1116 SECTION IX Pediatric Critical Care Hematology and Oncology (RBCs; particularly necessary in cases of major ABO incompati bility between donor and recipient) These RBCs can be trans fused to the d[.]
1116 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology (RBCs; particularly necessary in cases of major ABO incompatibility between donor and recipient) These RBCs can be transfused to the donor postoperatively PBSCs can be mobilized in patients recovering from chemotherapy (autologous) or by giving allogeneic donors cytokines, such as granulocyte colony-stimulating factor (G-CSF) Their stem cells then can be collected using an apheresis machine in an outpatient setting Collection of sufficient cells for transplantation may require several apheresis procedures Stem cells for allogeneic transplantation usually are collected on the day they are anticipated to be reinfused into the patient Autologous collection of stem cells requires cryopreservation of the cells until the day of reinfusion Dimethyl sulfoxide (DMSO) is added to the collection product to ensure cell viability, and the cells are frozen in liquid nitrogen until needed Stem cells can be collected from umbilical cord blood After delivery of the infant, sterile umbilical venous access is obtained, and the blood is collected into anticoagulated tubes This can be done either before or after delivery of the placenta A sample of this cord blood is used for HLA typing and infectious disease testing; the remainder is cryopreserved Reinfusion The day of stem cell reinfusion is referred to as day for the transplant period Cryopreserved stem cells are thawed in a water bath under sterile conditions and may be washed to remove the DMSO cryopreservant Stem cells are then infused into the patient though the indwelling central venous catheter These cells can migrate into the bone marrow on their own Blood transfusion–like complications can occur with reinfusion of stem cells; patients are generally placed on cardiac monitors with emergency medications available at the bedside during the infusion The infusion procedure is generally short, lasting anywhere from approximately 10 minutes to hours, depending on the volume of cells infusing Recovery Period After the reinfusion of stem cells, patients wait for count recovery to occur and receive treatment for any toxicities Allogeneic transplant patients receive immunosuppressive medicines to prevent GVHD Most patients are hospitalized for the entire transplant procedure, starting with the conditioning regimen However, there is a trend toward outpatient HCT, particularly in the autologous setting A typical hospitalization for HCT is to weeks, but it may be prolonged if umbilical cord blood is used or shortened for autologous transplants Complications Patients undergoing HCT are at high risk for complications that may require a stay in the pediatric intensive care unit (PICU) In one series, 19% of pediatric HCT patients required a PICU admission.32 In other published series, 6% to 25% of pediatric HCT patients required mechanical ventilation.33,34 Because of the high use of critical care services by HCT patients, it is beneficial for the pediatric intensivist to be familiar with their complications The reasons for these patients being at high risk for critical illness are multifactorial Many of these patients are undergoing HCT for an underlying disease that places them at risk for critical illness, such as malignancies, severe immunodeficiencies, and metabolic disorders To make room for the new hematopoietic progenitor cells, patients are given conditioning regimens with high doses of toxic chemotherapy and/or radiation This makes them severely immunocompromised, placing them at high risk for opportunistic infections The conditioning agents themselves cause significant oxidative stress and may be the common denominator behind many of these complications.35 While mortality rates for HCT patients requiring ICU care are quite high in comparison with the general ICU population, they appear to be improving Data from the 1980s showed mortality rates for mechanically ventilated pediatric HCT patients to be near 90%.34,36 However, more recent data indicate that the mortality rates continue to improve, with a report using the Virtual PICU Systems Database demonstrating a mortality rate of 42.5% for HCT patients requiring invasive positive-pressure ventilation.37–41 Some of the improvements seen in outcomes over the years may be due to differing characteristics of the patients, as very few studies reported severity of illness scores.36 In any case, no series reporting on mortality of pediatric HCT patients was able to predict with 100% certainty that a given patient would not survive Therefore, the critical care and transplant teams must work together and use their best judgment when making recommendations to families regarding appropriateness and duration of critical care services for this complex patient population Cardiac Complications Cardiac complications following HCT can occur during the immediate transplant period or can be late sequelae in survivors The heart may be injured during the