July 2019 FAQs

Is there literature to support the combined use of lactulose and rifaximin for the treatment of acute overt hepatic encephalopathy?

Introduction

In 2015, cirrhosis or chronic liver disease (CLD) were cited as the 10^th leading cause of mortality among males in the United States; it has also been estimated that approximately 18% of patients with a new diagnosis of CLD have cirrhosis at the time of diagnosis.¹ Patients with cirrhosis present with many complications, including variceal bleeding, ascites, jaundice, bacterial infections, and hepatic encephalopathy, thus causing management and treatment to become quite complex. Among the many complications of cirrhosis, one of the most debilitating is hepatic encephalopathy (HE), which has been observed in 50 to 70% of patients with cirrhosis and is associated with an increase in hospitalizations and decreased quality of life.^1,2  In 2003, over 40,000 patients were hospitalized due to HE and the incidence of hospitalization is steadily increasing over the years.^1,3 Hepatic encephalopathy is a sign of worsening health among patients with advanced liver disease; in patients with cirrhosis and severe HE, it has been estimated that mortality rates are greater than 50% in the first year alone.⁴

Several proposed mechanisms have been shown to contribute to HE, but the most understood pathway is through accumulation of systemic ammonia, primarily from the gastrointestinal (GI) tract.^2,4 Ammonia is a common byproduct from protein degradation from the diet and from metabolic activities of bacteria in the colon. In healthy individuals, ammonia is metabolized via the urea cycle in the liver and then excreted through the kidneys. However, in patients with liver dysfunction, ammonia is unable to be metabolized by the damaged liver, thus it accumulates and is released into the systemic circulation. Eventually it will cross the blood-brain barrier and lead to brain edema and neurological deficits of varying grades. Pharmacologic treatment is given to patients with HE to reduce the amount of ammonia that is absorbed and improve mental status.

Guideline recommendations

The European Association for the Study of the Liver (EASL) and American Association for Study of Liver Diseases (AASLD) published clinical practice guidelines on HE in patients with CLD in 2014.⁵ The gold standard for classifying the severity of HE is by the West-Haven Criteria (WHC), which are further described in Table 1. Clinically significant presentations of HE are referred to as overt hepatic encephalopathy (OHE) and are seen with WHC ≥ grade 2, while less severe presentations are referred to as covert hepatic encephalopathy (CHE) and are seen with WHC < grade 2. Currently, routine treatment is only recommended for OHE (WHC ≥ grade 2).

Per the guidelines, lactulose is the agent of choice for initial treatment of OHE. Recommended alternative agents for treatment include oral branched-chain amino acids (BCAAs), intravenous L-ornithine L-aspartate (LOLA), neomycin, or metronidazole; BCAAs or LOLA may also be initiated as add-on agents when patients are not responsive to lactulose. The guidelines discuss use of rifaximin in the context of its Food and Drug Administration (FDA)-approved indication: for the prevention of recurrent episodes of HE (most often as add-on therapy to lactulose).

Table 1. West-Haven Criteria^3,5

Treatment of acute overt hepatic encephalopathy

The initial recommended treatment and current standard of care for OHE is lactulose.^6-8 However, rifaximin is an additional medication that is approved for the prophylaxis of HE (usually in combination with lactulose), and is also used off-label to treat OHE.⁷ Dosing and additional considerations for the use of lactulose and rifaximin to treat OHE are summarized in Table 2.

As mentioned previously, the largest source contributing to OHE is the accumulation of ammonia that is produced by colonic bacteria.^6-8 Lactulose, a non-absorbable disaccharide, is metabolized by bacteria in the colon to produce short chain fatty acids, such as lactic acid or acetic acid, which decrease the overall pH in the GI tract. The acidic environment in the colon causes conversion of free ammonia to ammonium ions, which are less likely to be absorbed systemically, and also attracts additional ammonia from the systemic circulation into the gut to be converted to ammonium.

Rifaximin is a non-absorbable antibiotic with broad spectrum of activity and low incidence of resistance.^7,8 While lactulose traps ammonia in the GI tract, rifaximin targets and reduces the gut microbes to reduce the source of ammonia directly. Outside of its approval for the treatment of irritable bowel syndrome-associated diarrhea or traveler’s diarrhea, rifaximin is currently only FDA-approved as a prophylactic agent to reduce recurrence of OHE in adult patients. However, literature has shown that rifaximin may also be effective when used to treat acute cases of OHE. In 2012, a meta-analysis investigated whether rifaximin was a viable option to treat HE as a monotherapy compared to conventional therapy (monotherapy with lactulose, lactitol, neomycin, or paromomycin), and concluded that rifaximin was at least as effective as the other therapies and had a better adverse effect profile.⁹

Table 2. Lactulose and rifaximin dosing and considerations in the treatment of acute hepatic encephalopathy^6-9

Based on the fact that lactulose and rifaximin have both shown efficacy versus placebo in the treatment of OHE, and that the agents have differing mechanisms of action in the reduction of systemic ammonia, there has been increasing interest as to whether their combined use might lead to even greater clinical benefits in the management of OHE. Therefore, the purpose of this FAQ is to review the available literature describing the combined use of lactulose and rifaximin for the treatment of acute OHE.

