Cardioplegic Agent Research Articles

Effect of single-dose crystalloid cardioplegic agent compared to bloody cardioplegic agent in cardiac surgery in children with Tetralogy of Fallot.

BACKGROUNDCardioplegia is one of the main post-operative cardiac protective factors widely used in recent decades in the form of crystalloid (St. Thomas) and bloody solutions [del Nido (DN)]. The purpose of this study was to compare the effect of a crystalloid cardioplegic agent (St. Thomas) with that of a bloody cardioplegic agent (DN) in pediatric cardiac surgery among children with Tetralogy of Fallot (TOF).METHODSThis study was performed on 60 children with TOF, who were candidates for heart repair surgery. The participants were randomly divided into two groups of crystalloid cardioplegic agent and bloody cardioplegic agent. Operative outcomes such as required time for onset of heart arrest, duration of returning to normal heart rhythm, and cardiopulmonary bypass (CPB) time, and operative complications were compared between the two groups.RESULTSThe duration of returning to normal heart rhythm (50.43 ± 10.93 seconds vs. 43.03 ± 16.35 seconds; P = 0.044) and duration of inotropy (80.40 ± 27.14 hours vs. 63.20 ± 26.91 hours; P = 0.017) were significantly higher in the DN group compared to the St. Thomas group. However, there were no significant differences between the two groups in terms of heart arrest time, cross-clamp time, CPB time, supplementary lasix time, duration of intubation, and intensive care unit (ICU) and hospital length of stay (LOS) (P > 0.050).CONCLUSIONThe use of St. Thomas cardioplegic solution was more effective in reducing the duration of returning to normal heart rhythm and inotropy compared with DN cardioplegic agent, and a single dose of these two cardioplegic agents can keep the mean cardiac arrest duration within the range of 50-70 minutes. It seems that the use of St. Thomas cardioplegic solution can be suggested in pediatric heart surgery.

Prehospital adenosine, lidocaine, and magnesium has inferior survival compared with tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock.

Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour. Swine were randomized to: (1) TCCC, (2) 2 mL·kg vehicle control (VC), (3) 2 mL·kg ALM + drip, (4) 4 mL·kg ALM + drip, 5) 4 mL·kg ALM + delayed drip at 0.5 mL·kg·h, 6) 4 mL/kg VC, 7) 4 mL·kg ALM for 15 minutes + delayed drip at 3 mL·kg·h. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points. Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability. Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.

Intermittent warm blood cardioplegia versus crystalloid cardioplegia in coronary artery bypass grafting surgery patients: Is there any difference in the early postoperative period?

Aim. The purpose of this study was to assess the effectiveness of two types of cardioplegia solutions, namely, blood and crystalloid cardioplegia in terms of clinical outcomes in patients undergoing coronary artery bypass grafting.Methods. The retrospective study recruited 2,539 coronary artery bypass grafting patients, with 1,070 (45%) of them receiving crystalloid and 1,289 (55%) blood cardioplegia as a primary cardioplegic agent. Propensity score matching was performed to create comparable patient groups. The primary endpoint of the study was hospital mortality and different postoperative outcomes.Results. Patients receiving blood cardioplegia versus those with crystalloid cardioplegia were found out to have higher rate of acute kidney injury (15.7% vs 11.8%; OR=0.72; p=0.01) and postoperative ventilatory support (Ме=5:35 vs Me=5; p<0.05). During ventilatory support, the crystalloid cardioplegia patients demonstrated lower hemoglobin (Me=65 g/l vs Me=74 g/l; p<0.01) and hematocrit (Me=21% vs Mе=24%; p<0.01). Intraoperatively, packed red blood cells were administered in blood cardioplegia patients by 30% more often than in crystalloid cardioplegia ones (24% vs 19.6%; OR=0.77; p=0.02). Patients receiving crystalloid cardioplegia had a greater postoperative fluid balance (Me=1,700 ml vs Mе=1,350 ml; p<0.01) more frequent use of inotrope and vasopressor therapy (4.5% vs 2.8%; OR=1.64; p=0.04) and a longer stay in intensive care unit (p<0.01).No statistically significant differences were observed concerning perioperative and postoperative myocardial infarction, low cardiac output syndrome or intra-aortic balloon pumping, allogeneic blood transfusions in the postoperative period, episodes of atrial fibrillation, gastrointestinal complications, reoperation due to any cause, length of stay in hospital, hospital mortality.Conclusion. Blood cardioplegia might decrease the need in inotrope and vasopressor therapy, length of stay in intensive care unit, but it increases the rate of acute kidney injury, risk of allogeneic blood transfusions and durability of postoperative ventilatory support. Received 1 August 2018. Revised 18 October 2018. Accepted 22 October 2018.Funding: The study did not have sponsorship.Conflict of interest: Authors declare no conflict of interest.Author contributionsConception and study design: M.E. Evdokimov, A.A. Gornostaev, V.V. BazylevData collection and analysis: M.E. Evdokimov, A.A. Gornostaev, A.A. Schegolkov, A.V. BulyginStatistical analysis: A.A. Schegolkov, A.V. BulyginDrafting the article: A.A. Schegolkov, A.V. BulyginCritical revision of the article: M.E. Evdokimov, A.A. Gornostaev, V.V. BazylevFinal approval of the version to be published: V.V. Bazylev, M.E. Evdokimov, A.A. Gornostaev, A.A. Schegolkov, A.V. Bulygin