transplant process from a variety of pathophysiologic etiologies.42–44 First, previous cardiotoxic treatments and therapies, such as anthracyclines and iron overload from frequent RBC transfusions, may predispose the heart to subsequent injury during transplantation In addition, cardiotoxic therapies, such as cyclophosphamide and irradiation used as part of the preparative regimen, may further injure the recipient heart.45–47 Moreover, hyperhydration therapies, blood product transfusions, and impaired renal function may place further stress on the heart Sepsis, which commonly affects the HCT patient, has also been found to decrease cardiac contractility.48 More specific to the HCT patient, there are rare reports of acute GVHD affecting the heart and cardiovascular system.49 Further, transplant-associated thrombotic microangiopathy has been associated with cardiovascular complications such as pericardial effusions and pulmonary arterial hypertension.50,51 Additionally, in a small series of children treated for a primary immunodeficiency with HCT (n 10), cardiac chamber hypertrophy was reported to occur in those transplanted at less than year of age and who received high-dose corticosteroids for acute GVHD.52 Finally, there is evidence to suggest that genetic susceptibility may also play a role in HCT-related heart failure For example, using a nested case-control study design, it was noted that polymorphisms in the NAD(P)H oxidase subunit RAC2 as well as carbonyl reductase CBR1 were associated with a significant increase in the risk of acute heart failure among HCT recipients These findings suggest that acute heart failure occurs as a result of oxidative stress or metabolic derangements induced by cardiotoxic alcohol metabolites of anthracyclines and that variants of RAC2 and CBR1 modulate this risk.53 An analysis of 2821 adult and pediatric patients found that only 26 (0.9%) experienced a major or fatal cardiac complication in the first 100 days after transplant.54 Seven of the 26 cardiac CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation complications occurred in children Among the 26 patients with significant cardiac complications, 11 had evidence of heart failure, had pericardial tamponade, and 10 had dysrhythmias.54 All 11 patients with heart failure died compared with only one each with tamponade or a dysrhythmia All cases of heart failure occurred between day 26 and day 135 Four of the seven pediatric patients had heart failure Electrocardiographic abnormalities have been reported in as many as 11% of pediatric HCT recipients.44 In another report, the Associazione Italiana Ematologia Oncologia Pediatrica-BMT Group described their transplant-related toxicities in 636 pediatric patients transplanted for acute leukemia.55 In their experience, the incidence of moderate or severe cardiac toxicity in the first 90 days posttransplant varied by the type of transplant, with autologous recipients experiencing an incidence of 1.9% (4 in 216, deaths) and allogeneic recipients of a compatible related donor experiencing a comparable incidence of 2.4% (7 in 294, deaths) However, recipients of an allogeneic alternative donor experienced a 6.4% rate of these cardiac complications (8 in 126) with all experiencing an early death In that study, the presence of moderate or severe cardiac toxicity increased the relative risk of an early posttransplant death more than ninefold (relative risk [RR], 9.1; 95% confidence interval [CI], 2.8–29.6) and more so than toxicity to any other organ system The manifestations of the cardiac disease are varied; they include myocardial ischemia and pericarditis in addition to dysrhythmias, pericardial effusion, and progressive congestive heart failure One further cardiovascular complication that merits special attention in the pediatric HCT patient is the occurrence of pulmonary hypertension Pulmonary arterial hypertension in the setting of pediatric HCT has been reported with increased frequency once it was identified as a potential concern and assessed for with routine screening In one report, a routine day 17 echocardiogram detected elevated right ventricular pressures in 13% of the patients.56 In that report and others, pulmonary arterial hypertension was found to be associated with transplant-associated thrombotic microangiopathy.51,56 Additionally, pulmonary arterial hypertension is reported to occur in the setting of patients undergoing transplant for malignant infantile osteopetrosis.57 Pulmonary venoocclusive disease may also account for episodes of pulmonary arterial hypertension.58 The incidence of pulmonary venoocclusive disease in HCT patients is speculative given the limited available data.58 Pulmonary arterial hypertension is reported to be the proximate cause of death in pediatric patients undergoing HCT for hemophagocytic lymphohistiocytosis and idiopathic myelofibrosis.59,60 Independent of the cause, pulmonary arterial hypertension should always be suspected in the pediatric HCT patient with unexplained cardiopulmonary dysfunction, as emergent therapy may be life-saving Late cardiovascular toxicity occurring a year or more after HCT has also been