BMTCN REVIEW COURSE POST-TRANSPLANT ISSUES PART 2cmesyllabus.com/wp-content/...BMTCN_-REVV_-IV-POST... · BMTCN REVIEW COURSE POST-TRANSPLANT ISSUES – PART 2 David Rice, PhD, RN,

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


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


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


• 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


• 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)


• 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)


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)


• 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


• 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


Radiological findings four months after transplant for multiple

myeloma: hyperinflation of lungs, air trapping, flattening of diaphragm



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.


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.


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

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

Documents

BMTCN REVIEW COURSE POST-TRANSPLANT ISSUES PART 2cmesyllabus.com/wp-content/...BMTCN_-REVV_-IV-POST... · BMTCN REVIEW COURSE POST-TRANSPLANT ISSUES – PART 2 David Rice, PhD, RN,