Clinical trial NCT03671746: Inflammatory Markers in Trauma Patient Outcomes
Official title: Inflammatory Response to Trauma - Does Early Cytokine Modulation Improve Patient Outcome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Polytrauma
Keywords: Inflammatory cytokine
inflammation
trauma
opioid
Lead sponsor: University of Kentucky
Sponsor class: OTHER
First posted: 2018-09-14
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Compare the effectiveness of a NSAID to placebo in acute trauma setting.
Primary purpose: TREATMENT

Brief summary: It is unknown whether early modulation of inflammatory cytokines is associated with improved patient outcomes, reduced narcotic requirements in orthopaedic patient population, and improved patient subjective pain after hospital discharge. Preliminary animal and clinical studies have shown correlation between elevated blood cytokine concentrations during the acute phase of trauma and the development of post-traumatic complications. Early administration of nonsteroidal anti-inflammatory drug (NSAID) in animals significantly reduced inflammatory profiles, improved pulmonary edema, and enhanced arteriole vasoconstriction in response to hemorrhage. The ability to modify post-traumatic physiologic response via short-term administration of a non-steroidal anti-inflammatory drug (NSAID) may lead to improved patient outcome. In addition, given the current landscape for opioid epidemic in the United States, alternative non-opioid pain management during acute trauma has the potential to reduce opioid consumption and represents a pivotal component of multimodal analgesia strategy.

By doing this study, the investigators hope to learn how to provide the best care for all patients in the state of Kentucky. Patient participation in this research will last about 1 year.

Detailed description: Accidental trauma is the 4th leading cause of death in the United States, and it is associated with a complex inflammatory response. This response is associated with post-traumatic complications such as; multi-organ dysfunction syndrome (MODS), bacterial pneumonia, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and post-traumatic pain (PTP). It is unknown whether early modulation of inflammatory cytokines is associated with improved patient outcomes, reduced narcotic requirements, and improved patient subjective pain after hospital discharge.

Preliminary data has shown: (1) elevated blood cytokine concentrations during the acute phase of trauma are correlated with the development of fatal post-traumatic complications, (2) that early administration of a non-steroidal anti-inflammatory drug (NSAID) resulted in decreased blood serum levels of interleukin (IL-6), Prostaglandin E2 (PGE2), improved pulmonary edema, and enhanced arterioles ability to vasoconstrict in response to hemorrhage in animal models, and (3) that the addition of the internal physiologic parameters (inflammatory cytokines) to New Injury Severity Score (NISS - a marker of the external anatomical insult) significantly improves the ability to predict hospital length of stay of trauma patients when compared to NISS alone. The investigator's group is the first to use an integrative approach that combines the external anatomic injury data with the internal physiologic response for accurate prediction of a patient's clinical outcome. Therefore, if the investigators apply this same mindset to treatment, the investigators can improve the trauma patients' care by addressing both parameters as opposed to solely focusing on the external injury as done in the past. The ability to modify post-traumatic physiologic response via short-term administration of an NSAID may lead to improved patient outcomes.

Over the last decade, clinicians have remained puzzled over the safety of NSAID administration after fracture in terms of bone union. In addition, given the current landscape for the opioid epidemic in the United States, alternative non-opioid pain management during acute trauma has the potential to reduce opioid consumption and represents a pivotal component of multimodal analgesia strategy.

Eligibility criteria: Inclusion Criteria:

* Patients age 18 to 75
* New Injury Severity Score (NISS) \> 9, with musculoskeletal injury requiring surgical treatment

Exclusion Criteria:

* Patient age \< 18 or \> 75
* Patients who presented more than 24 hours after time of injury
* Patients with contraindications to NSAID therapy (i.e., patients with active hemorrhage, received blood products, traumatic brain injury (TBI), active gastrointestinal bleeding or ulceration, NSAID allergy, thromboembolism, or coagulopathy)
* Patients with pre-existing inflammatory condition (e.g., inflammatory arthropathy or bowel disease)
* Patients with preexisting immunocompromised/immunosuppressed condition or acquired immunodeficiency syndrome (AIDS)
* Patients with pre-existing comorbidities (e.g., coronary artery disease, myocardial infarction, chronic organ failure, chronic obstructive pulmonary disease, emphysema, asthma, etc.)