reported.61–63 Late cardiovascular complications following HCT include heart failure, dysrhythmias, hypertension, and cerebrovascular accidents Duncan et al recently reported on late cardiovascular complications among 661 pediatric allogeneic HCT patients.64 Cardiovascular complications assessed accounted for approximately 4% of survivors, including cardiomyopathy (3%), cerebrovascular accident (0.6%), coronary artery disease (0.2%), and cardiac-related death (0.5%) Several pathologic mechanisms of late congestive heart failure have been offered, including the same mechanisms causing acute heart failure, such as previous cardiotoxic agents (anthracyclines, alkylating agents, thoracic irradiation) in conjunction with 1117 cyclophosphamide and total body irradiation during conditioning regimens Despite the relatively low incidence of overt cardiac dysfunction, subclinical cardiac dysfunction appears relatively common in pediatric HCT recipients and may portend a poor outcome For example, in a case control study of 40 consecutive pediatric HCT patients, HCT patients were found to have similar left ventricular ejection fractions as controls.65 However, the HCT recipients were found to have significantly decreased rate-corrected velocity of circumferential fiber shortening, mitral inflow E velocity, and mitral septal annular E9 velocity Using speckle tracking echocardiography, HCT patients were also noted to have decreased left ventricular global circumferential systolic strain, circumferential systolic strain rate, circumferential diastolic strain rate, and longitudinal diastolic strain rate Strain echocardiography has also been used to assess changes in cardiac function among pediatric patients undergoing HCT for sickle cell disease and severe aplastic anemia.66 This technology has demonstrated initial decrease in function following transplant and subsequent improvement over time In another report, 100 pediatric HCT patients underwent a routine scheduled echocardiogram at day 17.56 At least one abnormality was noted in 30% of the children—most commonly, a pericardial effusion or an elevated estimated right ventricular pressure Survival was decreased in those children with any abnormality detected Pericardial effusion has been reported to occur in approximately 17% of pediatric HCT recipients It is asymptomatic in approximately half of the cases and is rarely the proximal cause of death.50 Despite that observation, HCT patients with a pericardial effusion have a significantly increased risk of mortality Additionally, a pericardial effusion may be anticipated in patients with a pretransplant prolonged corrected QT dispersion.49,50,67 In another assessment, the group at Cincinnati Children’s Hospital began performing screening echocardiograms on all HCT patients admitted to the PICU They observed abnormalities that required follow-up or intervention in 50% of patients The most common abnormalities noted were elevated right ventricular pressures, left ventricular systolic dysfunction, pulmonary hypertension, and pericardial effusions Two-thirds of the pericardial effusions found required pericardiocentesis, and all patients with pulmonary hypertension required treatment with pulmonary vasodilators.68 In addition to echocardiography and electrocardiography, biomarkers may also identify patients at risk for cardiac dysfunction Elevations in N-terminal pro B-type natriuretic peptide concentrations at day 14 after stem cell transplant can identify patients at risk of developing cardiac events during the first months after HCT.69,70 In summary, cardiac toxicity may present as an acute finding in the immediate posttransplant period with evidence of progressive heart failure, dysrhythmias, and pericardial effusions with tamponade Late cardiovascular complications are also being studied Although clinically evident late cardiac complications are being reported, there appear to be several subclinical findings detected by use of more involved testing The importance of these subclinical findings requires more study and is likely to be better understood as these children age further Pulmonary Complications The incidence of HCT-related pulmonary complications in children is reported to be between 12% and 25%.71,72 The need for mechanical ventilation support is the most frequent reason for admission of HCT patients to the PICU.32,38,40 Pulmonary 1118 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology TABLE Pulmonary Complications of Hematopoietic 93.1 Progenitor Cell Transplantation Complications Characteristics Treatment Early-Onset Pulmonary Complications Infection Positive test for infection Antimicrobials Diffuse alveolar hemorrhage Progressive bloody return on BAL Corticosteroids, FFP, plasmapheresis Idiopathic pneumonia syndrome Diffuse noninfectious lung injury Etanercept Engraftment syndrome Periengraftment pulmonary edema Corticosteroids Late-Onset Pulmonary Complications Bronchiolitis obliterans Obstructive lung disease Corticosteroids, macrolides Bronchiolitis obliterans organizing pneumonitis Restrictive lung disease Corticosteroids Idiopathic pneumonia syndrome Diffuse noninfectious