Typhlitis and Sinusoidal Obstruction Syndrome as Treatment-Associated ToxicitiesKristin M. Belderson, DNP MS RN CPON®Michael Hans, MS BSN RN-BC CPON® CPN®

Learning Objectives:
1. Identify the risk factors for typhlitis and sinusoidal obstruction syndrome.
2. State clinical indicators associated with typhlitis and sinusoidal obstruction syndrome.
3. Describe nursing management of the patient with typhlitis and sinusoidal obstruction syndrome.

Prompt identification and management of treatment-associated toxicities in pediatric oncology and stem cell transplant patients is important in order to continue delivering the antineoplastic therapy, reduce morbidity and mortality, and increase quality of life. Typhlitis and sinusoidal obstruction syndrome (SOS) are two lethal but treatable, gastrointestinal toxicities associated with common chemotherapy agents used in treatment regimens for pediatric oncology and stem cell transplant patients.TyphlitisTyphlitis, also referred to as necrotizing enterocolitis, is a localized inflammation and bacterial invasion of the cecum, an intraperitoneal pouch separating the ileum from the ascending colon that quickly can progress to perforation, necrosis, hemorrhage, and sepsis (Altinel et al., 2012; Gray et al., 2010; Kobos et al., 2014; Machado, 2010; McCarville et al., 2005; Schlatter, Snyder, & Freyer, 2002). Typhlitis appears in neutropenic patients and is linked with the cytotoxic effects of intensive chemotherapy regimens used as treatment for AML, ALL, lymphomas, solid tumors, and stem cell transplantation (Altinel et al., 2012; Gray et al., 2010; Haut, 2008; Machado, 2010; McCarville et al., 2005; Moran et al., 2009; Özçay, Kayıran, & Özbek, 2003; Özgen, Üzüm, Mızrak, & Saraç, 2010; Schlatter, Snyder, & Freyer, 2002; Shafey, Ethier, Traubici, Naqvi, & Sung, 2013). The most common bacterial organisms associated with typhlitis are Clostridium difficile and Pseudomonas aeruginosa, although Escherichia coli, Candida species, Klebsiella species, Streptococcus viridans, Clostridium septicum, and cytomegalovirus also have been implicated in typhlitis occurrences (El-Matary, Soleimani, Spady, & Belletrutti, 2011; Haut, 2008; Moran et al., 2009; Özçay, Kayıran, & Özbek, 2003; Shafey et al., 2013; Sundell, Boström, Edenholm, & Abrahamsson, 2011).Typhlitis development results from a combination of gastrointestinal mucosal damage and immunosuppression. The cecum is the predominant location affected due to its decreased vascularity, increased concentration of lymphoid tissue, increased bowel content stasis, and predisposition toward distension in comparison with other intestinal regions. Altered bowel wall integrity due to direct damage by malignant infiltrates, radiation and cytotoxic chemotherapy agents known to cause mucositis or other gastrointestinal effects, and prolonged neutropenia leads to bacterial or fungal microbial invasion (Altinel et al., 2012; El-Matary et al., 2011; Haut, 2008; Machado, 2010; Özçay, Kayıran, & Özbek, 2003; Schlatter, 18Snyder, & Freyer, 2002; Sundell et al., 2011). The subsequent infection and inflammation increases the tissue ischemia, eventually progressing to necrosis, perforation, and sepsis.Chemotherapy agents that prolong neutropenia or have gastrointestinal toxicities pose the greatest risk for patients to develop typhlitis. The anthracycline antibiotics idarubicin, doxorubicin, and daunorubicin cause mucosal injury in the form of stomatitis, nausea, vomiting, diarrhea, and colonic ulceration (Gray et al., 2010; Haut, 2008; McCarville et al., 2005; Moran et al., 2009). Cyclophosphamide, an alkylating agent, causes mucositis, nausea, vomiting, diarrhea, anorexia, and myelosuppression in high doses (Haut, 2008; Kobos et al., 2014). Cytarabine denudes colonic mucosa, as well as causes mucositis and myelosuppression (Moran et al., 2009; Özgen et al., 2010). Vincristine, a vinca alkaloid, leads to bowel hypomotility (Haut, 2008). Side effects of methotrexate and thioguanine (6-TG), as antimetabolites, include nausea, vomiting, anorexia, stomatitis, and diarrhea (Gray et al., 2010; Haut, 2008; McCarville et al., 2005). Additionally, thioguanine may cause intestinal necrosis and perforation. Corticosteroids, such as prednisone and dexamethasone, also play a critical role in the development of typhlitis because they impair tissue healing, promote proliferation of gastrointestinal flora, and alter the natural response to infection (Gray et al., 2010; Haut, 2008).Presenting symptoms for typhlitis include a clinical triad of fever, abdominal pain, and neutropenia (Altinel et al., 2012; El-Matary et al., 2011; McCarville et al., 2005; Özçay, Kayıran, & Özbek, 2003; Schlatter, Snyder, & Freyer, 2002). The abdominal pain may present initially