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How the Experts Treat Hematologic Malignancies
Las Vegas, NV
March 10, 2016
BMTCN REVIEW COURSE
POST-TRANSPLANT ISSUES – PART 2
David Rice, PhD, RN, NP
Director, Professional Practice and Education
Disclosures
No disclosures
Objectives
• Describe post transplant issues and give nursing care
considerations related to:
– Hepatic complications
– Renal complications
– Neurologic complications
– Genitourinary complications
– Endocrine complications
– Cardiac complications
– Pulmonary complications
Note: the primary reference source for this course is
Ezzone, S. (2013) Hematopoietic stem cell transplantation: a manual for nursing practice. Oncology Nursing Society, Pittsburgh, PA
Prevention and Risk Reduction Screening Diagnosis Treatment Survivorship End-of-life Care
Cancer Care Continuum
Acute Care Chronic Care End-of-Life Care
- Tobacco control
- Diet
- Physical activity
- Sun and environmental
- Alcohol use
- Chemoprevention
- Immunization
- Age and gender specific screening
- Genetic testing
-Biopsy
-Pathology reporting
-Histological
assessment
-Staging
-Biomarker assessment
-Molecular profiling
-Systemic Therapy
-Surgery
-Radiation
-HCT
-Surveillance for recurrences
- Screening for related cancers
- Hereditary cancer predisposition/ genetics
- Implementation of advance care planning
-Hospice Care
- Bereavement care
– Care planning – Palliative care – Psychosocial support – Prevention and management of long tern and late effects – Family Caregiver Support
http://www.nap.edu/catalog/18359/delivering-high-quality-cancer-care-charting-a-new-course-for
Hepatorenal complications
• Hepatic
– There are two general patterns of hepatic injury
• Acute inflammation / hepatocyte injury (AST and ALT elevated)
• Cholestatic injury (alkaline phosphatase and bilirubin* elevated)
– *Note that for hepatic injury, we are looking for increased
total and direct bilirubin, not just total bilirubin alone
Hepatorenal complications
• Hepatic
– More common after Allo HCT
• Can affect up to 80% of patients
• 5 -15% treatment related mortality
– Pretransplant factors
• Pre-existing liver disease (e.g. Hepatitis B or C) (Note: people
with cirrhosis of the liver are generally not candidates for HCT)
• Liver metastasis
• Infection or sepsis during conditioning regimen
• Intensive conditioning regimen, previous chemotherapy, prior
transplant, prior radiation to the liver
– Busulfan-based regimens are more likely to cause VOD, especially in conjunction with sirolimus as GVHD prophylaxis
• Mismatched or unrelated donor
Veno-occlusive Disease: Clinical Manifestations
(More currently called Hepatic Sinusoidal Obstructive Syndrome [SOS])
• Right upper quadrant (RUQ) pain
• Weight gain
• Ascites
• Edema
• Hepatomegaly
• Jaundice
Image used with permission: Elsevier Clinical Key © 2016
Veno-occlusive Disease: Diagnosis
VOD is a clinical diagnosis
• No single lab or radiology test which makes a diagnosis
• Clinical criteria (weight gain, ascites, jaundice, RUQ pain)
• Ultrasound findings can support the diagnosis by demonstrating ascites and abnormal flow in the portal vein (especially if flow is reversed)
• Liver biopsy can be performed to help with the diagnosis but is rarely done due to the potential morbidity
VOD: Modified Seattle Criteria and Baltimore Criteria
Seattle Criteria: Determine severity Mild No adverse effect of liver disease, AND
No medications required for diuresis or hepatic pain, AND
All symptoms, signs and laboratory features reversible
Moderate Adverse effects of liver disease present, AND
Sodium restriction or diuretics required, OR
Medication for hepatic pain required, AND
All symptoms, signs and laboratory features reversible
