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Table 1 Shows summary of the included trials key features

From: Histidine–tryptophan–ketoglutarate solution versus multidose cardioplegia for myocardial protection in cardiac surgeries: a systematic review and meta-analysis

Study ID Country Sample size Eligibility criteria HTK solution administration Type of MDC MDC administration
Ali et al. [16] Egypt 320 patients (160 in each group) The study included patients aged between 30 and 70 years, who were posted for various cardiac surgeries. Patients having unstable angina (class III/IV), LVEF < 40%, acute MI, renal failure history, or emergency cardiac surgery were excluded 30 ml/kg of the solution were administered over 6–7 min, at 4 °C, through an antegrade route. The solution was delivered within 12–15 min at an initial pressure of 80–100 mmHg, which was reduced to 40–60 mmHg after myocardial arrest Blood One liter of the 4:1 (blood:crystalloid) mixture was administered at ≤ 29 °C. The mixture was delivered through an antegrade route at a pressure of 80–100 mmHg, and was repeated every 30–45 min. Before myocardial perfusion, another warm blood retrograde dose was administered
Cvetković et al. [17] Serbia 104 patients (54 for HTK, and 50 for MDC) The study included adult patients undergoing CABG, having at least two angiographic graftable target vessels (> 2.0 mm in diameter, with ≥ 70% stenosis), LVEF ≥ 30%, and normal valves. Patients > 80 years, having MI within a month of the operation, reoperation, medical emergency off-pump CABG, ongoing myocardial ischemia, pericarditis, coronary endarterectomy, LV surgical restoration, left main stenosis > 50%, or serum creatinine > 200 µmol/L were excluded 20 mL/kg of the solution were administered over 6–8 min, at 4–8 °C, through an antegrade route Crystalloid An initial one liter of St.Thomas solution was administered, over 3–5 min, at 4–8 °C, through an antegrade route. This was followed by maintenance doses of 200 mL over 2 min every 20 min
Vivacqua et al. [18] US 110 patients (55 in each group) The study included patients undergoing a cardiovascular surgery that needs cardioplegia. Previous cardiovascular surgery, pregnancy, medical emergency, and dialysis were exclusion criteria 20 mL/kg of the solution were administered over 6–8 min, at 4–5 °C, through an antegrade route. In case of aortic insufficiency, a retrograde infusion was used Blood One liter of the 4:1 (blood:crystalloid) mixture was administered at 4–8 °C. The mixture was delivered through an antegrade route at a pressure of ≤ 300 mmHg. In case of aortic insufficiency, a retrograde infusion was used. A maintenance dose of 200 mL, with lower potassium 25 mEq/500 mL was delivered every 20 min thereafter
Gaudino et al. [19] Italy 60 patients (31 for HTK, and 29 for MDC) The study included patients undergoing elective mitral valve surgery. Patients with other valvular, coronary, or carotid pathology, previous cerebrovascular accident, any neurological risk factor, or pre-operative renal insufficiency were excluded 30 ml/Kg of the ice-cold solution were administered over 6–8 min, through an antegrade route, at a pressure of 100–110 mmHg Blood An initial 300 mL/min of the warm blood were administered over two minutes through an antegrade route. Subsequent doses of 200 mL/min over two minutes were delivered. Potassium (2 mEq/mL) was added at an initial rate of 150 mL/h, followed by 120, 90, 60 mL/h at subsequent doses, and maintenance rate of 40 mL/h. The doses were delivered every 15 min
Mercan et al. [25] Turkey 50 patients (25 in each group) The study included patients undergoing elective CABG, who were aged 40–80 years. Having valvulopathy, LVEF < 30%, chronic renal failure, impaired Liver function test result, emergency or redo surgery, history of cerebrovascular or carotid artery disease, history of cardiopulmonary resuscitation were exclusion criteria 20 ml/kg of the solution were administered through an antegrade route. A terminal warm cardioplegia was delivered Blood 15 ml/kg of the 4:1 (blood:crystalloid) mixture were administered at 4 °C initially, through an antegrade route. This was followed by a maintenance dose of 10 ml/kg every 20 min. A terminal warm cardioplegia was delivered