Clinical Impact of Custodiol Cardioplegic Solution on Patients Undergoing Complex Cardiac Surgery With Mild to Moderate Impairment of Left Ventricular Systolic Function

Background: The Bretschneider HTK solution is used widely for multiorgan preservation for transplantation, as well as a cardioplegic agent that allows single dose administration which is an attractive option for lengthy complex cardiac surgery. It was proved that it is simple to use, safe and practical. Moreover, it is considered to confer sufficient myocardial protection for more than 2 h of cardiac arrest. We undertook this descriptive study to analyze the performance of HTK solution in patients undergoing complex cardiac surgery with mild to moderate impairment of left ventricular systolic function. Patients and methods: A total of 50 patients underwent different complex cardiac surgery at national heart institute from January 2015 to November 2016 using single dose Custodiol cardioplegia as the primary and sole cardioplegic agent, their data was prospectively collected and their hospital outcome was analyzed as regards to ten study endpoints namely Prolonged ventilation, return to theatre for bleeding, renal failure, stroke, 30 days mortality, postoperative MI, need for inotropes, time on inotropes, ICU stay and hospital stay. Pre- and postoperative echocardiography was done to compare and evaluate the change of LV function using the parameters of End Systolic Dimension, End Diastolic Dimension, Fraction Shortening and Ejection Fraction of the left ventricle. Results: Half of the patients were males. Their age ranged between 16 – 65 years with a mean (standard deviation) of 47.46(11.10). preoperative ejection fraction ranged from 30 % to 49% with a mean (standard deviation) of 41.8 (6.32), the majority of them (64%) had NYHA class of 3 and half of them had CCS of 3. all patients were done electively. The most common procedure done was redo DVR 24% (12 patients) followed by Bentall operation 22%(11 patients). This is followed by CABG + MVR 7 patients (14%), then an equal number of 6 patients (12%) who underwent redo MVR post-infective endocarditis and CABG+ MVrep. The repair of tricuspid valve was done for 14 patients (28%) either with MVR or DVR. 4 patients (8%) had CABG +AVR for their combined lesions and another equal number of two patients (4%) underwent redo CABG and AVR + conduit (valve separate tube graft operation). prolonged ventilation occurred in 20% of the cases. An equal percentage of 6% of the patients had to return to the operative room and had postoperative MI. Renal failure occurred in 4% of the patients and as far as 30-day mortality is concerned, a similar 4% of patients died within this period. EF and FS were very similar when compared together (41.8 ± 6.32 %, 20.8 ± 2.35 % preoperatively compared to 41.92 ± 7.49%, 20.85 ± 3.25% postoperatively). P value was insignificant (0.937 and 0.929) respectively. Conclusion: A single dose of an HTK cardioplegic solution provides good myocardial protection in complex cardiac surgery with mild to moderate impairment of LV function and has a good immediate postoperative outcome.