Severe Adverse effects of liver disease present, AND
Symptoms, signs or laboratory features not resolved by day +100, OR
Death
http://bloodref.com/transplant/other/vodsos-diagnosis-severity
Veno-occlusive Disease: Treatment
Treatment is primarily supportive
• Mild and moderate cases may resolve spontaneously
• Prophylaxis is often given preemptively in allogeneic HCT
– Ursodiol PO BID
– Low-dose heparin continuous infusion • Neither has strong supportive evidence, but fairly low risk
• Nursing considerations: strict I/Os, monitor fluid status, weights
• Severe VOD can be treated with defibrotide
– Generally treated on compassionate use / investigational protocols
– Associated with significant bleeding risks
Severe Veno-occlusive Disease leads to Hepatorenal Syndrome
Symptoms
• Relative hypotension
• ↓ flow from hepatic vessels
• Renal vasoconstriction
• Urinary sodium retention
• Edema/ascites
• Reduced glomerular filtration rate (GFR)
• ↓ urine output
Treatment
• Restriction
– Protein
– Fluid
– Sodium
• Renal dose dopamine
• Diuretics
• Hemofiltration
• Continuous Arteriovenous
– Hemofiltration with Dialysis
(CAVHD)
– Continuous Renal
Replacement Therapy (CRRT)
* If VOD progresses to this point, the mortality rate is very high
Drug-Induced Liver Injury
• Conditioning regimen (busulfan, TBI-based regimens)
• Immunosuppressants – sirolimus, especially in conjunction with busulfan-based myeloablative regimens
• Antimicrobial agents – especially the azole medications
• Hyperalimentation (HAL) – Prolonged TPN can result in liver dysfunction
Graft-versus-host disease
The liver is a common site affected by GVHD.
Although not a hard and fast rule, hepatic GVHD tends to manifest itself as a rise in bilirubin and alkaline phosphatase (cholestatic picture) more than AST/ALT
Treatment follows GVHD paradigm
Renal Complications: Pathophysiology
• Epithelial cell damage – Nephrotoxic injury – Ischemic injury
• Compromised renal blood flow • Impaired ability to remove fluid, electrolytes and metabolic
waste • Increased
– Weight – Blood pressure – Serum creatinine & BUN
Image used with permission: Elsevier Clinical Key © 2016
Renal Complications During HCT
• General acute injury in HCT, since patients are required to have
adequate renal function to be eligible for HCT
– May be chronic
• Multiple types of injury possible
– Sepsis-induced renal injury (often due to hypotension and resulting
poor renal perfusion)
– Tumor lysis syndrome – aggressive tumors and high burden of
disease (rapid LDH and / or uric acid release damages kidneys)
– Thrombotic microangiopathy (TTP or Hemolytic uremic syndrome –
direct damage to the golmerular capillaries)
– Radiation nephritis – direct insult to kidneys
– Syndrome of inappropriate antidiuretic hormone (SIADH)
Renal Complications: Pre-renal
• Most common
• Poor perfusion
• Etiology
– Hypovolemia
– Impaired circulation
– Vascular constriction
Pre-renal Complications: Hypovolemia
• Dehydration
– Fever (increased insensible fluid losses)
– Excessive diuresis
– Gastrointestinal losses (i.e. diarrhea)
– Hemorrhage
• Capillary leak syndrome (CLS)
• Hepatorenal syndrome
Pre-renal Complications:
Capillary Leak Syndrome
Onset typically Day + 7 to +14
Capillary leak syndrome (or vascular leak syndrome) can result from high dose therapy, infection, sepsis, exogenous growth factor administration, cytokine flux, decreased peripheral vascular resistance, and increased
intravascular volume. It represents the movement of fluids and albumin into body tissues. While it
cannot be measured directly, positive fluid balance, positive weight gain, increased serum creatinine, and decreased serum albumin are all surrogates for the syndrome.
