Sinusoid occlusive syndrome (SOS) is increasingly replacing the term venulo-occlusive disease (VOD), because current research suggests that the initial target of this syndrome is primarily the liver sinusoids rather than the venule sinusoids (Kumar et al. 2003; DeLeve et al., 2002). This chapter uses SOS to reflect current language.
SOS was first reported to be linked to the use of Senecio tea in South Africa (Willmot & Robertson, 1920). Other studies described epidemics of VOD associated with the ingestion of plants that contained pyrrolizidine alkaloids (Datta et al., 1978; Tandon et al., 1976). The term VOD subsequently made its way into the scientific literature until recent research determined otherwise.
SOS was first described in Western culture in 1979 in recipients of bone marrow transplants (BMTs) (Berk et al., 1979; Jacobs et al., 1979). SOS also can occur in other settings (although it is rare), such as in patients receiving chemotherapy after high-dose radiation therapy (Fajardo & Colby, 1980), individuals who have ingested alkaloid toxins, and recipients of liver transplants (Sebagh et al., 1999).
Management of a patient with hepatic SOS continues to be the subject of intensive research. Until such time that successful modalities emerge, supportive care remains the first-line treatment. Prophylactic and treatment measures have been disappointing, but clinical research continues to focus on eliminating or diminishing the effects of SOS. Surprisingly, 70% of SCT recipients with SOS spontaneously overcome this disorder (Kumar et al., 2003), which emphasizes the need for intense supportive care until the disease resolves
Oncology nurses practicing in this setting carry many responsibilities in symptom management to support the recipient through numerous symptoms of SOS. In addition to reducing the physical discomforts of this syndrome, advanced nurse practitioners need to attend to the psychologic needs of patients who are great risk for morbidity and mortality. Those practicing in clinical trials for prevention and treatment of SOS can disseminate the results of ongoing research and nursing-sensitive outcomes (Kapustay & Buchsel, 2000). This chapter discusses the pathophysiology, risk factors, and medical management and nursing care for SOS in the SCT setting.
The histologic changes in the liver of the SCT recipient are caused by a number of events that make the liver vulnerable to the insults of co-morbidities before and during treatment. The pathophysiology of SOS is complex and remains somewhat unclear, but research in the rat model has contributed to new understanding of the histologic changes in the liver affected by SOS. Study rats given pyrrolizidine manifested the initial symptoms of SOS. Damage to the liver endothelium appeared to initiate a cascade of events that led to the loss of the endothelial cell fenestrations and the appearance of gaps in the lining, which were followed by extravasation of red cells into the space of Disse. This was followed by obstructions caused by engorged hepatocytes and red blood cells, leading to coagulation in the liver sinusoids. These obstructions are thought to result in the classic symptoms of water retention, weight gain, elevation of serum bilirubin, and painful hepatomegaly.
In summary, SOS manifests during the first 2 week after SCT. The classic signs and symptoms of SOS are weight gain, ascites, and pain in the upper right quadrant of the abdomen. Supportive care until the disease resolves, usually within several weeks, remains the gold standard of treatment. Current research is aimed at preventive and treatment measures, but no new agents or combinations of agents have as yet been accepted worldwide as curative measures.
EPIDEMIOLOGY AND ETIOLOGY
SOS is a specific treatment complication that can lead to substantial morbidity and treatment-related mortality. It develops in individuals who have a mutation in the gene encoding the PML nuclear body protein Sp110. Hepatic SOS is frequently linked to high-dose chemotherapy and total body irradiation in recipients of hematopoietic SCT; long-term use of azathioprine after organ transplantation; the use of other chemotherapeutic agents (e.g., oxaliplatin and CBV therapy [cyclophosphamide, VP-16, high-dose BCNU]) in the treatment of lymphoma; and the use of the Chinese herbal Gymura segetum. Although it occurs in patients treated with oxaliplatin, it is not associated with an increased risk of perioperative death. The incidence of hepatic SOS ranges from 0 to 70% (Helmy, 2006) and is decreasing. Disease risk is higher in patients with malignancies, hepatitis C virus infection, those who present late, when norethisterone is used to prevent menstruation, and when broad-spectrum antibiotics and antifungals are used during and after the conditioning therapy. Patients who undergo the transjugular intrahepatic portosystemic shunt (TIPS) procedure have a higher risk of developing SOS, because shunt dysfunction occurs in 50% of patients within 1 year. The prognosis varies, depending on the etiology and severity of the disease and on associated conditions. Patients who receive liver transplants have an average 5-year disease-free survival rate of 50% to 95% if the procedure was done at a specialized transplant center. Death most often is caused by renal or cardiopulmonary failure.