Literature review     

A review of the literature identified several randomized controlled trials (RCTs), as well as one meta-analysis that evaluated the safety and efficacy of combined use of lactulose plus rifaximin for the treatment of OHE. Individual RCTs will be summarized first, including 3 of 4 RCTs that were included in a recent meta-analysis (the fourth RCT is not available in English) as well as 1 additional RCT that was published after the meta-analysis. The meta-analysis, which included 4 RCTs and 6 observational studies, is also summarized below.

Randomized controlled trials

Four RCTs comparing a combination of lactulose plus rifaximin to monotherapy with lactulose alone for the treatment of OHE are summarized in Table 3 below.^10-13  In 2 of the studies, combination therapy was associated with an increase in the reversal of HE of approximately 30%; the authors concluded that combination therapy with lactulose and rifaximin is superior to monotherapy with lactulose alone.^12,13 However, the other 2 studies had conflicting results. One study found no difference between combination therapy and lactulose alone.¹⁰ The last study found that monotherapy with lactulose was associated with a greater reduction in WHC grade compared to combination therapy, but the significance of this difference was not statistically evaluated.¹¹

For secondary outcomes, 3 of the RCTs compared mortality rates between the treatment groups.^11-13 Two studies found that the combination of lactulose and rifaximin was associated with a reduction in mortality rates of approximately 20 to 25% compared to lactulose monotherapy.^12,13 One study found the exact opposite, and showed a 7% increase in mortality in the group treated with combination therapy, although the authors did not test for significance.¹¹ This study also compared the mean survival time between groups and showed no significant difference. The studies by Gill and Sharma also compared the length of stay in the hospital between treatment groups and showed a significant decrease in hospital stay of approximately 3 days with combination therapy compared to monotherapy.^12,13

The findings from these RCTs should be taken with caution, as all of the studies had relatively small sample sizes. In addition, the dosing of lactulose and rifaximin were variable among the studies, so it is unclear what the optimal dosing combination would be if these agents were used in combination in clinical practice to treat OHE. The study by Hasan et al also presented results that were inconsistent between the text and a results table that was provided within the article; therefore, it is unclear what the true values were for the results.¹¹

Table 3. Comparison of lactulose plus rifaximin versus lactulose alone for treatment of overt hepatic encephalopathy.^10-13

Meta-analysis

A recent meta-analysis performed by Wang and colleagues included a total of 10 studies (4 RCTs and 6 observational studies) in over 2,000 patients with HE that compared treatment with lactulose plus rifaximin to lactulose alone.¹⁴ The primary outcomes were clinical efficacy, which was defined as an improvement in neurological status or a significant decrease in WHC, and mortality rate. The meta-analysis for efficacy included 6 studies (4 RCTs and 2 observational studies) and showed that use of lactulose plus rifaximin significantly improved clinical efficacy compared to lactulose alone (risk difference [RD], 0.19; 95% confidence interval [CI] 0.09 to 0.29, p=0.0002). Seven studies (3 RCTs and 4 observational studies) were pooled to compare mortality; the results indicated a reduction in mortality with the combination of lactulose plus rifaximin compared to lactulose alone (RD, ‑0.11; 95% CI, ‑0.19 to -0.03, p=0.009). The authors evaluated the length of hospital stay as a secondary outcome (2 studies) and found a significant reduction in length of stay with lactulose plus rifaximin compared to lactulose alone (mean difference -2.89 days, 95% CI -3.52 to -2.25). The authors also pooled safety outcomes from 4 studies (1 RCT and 3 observational studies) by comparing adverse events and did not find a difference between treatment strategies (RD, -0.06, 95% CI -0.24 to 0.13, p=0.56).

Conclusion

Overall, the existing literature evaluating the safety and efficacy of the combined use of lactulose plus rifaximin contains conflicting results. Of the RCTs that are available, 2 have shown increased efficacy with combination therapy compared to lactulose monotherapy; however, 1 study showed no difference in efficacy with combination therapy, and another found that lactulose monotherapy was more effective. Trials that evaluated mortality and hospital length of stay as secondary outcomes generally showed a benefit with combination therapy, although 1 study showed a slight numerical increase in mortality rates with combination therapy. A single meta-analysis, which included 4 RCTs with small sample sizes and several observational studies, showed that combination therapy was associated with improved neurologic status, decreased hospital length of stay, decreased mortality, and a similar rate of adverse events compared to monotherapy. Based on the available literature it appears that there may be a potential benefit with the use of combination therapy with lactulose plus rifaximin to treat OHE; however, additional studies in larger patient populations will need to be performed to further elucidate where this treatment strategy might fit into the management of these patients.

