Custodiol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KUSTODIOL

Composition:

Active substances: sodium chloride, potassium chloride, magnesium chloride, histidine, histidine hydrochloride, tryptophan, mannitol, calcium chloride, α-ketoglutaric acid;

1000 ml of solution contain: sodium chloride 0.8766 g, potassium chloride 0.671 g, magnesium chloride hexahydrate 0.8132 g; histidine 27.9289 g, histidine hydrochloride monohydrate 3.7733 g; tryptophan 0.4085 g, mannitol 5.4651 g, calcium chloride dihydrate 0.00221 g; α-ketoglutaric acid 0.1461 g;

Excipients: potassium hydroxide, water for injections.

Pharmaceutical form. Perfusional solution.

Main physicochemical properties: clear pale yellow solution.

Pharmacotherapeutic group.

Solvents and diluents, including irrigation solutions. ATC code V07AB.

Pharmacological Properties

Pharmacodynamics.

Custodiol prolongs tolerance to ischemia in organs requiring protection mainly through two mechanisms:

1. The electrolyte composition of Custodiol suppresses cellular metabolism in organs. Thus, the energy demand of organs is reduced to a minimal level.
2. Anaerobic energy production is limited due to increased inhibition of glycolysis caused by decreased pH resulting from lactate accumulation. The histidine/histidine hydrochloride buffer delays the decline in tissue pH during organ ischemia. In this case, the contribution of anaerobic glycolytic energy production is increased.

α-Ketoglutaric acid is a substrate for aerobic energy production. Tryptophan exerts a membrane-protective effect.

Mannitol prevents the development of cellular edema. The overall osmolality of the solution is slightly lower than the normal osmolality of plasma and intracellular space.

Pharmacokinetics.

Depending on the nature and duration of the surgery, surgical techniques, and patient's body weight, the volume of the drug administered into the systemic circulation may range from 0.1 to 3 liters. α-Ketoglutaric acid is predominantly metabolized in the citric acid cycle. Histidine and tryptophan are mainly metabolized in the liver, but are partially excreted by the kidneys.

Mannitol is excreted unchanged by the kidneys.

Clinical characteristics.

Indications.

• Cardioplegia during cardiac surgery.
• Organ protection during surgery involving ischemia (heart, kidneys, liver).
• Organ preservation for transplantation (heart, kidneys, liver, lungs, pancreas), including arterial and venous grafts.
• Multiorgan protection.

Contraindications.

Currently unknown.

Interaction with other medicinal products and other forms of interaction.

Interaction with medicinal products commonly used prior to cardiac surgery (glycosides, diuretics, nitrates, antihypertensives, beta-blockers, and calcium antagonists) is unknown. Custodiol must not be mixed with other medicinal products.

Special precautions.

Custodiol is not intended for any type of injection or infusion.

Complete myocardial arrest renders the heart highly susceptible to excessive stretching. To prevent this, adequate drainage of the solution from the ventricle must be ensured, and the recommended volumes and perfusion pressure must not be exceeded. This is particularly important during cardiac surgery in infants and children. Inadequate cooling of the perfusion solution during cardioplegia may result in the so-called "calcium paradox," leading to myocardial cell death after myocardial protection. The solution must always be sufficiently cooled before use.

Use during pregnancy or breastfeeding.

Adequate controlled clinical studies on the use of the drug in pregnant women or women who are breastfeeding have not been conducted. The use of the drug during pregnancy or breastfeeding is possible only if the benefit to the woman outweighs the risk to the fetus or infant.

Ability to affect reaction rate when driving or operating machinery.

The drug is to be used exclusively under hospital conditions.

Method of Administration and Dosage.

1. Heart
   • Solution temperature: 5–8 °C.
   • Perfusion volume: 1 ml/min/g of estimated heart weight;

(for adults, normal heart weight is approximately 0.5% of body weight; for children, approximately 0.6%).