lung injury Etanercept Pulmonary venoocclusive disease Pulmonary hypertension Sildenafil, prostacyclin, defibrotide BAL, Bronchoalveolar lavage; FFP, fresh frozen plasma complications can be divided into early and late complications (Table 93.1) Early complications occur within the first 100 days after transplant The division into early and late complications is not absolute but may help the clinician in developing a differential diagnosis Early complications include infection, periengraftment respiratory distress syndrome (PERDS), pulmonary cytolytic thrombi (PCT), diffuse alveolar hemorrhage (DAH), and idiopathic pneumonia syndrome (IPS).73 Late-onset complications occur beyond months after HCT and include bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and IPS.74 Early Pulmonary Complications Periengraftment Respiratory Distress Syndrome PERDS occurs just as patients begin to show signs of neutrophil recovery This syndrome is likely caused by pulmonary leukoagglutination and inflammatory cytokines Patients may develop fever, rash, fluid retention, capillary leak, and pulmonary edema In severe cases, patients can develop multiorgan involvement.75 Engraftment syndrome may be related to a graft-versus-host response or, in some cases, a host-versus-graft response In mild cases, no treatment is necessary.75 In more severe cases, particularly if there is lung involvement, corticosteroids may be beneficial.75–77 Survival from PERDS is quite good in comparison with other pulmonary complications of HCT, in excess of 90%.78 Pulmonary Cytolytic Thrombi PCT is a rare pulmonary complication of HCT It was first described in a small case series of 13 patients published in 2000.79 Patients in this series presented with fever at a median of 72 days after HCT (range, 8–343 days) Two of the 13 patients also had a cough at presentation Chest computed tomography (CT) performed on these patients revealed pulmonary nodules Pathologic exam revealed necrosis and basophilic thromboemboli in the nodules Immunohistochemical staining demonstrated that the nodules contained entrapped leukocytes and disrupted endothelium Subsequent publications containing studies involving PCT describe the pulmonary nodules seen on CT as being bilateral and located primarily in the periphery, subpleural, and basilar areas of the lungs.80 Further investigation of pathologic samples discovered the leukocytes to be monocytes81 and described the lung parenchyma adjacent to the nodules to be infarcted, likely secondary to entrapped debris in surrounding vessels.80 PCT seems to be responsive to treatment with cyclosporine and corticosteroids Both radiologic and clinical improvement may be observed within to weeks of beginning treatment.79,82 Development of PCT in leukemia patients undergoing HCT may be associated with decreased risk of relapse.80 Diffuse Alveolar Hemorrhage Alveolar hemorrhage may be infectious or noninfectious in etiology However, the term DAH in an HCT patient generally refers to a noninfectious etiology The reported incidence ranges from 1% to 21% of HCT patients, with the highest incidence in patients with mucopolysaccharide storage diseases.83,84 It usually occurs in the early posttransplant period and is characterized by widespread alveolar injury, absence of infection, and progressively bloodier return of bronchoalveolar lavage fluid during bronchoscopy.85 Patients commonly present with respiratory distress and fever, and less commonly with hemoptysis.85 It can occur in both autologous and allogeneic transplants.85 The exact etiology of DAH is unknown, although it is associated with GVHD and engraftment.86–88 Endothelial injuries from chemotherapy and radiation, inflammation, undiagnosed infections, and immunemediated damage related to GVHD have all been postulated as the cause.85,87 Conventional critical care practice uses invasive mechanical ventilation with high positive end-expiratory pressure (PEEP) to tamponade bleeding as a first-line therapy in DAH In addition, successful use of high-dose corticosteroids has been described in case reports of DAH.85,89 However, no prospective studies have proven the benefit of this therapy.85,87 Despite this, corticosteroids remain the standard of care for DAH Fresh frozen plasma transfusions and plasmapheresis have been tried but are of uncertain benefit.85 Recombinant intravenous factor VIIa has also been used for refractory bleeding in DAH but has not been found to have an impact on survival.90,91 Intrapulmonary instillation of recombinant factor VIIa and tranexamic acid have been used in both adult and pediatric patients with pulmonary hemorrhage with promising results for hemorrhage control.92–94 The use of aminocaproic acid initially appeared promising in a small series of eight patients,95 but a much larger study failed to demonstrate any benefit.96 Idiopathic Pneumonia Syndrome The incidence of IPS in pediatric HCT patients has been reported to be between 2% and 15%.72,74,97–99 IPS is usually considered an early complication of transplant, but it has also been described as a late complication The diagnosis is established using the diagnostic criteria set by