Custodiol versus blood cardioplegia in complex cardiac operations: an Australian experience

A single or dual-dose strategy for myocardial protection is attractive in long operations, in avoiding the need to interrupt the procedure to re-administer cardioplegia. We hypothesized that a single administration of Bretschneider histidine-tryptophan-ketoglutarate (HTK) crystalloid solution (Custodiol) offers myocardial protection comparable with repeated tepid blood cardioplegia. We reviewed a prospectively compiled single-centre database containing all adult cardiac procedures performed from January 2005 to January 2011. Preoperative demographic and investigative data, operative variables and postoperative (30-day) mortality and morbidity were compared between the Custodiol and blood cardioplegia groups. The study primary endpoints were 30-day mortality, return to the operating theatre, myocardial infarction, stroke, postoperative requirement for an intra-aortic balloon pump, new renal failure, prolonged ventilation and re-admission to hospital within 30 days. Propensity score matching was performed to correct for any bias that may have been associated with the usage of Custodiol. A total of 1900 cardiac surgical procedures were identified of which 126 (7%) utilized Custodiol and 1774 (93%) used blood cardioplegia as the primary cardioplegic agent. After propensity-score matching, we were able to match 71 Custodiol cases one-to-one to those receiving blood cardioplegia. There were no statistically significant differences noted for any of the endpoints studied after propensity-score matching. In particular, the proportion of mortality (blood cardioplegia: 1 vs Custodiol 4%, P = 0.63) any mortality/morbidity (blood cardioplegia: 35 vs Custodiol: 39% P = 0.46) was similar between the groups. The use of Custodiol is convenient, simple and at least as safe as tepid blood cardioplegia for myocardial protection in complex cardiac operations. A randomized prospective comparison of myocardial protection strategies is warranted.

Esmolol cardioplegia: the cellular mechanism of diastolic arrest

Esmolol, an ultra-short-acting beta-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. In unpaced Langendorff-perfused rat hearts, esmolol (0.03-3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Ca(tr)) in electrically-stimulated rat ventricular myocytes at 23 and 34 degrees C. The decrease in contraction (by 72% at 23 degrees C, from 0.16 +/- 0.01 to 0.04 +/- 0.01 microm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Ca(tr) (from 0.13 +/- 0.02 to 0.07 +/- 0.02, P < 0.001). There was no additional effect on myofilament Ca(2+) sensitivity. Esmolol's effects on contraction and Ca(tr) were not shared or altered by the beta-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (I(Ca,L)) and the fast sodium current (I(Na)), with IC(50) values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively. Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca(2+) channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na(+) channels.

Targeting for cardioplegia: arresting agents and their safety

Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better cardioplegic agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a cardioplegic agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal cardioplegic agent. We also assess the suitability and clinical potential of previously-studied cardioplegic agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological agents in order to offer better cardioplegic solutions.

The cardioplegic agent 2,3 Butanedione Monoxime (BDM) does not alter the force frequency relation in human atrial myocardium

The cardioplegic agent 2,3 Butanedione Monoxime (BDM) does not alter the force frequency relation in human atrial myocardium

Abstract 1556: Esmolol As A Cardioplegic Agent; An Effect Beyond β-blockade

Esmolol, an ultra-short-acting β-blocker, is used in the treatment of hypertension and arrhythmias. We and others have shown that millimolar doses of esmolol is cardioprotective, and acts as a cardioplegic agent in both human and animal hearts. In vivo, the β-blocking effect explains the cardioprotective action but the mechanism for esmolol-induced arrest in isolated hearts is unknown. This study characterises the mode of action by which esmolol causes diastolic arrest at millimolar doses. Isolated rat ventricular myocytes were superfused with buffered Tyrode solution and electrically stimulated. We measured myocyte contraction by sarcomere shortening (SS) and calcium transient (Ca tr ) by fluorescence microscopy using fura-2 (340/380 nm ratio). Additional studies of L-type calcium currents ( I Ca,L ) using whole-cell voltage-clamping were conducted. Esmolol (0.3 mmol/L) decreased myocyte SS by 72% from 0.16±0.01 μm to 0.04±0.01 μm (mean±SE, n=7; P &lt;&lt; med &gt; 0.0001). The corresponding Ca tr fell from 0.13±0.02 to 0.07±0.02 (P&lt;&lt;med&gt;0.001), a decrease of 47%. Inhibiting the SR with thapsigargan (1 μmol/L) did not alter the effect of esmolol: the SS (in an elevated bathing [Ca] of 7 mmol/L) decreased from 0.16±0.007 to 0.05±0.002 μm, a drop of 69% (n=7), and Ca tr fell from 0.12±0.006 to 0.06±0.003 (50% decrease). This suggested that high dose esmolol inhibits the L-type Ca channels; this was confirmed by voltage-clamp studies (Fig ). In separate studies on skinned myocytes, esmolol had no effect on myofilament sensitivity to calcium. We conclude that high doses of the β-blocker esmolol (that are already used in cardiac surgery) cause diastolic arrest by inhibiting L-type Ca channels.

