Withdrawing Life Support from Mechanically Ventilated Recipients of Bone Marrow Transplants: A Case for Evidence-Based Guidelines

The use of bone marrow transplantation to treat malignant and nonmalignant disease is growing. In 1990, more than 10 000 bone marrow transplantations were done worldwide. The procedure has become standard therapy for aplastic anemia, acute and chronic myeloid leukemia, and lymphoma [1]. Autologous marrow transplantation is becoming more common for the treatment of neuroblastoma, breast cancer, and testicular cancer [1, 2]. Bone marrow transplantation can result in serious complications that lead to the need for mechanical ventilation. These complications include hepatic failure, pneumonia, adverse reactions to drugs, mucositis, massive intracranial hemorrhage, and septic shock. Patients who are older than 20 years of age, who receive a transplant while the malignant condition is in relapse, and who receive a graft that is not HLA-identical have a 50% chance of requiring mechanical ventilation after transplantation [3]. Decision making in these critically ill patients is complicated by their relatively young age, the potential for a cure of the underlying disease, and the uncertainty of the outcome [4, 5]. The emotional and physical burdens endured by the patients, their loved ones, and their caregivers are enormous. Scarce community financial resources and blood products are expended for a process that inevitably leads to the death of the patient. Early and accurate identification of patients destined to die is needed to relieve this burden without compromising the chances of potential survivors. Eleven studies [3, 6-15] have reported on 979 patients using mechanical ventilation who received bone marrow transplants (Table 1). In these studies, survival in bone marrow transplant recipients after they receive mechanical ventilation varied from 0% to 11%, although many studies enrolled fewer than 50 patients. Attempts to identify predictors of mortality have yielded conflicting results (Table 1). Older age, longer duration of mechanical ventilation, and more severe illness as measured by organ failure or Acute Physiology and Chronic Health Evaluation (APACHE) score have been associated with poor outcome, but not in every study. Even if older patients have a higher risk for death, this may be of little use in bedside decisions or discussions with family members. It would be more clinically useful to define a subgroup of patients whose survival is so low that reasonable physicians and patients would agree that intensive care can no longer effectively fulfill the goals of transplantation. Table 1. Survival of Bone Marrow Transplant Recipients after Mechanical Ventilation: Previous Studies* We hypothesized that combinations of hepatic failure, renal failure, hemodynamic instability, and lung injury would identify a group of patients whose survival rate approached zero. To address this question, we evaluated a cohort that was nearly equal in size to the number of bone marrow transplant recipients who had mechanical ventilation studied in published reports. Methods Design We used a nested casecontrol study design. Because marrow transplant recipients rarely survive after receiving mechanical ventilation, we defined cases as all survivors from the cohort and controls as a sample of the patients who died to conclude that no one with that combination of risk factors would survive. The control group of patients who did not survive allowed us to estimate the number of patients in the entire cohort who died with any given combination of risk factors [16]. From this, we estimated probability of survival with a specified combination of risk factors. Study Population The Fred Hutchinson Cancer Research Center (Seattle, Washington) does bone marrow transplantation in a high-risk, referral population. All patients are cared for by a multidisciplinary team led by an oncologist who is experienced with transplantation. Attending physicians and fellows specializing in pulmonary and critical care, infectious disease, gastroenterology, and nephrology are available 24 hours per day for in-house consultation. Patients are followed closely in Seattle for a minimum of 100 days after they receive their transplant. The Center maintains a computerized registry that includes demographic and long-term follow-up information for transplant recipients. All patients who required mechanical ventilation after receiving their first transplant between January 1980 and July 1992 were eligible for inclusion in the study. Patients who were ventilated for less than 24 hours after a procedure (open lung biopsy, bronchoscopy, or computed tomography) were excluded; the remaining patients form the study cohort. Patients who were intubated but only received continuous positive airway pressure and patients who were not intubated but who received noninvasive, mask ventilation were not defined as having mechanical ventilation. All patients who met the definition of a survivor were selected as