Custodiol (Solution) Instructions for Use

Marketing Authorization Holder

Dr. F. Kohler Chemie GmbH (Germany)

ATC Code

B05XA16 (Cardioplegic solutions)

Dosage Form

Custodiol

Solution for perfusion: 500 ml fl.; 1 L, 2 L or 5 L bags

Dosage Form, Packaging, and Composition

500 ml – bottles (10) – cardboard boxes.
1 L – polyethylene bags (6) – cardboard boxes.
2 L – polyethylene bags (4) – cardboard boxes.
5 L – polyethylene bags (2) – cardboard boxes.

Clinical-Pharmacological Group

Cardioplegic agent

Pharmacotherapeutic Group

Cardioplegic agent

Pharmacological Action

Cardioplegic solution. It provides effective heart protection under conditions of general moderate hypothermia during heart ischemia lasting up to 180 minutes after a single administration. CUSTODIOL contains a histidine buffer, which eliminates the need for preoxygenation. The hyponatremic buffer provides an intracellular mechanism for tissue protection. The use of CUSTODIOL increases the resistance of myocardial, kidney, liver, and other internal organ tissues to hypoxia due to the presence of balanced components in its composition that provide metabolic protection of cells and their ionic balance.

Indications

• Cardioplegia;
• Organ protection (heart, liver, kidneys, lungs) during transplantation, transport, and grafting from donor to recipient;
• Protection of a venous graft (mainly the great saphenous vein) during coronary artery bypass grafting.

ICD codes

Dosage Regimen

Heart. In adults, the solution, cooled to 5-8°C (41-46.4°F), is administered under a hydrostatic pressure of about 100 mm Hg (the bottle with the solution is placed 140 cm above the level of the heart) or using a pump with a constant flow rate and perfused through the coronary arteries. Within the first minute from the start of perfusion, the heart stops, and then the pressure is reduced to 40-50 mm Hg (the bottle is lowered to 50-70 cm above the level of the heart). In cases of significant coronary artery stenosis, pressure at the upper limit of the interval (i.e., about 50 mm Hg) is recommended. The total perfusion time is determined by the need for system equilibration and is 6-8 minutes.

In children, the heart is also perfused for 6-8 minutes at a perfusion pressure of 40-50 mm Hg and a solution flow rate of 1 ml/min/g of heart weight.

The kidney is perfused at a perfusion pressure not exceeding 120 mm Hg.

Liver. The solution consumption should be about 20 L (based on 300 ml per 1 kg of donor body weight) per one transplantation with a perfusion duration of about 10 minutes through a cannula with an internal diameter of 5 mm.

The venous graft (usually a part of the great saphenous vein) is placed in CUSTODIOL solution cooled to 5-8°C (41-46.4°F) (50-100 ml) and stored in it. It is implanted after removal from the solution.

Adverse Reactions

None have been detected in clinical practice or experiments, nor have they been reported in the literature. In case of possible entry of the drug into the general circulatory system, changes in sodium and calcium ion concentrations are insignificant. However, if the analysis of sodium and calcium ion levels in the extracorporeal circulation confirms their deficiency, both electrolytes should be replenished.

Contraindications

Currently unknown. The drug is not intended for any type of injection or infusion.

Special Precautions

Auxiliary equipment

• Perfusion set with a Y-connector for two bottles and a perfusion tube of the required length and an internal diameter of at least 5 mm.
• Perfusion cannulas (internal diameter from 2.5 to 6 mm)
• Tube clamps
• Perfusion stand up to 200 cm, height-adjustable, equipped with a measuring scale.
• Cooling unit (ensures cooling of the solution to 5-8 degrees Celsius).

Heart tolerance to ischemia is determined both by the flawless performance of perfusion from its very beginning and by myocardial temperature, temperature in the area of extracorporeal circulation, existing heart damage, etc. In general, under conditions of moderate systemic hypothermia (27-29°C (80.6-84.2°F)), 180-minute aortic cross-clamping is well tolerated by the heart without additional cooling, provided that the recovery stage does not exceed 20 minutes.