* Patients with chronic use of steroids, immuno-modulating drugs, or history of organ transplantation
* Patients receiving chronic opioid therapy or treatment for opioid use disorder
* Patients who are pregnant
* Patients with thermal injury

Primary outcomes:
measure: Length of Hospital Stay
timeFrame: Up to 30 days
Secondary outcomes:
measure: Morphine Milligram Equivalents in House
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Patient Pain Scores
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Interleukin 1a
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Interleukin 1b
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Interleukin 6
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Interleukin 10
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Prostaglandin E-2
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Post Traumatic Complications
timeFrame: Up to 30 days
measure: Mortality
timeFrame: Up to 30 days
measure: Change in Inpatient Subjective Pain Reports
timeFrame: Hospital Day 0 (Enrollment), Day 1, Day 2, Day 3, Day 4, Day 5
measure: Change in Outpatient Subjective Pain Reports
timeFrame: up to 365 days
Other outcomes:
Locations:
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Arun Aneja, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Braden JB, Fan MY, Edlund MJ, Martin BC, DeVries A, Sullivan MD. Trends in use of opioids by noncancer pain type 2000-2005 among Arkansas Medicaid and HealthCore enrollees: results from the TROUP study. J Pain. 2008 Nov;9(11):1026-35. doi: 10.1016/j.jpain.2008.06.002. Epub 2008 Jul 26.
citation: Lawal OD, Gold J, Murthy A, Ruchi R, Bavry E, Hume AL, Lewkowitz AK, Brothers T, Wen X. Rate and Risk Factors Associated With Prolonged Opioid Use After Surgery: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020 Jun 1;3(6):e207367. doi: 10.1001/jamanetworkopen.2020.7367.
citation: Mohamadi A, Chan JJ, Lian J, Wright CL, Marin AM, Rodriguez EK, von Keudell A, Nazarian A. Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery: A Systematic Review and Meta-(Regression) Analysis. J Bone Joint Surg Am. 2018 Aug 1;100(15):1332-1340. doi: 10.2106/JBJS.17.01239.
citation: Bosse MJ, MacKenzie EJ, Kellam JF, Burgess AR, Webb LX, Swiontkowski MF, Sanders RW, Jones AL, McAndrew MP, Patterson BM, McCarthy ML, Travison TG, Castillo RC. An analysis of outcomes of reconstruction or amputation after leg-threatening injuries. N Engl J Med. 2002 Dec 12;347(24):1924-31. doi: 10.1056/NEJMoa012604.
citation: Castillo RC, MacKenzie EJ, Webb LX, Bosse MJ, Avery J; LEAP Study Group. Use and perceived need of physical therapy following severe lower-extremity trauma. Arch Phys Med Rehabil. 2005 Sep;86(9):1722-8. doi: 10.1016/j.apmr.2005.03.005.
citation: O'Toole RV, Castillo RC, Pollak AN, MacKenzie EJ, Bosse MJ; LEAP Study Group. Determinants of patient satisfaction after severe lower-extremity injuries. J Bone Joint Surg Am. 2008 Jun;90(6):1206-11. doi: 10.2106/JBJS.G.00492.
citation: Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003 Aug;97(2):534-540. doi: 10.1213/01.ANE.0000068822.10113.9E.
citation: Sherwood GD, McNeill JA, Starck PL, Disnard G. Changing acute pain management outcomes in surgical patients. AORN J. 2003 Feb;77(2):374, 377-80, 384-90 passim. doi: 10.1016/s0001-2092(06)61206-4.
citation: Hsu JR, Mir H, Wally MK, Seymour RB; Orthopaedic Trauma Association Musculoskeletal Pain Task Force. Clinical Practice Guidelines for Pain Management in Acute Musculoskeletal Injury. J Orthop Trauma. 2019 May;33(5):e158-e182. doi: 10.1097/BOT.0000000000001430.
citation: Oyler DR, Slade E, Slavova S, Matuszewski PE, Lei F, Herndon B, Johnson S, Moghadamian ES. Effect of a Multimodal Analgesic Protocol on Short-Term and Long-Term Opioid Use After Orthopaedic Trauma. J Orthop Trauma. 2022 Aug 1;36(8):326-331. doi: 10.1097/BOT.0000000000002346. Epub 2022 Jan 6.
citation: Mir HR, Miller AN, Obremskey WT, Jahangir AA, Hsu JR. Confronting the Opioid Crisis: Practical Pain Management and Strategies: AOA 2018 Critical Issues Symposium. J Bone Joint Surg Am. 2019 Dec 4;101(23):e126. doi: 10.2106/JBJS.19.00285.
citation: Castillo RC, Raja SN, Frey KP, Vallier HA, Tornetta P 3rd, Jaeblon T, Goff BJ, Gottschalk A, Scharfstein DO, O'Toole RV; METRC. Improving Pain Management and Long-Term Outcomes Following High-Energy Orthopaedic Trauma (Pain Study). J Orthop Trauma. 2017 Apr;31 Suppl 1:S71-S77. doi: 10.1097/BOT.0000000000000793.