an expert panel convened by the National Institutes of Health (NIH) in 1993 Patients must exhibit widespread lung injury as evidenced radiographically by bilateral lung disease, signs and symptoms of pneumonia (cough, dyspnea, or CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation rales), abnormal lung function (increased alveolar to arterial oxygen gradient, pulmonary function testing with restrictive lung disease findings), and absence of an infectious etiology.100 The term IPS is often used interchangeably with idiopathic pneumonitis and interstitial pneumonitis in the literature However, interstitial pneumonitis is the histopathologic description in some cases of IPS Other cases of IPS will demonstrate histopathologic findings consistent with DAH or BOOP.100 IPS, interstitial pneumonitis, DAH, BOOP, and BOS are all considered noninfectious pulmonary complications of transplantation As prevention and treatment of infectious pulmonary complications have improved, these noninfectious complications are now the more troublesome.101 Inflammation plays a significant role in the development of IPS GVHD is known to be associated with high levels of inflammatory cytokines GVHD has consistently been found to be associated with IPS.74,97,102 Because of this association, there is debate in the literature as to whether IPS represents GVHD of the lung.100 However, the histopathology of IPS often does not resemble that of acute GVHD, which typically involves epithelial cell apoptosis.98 Some cases of IPS may be caused by an unidentified infection A retrospective study of stored bronchoalveolar lavage (BAL) samples from HCT patients with pulmonary complications detected human metapneumovirus in (3%) of 163 patients.103 Newer metagenomic techniques are being studied to more accurately find respiratory tract pathogens With improved detection of microbes, a more complete understanding of the pulmonary microbiome is essential in order to understand the role that various microbes play in causing disease.104 Because of the role of inflammation in IPS, corticosteroids have been used as therapy but have not been found to be universally efficacious.74,105 Therefore, since tumor necrosis factor-alpha (TNF-a) has been found to be an important mediator in mouse models of IPS, the soluble TNF-a-binding protein, etanercept, has been used in recent years Etanercept showed promise in an early phase I/II trial when given with systemic corticosteroids to patients with IPS Ten of 15 patients treated on the protocol were able to be weaned from supplemental oxygen.106 A retrospective study comparing etanercept and corticosteroids versus corticosteroids alone also demonstrated improved survival in the patients receiving etanercept.107 These promising results lead to a phase II trial of etanercept in pediatric IPS patients The phase II results were also encouraging, with a response rate of 71%, 28-day survival of 89%, and 1-year survival of 63%.108 The results were in contrast, however, to the parallel adult study, in which the 1-year survival was less than 25%.109 There were significant transplantrelated differences between the adult and pediatric patients that could explain the differences in outcomes The adult patients were also much less compliant with the etanercept dosing in comparison with the pediatric patients.98 Late Pulmonary Complications Bronchiolitis Obliterans Syndrome/Bronchiolitis Obliterans Organizing Pneumonia BOS and BOOP are late-onset noninfectious pulmonary complications of HCT Both complications are associated with chronic GVHD and are much more commonly observed after allogeneic transplant as opposed to autologous transplant.110–112 The NIH developed consensus criteria for BOS in 2005, with a proposed amendment in 2009, in order to facilitate communication in the literature The amended criteria include (1) absence of an 1119 infectious etiology, (2) evidence of chronic GVHD at another site, (3) forced expiratory volume less than 75% predicted or a decline of more than 10% from previous, and (4) forced expiratory volume in s/forced expiratory vital capacity less than 0.7 or residual volume/total lung capacity greater than 120% and CT findings of air trapping or bronchiectasis.112 The pathophysiology of BOS likely involves donor T cells causing an immune-mediated injury to lung epithelial cells This injury then causes the release of inflammatory mediators, leading to fibroblast migration, smooth muscle cell proliferation, and eventual deposition of collagen and fibrin in the airway lumens.112 Risk factors for the development of BOS include busulfan conditioning,113 allogeneic transplant,112 recurrent pulmonary infections,114 and chronic GVHD.115–117 Patients with BOS typically present to 12 months after HCT, are afebrile, and have nonspecific symptoms, such as a nonproductive cough and exertional dyspnea.112 They may have a history of recurrent respiratory infections and GVHD Radiographic findings, pulmonary function testing (PFT), and pathology results from lung biopsy are used to make the diagnosis.112 Patients with BOS have an obstructive pattern on PFT On highresolution chest CT, both