as diffuse and then progress to localized right lower quadrant pain. Additional symptoms include diarrhea, nausea, vomiting, abdominal tenderness and guarding, abdominal distension, and diminished or high-pitched bowel sounds (Gray et al., 2010; Haut, 2008; King, 2002; McCarville et al., 2005; Machado, 2010; Moran et al., 2009; Özçay, Kayıran, & Özbek, 2003; Özgen et al., 2010; Schlatter, Snyder, & Freyer, 2002; Shafey et al., 2013; Sundell et al., 2011). Diagnosis is confirmed by a variety of radiologic studies, including plain film abdominal X ray, ultrasound, and computed tomography (CT) scans. Though plain film X ray can document changes in gas patterns and dilatation of bowel segments, it is nonspecific and insensitive in determining the presence of typhlitis. Ultrasound is useful for determining bowel wall inflammation. CT scans provide increased sensitivity and specificity in differentiating typhlitis from other abdominal diagnoses, such as pneumatosis, and thus is the preferred diagnostic measure. Hallmark findings on CT include cecal wall thickening and pericolic fluid collection (Machado, 2010; McCarville et al., 2005; Schlatter, Snyder, & Freyer, 2002; Sundell et al., 2011).Medical management for the patient diagnosed with typhlitis includes monitoring blood chemistries and cultures, bowel rest, intravenous hydration and total parenteral nutrition, pain management, broad-spectrum antibiotic coverage for gram-positive and gram-negative organisms, and potential gastric decompression via a nasogastric tube (McCarville et al., 2005; Sundell et al., 2011). Surgical intervention may be indicated in the setting of bowel perforation.Nursing interventions for the patient with typhlitis include• alleviating discomfort with the use of opioid analgesia 19• frequent vital sign checks, including cardio-respiratory and pulse oximetry monitoring and performing full-body assessments• monitoring strict intake and output• frequent evaluation of patient’s pain score using age-appropriate pain scales• administering antibiotic and antiemetic therapy• assessing for volume losses and the need for fluid replacement resulting from diarrhea and vomiting• administering intravenous hydration and total parenteral nutrition• obtaining daily weights• managing nasogastric tubes and monitoring abdominal girths, as indicated• performing serial serum chemistries with electrolyte replacement as needed• providing patient and family psychosocial support.Due to the emergent nature of typhlitis, especially its rapid development and tenuous status, the nurse needs to provide information and frequent updates on the medical plan and progress to help ease anxiety, confusion, and fear (Haut, 2008; King, 2002).Sinusoidal Obstruction SyndromeSinusoidal obstruction syndrome (SOS) is a clinical condition in which damage to blood vessels of the liver leads to liver tissue damage that, in turn, can lead to liver failure, multi-organ failure, and death. Many still refer to SOS as veno-occlusive disease (VOD), although recent proposals have called to change the name to SOS (Hooke et al., 2011).SOS arises from damage to endothelial cells in the liver sinusoids (aka sinusoidal capillaries) and terminal hepatic venules, along with damage to the hepatocytes. The sinusoids and venules become fibrous and narrow resulting in obstruction of blood flow and necrosis of hepatocytes. The obstruction is further complicated by cytokines released from damaged cells. Cellular debris and fibrin, along with other clotting factors, deposit in the already congested lining of hepatic blood vessels. The increased resistance to blood flow causes portal hypertension. The liver enlarges from the congestion and protein rich fluid leaks into the peritoneal cavity. Multisystem organ failure and death can result. In the stem cell transplant setting, death almost always occurs with multisystem organ failure (Cefalo et al., 2010; Herring, Hesselgrave, Norville, & Madsen, 2011; Myers et al., 2013).Overall, preexisting liver disease, particularly hepatitis, is considered the largest risk factor for SOS. Further risk factors for SOS include treatment with stem cell transplant (SCT). SCT patients receiving busulfan or total body irradiation in their preparatory regimens showed the most frequent occurrence of SOS. Patients with beta thalassemia who have iron overload or receive methotrexate and cyclosporine prior to SCT are also at an increased risk (Capelli et al., 2009). Pharmacokinetic (PK) studies by Wall et al. (2010) of 24 patients found that the four patients who had SOS had higher levels of busulfan than the 20 who did not experience SOS, but the difference was not statistically significant. Kerl (2014) suggested dimethylacetamide (DMA), the solvent in IV