Background

Hematopoietic stem cell transplantation (HSCT) is a widely used therapy to treat a range of malignant and nonmalignant hematological diseases.1 Hepatic veno-occlusive disease (VOD), also called hepatic sinusoidal obstruction syndrome, is an early complication of HSCT that is associated with significant morbidity and mortality.2 Incidence has been reported in up to 60% of HSCT recipients, ranging from mild to severe.3 In severe cases, mortality exceeds 80% despite treatment.1

Veno-occlusive disease is believed to be caused by injury to the hepatic venous endothelium during HSCT conditioning,2 leading to sinusoidal obstruction.1 Diagnosis is based on a combination of the following signs and symptoms: (1) jaundice or elevated serum bilirubin levels, (2) hepatomegaly with right upper quadrant abdominal pain, and (3) ascites with or without unexplained weight gain.1 Risk factors for VOD include preexisting liver disease (elevated liver enzymes pre-HSCT) and the conditioning regimen (higher risk with busulphan and/or cyclophosphamide and high dose radiation).2 As many of the risk factors are not modifiable and VOD is difficult to treat, prevention of this complication is a high priority.1 No universal guidelines or recommendations exist regarding prophylactic therapy.1

The physical administration of medications during HSCT, including VOD prophylaxis, and the close clinical contact at the bedside means nurses play a vital role in the prevention, assessment, and monitoring of VOD.4 An understanding of the relevant literature is needed for nurses to provide care that is evidence based.

Objectives

A Cochrane review was performed to determine the effects of several different prophylactic treatments on the incidence of VOD, mortality, overall survival, quality of life, and the safety of these treatments in HSCT recipients.1

Interventions of Interest

Medications that have been used (alone or in combination) for prophylaxis of VOD in HSCT recipients include (1) heparin, (2) low-molecular-weight heparin, (3) danaparoid, (4) ursodeoxycholic acid, (5) prostaglandin E1, (6) glutamine, and (7) defibrotide.1 Prophylactic therapy is generally administered from the commencement of conditioning or infusion of stem cells, until neutrophil engraftment or 3 to 4 weeks after HSCT (most common time for VOD to develop).1 Some centers provide prophylaxis to all people undergoing HSCT, whereas others do so only for people deemed to be at high risk.1

Methods

A comprehensive search of the literature was conducted across the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. The conference abstracts for 3 international hematology-oncology societies were searched, as well as 2 trial registries. Citation searching, reference checking, and contact with study authors were also used to identify further studies. Only randomized controlled trials were included in the review, comparing one medication with another or with placebo. Studies including people of all ages undergoing HSCT for any condition were reviewed. Primary outcomes of interest were incidence of VOD and overall survival.1

Results

In total, 14 randomized controlled trials were included in the review. Four of these were studies comparing ursodeoxycholic acid (with or without additional treatment) against placebo or the same additional treatment or no treatment (total 612 participants). Results demonstrated that ursodeoxycholic acid may be useful in reducing the incidence of hepatic VOD (risk ratio, 0.60; 95% confidence interval [CI], 0.40-0.88; number needed to treat for an additional beneficial outcome, 15; 95% CI, 7-50). This was deemed low-quality evidence. However, there was no significant difference in overall survival (hazard ratio, 0.83; 95% CI, 0.59-1.18). This was also deemed low-quality evidence. In addition, there was no evidence of a difference between the treatment and control groups' incidence of hepatic VOD or survival in the studies investigating heparin, low-molecular-weight heparin, danaparoid, prostaglandin E1, glutamine, and defibrotide. The evidence quality for all outcomes was deemed low to very low owing to a high risk of bias in study methods, inconsistent results across studies, and ambiguity of results.1

Conclusions

The findings of this review indicate that there is low-quality or very-low-quality evidence that demonstrates that ursodeoxycholic acid reduces the incidence of hepatic VOD, mortality, and overall mortality caused by VOD in HSCT recipients. The use of heparin, low-molecular-weight heparin, danaparoid, prostaglandin E1, glutamine, and defibrotide is not supported by the literature. Further high-quality research is necessary to determine the best possible treatment for this serious complication.1

Implications for Practice

Although the evidence is limited and of low quality, it does indicate that there are benefits associated with administration of ursodeoxycholic acid in reducing the incidence of VOD and overall mortality in HSCT recipients. As prevention is preferable to treatment, it is recommended ursodeoxycholic acid should be given to HSCT recipients, especially those who are deemed to be "high risk" for developing VOD. Nurses can assist HSCT recipients to continue taking this oral medication (capsule or suspension) throughout the transplant trajectory, which is often complicated by painful mucositis.5 Despite the use of ursodeoxycholic acid as a prophylaxis, the evidence demonstrates that VOD remains a troubling complication of HSCT. To assist in preventing VOD, nurses can help to minimize the HSCT recipient's exposure to hepatotoxic agents. Nurses must also be vigilant for signs and symptoms of VOD, such as sudden weight gain, fluid retention, abdominal distention and pain, jaundice, and elevated bilirubin, to facilitate timely treatment.5

Full Cochrane Review

Cheuk DKL, Chiang AKS, Ha SY, Chan GCF. Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2015;Issue 5:CD009311. doi:10.1002/14651858.CD009311.pub.2

Available at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009311.pub2/abstract

Elise Button, RN, MAdPrac (Hons), BN, GCertPC, PhD(c)

Cochrane Nursing Care Field (CNCF)

Adelaide, South Australia, and

School of Nursing

Queensland University of Technology

Brisbane Cancer Care Services

Royal Brisbane Women's Hospital

Queensland, Australia

References