high- and low-attenuation areas are noted, as are bronchial dilation, bronchial thickening, vascular attenuation, and expiratory air trapping Biopsy specimens demonstrate submucosal bronchiolar fibrosis and luminal narrowing and obliteration.111 BOOP is also known as cryptogenic organizing pneumonia (COP) Patients with BOOP may present to months after HCT, which is earlier than BOS.112 They also tend to present more acutely than patients with BOS, presenting with fever, cough, dyspnea, and rales.112 Patients with BOOP have patchy air space disease on chest radiograph High-resolution chest CT demonstrates ground-glass opacifications, areas of consolidation, and pulmonary nodules.111 As opposed to patients with BOS, pulmonary function testing in BOOP reveals a restrictive lung disease pattern Biopsy specimens of BOOP contain granulation tissue in the distal airways, alveolar ducts, and peribronchial alveolar space.101,118 Like BOS, the pathophysiology seems to involve T cells and inflammatory cytokines leading to alveolar epithelial cell injury.112 For both BOS and BOOP, it is recommended that patients undergo BAL to rule out infection BOS may be diagnosed on clinical grounds to avoid open-lung biopsy and its associated risks The diagnosis of BOOP generally requires biopsy; however, a transbronchial specimen is often sufficient.111 The number of patients with BOS or BOOP reported in the literature is small Therefore, it is difficult to make firm recommendations regarding treatment or prognosis BOOP seems to have a better prognosis than BOS and may be reversible, while the goal of therapy in BOS is stabilization of disease It is believed that establishing the diagnosis early in order to begin therapy when the disease is less severe may be of benefit Therefore, serial PFTs are currently recommended in HCT patients at risk for pulmonary complications.115 BOS and BOOP may respond better to corticosteroids than other noninfectious pulmonary complications of HCT.74,101 First-line therapy for these complications remains a systemic corticosteroid burst with a prolonged taper over several months A recent trial of inhaled fluticasone, azithromycin, and montelukast (FAM) showed promise at halting the progression of BOS and enabled use of a shorter course of steroids.119 However, the use of azithromycin in patients transplanted for hematologic malignancies must be weighed against 1120 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology the newly identified risk of relapse when azithromycin was given early in the transplant course.120 Other therapies—such as inhaled cyclosporine, etanercept, infliximab, and extracorporeal photochemotherapy—have been described in case reports for BOS and require further study.111 Pulmonary Venoocclusive Disease Case reports of pulmonary venoocclusive disease (PVOD) in HCT patients have been infrequently described Patients have presented both early and late after HCT with increasing dyspnea and signs of right heart failure Cardiomegaly and pulmonary edema are noted on chest radiograph Evidence of pulmonary hypertension is detected on echocardiogram In patients who have undergone cardiac catheterization, high right atrial pressure, right ventricular pressure, and pulmonary artery pressures are observed, whereas the pulmonary artery wedge pressure is frequently normal Pathologic specimens demonstrate fibrosis of the venules and small pulmonary veins, whereas the larger pulmonary veins are typically normal Because the resistance to flow in the pulmonary veins is typically normal in PVOD, the pulmonary artery wedge pressure appears normal despite having increased resistance through pulmonary venules and small pulmonary veins Pulmonary arterial intimal fibrosis and hypertrophy may also be observed.58,121 PFT is normal for forced expiratory lung volume, functional vital capacity, and total lung capacity, but carbon monoxide diffusing capacity is typically less than 50%.122 Lung biopsy has historically been the gold standard for the diagnosis of PVOD However, this procedure carries a high risk of complication Mineo et al reported that the presence of two of three characteristic CT findings (ground-glass appearance, septal thickening, and mediastinal lymphadenopathy) was able to diagnose PVOD with 95.5% sensitivity and 89% specificity.122 Therefore clinical suspicion, PFT, and CT findings may be sufficient to make the diagnosis There may be a genetic predisposition to PVOD, as abnormalities in the bone morphogenetic receptor type II are reported in both PVOD and pulmonary hypertension patients.112 Corticosteroids, other immunosuppressive agents, and anticoagulation have been used without notable benefit Sildenafil and prostacyclin have been reported to be of some benefit in treating pulmonary hypertension However, these medications should be used with caution as they may worsen some patients by causing an increase in pulmonary edema.112 Theoretically, defibrotide may be beneficial given its efficacy in hepatic VOD Its use has been described in a case series of eight patients with osteopetrosis and pulmonary hypertension, in which four of the patients were believed to