citation: Marquez-Lara A, Hutchinson ID, Nunez F Jr, Smith TL, Miller AN. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev. 2016 Mar 15;4(3):e4. doi: 10.2106/JBJS.RVW.O.00055.
citation: Cepeda MS, Carr DB, Miranda N, Diaz A, Silva C, Morales O. Comparison of morphine, ketorolac, and their combination for postoperative pain: results from a large, randomized, double-blind trial. Anesthesiology. 2005 Dec;103(6):1225-32. doi: 10.1097/00000542-200512000-00018.
citation: McDonald EL, Daniel JN, Rogero RG, Shakked RJ, Nicholson K, Pedowitz DI, Raikin SM, Bilolikar V, Winters BS. How Does Perioperative Ketorolac Affect Opioid Consumption and Pain Management After Ankle Fracture Surgery? Clin Orthop Relat Res. 2020 Jan;478(1):144-151. doi: 10.1097/CORR.0000000000000978.
citation: Vadivelu N, Gowda AM, Urman RD, Jolly S, Kodumudi V, Maria M, Taylor R Jr, Pergolizzi JV Jr. Ketorolac tromethamine - routes and clinical implications. Pain Pract. 2015 Feb;15(2):175-93. doi: 10.1111/papr.12198. Epub 2014 Apr 16.
citation: Brown CR, Mazzulla JP, Mok MS, Nussdorf RT, Rubin PD, Schwesinger WH. Comparison of repeat doses of intramuscular ketorolac tromethamine and morphine sulfate for analgesia after major surgery. Pharmacotherapy. 1990;10(6 ( Pt 2)):45S-50S.
citation: Camu F, Van Overberge L, Bullingham R, Lloyd J. Hemodynamic effects of two intravenous doses of ketorolac tromethamine compared with morphine. Pharmacotherapy. 1990;10(6 ( Pt 2)):122S-126S.
citation: De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg. 2012 Feb;114(2):424-33. doi: 10.1213/ANE.0b013e3182334d68. Epub 2011 Sep 29.
citation: Jelinek GA. Ketorolac versus morphine for severe pain. Ketorolac is more effective, cheaper, and has fewer side effects. BMJ. 2000 Nov 18;321(7271):1236-7. doi: 10.1136/bmj.321.7271.1236. No abstract available.
citation: Gobble RM, Hoang HLT, Kachniarz B, Orgill DP. Ketorolac does not increase perioperative bleeding: a meta-analysis of randomized controlled trials. Plast Reconstr Surg. 2014 Mar;133(3):741-755. doi: 10.1097/01.prs.0000438459.60474.b5.
citation: Irizarry E, Restivo A, Salama M, Davitt M, Feliciano C, Cortijo-Brown A, Friedman BW. A randomized controlled trial of ibuprofen versus ketorolac versus diclofenac for acute, nonradicular low back pain. Acad Emerg Med. 2021 Nov;28(11):1228-1235. doi: 10.1111/acem.14321. Epub 2021 Jun 30.
citation: Motov S, Yasavolian M, Likourezos A, Pushkar I, Hossain R, Drapkin J, Cohen V, Filk N, Smith A, Huang F, Rockoff B, Homel P, Fromm C. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017 Aug;70(2):177-184. doi: 10.1016/j.annemergmed.2016.10.014. Epub 2016 Dec 16.
citation: Gillis JC, Brogden RN. Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs. 1997 Jan;53(1):139-88. doi: 10.2165/00003495-199753010-00012.
citation: Kinsella J, Moffat AC, Patrick JA, Prentice JW, McArdle CS, Kenny GN. Ketorolac trometamol for postoperative analgesia after orthopaedic surgery. Br J Anaesth. 1992 Jul;69(1):19-22. doi: 10.1093/bja/69.1.19.
citation: Reinhart DI. Minimising the adverse effects of ketorolac. Drug Saf. 2000 Jun;22(6):487-97. doi: 10.2165/00002018-200022060-00007.
citation: Lavoie A, Moore L, LeSage N, Liberman M, Sampalis JS. The New Injury Severity Score: a more accurate predictor of in-hospital mortality than the Injury Severity Score. J Trauma. 2004 Jun;56(6):1312-20. doi: 10.1097/01.ta.0000075342.36072.ef.
citation: Lavoie A, Moore L, LeSage N, Liberman M, Sampalis JS. The Injury Severity Score or the New Injury Severity Score for predicting intensive care unit admission and hospital length of stay? Injury. 2005 Apr;36(4):477-83. doi: 10.1016/j.injury.2004.09.039. Epub 2005 Jan 22.
