Abstract
Objective: We evaluated the effect of ketorolac on reducing the severity of acute pancreatitis.
Design and Setting: Randomized clinical trial performed in a University hospital.
Participants: There were 56 adult patients, with predicted severe acute pancreatitis, randomly divided into two groups.
Methods: The patients in the study group received intravenous ketorolac, 10 mg, three times daily from the time of enrollment for a maximum of 5 days, as needed, along with standard medical treatment. Primary outcome measure was the change in the serum level of high sensitive C-reactive protein (hs-CRP). Patients were also followed up in terms of hospitalization duration, need for intensive care unit (ICU), organ failure development, persistent organ failure, pancreatic necrosis, nutritional assessment, and mortality. The study continued to gather clinical follow-up information up to 4 months.
Results: Serum level of hs-CRP was significantly lower in the ketorolac group compared with the control group on days 3, 4, and 5. There were no significant differences in organ failure, pseudocyst formation, acute necrotic collection, mortality, and ICU transfer between groups. Days of hospitalization were significantly lower in the study group. The feeding start time was significantly shorter in the study group with no need for tube feeding in the ketorolac group. Frequency of NPO (not per oral) was significantly lower in the ketorolac group.
Conclusion: The use of ketorolac may improve feeding outcomes and shorten length of hospitalization in predicted severe acute pancreatitis.
Incidence of acute pancreatitis, an inflammatory condition of the pancreas, ranges from 4.9 to 35 per 100,000 population annually, and approximately 15% to 25% of all patients with acute pancreatitis develop severe acute pancreatitis.1,2 A damaged pancreas releases cytokines and activated pancreatic enzymes into the circulation, which could damage the pancreas and also develop systemic inflammatory response syndrome (SIRS) in the patient.3 A compensated anti-inflammatory response syndrome balances the SIRS, resulting in recovery. An imbalance between inflammatory and anti-inflammatory responses leads to severe organ failure.3 Research has further shown the early inhibition of proinflammatory cytokine activity with the administration of interleukin 10 (IL-10), an anti-inflammatory cytokine able to reduce the severity of experimental pancreatitis in animals4 and prevent the development of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in humans.5 With antipyretic, analgesic, and anti-inflammatory properties, ketorolac inhibits cyclooxygenase-1 and 2 enzymes, reducing the formation of prostaglandin precursors. Inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels are among other mechanisms proposed for ketorolac that contribute to anti-inflammatory effects.6 The extent of inflammation correlates with the severity of pancreatitis;3 therefore, it seems the early reduction of inflammation with ketorolac administration can decrease the development of organ failure and the outcomes of morbidity in acute pancreatitis. Additionally, delayed feeding caused by pain in acute pancreatitis and unused gastrointestinal tract, disrupts the tight junction of enterocytes and further increases inflammation and the risk of organ failure in patients.7 In the present research, it was hypothesized the administration of ketorolac could reduce the inflammation of pancreatitis and organ failure, shorten the duration of hospitalization, control pain and food intolerance, promote earlier feeding, and reduce the hospitalization time. A randomized, controlled clinical trial was established to determine these effects in patients with predicted severe acute pancreatitis.
Methods
We recruited 56 adult patients with predicted severe acute pancreatitis from a university hospital between September 2016 and February 2019. Prior to enrollment in the study, written informed consent was obtained from the participants. The study was approved by the Ilam University of Medical Sciences Ethics Committee, and it was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study adheres to Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Exclusion criteria were recurrent pancreatitis, chronic pancreatitis, heart disease, history of coronary artery bypass graft, hypertension, hemorrhagic diathesis, incomplete hemostasis, high risk of bleeding, hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAID), concurrent use of aspirin, other NSAIDs or pentoxifylline, active or history of peptic ulcer disease, recent or history of gastrointestinal bleeding or perforation, inflammatory bowel disease, asthma, pregnancy and lactating women, advanced renal disease, elevated/rising creatinine, and severe hepatic impairment or active hepatic disease.
