respiratory failure requiring mechanical ventilation, APACHE II score, and the development of MOF during the MICU stay. We did not find age or disease state to be reliable predictors of outcome in our study. These data differ from those of other centers in that we looked specifically at patients with BMTs admitted to a MICU for nonsurgical problems, and as such, postoperative surgical patients with brief periods of mechanical ventilation were not included. 5 In addition, this analysis is not limited to only medical patients requiring ICU admission for respiratory failure as in other series Our findings support those of Crawford and Petersen 8 reporting a mortality of 97 percent for nonsurgical patients with BMTs requiring mechanical ventilation. On the other hand, our results put into question the conclusion of these authors that mechanical ventilation is a precise surrogate for respiratory failure, as we found that 24 percent of patients admitted to the MICU with respiratory failure did not require mechanical ventilation. 8 In expanding this study to include nonintubated medical patients, we found that these individuals do rather well with an overall survival of 81 percent. This finding may be due to selection bias and may reflect subjective differences in clinical decision-making regarding the necessity of MICU admission. However, given the substantially smaller percentage of patients with BMTs admitted to the MICU at our institution compared with other series, this seems unlikely. s.s Given one report demonstrating that the effectiveness oficu care is based on the coordination of its delivery and a second suggesting that direct admission of unstable moderately ill patients to critical care units seems to reduce mortality, it is possible that transfer of patients with BMTs from the controlled environmental oncology unit to the MICU at our institution may have 16 averted further clinical deterioration and death. 15 Further study will be necessary to investigate this possibility. At the present time, in counseling patients with BMTs and their families regarding the benefits of MICU admission, the results of this study and those of the three other series in the literature may be utilized.s.s Patients who become critically ill but do not require mechanical ventilation may benefit from admission to the MICU and have a reasonable chance for discharge. Alternatively, the option of mechanical ventilation should be carefully discussed, as it is unlikely these patients will benefit from this intervention but instead will have prolonged ICU hospitalization at considerable emotional and financial cost to the patient, family, and others. Despite this, as Crawford and Petersen 8 point out, a 3 percent survival rate with confidence intervals of2 to 6 percent is not equivalent to medical futility and thus, this argument should not be used to actively withhold mechanical ventilation from this population. 17 Certainly, since the outcome for mechanically ventilated patients with BMTs has been replicated in two studies, these data should be used to counsel patients about their chances of survival with mechanical ventilation before BMT. ACKNOWLEDGMENT: The authors gratefully acknowledge the assistance of Dr. EdwardS. Schulman in reviewing the manuscript. REFERENCES Krowka MJ, Rosenow EC, Hoagland HC. Pulmonary mmplications of bone marrow transplantation. Chest 1985: 87: Outcome of MICU Admission after Bone Marrow Transplantation (Paz eta/)

5 2 Chan CK, Hyland RH, Hutcheon MA. Pulmonary complications following bone marrow transplantation. Clin Chest Med 199; 11: Paz HL, Crilley P, Coli WX, Patchefsky A, Brodsky I. Bronchiolitis obliterans following allogeneic bone marrow transplantation: the effect of preconditioning. Chest 199; 98:19S 4 Paz HL, Crilley P, Patchefsky A, Schiffman RA, Brodsky I. Bronchiolitis obliterans following autologous bone marrow transplantation. Chest 1992; 11: Afessa B, Tefferi A, Hoagland HC, Letendre L, Peters SG. Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc 1992; 67: Denardo SJ, Oye RK, Bellamy PE. Efficacy of intensive care for bone marrow transplant patients with respiratory failure. Crit Care Med 1989; 17:4-6 7 Crawford SW, Schwartz DA, Petersen FB, Clark JG. Mechanical ventilation after marrow transplantation: risk factors and clinical outcome. Am Rev Respir Dis 1988; 137: Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis 1992; 148: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13: Torrecilla C, Cortes JL, Chamorro C, Rubio JJ, Galdos P, Dominguez de Villota E. Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intensive Care Med 1988; 114: Seneff M, Knaus WA. Predicting patient outcome from intensive care: a guide to APACHE, MPM, SAPS, PRISM, and other prognostic scoring systems. J Intensive Care Med 199; 5: Hauser MJ, Tabak J, Baier H. Survival of patients with cancer in a medical intensive care unit. Arch Intern Med 1982; 142: Bartlett RH, Morris AH, Fairley HB, Hirch R, O'Connor N, Pontoppidan H. A prospective study of acute respiratory failure. Chest 1986; 89: Gillespie DJ, Marsh HMM, Divertie MB, Meadows JA. Clinical outcome of respiratory failure in patients requiring prolonged (>24 hours) mechanical ventilation. Chest 1986; 9: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. An evaluation of outcome from intensive care in major medical centers. Ann Intern Med 1986; 14: Ron A, Aronne LJ, Kalb PE, Santini S, Charlson ME. The therapeutic efficacy of critical care units: identifying subgroups of patients who benefit. Arch Intern Med 1989; 149: Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: its meaning and clinical implications. Ann Intern Med 199; 112: CHEST I 14 I 2 I AUGUST,