citation: Weisz RD, Fokin AA, Lerner V, Flynt A, Macias-Perez I, Pavliv L, Crawford M, Puente I. Intravenous Ibuprofen Reduces Opioid Consumption During the Initial 48 Hours After Injury in Orthopedic Trauma Patients. J Orthop Trauma. 2020 Jul;34(7):341-347. doi: 10.1097/BOT.0000000000001733.
citation: Singla N, Rock A, Pavliv L. A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. Pain Med. 2010 Aug;11(8):1284-93. doi: 10.1111/j.1526-4637.2010.00896.x. Epub 2010 Jun 30.
citation: Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clin Ther. 2009 Sep;31(9):1922-35. doi: 10.1016/j.clinthera.2009.08.026.
citation: Zhou HS, Li TT, Pi Y, Wang TH, Liu F, Xiong LL. Analgesic Efficacy of Intravenous Ibuprofen in the Treatment of Postoperative Acute Pain: A Phase III Multicenter Randomized Placebo-ControlledDouble-Blind Clinical Trial. Pain Res Manag. 2023 Mar 7;2023:7768704. doi: 10.1155/2023/7768704. eCollection 2023.
citation: Eberson CP, Pacicca DM, Ehrlich MG. The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient. J Pediatr Orthop. 1999 Sep-Oct;19(5):688-92.
citation: Ellis TA 2nd, Hammoud H, Dela Merced P, Nooli NP, Ghoddoussi F, Kong J, Krishnan SH. Multimodal Clinical Pathway With Adductor Canal Block Decreases Hospital Length of Stay, Improves Pain Control, and Reduces Opioid Consumption in Total Knee Arthroplasty Patients: A Retrospective Review. J Arthroplasty. 2018 Aug;33(8):2440-2448. doi: 10.1016/j.arth.2018.03.053. Epub 2018 Mar 27.
citation: Johnson P, Hustedt J, Matiski T, Childers R, Lederman E. Improvement in Postoperative Pain Control and Length of Stay With Peripheral Nerve Block Prior to Distal Radius Repair. Orthopedics. 2020 Nov 1;43(6):e549-e552. doi: 10.3928/01477447-20200721-14. Epub 2020 Aug 6.
citation: Walker CT, Gullotti DM, Prendergast V, Radosevich J, Grimm D, Cole TS, Godzik J, Patel AA, Whiting AC, Little A, Uribe JS, Kakarla UK, Turner JD. Implementation of a Standardized Multimodal Postoperative Analgesia Protocol Improves Pain Control, Reduces Opioid Consumption, and Shortens Length of Hospital Stay After Posterior Lumbar Spinal Fusion. Neurosurgery. 2020 Jul 1;87(1):130-136. doi: 10.1093/neuros/nyz312.
citation: Archer KR, Castillo RC, Wegener ST, Abraham CM, Obremskey WT. Pain and satisfaction in hospitalized trauma patients: the importance of self-efficacy and psychological distress. J Trauma Acute Care Surg. 2012 Apr;72(4):1068-77. doi: 10.1097/TA.0b013e3182452df5.
citation: Bot AG, Bekkers S, Arnstein PM, Smith RM, Ring D. Opioid use after fracture surgery correlates with pain intensity and satisfaction with pain relief. Clin Orthop Relat Res. 2014 Aug;472(8):2542-9. doi: 10.1007/s11999-014-3660-4. Epub 2014 Apr 29.
citation: Nota SP, Spit SA, Voskuyl T, Bot AG, Hageman MG, Ring D. Opioid Use, Satisfaction, and Pain Intensity After Orthopedic Surgery. Psychosomatics. 2015 Sep-Oct;56(5):479-85. doi: 10.1016/j.psym.2014.09.003. Epub 2014 Sep 6.
citation: Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017 Mar 17;66(10):265-269. doi: 10.15585/mmwr.mm6610a1.
citation: Morris BJ, Mir HR. The opioid epidemic: impact on orthopaedic surgery. J Am Acad Orthop Surg. 2015 May;23(5):267-71. doi: 10.5435/JAAOS-D-14-00163.
citation: Rodriguez-Buitrago A, Attum B, Enata N, Evans A, Okwumabua E, Gajari V, Obremskey WT, Jahangir A. Opiate Prescribing Practices After Common Isolated Lower Extremity Injuries. J Orthop Trauma. 2019 Mar;33(3):e93-e99. doi: 10.1097/BOT.0000000000001375.
citation: Castillo RC, MacKenzie EJ, Wegener ST, Bosse MJ; LEAP Study Group. Prevalence of chronic pain seven years following limb threatening lower extremity trauma. Pain. 2006 Oct;124(3):321-329. doi: 10.1016/j.pain.2006.04.020. Epub 2006 Jun 15.
