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Case based Presentation Neil McLean December 3, 2009 You are called for consult on Tower 14 and after thinking “Man I hate that floor” You arrive to find a 41 year old male who is 48 hours post allogenic hematopoietic stem cell transplant for CML. He is in obvious Respiratory distress on 90% Star Wars . List the 3 phases of HSCT. List the 3 phases of HSCT. Phase I: Pre-engraftment (0 – 30 days) Phase II: Early post-engraftment (30 – 100 days) Phase III: Late post-engraftment (> 100 days) List the 5 main pulmonary complications of BMT in the order of the phases in which they occur. • List the 5 main pulmonary complications of BMT in the order of the phases in which they occur. 1. 2. 3. 4. 5. Engraftment syndrome (Phase I) Diffuse alveolar hemorrhage (Phase I) Idiopathic pneumonia syndrome (Phase I – II) Bronchiolitis obliterans organizing pneumonia (BOOP) (Phase I – II) Bronchiolitis obliterans (Phase II – III) Occurs in 7 – 35% of HSCT recipients (autologous > allogeneic) Characterized by fever, erythematous rash, diarrhea, renal impairment and diffuse pulmonary infiltrates (from capillary leak), and may lead to multi-organ dysfunction. Occurs within 96h of engraftment (ANC > 500), with a median time of onset is 11 days post-transpant (4 – 25 days) Coincides with neutrophil recovery and thought to be due to cytokine release from these neutrophils. Diagnostic criteria: 1) Fever + evidence of pulmonary injury (hypoxemia or infiltrates) 2) absence of infection or cardiac dysfunction 3) Occuring within 5 days of neutrophil engraftment. Rapid clinical improvement with high-dose steroids Mortality ~ 25% Incidence ~ 5% (autologous > allogeneic) 40% of all causes of HSCT-related respiratory failure admitted to ICU Presents as dyspnea, fever, cough and hypoxemia, usually within 30 days of transplantation Hemoptysis reported in less than 20% CXR shows alveolar or interstitial infiltrates in middle and lower lung zones HRCT shows bilateral ground glass infiltrates Risk factors: Age > 40 Intensive chemotherapy before HSCT Total body irradiation WBC recovery GVHD No association between PT/PTT/platelets and DAH • • Diagnostic criteria 1. Evidence of pneumonitis 1. Absence of infection 1. Progressively bloodier return in BALs from separate subsegmental bronchi or > 20% hemosiderin-laden alveolar macrophages Restrospective studies show better outcomes with high-dose steroids (1 g methylpred for 3-5 days followed by a 2 – 4 week taper) • Case reports of good outcomes with Factor VIIa • Mortality ranges between 50 – 70% • Most common cause of death – multiple organ failure and sepsis Clinical features of pneumonia without evidence of infection Incidence ~ 10% (allogeneic > autologous) Median time of onset is 21 – 65 days Risk factors: Old age Malignancy other than leukemia Pretransplant chemotherapy Total body irradiation GVHD CMV positive donor Wide-ranging clinical spectrum from incidental radiographic abnormalities to ARDS Pathogenesis poorly defined, likely implicates lung tissue injury, inflammation, and cytokine release. • Diagnostic criteria: 1. Evidence of widespread alveolar injury (signs and symptoms of pneumonia, multilobar infiltrates, and widening A-a gradient) 2. Absence of active infection on BAL • Steroids are often used but have not been shown to be effective in largest studies • Case reports show improved lung function following the use of etanercept. • • • Overall mortality ~ 75% One year survival ~ 15% Hospital mortality for those requiring MV is > 95% Prevalence ~ 1.5% (allogeneic >> autologous) Present as dyspnea, dry cough, and fever occuring between 1 and 3 months following HSCT Imaging shows patchy airspace disease with ground glass attenuation and nodular opacities on CT PFTs show a restrictive pattern with decreased DLCO, without airflow obstruction. Diagnosis usually requires open lung biopsy. 80% of patients respond to to steroids with radiographic resolution within 1 to 3 months. Case fatality in HSCT patients ~ 20% Incidence of ~ 3.5% Inflammatory disease of the small airways occurring between 2 months and 9 years post-transplantation Leads to progressive obstructive airway disease with no parenchymal involvement. Most often present with dry cough, dyspnea and wheezing PFTs show irreversible airway obstruction CXR may show hyperinflation or be normal Steroids usually ineffective Chronic therapy with macrolides may slow the progression 5 year survival of HSCT patients is 10% with BO vs 40% w/o BO Which of the five main pulmonary complications of HSCT respond to steroids? Which of the five main pulmonary complications of HSCT respond to steroids? 