Case based PresentationNeil 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. Engraftment syndrome (Phase I)2. Diffuse alveolar hemorrhage (Phase I)3. Idiopathic pneumonia syndrome (Phase I – II)4. Bronchiolitis obliterans organizing pneumonia

(BOOP) (Phase I – II)5. 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 dysfunction3) 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. Engraftment syndrome2. Diffuse alveolar hemmorhage3. 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 infection-related.

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 Viral

CMV HSV VZV

Potential organisms:All of them…

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 ? Unchecked viral proliferation in lung ? Donor T-cell response (“graft vs lung”) Gancyclovir may cause neutropenia, and prolonged

therapy may lead to resistance HHV6

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 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

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. VOD (Phase I)2. Acute GVHD of the liver (Phase II)3. 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

immunosuppressants: 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.)

J Support Oncol 2004;2:223-247

• Change in MS and sz

• Dvp in 1st 2 months

• Other causes

• Hypoxemia

•Lytes

•Met Ac, sepsis

•Liver failure

•Meds

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 Strep, Listeria, Nocardia

Fungal 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 Usually 2dary 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

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 admissionsICU Mortality:  42.86%Hospital Mortality:  42.86%APACHE II (IV) scores:  25 (90)HSMR:  .7644

• FY2007/08:

25 admissionsICU 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.