citation: von Oelreich E, Eriksson M, Brattstrom O, Sjolund KF, Discacciati A, Larsson E, Oldner A. Risk factors and outcomes of chronic opioid use following trauma. Br J Surg. 2020 Mar;107(4):413-421. doi: 10.1002/bjs.11507. Epub 2020 Feb 7.
citation: Norman SB, Stein MB, Dimsdale JE, Hoyt DB. Pain in the aftermath of trauma is a risk factor for post-traumatic stress disorder. Psychol Med. 2008 Apr;38(4):533-42. doi: 10.1017/S0033291707001389. Epub 2007 Sep 10.
citation: Oostinga D, Steverink JG, van Wijck AJM, Verlaan JJ. An understanding of bone pain: A narrative review. Bone. 2020 May;134:115272. doi: 10.1016/j.bone.2020.115272. Epub 2020 Feb 13.
citation: Martin BC, Fan MY, Edlund MJ, Devries A, Braden JB, Sullivan MD. Long-term chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med. 2011 Dec;26(12):1450-7. doi: 10.1007/s11606-011-1771-0. Epub 2011 Jul 13.
citation: Van Zee A. The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health. 2009 Feb;99(2):221-7. doi: 10.2105/AJPH.2007.131714. Epub 2008 Sep 17.
citation: White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg. 2005 Nov;101(5 Suppl):S5-S22. doi: 10.1213/01.ANE.0000177099.28914.A7.
citation: Choban PS, Weireter LJ Jr, Maynes C. Obesity and increased mortality in blunt trauma. J Trauma. 1991 Sep;31(9):1253-7. doi: 10.1097/00005373-199109000-00009.
citation: Roberts CS, Pape HC, Jones AL, Malkani AL, Rodriguez JL, Giannoudis PV. Damage control orthopaedics: evolving concepts in the treatment of patients who have sustained orthopaedic trauma. Instr Course Lect. 2005;54:447-62.
citation: DeLong WG Jr, Born CT. Cytokines in patients with polytrauma. Clin Orthop Relat Res. 2004 May;(422):57-65. doi: 10.1097/01.blo.0000130840.64528.1e.
citation: McKinley TO, Gaski GE, Vodovotz Y, Corona BT, Billiar TR. Diagnosis and Management of Polytraumatized Patients With Severe Extremity Trauma. J Orthop Trauma. 2018 Mar;32 Suppl 1:S1-S6. doi: 10.1097/BOT.0000000000001114.
citation: Brochner AC, Toft P. Pathophysiology of the systemic inflammatory response after major accidental trauma. Scand J Trauma Resusc Emerg Med. 2009 Sep 15;17:43. doi: 10.1186/1757-7241-17-43.
citation: Tsirigotis P, Chondropoulos S, Gkirkas K, Meletiadis J, Dimopoulou I. Balanced control of both hyper and hypo-inflammatory phases as a new treatment paradigm in sepsis. J Thorac Dis. 2016 May;8(5):E312-6. doi: 10.21037/jtd.2016.03.47.
citation: Cuschieri J, Bulger E, Schaeffer V, Sakr S, Nathens AB, Hennessy L, Minei J, Moore EE, O'Keefe G, Sperry J, Remick D, Tompkins R, Maier RV; Inflammation and the Host Response to Injury Collaborative Research Program. Early elevation in random plasma IL-6 after severe injury is associated with development of organ failure. Shock. 2010 Oct;34(4):346-51. doi: 10.1097/SHK.0b013e3181d8e687.
citation: Frink M, Hsieh YC, Hsieh CH, Pape HC, Choudhry MA, Schwacha MG, Chaudry IH. Keratinocyte-derived chemokine plays a critical role in the induction of systemic inflammation and tissue damage after trauma-hemorrhage. Shock. 2007 Nov;28(5):576-81. doi: 10.1097/shk.0b013e31814b8e0d.
citation: Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis. Intensive Care Med. 2000 Aug;26(8):1076-81. doi: 10.1007/s001340051320.
citation: Hildebrand F, Giannoudis PV, van Griensven M, Chawda M, Pape HC. Pathophysiologic changes and effects of hypothermia on outcome in elective surgery and trauma patients. Am J Surg. 2004 Mar;187(3):363-71. doi: 10.1016/j.amjsurg.2003.12.016.
citation: Pape HC, Schmidt RE, Rice J, van Griensven M, das Gupta R, Krettek C, Tscherne H. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000 Oct;28(10):3441-8. doi: 10.1097/00003246-200010000-00012.
citation: Vanzant EL, Lopez CM, Ozrazgat-Baslanti T, Ungaro R, Davis R, Cuenca AG, Gentile LF, Nacionales DC, Cuenca AL, Bihorac A, Leeuwenburgh C, Lanz J, Baker HV, McKinley B, Moldawer LL, Moore FA, Efron PA. Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J Trauma Acute Care Surg. 2014 Jan;76(1):21-9; discussion 29-30. doi: 10.1097/TA.0b013e3182ab1ab5.
