Changes in outcomes (1996-2004) for pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation.

OBJECTIVE: To assess the following hypotheses regarding mechanically ventilated pediatric oncology patients, including those receiving hematopoietic stem cell transplant (HSCT) and those not receiving HSCT: 1) outcomes are more favorable for nontransplant oncology patients than for those requiring HSCT; 2) outcomes have improved for both populations over time; and 3) there are factors available during the time of mechanical ventilation that identify patients with a higher likelihood of dying. DESIGN: Retrospective review. SETTING: Free-standing, tertiary care, pediatric hematology oncology hospital. PATIENTS: All patients requiring invasive mechanical ventilation with a diagnosis of cancer or following HSCT from January 1996 to December 2004. INTERVENTIONS: Bivariate and multivariate analysis. Dates of admission were grouped into time periods for analysis: 1996-1998, 1999-2001, and 2002-2004. MEASUREMENTS AND MAIN RESULTS: There were 401 courses of mechanical ventilation (329 patients) analyzed. Forty-five percent of HSCT admissions (92 of 206) vs. 75% of non-HSCT oncology admissions (146 of 195) were extubated and discharged from the pediatric intensive care unit (p < .0001). Twenty-five percent of HSCT vs. 60% of non-HSCT admissions survived 6 months (p < .0001). Among admissions with an abnormal chest radiograph and a PaO2/FiO2 ratio <200, pediatric intensive care unit survival increased for each successive time period, with 45% of HSCT and 83% of non-HSCT admissions surviving during 2002-2004. In multivariate analysis of all study patients, Pediatric Risk of Mortality scores on the day of intubation, allogeneic HSCT, cardiovascular failure, hepatic failure, neurologic failure, a previous course of mechanical ventilation within 6 months, and the time period intubated were associated with mortality. With the exception of time period, these same variables were associated with mortality in multivariate analysis of only HSCT patients. CONCLUSIONS: HSCT patients who require mechanical ventilation have worse outcomes than non-HSCT oncology patients. Outcomes for both groups have improved over time. Allogeneic transplant, higher Pediatric Risk of Mortality scores, need for repeated mechanical ventilation, and concomitant organ system dysfunction are risk factors for death.

Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia after influenza.

Mortality after influenza is often due to secondary bacterial pneumonia with Streptococcus pneumoniae, particularly in the elderly. The reasons for the high fatality rate seen with this disease are unclear. To further characterize the pathogenesis of pneumonia after influenza in a mouse model, we examined the pathology and immunology that leads to fatal infection. Influenza-infected mice were either euthanized 24 h after secondary infection with S. pneumoniae for determination of pathology, bacterial cultures, and levels of immune effectors or were followed by use of a live imaging system for development of pneumonia. Influenza-infected mice challenged with each of 3 serotypes of pneumococcus developed a severe, necrotic pneumonia and met endpoints for euthanasia in 24 to 60 h. Strikingly elevated levels of both pro- and anti-inflammatory molecules including interleukins 6 and 10, macrophage inflammatory protein 1alpha, and chemokine KC were present in the blood. High levels of these cytokines and chemokines as well as tumor necrosis factor alpha, interleukin 1beta, and heme oxygenase 1 were present in the lungs, accompanied by a massive influx of neutrophils. Mortality correlated with the development of pneumonia and lung inflammation but not with bacteremia. This model has the potential to help us understand the pathogenesis of severe lung infections.

Outcome of severe sepsis in pediatric oncology patients.

