Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/721—Dextrans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

• the present invention relates to priming solutions used during cardiopulmonary bypass procedures.
• CPB cardiopulmonary bypass
• ECC extra corporeal circulation
• the patient In use, the patient is connected to the circuit, and the priming solution is mixed with the patient's blood. This causes significant dilution of the blood, which can be harmful to the patient. It is therefore important to reduce the harmful effects of the haemodilution and the priming solution.
• the blood volume is related to the size of the patient, a smaller patient having less volume and a larger patient having more volume.
• the volume of the priming solution depends largely on the circuit used. Generally, 1.5 to 2 litres of priming solution are used to fill the system, regardless of the patient's size.
• Fluid distribution in humans is divided between the extracellular fluid (ECF) and the intracellular fluid (ICF).
• ECF extracellular fluid
• ICF intracellular fluid
• the ECF is further distributed between the vascular space, which contains about 25% of the total ECF volume, and the interstitial space, which contains about 75% of the total ECF volume (Griffel et al, 1992).
• Isotonic solutions such as Ringer's lactate have a similar osmotic pressure to plasma and addition to the circulation does therefore not form a water potential gradient. This means that after dilution of the blood with an isotonic crystalloid solution, 75% of the solution will remain interstitially and 25% will remain in the vasculature (Griffel et al, 1992). The more crystalloid the solution that is given, the more interstitial oedema forms.
• Crystalloid solutions used for CPB are generally balanced salt solutions such as saline and Ringer's lactate or dextrose/mannitol solutions. Often they contain a mixture of salt and/or sugars.
• a hypertonic saline has been used for CPB (McDaniel et al, 1994). Such a hypertonic crystalloid solution creates a water potential gradient, thereby causing water to move from the interstitial compartment to the vasculature, due to the high osmotic pressure it provides. However, the effect is soon lost as the electrolytes move to the interstitium.
• Colloidal solutions are generally a mixture of a balanced salt solution and a large molecule, which cannot easily enter the interstitium and therefore remains longer in the vasculature, thereby providing an oncotic pressure.
• Large molecules that have been used over the years in colloidal priming solutions include albumin, gelatine, hydroxyethyl starch (HES) and, to some extent, dextrans. These molecules provide a colloidal osmotic pressure or a colloidal oncotic pressure.
• the terms "colloidal osmotic pressure” and “colloidal oncotic pressure” are used interchangeably within this application. In practice, this means that a hyperoncotic colloidal solution administered to the vasculature brings water out from the interstitial compartment into the vasculature.
• a hyperoncotic solution increases the total volume in the vasculature by a greater amount than the total volume being given. For example, a 25% albumin solution increases the volume in the vasculature almost five times the given volume (Griffel et al, 1992).
• Normal human oncotic pressure in the plasma is about 28 mmHg and a hyperoncotic solution must provide a higher oncotic pressure than this. The higher the oncotic pressure, the more water is shifted from the interstitium to the vasculature.
• Oedema is therefore reduced with hyperoncotic solutions and as a consequence the vascular resistance decreases, providing improved micro-circulation and reduced risk of hypo-perfusion.
• the brain is one of the regions that benefits the most from this change.
• Cognitive dysfunction post-cardiopulmonary bypass for open heart surgery has been reported to be as high as 70% (Iriz et al, 2005).
• An improvement in cognitive function was shown when a colloidal solution (F£ES) was used compared to a crystalloid solution (Iriz et al, 2005).
• Simple balanced salt solutions like Ringer's lactate or Ringer's acetate are sometimes used. These simple solutions provide a low oncotic pressure to the circulating blood, which leads to water leaking into the interstitial spaces and tissue, thereby forming oedema. This can be avoided by using a hyperosmotic solution. However, to maintain a stable oncotic pressure there is a need for a colloidal solution.
• Endogenous albumin is the major protein in plasma, providing about 80% of the oncotic pressure in a healthy person. It is, of course, the optimal molecule to use when endogenous and during normal body function. However, if non-endogenous albumin is used, it is expensive and the risk of transmitting infectious diseases can never be completely ruled out. Blood derived products can also cause
• Gelatines are modified collagen derivatives.