Kammerer et al. [20] Germany 107 patients (55 for HTK, and 52 for MDC) The study included patients undergoing elective mitral valve surgery. Patients with aortic valvulopathy or coronary artery disease were excluded Two liters f the solution were administered at 4 °C, through an antegrade route, with a pressure of 50 mmHg Blood Warm blood cardioplegia according to the modified Calafiore protocol, at 35 °C. 40 ml of 2 mmol/ml KCl and 10 ml of 2 mmol/ml MgSO4 were delivered. The solution was readministered every 20 min
Braathen et al. [10] Norway and Sweden 76 patients (38 in each group) The study included patients undergoing elective mitral valve surgery for mitral regurgitation (≥ grade 3). Patients with other valvulopathy or coronary artery stenosis (50%) were excluded 1800 mL of the solution were administered over 6–8 min, at 4–8 °C, through an antegrade route, with a pressure from approximately 2 m height Blood 900 mL of the 4:1 (blood:crystalloid) mixture were administered at 4–8 °C, through an antegrade route. A maintenance dose of 500 mL was delivered every 20 min thereafter. The solution was delivered with a pressure of ≤ 300 mmHg
Demmy et al. [21] US 136 patients (68 in each group) The study included patients between 35 and 80 years of age, undergoing CABG. Recent MI, valvulopathy that needs surgery, LVEF < 20%, need for mechanical circulatory support, prior CABG surgery, use of aprotinin, participation in another studies within a month of the operation, cardiogenic shock, or severe chronic obstructive lung disease were exclusion criteria Four liters of the solution were administered over 6–7 min, at 4–6 °C, through an antegrade route, with a pressure < 80 mmHg Crystalloid One liter of Plegisol solution was administered at 4–6 °C, through an antegrade route, with a pressure of 80 mmHg. The solution was readministered every 20 min, with a pressure of 40 mmHg. the solution was infused over 1–4 min
Arslan et al. [22] Turkey 48 patients (21 in each group) The study included patients undergoing CABG 10–15 mL/kg of the solution were administered as antegrade single doses Crystalloid 10–15 mL/kg of cold potassium solution were administered through antegrade route
Careaga et al. [23] Mexico 30 patients (15 in each group) The study included patients undergoing elective open heart surgery, who had no previous cardiac surgery 300 cc/kg of the solution were administered at 4–8 °C, through an antegrade route, with a pressure of 100 mmHg Crystalloid 300 cc/m2 of cold potassium solution were administered every 20 min, at 4–8 °C, through an antegrade route, with a pressure of 100–120 mmHg
Beyersdorf et al. [24] Germany 37 patients (12 for HTK, and 12 for MDC) The study included patients undergoing CABG Two liters of the solution were administered at 4–6 °C, with a pressure of 100 mmHg initially, and 50 mmHg after cardiac asystole Blood 250–300 mL/min of the 4:1 (blood:crystalloid) mixture were administered initially over 3 min, at 8–14 °C, with a pressure of 100 mmHg. Thereafter, a repeated dose of 200 mL/min over 2 min was delivered every 20 min. Following asystole, the potassium dose was reduced
Gallandat huet et al. [6] Netherlands 249 patients (132 for HTK, and 117 for MDC) The study included patients undergoing CABG 20–25 mL/kg of the solution were administered at 4 °C, through an antegrade route, by gravity from a height of 1.5 m. Reinfusion dose of 300–500 mL was delivered after 45 min or when needed. The total final amount is about 2500 ml Crystalloid One liter of ST.Thomas solution (alkalinized with 10 mmol/I sodium bicarbonate) was administered at 4 °C, through an antegrade route, with a pressure of 150 mmHg. The solution infused with a pressure bag at 150 mm Hg. The pressure in the aorta root is then about 70 mmHg (13). Reinfusion dose of 300–500 mL was delivered after 45 min or when needed. The total final amount is about 1700 ml
  1. HTK solution: Histidine–tryptophan–ketoglutarate solution, MDC: multiple dose cardioplegia, CABG: coronary artery bypass grafting, LV: left ventricle, LVEF: left ventricular ejection fraction, MI: myocardial infarction, US: United States