ORIGINAL ARTICLE
Safety of Single-Dose Histidine-Tryptophan-Ketoglutarate Cardioplegia During Minimally Invasive Mitral Valve Surgery Carlo Savini, MD,* Giacomo Murana, MD,* Marco Di Eusanio, MD, PhD,* Sofia Martin Suarez, MD, PhD,* Giuliano Jafrancesco, MD,* Sebastiano Castrovinci, MD,* Andrea Castelli, MD,Þ and Roberto Di Bartolomeo, MD*
Objective: Minimally invasive mitral valve surgery may require a prolonged period of myocardial ischemia. Cardioplegic solutions that necessitate a single dose for adequate myocardial protection are evoked to simplify surgery and result to be appealing in this setting. The aim of this study was to assess early outcomes after minimally invasive mitral valve surgery using one single dose of histidine-tryptophanketoglutarate solution (HTK; Custodiol) for myocardial protection. Methods: Between February 2003 and October 2012, a total of 49 consecutive patients underwent minimally invasive mitral valve surgery using a single dose of HTK solution for myocardial protection. The patients’ mean (SD) age was 57 (14) years; the preoperative ejection fraction was normal in all cases. The mean (SD) CPB time and aortic cross-clamp time were 148 (45) minutes and 97 (45) minutes, respectively. Results: The heart spontaneously restarted after cross-clamp removal in 37 patients (75.5%). Five patients (10.2%) required prolonged inotropic drug support. Postoperatively, no significant increase in myocardial cytonecrosis enzymes was found [mean (SD) creatine kinase isoenzyme MB, 77.14 (53.67) Kg/L at 3 hours, 71.2 (55.67) Kg/L at 12 hours, and 42.53 (38.38) Kg/L at 24 hours)], and no ischemic electrocardiogram modifications were observed before discharge. Conclusions: During minimally invasive mitral valve surgery, HTK solution provided excellent myocardial protection even after prolonged periods of cardioplegic arrest. The avoidance of repetitive infusions may reduce the risk for coronary malperfusion due to dislodgement of the endoaortic clamp (if used) and increase the surgeon’s comfort during the procedure. Key Words: Minimally invasive mitral valve surgery, Myocardial protection, HTK-Custodiol, Cardioplegia. (Innovations 2014;9:416Y420) Accepted for publication January 18, 2014. From the Departments of *Cardiac Surgery, and †Anesthesia and Resuscitation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. Presented at the Annual Scientific Meeting of the International Society for Minimally Invasive Cardiothoracic Surgery, June 12Y15, 2013, Prague, Czech Republic. Disclosure: The authors declare no conflicts of interest. Address correspondence and reprint requests to Carlo Savini, MD, Department of Cardiac Surgery, Ospedale S.Orsola-Malpighi, Via Massarenti 9, 40124 Bologna, Italy. E-mail: [email protected]. Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery ISSN: 1556-9845/14/0906-0416
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erfusion strategies and operative techniques for minimally invasive mitral valve repair have evolved over time, and adequate myocardial protection represents a key requirement in this setting. The histidine-tryptophan-ketoglutarate (HTK), or the Bretschneider cardioplegic solution (CPS) (Custodiol; Koehler Chemie, Alsbach-Haenlein, Germany), offers myocardial protection for a period longer than 3 hours when administered in a single dose.1Y4 This characteristic makes HTK highly appreciated during minimally invasive cardiac procedures. During the years, some concerns have emerged about the adequacy of myocardial protection offered by only a single dose of cardioplegia and about the hyponatraemia that follows the rapid administration of this low-sodium CPS.5,6 In the present study, we retrospectively assessed our results with Custodiol during minimally invasive mitral valve surgery.