• Perfusion pressure (should equal aortic root pressure):

for adults, initial pressure is 140–150 cm H₂O above heart level, equivalent to 100–110 mm Hg; after cardiac arrest, reduce pressure to 50–70 cm H₂O above heart level, equivalent to 40–50 mm Hg;

for newborns and infants, initial pressure is 110–120 cm H₂O above heart level, equivalent to 80–90 mm Hg; after cardiac arrest, reduce pressure to 40–50 cm H₂O above heart level, equivalent to 30–40 mm Hg. For patients with severe coronary sclerosis, maintain slightly higher pressure for a longer duration.

• Perfusion time:

at the specified dosage and pressure, perfusion time is approximately 6–8 minutes. This duration must not be shortened to ensure equilibration of the extracellular space.

• Perfusion methods:

hydrostatic perfusion with continuous monitoring of time and height above heart level, or perfusion using a perfusion pump with control of time and pressure at the aortic root.

• Cardioplegic reperfusion:

if reperfusion is required, the solution must be cooled to 5–8 °C for primary perfusion. Each reperfusion should last 2–3 minutes; in any case, perfusion pressure must correspond to the pressure at the end of the last minute of primary cardioplegic heart perfusion. Concurrent systemic hypothermia (27–29 °C) with ischemic tolerance of the heart using a heart-lung machine is well tolerated for up to 180 minutes after aortic clamping.

• Transport:

if the heart perfused with the drug is intended for transplantation, it must be placed in a container with cooled solution (2–4 °C) to ensure protection until implantation into the recipient.

1. Kidneys
   • Solution temperature: 5–8 °C;
   • Perfusion volume: 1.5 ml/min/g of estimated kidney weight (normal adult kidney weight is approximately 150 g);
   • Perfusion pressure (renal artery):

120–140 cm H₂O above kidney level, equivalent to 90–110 mm Hg at the tip of the perfusion catheter in the renal artery.

• Perfusion time:

at the specified dosage and pressure, perfusion time is approximately 8–10 minutes. This duration is necessary to ensure equilibration of the kidney’s extracellular space (including interstitial tissue and renal tubular system). This time must not be shortened.

• Additional measures:

to ensure optimal utilization of the drug’s protective properties for kidneys, intensive diuresis must be ensured before the start of perfusion (by pharmacological means and/or patient hydration).

• Perfusion methods:

hydrostatic perfusion with control of time and height above kidney level, or perfusion using a perfusion pump with control of time and pressure at the tip of the perfusion catheter.

• Transport:

if the kidney perfused with the drug is intended for transplantation, it must be stored in a container with cooled solution (2–4 °C) to ensure protection. Protection is maintained for up to 48 hours.

1. Liver
   • Solution temperature: 0–4 °C;
   • Perfusion volume:

if preservation of the liver, pancreas, and kidneys together (as a single block) in the organ donor is required, the necessary perfusion volume of the drug is 150–200 ml/kg body weight. For such combined protection, this corresponds to a perfusion volume of 8–12 liters of cooled solution for a patient weighing 70–80 kg.

• Perfusion pressure:

hydrostatic pressure perfusion is used (the container is placed at a height of 1 m above heart level).

• Perfusion time:

at the specified dosage and pressure, perfusion time is approximately 10–15 minutes, but in any case not less than 8 minutes.

• Additional measures:

in the organ donor, blood must be fully heparinized before the start of perfusion.

• Perfusion method:

the drug is administered into the renal aorta or iliac artery of the organ donor via a properly prepared perfusion tube (the system is air-free). Simultaneously with the start of perfusion, the surgeon opens the inferior vena cava of the donor patient. This allows the solution to flow out unobstructed. The entire volume of solution is administered via the abdominal aorta, thus including all abdominal organs in the protection. Bile ducts (intra- or extra-corporeal) must be carefully flushed with at least 100 ml of cooled solution using a small-sized catheter.

If only the liver or a part of the liver (e.g., in the case of a living donor) needs to be removed without any other organs, the perfusion volume should be proportionally reduced. Perfusion time must not be less than 8 minutes and usually lasts 10–15 minutes. In the latter case, adequate perfusion of both arterial and portal venous circulation must be ensured.