RISK PROFILE
The results of most large, well-conducted research studies agree on the primary risk factors, incidence, and morbidity and mortality rates for STC recipients who develop SOS. These studies include a multicenter study (N = 1653) from 73 SCT centers (Carreras et al., 1998); a cohort study of 355 patients (McDonald et al., 1993); and an extensive review of more than 32 studies (Kumar et al., 2003). The findings of other significant studies are consistent with those of these studies (Schoch et al., 2005; El-Sayed et al., 2004; Gooley et al., 2005; Bearman, 1995). Risk factors include the following:
• Pretransplant elevation in the serum aspartate aminotransferase (AST)
• Decreased albumin levels, decreased pseudocholinesterase
• Cirrhosis
• Metastatic liver disease
• Pretransplant hepatotoxic drug therapy (i.e., acyclovir, amphotericins, vancomycin, cyclophosphamide) (De Jonge et al., 2006)
• Karnovsky scores less than 90%
• Advanced age
• Previous STC transplantation
• Allogenic STC versus autologous
• Previous therapy with gemtuzumab
• Viral hepatitis C
• Use of cyclophosphamide, busulfan, or total body irradiation in conditioning regimens for SCT
• Administration of methotrexate for GVHD
• Possible cytomegalovirus (CMV) infection
PROGNOSIS
SOS is proportional to the extent of liver damage. The incidence of SOS ranges from 20% to 70%, depending on the diagnostic criteria used, the population studied, and the conditioning protocol. Patients with SOS usually succumb to multisystem organ failure and die of other causes, most commonly renal failure, pulmonary compromise requiring mechanical ventilation, cardiac failure, and bacteremia. Late complications of SOS are rare (Kumar et al., 2003).
PROFESSIONAL ASSESSMENT CRITERIA (PAC)
SOS typically occurs within the first 2 weeks after SCT. The classic symptoms are hepatomegaly, right upper quadrant pain, jaundice, and ascites. Computed tomography (CT) scans show periportal edema and small diameter of the right hepatic vein (less than 0.27 cm) (Ertuck et al., 2006). SCT recipients manifest numerous overlapping symptoms caused or mimicked by myriad complications of transplantation, especially in the early stages of SCT. For example, the clinical symptoms and laboratory findings for acute liver (GVHD) or fungal infections are similar (Kapustay & Buchsel, 2000).
Three recognized scales for diagnosing SOS are similar and are accepted by researchers in the worldwide community of transplant medicine. These are the Seattle Criteria, the Baltimore Criteria, and the Modified Seattle Criteria (Kumar et al., 2003).
1. As mentioned, the classic initial symptoms are manifested within the first 2 weeks of SCT. Symptoms are often overlooked early in SCT because of the administration of high volumes of intravenous fluids. Such symptoms include the following:
• Pain (upper right abdominal pain caused by enlarged liver and ascetics).
• Tender, enlarged liver (narcotics may be required for pain, which may be severe enough to require opioids).
• Asymptomatic weight gain thought to be due to water and salt retention by the kidneys (ascites may not be relieved by diuretics).
• Serum total bilirubin concentration greater than 2 mg/dL.
• Jaundice related to liver dysfunction.
• Renal dysfunction (occurs frequently, and 50% of cases require hemodialysis).
• Thrombocytopenia (may be due to increased consumption of platelets in the liver sinusoids and increased splenic sequestration related to portal hypertension).
• Coagulation factor deficiencies and prolonged prothrombin time.