Myocardial protection of immature rabbits: polarizing versus depolarizing

Background. This study was designed to identify the potassium-channel opener pinacidil as a cardioplegic agent vs hyperkalemic cardioplegia in terms of its efficacy in immature cardioprotection. Methods. By a Langendorff model, 21 hearts of 21- to 28-day-old New Zealand rabbits underwent 90 min of global hypothermic (15°C) ischemia protected with a different single dose of hypothermic (4°C) cardioplegia (pinacidil [50 μmol/l], St. Thomas’ solution combined with pinacidil [50 μmol/l], and St. Thomas’ solution). The percent recovery of the cardiac function, creatine kinase release, and cellular ultrastructure were compared. Results. Pinacidil (50 μmol/l) provided significantly the best postreperfused percentage recovery of the function than the other groups; pinacidil cardioplegia showed a significant reduction of creatine kinase release in the coronary flow compared with the other groups; St. Thomas’ solution combined with pinacidil showed the highest release. Percentage recovery of the coronary flow, water contents, and ultrastructural changes were similar between the groups. Conclusions. Pinacidil provided better protection during ischemia-reperfusion in the immature rabbit heart than St. Thomas’ solution, whereas pinacidil combined with St. Thomas’ solution showed the worst protective effects in immature hearts.

The Effect of Ischaemic Preconditioning on Cardiac Function After Potassium Channel Opener (Pinacidil) Cardioplegia at Hypothermia and Normothermia

Objectives: To determine the effect of ischaemic preconditioning on post-ischemic myocardial recovery in hearts arrested with Pinacidil at both hypothermia and normothermia; and to assess the efficacy of Pinacidil as a cardioplegic agent. Methods: Isolated ejecting Porton rat hearts were perfused at normothermia via a Langendorff apparatus, utilizing retrograde coronary perfusion at a constant pressure (70cm/H2O). All animals underwent a 30-min normothermic stabilization phase, thereafter being divided into the following groups. Hearts arrested with 50ml of hyperkalemic (16mmol/L) Krebs solution at 37°C (A; n = 15) or 15°C (B; n = 15); hearts arrested with 50ml of Pinacidil (100umol/L) at 37°C (C; n = 15) or 15°C (D; n = 15); hearts exposed to two 3 min episodes of 37°C zero flow ischaemia (preconditioning) and subsequently arrested with Pinacidil at 37°C (E; n = 15) or 15°C (F; n = 15). All hearts then underwent 60 min of global ischaemia at their respective cardioplegic temperatures, and 60 min of normothermic perfusion. Results: In non-preconditioned groups (A-D) at both hypo- and normothermia there were no significant differences between Pinacidil and hyperkalemic arrested hearts in reperfusion coronary flow, percentage recovery of developed pressure, or dP/dT max (systolic and diastolic). At normothermia, time to mechanical and electrical arrest was significantly longer in the Pinacidil group (C; 16.0 min and 21.0 min) than in the hyperkalemic group (A; 5.0 min and 7.6 min; p < 0.01). At hypothermia the incidence of reperfusion VF was significantly higher in the Pinacidil group (D; 40%) than the hyperkalemic group (B; 0%; p < 0.001). In the preconditioned groups (E & F) reperfusion coronary flow was significantly greater than in non-preconditioned groups (C & D) at both normo- and hypothermia. At hypothermia, preconditioned hearts (F), when compared to non-preconditioned hearts (D), displayed a significantly greater recovery of developed pressure (D; 84.3% c.f. 70.2% at 60 min; p < 0.04) and systolic dP/dT max (D; 84.7% c.f. 66.1%; p = 0.01) throughout reperfusion. Conclusions: Pinacidil affords myocardial protection similar to that of hyperkalemic cardioplegia despite significantly prolonged mechanical and electrical arrest times. Furthermore, at hypothermia, ischaemic preconditioning confers a myocardial protective benefit in addition to that provided by Pinacidil alone. Thus, Pinacidil cardioplegia in combination with hypothermia and ischaemic preconditioning is an effective and promising cardioprotective strategy.

