Ketorolac use and risk of bleeding after appendectomy in children with perforated appendicitis

  • Paige Kingston
    Affiliations
    Division of Pediatric Surgery, Children's Hospital Los Angeles; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Blvd. MS #100, Los Angeles, Los Angeles, CA 90027, United States
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  • Danny Lascano
    Affiliations
    Division of Pediatric Surgery, Children's Hospital Los Angeles; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Blvd. MS #100, Los Angeles, Los Angeles, CA 90027, United States
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  • Shadassa Ourshalimian
    Affiliations
    Division of Pediatric Surgery, Children's Hospital Los Angeles; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Blvd. MS #100, Los Angeles, Los Angeles, CA 90027, United States
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  • Christopher J. Russell
    Affiliations
    Division of Hospital Medicine, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles 4650 Sunset Blvd, Los Angeles, CA 90027, United States
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  • Eugene Kim
    Affiliations
    Division of Pain Medicine, Children's Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, United States
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  • Lorraine I. Kelley-Quon
    Correspondence
    Corresponding author at: Division of Pediatric Surgery, Department of Surgery, Clinical Surgery and Preventive Medicine, Children's Hospital of Los Angeles, Keck School of Medicine of the University of Southern California, 4650 Sunset Blvd. MS #100, Los Angeles, Los Angeles, CA 90027, United States.
    Affiliations
    Division of Pediatric Surgery, Children's Hospital Los Angeles; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Blvd. MS #100, Los Angeles, Los Angeles, CA 90027, United States

    Department of Population and Public Health Sciences, University of Southern California, 2001 N Soto St, Los Angeles, CA 90032, United States
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Published:November 25, 2021DOI:https://doi.org/10.1016/j.jpedsurg.2021.11.019

      Highlights

      • Perioperative ketorolac use alone is not associated with an increased risk of significant bleeding in children with perforated appendicitis who undergo appendectomy.
      • Extended ketorolac use or combined ibuprofen use is associated with increased risk of bleeding requiring blood transfusion after appendectomy.

      Abstract

      Background

      Ketorolac is an opioid sparing agent commonly used in children. However, ketorolac may be avoided in children with peritonitis owing to a possible increased risk of bleeding.

      Methods

      A retrospective cohort study of healthy children 2–18 years who underwent appendectomy for perforated appendicitis was performed using the Pediatric Health Information System (2009–2019). Multivariable logistic regression was used to evaluate the association between perioperative ketorolac use and postoperative blood transfusions within 30 days of surgery, adjusting for patient and hospital level factors. An interaction between ketorolac and ibuprofen was evaluated to identify synergistic effects.

      Results

      Overall, 55,603 children with perforated appendicitis underwent appendectomy and 82.3% (N = 45,769) received ketorolac. Of those, 32% (N = 14,864) also received ibuprofen. Receipt of a blood transfusion was infrequent (N = 189, 0.3%). On multivariable logistic regression analysis, perioperative ketorolac administration was associated with decreased odds of a blood transfusion (OR 0.53, 95% CI: 0.35–0.79). However, children receiving ketorolac and ibuprofen were more likely to require a blood transfusion (OR 1.99, 95% CI: 1.42–2.79). In a subset of children receiving ketorolac, each additional day of ketorolac was associated with an increase odds of blood transfusion (OR 1.39, 95% CI: 1.30–1.49).

      Conclusion

      Perioperative ketorolac alone is not associated with an increased risk of significant bleeding in children undergoing appendectomy for perforated appendicitis. However, use of both ketorolac and ibuprofen during hospitalization was associated with increased risk of bleeding, although precise timing of administration of these medications was unable to be determined. Extended ketorolac use was also associated with increased risk of bleeding requiring blood transfusion.

      Level of evidence

      Level III.

      Keywords

      Abbreviations:

      PHIS (Pediatric Health Information System), ICD-9/10-CM (International Disease Classification Ninth or Tenth Revision Clinical Modification), NSAID (non steroidal anti-inflammatory drug)
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      References