References

1. Flamm S. Complications of cirrhosis in primary care: recognition and management of hepatic encephalopathy. Am J Med Sci. 2018;356(3):296-303.
2. Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol. 2015;13(12):2048-2061.
3. Elwir S, Rahimi R. Hepatic encephalopathy: an update on the pathophysiology and therapeutic options. J Clin Transl Hepatol. 2017;5(2):142-151.
4. Wijdicks EFM. Hepatic encephalopathy. N Engl J Med. 2016;375(17):1660-1670.
5. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. Hepatology. 2014;60(2):715-735.
6. Lactulose [package insert]. Philadelphia, PA: Lannett Company, Inc.; 2018.
7. Ferenci P. Hepatic encephalopathy in adults: treatment. UpToDate. Waltham, MA: UpToDate; 2019. https://www.uptodate.com/. Accessed June 18, 2019.
8. Micromedex Solutions [database online]. Greenwood Village, CO: Truven Health Analytics; 2019. https://www.micromedexsolutions.com/micromedex2/librarian/. Accessed June 18, 2019.
9. Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012;18(8):767-777.
10. Butt NI, Butt UI, Kakar, AATK, Malik T, Siddiqui AM. Is lactulose plus rifaximin better than lactulose alone in the management of hepatic encephalopathy? J Coll Physicians Surg Pak. 2018;28(2):115-117.
11. Hasan S, Datta S, Bhattacherjee S, Banik S, Saha S, Bandyopadhyay D. A randomized controlled trial comparing the efficacy of a combination of rifaximin and lactulose with lactulose alone in the treatment of overt hepatic encephalopathy. J Assoc Physicians India. 2018;66(1):32-36.
12. Gill ML, Niaz T, Aziz H, Khan S. P440 outcomes of rifaximin plus lactulose versus lactulose alone in treatment of overt hepatic encephalopathy. J Hepatol. 2014;60(1 Suppl):S215.
13. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458-1463.
14. Wang Z, Chu P, Wang W. Combination of rifaximin and lactulose improves clinical efficacy and mortality in patients with hepatic encephalopathy. Drug Des Devel Ther. 2018;13:1-11.

Prepared by:

Kevin Chau
PharmD Candidate, Class of 2021
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Jessica Zacher, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2019

The information presented is current as of June 02, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the evidence for rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis?

Non-steroidal anti-inflammatory drugs (NSAIDs), specifically rectal indomethacin and diclofenac, are recommended for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).^1,2 However, there is conflicting evidence regarding the benefits of prophylactic treatment based on the level of PEP risk.³ This review will address the value of universal prophylaxis with rectal indomethacin and potential alternatives for PEP prevention.

Background

Endoscopic retrograde cholangiopancreatography is a procedure used for the diagnosis and management of a wide variety of biliary disorders.⁴ The technique involves the insertion of a specialized upper endoscope into the duodenum to allow for instruments to be passed into the bile and pancreatic ducts. Since its introduction to practice, ERCP has evolved into a predominantly therapeutic tool due to the utilization of other less invasive diagnostic imaging modalities, such as magnetic resonance cholangiopancreatography and endoscopic ultrasound examination. However, several potentially serious adverse events are associated with the procedure, the most common being pancreatitis.³ Other complications include bleeding, infectious adverse events, cholangitis, cholecystitis, perforation, and cardiopulmonary adverse events.

The incidence of PEP was estimated at about 3.5% in a recent systematic review of twenty-one studies,⁵ but approximations range from 1.6% to 15.1% in trials.^6,7 While some controversy surrounds the definition of PEP, the majority of trials apply the consensus classification originally established by Cotton et al in 1991: (i) new or increased abdominal pain that is clinically consistent with acute pancreatitis; (ii) associated pancreatic enzyme elevation at least 3-fold the upper limit of normal 24 hours after the procedure; and (iii) resultant hospitalization or prolongation of existing hospitalization of at least 2 nights.⁸ While the pathogenesis of PEP is not fully understood, the most widely reported mechanism involves an initial pancreatic injury that leads to the premature activation of proteolytic enzymes, which subsequently initiates an inflammatory cascade resulting in local and systemic effects.³

Guideline recommendations

The American Society for Gastrointestinal Endoscopy published a guideline on the management of adverse events associated with ERCP in 2017.¹  For those undergoing ERCP, the authors recommend rectal NSAIDs for the prevention of PEP in high-risk patients without contraindications. They further suggest that it is reasonable to consider rectal indomethacin in average-risk patients. Additionally, pancreatic duct stenting is recommended to reduce the incidence and severity of PEP in high-risk patients. Similarly, the European Society of Gastrointestinal Endoscopy published an official statement addressing the prophylaxis of PEP in 2014.² The guideline recommends routine rectal diclofenac or indomethacin immediately before or after ERCP in all patients without contraindication. The placement of pancreatic duct stents is also endorsed in high-risk patients. Lastly, the American College of Gastroenterology also conditionally recommends the use of post-procedural rectal NSAIDs or pancreatic duct stents in high-risk patients.⁹

Literature review

Multiple recent meta-analyses have been published evaluating NSAIDs for the prevention of PEP (Table 1). The analyses vary in their inclusion criteria, but they all evaluate randomized controlled trials comparing one or more NSAID to a control. Overall, studies evaluating NSAIDs as a class have found them to be effective in reducing the incidence of PEP in the overall, high-risk, and average-risk populations.^10-17 The average absolute risk reduction with NSAID administration compared to placebo was approximately 5%, correlating to a number needed to treat of 20. Subgroup analyses identified that the rectal route and the use of indomethacin or diclofenac were the preferred route and agents. There were no analyses finding a significant difference between indomethacin and diclofenac, but the estimated pooled risk reduction generally showed that rectal diclofenac may be more effective than rectal indomethacin. Meta-analyses evaluating only rectal indomethacin found it to be effective in the overall pooled population,^18-21 but a statistically significant reduction in PEP risk in average risk patients was not seen in most analyses.^19-21 The analysis by He and colleagues was the exception and its analysis found that average risk patients also had their risk for PEP reduced.¹⁸ This meta-analysis included a large randomized controlled trial by Luo and colleagues, which was excluded from other analyses due to the study’s intention; it evaluated 2 strategies for indomethacin administration – universal pre-ERCP administration versus selective post-ERCP administration to high risk patients only.²²