• ↑ Capillary permeability
• Fluid retention • Weight gain • Ascites • Pulmonary edema
Capillary Leak Syndrome: Etiology
Any critically and acutely ill patient is at risk
Aspiration
Pneumonitis
Radiation therapy
Poor perfusion to the lung
Sepsis – Cytokine Release Syndrome
Disseminated intravascular coagulopathy (DIC)
Chemotherapy
Immunotherapy
CAR T-cell clinical trials
IL-2
Pre-renal Complications:
Impaired Circulation
• Impaired circulation of blood volume
– Septic shock
• ↓ mean arterial pressure (MAP)
• ↓ nephron perfusion
– Congestive heart failure
• ↓ cardiac output
• ↓ kidney perfusion
Renal Complications: Intra-renal
• Acute tubular necrosis
– Nephrotoxic drugs
– Prolonged ischemia (often due to a pre-renal insult)
• Tumor lysis syndrome – due to an influx of toxic metabolites such as uric acid and phosphate
– Dying cells release phosphate and uric acid as their DNA is broken down
– Toxic, if large quantities
– Rare in BMT but relatively common with chemotherapy, especially in newly diagnosed patients with ALL or aggressive lymphomas with large tumor burden
Intra-renal Complications:
Acute Tubular Necrosis
• Renal tubule damage
– Etiology • Nephrotoxic drugs
– Chemotherapy (clofarabine, methotrexate, cisplatin are well-known culprits)
– Immunosuppressive agents (especially Tacrolimus)
– Antifungals (especially amphotericin, less likely other agents)
– Antibiotics (especially aminoglycosides such as tobramycin and gentamicin, less likely but potentially with vancomycin)
– Antivirals (foscarnet, gancyclovir)
Post-renal Complications:
Hemorrhagic Cystitis
• Etiology – Chemotherapy (cyclophosphamide) – Viral infections (adenovirus or BK virus) – Radiation
• Symptoms – Dysuria – Urgency – Bladder spasms – Hematuria (gross blood and clots)
• Diagnosis – Ultrasound – Urology consult
Image used with permission: Elsevier Clinical Key © 2016
Hemorrhagic Cystitis – medical / nursing
management and treatment
• Prevention – Aggressive IV hydration / Strict intake and output
– Mesna® prophylaxis
• Treatment – Continuous bladder irrigation – 500ml to 2 L/hr
– Maintain platelet count
– Cystoscopy with cauterization if there is a visible lesion
– Urine culture and treatment of underlying infection
– Alum irrigation of bladder for persistent bleeding
– Phenazopyridine for dysuria (no “magic bullet” for bladder spasm pain)
– Platelet transfusion
– Pain management
24
Intra-Renal Complications:
Hemolytic Uremic Syndrome
Clinical features
• Thrombocytopenia
• Hematuria
• Hypertension
• Renal failure
• Microangiopathic hemolytic anemia – increase schistocytes and nucleated RBCs in the peripheral blood
• Diffuse endothelial damage
Hemolytic Uremic Syndrome:
Clinical Manifestations
• Bruising, bleeding, petechiae
• Central nervous system changes
• Fatigue, pallor
• Renal failure
• Fever
• ↑ LDH
Hypertension During HCT: Definitions
• Significant hypertension – Above 95th percentile for age – Goal to reduce over several days
• Hypertensive urgency
– Severe (well above 95th percentile for age) – Goal to reduce within 24 hours
• Hypertensive emergency
– Severe – Goal to reduce immediately to prevent end-organ damage
Antihypertensives used in HCT
Therapeutic Categories Mechanism of Action Drug Names
Calcium channel blockers ↓ calcium entry into
smooth muscle, causes
vasodilatation
Nifedipine
Amlodipine
Direct vasodilators Direct arteriolar dilation Hydralazine
ACE inhibitors Potent vasoconstrictor Enalapril, lisinopril
Combination alpha/beta
receptor blockers ↑ renins are reduced Labetalol
Beta-blockers Block binding of beta1 receptors, also relaxes myocardium
Metoprolol, atenolol
Alpha2-agonist Alpha2 agonist which decreases peripheral vascular resistance
Clonidine
Radiation Nephritis
• Late syndrome
– 3 to 13 months post–HCT
• Clinical Features
– ↑ BUN & creatinine
– Anemia & hypertension
• Risk factors
– Multi-agent conditioning regimens
– Total body irradiation
Renal Complications: Nursing Assessment
• Weight
• Strict I&O