MATERIALS AND METHODS Clinical Characteristics From February 2003 to October 2012, a total of 49 consecutive patients underwent minimally invasive mitral valve surgery with a single dose of HTK solution for myocardial protection, using either the Chitwood clamp (Scanlan International, Inc., Minneapolis, MN USA) or the endoclamp system. Twenty-five patients were men (71.8%), and the mean (SD) age was 61.1 (9.3) years. The preoperative ejection fraction was normal in all patients [63.7 (8.4)], two patients had peripheral vascular disease, two had chronic obstructive pulmonary disease, and two had cerebrovascular disease. Mitral valve insufficiency (83.67%), rheumatic mitral valve stenosis disease (4.08%), and functional mitral regurgitation (2.04%) represented the main indications to surgery (Table 1). All patients underwent preoperative and predischarge transthoracic echocardiography (TTE) and intraoperative transesophageal echocardiography (TEE) (Table 1). Left ventricle (LV) end-diastolic and end-systolic volumes were estimated using the Simpson biplane method, and LV ejection fraction was derived. Regional wall motion was analyzed using a 17-segment model as well as the scoring system recommended by the American Society of Echocardiography and the European Association for Echocardiography. Innovations & Volume 9, Number 6, November/December 2014
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Innovations & Volume 9, Number 6, November/December 2014
Surgical Techniques
TABLE 1. Baseline Characteristics Age, mean (SD), y Male sex, n (%) BSA, mean (SD) Hypertension, n (%) COPD, n (%) Diabetes, n (%) PAD, n (%) Stroke, n (%) NYHA III/IV, n (%) Valve pathology, n (%) Stenosis Regurgitation Mixed lesion History of AF, n (%) Creatinine, mean (SD), mg/dL Hct, mean (SD), % LVEF, mean (SD), %
HTK Cardioplegia in Minimally Invasive Surgery
57.3 (14.1) 25 (71.8) 1.77 (0.19) 12 (24.49) 2 (4.08) 3 (6.12) 2 (4.08) 2 (4.08) 7 (14.28) 2 (4.08) 41 (83.67) 6 (12.24) 5 (10.2) 1.5 (0.71) 37.3 (4.4) 63.7 (8.4)
AF indicates atrial fibrillation; BSA, body surface area; COPD, chronic obstructive pulmonary disease; Hct, hematocrit; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PAD, peripheral arterial disease.
All procedures were performed through a small anterolateral right thoracotomy using Port-Access technology (HeartPort Inc., Redwood City, CA USA), as previously described.7 The Chitwood clamp was used in 37 patients (75.5%), and in the remaining patients, the aorta was occluded from the inside with the endoaortic balloon (n = 12, 24.5%). The endoclamp was adequately positioned using TEE, and the balloon was inflated. Adenosine (0.25 mg/kg) was injected at the tip of the balloon to achieve a brief cardiac arrest before complete balloon inflation and to prevent the balloon from migrating toward the brachiocephalic trunk during inflation. The use of adenosine is particularly useful at the beginning of the cross-clamping to fasten the plegic power of the HTK solution. After aortic occlusion, one single dose of Custodiol solution was delivered for a period of 6 to 8 minutes (20Y25 mL/kg) at the balloon tip via a roller pump into the aortic root with a perfusion pressure (aortic root pressure) of 40 to 60 mm Hg. No additional cardioplegic doses were delivered. The left atrium was contemporarily opened parallel to the interatrial septum. Subsequently, mitral valve surgery was performed, as indicated. All patients underwent a complete TEE examination intraoperatively after the surgical procedure and a TTE examination before hospital discharge.
Biochemical Analysis Primary outcomes included hospital mortality, low cardiac output syndrome (LCOS) (defined by the need for inotropic and/or intra-aortic balloon pump support), myocardial infarction (MI) [which includes both electrocardiogram-defined (ECG-defined) and/or enzyme-defined MI], and rhythm disturbances [ventricular fibrillation (VF) after cross-clamp release and new postoperative atrial fibrillation (AF)].
