Custodiol htk solution

Description

Composition

1,000 ml CUSTODIOL contain:

 0.8766 g
Sodium chloride
= 15.0 mmol/l
 0.6710 g
Potassium chloride
= 9.0 mmol/l
 0.1842 g
Potassium hydrogen 2-Ketoglutarate
= 1.0 mmol/l
 0.8132 g
Magnesium chloride · 6 H 2 O
= 4.0 mmol/l
 3.7733 g
Histidine · HCl · H 2 O
= 18.0 mmol/l
27.9289 g
Histidine
= 180.0 mmol/l
 0.4085 g
Tryptophan
= 2.0 mmol/l
 5.4651 g
Mannitol
= 30.0 mmol/l
 0.0022 g
Calcium chloride - 2H 2 O
= 0.015 mmol/l
in sterile Water for injection
Anion: Cl - 50 mval

Physical Properties

pH 7.02-7.20 at 25°C (pH 7.4-7.45 at 4°C)

Osmolality: 310 mosmol/kg

Caution:  Federal law restricts sale of this device to or on the order of a physician or licensed practitioner.

INDICATIONS FOR USE

CUSTODIOL HTK Solution is indicated for perfusion and flushing of donor kidneys, liver, and heart prior to removal from the donor or immediately after removal from the donor. The solution is left in the organ vasculature during hypothermic storage and transportation (not for continuous perfusion) to the recipient.

WARNINGS AND PRECAUTIONS

Warning:  Perfusion of the kidney, liver and/or heart should be carried out with a maximum hydrostatic pressure of 120 mm Hg.

Warning:  CUSTODIOL is not indicated for intravenous or intraarterial administration. It is indicated only for selective perfusion of the kidney, liver and heart and for cooling of the surface areas, i.e., for the preservation of the donor organ during the transport from donor to recipient. CUSTODIOL may not be used for systemic infusion.

Warning:  CUSTODIOL is not indicated for continuous perfusion.

Warning:  Keep out of reach of children.

Caution:  The product must be used before the expiration date stated on the package.

Caution:  The product must be stored according to the recommendations prior to use.

ADVERSE EVENTS

No side effects have been encountered that could be attributed to this product.

Interactions with other Medical Products

Interactions with such therapeutic agents as glycosides, diuretics, nitrates, antihypertensives, beta blockers and calcium antagonists, which are used perioperatively, have not been reported.

OVERDOSES (Symptoms, Countermeasures)

In the case of entry of the HTK solution into the general circulation, the resultant change in the concentration of sodium and calcium is very slight. After checking sodium and calcium levels in the extracorporeal circulation both of these electrolytes should be replaced if necessary.

INSTRUCTIONS FOR USE (Recommendations)

Required Equipment:

Perfusion apparatus with a Y-piece for bottle or bags

Perfusion cannula tube 2.5 to 3 mm

Tube clamp

Perfusion stand with a height setting of up to 200 cm with tape measure.

Cooling Equipment (5 to 8° C) for use in cardiac surgery

Perfusion tube with an internal diameter of 6 mm

Transport Container with sterile pouch for transport of the cooled organ from donor to recipient.

Filtration of CUSTODIOL is not necessary or recommended.

Tolerance of Ischemia by the Kidney

The kidney may be stored with ice cold CUSTODIOL solution at about 2 to 4°C with a period of (cold) ischemia of up to 48 hours. Warm ischemia time, that is to say the average time period required for the completion of anastomosis of the vessels, is usually 30 minutes. Taking this time as a basis, the organ recovers completely with optimal immediate function within 24 hours.

Tolerance of Ischemia by the Liver

The liver may be stored with ice cold CUSTODIOL solution at about 2 to 4°C with a period of (cold) ischemia of up to 15 hours. Warm ischemia time, that is to say the average time period required for the completion of anastomosis of the vessels, is usually 30 minutes. Taking this time as a basis, the organ recovers completely with optimal immediate function within 24 hours.

Tolerance of Ischemia by the Heart

The Heart may be stored with ice cold CUSTODIOL solution at about 2 to 4°C with a period of (cold) ischemia of up to 4 hours. Warm ischemia time, that is to say the average time period required for the completion of anastomosis of the vessels, is usually 30 minutes.

Introduction of Renal Perfusion

Following successful laparotomy, the kidney is prepared by ligature of the capsular vessels. The perfusion catheter for selective kidney perfusion is fixed in the renal artery using a tourniquet. Cold perfusion (2-4°C) is performed under hydrostatic pressure (maximum of 120 mmHg). Within the first minute of perfusion, the renal vein is incised and clamped off adjacent to the vena cava. The escaping perfusate is removed from the abdominal cavity. After approximately 10 minutes of perfusion, the kidney is resected before transplantation.