If atrial or ventricular activity is detected during the period of artificial cardiac arrest, an additional amount of CUSTODIOL, cooled to 5-8°C (41-46.4°F), is perfused under the same conditions. It should be remembered that achieving the specified duration of myocardial protection assumes effective equalization of temperatures across myocardial areas, as well as maximally balanced filling of the intracellular and intercellular space of the myocardium with CUSTODIOL solution.

Onset of cardioplegia. After connecting the heart-lung machine, a purse-string or U-shaped suture (PDS 4-0) with a loop for securing the perfusion cannula and a vent drain is placed at the highest point of the ascending aorta. The solution should be taken out of the refrigerator immediately before its use to avoid heating of the liquid under the influence of the environment. Saturation of the solution with pure oxygen or a mixture of oxygen and carbon dioxide is not required; moreover, it may have a negative effect. The solution contains a sufficient amount of oxygen (0.6 vol.%) necessary to meet the needs of the arrested heart under cardioplegia conditions (temperature 10°C (50°F), perfusion rate 0.2 ml/min/100 g of heart weight). When connecting the perfusion system to the container with the cardioplegic solution, attention should be paid to thorough venting of the hose system: the air bubble trap in the system must be completely filled with solution to prevent the formation of micro air bubbles due to high pressure. Immediately before cross-clamping the aorta, a puncture – incision is made between the legs of the U-shaped suture and the perfusion cannula, attached to the perfusion hose, is inserted, after which the tourniquet is tightened.

After cross-clamping the aorta, the cardioplegic solution cooled to 5-8°C (41-46.4°F) is perfused into the aortic root and coronary system with full shunting under hydrostatic pressure (the height of the perfusion container above the level of the heart is initially about 140 cm = 100 mm Hg). High perfusion pressure is required for:

A) ensuring flawless closure of the aortic valves;

B) achieving rapid washing out of blood from the coronary system and, consequently, rapid cardiac arrest;

C) rapid cooling of the heart and thereby additional protection of the heart from primary oxygen deficiency. Within 20-40 seconds after the start of perfusion, the heart stops contracting.

In order not to expose the non-working heart to the danger of excessively high perfusion pressure, the vessel with the cardioplegic solution should be lowered to 50-70 cm above the level of the heart after cardiac arrest.

In cases of pronounced coronary artery stenoses, a higher perfusion pressure is required (about 70 cm from the level of the vessel to the level of the heart). The total duration of cardioplegic solution administration should be 6-8 minutes, which is sufficient to ensure homogeneous distribution and equilibration of the solution. With the start of solution delivery, the right atrium is opened at the cannulation site and the perfusate is aspirated through an additional cannula inserted into the superior vena cava. If a significant amount of cardioplegic solution still enters the heart-lung machine, a calcium salt solution is introduced into the circulating flow to prevent the resulting drop in blood pressure.

Clinical experience shows that on small hearts (children, newborns), CUSTODIOL, used under the conditions described above, provides the same effectiveness of functional protection as in adults. The total perfusion duration here should also be at least 6-8 minutes at a hydrostatic pressure of 40-50 mm Hg. The preferred solution flow rate is 1 ml/min/g of heart weight.

End of cardioplegia. Cardioplegia ends with the opening of the aorta after connecting the coronary system to the circulatory system. A very weakened myocardium is recommended to be perfused at low blood pressure (about 2 minutes at a mean arterial pressure of 40 mm Hg). The perfusion pressure can then be normalized as myocardial activity increases. Often, myocardial activity recovers spontaneously. If this does not happen, a single defibrillation is sufficient. “Resuscitation” of the heart should be carried out with a balanced acid-base status, normal blood concentrations of sodium, potassium, and calcium ions (especially normal calcium ion concentration) and at a heart temperature of 32-36°C (89.6-96.8°F). Lower temperatures lead to increased fibrillation, while higher temperatures worsen myocardial recovery due to excessive energy inflow.