Venous blood samples were collected before the operation as well as 6, 12, 24, and 48 hours postoperatively. Laboratory measurements of serum enzymes indicative of myocardial cell damage were creatine kinase (CK) and its MB fraction. Diagnostic criteria for perioperative MI or ischemia were ECG abnormalities according to European Society of Cardiology/American Heart Association guidelines and CK-MB
FIGURE 1. Creatine kinase isoenzyme MB at 3, 12, and 24 hours postoperatively according to the cross-clamp time (G100 minutes or Q100 minutes). P values were less than 0.4 at 3 hours, P G 0.5 at 12 hours, and P G 0.3 at 24 hours between the groups. CK-MB, Creatine kinase isoenzyme MB. Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery
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TABLE 2. Operative Data CPB time Cross-clamp time Amount of cardioplegic solution, mL Ultrafiltration in CPB, mL Diuresis in CPB Lowest Hct in CPB Hct end of CPB Mitral valve repair Mitral valve replacement Internal defibrillation after X-clamp removal
148.6 (45) 97.9 (45) 1769.4 (461.5) 936.95 (498.2) 652.85 (461.9) 29.95 (3.37) 34.36 (2.24) 41 (83.67%) 8 (16.32%) 12 (24.49%)
Values are presented as mean (SD) or number (percentage). CPB indicates cardiopulmonary bypass; Hct, hematocrit.
levels 910% than total CK.8 Arterial blood gas analysis, which was taken approximately every 30 minutes intraoperatively and every 3 hours during the first day after operation, was gathered for each patient.
Electrocardiogram A 12-lead ECG was recorded before surgery; at 1 hour and 6 hours postoperatively; as well as on the first, the second, and the seventh day after the operation. Diagnostic criteria for perioperative MI or ischemia, in the absence of LV hypertrophy or left bundle branch block, were new STelevation at the J point in at least two contiguous leads of 2 mm or greater in men or 1.5 mm or greater in women in leads V2 to V3 and/or of 1 mm or greater in other contiguous chest leads or the limb leads as well as new horizontal or downsloping ST depression of 0.05 mV or greater in two contiguous leads or T inversion of 0.1 mV or greater in two contiguous leads with prominent R wave or R/S ratio of greater than 1.6
Data Analysis Descriptive statistics, correlations, and paired t tests are reported as mean (SD) for continuous variables and as frequencies and percentages for categorical variables, unless otherwise noted. Variables were analyzed with IBM SPSS 20 software (SPSS Inc, Chicago, IL USA).
RESULTS Intraoperatively, the mitral valve was repaired in 44 cases (89.8%) and replaced in 5 cases (10.2%). Two patients required
a second cardiopulmonary bypass (CPB) run with aortic clamping and reinfusion of CPS because of an inadequate valve repair with a significant residual mitral regurgitation. Overall, the mean (SD) CPB time was 148.6 (45) minutes, and aortic cross-clamp duration was 97.9 (45) minutes. The heart, after removal of the cross-clamp, restarted spontaneously in 37 cases (75.5%), and ventricular arrhythmias requiring electrical cardioversion to sinus rhythm occurred in the remaining 12 cases (24.5%). The incidence of AF in the postoperative period occurred in 12 patients (24.49%). There were no operative/ hospital deaths or major postoperative complications. At 3, 12, and 24 hours after surgery, no significant modifications in myocardial cytonecrosis enzymes were found, regardless of cross-clamp time duration (9100 or G 100 minutes) (Fig. 1). Consistently, no ischemic ECG modifications were observed before discharge. None of the patients developed LCOS postoperatively, and only five patients (10.2%) needed mild-to-moderate postoperative inotropic support. The overall frequency of postoperative neurologic events and acute renal dysfunction was 2% (n = 1) and 0%, respectively. The amount of units of blood transfused during either the perioperative period or the postoperative course was 0.14 (0.35) [minimum (min), 0; maximum (max), 4] (Table 3). The mean (SD) assisted ventilation time was 9.3 (15.9) hours (min, 4; max, 18), and the mean (SD) intensive care unit stay was 1.69 (1.44) days (min, 1; max, 4) (Table 2). Predischarge TTE showed a preserved LV ejection fraction [61.2 (6.8)], with no significant differences compared with the preoperative status [63.7 (8.4)].