Guidelines from the American College of Gastroenterology8 and International Association of Pancreatology/American Pancreatic Association9 recommend the following predictors for prognostication and prediction of the severity of acute pancreatitis: (1) age >55 years, (2) obesity (body mass index >30 kg/m2), (3) altered mental status, (4) comorbid disease, (5), SIRS (presence of >2 of the following criteria: pulse >90 beats/min, respirations >20/min or PaCO2 <32 mm Hg, temperature >38°C or <36°C, white blood cell count >12,000 or <4,000 cells/mm3 or >10 percent immature neutrophils), (6) hematocrit (HCT) >44 percent, (7) rising HCT, (8) elevated blood urea nitrogen (BUN), (9) rising BUN and (10) radiologic findings of pleural effusions or pulmonary infiltrates or multiple or extensive extra pancreatic collections. In our study, the patients were selected based on the presence of more than three scores of BISAP scoring system or HCT >44% or BUN >22.
The patients were randomly divided into two groups, and randomization was performed according to a computergenerated random number table. A physician who was not a member of the research team was unblinded to the treatment assignment; meanwhile, the patients, investigators, and all clinical personnel remained blinded to the randomization. The study group received 10 mg intravenous injection of ketorolac three times a day up to 5 days, as needed. In the control group, meperidine was administered for pain control. Management of pancreatitis for all patients not per oral (NPO) condition and adequate intravenous fluids of lactated ringers solution or normal saline initially bolused at 20 mL/kg; this was followed by 3 mL/kg per hour to maintain urine output >0.5 mL/kg per hour. The volume status was monitored by HCT, BUN, and urine output. Other supportive therapies for organ failure were performed as indicated. No antibiotics were used.
Upon admission, high sensitive C-reactive protein (hs-CRP) was measured, and standard laboratory tests were conducted. Measurement of hs-CRP was repeated daily up to day 5 of hospitalization.
Following the completion of fluid volume resuscitation (within 24–48 hours of admission), feeding was started for each patient. In patients who could tolerate oral feeding, standard polymeric formula was initiated at a trophic rate. According to the standards of hospital, in subjects intolerant of oral feeding within 4 days, nasogastric tube was inserted and tube feeding with standard polymeric formula was commenced. Enteral feeding was performed eight times a day through intermittent technique. The volume of administration (starting from 50 milliliter) was specified based on the calorie needs and tolerance of patients. Calorie needs were measured and calorie intake was recorded daily for each individual during the study period.
Local complication was defined as pancreas liquefaction or necrosis and pseudocyst formation. Pancreatic pseudocyst is an encapsulated, mature fluid collection occurring outside the pancreas with a well-defined wall with minimal or no necrosis. Acute pancreatic necrosis is an acute necrotic collection containing a variable amount of fluid and necrosisyet lacking a definable wall. No intervention was performed for local complications. Radiologic assessment was carried out on day 5 with pancreatic protocol CT scanning in patients who were not adequately responsive to treatment. In all patients, ultrasound for pseudocyst detection was performed two months later.
Primary outcome measure was the change in the serum level of hs-CRP. Patients were also followed up in terms of hospitalization duration, need for ICU care, development of organ failure, persistent organ failure, pancreatic necrosis, and mortality. Organ failure was defined by shock (systolic blood pressure <90 mmHg), pulmonary insufficiency (PaO2/FiO2 ≤300), or renal failure (serum creatinine ≥1.9 mg/dL).
Nutritional assessments were time of beginning and tolerance to nutrition, daily nutritional administration, and the frequency that subjects were made NPO (not per oral) because of pain, nausea, or vomiting after refeeding. The study continued to gather clinical follow-up information up to four months.
Statistical Analysis
We did not find a study with similar objectives for calculating the sample size. We conducted a small pilot study with 10 patients in each group to get the required estimates and perform a proper sample size calculation. We found that on day 3, serum hs-CRP level was 24 mg/L lower in the ketorolac group in comparison with controls. Thus, the minimum sample size estimation for each group was 28 at a power (1-β) of 80% and α = 0.05 for a two-arm parallel study.