• the collagen is generally obtained from bovine material.
• the gelatines used are urea-bridged or otherwise connected heterogeneous peptide polymers. Apart from the apparent risk of transmission of infectious disease, the modified gelatines are known to cause anaphylactic reactions. The reactions can either be due to histamine release or can be antibody-mediated.
• HES Hydroxyethyl starch
• Amylopectin is a highly branched glucose polymer and it is modified to HES through hydroxyethyl substitutions. The substitutions make it less vulnerable to amylase degradation and therefore more stable in the blood.
• HES is a heterogeneous mixture of particles of different sizes and degrees of substitution. The smaller molecules are rapidly excreted in the urine, while the largest molecules can be taken up by tissue and remain in the body for weeks, months and even years.
• Administration does carry a risk of anaphylactic reactions, as well as disturbances in the complement and coagulation systems. An underestimated side effect is persistent itching, believed to be related to the accumulation of the largest molecules in the body. The onset of the itching is often delayed and therefore it is not always associated with the use of HES.
• Dextran is a heterogeneous, bacterially-produced glucose polymer with molecular weights ranging from thousands to millions of Daltons. However, commercially produced dextran is generally hydrolysed to smaller fractions. Commercial dextrans often have a mean molecular weight of 1, 40, 60 or 70 kDa. The actual weight of individual dextran molecules in each commercial sample may vary. For example, a Dextran 40 sample will include molecules with a range of weights, but the mean molecular weight will be 40 kDa. Dextran 1 is not used to create oncotic pressure in colloidal solutions due to its small mean molecular size. Dextrans are much less branched than HES molecules and are therefore also more extended than HES or albumin, which are more globular. Dextran molecules are also not charged, unlike proteins. Dextrans can be modified in various ways to alter their properties. Such modified dextrans are contemplated for use in the solution as disclosed.
• dextrans are considered pharmacologically inert, they provide various effects on the immune system as well as the coagulation system. The exact mechanisms involved are not known, but it is thought to be due to steric effects. For example, dextran is known to reduce thrombogenesis and it has been used instead of or in combination with the anti-coagulant heparin for this purpose. Many coagulation factor interactions have been hypothesized, but the most well documented interactions are with platelets and Factor VIII (Grocott et al, 2002).
• dextran makes it very favourable for use in colloidal priming solutions. It is cheap compared to albumin, and it has better coating properties than HES. It also has been shown to reduce ischemic reperfusion injury, and it is easily extracted from the body.
• Dextran does have a risk of anaphylactic reaction. However, this risk can be reduced through pre-administration of a dextran with a low molecular weight, such as Dextran 1. This pre-administration means that dextran has a smaller risk of anaphylactic reaction when compared with that for the other large molecules. It is thought that the small dextran molecules bind to the immunoglobulins involved in the reaction, thereby preventing aggregation of the immunoglobulins and an anaphylactic reaction (USP 4,201,772). Due to the small molecular weight of Dextran 1, a small dose in terms of grams outnumbers the larger molecules from colloidal preparations, thereby creating effective prophylaxis.
• Dextran is known to increase capillary flow. This is achieved partly through reducing the viscosity of the blood and the oncotic action, thereby reducing swelling and opening the capillaries, and partly because it prevents leukocytes sticking to the microvasculature, which would otherwise cause further narrowing of the vessels.
• dextrans are not more widely used in CPB priming solutions is the dose dependent risk of bleeding on their administration. It may be the dextran' s effect on the coagulation system which increases the risk of bleeding when used in sufficient concentrations to provide a functional hyperoncotic pressure.
• Dextrans are sometimes used in resuscitation solutions for trauma patients because of their beneficial properties. Due to risk of bleeding, there is a set limit of 1.5 g dextran per kg body weight and 24 hours. This limit has not been specified for use of dextrans in colloidal priming solutions for CPB. However, bleeding is even more of a concern in relation to CPB, as the patient is already at risk of bleeding
• the recommended dose limit for dextrans may be lower than 1 to 1.5 g/kg body weight and 24 hours during CPB (Gu et al, 2006).
• CPB ulcerative colitis .