Kidney tolerance to ischemia. The kidney can be stored in the cold drug solution (at 2-4°C (35.6-39.2°F)) for up to 48 hours (so-called cold ischemia time). The warm ischemia time, which refers to the time required for complete vascular anastomosis, is usually 30 minutes. Taking this time interval into account, it is believed that complete restoration of organ functions is possible if no more than 24 hours have passed since the engraftment. From both a theoretical and practical standpoint, this time is sufficient for in situ operations. Thus, when using CUSTODIOL, the preservation of the kidney in terms of ischemic damage increases by 2-3 times.

Onset of kidney transplantation. If the laparotomy is successful, the kidney is prepared by ligating the capsular vessels. A catheter for selective perfusion is fixed in the renal artery using a tourniquet. Perfusion is carried out under hydrostatic pressure. In the first minute of perfusion, the renal vein is cut and pressed against the vena cava. The escaping perfusate is aspirated from the abdominal cavity. Perfusion is carried out for about 10 minutes. If transplantation is planned next, resection is performed; if tumor excision is planned, the kidney is left in place.

Liver tolerance to ischemia. According to literature data, the liver, transplanted 21 hours after ischemia, functions normally. However, it is also known that with preservation times of more than 12 hours, the indicators of so-called primary disorders can increase. At the same time, it can be stated that when protecting the liver with CUSTODIOL for 12 hours, the least number of disorders in the form of biliary anastomoses occurs.

Onset of liver transplantation. Usually, the Harvesting Center decides whether to perform liver perfusion in situ followed by preparation or vice versa. There are no standardized data on the conditions of CUSTODIOL use yet. As a recommendation, perfusion of about 20 L of the drug, cooled to 5-8°C (41-46.4°F) (based on 300 ml per kg of donor body weight), can be suggested. If the Harvesting Center decides to perform perfusion according to the aorta – portal vein scheme, the need for both a pressure pump and a separate aortic line is eliminated. All main line tubes should have the maximum possible diameter. This also applies to the cannula, which should have an internal diameter of at least 5 mm. Under these conditions, it is sufficient to perfuse the organ for 10 minutes. If the entire solution is intended to be delivered through the aorta, it is necessary to use a system with a Y-connector, tubes and a cannula with the largest possible internal diameter (at least 5 mm). The solution flows, as in the previous version, by gravity, and it is recommended to decompress the liver before starting perfusion.

Transport of donor organs. Organs (heart, kidneys, lungs) are transported from the donor to the recipient in special bags of appropriate size, filled with the drug at a temperature of about 0°C (32°F). The organ must be completely covered with the solution. The bag is sealed with adhesive tape and placed in a 2nd bag, also filled with the cold drug (in case of damage to the 1st bag and for improved thermostating). The organ in the double bag is placed in a sterile plastic transport container filled with ice. Donor information, copies of laboratory test results, and blood samples are attached. Delivery of the organ to the place of use should be carried out as soon as possible.

Overdose

In case of possible entry of CUSTODIOL into the general circulatory system, changes in sodium and calcium concentrations are insignificant. However, if the analysis of sodium and calcium in the extracorporeal circulation confirms their deficiency, both electrolytes should be replenished.

Drug Interactions

There are no reports of any interactions with such pharmaceutical drugs as glycosides, diuretics, nitrates, antihypertensive drugs, calcium antagonists, beta-blockers used in the preoperative period.

Storage Conditions

Storage conditions: store at a temperature of 8-15°C (46.4-59°F) in places protected from light and inaccessible to children!

Use within the period indicated on the packaging!

Shelf Life

Shelf life: the shelf life is 1 year and is indicated on the packaging.

Do not use after the expiration date!

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.