DISCUSSION Perfusion strategies and operative techniques for minimally invasive mitral valve repair have evolved over time.9 Ideally, every surgical technique should allow a practicing surgeon to continue to use familiar tools and approaches to cardiac operations. Of course, this is not always possible in minimally invasive cardiac surgery (MICS) because of different instruments and approaches that are often necessary. Surgeons performing MICS most frequently protect the myocardium through standard intermittent blood or crystalloid cardioplegia. Data available in the literature have shown blood and crystalloid cardioplegia solutions to be associated with similar results in terms of postoperative MI and death.10Y13 However, these solutions often require intermittent multiple
FIGURE 2. Lines showing the trend of creatine kinase isoenzyme MB (CK-mB) 3, 12, 24, and 48 hours postoperatively (A) and lactate 1, 6, 12, and 24 hours postoperatively (B).
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TABLE 3. Clinical Outcomes In-hospital mortality ICU stay, d MAV, h CK-MB 3 h CK-MB 12 h CK-MB 24 h Lactic acid 6 h Lactic acid 24 h Inotropic support 9 24 h Reoperation for bleeding Periopertive MI Neurologic complications Postoperative red blood cell transfusion Fresh frozen plasma Creatinine 48 h Postoperative AF LVEF at discharge, %
0 (0%) 1.69 (1.44) 9.3 (15.9) 77.14 (53.67) 71.20 (55.67) 42.53 (38.38) 1.2 (0.45) 1.1 (0.35) 5 (10.2%) 2 (4.08%) 0 (0%) 1 (2.04%) 0.14 (0.35) 0.04 (0.2) 0.60 (0.52) 12 (24.49%) 61.2 (6.8)
Values are presented as mean (SD) or number (percentage). AF indicates atrial fibrillation; CK-MB, creatine kinase isoenzyme MB; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MAV, mechanical-assisted ventilation; MI, myocardial infarction.
administrations, every 20 to 40 minutes. If this does not represent a concern during conventional surgery, in MICS, it can increase the difficulties of an already demanding approach, especially if we consider the limited surgical field and the use of an aortic endoclamp, which exposes to a high risk for dislodgement during the reinfusion. In our institution, the HTK solution is routinely used in all conventional cardiac interventions with anticipated prolonged period of myocardial ischemia. The main advantage of this solution is that it allows, after a single dose, a safe cardioplegic arrest up to 2 hours, which represents a period in which almost every cardiac operation can be carried out. Given our favorable
HTK Cardioplegia in Minimally Invasive Surgery
results in conventional cardiac surgery, we have extended the use of HTK solution also to the HeartPort procedures, with satisfactory early results.14 We found that this strategy of myocardial protection translated into a remarkably low incidence of myocardial injury and need for inotropic support (Figs. 1, 2) as well as low postoperative alterations of serum lactate (Fig. 2). All these findings finally support a preserved contractile myocardial function at discharge (Table 3). In addition, we observed that, with the HTK solution, short and long periods of cross-clamp time (9100 minutes) were associated with a similar serum release of myocardial cytonecrosis enzymes (Fig. 1). In our opinion, these data remark the goodness of our approach integrating minimal invasiveness with an appropriate myocardial protection protocol, which is, now, well standardized in our institution. Braathen et al15 recently published a prospective, randomized study comparing the HTK solution with repetitive administration of cold-blood cardioplegia. The authors concluded that, in elective mitral valve surgery, both strategies were equivalent to protect the myocardium. Other studies comparing Custodiol with conventional intermittent cardioplegia have questioned some limits as a consequence of its administration. Increased rate of VF as the first rhythm after reperfusion with Custodiol cardioplegia is documented16 and not clear. Our relatively low occurrence of VF may support a well-established myocardial protection protocol improved over time. Hemodilution after a large volume of cardioplegia infusion is another critical point. To maintain a stable hemoconcentration during the perioperative period, we performed a careful ultrafiltration during extracorporeal circulation as well as a strict use of diuretic drugs in intensive care and ward units (Fig. 3). This approach enabled us to use a minimal amount of blood transfusions during the postoperative course.