Data were analyzed using SPSS software V.21. Characteristics of the patients were expressed in frequencies and percentages for categorical variables. The quantitative variables with normal distribution were summarized as mean and standard deviation. Non-normal quantitative variables were presented by median and their first and third quartiles. The data were analyzed according to the intention to treat analysis principle.
Differences between variables were evaluated using t-test, Mann-Whitney U-test, and the Chi-square or Fisher Exact test. Analysis of covariance (ANCOVA) was employed to detect the exact effect of ketorolac on the serum level of hs-CRP and the duration of hospitalization. In that analysis, adjustments were made based on the covariates including BMI and acute physiologic assessment and chronic health evaluation (APACHE) II score. The Log rank test was applied for mortality. A two-sided P value of less than 0.05 was considered as significant.
Results
There were 74 patients who met all the inclusion criteria and were eligible for consent; 18 refused to participate, and 56 patients consented to participation, completed the study, and were randomly divided into two groups of ketorolac and control. Disposition of patients throughout the study is shown in Figure 1. We included 24 men and 32 women with a mean age of 47.9 ± 11.5 (range 26-51). The most frequent cause of severe acute pancreatitis was biliary stones in both groups; on admission, the cases and controls were also similar with regards to age, sex, BMI, APACHE, SIRS score, and pancreatic necrosis or organ failure. The basal characteristics of the patients are presented in Table 1.
CONSORT Flow Diagram
Basal characteristics of patients
Inflammatory Outcomes
Table 2 depicts the changes in serum hs-CRP level during the study period. Basal hs-CRP level was similar in both groups. There was an insignificant increase in the serum hs-CRP level of the control group on day 2, after which time, it had a decreasing slope. In the ketorolac group, serum hs-CRP level had a decreasing trend from day 1 to day 5.
Inflammatory outcomes of the ketorolac and control groups
Serum hs-CRP was reduced to 24% of enrollment levels on day 3, 38% on day 4, and 66% on day 5 in the ketorolac group, which is a significant decrease as analyzed by paired t-test (P <0.001 in all). This reduction was 4% (P=0.3), 8% (P=0.09), and 30% (P<0.001) on days 3, 4 and 5, respectively in the controls.
There was a significant difference between ketorolac and the controls in terms of the reduction in the serum hs-CRP levels on days 3, 4, and 5. To control the covariates, APACHE score and BMI were entered in the ANCOVA model, but no difference was detected (P<0.001 in all). The partial Eta Squared values were 0.21, 0.38, and 0.68 on days 3, 4, and 5, respectively. In other words, the effect of ketorolac on reducing the serum level of hs-CRP increased with time.
Feeding Outcomes
Table 4 shows the nutritional outcomes. In both oral and tube feeding, the formula was polymeric standard (15% protein) starting with trophic feeding. The time interval to start feeding was significantly shorter in the ketorolac group compared to the control group. On the third day of admission, 11 (40%) of the patients in the ketorolac group and 3 (11%) patients in the control group tolerated oral feeding. On day 4, oral feeding was initiated for another 11 (40%) patients in the ketorolac group and 11 (39%) patients in the control group. On day 5, all 28 patients in the ketorolac group underwent oral feeding. On day 5, oral feeding was commenced for another 8 (29%) patients, and tube feeding was started for the remaining 6 (21%) patients in the control group.
Clinical outcomes of the ketorolac and control groups
Nutritional outcomes of ketorolac and control groups
The ability to deliver nutrition was higher in the ketorolac group, and it reached the targeted energy intake significantly sooner. Intolerance to diet (abdominal pain, nausea, and vomiting after re-feeding), which leads to feeding stoppage, was significantly lower in the ketorolac group.
Clinical Outcomes
There were no significant differences in any clinical outcomes except for length of hospitalization. In the ketorolac group, persistence and new-onset organ failure was lower compared to the control group but it was not statistically significant. There was one case of pulmonary failure in the ketorolac group and two cases of renal failure and three cases of pulmonary failure in the control group. All organ failures occurred as early complication (in the first 2 weeks). Acute necrotic collection was detected in one control patient during hospitalization. Hospitalization time was significantly higher in the control group, and no difference was seen using ANCOVA model with controlled covariates, APACHE score, and BMI (P<0.001). Following discharge, one patient in the ketorolac group and three patients in the control group returned to the hospital due to pseudocyst formation.
