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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