Drugs with anti-inflammatory effects to improve outcome of traumatic brain injury: a meta-analysis

Marieke Begemann, Mikela Leon, Harm Jan van der Horn, Joukje van der Naalt, Iris Sommer, Marieke Begemann, Mikela Leon, Harm Jan van der Horn, Joukje van der Naalt, Iris Sommer

Abstract

Outcome after traumatic brain injury (TBI) varies largely and degree of immune activation is an important determinant factor. This meta-analysis evaluates the efficacy of drugs with anti-inflammatory properties in improving neurological and functional outcome. The systematic search following PRISMA guidelines resulted in 15 randomized placebo-controlled trials (3734 patients), evaluating progesterone, erythropoietin and cyclosporine. The meta-analysis (15 studies) showed that TBI patients receiving a drug with anti-inflammatory effects had a higher chance of a favorable outcome compared to those receiving placebo (RR = 1.15; 95% CI 1.01-1.32, p = 0.041). However, publication bias was indicated together with heterogeneity (I2 = 76.59%). Stratified analysis showed that positive effects were mainly observed in patients receiving this treatment within 8 h after injury. Subanalyses by drug type showed efficacy for progesterone (8 studies, RR 1.22; 95% CI 1.01-1.47, p = 0.040), again heterogeneity was high (I2 = 62.92%) and publication bias could not be ruled out. The positive effect of progesterone covaried with younger age and was mainly observed when administered intramuscularly and not intravenously. Erythropoietin (4 studies, RR 1.20; p = 0.110; I2 = 76.59%) and cyclosporine (3 studies, RR 0.75; p = 0.189, I2 = 0%) did not show favorable significant effects. While negative findings for erythropoietin may reflect insufficient power, cyclosporine did not show better outcome at all. Current results do not allow firm conclusions on the efficacy of drugs with anti-inflammatory properties in TBI patients. Included trials showed heterogeneity in methodological and sample parameters. At present, only progesterone showed positive results and early administration via intramuscular administration may be most effective, especially in young people. The anti-inflammatory component of progesterone is relatively weak and other mechanisms than mitigating overall immune response may be more important.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Flow diagram of the systematic search and study selection.
Figure 2
Figure 2
Meta-analysis including 15 studies evaluating the effect of drugs with anti-inflammatory properties on a favorable outcome in TBI patients.
Figure 3
Figure 3
Funnel plot showing publication bias in the overall analyses (15 studies), including imputed studies (black circles).
Figure 4
Figure 4
Moderator analysis for the 8 progesterone studies, risk ratio covaries with mean age of the included study samples.

References

    1. Finnie J. Neuroinflammation: Beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology. 2013;21:309–320. doi: 10.1007/s10787-012-0164-2.
    1. Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, Bullock MR, Choi SC, Clifton GL, Contant CF, Coplin WM, Dietrich WD, Ghajar J, Grady SM, Grossman RG, Hall ED, Heetderks W, Hovda DA, Jallo J, Katz RL, Knoller N, Kochanek PM, Maas AI, Majde J, Marion DW, Marmarou A, Marshall LF, McIntosh TK, Miller E, Mohberg N, Muizelaar JP, Pitts LH, Quinn P, Riesenfeld G, Robertson CS, Strauss KI, Teasdale G, Temkin N, Tuma R, Wade C, Walker MD, Weinrich M, Whyte J, Wilberger J, Young AB, Yurkewicz L. Clinical trials in head injury. J. Neurotrauma. 2002;19:503–557. doi: 10.1089/089771502753754037.
    1. Benedictus MR, Spikman JM, van der Naalt J. Cognitive and behavioral impairment in traumatic brain injury related to outcome and return to work. Arc. Phys. Med. Rehabil. 2010;91:1436–1441. doi: 10.1016/j.apmr.2010.06.019.
    1. Cifu D, Caruso D. Traumatic Brain Injury: Rehabilitation Medicine Quick Reference. 1. Demos Medical Publishing: New York; 2010.
    1. Cederberg D, Siesjö P. What has inflammation to do with traumatic brain injury? Childs Nerv. Syst. 2010;26:221–226. doi: 10.1007/s00381-009-1029-x.
    1. Russo M, McGavern D. Inflammatory neuroprotection following traumatic brain injury. Science (NY) 2016;353:783–785. doi: 10.1126/science.aaf6260.
