Transcript BMT in the ICU - UBC Critical Care Medicine, Vancouver BC

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)
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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)
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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.
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Rapid clinical improvement with high-dose steroids
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Mortality ~ 25%
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Incidence ~ 5% (autologous > allogeneic)
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40% of all causes of HSCT-related respiratory failure admitted to ICU
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Presents as dyspnea, fever, cough and hypoxemia, usually within 30 days of transplantation

Hemoptysis reported in less than 20%
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CXR shows alveolar or interstitial infiltrates in middle and lower lung zones
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HRCT shows bilateral ground glass infiltrates
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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
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Clinical features of pneumonia without evidence of infection
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Incidence ~ 10% (allogeneic > autologous)
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Median time of onset is 21 – 65 days
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Risk factors:
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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.
•
•
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Overall mortality ~ 75%
One year survival ~ 15%
Hospital mortality for those requiring MV is > 95%
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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%
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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.
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Most often present with dry cough, dyspnea and wheezing
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PFTs show irreversible airway obstruction
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CXR may show hyperinflation or be normal
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Steroids usually ineffective
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Chronic therapy with macrolides may slow the progression
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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
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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
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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…
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Viral
CMV
 HSV
 VZV

Lower risk in phase III
ONCOLOGY AND CRITICAL CARE
0749-0704/
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Lung
Urinary tract
Skin/soft tissue
Sinuses
Vascular access devices
GI (inc. esophagus)
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Hand washing!
Isolation
“reverse” isolation, gowns/gloves/masks for
visitors
 Single rooms
 Negative pressure
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Antimicrobial Prophylaxis
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Acyclovir, Gancyclovir (allogenic HSCT)
Fluconazole (allogenic HSCT)
TMP/SMX
 Aspergillus prophylaxis has been problematic, i.e. risk
profile of amphotericin B
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Other routine antimicrobial prophylaxis for febrile
neutropenia not supported by IDSA.
IDSA Guidelines, 2002
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Prevent organ failure (due to SIRS)
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i.e. prevent certain death
Minimize drug adverse effects (from shotgun
approach to antimicrobial therapy)
Prevent resistance
Save a few bucks.
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Cytomegalovirus pneumonitis
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HHV6
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? 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
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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
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Mucositis
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GVHD
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Medication induced diarrhea
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Enteritis
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Typhlitis
Infectious
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++ common especially with myeloablative
chemo
If 2ndary to BMT, associate with worse clinical
outcome
Nutrition
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TPN: used with allo BMT ( risk of mucositis)
TPN maintains Wt but no effect on survival
Management

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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
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Risk Factor:
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HLA disparity
Age
•
Skin:
–
•
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Maculopapular rash, puritus
Liver
GI:
–
Diarrhea:
• can > 10L/d,
• Watery
–
–
–
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GI Bleeding
Abdo pain, Fever, N/V
Mucosal damage = Portal of entry for infection
Immunosuppression
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Diagnosis
Classic rash + diarrhea +  bili in first 100 days
post transplant
 Biopsy of skin, liver OR rectum
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Prevention:
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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

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Response 50-80%
J Support Oncol 2004;2:223-247
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43% prevalence after allo HSCT
Usually mild
Causes
GVHD
 Infectious Colitis
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 Pseudomembranous: C. Difficile
 Viral: CMV, Rotavirus, Adenovirus, HSV, HZV
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Typhlitis
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Typhlon = cecum
Clostridial infection
Complication of severe neutropenia post
chemo
Superinfection may lead to necrotizing
inflammation of ileocecal region
Sx: Abdo pain, fever, neutropenia
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Caused by EBV
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Proliferation of engrafted B lymphocytes
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Rare!
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Mural infiltration
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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
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Due to endothelial damage by high-dose chemotherapy
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Usually develops within the first 21 days
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Presents as weight gain, tender hepatomegaly and
jaundice (the latter may be delayed)
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Diagnosis based on clinical picture and timecourse
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Portal dopplers show diminished or reversed portal blood flow
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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
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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
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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
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Related to chemotherapy
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(various mechanisms; see next slide)
Related to complications of therapy
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Intravascular volume depletion +/- ATN
 Emesis, diarrhea, acute illness
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Sepsis
Exacerbation of underlying renal disease
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Antibiotics:
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Ampho B
Aminoglycosides
Acyclovir
immunosuppressant
s:
Cyclosporine
 FK 506
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“Be renal-protective…”
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i.e. optimize intravascular volume and renal
perfusion
Minimize nephrotoxic drugs/contrast
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You are on rounds the next day when the
patient develops seizures
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Metabolic encephalopathy
Drug toxicity
Infections
Muscle weakness
Cerebrovascular events
(Seizures)
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Cause of death in 7% of HSCT pt
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Risk Factors:
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High-dose chemo
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Immunosuppressive therapy
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GVHD
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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
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High-dose busulfan
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10% have seizures, need prophylaxis
Steroid induced psychosis, myopathy
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More common in allo HSCT
Causes:
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Intracranial bleed
Infarction: infectious ( aspergillus) and non
infectious (rare, DIC)
Poor outcome, mortality 69%
Same management, need to r/o infx
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Bacterial
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Fungal
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Strep, Listeria, Nocardia
Aspergillus: main cause of CNS infx, usually
dissemintated disease
Zygomycetes, Candida
Virus
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CMV, HSV, Adenovirus, VZV, HHV6, JC virus
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Symptoms
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Meningeal signs
May have no sx because immunocompromised
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CSF PCR useful for dx
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Minimal abnormalities in CSF
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Polyneuropathies
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GBS like disorder
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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
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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.