The ability to prevent mild versus moderate-to-severe PEP was analyzed in several meta-analyses.^{10,14,15,18,21} Most did not find a difference in the ability of NSAIDs to prevent both mild and moderate-to-severe PEP,^14,15,18,21 but Serrano and colleagues found that the significant benefit of NSAIDs were only preserved with the prevention of mild pancreatitis, not moderate or severe.¹⁰ The preferred timing for administration was also analyzed in subgroup analyses in several reviews.^11-16,18,21 Most meta-analyses found that both pre- and post-ERCP administration was effective,^11-16,18 but Wan and colleagues only observed a significant benefit with indomethacin in pre-ERCP administration and not post-ERCP administration.²¹

Table 1. Meta-analyses evaluating NSAIDs for the prevention of PEP (published 2017 to 2019).

Controversy remains regarding the optimal patient population to target with rectal NSAIDs for the prevention of PEP. While several randomized controlled trials assessing the efficacy of rectal NSAIDs in unselected or average risk patients showed a reduction in the incidence of PEP in treated patients, others found no benefit in this population. To address these conflicting outcomes and the relatively small sample sizes of randomized controlled trials, several studies have evaluated approaches to implementing different protocols for rectal indomethacin or diclofenac administration in patients undergoing ERCP. Luo and colleagues randomized patients to either a universal strategy (all patients, regardless of risk) or a risk-stratified strategy (only high-risk patients) of indomethacin administration.²² This study found a significant reduction in the incidence of PEP with universal administration compared to targeted administration. Sheiybani et al also compared multiple strategies, including a universal versus a risk-stratified approach with diclofenac. In contrast, the authors found no difference in the rate of PEP with the universal and risk-stratified approaches. Additionally, there are several single-center evaluations comparing universal use with no NSAID prophylaxis with conflicting results. Institutions that had lower overall rates of PEP or higher rates of low-risk patients tended to find no benefit with universal rectal NSAID therapy,^23,24 while institutions with generally higher rates of PEP did find a significant benefit with universal prophylactic rectal NSAID use.^25-27

Table 2. Impact of indomethacin or diclofenac protocols on PEP incidence.^22-27

Indomethacin alternatives

The NSAIDs were commonly evaluated as a class in meta-analyses and subgroup analyses found that only rectal indomethacin and rectal diclofenac demonstrated consistent efficacy. Unfortunately, rectal diclofenac is not a commercially available product in the United States and compounding recipes were not identified in the literature. Other NSAIDs and routes evaluated for the prophylaxis of PEP, including intravenous ketoprofen, oral celecoxib, rectal naproxen, and intramuscular diclofenac, have not been successful in preventing PEP.^28-30 Intramuscular diclofenac has been evaluated in a couple studies with conflicting results, with one showing no benefit and the other demonstrating a benefit compared to no therapy.^31,32 Available options in the United States that have demonstrated success with reducing the risk of PEP include aggressive intravenous hydration with lactated Ringer’s and pancreatic stents. Aggressive intravenous hydration with lactated Ringer’s has been successful in reducing the rate of PEP in several randomized controlled trials compared to standard intravenous hydration; a meta-analysis of 7 trials calculated a odds ratio (OR) of 0.47 (95% confidence interval [CI], 0.30 to 0.72) in favor of aggressive hydration.³³ A common regimen for aggressive hydration is 3 mL/kg/h during ERCP and for 8 hours afterwards, combined with 20 mL/kg bolus after ERCP. Aggressive hydration with lactated Ringer’s solution has been compared to rectal indomethacin administration in one double-blind randomized controlled trial.³⁴ Hydration did outperform indomethacin (rate of PEP, 12.9% vs 25.8%). Unfortunately, this study used a 50 mg dose for indomethacin and the baseline rates of PEP (no therapy PEP rate was 32.3%) was much higher than what has been observed in the United States, so the external validity of these data are limited. Pancreatic stents have also been evaluated in several trials and a recent meta-analysis found that they are also successful in reducing the incidence of PEP compared to no therapy (OR, 0.28; 95% CI, 0.18 to 0.42).³⁵

Conclusion

The utility of universal rectal indomethacin for PEP is still unclear. Meta-analyses evaluating randomized controlled trials have generally found both rectal indomethacin and rectal diclofenac to significantly reduce the risk of PEP. Interestingly, observational data and studies evaluating different protocols for NSAID administration (universal use vs selective use vs no use) have not consistently found value in universal rectal indomethacin or diclofenac administration. Some of the discrepancy may be due to differences in the populations recruited into trials compared to general populations encountered in hospitals. The rates of PEP in clinical trials were generally much higher than those observed in cohort studies, suggesting that clinical trials were more likely to include higher risk patients. The most recent guideline addressing PEP recommends selective use of rectal indomethacin or diclofenac in high risk patients. While rectal indomethacin does have documented evidence to reduce the incidence of PEP, the relative value of the agent is likely dependent on an institution’s specific population and baseline rates of PEP. Potential alternatives that can be considered include aggressive intravenous hydration and placement of pancreatic stents, though the latter is only recommended for high-risk patients in the current guidelines.

