Table 5.
Summary of pharmacological interventions.
| Intervention (no. of papers) | Type of Study, Surgery | Author (year) [reference]1* | No.2† | Inflammatory Biomarker(S) Suppressed Yes–No: Biomarker3‡ | Clinical Benefit Yes–No: Outcome Modified | Comment |
| Methylprednisolone (6) | RCT, CABG | Giomarelli (2003) [55]4* | 105† | Yes: IL-6, IL-8, IL-10, TNFα6‡ | Yes: CK-MB, A-a O2 gradient | 1 g preoperatively, 5 × 125 mg postoperatively; improved myocardial protection creatine kinase MB fraction (CK-MB) and A-a O2 gradient |
| RCT, CABG | Demir (2009) [56] | 15 | Yes: IL-6, IL-10 | Yes: ICU stay, NSE | 1 g before CPB; improved intensive care unit (ICU) length of stay and levels of neuron specific enolase (NSE) | |
| RCT, CABG | Fillinger (2002) [57] | 15 | Yes: IL-6, IL-10 | No | 15 mg/kg preoperatively, 4 × .3 mg/kg postoperatively; less nausea but no other changes in clinical outcomes | |
| RCT, CABG | McBride (2004) [58] | 18 | Yes: IL-8, IL-10, TNF | No | 30 mg/kg before induction; no changes in clinical outcomes | |
| RCT, CABG | Bourbon (2004) [59] | 12 | Yes: IL-6, TNF | No | 10 mg/kg preoperatively; no clinical changes, no adverse events | |
| RCT, CABG | Liakopoulos (2007) [60] | 40 | Yes: IL-6, IL-18, IL-10, TNF, CRP | No | 15 mg/kg bolus preoperatively; improved troponin (Tn) T but worsened pulmonary shunt, hyperglycemia, and lactic acidosis | |
| Dexamethasone (6) | RCT, CABG | Von Spiegel (2004) [61] | 10 | N/D7§ | Yes: lung water | 1 mg/kg after induction; improvement in lung water; mild benefit |
| RCT, CABG | Halvorsen (2003) [62] | 147 | N/D | No | 4 mg perioperatively + 4 mg postoperatively; no change in hard clinical end points, inotrope use, or reoperation rates | |
| RCT, CABG | Loef (2004) [63] | 10 | N/D | No | 1 mg/kg at induction + .5 mg/kg postoperatively; significant glycosuria, controlled through insulin; no clinical benefit | |
| RCT, mixed valve/CABG | Yared (2007) [64] | 37 | No | No | .6-mg/kg bolus; no clinical benefit and could not demonstrate inflammatory suppression to a range of markers | |
| RCT, CABG | Sobiesky (2008) [65] | 13 | Yes: IL-6 | No | 100-mg bolus after induction; no change A-a O2 gradient or ICU stay; no clinical benefit | |
| RCT, CABG | Amr (2009) [66] | 50 | Yes: IL-6, IL-8 | No | 1 mg/kg at induction + .5 mg/kg postoperatively; significant hyperglycemia; no change in hard end points; no benefit | |
| Hydrocortisone (1) | RCT, mixed valve/CABG | Halonen (2007) [67] | 120 | Yes: CRP | No | 100 mg days 1–4 of operation; no change to any prespecified clinical end points |
| Cochrane review (1) | meta-analysis valve/CABG | Dieleman (2011) [68] | 1807 | N/D | No | No beneficial effect of corticosteroid use on mortality, cardiac, and pulmonary complications |
| C1 esterase inhibitor (2) | RCT, emergency CABG | Thielmann (2006) [69] | 28 | Yes: C3, C4 | Yes: cTnI | 40-IU/kg bolus + 20 IU/kg infusion showed myocardial protection (Trop. I) with earlier treatment from acute STEMI |
| RCT, emergency CABG | Fattouch (2007) [70] | 38 | Yes: C3a, C4 | Yes: ICU stay, cTnI | 1000 IU Cl INH provided convincing improvement in ICU length of stay and cardiac function (cTnI and wall motion) | |