• a patient of 50 kg receives as much priming solution as a patient of 100 kg, resulting in a doubled dose in the smaller patient.
• a further point is that the administration of the whole dose during CPB priming is instant and not delayed over 24 hours.
• much of the research referred to in relation to fluid distribution and effects of colloids and crystalloids comes from the field of resuscitation and not CPB, the differences between these two fields must be remembered. The main difference is that in resuscitation, a lost blood volume is being replaced by an infused fluid with the aim of increasing the volume in the vasculature and thereby restoring blood pressure.
• CPB coagulation-in-phosphatidylcholine
• the priming solution is not used to replace lost volume, but instead it adds circulating volume to be able to fill not only the vasculature, but also the extra corporeal circuit, with fluid.
• CPB in itself causes changes to the inflammatory and coagulation pathways, partly through contact with the bypass circuit surfaces. Heparin is also used in conjunction with CPB, further affecting the coagulation pathway.
• a priming solution consisting of a mixture of 1.5 litres of 3.5% Dextran 40 and 0.5 litres of Ringer's solution.
• the solution works similarly to an albumin containing solution.
• the dextran solution used contains a relatively low Dextran 40 concentration, which may not provide a functional hyperoncotic pressure. There is no mention of the addition of a lower molecular weight dextran.
• a non-oncotic dextran is defined as a dextran with a mean molecular weight lower than 5 kDa.
• An oncotic dextran is defined as a dextran with a mean molecular weight of above 20 kDa.
• a balanced salt solution is one comprising ions in concentrations that are similar to those in blood.
• the salt solution is isotonic or almost isotonic, and can be exemplified by Ringer's lactate, Ringer's acetate, normal saline, PBS or a cell culture medium.
• a functional hyperoncotic pressure is an oncotic pressure such that when a solution with the functional hyperoncotic pressure is mixed with blood in the patient, the oncotic pressure in the blood is maintained within normal patient values.
• the reason for using this definition is because the effective oncotic pressure provided by a dextran solution mixed with blood in a patient cannot simply be calculated using van't Hoff s law.
• 35 g/1 corresponds approximately to 37 mmHg or 1.3 times the oncotic pressure of plasma
• 45 g/1 corresponds approximately to 48 mmHg or about 1.7 times the oncotic pressure of plasma
• 55 g/1 corresponds approximately to 63 mmHg or about 2.1 times the oncotic pressure of plasma.
• the exact numbers will vary between measurement methods.
• the in vivo situation also immediately changes the functional oncotic pressure.
• a cardiopulmonary bypass priming solution comprising a balanced salt solution and a combination of oncotic and non-oncotic dextran molecules. It was unexpectedly found that the solution as disclosed does not cause dose dependent bleeding when used as the priming solution for cardiopulmonary bypass.
• the oncotic dextran is Dextran 40
• the non-oncotic dextran is Dextran 1.
• the functional hyperoncotic pressure should be sufficient to maintain oncotic pressure in the patient during the CPB procedure and is preferably similar to the hyperoncotic pressure provided by 35 to 55 g/1 of Dextran 40.
• a sample of Dextran 40 comprises dextran molecules with a range of molecular weights, but with a mean molecular weight of 40 kDa.
• a dextran with a mean molecular size distribution between 20 and 80 kDa, preferably between 20 and 60 kDa, more preferably between 30 and 55 kDa or even more preferably between 35 and 45 kDa could be optimised for an alternative solution.
• the concentration of the oncotic dextran is equivalent to between 35 and 55 g/1 of Dextran 40 and the non-oncotic dextran concentration would be equivalent to between 1 and 10 g/1 of Dextran 1, preferably equivalent to between 1 and 5 g/1 of Dextran 1.
• the concentration of Dextran 1 may be between 1 and 10 g/1, preferably between 1 and 5 g/1 Dextran 1. This should not induce an increased dose dependant risk of bleeding.
• a further improvement with the solution as disclosed can be clearly observed by following the fluid level in the venous reservoir while on bypass.
• the level increased in all cases and there was no need for extra fluid.
• the level diminished in all cases, and fluid had to be added to keep the fluid level in the venous reservoir over the minimum level set for safety reasons and to be able to keep the perfusion flow up.