References

1. Chandrasekhara V, Khashab MA, Muthusamy VR, et al. Adverse events associated with ERCP. Gastrointest Endosc. 2017;85(1):32-47.
2. Dumonceau JM, Andriulli A, Elmunzer BJ, et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – updated June 2014. Endoscopy. 2014;46(9):799-815.
3. Parekh PJ, Majithia R, Sikka SK, Baron TH. The “Scope” of post-ERCP pancreatitis. Mayo Clin Proc. 2017;92(3):434-448.
4. Krishnamoorthi R, Ross A. Endoscopic management of biliary disorders: diagnosis and therapy. Surg Clin North Am. 2019;99(2):369-386.
5. Andriulli A, Loperfido S, Napolitano G, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol. 2007;102(8):1781-1788.
6. Loperfido S, Angelini G, Benedetti G, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48(1):1-10.
7. Cheng CL, Sherman S, Watkins JL, et al. Risk factors for post-ERCP pancreatitis: a prospective multicenter study. Am J Gastroenterol. 2006;101(1):139-147.
8. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc. 1991;37(3):383-393.
9. Tenner S, Baillie J, DeWitt J, Vege SS. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108(9):1400-1415; 1416.
10. Serrano JPR, de Moura DTH, Bernardo WM, et al. Nonsteroidal anti-inflammatory drugs versus placebo for post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and meta-analysis. Endosc Int Open. 2019;7(4):e477-e486.
11. Liu L, Li C, Huang Y, Jin H. Nonsteroidal anti-inflammatory drugs for endoscopic retrograde cholangiopancreatography postoperative pancreatitis prevention: a systematic review and meta-analysis [published online ahead of print Sep 24, 2018]. J Gastrointest Surg. doi: 10.1007/s11605-018-3967-7.
12. Lyu Y, Cheng Y, Wang B, Xu Y, Du W. What is impact of nonsteroidal anti-inflammatory drugs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2018;18(1):106.
13. Yang C, Zhao Y, Li W, et al. Rectal nonsteroidal anti-inflammatory drugs administration is effective for the prevention of post-ERCP pancreatitis: An updated meta-analysis of randomized controlled trials. Pancreatology. 2017;17(5):681-688.
14. Yu LM, Zhao KJ, Lu B. Use of NSAIDs via the rectal route for the prevention of pancreatitis after ERCP in all-risk patients: an updated meta-analysis. Gastroenterol Res Pract. 2018;2018:1027530.
15. Hou YC, Hu Q, Huang J, Fang JY, Xiong H. Efficacy and safety of rectal nonsteroidal anti-inflammatory drugs for prophylaxis against post-ERCP pancreatitis: a systematic review and meta-analysis. Sci Rep. 2017;7:46650.
16. Patai A, Solymosi N, Mohacsi L, Patai AV. Indomethacin and diclofenac in the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis of prospective controlled trials. Gastrointest Endosc. 2017;85(6):1144-1156.
17. Shen C, Shi Y, Liang T, Su P. Rectal NSAIDs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in unselected patients: Systematic review and meta-analysis. Dig Endosc. 2017;29(3):281-290.
18. He X, Zheng W, Ding Y, Tang X, Si J, Sun LM. Rectal indomethacin is protective against pancreatitis after endoscopic retrograde cholangiopancreatography: systematic review and meta-analysis. Gastroenterol Res Pract. 2018;2018:9784841.
19. Feng Y, Navaneethan U, Zhu X, et al. Prophylactic rectal indomethacin may be ineffective for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis in general patients: A meta-analysis. Dig Endosc. 2017;29(3):272-280.
20. Inamdar S, Han D, Passi M, Sejpal DV, Trindade AJ. Rectal indomethacin is protective against post-ERCP pancreatitis in high-risk patients but not average-risk patients: a systematic review and meta-analysis. Gastrointest Endosc. 2017;85(1):67-75.
21. Wan J, Ren Y, Zhu Z, Xia L, Lu N. How to select patients and timing for rectal indomethacin to prevent post-ERCP pancreatitis: a systematic review and meta-analysis. BMC Gastroenterol. 2017;17(1):43.
22. Luo H, Zhao L, Leung J, et al. Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial. Lancet. 2016;387(10035):2293-2301.
23. Del Olmo Martinez L, Velayos Jimenez B, Almaraz Gomez A. Rectal diclofenac does not prevent post-ERCP pancreatitis in consecutive high-risk and low-risk patients. Rev Esp Enferm Dig. 2018;110(8):505-509.
24. Rainio M, Lindstrom O, Udd M, Louhimo J, Kylanpaa L. Diclofenac does not reduce the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis in low-risk units. J Gastrointest Surg. 2017;21(8):1270-1277.
25. Sheiybani G, Brydon P, Toolan M, Linehan J, Farrant M, Colleypriest B. Does rectal diclofenac reduce post-ERCP pancreatitis? A district general hospital experience. Frontline Gastroenterol. 2018;9(1):73-77.
26. Thiruvengadam NR, Forde KA, Ma GK, et al. Rectal indomethacin reduces pancreatitis in high- and low-risk patients undergoing endoscopic retrograde cholangiopancreatography. Gastroenterology. 2016;151(2):288-297.
27. Leerhoy B, Nordholm-Carstensen A, Novovic S, Hansen MB, Jorgensen LN. Diclofenac is associated with a reduced incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis: results from a Danish cohort study. Pancreas. 2014;43(8):1286-1290.
28. de Quadros Onofrio F, Lima JCP, Watte G, et al. Prophylaxis of pancreatitis with intravenous ketoprofen in a consecutive population of ERCP patients: a randomized double-blind placebo-controlled trial. Surg Endosc. 2017;31(5):2317-2324.
29. Kato K, Shiba M, Kakiya Y, et al. Celecoxib oral administration for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized prospective trial. Pancreas. 2017;46(7):880-886.
30. Mohammad Alizadeh AH, Abbasinazari M, Hatami B, et al. Comparison of rectal indomethacin, diclofenac, and naproxen for the prevention of post endoscopic retrograde cholangiopancreatography pancreatitis. Eur J Gastroenterol Hepatol. 2017;29(3):349-354.
31. Park SW, Chung MJ, Oh TG, et al. Intramuscular diclofenac for the prevention of post-ERCP pancreatitis: a randomized trial. Endoscopy. 2015;47(1):33-39.
32. Ucar R, Biyik M, Ucar E, et al. Rectal or intramuscular diclofenac reduces the incidence of pancreatitis afterendoscopic retrograde cholangiopancreatography. Turk J Med Sci. 2016;46(4):1059-1063.
33. Zhang ZF, Duan ZJ, Wang LX, Zhao G, Deng WG. Aggressive hydration with lactated ringer solution in prevention of postendoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. J Clin Gastroenterol. 2017;51(3):e17-e26.
34. Masjedizadeh A, Fathizadeh P, Aghamohamadi N. Comparative effectiveness of aggressive intravenous fluid resuscitation with lactated Ringer’s solution and rectal indomethacin therapy in the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: a double blind randomised controlled clinical trial. Prz Gastroenterol. 2017;12(4):271-276.
35. Vadala di Prampero SF, Faleschini G, Panic N, Bulajic M. Endoscopic and pharmacological treatment for prophylaxis against postendoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis and systematic review. Eur J Gastroenterol Hepatol. 2016;28(12):1415-1424.

