BMT IN THE ICU Case based Presentation Neil

BMT IN THE ICU Case based Presentation Neil Mc. Lean 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.

PULMONARY COMPLICATIONS OF HSCT

Question # 1 � List the 3 phases of HSCT.

Question # 1 � 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)

Question # 2 � List the 5 main pulmonary complications of BMT in the order of the phases in which they occur.

Question # 2 • 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)

Timecourse of complications of HSCT

Engraftment syndrome � 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 96 h 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%

Diffuse alveolar hemorrhage � 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

Diffuse alveolar hemorrhage • Diagnostic criteria 1. Evidence of pneumonitis 2. Absence of infection 3. 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

Idiopathic pneumonia syndrome � 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.

Idiopathic pneumonia syndrome • 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% • •

BOOP � 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%

Bronchiolitis obliterans � 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

Question #3 � Which of the five main pulmonary complications of HSCT respond to steroids?

Question #3 � 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

INFECTIOUS COMPLICATIONS OF BONE MARROW TRANSPLANT

� � � 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

Usual Suspects 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/

Sites (necessitating full physical exam) � � � Lung Urinary tract Skin/soft tissue Sinuses Vascular access devices GI (inc. esophagus)

Prevention � � Hand washing! Isolation � “reverse” isolation, gowns/gloves/masks for visitors � Single rooms � Negative pressure

A few more ounces of prevention…

Prevention � 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

Identification of offending organism… � 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.

Specific Viral Infections � Cytomegalovirus pneumonitis ? Unchecked viral proliferation in lung � ? Donor T-cell response (“graft vs lung”) � Gancyclovir may cause neutropenia, and prolonged therapy may lead to resistance � � HHV 6 � � 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

Major GI complications � Mucositis � GVHD � Medication induced diarrhea � Enteritis � Typhlitis � Infectious

Mucositis � � � ++ common especially with myeloablative chemo If 2 ndary 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

Mucositis � Interventions for preventing oral mucositis for patients with cancer receiving treatment, Cochrane Review 2007 � Amifostine: cytoprotective metabolite � “Chinese medicine” � Hydrolytic enzymes � Ice chips

Graft vs Host Disease � Following allogenic HSCT, acute ~3 -5 wks 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

GVHD • Skin: – • • Maculopapular rash, puritus Liver GI: – Diarrhea: • can > 10 L/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

GVHD � Prevention: � Immunosuppression after allo BMT to decrease T- cell 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

Enteritis � � � 43% prevalence after allo HSCT Usually mild Causes � GVHD � Infectious Colitis Pseudomembranous: C. Difficile Viral: CMV, Rotavirus, Adenovirus, HSV, HZV � Typhlitis

Typhlitis - Neutropenic Colitis � � � Typhlon = cecum Clostridial infection Complication of severe neutropenia post chemo Superinfection may lead to necrotizing inflammation of ileocecal region Sx: Abdo pain, fever, neutropenia

Post-Transplant Lymphoproliferative Disease � Caused by EBV � Proliferation of engrafted B lymphocytes � Rare! � Mural infiltration

� Your labs come back and his LFT’s are elevated

HEPATIC COMPLICATIONS OF HSCT

Question # 1 � What are three major causes of liver dysfunction post HSCT?

Question # 1 � What are 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)

Timecourse of hepatic complications of HSCT

Veno-occlusive disease (VOD) • 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)

Veno-occlusive disease • 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

Graft vs host disease • Rarely causes fulminant liver failure • Usually occurs within the 1 st 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

Viral hepatitis � 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

Renal Complications of Bone Marrow Transplant � 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

Low numbers, but high mortality

Antibiotics: Ampho B Aminoglycosides Acyclovir immunosuppressant s: Cyclosporine FK 506

As our nephrology colleagues suggest: � “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

Neurologic Complications � � � Metabolic encephalopathy Drug toxicity Infections Muscle weakness Cerebrovascular events (Seizures)

Neuro Complications � 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. )

Metabolic encephalopathy • Change in MS and sz • Dvp in 1 st 2 months • Other causes • Hypoxemia • Lytes • Met Ac, sepsis • Liver failure • Meds J Support Oncol 2004; 2: 223 -247

Drug toxicity � Cyclosporin and FK 506 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

Cerebrovascular accidents � � 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

CNS Infection � Bacterial � Strep, Listeria, Nocardia � Fungal � Aspergillus: main cause of CNS infx, usually dissemintated disease � Zygomycetes, Candida � Virus � CMV, HSV, Adenovirus, VZV, HHV 6, JC virus

Infection � Symptoms � Meningeal signs � May have no sx because immunocompromised � CSF PCR useful for dx � Minimal abnormalities in CSF

Peripheral Nervous System � Polyneuropathies � Usually 2 dary to chemo � GBS like disorder � 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

ICU MORTALITY IN BMT PATIENTS SPH case based presentation

Predicting Morality Price et al. , Am J Respir Crit Care Med, 1998.

Observations from the ICU Naeem et al. , Bone Marrow Transplantation, 2006.

More observations… Scales et al. , Critical Care 2008.

And some more… Price et al. , Am J Respir Crit Care Med, 1998.

Now in a different format… Price et al. , Am J Respir Crit Care Med, 1998.

Recent Trends of Improvement Naeem et al. , Bone Marrow Transplantation, 2006.

The VGH experience • FY 2008/09: 14 admissions ICU Mortality: 42. 86% Hospital Mortality: 42. 86% APACHE II (IV) scores: 25 (90) HSMR: . 7644 • FY 2007/08: 25 admissions ICU mortality: 16. 00% Hospital mortality: 28. 00% APACHE II (IV) scores: 26 (90) HSMR: . 4557

Bottom Line • • 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.

Discussion