Please see accompanying Prescribing Information.
© 2015 Essential Pharmaceuticals, LLC ESS 2015-1 01/15
• REFERENCES •1) S.-Y. Sung, C.-Y Lin, J.-Y. Song et al., Myocardial protection
in donor heart preservation: A comparison between Bretschneider’s histidine-trytophan-ketogluterate solution and cold blood Cardioplegia. Transplant Proceedings, 2014 46, 1077-1081
2) KreshJY,etal.TherelativebufferingpowerofCardioplegiasolutions.TheJournalofThoracicandCardiovascularSurgery1987 Feb. 43 (2) 309-11
3) M.Garlicki,J.Kolcz,etal.,MyocardialProtectionforTransplantation. Transplantation Proceedings 1999, 31, 2079-2083
4) K.GU,S.Kinetal.,HTKSolutionismoreeffectivethanUWsolutionforcardiacpreservation.TransplantationProceedings,1996 Vol 28 1906-1907
5) S. Lee, C-S Huang, et al., Histidine-tryptophan-ketogluterate or Celsior:Whichismoresuitableforcoldpreservationforcardiacgraftsfromolderdonors?AnnThoracSurg2011;91:755-63
6) J.Ackemann,W.Gross,etal.,CelsiorvsCustodiol:earlypostischemicrecoveryafterCardioplegiaandischemiaat5°C.AnnThoracSurg2002;74:522-9
• TRULY READY TO USE •
ORGAN PRESERVATION SOLUTION
HEART
Formoreinformation,e-mailusat [email protected] (377-7763)
Visit our websites at www.custodiol.com www.essentialpharma.com
Please see accompanying PrescribingInformation.
100 Princeton South Corporate Center Suite 140 Ewing, NJ 08628
Please see accompanying Prescribing Information.
© 2015 Essential Pharmaceuticals, LLC ESS 2015-1 01/15
• REFERENCES •1) S.-Y. Sung, C.-Y Lin, J.-Y. Song et al., Myocardial protection
in donor heart preservation: A comparison between Bretschneider’s histidine-trytophan-ketogluterate solution and cold blood Cardioplegia. Transplant Proceedings, 2014 46, 1077-1081
2) KreshJY,etal.TherelativebufferingpowerofCardioplegiasolutions.TheJournalofThoracicandCardiovascularSurgery1987 Feb. 43 (2) 309-11
3) M.Garlicki,J.Kolcz,etal.,MyocardialProtectionforTransplantation. Transplantation Proceedings 1999, 31, 2079-2083
4) K.GU,S.Kinetal.,HTKSolutionismoreeffectivethanUWsolutionforcardiacpreservation.TransplantationProceedings,1996 Vol 28 1906-1907
5) S. Lee, C-S Huang, et al., Histidine-tryptophan-ketogluterate or Celsior:Whichismoresuitableforcoldpreservationforcardiacgraftsfromolderdonors?AnnThoracSurg2011;91:755-63
6) J.Ackemann,W.Gross,etal.,CelsiorvsCustodiol:earlypostischemicrecoveryafterCardioplegiaandischemiaat5°C.AnnThoracSurg2002;74:522-9
• TRULY READY TO USE •
ORGAN PRESERVATION SOLUTION
HEART
Formoreinformation,e-mailusat [email protected] (377-7763)
Visit our websites at www.custodiol.com www.essentialpharma.com
Please see accompanying PrescribingInformation.
100 Princeton South Corporate Center Suite 140 Ewing, NJ 08628
INTRODUCTIONCUSTODIOL® HTK SOLUTION
Custodiol ® HTK Solution is intended forperfusionandflushingofheart(anddonor liver, kidney, pancreas) prior to removalfromthedonorforpreserving
these organs during hypothermic storage and transport totherecipient.Itisbasedontheprincipalofinactivatingorganfunctionbywithdrawalofextracellularsodiumandcalcium,togetherwithintensebufferingoftheextracellularspacebymeansofhistidine/histidineHCI,soastoprolongtheperiodforwhichtheorganswilltolerateinterruptionofbloodandoxygen.