• Encephalopathy
2. The initial diagnosis of SOS is made primarily on the basis of the classic symptoms. Other diagnostic approaches include the following:
• Transjugular biopsies, rather than percutaneous needle biopsies, are done because of the high risk of thrombocytopenia and abnormal coagulopathies. Histopathology may reveal hepatic venular occlusion, sinusoidal fibrosis, phlebosclerosis, hepatocyte necrosis, and luminal narrowing of the hepatic venules.
• Ultrasound scanning has not been a useful tool in the STC setting, but it is useful for making a differential diagnosis regarding disorders that mimic SOS, such as hepatomegaly, ascites, and hepatic vein dilation.
• Doppler findings of portal hypertension can be useful.
• Magnetic resonance imaging (MRI) may support ultrasound findings, but it is not useful for diagnosing SOS.
3. Pretransplantation assessment:
• History of risk factors for morbidity and mortality related to SCT.
• History of co-morbidities, particularly hepatitis C infection.
4. Assessment during stem cell transplantation:
• Right upper quadrant pain.
• Increased abdominal girth.
• Weight gain, fluid retention.
• Thrombocytopenia with increased platelet requirements.
• Jaundice
• Psychological distress
• Renal dysfunction secondary to intraperitoneal pressure.
• Hepatic encephalopathy secondary to liver inability to metabolize waste products and the metabolites of drugs (i.e., confusion, lethargy, disorientation).
• Anxiety, depression, fear of dying.
• Lung biopsy shows fibrosis, positive staining for TGF-1 or TGF-B1 or increased osteonectin expression (Murase et al., 1995).
• Broncholavage shows increased hyaluronan.
NURSING CARE AND TREATMENT
1. Maintain fluid and electrolyte balance, strict I & O; daily weights; measure abdominal girth, estimate insensible losses
2. Assess and manage pain using a recognized pain scale.
3. Postural blood pressure and heart rate; assess for peripheral edema.
4. Limit sodium intake; minimize fluids to prevent fluid from entering interstitial spaces, particularly pulmonary fluid; monitor serum sodium levels.
5. Auscultate lung fields for crackles and adventitious breath sounds; assess for decreased chest expansion secondary to possible pulmonary distress.
6. Assess for bleeding after liver biopsies; monitor complete blood count (CBC).
7. Anticipate that confounding symptoms of liver graft versus host disease may obscure diagnosis of SOS.
8. Administer medications specific for SOS (e.g., anticoagulants) if ordered.
9. Use relaxation techniques (e.g., imagery or music therapy) to reduce anxiety.
10. Ensure patient safety, especially for those with encephalopathy.
11. Assess spirituality of patient and support patient in meeting spiritual needs.
12. Prophylactic and treatment measures with ursodiol (UDCA), defibrotide, and low-dose heparin have centered on anticoagulant therapy but have had mixed results in clinical trials (Negrin,and Bonis 2006; Essel et al., 1998; Strausser & McDonald, 1999; Bearman et al., 1997). The use of type plasminogen activator (tPA) to treat SOS appeared promising in case studies and small trials, but larger trials determined that these patients typically have thrombocytopenia. tPA heightens bleeding, which prevents its use in a patient at significant risk for bleeding. At that time, further study was halted (Bearman et al., 1997). Other approaches have met with negative or inconsistent results. These include the use of high-dose methylprednisolone (Khoury et al., 2000); transjugular intrahepatic portosystemic shunts (Azoulay et al., 2000), and orthoptic liver transplantation (Dowlati et al., 1995). Defibrotide, initially found to have positive results in compassionate use studies, was further investigated by Richardson and colleagues (2002) in a multiinstitutional study (N = 88). No adverse events related to the treatment were noted, and SOS resolved in 36% of high-risk patients studied. More recently this agent has been tested as a prophylactic agent in combination with low-dose heparin in an historically controlled study (N = 52) (Chalandon et al., 2004). None of the patients in the treatment arm developed SOS or adverse effects related to this therapy. The researchers encourage further study in randomized controlled trials.
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