    1. Schmidt OI, Heyde CE, Ertel W, Stahel PF. Closed head injury—An inflammatory disease? Brain Res. Rev. 2005;48:388–399. doi: 10.1016/j.brainresrev.2004.12.028.
    1. Morganti-Kossmann MF, Rancan M, Stahel P, Kossmann T. Inflammatory response in acute traumatic brain injury: A double-edged sword. Curr. Opin. Crit. Care. 2002;8:101–105. doi: 10.1097/00075198-200204000-00002.
    1. Lenzlinger P, Morganti-Kossmann M, Laurer H, Mcintosh T. The duality of the inflammatory response to traumatic brain injury. Mol. Neurobiol. 2001;24:169–181. doi: 10.1385/MN:24:1-3:169.
    1. Zhou ZW, Li F, Zheng ZT, Li YD, Chen TH, Gao WW, Chen JL, Zhang JN. Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury. Brain Behav. 2017;7:E00827. doi: 10.1002/brb3.827.
    1. Meng Y, Xiong Y, Mahmood A, Zhang Y, Qu C, Chopp M. Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. J. Neurosurg. 2011;115:550–560. doi: 10.3171/2011.3.JNS101721.
    1. Yatsiv I, Grigoriadis N, Simeonidou C, Stahel PF, Schmidt OI, Alexandrovitch AG, Tsenter J, Shohami E. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J. 2005;19:1701–1703. doi: 10.1096/fj.05-3907fje.
    1. Bergold P. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp. Neurolog. 2016;275:367–380. doi: 10.1016/j.expneurol.2015.05.024.
    1. Blumbergs PC. Pathology. In: Reilly PL, Bullock R, editors. Head Injury. Pathophysiology and Management. London: Hodder Arnold; 2005. pp. 41–72.
    1. Mazzeo AT, Brophy GM, Gilman CB, Alves ÓL, Robles JR, Hayes RL, Povlishock JT, Bullock MR. Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: Results from a prospective randomized trial. J. Neurotrauma. 2009;26:2195–2206. doi: 10.1089/neu.2009.1012.
    1. Sommer I, Van Westrhenen R, Begemann M, De Witte L, Leucht S, Kahn R. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: An update. Schizophr. Bull. 2014;40:181–191. doi: 10.1093/schbul/sbt139.
    1. Chen G, Shi JX, Qi M, Wang HX, Hang CH. Effects of progesterone on intestinal inflammatory response, mucosa structure alterations, and apoptosis following traumatic brain injury in male rats. J. Surg. Res. 2008;147:92–98. doi: 10.1016/j.jss.2007.05.029.
    1. Lei B, Mace B, Dawson HN, Warner DS, Laskowitz DT, James ML, et al. Anti-inflammatory effects of progesterone inlipopolysaccharide-stimulated BV-2 microglia. PloS one. 2014;9(7):e103969. doi: 10.1371/journal.pone.0103969.
    1. Shukla D, Devi BI, Agrawal A. Outcome measures for traumatic brain injury. Clin. Neurol. Neurosurg. 2011;113:435–441. doi: 10.1016/j.clineuro.2011.02.013.
    1. Lin C, He H, Li Z, Liu Y, Chao H, Ji J, Liu N. Efficacy of progesterone for moderate to severe traumatic brain injury: A meta-analysis of randomized clinical trials. Sci. Rep. 2015;5:13442. doi: 10.1038/srep13442.
    1. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann. Emerg. Med. 2007;49:391–402. doi: 10.1016/j.annemergmed.2006.07.932.
    1. Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, Epo Severe TBI, Investigators T, Baldwin A, Rivera Lara L, Saucedo-Crespo H, Ahmed O, Sadasivan S, Ponce L, Cruz-Navarro J, Shahin H, Aisiku IP, Doshi P, Valadka A, Neipert L, Waguspack JM, Rubin ML, Benoit JS, Swank P. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial. JAMA. 2014;312:36–47. doi: 10.1001/jama.2014.6490.
    1. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. Chichester: Wiley; 2009.
    1. Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Database Syst. Rev. 2005;1:CD000196.
    1. Gregson B, Todd NV, Crawford D, Gerber CJ, Fulton B, Tacconi L, Crawford PJ, Sengupta RP. CRASH trial is based on problematic meta-analysis. BMJ. 1999;319:578. doi: 10.1136/bmj.319.7209.578.
    1. CRASH Trial Collaborators Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH trial): Randomised placebo-controlled trial. Lancet. 2004;364:1321–1328. doi: 10.1016/S0140-6736(04)17188-2.