• SingleDoseofBretschneider’sHTKsolutioncouldeffectivelyreducepumpingtimeandaffordsimilarmyocardial protection compared with repeated dosesofCBCinthepreservationofdonated hearts(1)
• Containslowerconcentrationsofsodiumandcalcium and induces cardiac arrest by deprivation ofextra-cellularsodiumforactionpotential (1)
• Ketogluterate provides high energy production via adenosinetriphosphateduringreperfusionandtryptophan stabilizes cell membranes
• Manitolactsinosmoticregulationofthecellmembrane
• ThemajoradvantagesofHTKsolutionarederivedfromhistidine,whichactsasabuffer,enhancingtheefficiencyofanaerobicglycolysis.Kreshetal.foundthatahistidineprotein-typebuffersolutionwassuperior to bicarbonate-based and tromethamine-based hyperkalmic crystalloid cardioplegic solutions forstabilizingintracellularpHandpostoperativebiochemical and mechanical data(2)
A COMPARISON IN DONOR HEART PRESERVATION: A COMPARISON BETWEEN BRETSCHNEIDER’S HISTIDINE-TRYPTOPHANE-KETOGLUTERATE SOLUTION AND COLD BLOOD CARDIOPLEGIA
ThisstudyaimedtocomparetheefficacyofmyocardialprotectionusingsingledoseofBretschneider’shistidine-tryptophan-ketogluterate (HTK) solution and repeateddosesofcoldbloodcardioplegia(CBC)indonorheartpreservationforhearttransplant.(1)
TheauthorsconcludedthatasingledoseofHTKsolutionorrepeateddosesofCBCsolutionaffordsimilarmyocardialprotectioninthepreservationofdonated hearts.(1)
Multivariateanalysisshowthesignificantreducedpumping time in HTK group (P = .002)
Clinical Variable HTK (n = 16) STH (n = 45) P Value_____________________________________________________________________________________________________Inotropic score at 19.4 ± 15.5 7.1 ± 6.3 <.001 24 h postoperatively_____________________________________________________________________________________________________Pumping Time (min) 158.3 ± 32.0 173.9 ± 33.2 .002_____________________________________________________________________________________________________LIVEF (%) at 7 d 62.0 ± 4.4 60.7 ± 7.3 .806 Postoperatively_____________________________________________________________________________________________________Age (y) 50.7 ± 11.5 50.6 ± 12.5 .648
_____________________________________________________________________________________________________
MultivariateAnalysisofSurvivingPatientsData are shown as mean ± standard deviation.
Abbreviations:LVEF,leftventricularejectionfraction;HTK,histidinetryptophanketoglutaratesolution;STH,StThomas’Hospitalsolution
HEARTMYOCARDIAL PROTECTION FOR TRANSPLANTATION(3)
The present study is a randomized clinical trial assessing preservation
ofthedonorheartusingthreecommonCardioplegicsolutions. (Table 1)(3)
Based on collected results it seems obvious that all threesolutionsareinthesamerangeofeffectivenessinregard to myocardial protection.(3)
HTK SOLUTION COMPARED TO UW FOR CARDIAC TRANSPLANTATION(4)
ThepurposeofthisstudywastoaccesstheefficacyofHTKsolutionascomparedwithUWsolutioninexperimentalheartpreservation.(4)
Thistableshowstherecoveryofhemodynamicdataontheheartfor8and12hoursofpreservation.Following8hoursofpreservationtherecoveryofAF,CF,CO,SPandRPPinHTKgroup(2)wssignificantlyincreasedcompared with that in group 1 (P<.05).(4)
In our study, histologic changes in the zero biopsies analysisofdonordata,totalischemictime,reperfusiontime, mortality rate, and hemodynamic parameters indicated that HTK cardioplegia is more optimal in our conditions.(3)
WefoundabetterrecoveryofcardiacfunctionandlowerleakageofCPKintheheartsstoredinHTKsolutioncomparedwiththoseinUWsolutionfollowing8hoursofstorage.(4)
TheefficacyofHTKSolutionisattributedtothehighbufferingcapacityprovidedbythehistidine,whichsuppresses ischemia-induced acidosis and sustains a cytosolicATOlevel.