Introduction of Hepatic Perfusion

The donor should be heparinised appropriately, and the aorta or the iliac bifurcation and the portal vein will be exposed. The perfusion tubing should be of the largest possible diameter and the cannulae should have an internal bore of at least 5 mm. Because of the low viscosity of the solution, perfusion is performed under hydrostatic pressure only (maximum of 120 mmHg). Perfusion of the portal vein can be performed by cannulating the superior or inferior mesenteric vein and advancing the catheter up to the origin of the portal vein. After performing cannulation, clamping off the aorta and opening the vena cava, bubble-free perfusion is begun via both lines simultaneously. As a general rule, 8-12 liters of HTK at 2-4°C should be perfused (about 300 ml per kg of body weight) and this will require about 10 minutes.

Should the center decide to use the so-called aorto-single flush technique, the total amount of the preservation solution needed is perfused only via the aortal line. Once again, a pressurized infusion is not necessary or recommended. A Y-perfusion system is recommended in addition to perfusion tubing of the largest possible caliber and perfusion cannulae with an internal bore of at least Charrière 15 (5 mm). The time required for perfusion is extended by about 5 minutes.

At the implant site, the back-table preparation includes the reperfusion of approximately 500 ml cold HTK solution. The perfusion is stopped when the anastomoses of the inferior vena cava are completed at the end of the second warm ischemia time. It is permissible, in view of the flow properties and low potassium concentration of the HTK solution, to perform flushing of the organ or testing for leaks in the anastomoses with HTK solution itself, if necessary. Alternatively, any standard flushing solution may be used. Simultaneous reperfusion via the artery and the portal vein are preferable, though primary reperfusion through the portal vein alone is acceptable.

Introduction of Cardiac Perfusion

The inactivation of the heart renders it susceptible to overstretching. Decompression of the left ventricle must therefore be performed at the commencement of cardioplegia. For adult hearts the following recommendation is appropriate: The solution, cooled to 5°C-8°C, is perfused into the coronary arteries by hydrostatic pressure of 100 mmHg (equivalent to initial height of perfusion bottle above level of heart = 140 cm). After cardiac arrest has ensued (within the first minute after starting perfusion) the perfusion bottle should be lowered to about 50-70 cm above the level of the heart, equivalent to 40-50 mmHg. In patients with pronounced coronary stenosis, a higher perfusion pressure (about 50 mmHg) will be necessary for a somewhat longer time. The overall perfusion time should be 6-8 minutes, so as to ensure homogeneous equilibration. Even for small hearts, a perfusion rate of 1 ml/min/gram-estimated-heart-weight at a perfusion pressure of 40-50 mmHg and a perfusion time of 6-8 min should be enough to ensure equilibration. The heart may then be excised. The heart should tolerate a cold ischemic time of up to four hours.

Transport of a Donor Organ

The transport of a donor organ to the recipient utilizes a sterile pouch accommodating the size of the organ in an ice cold CUSTODIOL solution. The organ must be completely covered by the solution. The pouch is sealed with adhesive tape and is placed into a second container which is also filled with CUSTODIOL solution in order to prevent a breakdown of insulation and cooling by trapped air. The double-bagged organ is placed into a sterile plastic container and closed with a secure lid. The plastic bag is then placed into a transport container packed with ice for transport. Information about the donor, copies of the laboratory results and blood samples from the donor are also included. The transport of the donor organ in CUSTODIOL solution must be accomplished as quickly as possible.

CLINICAL EXPERIENCE

Kidney Transplant Trials

A major multi-center prospective randomized clinical trial has been carried out in Europe comparing three perfusion and preservation solutions for use in kidney transplants 1 . The three solutions were the CUSTODIOL HTK solution, the Belzer UW solution, and the Euro-Collins (EC) solution. Forty-seven centers participated and followed a strict protocol. Over a thousand kidneys were included in the study. In the HTK-UW study, there were 342 donors and 611 transplants (the UW group had 168 donors and 297 transplants, the HTK group had 174 donors and 314 transplants). In the HTK-EC study, there were 317 donors and 569 transplants (the EC group had 155 donors and 277 transplants, the HTK group had 162 donors and 292 transplants).

This study directly compared kidney survival in the HTK group with the UW group, and also with the EC solution, and showed that for kidney transplants, the HTK solution performs as well overall as the UW solution, and significantly better than EC solution for initial nonfunction. The average cold ischemia time in the HTK-UW study was 25.8 hours in the HTK group and 25.5 hours in the UW group. In the HTK-EC group, the average cold ischemia time was 24.1 hours in the HTK group and 24.2 hours in the EC group. The overall kidney survival rates from the 47-center study for HTK versus UW, and HTK versus EC, at four time points were:

  HTK UW HTK EC
  1 Month
91% 91% 85% 86%
12 Months
83% 82% 80% 74%
24 Months
77% 74% 76% 71%
36 Months
74% 68% 70% 67%

Delayed graft function that required two or more dialysis sessions during the first week was 20% (107/544) in the pooled HTK groups, 25% (66/266) for the UW group, and 32% (85/268) for the EC group. Initial nonfunction (INF) occurred in 33% of the kidneys in both HTK and UW groups, and in the other study, INF occurred in 29% of the HTK group and 43% of the EC group.