Prepared by:

Samantha Spencer, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

Kelsey Bridgeman, PharmD
PharmD Graduate, Class of 2019
University of Illinois at Chicago College of Pharmacy

July 2019

The information presented is current as of May 28, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the optimal duration of antimicrobial surgical site infection prophylaxis in cardiac surgery? 

Introduction

The use of preoperative antibiotics to prevent surgical site infection (SSI) in cardiac surgery is well established and supported by multiple national and international groups.^1-4 Similar to other surgical specialties, prophylactic antibiotics for cardiac surgery should be started within 1 hour and ideally within 30 minutes of surgical incision; exceptions made for antibiotics with longer infusions times (vancomycin, fluoroquinolones, etc).^1,5 Redosing or prolonging SSI prophylaxis is generally not recommended unless the surgery exceeds the recommended redosing interval of the antimicrobial from the time of administration, or the patient experiences excessive bleeding or has factors that may decrease the half-life of prophylactic agents (burn patients, etc).^1,4 However, circumstances unique to cardiac surgery patients may increase their risk for an SSI during procedures.^1,4,6 Therefore, although controversial, some experts recommend extending the duration of  antimicrobial SSI prophylaxis into the postoperative period for cardiac surgery patients.^4,6

Infection risk in cardiac surgery

The incidence of SSIs following cardiac surgery is estimated to range from 1 to 8%.⁷ Many cardiac procedures utilize cardiopulmonary bypass, which not only intrinsically increases the risk for SSI, but may also alter the pharmacokinetics of medications administered during this time.^1,8 Dosing of antimicrobials during cardiopulmonary bypass is not well established and often based on small studies and anecdotal data; therefore, the duration of antimicrobial coverage achieved from the preoperative and intraoperative doses is not well defined.¹ Bleeding and blood transfusion, advanced age, smoking history, and presence of obstructive lung disease, diabetes, or obesity also put cardiac surgery patients at an increased risk for SSIs, secondary to decreased collagen synthesis, vasoconstriction, and/or increased immunosuppression.^7-10 Furthermore, cardiac surgeries may utilize invasive devices that stay in place after surgery and patients are also likely to have a prolonged duration of intubation.^1,9 Both of these factors increase the risk for postoperative infections in general, although the impact on the development of an SSI specifically is unclear.^8,9

Standards of care

Current recommendations for the duration of SSI prophylaxis for cardiac procedures are based on a joint guideline from the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA), which was last updated in 2013.¹ This publication references several studies supporting prophylaxis durations ranging from a single dose preoperatively, up to 24 hours postoperatively; authors also acknowledge that durations up to 48 hours have been used anecdotally for cardiothoracic procedures. Based on expert consensus, this guideline recommends SSI prophylaxis for the duration of the cardiac procedure and for no longer than 24 hours after the procedure.