Inconclusion,HTKsolutionismuchmoreeffectivethanUWsolutionforheartpreservation.HTKmayleadtobettertechniquesofheartpreservationfortransplantation.(4)
Mortality Mortality Mortality Summary 2 days 14 days 90 days _____________________________________________________________Solution n % n % n % n %_____________________________________________________________Celsior 1 4.0 3 11 4 14 4 14HTK 6 5.0 17 12 17 12 17 12UW 3 4.0 9 13 11 16 11 17
Table 1. Composition ofUW,HTKand Celsior
Solutions
Substrates (mmol/L) UW HTK Celsior _____________________________________________Lactobionate 100 - 80Raffinose 30 - -NA+ 30 15 -K+ 125 10 -MG++ 5 4 -CI- - 50 -H2P04- 25 - -SO4- 5 - -Adenosine 5 - -Allopurinal 1 - -Glutathione 3 - 3Insulin 100 - -Dexamethasone 8 - -HES 50 - -Bactrimml/L 0.5 - -Osmolarity 320 310 320PH(Ost.C) 7.4 7.2 7.3Mannitol - 30 60Glutamate - - 20CaCl2 - 0.015 0.245NAOH - - 100KCl - 9 15MgCl2 - 4 13Histidine - 198 30Tryptophan - 2 -Ketogluturate - 1 -
Mortality in the 224 Recipients
Cardiac Functional Recovery (%)mean=SE*,<.05vs.Group1#,<.05vsGroup3CO;cardiacoutput,AF;aorticflow,CF;
coronaryflow;RPPratepressureproduct
Time_____________________________________________________________Group (h) CO AF CF RPP_____________________________________________________________1.UW(n=7) 8 49.7±2.4 47.4±4.2 57.1±6.2 71.0±1.8_____________________________________________________________2. HTK (n = 8) 8 78.1 ± 5.9* 71.5 ± 8.6* 87.8 ± 5.8* 83.6 ± 4.4*_____________________________________________________________3.UW(n=5) 12 16.6±3.4 10.7±2.4 37.6±8.4 40.9±8.2_____________________________________________________________4. HTK (n = 5) 12 29.7 ± 1.4# 24.2 ± 2.5# 4.26 ± 1.5 56.7 ± 4.1
HEARTThis study compared the protective effectsoftwowidelyusedpreservationsolutions, histidine-tryptophan-ketogluterate (HTK) and Celsior (CEL) forischemia-reperfusioninjuryusing
a rat heterotopic heart transplantation model with older donors(5)
TheauthorsconcludedthatHTKexhibitssuperiorprotections during cold storage in a syngenic rat heart transplantation model compared with CEL.(5)
HTKSolutionPreservesATPLevelsinCardiacGrafts (5)
HTK-TreatedGraftshavelessmetobolicstress(5)
HH
H
100
80
60
40
20
0
Rela
tive
ATP
leve
l(%
of c
ontr
ol)
0 hr 6 hr 12 hr 18 hr
Saline
CEL
HTK
H * *
A
CEL=Celsior;CPK=creatinephosphokinase;HMGB1=high-mobilitygroupbox1;HTK=histidine-tryptophan-ketoglutarate;MDA=malondialdehyde.
aValuesaremeans±SD;p values vs CEL are shown.
TABLE 1. MYOCARDIAL DAMAGE AND LIPID PEROXIDATION
100
80
60
40
20
0
Rela
tive
ATP
leve
l(%
of c
ontr
ol)
0 hr 6 hr 12 hr 18 hr
Saline
CEL
HTKB
*
Hearts From Younger Donors (n = 5) Hearts From Older Donors (n = 5)
Markers Saline CEL HTK p Valueª Saline CEL HTK p Valueª
Serum CPK (IU/l)
Serum troponinI(pg/mL)
Serum HMGB1(ng/mL)
5,360.8 ± 1,385.8
127.3 ± 37.5
1.32 ± 0.62
2,336.6 ± 841.0
37.4 ± 18.5
1.15 ± 0.55
1,946.1 ± 837.1
40.6 ± 20.1
1.15 ± 0.21
0.402
0.312
0.462
9,594.8 ± 1,526.7
304.1 ± 9.1
3.17 ± 1.79
8,094.1 ± 673.0
184.8 ± 33.0
2.33 ± 0.52
4,620.3 ± 441.4a
141.7 ± 36.5a
0.98 ± 0.75a
0.048
0.0184
0.0258
Tissue MDA (umol/mgtotal protein)
1.38 ± 0.43 1.11 ± 0.14 1.00 ± 0.42 0.15 2.57 ± 0.84 1.34 ± 0.18 0.8 ± 0.13 0.0014
Of myocardial damage
Of oxidative damage
________________________________________________________________________________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
________________________________________________________________________________________________________________________________
________________________________________________________________________________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
CELSIOR VS CUSTODIOL TheaimofthisexperimentalstudywastocomparetheprotectiveefficacyofthecardioplegicsolutionsCelsiorand Custodiol. Canine hearts were
examinedwithregardtoenergymetabolismandearlypost-ischemicrecoveryafter8or12hoursofischemiaat5°C.(6)
The authors concluded that, in the canine heart, Celsior showed no advantage over Cardioplegia with Custodiol. Differenceswereobservedhowever,whichmaybeclinicallyimportantespeciallyinthecaseoflongstoragetimes.