OBJECTIVE: To describe survival to intensive care unit (ICU) discharge and 6-month survival in a large cohort of pediatric oncology patients with severe sepsis. DESIGN: Retrospective analysis. SETTING: The ICU of a single pediatric oncology center. PATIENTS: Patients with cancer admitted to the ICU of St. Jude Children's Research Hospital between January 1, 1990, and December 31, 2002, who met the following criteria: 1) severe sepsis by ACCP/SCCM (American College of Chest Physicians/Society of Critical Care Medicine) Consensus Conference criteria and 2) receipt of fluid boluses of > or =30 mL/kg to correct hypoperfusion or receipt of a dopamine infusion of >5 microg.kg.min for inotropic support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data evaluated were demographic variables, oncologic diagnosis and time from diagnosis to ICU admission, Pediatric Risk of Mortality III score and absolute neutrophil count at admission, use of inotropes or pressors, use of mechanical ventilation, maximum organ system failure score, blood culture results, survival to ICU discharge, and 6-month survival. We identified 446 ICU admissions of 359 eligible patients. Overall ICU mortality was 76 of 446 (17%): 40 of 132 (30%) in post-bone marrow transplant (BMT) admissions and 36 of 314 (12%) in non-BMT admissions (p < .0001). In the 106 admissions requiring both mechanical ventilation and inotropic support, ICU mortality was 68 of 106 (64%). Regarding individual patients, 6-month survival was 170 of 248 (69%) among non-BMT patients vs. 43 of 111 (39%) for BMT patients (p < .001). When the 38 patients who survived to ICU discharge after requiring both mechanical ventilation and inotropic/vasopressor support are considered, 27 (71%) were alive 6 months after ICU discharge (22 of 27 [81%] non-BMT vs. 5 of 27 BMT [19%; p < .001]). ICU mortality varied by causative pathogen, from 63% for fungal sepsis (12 of 19) to 9% (5 of 53) for Gram-negative sepsis. Logistic regression analysis of factors significantly associated with ICU mortality in admissions requiring both mechanical ventilation and inotropic support identified four variables: BMT (odds ratio, 2.9; 95% confidence interval, 1.1-7.4; p = .03); fungal sepsis (odds ratio, 10.7; 95% confidence interval, 1.2-94.4; p = .03); use of multiple inotropes (odds ratio, 4.1; 95% confidence interval, 1.4-11.8; p = .01); and Pediatric Risk of Mortality III score (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; p = .04). CONCLUSIONS: In a large series of pediatric oncology patients with severe sepsis, ICU mortality was only 17% overall, although mortality remained quite high in the higher acuity patients. Mortality among the higher acuity patients was significantly associated with only a small number of variables. The number of patients alive at 6 months and the encouraging ICU survival rate further justifies the use of aggressive ICU interventions in this population.

Heme oxygenase-1 messenger RNA expression is induced in peripheral blood mononuclear cells of pediatric cancer patients with systemic inflammatory response syndrome.

OBJECTIVE: To determine whether heme oxygenase-1 messenger RNA expression in peripheral blood mononuclear cells is induced in pediatric cancer patients with the systemic inflammatory response syndrome (SIRS) and whether this expression correlates with the heme oxygenase-1 products, bilirubin and carboxyhemoglobin. DESIGN: Prospective, controlled study. SETTING: A tertiary care pediatric oncology hospital. PATIENTS: Fourteen patients admitted to the intensive care unit with a diagnosis of SIRS by American College of Chest Physicians/Society for Critical Care Medicine consensus criteria and 17 control patients (off therapy, no acute illness). INTERVENTIONS: Blood for bilirubin, carboxyhemoglobin, and heme oxygenase-1 messenger RNA expression was collected at study entry. SIRS patients continued to have samples collected every 12 hrs for 1 wk or until intensive care unit discharge. Heme oxygenase-1, bilirubin, and carboxyhemoglobin levels of SIRS patients were compared with controls, and correlation between heme oxygenase-1 and products was assessed. MEASUREMENTS AND MAIN RESULTS: Within 48 hrs of study entry, maximum heme oxygenase-1 expression for all SIRS patients compared with controls was 5.5 +/- 1.0 vs. 1.1 +/- 0.1 (p < .0006). Maximum expression was > or =2.3-fold in 13 of 14 SIRS patients. Maximum heme oxygenase-1 expression also differed from minimum (5.5 +/- 1.0 vs. 1.6 +/- 0.3, p < .003). Maximum bilirubin and carboxyhemoglobin levels within 48 hrs of study entry differed between SIRS patients and controls (3.0 +/- 0.8 vs. 0.3 +/- 0.1, p = .006; and 1.2 +/- 0.2 vs. 0.6 +/- 0.1, p = .001, respectively). Bilirubin, but not carboxyhemoglobin, correlated with heme oxygenase-1 expression (p = .0013). CONCLUSIONS: Heme oxygenase-1 messenger RNA, bilirubin, and carboxyhemoglobin levels were increased within 48 hrs of admission in pediatric cancer patients with SIRS. Heme oxygenase-1 expression correlated with serum bilirubin levels. The increase in heme oxygenase-1 expression may add to the understanding of the increase in serum bilirubin observed in patients with SIRS/sepsis. These findings support a role for heme oxygenase-1 in the physiologic response to inflammatory stress.