There was no in hospital mortality in either groups. Following discharge, 4-month mortality was observed in three patients of the control group. Based on the Log rank test, survival within 4 months was marginally lower in the control group compared with the ketorolac, a difference which was not statistically significant (P=0.076). Ketorolac was not accompanied by any side effects in the patients.
Discussion
In this study, the effectiveness of ketorolac was evaluated in predicted severe acute pancreatitis. In patients receiving ketorolac, serum hs-CRP level was reduced faster, and they were discharged sooner. Additionally, in the ketorolac group, a significantly better food tolerance was observed, feeding was initiated earlier than the controls, and there was no need for tube feeding. There was no difference in organ failure or mortality.
In acute pancreatitis, the extent of inflammation correlates with the severity of pancreatitis and the goal of management is to reduce the inflammation. In the pathogenesis of acute pancreatitis, chemo-attraction of leukocytes occurs; furthermore, pro-inflammatory cytokines (tumor necrosis factor, interleukins 1, 6, and 8), arachidonic acid metabolites (prostaglandins, platelet-activating factor, and leukotrienes), proteolytic and lipolytic enzymes, and reactive oxygen metabolites are released by activated granulocytes/macrophages. These factors induce pancreatic damage.10
In the liver, CRP rises steadily in relation to the severity of pancreatitis and in response to interleukin-1 and interleukin-6. C-reactive protein, a sensitive and nonspecific marker of inflammation, can predict complication and prognosis in acute pancreatitis. As a potent NSAID, ketorolac inhibits cyclooxygenase-1 and 2 enzymes, preventing the production of prostaglandin precursors with analgesic and anti-inflammatory properties.
In a double-blinded randomized control trial, Vege, et al11 found the use of pentoxifillyne, an inhibitor of tumor necrosis factor in patients with predicted severe acute pancreatitis, was associated with fewer ICU admissions and lower hospitalization time. In their study, serum TNF-α, CRP, interleukin-1, and interleukin-6 levels decreased more in pentoxifillyne group. The reduction, however, was not statistically significant, which may be due to the small sample size (14 in each group).
Some studies have evaluated the preventive effects of rectal indomethacin or diclofenac in post-ERCP pancreatitis, with a meta-analysis confirming their protective effect.12 Another meta-analysis showed that rectal indomethacin administration prior to ERCP was effective in the prevention of post-ERCP pancreatitis in high-risk patients.13 Phospholipase A2 activity was inhibited by rectal NSAIDs in acute pancreatitis, possibly regulating proinflammatory mediators.
Conversely, early feeding had an impact on attenuating the inflammatory response by itself.14 The old approach of putting the pancreas at rest in acute pancreatitis and feeding the patient with parenteral nutrition has been changed. In fact, the results of a meta-analysis showed that in severe acute pancreatitis, the use of gastrointestinal tract for feeding reduced mortality, infectious complications, organ failure, and surgical intervention rate in comparison to parenteral nutrition.15,16 The American Society of Enteral and Parenteral Nutrition suggests in patients intolerant of oral feeding, enteral feeding should be initiated as a trophic rate.17 Patients with moderate to severe acute pancreatitis refuse oral feeding due to nausea, vomiting, and abdominal pain secondary to gastric stasis and abdominal distention following pancreas inflammation. Food intolerance is also present in early tube feeding.18 With the increase in pancreatic inflammation, the severity of intolerance increases and feeding becomes more problematic.19 The results of our study showed all patients in the ketorolac group tolerated oral feeding without the need for tube feeding. In addition, the time interval for feeding initiation was shorter in the ketorolac group, possibly attributed to the potent anti-inflammatory properties of ketorolac and its analgesic effects. Accordingly, the frequency of NPO was lower in patients receiving ketorolac along with fewer days of hospitalization.