1 de Boer J, De Meester J, Smits JMA, Doxiadis IIN, Groenewoud AF, Persijn GG (1999). Eurotransplant randomized multicenter study comparing kidney graft preservation with HTK, UW, and EC. Transplantation in press, publication about December 1999

Liver Transplant Trials

Several clinical studies have been reported that examined the performance of CUSTODIOL HTK Solution in liver transplants. These studies have collected data on survival rates and other outcome measures. The primary evidence for effectiveness has come from a four-center prospective clinical study carried out under the auspices of the Eurotransplant organization of Leiden, The Netherlands. The four centers were located at Essen, Innsbruck, Gottingen, and Vienna. The results from this and other studies are discussed below.

Gubernatis summarized the experience at the Medizinische Hochschule Hanover, Clinic for Abdominal and Transplantation Surgery, for livers preserved in UW solution and in HTK solution.

This was a retrospective study of transplants conducted at Hanover between 1988 and 1996. During this period there were 515 liver transplants using the UW solution and 232 using HTK solution. These transplants were carried out in 416 patients using UW and 197 using HTK (some were re-transplants). The survival curves for all patients out to five years were essentially indistinguishable and certainly not significantly different statistically. An update on the Han-over experience through 1999 showed that 461 livers had been preserved with HTK solution and 607 with UW solution. Prof. Gubernatis reiterated his earlier conclusion that the two solutions were equivalent in their ability to preserve the liver for transplant.

A randomized prospective study was organized under the direction of Prof. J. Erhard at Essen, comparing 30 livers preserved with HTK Solution with 30 livers preserved with UW solution. There were two cases of initial nonfunction (INF) in the UW group and one case of INF in the HTK group. Graft survival at 3 months was 87% in the HTK group and 80% in the UW group (p = 0.21). Patient survival at 30 months was 77% in the HTK group and 74% in the UW group.

A multi-center prospective clinical study was carried out in Europe to evaluate the performance of the HTK solution in liver transplants. 2 Four transplant centers participated. 228 livers were included in the study (205 were initial transplants, 23 were re-transplants). This trial took place during 1996-1999 under the auspices of Eurotransplant. The four transplant centers participating were: Innsbruck Transplant Center; Vienna Transplant Center; University Clinic, Essen; and University Hospital, Göttingen. The (patient) survival rate at one year observed in this study was 82.5%. The following table shows the patient survival at different times in the direct comparison study at Essen, the four-center prospective study, and the Hanover retrospective study. These data show that the patient survival rates for HTK-preserved livers are similar to those for UW-preserved livers.

2 Pokorny H, Grünberger T, Rockenschaub S, Windhager T, Rosensting A, Lange R, et al (2000). Preservation of the liver with HTK--a multicenter experience. Poster presented at International Congress of the Transplant Society, Rome, Italy.

  HTK-Ess UW-Ess HTK (4-Ctr) HTK-Han UW-Han
1 Month 87% * 80% *      
3 Months     82.5%    
12 Months       71% 72%
30 Months 77% 74%   69% 67%
* Graft survival

Heart Transplant Trials

Several clinical studies have been reported that examined the performance of CUSTODIOL HTK Solution in heart transplants. These studies have collected data on survival rates and other outcome measures.

At the Bad Oeynhausen transplant center, during the period 1989-2002, 1233 hearts were preserved with the HTK Solution. 19 hearts were preserved with other solutions. The data reported here represent the entire experience of the center, with no cases excluded. The following table summarizes the experience at Bad Oeynhausen:

The Bad Oeynhausen Experience
in Cardiac Transplantation
 
HTK Solution
Other Solutions *
Number of Subjects
1233
19
Age of Donor
 Median
33.8
36.2
 Minimum
0
16
 Maximum
72
65
Donor Cause of Death
 Traumatic Bleeding
501
6
 Spontaneous Bleeding
491
9
 Hypoxia
97
2
 Gun Shot Wound
33
1
 Domino
1
1
 Cerebral Ischemia
43
 Brain Tumor
31
 Intoxication
18
 Other
18
Cold Ischemia Time
 Median
194.6
213.1
 Standard Deviation
42.3
43.1
 Minimum
68
108
 Maximum
340
289
Recipient Gender
 Male
1014 (82.2 %)
17 (89.5 %)
 Female
219 (17.8 %)
2 (10.5 %)
Recipient Age
 Median
50.4
53.9
 Standard Deviation
17.0
13.3
 Maximum
77.9
66.4
 Minimum
0
15.5
Recipient Diagnosis
 Cardiomyopathy
625
8
 Coronary Artery Disease
479
9
 Valve Disease
65
1
 Congenital Disease
37
 Retransplant
21
1
 Acute Myocarditis
2
 Other Diseases
4
Causes of Death Post-TX
 Graft Rejection
52
1
 MOF
25
 Graft Vasculopathy
3
 Acute Bleeding
1
 Infection
49
2
 Acute left ventricular
  failure
11
 Right Ventricular
  Failure
13
 Neurological
  Complications
13
2
 Pulmonary
  Complications
3
 Abdominal
  Complications
6
 Perioperative
  Complications
8
Primary Graft Failure
23 (1.9%)
0
Deaths in First Year
248 (21%)
7 (37%)
Deaths in First Three   Months
184 (16%)
5 (27%)
*The other solutions included UW, Roe, Ringer's lactate, normal saline, Plasmalyte A, Plegisol, Carmichael's, and Stanford.

Wieselthaler et al 3 . reported a randomized prospective study conducted at the University of Vienna comparing CUSTODIOL solution to Celsior, another cardiac cold storage solution. 48 patients were randomized to either the CUSTODIOL group or the Celsior group. Following are the results from this study:

3 Wieselthaler GM, Chevtchik O, Konetschny, Moldi R, Milinger E, Mares P, Griessmacher A, Grimm M. Wolner E, Laufer G (1999). Improved graft function using a new myocardial preservation solution. Preliminary data a randonmized prospective study. Transplantation Proceedings , 31: 2067-2070

  HTK Celsior
Number of Subjects
24
24
Perioperative Graft   Failure
2/24 (8.3%)
2/24 (8.3%)
Patient Survival at 30 Days
22/24 (91.7%)
23/24 (95.8%)
Graft Survival at 30 Days
22/25 (88.0%)
23/25 (92.0%)
Spontaneous Stable Cardiac Rhythm Immediately after Opening Aortic Cross-Clamp
9/24 (37.5%)
19/24 (79.2)%
Cold Ischemia Time (Min)
 Mean
199
183
 Standard Deviation
54
43
 Minimum
96
165
 Maximum
290
282
Donor Age (Yrs)
 Mean
38
38
 Standard Deviation
12
11
Recipient Age (Yrs)
 Mean
55
57
 Standard Deviation
9
11
Donor Heart Dysfunction
7/24
2/24
Causes of First Graft Failure
 Infection
1
 Acute Graft Failure
2
1
Deaths in Retransplanted Patients
1/1
0/1

Adverse Events Observed in the Clinical Studies

Kidney Studies

There were no unexpected adverse events in these clinical studies. The adverse events that occurred were expected because of the nature of transplantation. None are believed to be affected by any of the solutions.

Kidney failure rates in the first 48 hours were comparable in all groups: UW-15/297 and HTK-18/314; EC-15/277 and HTK-13/272.

In the HTK-UW kidney study, acute rejection episodes occurred in 99/314 (32%) in the HTK group and 105/297 (35%) in the UW group. In the HTK-EC study, acute rejection episodes occurred in 99/292 (34%) in the HTK group and 108/277 (39%) in the EC group.

Liver Studies

There were no unexpected adverse events in these clinical studies. The adverse events that occurred were expected because of the nature of transplantation.

In the multi-center trial, primary disfunction rate (PDF) was 10.3%, with a primary non-function rate (PNF) of 3.6%. Bile duct complications were seen in 19% of transplants. This compares with data from Eurotransplant on the UW solution: PDR of 15.2% and PNR of 7.8%.

Heart Studies

There were no unexpected adverse events in these clinical studies. The adverse events that occurred were expected because of the nature of heart transplantation.

In the Bad Oeynhausen experience, the primary dysfunction rate (PNF) was 1.9%.

How Supplied

Bottles of                     500 ml

Bottles of                   1000 ml

Bags of                      2000 ml

Bags of                      5000 ml

Store at +2°C to +15°C (35°F-59°F) and protect from light.

Registration               # : K 992209

                                 # : K 020924

                                 # : K 032794

Distributed by

Odyssey Pharmaceuticals, Inc.

East Hanover, NJ 07936

Manufactured by

DR. FRANZ KOHLER CHEMIE GMBH

P.O. Box 1117, D-64659 Alsbach-Hähnlein, Germany

P08-0725 / 10500216                                     Iss. 5/04

Hide
(web5)