1. 2. 3. Engraftment syndrome Diffuse alveolar hemmorhage BOOP (IPS and BO do not) The patient is intubated and transferred to the ICU. On arrival you note that he is febrile and hypotensive 20% of all deaths post BMT are infectionrelated. This includes the burden of respiratory failure requiring mechanical ventilation, a harbinger of poor outcome. Immunosuppression makes BMT patients particularly prone to infection, including community-acquired, hospital-acquired and opportunistic organisms. Current Opinion in Critical Care 2001, 7:362–366 Gram negatives (esp. early) Gram positives PJP Fungi Candida spp- 40% mortality with candidemia; 90% with deep infections Aspergillus spp Potential organisms: All of them… Viral CMV HSV VZV Lower risk in phase III ONCOLOGY AND CRITICAL CARE 0749-0704/ Lung Urinary tract Skin/soft tissue Sinuses Vascular access devices GI (inc. esophagus) Hand washing! Isolation “reverse” isolation, gowns/gloves/masks for visitors Single rooms Negative pressure Antimicrobial Prophylaxis Acyclovir, Gancyclovir (allogenic HSCT) Fluconazole (allogenic HSCT) TMP/SMX Aspergillus prophylaxis has been problematic, i.e. risk profile of amphotericin B Other routine antimicrobial prophylaxis for febrile neutropenia not supported by IDSA. IDSA Guidelines, 2002 Prevent organ failure (due to SIRS) i.e. prevent certain death Minimize drug adverse effects (from shotgun approach to antimicrobial therapy) Prevent resistance Save a few bucks. Cytomegalovirus pneumonitis HHV6 ? Unchecked viral proliferation in lung ? Donor T-cell response (“graft vs lung”) Gancyclovir may cause neutropenia, and prolonged therapy may lead to resistance Cofactor in CMV pneumonitis Respiratory Syncytial Virus Parainfluenza Virus 3 Influenza A Risk factor for pulmonary aspergillosis The patient is broadly covered with antibiotics, antivirals and antifungals. He is started on vasopressors. The nurse has placed a NG tube and is asking you if its ok to feed him Mucositis GVHD Medication induced diarrhea Enteritis Typhlitis Infectious ++ common especially with myeloablative chemo If 2ndary to BMT, associate with worse clinical outcome Nutrition TPN: used with allo BMT ( risk of mucositis) TPN maintains Wt but no effect on survival Management Need adequate pain relief Palifermin: recombinant human keratinocytic GF-1 J Support Oncol 2004;2:223-247 Interventions for preventing oral mucositis for patients with cancer receiving treatment, Cochrane Review 2007 Amifostine: cytoprotective metabolite “Chinese medicine” Hydrolytic enzymes Ice chips Following allogenic HSCT, acute ~3-5wks Incidence 20 to 80% Donor T lymphocytes recognize the histocompatibility Ag of host tissue as foreign Median onset 19 days post transplantation Risk Factor: HLA disparity Age • Skin: – • • Maculopapular rash, puritus Liver GI: – Diarrhea: • can > 10L/d, • Watery – – – • GI Bleeding Abdo pain, Fever, N/V Mucosal damage = Portal of entry for infection Immunosuppression Diagnosis Classic rash + diarrhea + bili in first 100 days post transplant Biopsy of skin, liver OR rectum Prevention: Immunosuppression after allo BMT to decrease Tcell activation Cyclo. Tacro, MTX, steroids Treatment Continue original immunosuppression 1-2: Topical steroids, low dose prednisone 3-4: High-dose methylpred Response 50-80% J Support Oncol 2004;2:223-247 43% prevalence after allo HSCT Usually mild Causes GVHD Infectious Colitis Pseudomembranous: C. Difficile Viral: CMV, Rotavirus, Adenovirus, HSV, HZV Typhlitis Typhlon = cecum Clostridial infection Complication of severe neutropenia post chemo Superinfection may lead to necrotizing inflammation of ileocecal region Sx: Abdo pain, fever, neutropenia Caused by EBV Proliferation of engrafted B lymphocytes Rare! Mural infiltration Your labs come back and his LFT’s are elevated What are the three major causes of liver dysfunction post HSCT? What are the three major causes of liver dysfunction post HSCT? 1. 