In 2017, two additional SSI prophylaxis guidelines were published jointly by the American College of Surgeons (ACS) and SIS, as well as by the Centers for Disease Control and Prevention (CDC).^2,3 Unfortunately, neither of these publications provide further guidance on the duration of antimicrobial prophylaxis for cardiac procedures, and the ACS/SIS guideline notes that the optimal duration of antibiotic prophylaxis for this population remains unknown. The remainder of this review will focus on newer data comparing various durations of antimicrobial SSI prophylaxis after cardiac surgery. Of note, data for SSI prophylaxis in cardiac device insertion procedures (pacemaker placement, etc) is outside of the scope of this review; the use of a single pre-surgical dose is well established for these procedures.¹

Newer data

A 2014 prospective, multicenter, cohort study sought to examine the impact of various modifiable perioperative practices, including duration of SSI prophylaxis, on postoperative infections and mortality among 5,158 patients undergoing cardiac surgery.¹⁰ The majority of patients in the study were males in their 60s undergoing elective procedures (~74%); isolated coronary artery bypass graft (CABG) and isolated valve repair were the most common types of procedures (~33 and 36%, respectively). The mean operating time was 252 minutes (range 198 to 312) across groups. Of the 237 patients who developed a postoperative infection, SSI of the chest or groin was rare, occurring in only 26 and 10 patients, respectively. Of the patients who developed any major infection (pneumonia, etc), a prolonged duration of SSI prophylaxis for more than 48 hours after surgery significantly increased the risk for infection by almost 6-fold when compared to durations of prophylaxis lasting 24 to 48 hours (hazard ratio [HR], 5.90; 95% confidence interval [CI], 4.25 to 8.19); there was no difference in the risk for infection in patients administered 0 to 24 hours versus 24 to 48 hours of antibiotics (HR, 1.14; 95% CI, 0.83 to 1.55). Authors of this study did not stratify results for the patients who developed an SSI specifically.

In contrast, a 2015 retrospective observational study by Hamouda et al evaluated the impact of 32- versus 56-hour perioperative antibiotic regimens specifically on the incidence of various SSIs; a total of 1096 cardiac surgery patients were included in the analysis.¹¹ Similar to the study by Gelijns et al, the majority of patients in this study were males in their 60s undergoing elective procedures (~68%); isolated CABG was the most common type of procedure (~89%). The mean operating time was 218 ± 55 minutes across groups. Results demonstrate that the incidence of the primary outcomes, including deep sternal wound infection (DSWI), superficial sternal wound infection (SSWI) and vein harvesting site infection (VHSI), was low across both 32- and 56-hour prophylaxis groups (1.8 vs 1.4%, 2.7 vs 1.7%, and 0.9 vs 0.3%, respectively); all p-values for the difference between 32- and 56-hour groups were not statistically significant. There were also no statistically significant differences between groups across secondary endpoints, including respiratory tract infection, urinary tract infection, and all-cause mortality. The incidence of infection-related mortality after 30 days was 1.2 versus 0.7% in the 32- and 56-hour prophylaxis groups, respectively. Among patients with an increased risk for nosocomial infection (age >80 years, longer operating times, etc), neither regimen proved to be superior.

Lastly, a large meta-analysis by Lador et al, where 23 of the 59 included trials compared short and long durations of antimicrobial SSI prophylaxis, was published in 2012 but was not available at the time of development of the 2013 ASHP guidelines.¹² This analysis included studies of patients undergoing CABG, valve repair, aortic or other cardiac surgery, and excluded trials of heart transplant patients or those where >10% of the surgical population was non-cardiac; antimicrobial regimens varied across studies. The short-duration arm included both studies of postoperative prophylaxis regimens lasting ≤24 and >24 hours (the average duration was 48 hours [range 30 to 60]), while the long-duration arm included prophylaxis that was more than 24 hours longer than the short-duration arm (average not provided by authors). When considering DSWI (the primary outcome), a shorter duration of prophylaxis, specifically prophylaxis lasting ≤24 hours after surgery, increased the risk of this outcome (relative risk [RR], 1.83; 95% CI, 1.25 to 2.66) compared to the longer durations (ie, the long-duration arm). Interestingly, as long as the shorter prophylaxis provided ≥24 h postoperative coverage, there were no significant differences between short vs long duration of prophylaxis (RR, 0.77; 95% CI, 0.39 to 1.50). Duration of prophylaxis ≤24 hours postoperatively also increased the risk of the following outcomes: any sternal wound infection (RR, 1.40; 95% CI 1.15 to 1.71), gram-positive SSI (RR, 1.41; 95% CI, 1.08 to 1.84), surgical intervention for SSI (RR, 1.55; 95% CI, 1.08 to 2.20), and endocarditis (RR, 4.42; 95% CI, 1.26 to 15.49). There was no difference in any of the aforementioned outcomes when comparing postoperative prophylaxis regimens lasting >48 hours, therefore, authors conclude that continuation of prophylaxis up to 48 hours postoperatively may be beneficial. The results of this meta-analysis corroborate with an earlier analysis by Mertz et al, which included 7893 patients across 12 studies undergoing open heart surgery.^12,13 The analysis by Mertz et al, which is referenced by the 2013 ASHP guidelines, compared the risk of sternal SSIs with antibiotic prophylaxis lasting <24 hours and ≥24 hours.^1,13  While authors identified a 38% reduced risk of sternal SSI in patients with prophylaxis durations ≥24 hours, the lack of standardized practices across studies was of concern.¹³