citation: Gaski GE, Metzger C, McCarroll T, Wessel R, Adler J, Cutshall A, Brown K, Vodovotz Y, Billiar TR, McKinley TO. Early Immunologic Response in Multiply Injured Patients With Orthopaedic Injuries Is Associated With Organ Dysfunction. J Orthop Trauma. 2019 May;33(5):220-228. doi: 10.1097/BOT.0000000000001437.
citation: Stutz CM, O'Rear LD, O'Neill KR, Tamborski ME, Crosby CG, Devin CJ, Schoenecker JG. Coagulopathies in orthopaedics: links to inflammation and the potential of individualizing treatment strategies. J Orthop Trauma. 2013 Apr;27(4):236-41. doi: 10.1097/BOT.0b013e318269b782.
citation: Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009 Jan;101(1):36-47.
citation: McKinley TO, Gaski GE, Zamora R, Shen L, Sun Q, Namas RA, Billiar TR, Vodovotz Y. Early dynamic orchestration of immunologic mediators identifies multiply injured patients who are tolerant or sensitive to hemorrhage. J Trauma Acute Care Surg. 2021 Mar 1;90(3):441-450. doi: 10.1097/TA.0000000000002998.
citation: Waydhas C, Nast-Kolb D, Trupka A, Zettl R, Kick M, Wiesholler J, Schweiberer L, Jochum M. Posttraumatic inflammatory response, secondary operations, and late multiple organ failure. J Trauma. 1996 Apr;40(4):624-30; discussion 630-1. doi: 10.1097/00005373-199604000-00018.
citation: Malik A, Kanneganti TD. Function and regulation of IL-1alpha in inflammatory diseases and cancer. Immunol Rev. 2018 Jan;281(1):124-137. doi: 10.1111/imr.12615.
citation: Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018 Jan;281(1):8-27. doi: 10.1111/imr.12621.
citation: Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011 Apr 7;117(14):3720-32. doi: 10.1182/blood-2010-07-273417. Epub 2011 Feb 8.
citation: Aneja A, Landy DC, Mittwede PN, Albano AY, Teasdall RJ, Isla A, Kavolus M. Inflammatory cytokines associated with outcomes in orthopedic trauma patients independent of New Injury Severity score: A pilot prospective cohort study. J Orthop Res. 2022 Jul;40(7):1555-1562. doi: 10.1002/jor.25183. Epub 2021 Nov 2.
citation: Berg DJ, Zhang J, Lauricella DM, Moore SA. Il-10 is a central regulator of cyclooxygenase-2 expression and prostaglandin production. J Immunol. 2001 Feb 15;166(4):2674-80. doi: 10.4049/jimmunol.166.4.2674.
citation: Harizi H, Gualde N. Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators. Cell Mol Immunol. 2006 Aug;3(4):271-7.
citation: Chu CH, Chen SH, Wang Q, Langenbach R, Li H, Zeldin D, Chen SL, Wang S, Gao H, Lu RB, Hong JS. PGE2 Inhibits IL-10 Production via EP2-Mediated beta-Arrestin Signaling in Neuroinflammatory Condition. Mol Neurobiol. 2015 Aug;52(1):587-600. doi: 10.1007/s12035-014-8889-0. Epub 2014 Sep 14.
citation: Spruijt NE, Visser T, Leenen LP. A systematic review of randomized controlled trials exploring the effect of immunomodulative interventions on infection, organ failure, and mortality in trauma patients. Crit Care. 2010;14(4):R150. doi: 10.1186/cc9218. Epub 2010 Aug 5.
citation: Dionne RA, Khan AA, Gordon SM. Analgesia and COX-2 inhibition. Clin Exp Rheumatol. 2001 Nov-Dec;19(6 Suppl 25):S63-70.
citation: Xiang L, Lu S, Fuller W, Aneja A, Russell GV, Jones LB, Hester R. Impaired blood pressure recovery to hemorrhage in obese Zucker rats with orthopedic trauma. Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H340-8. doi: 10.1152/ajpheart.00439.2011. Epub 2011 Oct 14.
citation: Xiang L, Hester RL, Fuller WL, Sebai ME, Mittwede PN, Jones EK, Aneja A, Russell GV. Orthopedic trauma-induced pulmonary injury in the obese Zucker rat. Microcirculation. 2010 Nov;17(8):650-9. doi: 10.1111/j.1549-8719.2010.00061.x.