    1. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Crit. Care. 2008;12:R61. doi: 10.1186/cc6887.
    1. Aminmansour B, Nikbakht H, Ghorbani A, Rezvani M, Rahmani P, Torkashvand M, Nourian M, Moradi M. Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: A randomized clinical trial with placebo group. Adv. Biomed. Res. 2012;1:58–58. doi: 10.4103/2277-9175.100176.
    1. Shakeri M, Boustani MR, Pak N, Panahi F, Salehpour F, Lotfinia I, Meshkini A, Daghighi S, Khani M, Taghiloo D. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clin. Neurol. Neurosurg. 2013;115:2019–2022. doi: 10.1016/j.clineuro.2013.06.013.
    1. Skolnick B, Maas A, Narayan R, Van der Hoop R, MacAllister T, Ward J, Nelson NR, Stocchetti N. A clinical trial of progesterone for severe traumatic brain injury. N. Eng. J. Med. 2014;371:2467–2476. doi: 10.1056/NEJMoa1411090.
    1. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG. Very early administration of progesterone for acute traumatic brain injury. N. Eng. J. Med. 2014;371:2457–2466. doi: 10.1056/NEJMoa1404304.
    1. Soltani Z, Shahrokhi N, Karamouzian S, Khaksari M, Mofid B, Nakhaee N, Reihani H. Does progesterone improve outcome in diffuse axonal injury? Brain Inj. 2017;31:16–23. doi: 10.1080/02699052.2016.1213421.
    1. Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, Bailey M, Cooper DJ, Duranteau J, Huet O, Mak A. Erythropoietin in traumatic brain injury (EPO-TBI): A double-blind randomised controlled trial. Lancet. 2015;386:2499–2506. doi: 10.1016/S0140-6736(15)00386-4.
    1. Li ZM, Xiao YL, Zhu JX, Geng FY, Guo CJ, Chong ZL, Wang LX. Recombinant human erythropoietin improves functional recovery in patients with severe traumatic brain injury: A randomized, double blind and controlled clinical trial. Clin. Neurol. Neurosurg. 2016;150:80–83. doi: 10.1016/j.clineuro.2016.09.001.
    1. Bai XF, Gao YK. Recombinant human erythropoietin for treating severe traumatic brain injury. Medicine. 2018;97:e9532. doi: 10.1097/MD.0000000000009532.
    1. Hatton J, Rosbolt B, Empey P, Kryscio R, Young B. Dosing and safety of cyclosporine in patients with severe brain injury. J. Neurosurg. 2008;109:699–707. doi: 10.3171/JNS/2008/109/10/0699.
    1. Sinha S, Raheja A, Samson N, Goyal K, Bhoi S, Selvi A, Sharma P, Sharma BS. A randomized placebo-controlled trial of progesterone with or without hypothermia in patients with acute severe traumatic brain injury. Brain Inj. 2016;30:687.
    1. Aminmansour B, Fard S, Habibabadi M, Moein P, Norouzi R, Naderan M. The efficacy of cyclosporine-A on diffuse axonal injury after traumatic brain injury. Adv. Biomed. Res. 2014;3:35. doi: 10.4103/2277-9175.125031.
    1. Howard RB, Sayeed I, Stein DG. Suboptimal dosing parameters as possible factors in the negative phase III clinical trials of progesterone for traumatic brain injury. J. Neurotrauma. 2017;34:1915–1918. doi: 10.1089/neu.2015.4179.
    1. Cutler SM, Pettus EH, Hoffman SW, Stein DG. Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury. Exp. Neurol. 2005;195:423–429. doi: 10.1016/j.expneurol.2005.06.003.
    1. Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG. Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats. Horm. Behav. 2013;64:527–538. doi: 10.1016/j.yhbeh.2013.06.009.
    1. Cherian L, Goodman J, Robertson C. Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J. Pharmacol. Exp. Ther. 2007;322:789–794. doi: 10.1124/jpet.107.119628.
    1. Si D, Li J, Liu J, Wang X, Wei Z, Tian Q, Wang H, Liu G. Progesterone protects blood-brain barrier function and improves neurological outcome following traumatic brain injury in rats. Exp. Ther. Med. 2014;8:1010–1014. doi: 10.3892/etm.2014.1840.