• Transplantation:

if organ transport for transplantation is required, after removal, the liver must be placed in a container with cooled solution. The organ must be completely submerged in cooled Custodiol. General recommendation is that ischemia time should not exceed 12–15 hours under normal conditions. If the liver is to function in place of the removed organ (e.g., for tumor enucleation), it must be stored in cooled solution throughout the entire procedure. Immediately after completion of the so-called "bench surgery," the liver is autotransplanted.

1. Protection of the pancreas

For protection of the pancreas, solution temperature, volume, pressure, and perfusion time are based on the recommendations provided in section "3. Liver," including for the organ donor.

1. Transplantation of veins and/or arteries

Venous (usually a segment of the great saphenous vein) or arterial (usually a segment of the internal thoracic artery) grafts are cooled and stored in cooled drug solution (approximately 50–100 ml) at 5–8 °C. After removal from the solution, the venous or arterial segment is immediately implanted.

1. Multi-organ protection

The main technical perfusion procedures are now largely standardized and described in relevant surgical manuals. Regarding perfusion techniques, atmospheric pressure perfusion using perfusion systems with the largest possible size is most widely applied worldwide. Even at low temperatures, Custodiol has exceptionally low viscosity. This allows large volumes to be administered at low pressure and low temperatures required for perfusion.

Multi-organ protection with Custodiol is not limited by perfusion volume but is based on a minimum perfusion time of 8–10 minutes. This means that by administering large volumes of cooled Custodiol (0–4 °C), rapid effective cooling can be achieved, thus ensuring organ protection over a prolonged period.

1. Transport of donor organ

Technical procedures for ensuring hypothermic storage vary slightly between individual medical institutions, but the "triple bag technique" is currently widely used worldwide. The organ removed from the donor is usually transported to the recipient in a specially designed sterile bag (depending on its size: heart/kidneys), in which the organs are immersed in ice-cold perfusion solution Custodiol. Organs must be completely covered by the solution. The bag is tightly sealed with adhesive tape or a similar device and placed into a second container also filled with perfusion solution Custodiol to prevent any damage to the insulating material or air entry. The organ, protected by double packaging, is placed into a sterile plastic container and tightly closed with a lid. This container is placed inside a transport box filled with ice. Donor information, copies of laboratory reports, and donor blood samples must be included. Transport of the donor organ in perfusion solution Custodiol must be as rapid as possible.

Children. Can be used from the first days of life.

Overdose.

Large volumes of the drug entering the systemic circulation may lead to excessive increase in circulating volume and cause electrolyte imbalances (hypocalcemia, hyponatremia, hypermagnesemia, hyperkalemia). Regular monitoring of serum electrolytes is recommended.

During the first 24 hours, transient increases in plasma levels of tryptophan and histidine may occur. No adverse effects on metabolism have been reported.

Side effects.

Unknown.

Shelf life. 1 year.

Do not use the medicinal product after the expiry date.

Storage conditions. Store in a light-protected place at a temperature of 2 to 8 °C. Keep out of reach of children.

Incompatibility. Unknown.

Packaging.

500 ml or 1000 ml in glass bottles; 2 l or 5 l in bags; or 1 l in a bag placed in a vacuum package; 1 vacuum-packed bag per cardboard box.

Prescription status. Prescription only. For use under hospital conditions.

Manufacturer.

Dr. Franz Kohler Chemie GmbH, Germany.

Manufacturer's address.

Werner-von-Siemens-Strasse 14-28, 64625 Bensheim, Germany.

Marketing Authorisation Holder.

Dr. Franz Kohler Chemie GmbH, Germany.

Address of the Marketing Authorisation Holder.

Werner-von-Siemens-Strasse 14-28, 64625 Bensheim, Germany.

In case of adverse events, side effects, or lack of therapeutic effect, please report to the competent authority or to the Contact Person of Dr. Franz Kohler Chemie GmbH responsible for pharmacovigilance in Ukraine via email at [email protected] or by phone at (044) 585-04-60.