citation: Peirce RJ, Fragen RJ, Pemberton DM. Intravenous ketorolac tromethamine versus morphine sulfate in the treatment of immediate postoperative pain. Pharmacotherapy. 1990;10(6 ( Pt 2)):111S-115S.
citation: Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest. 2008 Jul;134(1):117-25. doi: 10.1378/chest.07-2800. Epub 2008 Apr 10.
citation: Malek R, Soufi S. Pulmonary Edema. 2023 Apr 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK557611/
citation: Singbartl K, Kellum JA. AKI in the ICU: definition, epidemiology, risk stratification, and outcomes. Kidney Int. 2012 May;81(9):819-25. doi: 10.1038/ki.2011.339. Epub 2011 Oct 5.
citation: Kobbe P, Vodovotz Y, Kaczorowski DJ, Billiar TR, Pape HC. The role of fracture-associated soft tissue injury in the induction of systemic inflammation and remote organ dysfunction after bilateral femur fracture. J Orthop Trauma. 2008 Jul;22(6):385-90. doi: 10.1097/BOT.0b013e318175dd88.
citation: Sikka G, Miller KL, Steppan J, Pandey D, Jung SM, Fraser CD 3rd, Ellis C, Ross D, Vandegaer K, Bedja D, Gabrielson K, Walston JD, Berkowitz DE, Barouch LA. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. Exp Gerontol. 2013 Feb;48(2):128-35. doi: 10.1016/j.exger.2012.11.001. Epub 2012 Nov 13.
citation: Vadivelu N, Chang D, Helander EM, Bordelon GJ, Kai A, Kaye AD, Hsu D, Bang D, Julka I. Ketorolac, Oxymorphone, Tapentadol, and Tramadol: A Comprehensive Review. Anesthesiol Clin. 2017 Jun;35(2):e1-e20. doi: 10.1016/j.anclin.2017.01.001. Epub 2017 Apr 14.
citation: Rogero MM, Calder PC. Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids. Nutrients. 2018 Mar 30;10(4):432. doi: 10.3390/nu10040432.
citation: Almahmoud K, Namas RA, Abdul-Malak O, Zaaqoq AM, Zamora R, Zuckerbraun BS, Sperry J, Peitzman AB, Billiar TR, Vodovotz Y. Impact of Injury Severity on Dynamic Inflammation Networks Following Blunt Trauma. Shock. 2015 Aug;44(2):101-9. doi: 10.1097/SHK.0000000000000395.
citation: Namas RA, Vodovotz Y, Almahmoud K, Abdul-Malak O, Zaaqoq A, Namas R, Mi Q, Barclay D, Zuckerbraun B, Peitzman AB, Sperry J, Billiar TR. Temporal Patterns of Circulating Inflammation Biomarker Networks Differentiate Susceptibility to Nosocomial Infection Following Blunt Trauma in Humans. Ann Surg. 2016 Jan;263(1):191-8. doi: 10.1097/SLA.0000000000001001.
citation: Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, Hayden DL, Hennessy L, Moore EE, Minei JP, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Brownstein BH, Mason PH, Baker HV, Finnerty CC, Jeschke MG, Lopez MC, Klein MB, Gamelli RL, Gibran NS, Arnoldo B, Xu W, Zhang Y, Calvano SE, McDonald-Smith GP, Schoenfeld DA, Storey JD, Cobb JP, Warren HS, Moldawer LL, Herndon DN, Lowry SF, Maier RV, Davis RW, Tompkins RG; Inflammation and Host Response to Injury Large-Scale Collaborative Research Program. A genomic storm in critically injured humans. J Exp Med. 2011 Dec 19;208(13):2581-90. doi: 10.1084/jem.20111354. Epub 2011 Nov 21.
citation: Pape HC, Marcucio R, Humphrey C, Colnot C, Knobe M, Harvey EJ. Trauma-induced inflammation and fracture healing. J Orthop Trauma. 2010 Sep;24(9):522-5. doi: 10.1097/BOT.0b013e3181ed1361.
citation: Mazzocca AD, McCarthy MB, Intravia J, Beitzel K, Apostolakos J, Cote MP, Bradley J, Arciero RA. An in vitro evaluation of the anti-inflammatory effects of platelet-rich plasma, ketorolac, and methylprednisolone. Arthroscopy. 2013 Apr;29(4):675-83. doi: 10.1016/j.arthro.2012.12.005. Epub 2013 Feb 6.
citation: Zhang W, Mei R, Wu S. Ketorolac tromethamine represses senescence in aging articular chondrocytes. Biosci Biotechnol Biochem. 2022 Jun 25;86(7):837-845. doi: 10.1093/bbb/zbac047.