• Estimate insensible loss • Adult – approximately 800 mL / day (= heat loss of about 480 kCal /
day)
• Increases with fever, rigors
• Postural blood pressure / orthostatic measurements
• Heart rate
• Abdominal girth
• Lung exam
• Peripheral edema
• Mental status
• Monitor labs
Neurologic Complications
• Delirium
– Conditioning regimen, drug therapy, metabolic disturbances
– Age
• Seizures
– Associated with bulsulfan – prophylaxis given
– May occur with BCNU
– Rarely may occur with DMSO
• Metabolic encephalopathy
– Metabolic acidosis
– Renal or hepatic failure
– Sepsis
– Hypoxemia
– Electrolyte disturbances
Neurologic Complications
• Leukoencephalopathy
– Syndrome of unclear etiology which results in irreversible damage
in the brain’s white matter
• Associated with ALL, cranial radiotherapy, and intrathecal
methotrexate
• PML – Progressive Multifocal Leukoencephalopathy
– Allo patients who experienced prolonged immunosuppression
– Rare and extremely high mortality rate
– Confusion, visual and speech disturbances, imbalance
• Posterior Reversible Encephalopathy Syndrome (PRES)
– Calcineurin inhibitor toxicity (toxic levels of CSA or tacrolimus)
– Reversible by dose adjustment
– Symptoms of visual disturbances, altered mental status,
hypertension, headache, seizures
Neurologic Complications
• Infectious sources causing CNS infection
– Viral
– Bacterial (less common)
– Fungus
• Present with headache, nuchal rigidity, seizures, mental status
changes, delirium and depressed sensorium
Neurologic Complications – Medications which may
cause neurotoxicity
Cancer agents Immuno-
suppressive
therapy
Antifungals Antimicrobials Antivirals Miscellaneous
Busulfan Cyclosporine Amphotericin B Penicillins* Acyclovir Benzodiazepines
Cytarabine Tacrolimus Voriconazole Cephalosporins* Ganciclovir Narcotics*
Ifosfamide Muromonab Asoniazid* Anesthetics
Paclitaxel Metronidazole* Antiepileptics
Mechlorethamin
e
Rifampin* DMSO*
Cisplatin Linezolid
Methotrexate
5-Fluorouracil
Procarbazine
BCNU
*Can also cause seizures
Alterations in hepatic or renal function and low albumin may alter metabolism and so can produce neurotoxicity at lower
doses than usual. Adapted from Ezzone (2013)
Neurologic Complications
• Cerebrovascular
– Post-transplant hypercoaguable state
• Decrease in protein C and antithrombin
• Increase in fibrinogen
– Prolonged thrombocytopenia
• Risk of
– Intracranial hemorrhage, subdural hematoma, and ischemic stroke
Neurologic Complications - Immune-mediated neurologic
toxicities
• Late, rare complication, usually associated with cGVHD
– Peripheral nervous system
• Chronic inflammatory demyelinating polyneuropathy
• Guillain-Barre syndrome
– Rapidly progressing symmetrical ascending motor weakness, numbness
and hyporeflexia
– Myasthenia gravis
• Ptosis and extraocular muscle weakness
– Polymyositis
• Fatigable weakness
– Central nervous system
• Vasculitis
• Demyelinating disease of the CNS
• Immune-mediated encephalitis
Genitourinary complications
• Vaginal sicca
• Vaginal atrophy, stenosis or inflammation
– If cGVHD related, may respond to topical corticosteroid,
Cyclosporine or Tacrolimus
– Use of vaginal lubricants and dilators
– Low-dose topical estrogen (vaginal atrophy)
• Hemorrhagic cystitis
• Nephrotic syndrome may develop (cGVHD or renal insult)
– Edema
– Proteinuria
Endocrine complications
• Hyperglycemia
– Steroid-induced hyperglycemia
– Literature suggests tight control of serum glucose during transplant
course may improve outcomes
• Syndrome of Inappropriate Anti-Diuretic Hormone
– Cyclophosphamide common culprit (although many drugs can
cause SIADH)
– Release of antidiuretic hormone
• Fluid retention
– Hydration
– Diuretics
– Monitor weight, intake and output, lung sounds
• Hypothyroidism – usually resulting from radiation to the mediastinum
and total body irradiation
Post Transplant Complications: Cardiac
• Incidence 25%
• Mortality rare
• Pre-transplant screening
o Echocardiogram – Ejection Fraction ≥ 50%
o EKG baseline