Myocardial protection: The efficacy of an ultra-short-acting β-blocker, esmolol, as a cardioplegic agent

Objective: During myocardial revascularization, some surgeons (particularly in the United Kingdom) use intermittent crossclamping with fibrillation as an alternative to cardioplegia. We recently showed that intermittent crossclamping with fibrillation has an intrinsic protection equivalent to that of cardioplegia. In this study we hypothesized that arrest, rather than fibrillation, during intermittent crossclamping may be beneficial. Because esmolol, an ultra-short-acting β-blocker, is known to attenuate myocardial ischemia-reperfusion injury, we compared the protective effect of esmolol arrest with that of intermittent crossclamping with fibrillation and conventional cardioplegia (St Thomas' Hospital solution). Methods: Isolated rat hearts were Langendorff perfused at either constant flow (14 mL/min) or constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer (37°C), and left ventricular developed pressure was assessed. In study 1 (constant flow perfusion) 8 groups (n = 6 hearts per group) were studied: (1) 40 minutes of global ischemia; (2) 2 minutes of St Thomas' Hospital infusion and 40 minutes of ischemia; (3) multidose (every 10 minutes) infusions of St Thomas' Hospital solution during 40 minutes of ischemia; (4) 2 minutes of esmolol infusion and 40 minutes of ischemia; (5) multidose (every 10 minutes) esmolol infusions during 40 minutes of ischemia; (6) continuous infusion of esmolol for 40 minutes during coronary perfusion; (7) intermittent (4 × 10 minutes) ischemia with ventricular fibrillation; and (8) intermittent (4 × 10 minutes) ischemia preceded by intermittent esmolol administration. All protocols were followed by 60 minutes of reperfusion. Further experiments (study 2) examined the esmolol administration method in hearts perfused by constant pressure. Results: An optimal arresting dose of 1.0 mmol/L esmolol was established. In study 1 recovery of left ventricular developed pressure (expressed as percentage of preischemic value) was 7% ± 4%, 28% ± 8%, 70% ± 5%, 8% ± 1%, 90% ± 4%, 65% ± 3%, 71% ± 5%, and 76% ± 5% in groups 1 to 8, respectively. Intermittent esmolol arrest with global ischemia provided equivalent myocardial protection to intermittent crossclamping with fibrillation, continuous esmolol perfusion, and multidose St Thomas' Hospital solution. Surprisingly, multidose esmolol infusion was more protective than all other treatments. In further experiments (study 2) optimal recovery was obtained with multiple esmolol infusions (by constant flow or constant pressure), but continuous esmolol infusion (at constant flow) was less effective than constant pressure infusion. Conclusions: Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia.J Thorac Cardiovasc Surg 2001;122:993-1003

Potassium channel openers: are they effective as pretreatment or additives to cardioplegia?

Background. This study was designed to test the hypothesis that the potassium channel opener pinacidil (Pin) as a pretreatment (PT) agent or additive to St. Thomas’ solution (StT) could enhance myocardial protection.Methods. In a parabiotic rabbit Langendorff model, 36 hearts underwent global normothermic ischemia (1 hour) followed by reperfusion (30 minutes). Cardioplegia (50 mL, every 20 minutes) consisted of: StT; PinPT/StT, where Pin PT preceded StT arrest; Pin alone; Pin in StT (Pin/StT); and Pin in low potassium StT. Systolic function after reperfusion (percent recovery of developed pressure) and compliance (diastolic slope from pressure–volume relationship) were measured.Results. There was no significant difference between StT and PinPT/StT in percent recovery of developed pressure (51.54% ± 3.5%, 42.17% ± 4.0%, respectively) or compliance. Likewise, no significant differences occurred between Pin, StT, Pin/StT, and Pin in low potassium StT in percent recovery of developed pressure (58.99% ± 4.8%, 51.54% ± 3.5%, 53.09% ± 3.2%, 66.43% ± 7.3%, respectively) or compliance.Conclusions. Pin is as effective a cardioplegic agent as StT; however, its use as a pretreatment or additive to traditional and Pin in low potassium StT provided no additional benefit in functional recovery.