    1. Cutler S, Cekic M, Miller D, Wali B, Vanlandingham J, Stein D. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J. Neurotrauma. 2007;24:1475–1486. doi: 10.1089/neu.2007.0294.
    1. Hua F, Wang J, Ishrat T, Wei W, Atif F, Sayeed I, Stein D. Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: Effect of exogenous progesterone. J. Neuroinflamm. 2011;8:42. doi: 10.1186/1742-2094-8-42.
    1. Pan ZY, Zhao YH, Huang WH, Xiao ZZ, Li ZQ. Effect of progesterone administration on the prognosis of patients with severe traumatic brain injury: A meta-analysis of randomized clinical trials. Drug Des. Devel. Ther. 2019;13:265–273. doi: 10.2147/DDDT.S192633.
    1. Stein DG, Cekic MM. Progesterone and vitamin d hormone as a biologic treatment of traumatic brain injury in the aged. PM R. 2011;3:S100–S110. doi: 10.1016/j.pmrj.2011.03.010.
    1. Kawakami M, Iwasaki S, Sato K, Takahashi M. Erythropoietin inhibits calcium-induced neurotransmitter release from clonal neuronal cells. Biochem. Biophys. Res. Commun. 2000;279:293–297. doi: 10.1006/bbrc.2000.3926.
    1. Lee J, Cho Y, Choi K, Kim W, Jang B, Shin H, Ahn C, Lim TH, Yi H. Efficacy and safety of erythropoietin in patients with traumatic brain injury: A systematic review and meta-analysis. Am. J Emerg. Med. 2019;37:1101–1107. doi: 10.1016/j.ajem.2018.08.072.
    1. Gantner DC, Bailey MJ, Presneill J, French C, Nichol A, Little L, Bellomo R. erythropoietin to reduce mortality in traumatic brain injury: A post-hoc dose-effect analysis. Ann. Surg. 2018;267:585–589. doi: 10.1097/SLA.0000000000002142.
    1. Pahl A, Zhang M, Török K, Kuss H, Friedrich U, Magyar Z, Szekely J, Horvath K, Brune K, Szelenyi I. Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787. J. Pharmacol. Exp. Ther. 2002;301:738–746. doi: 10.1124/jpet.301.2.738.
    1. Yadav S, Pawar G, Kulkarni P, Ferris C, Amiji M. CNS delivery and anti-inflammatory effects of intranasally administered ayclosporine-A in cationic nanoformulations. J. Pharmacol. Exp. Ther. 2019;370:843–854. doi: 10.1124/jpet.118.254672.
    1. Sullivan P, Sebastian A, Hall E. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. J. Neurotrauma. 2011;28:311–318. doi: 10.1089/neu.2010.1646.
    1. Joseph B, Khan M, Rhee P. Non-invasive diagnosis and treatment strategies for traumatic brain injury: An update. J. Neurosci. Res. 2018;96:589–600. doi: 10.1002/jnr.24132.
    1. Goldstein F, Caveney A, Hertzberg V, Silbergleit R, Yeatts S, Palesch Y, Levin HS, Wright DW. Very early administration of progesterone does not improve neuropsychological outcomes in subjects with moderate to severe traumatic brain injury. J. Neurotrauma. 2017;34:115–120. doi: 10.1089/neu.2015.4313.
    1. Wilson J, Pettigrew L, Teasdale G. Emotional and cognitive consequences of head injury in relation to the Glasgow outcome scale. J. Neurol. Neurosurg. Psychiatry. 2000;69:204–209. doi: 10.1136/jnnp.69.2.204.
    1. Gruenbaum SE, Zlotnik A, Gruenbaum BF, Hersey D, Bilotta F. Pharmacologic neuroprotection for functional outcomes after traumatic brain injury: A systematic review of the clinical literature. CNS Drugs. 2016;30:791–806. doi: 10.1007/s40263-016-0355-2.
    1. Sanchez-Aguilar M, Tapia-Perez JH, Sanchez-Rodriguez JJ, Vinas-Rios JM, Martinez-Perez P, de la Cruz-Mendoza E, Sánchez-Reyna M, Torres-Corzo JG, Gordillo-Moscoso A. Effect of rosuvastatin on cytokines after traumatic head injury. J. Neurosurg. 2013;118(3):669–675. doi: 10.3171/2012.12.JNS121084.
    1. Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: A phase II randomized control trial. J. Cerebr. Blood F. Met. 2014;34(5):845–851. doi: 10.1038/jcbfm.2014.23.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit