Htk costodial clinical effect edited nice

Cinical Impact of Histidine Ketogutarate Tryptophan(HTK)

Cardioplegia solution

on the Perioperative period in open heart

surgery patient

Cinical Impact OF HTK Cardioplegia solution

Introduction

o The needs of the surgeon include rapid induction, maintenance and easy reversal of cardiac arrest, a relaxed heart to allow for mobilization and traction, a preferably bloodless and unobscured field, and sufficient time for adequate correction of cardiac or coronary defects

o Spectrum of myocardial ischemic injury Acute ischemic dysfunction Preconditioning Stunning Hibernation Necrosis vs. Apoptosis

HISTORY

Brief history of the development of surgical cardioprotection

o A. Early Developments.

o B Survival and Success

o C. International Reawakening.

o Since the introduction and acceptance in the early 1970’s of modern surgical protection by Cardioplegia.

A. Early Developments

o Cool the whole patient to slow the rate of metabolism. The chest was opened, operation, and closed rapidly before rewarming.

o 1953, Lewis and Taufic the first open-heart (without the CPB), ASD closure with circulatory arrest.

o 1954, Gibbon development the heart lung machine allowed brain ischemia but the heart become ischemic and some operations, mortality rate 65%.

o Continue to beat intermittently.

John H. Gibbon

A. Early Developments

o 1955, Melrose and colleagues introduced the concept of “elective reversible cardiac arrest”.o Potassium citrate (77-309 mmlo/L) added to blood at 37 oC.o In animals, potassium citrate 2.5%(77mmlo/L) in blood with good

results (1950-1960).

o Potassium citrate was associated with myocardial injury, heart necrosis. As the use of potassium based Cardioplegia was abandoned for about 15 years. .

o 1960s, continuous coronary perfusion, with electrically induced ventricular fibrillation.

A. Early Developmentso 1970s, Buckberg and colleagues demonstrated that

fibrillation caused sub endocardial necrosis , LV fibrillation out of favor (avoid fibrillation 29-32 o C).

o Intermittent coronary perfusion.

o Ischemic preconditioning.

o In the late 1960 s and early 1970 s Shumway was protecting the heart with “profound” topical

hypothermia. Cooley, normothermic ischemia and first to describe the

“stone heart”.

B. Survival and Successo During the 1960s, in Germany. Holscher, suggested magnesium

chloride plus procaine amide of cardioprotection.

o 1960s “bretschneider solution” in Gottingen, German. developed a number of “intracellular” solutions employing sodium plus calcium depletion

o 1960s, Kirsch, in hamburg.

o 1964 Sondergaard in Denmark introduced the Bretschneider solution no. 3 into clinical.

o In 1975 he report 100 AV operation with a low 6% mortality. (pioneer of modern cardioplegia)

o Bretschneider and associates remained underrated for an unfortunately long time.

C. International Reawakening

o 1970s. In the United states. In USA Gay, Levitsky, Roe, Tyers and Buckberg reassessed the use of potassium below 40 mM

o Gay and Ebert, 25 mmol/L potassium chloride in dog, good protection.

o Roe and colleagues reported in 204 patients using potassium Cardioplegia with a mortality of 5.4 %.

o Tyers and co workers, over 100 patients using 25 mmol/L potassium with good myocardial protection.

o 1975, Braimbrideg was first introduced St. Thomas’ Hospital Cardioplegia.

Noncoronary collateral flow Buckberg 1979

o Can deliver blood to the heart via bronchial, mediastinal, tracheal, esophageal, and diaphragmatic arteries.

o Flow may vary from 3 – 10 % of normal coronary flow (normal 250 ml/Min).

o Advantage providing oxygen and substrates to the ischemic tissue.

o Negative effect by washing out cold cardioprotective solutions .

o Intro the heart at the onset of ischemia

The composition of the Bretschneider (BR) and the St. Thomas’ Hospital (STH)

Characteristics of cardioplegic protection

o There are really only two types of cardioplegic solutiono Intracellular type (Bretschneidr solution)o Extracellular type (St. Thomas’ , Buckberg solution)

o Intracellular type used predominantly for preservation of the heart and abdominal organs

o Extracellular type used predominantly for cardiac surgery

Custodiol HTK solution

A product approved by US FDA as a Medical Device

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

0.8132 g Magnesium chloride · 6 H2O = 4.0 mmol/l

3.7733 g Histidine · HCI · H2O = 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 · 2 H2O = 0.015 mmol/l 0.1842

g Potassium hydrogen 2-ketoglutarate = 1.0 mmol/l

o in sterile Water for injectionAnion: Chloride 50 mEq

o Physical PropertiespH 7.02 - 7.20 at 25ºC (77° F) [pH 7.4 - 7.45 at 4ºC (39.2° F)] Osmolality: 310 mosmol/kg

Principles underlying the protection of the heart

o Inducing rapid and complete Cardiac Arrest

o Slowing the onset of irreversible injury by Hypothermia

o Appropriate buffering, Maintain pH Histidine/bicarb/ THAM/ blood

o Avoidance of Substrates depletion, ketoglutarate/glucose

o Attention to intracellular Edema ,mannitol/glucose/albumin

o Optimizing reperfusion to maximize Post ischemic

Inducing rapidand complete Cardiac Arrest HTK solution

Depolarized Arrest

Polarized Arrest

Inhibition of Ca influx

Myocardial O2 consumptions

o Myocardial O2 consumptions at 37 oC

Beating (full, perfused) 10.0 ml/100gr/min

Beating (empty, perfused) 5.5 ml/100gr/min

Fibrilating (empty, perfused) 6.5 ml/100gr/min

Cardioplegia (empty, crossclamp) 1.0 ml/100gr/min

Complete Cardiac Arrest

Inhibition of Ca influx

in HTK technique

Inhibition of Ca influx Nondepolarized

o Reduce Ionic movement Na Ca ions

o Threshold potential not be reached and window will not be activated,

o Reduce myocardium energy, minimizing transmembrane gradients

Cardioplegia and the Calcium Paradox► Important observations were made on the sarcolemmal sodium–

calcium exchange (Langer 1977), on the SR for intracellular calcium storage-release

► multiple roles of calcium when formulating cardioplegic solutions and when applying them in combination with hypothermia

► A controversial issue was the use of calcium-free coronary infusates and the possibility that an extensive calcium washout might induce a calcium paradox.

► Thus when calcium is reintroduced to a myocardium with a sarcolemma depleted, cell calcium overload with contracture and membrane injury is immediate and massive , “stone heart”

Cardioplegia and the Calcium Paradox► Studies indicated that the calcium-free Bretschneider solutions might

induce a calcium paradox

► However, these solutions were apparently safe since they were sodium poor and applied under deep hypothermia

► Stabilize the sarcolemma against removal of a critical fraction of calcium

► In retrospect, the myocardial injuries inflicted by the Melrose solution (Melrose 1980) might be interpreted as the consequences of citrate induction of a calcium paradox

► It is of interest to note that the most recent of the Bretschneider HTK solutions (Custodiol) is formulated with a minor calcium additive (20 mM).

Ionic interactions and Calcium control

Sodium-poor coronary infusates and optimal calcium. The accumulated creatine kinase (CK)release during reperfusion (15 min) after ischemia (30 min) in isolated normothermic rat hearts isshown.

O preischemia <2 minute with Bretschneider solution no 3 devoid of or supplemented with calcium.

♦ preischemia >2 minute with Bretschneider solution devoid of calcium.

The dotted line shows the level ofCK release on reperfusion of control hearts. (Reproduced from Jynge 1982 by permission ofEditrice CLUEB, Bologna)

Concepts and Issues

o Energy, Metabolism and Recovery from Ischemia

o Key to myocardial protection was found in cell energetics and in the content and function of ATP.

o Time and temperature limits for expected survival from surgical ischemia;

o Mechanisms and causes of ischemia-induced contracture.

Time and temperature limits for expected survival from surgical ischemia

t-ATP as the time required For myocardial

ATP to fall from about 6 mmol/g wet weight to 4 mmol/g wet weight

This levelwas shown to be critical for functional recovery from ischemia and rapid weaning from CPB

Time and temperature limits for expected survival from surgical ischemia

Myocardial content of ATP, creatine phosphate (CP) and lactate during ischemia. Control hearts and heartsreceiving initial perfusion with nonbuffered Bretschneider solution no 3 and buffered BretschneiderHTK solution. Results were obtained from isolated dog hearts kept ischemic at amyocardial temperature of25C. (Reproduced from Preusse 1993 by permission of Kluwer Academic Publishers)

Myocardial O2 consumption

Oxygen Demand reduction

o Normothermic Arrest (37 oC) 1.00 mL/100g/min 90%

o Hypothermic Arrest (22 oC) 0.30 mL/100g/min 97%

o Hypothermic Arrest (10 oC) 0.14 mL/100g/min ~ 97%

Buckberg GD, Brazier JR, Nelson RL, et al;J Thorac Cardiovasc Surg 1977;73:87-94

Hypothermia: The Second Component of Protection

o lowers metabolic rate

o decrease myocardial energy requirements

o membrane stability promoting electromechanical quiescence

o every 10 oC in temperature, enzyme activity halved

o regional variations !

Bigelow, Lindsay, Greenwood- 1950 Shumway and Lower- 1959

Hypothermia: The Second Component of Protection

Additive protection of hypothermia in combination with cardioplegia(A) post ischemic recovery of aortic flow after 30 min reperfusion in rat heart Hypothermia alone or hypothermia + cardioplegia and 120 min of global hypothermic *p <0.05 compared to Hypothermia alone.(B) Cardiac output in the in situ dog heart before bypass (control) and 15 min post bypass After 120 min of global hypothermic (20

oC) ischemia with 2 min infusions of hypothermia alone or

hypothermia + cardioplegia

Redrawn from hearse et al.

Hypothermia injuryEffects on : Pitfalls

o The induction of rapid myocardial hyphthermia (at 0-4 oC)

o Calcium sequestration increase intra cellular Ca

o Sodium pump is inhibited will lead to intracellular sodium and chloride accumulation down the concentration gradient

o Osmotic homeostasis (cell swelling), Anion: Chloride

Lichtenstein SV, Ashe KA, Dalati HE, et al.

J Thorac Cardiovasc Surg 1991;101:269-74

The optimal temperature during hypothermic

► Temperature around 10-20 oC were optimal.

► Water temperature 4 oC, cooling myocardium to 10-20 oC

Noncoronary collateral inflow of bloodo According to recommendations the Bretschneider HTK solution

has to be infused in a single-dose. Perfusion time about 6-8 minutes

o As a consequence of gradual noncoronary collateral inflow of blood, myocardial protection with the otherwise superior BR-HTK was reduced but slightly improved with STH-2.

o Documented that electromechanical reactivation required less washout of cardioplegic solution after arrest with the HTK solution than with the STH-2 solution.

Manipulation of metabolism and substrate utilization

o Glucose and glycolytic intermediates during ischemia Promote glycolytic anaerobic ATP (2 ATP) Intracellular acidosis and lactate production

o Glucose or lactate were not recommended as additives (hearse et al. 1978)

o The hearse group showed stimulation of glycolysis in zero flow conditions was deleterious

Optimizing reperfusion to maximize post ischemic recovery

o Compared to unmodified blood reperfusion on left ventricular function (systolic pressure) at increasing diastolic volume

o Hypocalcemia (avoid Ca overload, myocardium stunning)

o Optimize the recovery of energy metabolism

Optimizing reperfusion to maximize post ischemic recovery

o Ischemic and Reperfusion injury phase cell damage following ischemia is biphasic; injury being initiated during ischemia exacerbated during reperfusion

o The best approach to avoiding reperfusion injury Control ionic disturbances Hypocalcaemia avoid Ca overload Amino acid ketoglutarate (Krebs-cycle intermediates) Reperfusion Pressure had preferably to be lowered Ventricular fibrillation had to be rapidly converted Residual air within heart chambers and Coronary had to be taken

care Combat free radical production and oxidative stress with histidine

RU

LES

HISTIDINE ACTS AS A BUFFER

TRYTOPHAN stabilizes cell membranes

KETOGLUTARATE improves high energy ATP

AndMANNITOl decrease cellular edema

HISTIDINE ACTS AS

A free radical scavenger

Phamocology HTK o Costodiol prolongs ischemia tolerance in organs requiring

protection mainly by two mechanisms of action

o The electrolyte composition of Custodiol prevent the trigger of energy consuming activation processes. Nondepolarized cardiacarrest thus minimizing transmembrane gradients

o Anaerobic energy production is limited by increasing inhibition of glycolysis Buffer histidine retards the fall in PH during organ ischemia Ketoglutarat is a substrate for aerobic energy production Tryptophan has been claimed to have a membrane protective action Mannitol is considered to prevent the emergence of cell edema

Dosage and Administration

► Perfusion time : about 6-8 minutes

► Perfusion Technique: Hydrostatic perfusion Perfusion pump

► The ischemia tolerance of the heart when using the HLM : 180 minutes

► The basic perfusion technique Low Temperatures, and extremely low viscosity Large volumes under low pressures and low temperatures

necessary for perfusion

Dosage and Administration

o Temperature of solution 5-8 oC

o Perfusion Volume 40-50 cc/Kgo Perfusion Pressure (pressure in the aortic root)

Audults– Initially 140-150 cmH2O above the level of the heart = 100-110 mmHg– After cardiac arrest, reduce to 50-70 cmH2O = 40-50 mmHg

Infants and young children– Initially 110-120 cmH2O above the level of the heart = 80-90 mmHg– After cardiac arrest, reduce to 40-50 cmH2O = 30-40 mmHg

► In patients with CAD higher pressures should be maintained for long periods

Only solution used as Single Shot Cardioplegia for prolonged ischemia

o No surface cooling

o No retro cardiac cooling

o No obligatory reperfusion

o High rate of spontaneous return to sinus rhythm

o Minimized cell necrosis

o Less depletion of ATP stores

o Remarkably increased protective potency

Toxicological properties

Circulation volume overloading or Second dose and may by add Hemoconcentrator or diuretic drug

Disturbances of electrolyte balance hyponateremia, hypocalcemia.

Plasma levels of the amino acids tryptopan and histidine may be elevate during the first 24 hrs. Induce acidosis during CPB time

Custodiol® is mainly used in the cases

Long period operation or some complicated cardiac surgeries with long term cross-clamping time.

complex congenital heart disease, arterial switch operation Aortic Aneurysms Hypertrophic Obstructive Cardiomyopathy Robotic Cardiac surgery Minimally MV surgery Aortic Valve Mitral Valve Defects CABG

PUBLISHED CLINICAL

WITHEXPERIENCE

HTK

HTK Cardioplegic solution in Open heart surgery : In Mexico 2001

Careaga G, Salazar D, Téllez S, Sánchez O, Borrayo G, Argüero R.

Compare HTK solution with crystalloid CPS

METHODS: Prospective, randomized control trial o 30 patients for opern heart surgery (CAG , Valve ,CABG + VALVE, Congenital heart disease correction )

o group I (n = 15), Bretschenider solution (HTK)o group II (n = 15) with conventional crystalloid cardioplegia.

RESULTS: o During reperfusion, there was no differenceo Postoperative period group I had a lower incidence of arrhythmias (p =

0.001). Inotropic support (p = 0.003) and length-of-stay in the intensive care unit (p = 0.037) were lower in group I.

o There were no deaths in either group.

The myocardial protection of HTK cardioplegic solution on the long-term ischemic period in pediatric

heart surgery in China 2008Liu J, Feng Z, Zhao J, Li B, Long C.

Compare HTK solution with crystalloid CPS

• METHODS: Retrospective, randomized control trial

• 118 infants 2-5 year old who underwent open-heart surgery between January 2004 and December 2007.

• group H (n = 63) with one single perfusion with HTK solution• group S (n = 55) with conventional St. Thomas crystalloid cardioplegia

Compare HTK solution with crystalloid CPS

RESULTS: o During reperfusion, the spontaneous re-beating rate was higher

in group H (*p < 0.05).

o There were no differences in doses of inotropic agent and creatinekinase (CK) values on postoperative day 1

o The level of CK in group H was significantly less than that in group S on postoperative day 2 (*p < 0.01).

o The mortality in group H was lower than in group S (p < 0.05).

o The HTK group had shorter cross-clamping time and more frequent spontaneous defibrillation than St. Thomas group.