A reversible generalized movement disorder in critically ill children with cancer.

INTRODUCTION: Some children treated for cancer become critically ill because of immune suppression and sepsis requiring prolonged intensive care support and assisted ventilation. METHODS: Over a 3-year-period, we have identified six children (four with brain tumors) who developed a generalized movement disorder during a protracted intensive care unit stay. Median age was 2 years (range 1-6 years). Movement disorder developed while receiving multiple medications. RESULTS: Sedation was achieved with midazolam and opioid infusions. Dystonic posturing of limbs, jaw movements, tongue thrusting, and intermittent eye deviations were present in all. Movements increased if the child was stimulated and an electroencephalogram performed in five children excluded seizures. CONCLUSIONS: This movement disorder should be differentiated from seizures to prevent inappropriate treatment. Exacerbation with stimulation is a clinical clue to the correct diagnosis and an electroencephalogram can help differentiate this movement disorder from seizures.

Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia.

BACKGROUND: Life-threatening pulmonary complications that coincide with cell lysis during early chemotherapy and that mimic systemic inflammatory response syndrome (SIRS) have been reported in patients with acute myeloid leukemia (AML). METHODS: We reviewed the records of patients with de novo AML, excluding M3 and Down syndrome, treated at our institution between 1991 and 2002 to determine the prevalence of severe SIRS with grade 3/4 pulmonary complications and to identify AML subtypes associated with severe SIRS. To examine the role of cell lysis, we compared leukocyte reduction in AML subtypes affected by severe SIRS with that in unaffected subtypes. RESULTS: Of 155 patients, 5 (3 with M4eo and 2 with M5) experienced severe pulmonary complications attributed to tumor lysis, met the criteria for severe SIRS, and showed no clear evidence of infection. Four required pressor support for severe hypotension. Severe SIRS was significantly more common in myelomonocytic or monocytic AML (M4/M4eo/M5) than in other subtypes (P = 0.010) and significantly more common in M4eo than in M4/M5 (P = 0.008). Among 112 cases for which information was available, leukocyte reduction was significantly greater in patients with M4/M4eo/M5 than among others during the first 4 days of chemotherapy (P = 0.015). Leukocyte reduction was significantly more rapid among patients who had severe SIRS than among others (P = 0.008). CONCLUSIONS: Patients with M4/M4eo/M5 AML, especially M4eo, experience life-threatening cardiopulmonary complications of tumor lysis that meet the criteria for severe SIRS. This observation may reflect more rapid cell reduction and the unique biology of this subtype.

Pathophysiology-directed therapy for acute hypoxemic respiratory failure in acute myeloid leukemia with hyperleukocytosis.

A 17-year-old with acute myeloid leukemia M4 and hyperleukocytosis developed fulminant hypoxemic respiratory failure at presentation. After failing to respond to conventional mechanical ventilation and leukapheresis, he was started on inhaled nitric oxide (iNO) with dramatic improvement in oxygenation. Following graduated chemotherapy, his pulmonary status again deteriorated coincident with tumor lysis. After failing to respond to increases in iNO, he was placed in prone position with immediate improvement. The patient was successfully extubated. Patients with myelomonocytic leukemias are at risk for early death due to pulmonary complications. The use of adjuvant therapies directed by specific pathophysiology might decrease this risk.