have VOD Two of the four patients had a favorable response to defibrotide However, these numbers are much too small to form any definitive conclusions.123 Critical Care for Pulmonary Complications Mechanical Ventilatory Support The majority of patients with pulmonary complications in the ICU are admitted for positive-pressure ventilation Debate continues over which patients may benefit from noninvasive ventilation (NIV) versus invasive mechanical ventilation (IMV) and which ventilatory strategies should be used once IMV is needed Data from immunocompromised adults suggest that a trial of NIV is warranted In a meta-analysis, Wang et al found that immunocompromised patients treated with NIV had a lower mortality rate, shorter hospital stay and shorter duration of mechanical ventilatory support when compared with patients treated with IMV They also found that approximately half of the patients were successfully managed with NIV and avoided intubation.124 The outlook may not be as promising for NIV in the pediatric HCT population Duncan et al found in a retrospective multicenter study of pediatric HCT patients requiring ICU care that only 24% were able to be successfully managed with NIV.38 Rowan et al found in their multicenter retrospective study of ventilatory management of pediatric HCT patients with respiratory failure that 41% of patients who required IMV failed an initial trial of NIV Moreover, patients who received NIV prior to intubation had a significantly higher mortality rate (70.3% vs 53.4%) than patients who were intubated at the outset (odds ratio [OR], 2.1; P 01).125 A practical approach may be to allow a brief trial of NIV support in select pediatric HCT patients and to follow closely for signs of improvement in respiratory status If no improvement is observed in work of breathing and/or oxygen requirement within a few hours of aggressive titration of NIV support, IMV should be strongly considered Rowan et al reviewed multicenter mechanical ventilation practices in pediatric HCT patients.125 Although they were not able to find evidence to support any particular mode of ventilation being superior to another, their results provide useful insight Patients treated with high-frequency oscillatory ventilation (HFOV) had a higher mortality rate than those treated with conventional mechanical ventilation However, when HFOV was started within the first 48 hours, there was a trend toward improved survival when compared with conventional mechanical ventilation (CMV) or later transition to HFOV There were no survivors in the group of patients transitioned to HFOV after days of CMV Therefore, HFOV may be more effectively used if initiated early in the course of mechanical ventilation.126 Further analysis of the data revealed that patients receiving traditional lung-protective ventilatory management with peak inspiratory pressure of 31 cmH2O or less and PEEP/fraction of inspired oxygen (Fio2) titration per the ARDSNet protocol had improved survival Interestingly, for every day that patients received an Fio2 greater than 0.6, they had a significant increase in their mortality risk (OR, 4.6; P , 0001).127 Oxygen toxicity may be of particular concern in HCT patients given the extreme oxidative stress that they experience during conditioning.128 Adjunctive Therapies A post-hoc analysis of a multicenter trial of calfactant (calf lung– derived surfactant) in mechanically ventilated pediatric patients with acute lung injury suggested possible benefit in the subgroup of immunocompromised patients.129 However, a subsequent trial of calfactant in pediatric patients with acute lung injury with leukemia, lymphoma, or a history of HCT was stopped early due to futility, making this therapy unlikely to be beneficial.130 Extracorporeal membrane oxygenation (ECMO) has infrequently been used as a heroic measure for HCT patients with severe lung injury A recently published review of the Extracorporeal Life Support Organization database reported three survivors to hospital discharge of the 29 pediatric HCT patients who received ECMO support after HCT.131 The authors concluded that while outcomes of ECMO in HCT patients are very poor, it should be considered in select patients who received HCT for a nonmalignant condition or a malignancy with a low risk of relapse Lung transplantation has been reported in children who have developed chronic respiratory failure as a complication of HCT in multiple case series in the literature.132–136 Of the patients reported, survival appears to be comparable to lung transplantation ... case reports of DAH.85,89 However, no prospective studies have proven the benefit of this therapy.85,87 Despite this, corticosteroids remain the standard of care for DAH Fresh frozen plasma transfusions... PVOD However, this procedure carries a high risk of complication Mineo et al reported that the presence of two of three characteristic CT findings (ground-glass appearance, septal thickening, and... improvement in respiratory status If no improvement is observed in work of breathing and/or oxygen requirement within a few hours of aggressive titration of NIV support, IMV should be strongly