2. 3. VOD (Phase I) Acute GVHD of the liver (Phase II) Viral hepatitis (Phase II) • Reported in 20 – 50 % of patients following HSCT • Arises from thrombosis to small central hepatic venules • Due to endothelial damage by high-dose chemotherapy • Usually develops within the first 21 days • Presents as weight gain, tender hepatomegaly and jaundice (the latter may be delayed) • Diagnosis based on clinical picture and timecourse • Portal dopplers show diminished or reversed portal blood flow • • • Transjugular biopsy can be used to confirm the diagnosis but is rarely performed as there is still a risk of major bleeding. Management is supportive though there is some evidence for the use of alteplase + heparin, defibrotide, or antithrombin concentrates. Fatal in 25 – 50 % of patients • • • • Rarely causes fulminant liver failure Usually occurs within the 1st three months post-HSCT (often predated by skin and GI tract involvement) Most often presents as an elevation in conjugated bilirubin and alkaline phosphatase. Treatment involves steroids and immunosuppressives Adenovirus, HSV, and herpes zoster can all cause fulminant liver failure in these patients CMV may also cause hepatitis, but it is rarely severe. Your pt is now fully ventilated and supported hemodynamically and the nurse reports, he has had no urine output over the past 3 hours Related to chemotherapy (various mechanisms; see next slide) Related to complications of therapy Intravascular volume depletion +/- ATN Emesis, diarrhea, acute illness Sepsis Exacerbation of underlying renal disease Antibiotics: Ampho B Aminoglycosides Acyclovir immunosuppressant s: Cyclosporine FK 506 “Be renal-protective…” i.e. optimize intravascular volume and renal perfusion Minimize nephrotoxic drugs/contrast You are on rounds the next day when the patient develops seizures Metabolic encephalopathy Drug toxicity Infections Muscle weakness Cerebrovascular events (Seizures) Cause of death in 7% of HSCT pt Risk Factors: High-dose chemo Immunosuppressive therapy GVHD Thrombocytopenia Crit Care Med 2006 Vol. 34, No. 9 (Suppl.) • Change in MS and sz • Dvp in 1st 2 months • Other causes • Hypoxemia •Lytes •Met Ac, sepsis •Liver failure •Meds J Support Oncol 2004;2:223-247 Cyclosporin and FK506 Tremor, H/A, hallucinations, HTN Cortical blindness, sz, encephalopathy Generalized cerebelar dysfunction, hemiparesis, quadriplegia High-dose busulfan 10% have seizures, need prophylaxis Steroid induced psychosis, myopathy More common in allo HSCT Causes: Intracranial bleed Infarction: infectious ( aspergillus) and non infectious (rare, DIC) Poor outcome, mortality 69% Same management, need to r/o infx Bacterial Fungal Strep, Listeria, Nocardia Aspergillus: main cause of CNS infx, usually dissemintated disease Zygomycetes, Candida Virus CMV, HSV, Adenovirus, VZV, HHV6, JC virus Symptoms Meningeal signs May have no sx because immunocompromised CSF PCR useful for dx Minimal abnormalities in CSF Polyneuropathies GBS like disorder Usually 2dary to chemo Asc motor weakness, dysesthesias, cramps IVIG, steroids, plasmapharesis Polymyositis Associated with chronic GVHD Proximal weakness, arthralgia, CK Dx: EMG, muscle biopsy A few hours later, this patient is on rocket fuel, CVVHDF, heavy sedation and he develops pulseless VTach. A code is run, but unfortunately you are not able to reestablish a pulse SPH case based presentation Price et al., Am J Respir Crit Care Med, 1998. Naeem et al., Bone Marrow Transplantation, 2006. Scales et al., Critical Care 2008. Price et al., Am J Respir Crit Care Med, 1998. Price et al., Am J Respir Crit Care Med, 1998. Naeem et al., Bone Marrow Transplantation, 2006. • FY2008/09: 14 admissions ICU Mortality: 42.86% Hospital Mortality: 42.86% APACHE II (IV) scores: 25 (90) HSMR: .7644 • FY2007/08: 25 admissions ICU mortality: 16.00% Hospital mortality: 28.00% APACHE II (IV) scores: 26 (90) HSMR: .4557 • • Since overall survival of transplant patients admitted to the ICU has been increasing over the past decades, it is not possible to easily determine whether admission to an ICU will be futile for any one individual patient. Decisions concerning which patients are appropriate for ICU care and how long to continue aggressive therapy are complex issues requiring significant deliberation.