• Causes
o Conditioning regimen and prior treatments:
• Anthracyclines – Cumulative doses ≥ 400 mg/m2 (Doxorubicin, Daunorubicin)
– Early post HCT damage can cause necrosis and fibrosis and can be irreversible
• Cyclophosphamide
• Mediastinal radiation
• Total body irradiation
• Pre-existing cardiac disease
• Sepsis / inflammation
Cardiotoxic Side Effects
• Cardiac arrhythmia is the most common cardiotoxic side
effect of HSCT, followed by congestive heart failure,
pericarditis, pericardial effusion, and pulmonary edema
(Deaver, 2008; Soubani, 2006)
• Calcineurin inhibitors (Tacrolimus, Sirolimus) often
associated with hyper tension
– May be concurrent hyperkalemia
Arrhythmias
Cardiac arrhythmias may
be precipitated by:
• Electrolyte imbalances
• Hypoxemia
• Sepsis
• Multi-Organ System
Failure
• Vasopressors
Treatments that may
precipitate arrhythmias: • Carmustine
• Cyclophosphamide
• Cytarabine
• Etoposide
• Ifosfamide
• Busulfan
• Radiation
Most Common Arrhythmias
• Supraventricular
tachyarrhythmias, most
commonly atrial
fibrillation or atrial flutter
that develops in the early
port-transplant period and
spontaneously resolves
within three days of onset
• Rate control with
amiodarone or cardizem is
initiated if correcting the
precipitating factors is not
successful (Soubani,
2006)
Image used with permission: Elsevier Clinical Key © 2016
Pericardial Effusion and Tamponade
• Cyclophosphamide toxicity,
viral or bacterial infection, or
renal failure may contribute to
the development of
pericardial effusion and
tamponade
• Aggressive treatment with
pericardiectomy or
pericardiocentesis is
indicated in the instance of
hemodynamic impairment
(Soubani, 2006)
• Hemodynamic impairment
generally occurs when
pericardial effusion
progresses to pericardial
tamponade
Images used with
permission: Elsevier
Clinical Key © 2016
Pericarditis - Symptoms
Sentinel symptom is retrosternal pain exacerbated upon inhalation or
assuming a supine position
– Relief from pain often is obtained when the patient sits up and leans
forward
– This also is the position in which the characteristic pericardial friction rub is
best auscultated along the left sternal boarder
Hallmark signs of pericardial tamponade include:
– Pulsus paradoxus Definition: On inspiration, a drop in systemic arterial
pressure greater than 10mmHg
– Hypotension
– Distant heart sounds
– Tachypnea
– Dyspnea
– Elevated central venous pressure (this is considered an oncologic
emergency) (Burgunder, 2007)
Infectious Pericarditis
Marked decrease in heart size after
cardiac pericentesis
Images used with
permission: Elsevier
Clinical Key © 2016
Cardiac Complications
Nursing assessment
Tachycardia: assess rate and for irregular rhythm
Tachypnea: assess respiratory rate, use of accessory
muscles, general respiratory status
Blood Pressure
Fluid balance
Timeline for pulmonary complications post HCT
Assessment of Pulmonary Complications
• Plain chest x-ray remains the mainstay for assessing patients for pulmonary complications
• CT scan may be ordered for more definitive diagnosis when chest x-ray becomes abnormal
• Pulmonary Function Test (PFT)
• Bronchoalveolar lavage (BAL) – diagnosis of pulmonary infections
• Lung Biopsy
Pulmonary complications
• Pleural effusions
– Fluid overload, CHF, dyspnea, tachypnea, cough, weight gain,
bilateral rales, hypoxemia
– Diuretics, oxygen support, thoracentesis, if needed
• Pulmonary embolism
• Idiopathic Pneumonia Syndrome
– Diffuse interstitial pneumonitis and alveolar injury
– Hypoxemia, dyspnea, non-productive cough, non-specific infiltrates
on x-ray
– Supportive treatment
Diffuse Alveolar Hemorrhage
Signs Sudden onset dyspnea, cough, hemoptysis rare
Symptoms Crackles, progressive hypoxemia, fever
X ray Diffuse consolidation
BAL Progressively bloody return
Cytology Hemosiderin laden macrophages
Treatment Platelet transfusion support, oxygen
support, high dose corticosteroids
Figure 1. Schematic diagram of the time of occurrence of IPS, BOOP, and BOS.