Comparison of Clinical Outcome Between Histidine-Triptophan-

Ketoglutalate Solution and Cold Blood Cardioplegic Solution in Mitral Valve Replacement :

Japan 1998J Card Surg

Compare HTK solution with Cold blood CPS

METHODS: Prospective, randomized control trial• 46 patients who underwent mitral valve replacement• HTK group I (n = 20) Bretschenider solution• CBC group II (n = 27) cold blood cardioplegia.

Compare HTK solution with Cold blood CPS

Result:

o The doses of inotropic agent at the end of extracorporeal circulation did not different

o Creatine kinase values (units) on day 1 and day 2 were 1140 ± 412, 921 ± 436 for the HTK group and 904 ± 335,816 ± 420 for the CBC group, respectively (*p = NS).

o Spontaneous defibrillation occurred in 26% of the CBC group and 90% of the HTK group (*p < 0.05).

o Pacing was temporarily used in 20% of the HTK group and 44% of the CBC group after extracorporeal circulation (*p < 0.05).

One single dose of histidine–tryptophan–ketoglutarate solution gives equally good myocardial protection in

elective mitral valve surgery as repetitive cold blood cardioplegia :

Sweden 2010Bjørn Braathen, MD, Anders Jeppsson, MD, PhD, Henrik Scherstén, MD, PhD, Ole M.

Hagen, MD, Øystein Vengen, MD, PhD, Helena Rexius, MD, PhD, Vincenzo Lepore, MD, PhD, Theis Tønnessen, MD, PhD

Compare HTK solution with Cold blood CPS

METHODS: Prospective, randomized control trial

• 76 patients who underwent mitral valve replacement• HTK group I (n =38) Bretschenider solution : hydrostatic pressure 2 m• CBC group II (n = 27) cold blood cardioplegia.

Results• No significant difference in creatine kinase MB and troponin-T

between two groups was found at any time point. • The HTK group only and significantly more spontaneous ventricular

fibrillation after release of crossclamping in the HTK group.

Pulmonary artery perfusion with HTK solution prevents lung injury in

infants after cardiopulmonary bypass : China 2010

LI Jian-an, LIU Ying-long, LIU Jin-ping and LI Xiao-feng

lung injury; HTK solutioncardiopulmonary bypass

METHODS: Prospective, randomized control trial

• 24 consecutive infants with congenital heart defects and pulmonary hypertension

• perfused group (n=12) • control group (n=12).

• Oxygen index, alveolar-arterial O2 gradient, serum levels of malondialchehyche (MDA), interleukin (IL)-6, -8, -10, soluble intercellular adhesion molecule-1 (sICAM-1), and P-selectin were measured before commencement and serially for 48 hours after termination of bypass.

lung injury; HTK solutioncardiopulmonary bypass

Results

o Oxygenation values were better preserved in the perfused group

o IL-6 increased immediately after CPB in both groups and returned to baseline at 48 hours after CPB, but it was restored faster and earlier in the perfused group.

o IL-8, sICAM-1, and MDA remained at baseline at each point after CPB in the perfused group and elevated significantly immediately after CPB in the control group, except for sICAM-1.

lung injury; HTK solutioncardiopulmonary bypass

Results

o IL-10 increased immediately after CPB and decreased to baseline at 48 hours after CPB in both groups, but the IL-10 level in the perfused group was significantly higher than in the control group at 12 hours after CPB.

o The serum P-selectin levels in the control group immediately after CPB were significantly higher than prebypass levels.

o Moreover, there were no significant differences in postoperative clinical characters, except for the intubated time.

o Conclusion In infants with congenital heart defects, pulmonary perfusion with hypothermic HTK solution during cardiopulmonary bypass could ameliorate lung function and reduce the inflammatory response.

Conclusion

• After an exciting period of experimentation and early clinical application cardioplegia undergone further developments

• First of all based on thorough analyses of its practical adaptation both in general and as applied in different intraoperative Situations.

• Apparent that an in-depth knowledge of both surgical procedures and the pathophysiology of myocardial ischemia.

THANK YOU

Cinical Impact OF HTK Cardioplegia solution