| Complement C5 inhibitor (2) | RCT, mixed valve/CABG | Verrier (2004) [71] | 1378 | Yes: serum complement activity | No | Multicenter trial; missed primary end point 30-day death/Ml in CABG, but significant risk reduction in intent to treat analysis |
| RCT, mixed valve/CABG | Smith (2011) [72] | 2156 | Yes: serum complement activit1 | Yes: mortality | Analysis of combined PRIMO-CABG I and II trials; highest risk patients showed significant benefit at 30-day mortality | |
| Complement receptor 1 inhibitor (1) | RCT, mixed valve/CABG | Lazar (2004) [73] | 72 | Yes: C3a, C5b-9 | No | Striking gender bias; soluble CR1 significantly inhibited death/MI in males but not females; overall no benefit |
| Neutrophil elastase inhibitor (1) | RCT, valve | Fujii (2010) [74] | 6 | Yes: IL-6, IL-8, NE | Yes: PaO2/FiO2 ratio | Infusion of neutrophil elastase inhibitor significantly improved PaO2/FiO2 ratio |
| Urinary protease inhibitor (2) | RCT, CABG | Bingyang (2007) [75] | 15 | Yes: IL-6, IL-8, NE, TNFα | Yes: ventilator time, A-a O2 gradient | Documented antiprotease activity is against neutrophil elastase; improved ventilator time and A-a O2 gradient |
| RCT, valve | Song (2011) [76] | 24 | No | Yes: ICU stay | Infusion or urintary proteas inhibitor significantly improved ICU stay; no change in inflammatory mediators | |
| Sodium nitroprusside (1) | RCT, CABG | Gol (2002) [77] | 10 | Yes: IL-6 | Yes: ICU stay, inotropes | Na nitroprusside (NO donor) intravenously after x-clamp release; convincing improvement ICU stay and need for inotropes |
| Intervention (no. of papers) | Type of Study, Surgery | Author (year) [reference]8* | No.9† | Inflammatory Biomarker(S) Suppressed Yes–No: Biomarker10‡ | Clinical Benefit Yes–No: Outcome Modified | Comment |
| Aminophylline (2) | RCT, valve | Luo (2004) [78] | 15 | Yes: IL-8, IL-10, TNFα | Yes: ICU stay, ventilator time | Perioperative aminophylline infusion significantly improved ventilator time and ICU length of stay |
| RCT, valve | Luo (2007) [79] | 15 | Yes: neutrophil myeloperoxidase | Yes: cTnI | Significant myocardial protection (TnI); fewer neutrophils in coronary sinus with less myeloperoxidase on biopsies | |
| Glutamine (1) | RCT, mixed valve/CABG | Engel (2009) [80] | 31 | Yes: IL-2, IFN-γ, NE | No | Infusion of glutamine after induction to postoperative day 3 did not affect ventilation time, ICU stay, or organ dysfunction |
| Taurine (1) | RCT, CABG | Doddakula (2010) [81] | 15 | Yes: IL-6 | No | Infusion of a 2% solution of the antioxidant agent taurine did not affect hard clinical end points or ICU stay |
| Erythropoietin (1) | RCT, mixed valve/CABG | Poulsen (2009) [82] | 22 | No | No | 2 × 500 IU/kg doses at days −1 and +1; no change in prespecified clinical outcomes |
| Aprotinin (1) | RCT, CABG | Kipfer (2003) [83] | 15 | No | No | Bleeding and transfusion benefits; no change in permitted clinical outcomes |
| Dual-dose tranexamic acid (1) | RCT, CABG | Jimenez (2011) [84] | 80 | No | No | Double-dose TXA (40 + 40 mg/kg) versus single-dose control; unwanted trend towards increased mortality and seizures |
| N-acetyl cysteine (1) | RCT, CABG | El-Hamamsy (2007) [85] | 50 | No | No | Intravenous infusion; concerning trend toward increased death and MI; also trend toward myocardial injury (CK-MB and TnT) |