cases. All other patients in the cohort, including those who died while receiving mechanical ventilation, those who died after extubation with prolonged hospital survival, and those who were discharged and died less than 30 days after extubation, were considered nonsurvivors and thus potential controls. To control for changes in medical care during the 12 years of the study and to maximize statistical power, two nonsurvivors (controls) were matched by year of transplantation to each survivor (case) [16]. Data Abstraction Four experienced critical care chart abstractors (including the two authors and a nurse-clinician specializing in bone marrow transplantation) recorded laboratory, hemodynamic, and treatment variables for each day of mechanical ventilation. Survivor and nonsurvivor charts were evenly distributed among abstractors, who were blinded to mortality as much as possible. Fractional inspired oxygen concentration and positive airway pressure requirements were recorded every 8 hours during mechanical ventilation. Scores on APACHE III were calculated using the published weights for the physiologic variables [17]. All patients were assigned chronic health points for metastatic cancer, leukemia, or lymphoma according to diagnosis. Because most patients were heavily sedated and many received neuromuscular blocking agents, Glasgow Coma Scores could not reliably be ascertained and the APACHE III scores did not include a contribution from this variable. Scores on APACHE III calculated without a Glasgow Coma Score range from 0 to a theoretical maximum of 272. Patient demographics and long-term survival were taken from the computerized database of the Fred Hutchinson Cancer Research Center. Variable Definitions The definition of survival used to identify cases was chosen as a compromise between meaningful long-term survival, which may result from many factors (including the success of transplantation), and short-term survival, which is more directly related to the outcome of mechanical ventilation. Survival for 30 days after extubation with subsequent hospital discharge may not be as meaningful an end point as 6- or 12-month survival, but death after hospital discharge is difficult to relate to the efficacy of mechanical ventilation or intensive care. Definitions of risk factors were developed before data abstraction and were intentionally selected to reflect relatively minor physiologic impairment. Hepatic and renal failure was defined as a total bilirubin level greater than 68 mmol/L (4 mg/dL) and a serum creatinine level greater than 177 mmol/L (2 mg/dL) during the first 3 days of mechanical ventilation. Vasopressor use, which we used as a proxy for hemodynamic instability, was defined as dopamine, more than 5 g/kgmin1, or norepinephrine, epinephrine, or phenylephrine for more than 4 hours in any 24-hour period. Dopamine administered to increase splanchnic blood flow ( 5 g/kgmin1) and drugs used to increase cardiac output or heart rate (dobutamine, amrinone, or isoproterenol) were not included as vasopressors. Lung injury was defined as a fraction of inspired oxygen concentration greater than 0.6 or positive end-expiratory pressure greater than 5 cm H2O at any of the three daily recorded values after the first 24 hours of mechanical ventilation. We evaluated this variable after the initial 24 hours of mechanical ventilation because many patients who receive high inspired oxygen concentrations during the initial phase of critical illness are rapidly weaned from this level of support. Patients who met these criteria at any time during the period of data collection were counted as having the given risk factor. Thus, patients who received vasopressors for 12 hours on the first day of mechanical ventilation and who required an inspired oxygen concentration of 0.8 after another 3 days were counted as having vasopressor and lung injury risk factors. Such patients were considered to meet the combined criterion of lung injury and vasopressors on day 3 after mechanical ventilation. Statistical Analysis Continuous variables were compared by using the Student t-test or the Wilcoxon rank-sum test, depending on distribution. Categorical variables in matched cases and controls were compared using the Mantel-Haenszel chi-square test [18]. Trends over time in the continuous variables of timing of mechanical ventilation, age, and APACHE III score were evaluated using linear regression. Trends over time in the categorical variables of fractions of patients intubated, patient survival, and patients receiving an unmatched transplant were evaluated by using the chi-square test for trend. Statistically significant trends were indicated by a regression coefficient for year of transplant or a chi-square test for trend with a P value less than 0.05. Exact CIs for ratios were calculated from the binomial distribution. Analyses were done on a personal computer using STATA software (Stata Corp., College Station, Texas). The probability for survival of patients with one or more of the study risk factors