Satoshi Yoshihara, Gregory Yanik, Kenneth R. Cooke, Shin Mineishi
Bronchiolitis Obliterans Syndrome (BOS), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), and Other Late-Onset
Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation
null, Volume 13, Issue 7, 2007, 749–759
http://dx.doi.org/10.1016/j.bbmt.2007.05.001
Bronchiolitis Obliterans Syndrome (BOS)
Bronchiolitis Obliterans Organizing Pneumonia (BOOP)
Bronchiolitis Obliterans Syndrome (BOS)
• Obstructive airway disease from granulation tissue
plugs in the lumens of the small airways
• Onset – three months to two years post HCT
• Clinical course may be mild with slow deterioration
• Symptoms:
o Wheezing
o Non-productive cough
o DOE
Bronchiolitis Obliterans Syndrome (BOS)
• Risk Factors:
o Use of CSA with prednisone for GVHD prophylaxis
o Low serum IgG
o TBI preparative regimens
• Diagnosis:
o High resolution CT scan of chest – represents
pulmonary air trapping and poorly defined lung
margins
o Pulmonary Function Test
o Treatment:
o High dose steroids – and taper
Bronchiolitis Obliterans Syndrome (BOS)
Radiological findings four months after transplant for multiple
myeloma: hyperinflation of lungs, air trapping, flattening of diaphragm
Image used with permission: Elsevier Clinical Key © 2016
Bronchiolitis Obliterans Syndrome (BOS)
Rare in transplant population: 5-30%
Associated risk factors:
o Methotrexate
o CMV infection
o Busulfan
o Carmustine
Can occur at any time during transplant course
Treatment:
o Steroids
o Supportive care Figure 3. CT scan of BOS. Mosaic pattern of air trapping is clearly shown in expiratory phase.
Satoshi Yoshihara, Gregory Yanik, Kenneth R. Cooke, Shin Mineishi
Bronchiolitis Obliterans Syndrome (BOS), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), and
Other Late-Onset Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell
Transplantation
null, Volume 13, Issue 7, 2007, 749–759 http://dx.doi.org/10.1016/j.bbmt.2007.05.001
Figure 4. CT scan of BOOP. Consolidation and nodules are shown.
Satoshi Yoshihara, Gregory Yanik, Kenneth R. Cooke, Shin Mineishi
Bronchiolitis Obliterans Syndrome (BOS), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), and Other Late-Onset
Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation
null, Volume 13, Issue 7, 2007, 749–759
http://dx.doi.org/10.1016/j.bbmt.2007.05.001
Comparison of Clinical Presentations of BOS and BOOP
BOS BOOP
Symptom Progressive dyspnea
Non productive cough
Wheezing
Fever
Non productive cough
Dyspnea (usual mild)
Physical examination Wheezing Rales
Lab data Non specific Elevated level of C Reactive
Protein
Increased neutrophil
PFT Obstructive lung disease Restrictive lung disease
FEV1/FVC Decreased Normal
TLC Normal Decreased
DLCO Decreased Decreased
Radiology / CT Scan Air trapping (expiration phase)
Mosaic perfusion
Bronchiectasis
Bronchial wall thickening
Centrilobular nodules
Consolidation
Ground glass opacity
Nodules
http://www.sciencedirect.com/science/article/pii/S1083879107002741
Pulmonary Complications: Typical Onset Timeline
Day 0 to day +30 Day +31 to day +100 Greater than +100
Pulmonary edema
Pleural effusion
Idiopathic pneumonia
Diffuse alveolar
hemorrhage
Acute Respiratory
Distress Syndrome
Infection
Pulmonary VOD –
pulmonary arterial
hypertension
Acute Respiratory
Distress Syndrome
Early Bronchiolitis
obliterans organizing
pneumonia
Infection
Chemotherapy
associated pulmonary
toxicity
Infection
Bronchiolitis obliterans
syndrome
Chemotherapy induced
pulmonary toxicity
Radiation induced
pulmonary toxicity
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