| Lidocaine (1) | RCT, mixed valve/CABG | Mathew (2009) [86] | 114 | No | No | Interaction of lidocaine with diabetes caused significant postoperative cognitive decline |
| Ethylpyruvate (1) | RCT, mixed valve/CABG | Bennett-Guerrero (2009) [87] | 49 | No | No | Infusion of ethyl pyruvate did not affect death, MI, ARF, or a raft of clinical markers or hospital resource end points |
| Propofol (1) | RCT, valve | An (2008) [88] | 15 | Yes: IL-8, oxidative stress | Yes: ICU stay, ventilation time | Propofol targeted infusion during cross-clamp improved ventilation time, lung compliance and ICU stay |
| Isoflurane + propofol (1) | RCT, CABG | Huang (2011) [89] | 30 | Yes:IL-6, TNFα, oxidative stress | Yes: CK-MB, cTnI | Synergistic protective effect of isoflurane with propofol on ICU stay and myocardial protection (CK-MB and TnI) |
| Sevoflurane (2) | RCT, valve | Kawamura (2006) [90] | 13 | Yes: IL-6, IL-8 | Yes: CK-MB, TnT | Fentanyl + sevoflurane anesthesia versus fentanyl + propofol control; convincing myocardial protection (CK-MB and TnT) |
| RCT, valve | Cho (2009) [91] | 15 | Yes: IL-6, IL-10 | No | Sevoflurane anesthesia versus fentanyl + midazolam control; no change in ICU stay or other clinical end points | |
| NO gas (1) | RCT, valve | Gianetti (2004) [92] | 14 | Yes: soluble P-selectin | Yes: CK-MB, cTnI, BNP | Continuous NO inhalation perioperatively and in ICU; protection of myocardial injury markers (CK-MB, TnI, and BNP) |
| L-Arginine in cardioplegia (1) | RCT, CABG | Colagrande (2006) [93] | 33 | Yes: IL-6, TNFα | Yes: ICU stay, CK-MB, cTnI | L-arginine (nitric oxide substrate) added to cardioplegia; convincing improvement in ICU stay, CK-MB, and TnI |
| Propionyl L-Carnitine (1) | RCT, CABG | Lango (2005) [94] | 21 | Yes: endothelin, oxidative stress | Yes: lactate | Diabetic cohort; propionyl L-carnitine in cardioplegia significantly improved cardiac index, SVR, PVR, and lactate |
| Adenosine (1) | RCT, valve | Koksal (2008) [95] | 15 | Yes: neutrophil count | No | Adenosine as an adjunct to cardioplegia did not improve clinical end points or confer significant myocardial protection |
| Hydroxyethyl starch in prime (1) | RCT, valve | Choi (2010) [96] | 28 | Yes: NE | No | Hydroxyethyl starch used as priming solution, versus albumin control, did not affect ICU stay or inotrope use |
| Gelatin colloid (1) | RCT, CABG | Tamayo (2008) [97] | 22 | No | No | Priming with gelatin colloid, versus crystalloid control, had no effect on ventilation time, ICU stay, or need for inotropes |
| N-acetyl cysteine (1) | RCT, CABG | Liu (2009) [98] | 15 | No | No | In cardioplegia; no change in hard clinical end points but same trend as with intravenous infusion toward myocardial injury (CK-MB) |
*
Number in square bracket refers to reference number in the Appendix B.
†
N = number of subjects in treatment group.
‡
Abbreviations used: RCT, randomized controlled trial; CABG, coronary artery bypass grafting; IL, interleukin; TNF, tumor necrosis factor; NE, neutrophil elastase; CRP, C-reactive protein; A-a O2, arterial–alevolar oxygen gradient; CK-MB, creatine kinase MB fraction; cTn, cardiac-specific troponin; ICU, intensive care unit; STEMI, ST-elevation myocardial infarction.
§
N/D, not done.