Discussion

Patients undergoing cardiac surgery may face unique circumstances that increase their risk for SSI relative to other surgical populations.^8,11 However, the risks of prolonged SSI prophylaxis are significant and include the development of drug-resistant bacteria, Clostridium difficile infection (CDI), and other adverse events.^10,11

Since the development of the 2013 ASHP guideline for SSI prophylaxis, 2 observational trials and 1 meta-analysis have examined the optimal duration of postsurgical SSI prophylaxis in cardiac surgery patients.^10-12 Unfortunately, this newer data does not allow for more firm conclusions on the optimal duration of postoperative antimicrobial prophylaxis in this setting. The observational studies by Gelijns et al and Hamouda et al both suggest that extended prophylaxis does not yield any benefits. Gelijns et al, while providing additional data in support of discontinuing SSI prophylaxis ≤48 hours postoperatively, did not power their study to find a difference in prophylaxis durations lasting <24 versus 24 to 48 hours after surgery. This study also failed to stratify the results based on the type of infection, the most common of which were pneumonia (~52%) and bloodstream infection (~24%). Likewise, Hamouda et al failed to disclose the exact duration of postoperative antibiotics, therefore, it is unclear how many hours of antibiotics were given pre- versus post-operatively within the 32- and 56-hour studied timeframes; this study also lacked power to find a difference between these timeframes. To the contrary, a large 2012 meta-analysis by Lador et al demonstrates an increased risk of SSI and endocarditis with shorter durations of prophylaxis (ie, those lasting <24 hours). However, the heterogeneity of included studies, including surgical techniques, selected antimicrobials, resistance patterns, and overall postoperative management of patients, prevents the ability to draw firm conclusions on efficacy and safety to extended SSI prophylaxis. Similar inconsistencies also prevented authors of the 2013 ASHP guideline from drawing more definitive conclusions regarding the duration of postoperative SSI prophylaxis based on the results of a similar meta-analysis by Mertz et al. A pending study in this arena hopes to provide another piece of evidence to this ongoing debate.¹⁴

Conclusion and recommendation

More research is needed to determine the optimal duration of antimicrobial SSI prophylaxis after cardiac surgery for preventing not only SSIs but also other common postsurgical infections like pneumonia and CDI. In this population, available guidelines and newer evidence do not support continuing SSI prophylaxis beyond 48 hours postoperatively; however, it remains unclear exactly how long prophylaxis should continue. Therefore, the decision to continue antibiotic prophylaxis after the end of surgery and up to 48 hours postoperatively needs to be carefully weighed against potential risks, including the development of drug-related adverse events, drug resistance, and CDI, as well as the financial burden to the institution and patient.

Reference:

1. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health-Syst Pharm. 2013; 70(3):195-283.
2. Ban KA, Minei JP, Laronga C, et al. American College of Surgeons and Surgical Infection Society: Surgical site infection guidelines, 2016 update. J Am Coll Surg. 2017;224(1):59-74.
3. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection. JAMA Surg. 2017;152(8):784-791.
4. World Health Organization (WHO). Global guidelines for the prevention of surgical site infection. WHO website. https://www.who.int/gpsc/ssi-prevention-guidelines/en/. Updated November 2016. Accessed June 12, 2019.
5. Anderson DJ, Podgorny K, Berrios-Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(Suppl. 2):S66-88.
6. Anderson ND. Antibiotic prophylaxis in cardiac surgery: If some is good, how come more is not better? J Thorac Cardiovasc Surg.2016;151(2):598-599.
7. Bustamante-Munguira J, Herrera-Gómez F, Ruiz-Álvarez M, Figuerola-Tejerina A, Hernández-Aceituno A. A new surgical site infection risk score: Infection Risk Index in Cardiac Surgery. J Clin Med. 2019;8(4):480.
8. Musallam E. The predictors of surgical site infection post cardiac surgery: a systematic review. J Vasc Nurs. 2014;32(3):105-118.
9. Wendler O, Baghai M, Infections post-cardiac surgery. J Am Coll Cardiol. 2014;64(4):382-384.
10. Gelijns AC, Moskowitz AJ, Acker MA, et al. Management practices and major infections after cardiac surgery. J Am Coll Cardiol. 2014; 64(4):372.
11. Hamouda K, Oezkur M, Sinha B, et al. Different duration strategies of perioperative antibiotic prophylaxis in adult patients undergoing cardiac surgery: an observational study. J Cardiothorac Surg. 2015;10(25).
12. Lador A, Nasir H, Mansur N, et al. Antibiotic prophylaxis in cardiac surgery: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67:541–550.
13. Mertz D, Johnstone J, Loeb M. Does duration of perioperative antibiotic prophylaxis matter in cardiac surgery? A systemic review and meta-analysis. Ann Surg. 2011;254:48–54.
14. Van Oostveen RB, Romero-Palacios A, Whitlock R, et al. Prevention of infections in cardiac surgery study (PICS): study protocol for a pragmatic cluster-randomized factorial crossover pilot trial. Trials. 2018;19(1):688.

Prepared by:

Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2019

The information presented is current as of June 14, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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