• the cardiac output and the MAP were significantly higher in the 2-hour post ECC time with the solution as disclosed, reflecting a larger blood volume.
• the solution as disclosed provides a functional hyperoncotic pressure as intended, without inducing any excess bleeding either during or post procedure.
• the amount of bleeding was found not to correlate with the patient weight when using the solution as disclosed.
• the oncotic pressure was also shown to be maintained and stable during the CPB when a solution as disclosed was used.
• a balanced salt and dextran solution comprising oncotic and non-oncotic dextran molecules, provides sufficient oncotic pressure to maintain the oncotic pressure in the patient's blood during the CPB, without causing dose dependant bleeding.
• the concentration of the oncotic dextran molecule should be equivalent to between 35 and 55 g/1 of Dextran 40 and the concentration of the non-oncotic dextran should be equivalent to between 1 and 10 g/1 of Dextran 1.
• the concentration of the oncotic dextran molecule should be equivalent to between 40 and 50 g/1 of Dextran 40 and the concentration of the non- oncotic dextran should be equivalent to between 1 and 5 g/1 of Dextran 1.
• a method of maintaining oncotic pressure in a patient during a cardiopulmonary bypass procedure comprising contacting the patient with a priming solution as disclosed.
• the patient is human.
• cardiopulmonary bypass priming solution as disclosed and a cardiopulmonary bypass apparatus.
• Figure 1 is a graph showing the infusion in ml during the procedure for both the solution as disclosed and Ringer's acetate;
• Figure 2 is a graph showing the amount of fluid remaining in the reservoir of the extra corporeal circuit at the end of the procedure for both the solution as disclosed and Ringer' s acetate;
• Figure 3 is a graph showing the volume of urine produced during the procedure with both the solution as disclosed and Ringer's acetate;
• Figure 4 is a graph showing the volumes remaining in specific areas with both the solution as disclosed and Ringer's acetate
• Figure 5 is a graph showing the oncotic pressure during the procedure with both the solution as disclosed and Ringer's acetate
• Figure 6 is a graph showing how the activated clotting time varies during the procedure with both the solution as disclosed and Ringer's acetate
• Figure 7 is a graph showing how bleeding varies during the procedure with both the solution as disclosed and Ringer's acetate;
• Figure 8 is a graph showing the correlation between the amount of bleeding intra- operatively and the weight of the patient;
• Figure 9 is a graph showing the correlation between the amount of bleeding intra- operatively and the weight of the patient.
• An envelope with sixteen identical notes was used. The notes were marked either crystalloid or oncotic group.
• a stabilization period of 30 minutes began, during which the last 15 minutes were registered as baseline.
• ECC extra corporeal circulation
• a hard-shell venous/cardiotomy reservoir with an oxygenator and an arterial filter was used in all perfusions.
• the perfusion circuits were assembled and primed according to the manufacturer's instructions.
• a centrifugal pump was chosen as the arterial pump for the perfusions. No filtration to reduce the numbers of platelets prior to perfusion took place.
• the pump flow was set to 65 ml/kg/min, the pump flow/gas ratio was kept 1 : 1.2 and the Fi0 2 was set to 0.5 during the 60 min perfusion period. Ventilation was disconnected at all times during ECC.
• Two central venous and two arterial lines were established through the neck vessels for blood sampling, drug administration and pressure monitoring.
• a pulmonary artery line was placed by direct puncture of the pulmonary artery after performance of median sternotomy. The reason for having two venous and arterial lines was to allow blood sampling with minimal disturbance of the pressure monitoring in the other lines.
• the three pressure-monitoring catheters were calibrated to atmospheric pressure at the level of the right atrium, the intra-thoracic aorta and the pulmonary artery respectively.
• Blood pressure, MAP (Mean arterial pressure), CVP (central venous pressure), PAP (pulmonary arterial pressure), heart rate, pump flow, pump rpm, pump pressure and temperature were continuously measured and monitored with a fluoroscope. Cystotomy for urine output measurements was performed in all animals. Central body temperature was measured in naso-pharynx. Also, two ultrasonic blood flow probes were placed around the right carotid artery and the pulmonary artery.