TABLE 2. MYOCARDIAL ENERGY METABOLISM DURING ISCHEMIA
8HoursIschemiaat5°CTherewasnosignificantdifferenceinmyocardialATPcontentbetweenpreservationsolutionsafter8hours.After12hours,heartsoftheCustodiolgroupcontainedsignificantlymoreATPcompared with Celsior-treated hearts (p<0.05).TheATP/ADPratiowassignificantlyhigherinCustodiol-treatedheartsafterbothischemictimes.(p < 0.01, 12 hours p < 0.05)(6)
12HoursIschemiaat5°CHeartswereperfusedwithCustodiolorCelsiorandstoredat5°Cfor8or12hours.Valuesaremeans±SEMoffiveexperiments(givenasµmol/gdryweight).ªSignificantlydifferentfromcorrespondingischemictimeoftheCustodiolgroup;p<0.05.ᵇSignificantlydifferentfromcorrespondingischemictimeoftheCustodiolgroup;p<0.01.ADP=adenosinediphosphate;AMP=adenosinemonophosphate;ATP=adenosinetriphosphate.
Custodiol® Celsior®
Phosphocreatine
ATP
ADP
AMP
ATP/ADPratio
Lactate
Glycogen
5.1 ± 0.3
20.1 ± 0.6
6.4 ± 0.3
1.4 ± 0.1
3.2 ± 0.2
99.3 ± 3.7
142.3 ± 18.7
4.0±0.2ª
17.7 ± 1.3
7.0 ± 0.3
1.7 ± 0.1
2.5±0.1ᵇ
81.5±8.1ª
155.8 ±11.3
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
Phosphocreatine
ATP
ADP
AMP
ATP/ADPratio
Lactate
Glycogen
3.2 ± 0.5
14.1 ± 1.6
6.3 ± 0.4
2.1 ± 0.3
2.3 ± 0.0
134.4 ± 6.3
111.2 ± 16.8
2.4 ± 0.5
11.3±1.0ª
6.9 ± 0.5
2.4 ± 0.2
1.6±0.1ª
116.2 ± 11.3
119.6 ± 23.8
Custodiol® Celsior®
HEART
Fold
ed F
lap
for P
I
Layo
ut P
I to
11 x
17
1/1
Blac
k (fo
lded
to 3
.4 x
5.5
)
Incidenceofarrhythmiasduringreperfusion
.........
Ventremoved
0
10
20
30
40
50
60
inci
dent
s of
am
hyth
mia
s [%
]
11 12 13 14 15 16 17 18 19 20reperfusion [min]
CEL
HTK
HeartswereperfusedwithCustodiol(—○—,—•—)orCelsior(—▼—,——)andstoredat5°Cfor8hours(—•—,—▼—ª)or12hours(—○—,——).Valuesaremeans±SEM,n=7foreachgroup.ªSignificantlydifferentfromcorrespondingischemictimeoftheCustodiolgroup;analysisofvariancep < 0.01.
Comparingtheincidenceofarrhythmiasduringthefirst20minutesofreperfu-sion, Celsior-treated hearts showed a higher rate - arrhythmic beats than Custodiol-treatedheartsafter8hoursas
wellasafter12hoursofischemia.Thedifferencewassignificantafter8hours(ANOVA,p<0.01)butnotafter12hoursofischemia.(6)
HEART
ΔΔ
Please see accompanying Prescribing Information.
© 2015 Essential Pharmaceuticals, LLC ESS 2015-1 01/15
• REFERENCES •1) S.-Y. Sung, C.-Y Lin, J.-Y. Song et al., Myocardial protection
in donor heart preservation: A comparison between Bretschneider’s histidine-trytophan-ketogluterate solution and cold blood Cardioplegia. Transplant Proceedings, 2014 46, 1077-1081
2) KreshJY,etal.TherelativebufferingpowerofCardioplegiasolutions.TheJournalofThoracicandCardiovascularSurgery1987 Feb. 43 (2) 309-11
3) M.Garlicki,J.Kolcz,etal.,MyocardialProtectionforTransplantation. Transplantation Proceedings 1999, 31, 2079-2083
4) K.GU,S.Kinetal.,HTKSolutionismoreeffectivethanUWsolutionforcardiacpreservation.TransplantationProceedings,1996 Vol 28 1906-1907
5) S. Lee, C-S Huang, et al., Histidine-tryptophan-ketogluterate or Celsior:Whichismoresuitableforcoldpreservationforcardiacgraftsfromolderdonors?AnnThoracSurg2011;91:755-63
6) J.Ackemann,W.Gross,etal.,CelsiorvsCustodiol:earlypostischemicrecoveryafterCardioplegiaandischemiaat5°C.AnnThoracSurg2002;74:522-9
• TRULY READY TO USE •
ORGAN PRESERVATION SOLUTION
HEART
Formoreinformation,e-mailusat [email protected] (377-7763)
Visit our websites at www.custodiol.com www.essentialpharma.com
Please see accompanying PrescribingInformation.
100 Princeton South Corporate Center Suite 140 Ewing, NJ 08628