Potassium-channel opener cardioplegia is superior to St. Thomas’ solution in the intact animal

Background. In isolated hearts, the potassium-channel opener pinacidil is an effective cardioplegic agent. This study tested the hypothesis that pinacidil is superior to St. Thomas’ solution in the more clinically relevant intact animal.Methods. Sixteen pigs were placed on full cardiopulmonary bypass. Hearts underwent 2 hours of global ischemia (10° to 15°C). Either St. Thomas’ or 100 μmol/L pinacidil was administered every 20 minutes (10 mL/kg). Preischemic and postreperfusion slopes of the preload-recruitable stroke work relationship were determined. Changes in myocardial adenine nucleotide levels and cellular ultrastructure were analyzed.Results. Pinacidil cardioplegia resulted in an insignificant change in the slope of the preload-recruitable stroke work relationship (40.6 ± 2.1 mm Hg/mm before ischemia and 36.5 ± 3.7 mm Hg/mm after ischemia; p = 0.466). In contrast, St. Thomas’ solution resulted in a significant decrease in the slope after reperfusion (34.3 ± 5.5 mm Hg/mm and 13.5 ± 2.3 mm Hg/mm; p = 0.003). Adenine nucleotide levels, myocardial tissue water, and ultrastructural changes were similar between groups.Conclusions. Pinacidil ameliorated myocardial stunning associated with traditional hyperkalemic cardioplegia without causing significant differences in cellular metabolism.

The superiority of pinacidil over adenosine cardioplegia in blood-perfused isolated hearts

Background. Our laboratory has shown that the potassium-channel opener pinacidil is an effective cardioplegic agent. A theoretical benefit of cardioplegia with potassium-channel openers is that it arrests the heart at hyperpolarized membrane potentials, a state of minimal metabolic requirement. This study was designed to examine another nondepolarizing agent, adenosine, and to test the hypothesis that it could provide comparable cardioprotection or augment potassium-channel opener cardioplegia. Methods. Using the blood-perfused Langendorff technique, isolated rabbit hearts were arrested for 30 minutes of global normothermic ischemia. Cardioplegia consisted of either Krebs-Henseleit solution alone (control) or with pinacidil (50 μmol/L), adenosine (200 μmol/L to 1 mmol/L), or pinacidil + adenosine (200 μmol/L). Recovery of developed pressure and coronary flow were recorded. Results. Postischemic functional recovery for control, pinacidil, adenosine, and adenosine + pinacidil groups was 44.1% ± 3.4%, 59.5% ± 5.2% ( p < 0.05 versus control), 37.0% ± 4.5%, and 56.0% ± 2.9%, respectively. Conclusions. Adenosine, alone or as adjunct to pinacidil cardioplegia, was not an effective cardioplegic agent, despite shorter times to electromechanical arrest than control. The ineffectiveness of adenosine suggests that the cardioprotective properties of potassium-channel openers involve mechanisms other than the avoidance of membrane depolarization.

The adenosine-triphosphate–sensitive potassium-channel opener pinacidil is effective in blood cardioplegia

Background. This study was designed to evaluate the adenosine-triphosphate–sensitive potassium channel opener pinacidil as a blood cardioplegic agent. Methods. Using a blood-perfused, parabiotic, Langendorff rabbit model, hearts underwent 30 minutes of normothermic ischemia protected with blood cardioplegia (St. Thomas’ solution [n = 8] or Krebs-Henseleit solution with pinacidil [50 μmol/L, n = 8]) and 30 minutes of reperfusion. Percent recovery of developed pressure, mechanical arrest, electrical arrest, reperfusion ventricular fibrillation, percent tissue water, and myocardial oxygen consumption were compared. Results. The percent recovery of developed pressure was not different between the groups (52.3 ± 5.9 and 52.8 ± 6.9 for hyperkalemic and pinacidil cardioplegia, respectively). Pinacidil cardioplegia was associated with prolonged electrical and mechanical activity (14.4 ± 8.7 and 6.1 ± 3.9 minutes), compared with hyperkalemic cardioplegia (1.1 ± 0.6 and 1.1 ± 0.6 minutes, respectively; p < 0.05). Pinacidil cardioplegia was associated with a higher reperfusion myocardial oxygen consumption (0.6 ± 0.1 versus 0.2 ± 0.0 mL/100 g myocardium/beat; p < 0.05) and a higher percent of tissue water (79.6% ± 0.7% versus 78.6% ± 1.2%; p < 0.05). Conclusions. Systolic recovery was not different between groups, demonstrating comparable effectiveness of pinacidil and hyperkalemic warm blood cardioplegia.