• a calibrated transducer was incorporated between the tracheal tube and the ventilator to measure the end-tidal carbon dioxide. Blood samples were taken for blood gases, lactate, glucose, oncotic pressure, ACT and osmolarity as base, 30 min and 60 min of ECC and 30 min, 60 min, 90 min and 120 min post ECC.
• Blood samples were taken from the right atrium, carotid artery and pulmonary arteries and analyzed for blood gases and oxygen saturation, haemoglobin and haematocrit.
• the two groups did not differ significantly in any measured variable at base line.
• the total fluid balance was +1.8 litres in the crystalloid group compared to -18 ml in the oncotic group (p ⁇ 0.001) ( Figure 4).
• the oncotic pressure was significantly higher (p ⁇ 0.001) in the oncotic group, on average 19 mmHg compared to 13 mmHg in the crystalloid group, during ECC as well as post ECC. There was no significant difference in osmolarity between the two groups.
• the haematocrit was significantly lower (p ⁇ 0.001) during the ECC and post ECC in the oncotic group (Figure 5).
• MAP was significantly lower (p ⁇ 0.05) in the oncotic group (around 65 mmHg) compared to the crystalloid group (around 85 mmHg), whereas the opposite appeared post ECC.
• the cardiac output was around 4 1/min in both groups and it was similar post ECC in the crystalloid group.
• SVR systemic vascular resistance
• PVR pulmonary vascular resistance
• the study was performed according to recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964. Approval from the Ethics Committee was obtained for the study. All patients entering the study had given their written consent.
• the study was designed and performed as a prospective, randomised user blind study, with two groups, Control group and PrimeECCTM (Test) group, running parallel to each other.
• the randomization was prepared by a biostatistician from the Competence Centre for Clinical Research at the University Hospital of Lund.
• the randomization list was stored at the hospital pharmacy, which packaged the study solution.
• the local pharmacy prepared both the test solution and the control solution in identical bags. The day of the surgery, the bags were delivered from the pharmacy to the perfusionist.
• a logbook of study products was prepared by the pharmacy and the randomization number of the study treatment was also verified in the hospital records. There were 20 patients included in each group, with a total of 40 patients.
• the crystalloid group (Control) of patients received a Ringer-acetate and mannitol solution as a priming solution and the oncotic (Test) group (PrimeECCTM) received a dextran based hyperoncotic solution as disclosed.
• Competence Centre for Clinical Research at the University Hospital of Lund had prepared procedures to handle the situation.
• the principal investigator was instructed to contact the biostatistician at the centre for clinical research, who according to their routines prepared and randomized additional patients for entering the study so that the study, when finished, had two groups with 20 patients in each group and a total of 40 patients.
• composition as follows:
• Reference product (Control group) The reference products were taken from the marketing stock at the pharmacy.
• composition as follows:
• composition as follows:
• the HLM used was an HL20 (Jostra AG, Hechingen, Germany).
• a hard-shell venous/cardiotomy reservoir with an oxygenator (Quadrox + VKD 4201, Jostra AG, Hechingen, Germany) and an arterial filter (Quart, Jostra AG, Hechingen, Germany) was used in all perfusions and tubing was from the same company.
• the perfusion circuits were assembled and primed according to the manufacturer's instructions.
• the blood parameters were measured with a Radiometer's ABL725 instrument except for the oncotic pressure which was measured with a colloid osmometer (Wescor Inc, Logan, Utah, USA) using a semi-permeable membrane with the size of 30 000 Daltons.
• Fluid balance measurements were registered as baseline during anaesthetic preparation but prior to initiation of CPB, and then at 30 minutes, 60 minutes and 120 minutes after initiation of CPB, and at the first post-operative day after termination of CPB.
• ⁇ Values for colloidal oncotic pressure (COP) and haematocrit were registered as baseline during anaesthetic preparation but prior to initiation of CPB and then at 30 minutes, 60 minutes and 120 minutes after initiation of CPB and at the first post-operative day after termination of CPB.
• PrimeECCTM group Once at the ICU, all patients were treated according to standard procedures which means that the data does not necessarily show the requirement of fluids for each patient.

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