In acute pancreatitis, intestinal permeability ranges from mild to severe forms. It has been shown that the use of gastrointestinal tract for feeding maintains intestinal integrity and reduces the translocation of bacteria in mesenteric lymph nodes and plasma endotoxin levels.20 Starvation changes the composition of intestinal microbiotia and promotes proinflammatory patterns. The American Society of Parenteral and Enteral Nutrition reported in patients with moderate to severe acute pancreatitis, failure to start tube feeding for more than 3 to 4 days following admission ensues the risk of worsened nutrition status and development of SIRS, organ failure, and infection.17 Based on this recommendation, we started tube feeding on day 5 in all patients unable to be fed. In the control group, 21% of patients were on tube feeding. All patients who received ketorolac were started oral feeding prior to day 5 of admission with no need for tube feeding.
Reduced inflammation and earlier feeding were observed in the ketorolac group, which may be the reasons for fewer organ failures and ICU stays and the prevented progress of predicted severe acute pancreatitis to severe forms.
Strengths and Weaknesses
We examined the effect of ketorolac injection on feeding and clinical outcomes in predicted severe acute pancreatitis for the first time. Ketorolac was not accompanied by any side effects in patients; they were followed to investigate the survival within 4 months.
However, the present study had some weaknesses. As there were no similar studies, rather than clinical outcomes, we selected the changes in serum hs-CRP level for primary endpoint. As a result, we were unable to detect the effect of ketorolac on the clinical outcomes. Although the duration of hospitalization was significantly lower in the ketorolac group, the risk of organ failure and mortality might increase with larger sample sizes. Furthermore, a physician was unblinded to the study intervention, although the participants, data collectors, outcome adjudicators, and data analysts were unaware of the treatment groups.
Conclusion
Using ketorolac, we were able to reduce the hospitalization time and improve feeding outcomes with no need for tube feeding. The feeding start time was significantly shorter in the study group with no need for tube feeding in the ketorolac group. Frequency of NPO (not per oral) was significantly lower in the ketorolac group. The ability to deliver nutrition was higher in the ketorolac group, and it reached the targeted energy intake significantly sooner. Intolerance to diet (abdominal pain, nausea, and vomiting after refeeding), which leads to feeding stoppage, was significantly lower in the ketorolac group.
Author Contributions
All authors had access to the study data and contributed to the study conception and design. Material preparation, data collection and analysis were performed by S.S, Z.V and E.S. The first draft of the manuscript was written by Z.V. and all authors commented on previous versions of the manuscript. All authors reviewed and approved the final manuscript.
Acknowledgements
We convey our gratitude to the Ilam University of Medical Sciences, Ilam, Iran. The manuscript has been submitted as a preprint in Research Square (https://www.researchsquare.com/article/rs-47968/v1). The authors are solely responsible for the data and the content of the paper.
Footnotes
Disclosure: This trial was registered with ClinicalTrials.gov: NCT02885441, Date: August 31, 2016.
- Received February 11, 2021.
- Revision received July 26, 2021.
- Revision received August 5, 2021.
- Accepted September 22, 2021.
References
- 1.↵Vege SS, Yadav D, Chari ST. Pancreatitis. In: GI Epidemiology. 1st ed. Talley NJ, Locke GR, Saito YA, eds. Malden, MA; Blackwell Publishing: 2007.
- 2.↵Singh RK, Poddar B, Baronia AK, Audit of patients with severe acute pancreatitis admitted to an intensive care unit. Indian J Gastroenterol. 2012;31(5):243-252. doi:10.1007/s12664-012-0205-1
- 3.↵Raraty MG, Connor S, Criddle DN, Sutton R, Neoptolemos JP. Acute pancreatitis and organ failure: pathophysiology, natural history, and management strategies. Curr Gastroenterol Rep. 2004;6(2):99-103. doi:10.1007/s11894-004-0035-0
- 4.↵Van Laethem JL, Eskinazi R, Louis H, Rickaert F, Robberecht P, Devière J. Multisystemic production of interleukin 10 limits the severity of acute pancreatitis in mice. Gut. 1998;43(3):408-413. doi:10.1136/gut.43.3.408
- 5.↵Singh P, Lee T, Davidoff S, Efficacy of Interleukin 10 (IL-10) in the prevention of post-ERCP pancreatitis: a meta-analysis. Gastrointest Endosc. 2002; 55:AB150.