busulfan, might be related to SOS, but testing was inconclusive. Nonetheless, the20risk increases if a patient experiences multiple transplants with myeloablative preparations. Furthermore, the incidence is lower for autologous SCT patients than for allogeneic SCT patients. French et al. (2013) reported one incidence of fatal SOS out of eight patients who received MIBG followed by a conditioning regimen of busulfan and melphalan for an autologous SCT to treat refractory neuroblastoma.Although SCT patients have a high risk for SOS, there are other risk factors. Other conditions implicated in SOS include rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide, as well as Wilm’s tumor treated with vincristine and actinomycin. Cecinati (2009) reported SOS in an 11 month old patient with neuroblastoma treated with vincristine, doxorubicin, and actinomycin. In these cases, no studies have been able to determine if the incidence of SOS is due to just one of the drugs or if the combination of drugs leads to the condition. Ferrugia et al. (2011) described hepatopathy-thrombocytopenia syndrome, a condition similar to and less severe than SOS, as the result of actinomycin. SOS has been reported with patients receiving gemtuzumab and 6-thioguanine (Hooke et al., 2011). SOS resulting from chemotherapy not related to SCT has been shown to be less severe than that associated with SCT (Cefalo et al., 2010; Hooke et al., 2011). Other risk factors include positive cytomegalorvirus (CMV) status and a pre-transplant fever. Females have a higher incidence than males.Signs and symptoms of SOS are usually visible within 30 days from the start of treatment for disease, and typically within 7–21 days post infusion of stem cells. In the classic presentation of a patient with SOS, a child will demonstrate hyperbilirubinemia, painful hepatomegaly, and greater than 5% weight gain (Hooke et al., 2011; Lassau et al., 2002; Nixon, 2014). Often the first sign is thrombocytopenia that does not resolve with transfusions (Cefalo et al., 2010). Other signs include coagulopathy, ascites, jaundice, pruritus, and encephalopathy. Diagnosis is made based on presenting signs, along with radiological imaging confirmation. Doppler ultrasound of the hepatic portal vein has been shown to determine severity of the disease (Cefalo et al., 2010). A liver biopsy is rarely used to confirm diagnosis due to the clotting abnormalities associated with SOS (Lassau et al., 2002).Medical management of SOS has evolved in recent years. In the past, supportive care and recombinant tissue plasminogen activator (rTPA) were used with good results, yet required close monitoring due to risk of bleeding. More recently, defibrotide has been shown to reverse SOS in patients who have received SCT, as well as those who have not received SCT, and the side effects from defibrotide have been minimal (Cecinati et al., 2009). Additional treatments include high doses of methylprednisolone, which have shown to be more effective when given early in the course of the disease (Meyers, 2013). For some patients with SOS who did not receive SCT, chemotherapy is held and, later, either discontinued or reintroduced at lower doses (Hooke et. al., 2011). Supportive care includes the use of diuretics for fluid retention, management of fluid balance with the consideration of fluid restrictions, and monitoring liver and kidney functions, pain medications, thrombolytics, and platelet transfusions (Cefalo et al., 2010; Hooke et al., 2011).21Prophylactic doses of defibrotide have shown to help prevent SOS with little to no side effects from the drug (Cefalo et al., 2010). Prophylactic ursodeoxycholic acid, ursodeoxycholic acid with vitamin E, and ursodeoxycholic acid with low molecular weight heparin have shown some effectiveness as well (Cefalo et al., 2010; Gocke, Kuskonmaz, Cetin, Uckan Cetinkaya, & Tuncer, 2013; Valteau-Couanet, 2014). Nonetheless, defibrotide appears to be the most effective prophylactic treatment (Capelli et al., 2009; Qureshi, Marshall, & Lancaster, 2008).Hooke et al. (2011) and Nixon (2014) identify several nursing interventions for the patient with SOS, including• identifying patients at risk• measuring weight and abdominal girth twice daily• pain management• close monitoring of intake and output• close monitoring of liver and kidney functions• monitoring for signs and symptoms of bleeding• monitoring platelet count and coagulation studies• administration of platelets as needed• skin care to manage pruritus• maintenance of IV access• fluid restriction• providing emotional support of patient and family.22

	Created by Claire Campbell almost 8 years ago

Paper taken from study material for APHON Biotherapy/Chemotherapy Review

Recent APHON articles on Typhlitis and SOS