        • Glass C.C.
        • Rangel S.J.
        Overview and diagnosis of acute appendicitis in children.
        Semin Pediatr Surg. 2016; 25: 198-203https://doi.org/10.1053/j.sempedsurg.2016.05.001
        • St Peter S.D.
        • Aguayo P.
        • Fraser J.D.
        Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial.
        J Pediatr Surg. 2010; 45: 236-240https://doi.org/10.1016/j.jpedsurg.2009.10.039
        • Rentea R.M.
        • St Peter S.D.
        Contemporary management of appendicitis in children.
        Adv Pediatr. 2017; 64: 225-251https://doi.org/10.1016/j.yapd.2017.03.008
        • Mahdi E.M.
        • Ourshalimian S.
        • Russell C.J.
        Fewer postoperative opioids are associated with decreased duration of stay for children with perforated appendicitis.
        Surgery. 2020; 168: 942-947https://doi.org/10.1016/j.surg.2020.04.060
        • Memtsoudis S.G.
        • Poeran J.
        • Zubizarreta N.
        Association of multimodal pain management strategies with perioperative outcomes and resource utilization.
        Anesthesiology. 2018; 128https://doi.org/10.1097/ALN.0000000000002132
        • McLaughlin D.C.
        • Cheah J.W.
        • Aleshi P.
        Multimodal analgesia decreases opioid consumption after shoulder arthroplasty: a prospective cohort study.
        J Shoulder Elb Surg. 2018; 27: 686-691https://doi.org/10.1016/j.jse.2017.11.015
        • Cozowicz C.
        • Poeran J.
        • Zubizarreta N.
        Non opioid analgesic modes of pain management are associated with reduced postoperative complications and resource utilisation: a retrospective study of obstructive sleep apnoea patients undergoing elective joint arthroplasty.
        Br J Anaesth. 2019; 122: 131-140https://doi.org/10.1016/j.bja.2018.08.027
        • Bass K.D.
        • Heiss K.F.
        • Kelley-Quon L.I.
        Opioid use in children's surgery: awareness, current state, and advocacy.
        J Pediatr Surg. 2020; 55: 2448-2453https://doi.org/10.1016/j.jpedsurg.2020.02.015
        • Manworren R.C.B.
        • McElligott C.D.
        • Deraska P.V.
        Efficacy of analgesic treatments to manage children's postoperative pain after laparoscopic appendectomy: retrospective medical record review.
        AORN J. 2016; 103 (e1-317.e11): 317https://doi.org/10.1016/j.aorn.2016.01.013
        • Adams A.J.
        • Buczek M.J.
        • Flynn J.M.
        Perioperative ketorolac for supracondylar humerus fracture in children decreases postoperative pain, opioid usage, hospitalization cost, and length-of-stay.
        J Pediatr Orthop. 2019; 39https://doi.org/10.1097/BPO.0000000000001345
        • Munro H.M.
        • Walton S.R.
        • Malviya S.
        Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents.
        Can J Anesth. 2002; 49 (Can d'anesthésie): 461-466https://doi.org/10.1007/BF03017921
        • Naseem H.U.R.
        • Dorman R.M.
        • Ventro G.
        Safety of perioperative ketorolac administration in pediatric appendectomy.
        J Surg Res. 2017; 218: 232-236https://doi.org/10.1016/j.jss.2017.05.087
        • Greer I.A.
        Effects of ketorolac tromethamine on hemostasis.
        Pharmacotherapy. 1990; 10: 71S-76S
        • Kim J.S.
        • Kaufman J.
        • Patel S.S.
        Antiplatelet effect of ketorolac in children after congenital cardiac surgery.
        World J Pediatr Congenit Heart Surg. 2018; 9: 651-658https://doi.org/10.1177/2150135118799041
        • McNicol E.D.
        • Rowe E.
        • Cooper T.E.
        Ketorolac for postoperative pain in children.
        Cochrane Database Syst Rev. 2018; 2018https://doi.org/10.1002/14651858.CD012294.pub2
        • Feudtner C.
        • Feinstein J.A.
        • Zhong W.
        Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation.
        BMC Pediatr. 2014; 14: 199https://doi.org/10.1186/1471-2431-14-199
        • Chan K.H.
        • Moser E.A.
        • Cain M.
        Validation of antibiotic charges in administrative data for outpatient pediatric urologic procedures.
        J Pediatr Urol. 2017; 13: 185-186https://doi.org/10.1016/j.jpurol.2017.01.009
        • Miller T.P.
        • Troxel A.B.
        • Li Y.
        Comparison of administrative/billing data to expected protocol-mandated chemotherapy exposure in children with acute myeloid leukemia: a report from the children's oncology group.
        Pediatr Blood Cancer. 2015; 62: 1184-1189https://doi.org/10.1002/pbc.25475
        • Pennington E.C.
        • Feng C.
        • St Peter S.D.
        Use of mechanical bowel preparation and oral antibiotics for elective colorectal procedures in children: is current practice evidence-based?.
        J Pediatr Surg. 2014; 49: 1030-1035https://doi.org/10.1016/j.jpedsurg.2014.01.048
        • Azur M.J.
        • Stuart E.A.
        • Frangakis C.
        Multiple imputation by chained equations: what is it and how does it work?.
        Int J Methods Psychiatr Res. 2011; 20: 40-49https://doi.org/10.1002/mpr.329
        • Kokoska E.R.
        • Bird T.M.
        • Robbins J.M.
        Racial disparities in the management of pediatric appenciditis.
        J Surg Res. 2007; 137: 83-88https://doi.org/10.1016/j.jss.2006.06.020
        • Gupta A.
        • Daggett C.
        • Drant S.
        Prospective randomized trial of ketorolac after congenital heart surgery.
        J Cardiothorac Vasc Anesth. 2004; 18: 454-457https://doi.org/10.1053/j.jvca.2004.05.024
        • Rusy L.M.
        • Houck C.S.
        • Sullivan L.J.
        A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy.
        Anesth Analg. 1995; 80: 226-229https://doi.org/10.1097/00000539-199502000-00004
        • Gao B.
        • Remondini T.
        • Dhaliwal N.
        Incidence of bleeding in children undergoing circumcision with ketorolac administration.
        Can Urol Assoc J. 2018; 12: E6-E9https://doi.org/10.5489/cuaj.4632
      1. U.S. Food and Drug Administration. Ketorolac Tromethamine Injection. Accessed January 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/074802s038lbl.pdf

        • Misurac J.M.
        • Knoderer C.A.
        • Leiser J.D.
        Nonsteroidal anti-inflammatory drugs are an important cause of acute kidney injury in children.
        J Pediatr. 2013; 162https://doi.org/10.1016/j.jpeds.2012.11.069
        • Forrest J.B.
        • Heitlinger E.L.
        • Revell S.
        Ketorolac for postoperative pain management in children.
        Drug Saf. 1997; 16 (DRUG Exp): 309-329
        • Litalien C.
        • Jacqz-Aigrain E.
        Risks and benefits of nonsteroidal anti-inflammatory drugs in children.
        Paediatr Drugs. 2001; 3: 817-858https://doi.org/10.2165/00128072-200103110-00004
        • Collier D.N.
        • Billings C.
        • Serwint J.R.
        Nonsteroidal anti-inflammatory drugs and abdominal pain.
        Pediatr Rev. 2007; 28: 75-77https://doi.org/10.1542/pir.28-2-75