- 6.↵Howard ML, Isaacs AN, Nisly SA. Continuous Infusion Nonsteroidal Anti-Inflammatory Drugs for Perioperative Pain Management. J Pharm Pract. 2018;31(1):66-81. doi:10.1177/0897190016665539
- 7.↵Eslamian G, Ardehali SH, Baghestani AR, Vahdat Shariatpanahi Z. Effects of early enteral bovine colostrum supplementation on intestinal permeability in critically ill patients: A randomized, double-blind, placebo-controlled study. Nutrition. 2019;60:106-111. doi:10.1016/j.nut.2018.10.013
- 8.↵Tenner S, Baillie J, DeWitt J, Vege SS; American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis [published correction appears in Am J Gastroenterol. 2014 Feb;109(2):302]. Am J Gastroenterol. 2013;108(9):1400-1416. doi:10.1038/ajg.2013.218
- 9.↵Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13(4 Suppl 2):e1-e15. doi:10.1016/j.pan.2013.07.063
- 10.↵Chan YC, Leung PS. Acute pancreatitis: animal models and recent advances in basic research. Pancreas. 2007;34(1):1-14. doi:10.1097/01. mpa.0000246658.38375.04
- 11.↵Vege SS, Atwal T, Bi Y, Chari ST, Clemens MA, Enders FT. Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot, Double-Blind, Placebo-Controlled, Randomized Trial. Gastroenterology. 2015;149(2):318-20.e3. doi:10.1053/j.gastro.2015.04.019
- 12.↵Garg R, Mohan BP, Krishnamoorthi R, Rustagi T. Pre-endoscopic retrograde cholangiopancreatography (ERCP) administration of rectal indomethacin in unselected patients to reduce post-ERCP pancreatitis: A systematic review and meta-analysis. Indian J Gastroenterol. 2018;37(2):120-126. doi:10.1007/s12664-018-0841-1
- 13.↵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 metaanalysis. BMC Gastroenterol. 2017;17(1):43. Published 2017 Mar 15. doi:10.1186/s12876-017-0599-4
- 14.↵Louie BE, Noseworthy T, Hailey D, Gramlich LM, Jacobs P, Warnock GL. 2004 MacLean-Mueller prize enteral or parenteral nutrition for severe pancreatitis: a randomized controlled trial and health technology assessment. Can J Surg. 2005;48(4):298-306.
- 15.↵Cao Y, Xu Y, Lu T, Gao F, Mo Z. Meta-analysis of enteral nutrition versus total parenteral nutrition in patients with severe acute pancreatitis. Ann Nutr Metab. 2008;53(3-4):268-275. doi:10.1159/000189382
- 16.↵Yi F, Ge L, Zhao J, Meta-analysis: total parenteral nutrition versus total enteral nutrition in predicted severe acute pancreatitis. Intern Med. 2012;51(6):523-530. doi:10.2169/internalmedicine.51.6685
- 17.↵McClave SA, Taylor BE, Martindale RG, Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) [published correction appears in JPEN J Parenter Enteral Nutr. 2016 Nov;40(8):1200]. JPEN J Parenter Enteral Nutr. 2016;40(2):159-211. doi:10.1177/0148607115621863
- 18.↵Sun JK, Li WQ, Ke L, Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe acute pancreatitis compared with delayed enteral nutrition: a prospective pilot study. World J Surg. 2013;37(9):2053-2060. doi:10.1007/s00268-013-2087-5
- 19.↵Cicalese L, Sahai A, Sileri P, Acute pancreatitis and bacterial translocation. Dig Dis Sci. 2001;46(5):1127-1132. doi:10.1023/a:1010786701289
- 20.↵Arutla M, Raghunath M, Deepika G, Efficacy of enteral glutamine supplementation in patients with severe and predicted severe acute pancreatitis-A randomized controlled trial. Indian J Gastroenterol. 2019;38(4):338-347. doi:10.1007/s12664-019-00962-7