Advantages of continuous hyperpolarized arrest with pinacidil over St. Thomas' hospital solution during prolonged ischemia

Objective: The potassium channel opener, pinacidil, has been shown to be an effective cardioplegic agent over short periods of ischemia. However, clinical settings typically involve longer ischemic periods. This study tested the hypothesis that myocardial protection with a potassium channel opener is feasible during prolonged periods of arrest and is comparable with the traditional St. Thomas' Hospital solution. Methods: With a blood-perfused, isolated rabbit heart model, hearts underwent 1 hour of global normothermic ischemia followed by 30 minutes of reperfusion. During ischemia, three different cardioplegic solutions were administered either intermittently by infusion every 20 minutes or as continuous low-flow cardioplegia (150 ml total volume in all groups): (1) Krebs-Henseleit solution alone (control), (2) Krebs-Henseleit solution + pinacidil (50 μmol/L), or (3) St. Thomas' Hospital solution. Initial potassium channel opener infusions contained 5 mmol/L procaine. Postreperfusion systolic function (percent of developed pressure) was measured. Compliance changes were integrated from the end-diastolic pressure/volume relationships. Results: For intermittent cardioplegia, only St. Thomas' Hospital solution improved function (62.5% ± 4.0%) versus control (43.6% ± 3.3%, p < 0.001). However, with continuous cardioplegia, only pinacidil (75.6% ± 4.8%) exceeded control (62.7% ± 2.2%, p < 0.001) and was significantly better than St. Thomas' Hospital solution. Compared with the intermittent control group, all other groups showed significant preservation of preischemic diastolic properties. Conclusions: Myocardial protection during a longer, more clinically relevant ischemic period is feasible with a potassium channel opener only when it is given continuously. Continuous low-flow pinacidil cardioplegia was superior to St. Thomas' Hospital solution given either as an intermittent or continuous infusion. (J Thorac Cardiovasc Surg 1998;116:131-8)

Volatile cardioplegia: fast normothermic cardiac arrest induction and recovery with halothane in isolated rat hearts

To study the effect of halothane as a cardioplegic agent, ten Wistar rats were anesthetized by ether inhalation and their hearts were perfused in a Langendorff system with Krebs-Henseleit solution (36 degrees C; 90 cm H2O pressure). After a 15-min period for stabilization the control values for heart rate, force(T), dT/dt and coronary flow were recorded and a halothane-enriched solution (same temperature and pressure) was perfused until cardiac arrest was obtained. The same Krebs-Henseleit solution was reperfused again and the parameters studied were recorded after 1, 3, 5, 10, 20 and 30 min. Cardiac arrest occurred in all hearts during the first two min of perfusion with halothane-bubbled solution. One minute after reperfusion without halothane, the following parameters reported in terms of control values were obtained: 90.5% of control heart rate(266.9 +/- 43.4 to 231.5 +/- 71.0 bpm), 20.2% of the force (1.83 +/- 0.28 to 0.37 +/- 0.25 g), 19.8% of dT/dt (46.0 +/- 7.0 to 9.3 +/- 6.0 g/s) and 90.8% of coronary flow (9.9 +/- 1.5 to 9.4 +/- 1.5 ml/min). After 3 min of perfusion they changed to 99.0% heart rate (261.0 +/- 48.2), 98.9% force (1.81 +/- 0.33), 98.6 dT/dt (45.0 +/- 8.2) and 94.8% coronary flow (9.3 +/- 1.4). At 5 min 100.8% (267.0 +/- 40.6) heart rate, 105.0% (1.92 +/- 0.29) force and 104.4% (48.2 +/- 7.2) dT/dt were recorded and maintained without significant differences (P > 0.01) until the end of the experiment. These data demonstrate that volatile cardioplegia with halothane is an effective technique for fast induction of and prompt recovery from normothermic cardiac arrest of the rat heart.