citation: Carvalho B, Lemmens HJ, Ting V, Angst MS. Postoperative subcutaneous instillation of low-dose ketorolac but not hydromorphone reduces wound exudate concentrations of interleukin-6 and interleukin-10 and improves analgesia following cesarean delivery. J Pain. 2013 Jan;14(1):48-56. doi: 10.1016/j.jpain.2012.10.002. Epub 2012 Dec 4.
citation: Kim MH, Hahm TS. Plasma levels of interleukin-6 and interleukin-10 are affected by ketorolac as an adjunct to patient-controlled morphine after abdominal hysterectomy. Clin J Pain. 2001 Mar;17(1):72-7. doi: 10.1097/00002508-200103000-00010.
citation: Singh P, Rastogi S, Bansal M, Kumar S, Singh R, Nishad SG, Reddy MP, Anand KR, Kumar S, Thayath MN. A prospective study to assess the levels of interleukin-6 following administration of diclofenac, ketorolac and tramadol after surgical removal of lower third molars. J Maxillofac Oral Surg. 2015 Jun;14(2):219-25. doi: 10.1007/s12663-013-0609-1. Epub 2014 Feb 18.
citation: Kuchalik J, Magnuson A, Tina E, Gupta A. Does local infiltration analgesia reduce peri-operative inflammation following total hip arthroplasty? A randomized, double-blind study. BMC Anesthesiol. 2017 May 3;17(1):63. doi: 10.1186/s12871-017-0354-y.
citation: Namas RA, Almahmoud K, Mi Q, Ghuma A, Namas R, Zaaqoq A, Zhu X, Abdul-Malak O, Sperry J, Zamora R, Billiar TR, Vodovotz Y. Individual-specific principal component analysis of circulating inflammatory mediators predicts early organ dysfunction in trauma patients. J Crit Care. 2016 Dec;36:146-153. doi: 10.1016/j.jcrc.2016.07.002. Epub 2016 Jul 11.
citation: Levy RM, Mollen KP, Prince JM, Kaczorowski DJ, Vallabhaneni R, Liu S, Tracey KJ, Lotze MT, Hackam DJ, Fink MP, Vodovotz Y, Billiar TR. Systemic inflammation and remote organ injury following trauma require HMGB1. Am J Physiol Regul Integr Comp Physiol. 2007 Oct;293(4):R1538-44. doi: 10.1152/ajpregu.00272.2007. Epub 2007 Jul 25.
citation: Giannoudis PV, Giannoudi M, Stavlas P. Damage control orthopaedics: lessons learned. Injury. 2009 Nov;40 Suppl 4:S47-52. doi: 10.1016/j.injury.2009.10.036.
citation: Billiar TR, Hunt BJ, Bailly S. Targeting inflammation in traumatic injury: entering a new era. Intensive Care Med. 2023 Aug;49(8):977-978. doi: 10.1007/s00134-023-07152-2. Epub 2023 Jul 19. No abstract available.
citation: Namas R, Ghuma A, Hermus L, Zamora R, Okonkwo DO, Billiar TR, Vodovotz Y. The acute inflammatory response in trauma / hemorrhage and traumatic brain injury: current state and emerging prospects. Libyan J Med. 2009 Sep 1;4(3):97-103. doi: 10.4176/090325.
citation: Giannoudis PV, Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, Bone Healing, and Anti-Inflammatory Drugs: An Update. J Orthop Trauma. 2015 Dec;29 Suppl 12:S6-9. doi: 10.1097/BOT.0000000000000465.
citation: Dodwell ER, Latorre JG, Parisini E, Zwettler E, Chandra D, Mulpuri K, Snyder B. NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies. Calcif Tissue Int. 2010 Sep;87(3):193-202. doi: 10.1007/s00223-010-9379-7. Epub 2010 Jun 15.
citation: Foster JA, Kavolus MW, Landy DC, Pectol RW, Sneed CR, Kinchelow DL, Griffin JT, Hawk GS, Aneja A. Low-Dose Short-Term Scheduled Ketorolac Reduces Opioid Use and Pain in Orthopaedic Polytrauma Patients: A Randomized Clinical Trial. J Orthop Trauma. 2023 Sep 25. doi: 10.1097/BOT.0000000000002703. Online ahead of print.
citation: Foster JA, Hawk GS, Landy DC, Griffin JT, Bernard AC, Oyler DR, Southall WGS, Muhammad M, Sierra-Arce CR, Mounce SD, Borgida JS, Xiang L, Aneja A. Does Scheduled Low-Dose Short-Term NSAID (Ketorolac) Modulate Cytokine Levels After Orthopaedic Polytrauma? A Secondary Analysis of a Randomized Clinical Trial. J Orthop Trauma. 2024 Jul 1;38(7):358-365. doi: 10.1097/BOT.0000000000002807.