Detachment of low-force bridges contributes to the rapid tension transients of skinned rabbit skeletal muscle fibres.

1. To probe the cross-bridge cycle and to learn more about the cardioplegic agent BDM (2,3-butanedione monoxime), its effects on the force-velocity properties and tension transients of skinned rabbit muscle fibres were studied at 1-2 degrees C and pH 7.0. 2. Three millimolar BDM decreased isometric force by 50%, velocity by 29%, maximum power by 73%, and stiffness by 25%, so that the relative stiffness (stiffness/force ratio) increased by 50% compared with reference conditions in the absence of BDM. 3. Tension transients obtained under the reference condition (0 BDM) could be represented by three components whose instantaneous stiffness accounted for the initial (Phase 1) force deviation and whose exponential recoveries caused the rapid, partial (Phase 2) force recovery following the step. The fastest component had non-linear extension-force properties that accounted for about half the isometric stiffness and it recovered fully. The two slower components had linear extension-force properties that together accounted for the other half of the sarcomere stiffness. These components recovered only partially following the step, producing the intermediate (T2) level which the force approached during Phase 2. 4. Matching the force transients obtained under test conditions (3 mM BDM) required three alterations: (1) reducing the amplitude of the two slower components by 50%, in proportion to isometric force, (2) adding a non-relaxing component and (3) decreasing the amplitude of the rapidly recovering component by 12.5% so that its relative amplitude (amplitude/isometric force) was increased by 75%. The non-recovering component and the increase in relative amplitude of the rapid component were responsible for the increase in relative stiffness of the fibres produced by BDM. The rapidly recovering component had the same time constant and step-size-dependent recovery rates as the fastest of the three mono-exponential components isolated from the tension transient response under the reference condition. BDM therefore appeared to augment the fastest component of the tension transient under the reference condition. 5. The results suggest that BDM detains cross-bridges in low-force, attached states. Since these bridges are attached, they contribute to sarcomere stiffness. Since they are detained, relaxation or reversal of their immediate responses is probably due to bridge detachment rather than to their undergoing the power stroke. The observation that a portion of the test response matched the fastest component of the reference response when the amplitude of the fastest component was increased suggests that a part of the normal rapid, transient tension recovery following a release step is due to detachment of low-force bridges moved to negative-force positions by the step.

Myocardial protection with pinacidil cardioplegia in the blood-perfused heart

Adenosine triphosphate-sensitive potassium-channel openers are potent vasodilators that have been found to be cardioprotective during myocardial ischemia. The potassium-channel opener pinacidil was investigated to determine its efficacy as a cardioplegic agent. A blood-perfused, parabiotic, isolated rabbit heart Langendorff preparation was used. Fifty-six hearts underwent 30 minutes of global normothermic ischemia after a 50-mL infusion of cardioplegia, followed by 60 minutes of reperfusion. The cardioplegia consisted of Krebs-Henseleit solution with either vehicle alone (control), 20 mmol KCl, or pinacidil (10, 50, 100, 150, or 200 mumol/L). The developed pressure was measured at baseline and after reperfusion. Coronary blood flow was measured with an in-line ultrasonic probe. Pinacidil (50 mumol/L), as opposed to potassium cardioplegia, provided significantly better postischemic percentage recovery of developed pressure compared with controls (68.3% +/- 4.0% versus 44.6% +/- 5.5%; p < 0.05). The time until electrical arrest was significantly shorter in the hyperkalemic group than in all other groups. Linear end-diastolic pressure-volume relationships revealed an increase in slope after ischemia in all groups. Coronary flow after 5 minutes of reperfusion was significantly higher in both the 50-mumol/L and 100-mumol/L pinacidil groups compared with traditional hyperkalemic arrest, and this returned to baseline after 15 minutes. The potassium channel opener pinacidil provided dose-dependent myocardial protection during global ischemia in the blood-perfused rabbit heart model. Potassium-channel openers are a promising class of drugs that may provide an alternative to traditional hyperkalemic cardioplegia.