FIGURE 3. The line depicts the hematocrit (HTC) trend in the first 3 days postoperatively. Red values represent the mean cardioplegic solution (CPS) and the mean ultrafiltration (UFT) during extracorporeal circulation (ECC). Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery
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It may also be argued that the HTK solution (which is almost a sodium-free solution) frequently results in acute sodium concentration changes, potentially increasing postoperative incidence of seizure.5 In a series of 25 patients, Lindner et al17 showed no significant change in osmolality after measuring serum sodium and osmolality during the perioperative period. Others have observed hyponatremia without clinical consequence.18 These findings demonstrated that brain complications are possible only in hypotonic hyponatremia, in which a shift of free water from the extracellular to the intracellular space happens, resulting in cerebral edema. However, because the HTK solution is a slightly hypertonic solution, the administration to a patient results in isotonic hyponatremia not requiring hypertonic saline correction. According to this evidence, in this small series, none of our patients experienced serum sodium fluctuation during CPB, and only one patient had a neurologic complication not related to this phenomenon. Furthermore, we reported a very low occurrence of renal complications, low incidence of AF, and excellent clinical outcomes (Table 3). This study carries limitations mainly inherent to its retrospective design and small population size. Larger studies are certainly warranted to demonstrate the effectiveness of HTK crystalloid cardioplegia in minimally invasive surgery compared with the other types of CPSs. In conclusion, a single dose of antegrade HTK crystalloid cardioplegia seems to be a safe and effective strategy to protect the myocardium during minimally invasive mitral valve procedures. Our approach with routinary use of Custodiol gave the advantage to be more flowing during mitral surgery compared with repetitive administration of conventional (blood or crystalloid) cardioplegia.
REFERENCES 1. Arslan A, Sezgin A, Gultekin B, et al. Low-dose histidine-tryptophanketoglutarate solution for myocardial protection. Transplant Proc. 2005; 37:3219Y3222. 2. Careaga G, Salazar D, Te´llez S, Sa´nchez O, Borrayo G, Argu¨ero R. Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients. Arch Med Res. 2001;32:296Y299.
3. Sunderdiek U, Feindt P, Gams E. Aortocoronary bypass grafting: a comparison of HTK cardioplegia vs. intermittent aortic cross-clamping. Eur J Cardiothorac Surg. 2000;18:393Y399. 4. Holper K, Meisner H, Ha¨hnel C, Massoudy P. Technical refinements in myocardial protection: infantsVadults. Thorac Cardiovasc Surg. 1998; 46(suppl 2):292Y295. 5. Kim JT, Park YH, Chang YE, et al. The effect of cardioplegic solutioninduced sodium concentration fluctuation on postoperative seizure in pediatric cardiac patients. Ann Thorac Surg. 2011;91:1943Y1948. 6. Ji B, Liu J, Long C, Yang K, Zheng Z. Potential risk of hyponatremia using histidine-tryptophan-ketoglutarate solution during pediatric cardiopulmonary bypass. Ann Thorac Surg. 2012;93:2120Y2121. 7. Schroeyers P, Wellens F, De Geest R, et al. Minimally invasive videoassisted mitral valve surgery: our lessons after a 4-year experience. Ann Thorac Surg. 2001;72:S1050YS1054. 8. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126:2020Y2035. 9. Grossi EA, Loulmet DF, Schwartz CF, et al. Evolution of operative techniques and perfusion strategies for minimally invasive mitral valve repair. J Thorac Cardiovasc Surg. 2012;143(suppl):S68YS70. 10. Guru V, Omura J, Alghamdi AA, Weisel R, Fremes SE. Is blood superior to crystalloid cardioplegia? A meta-analysis of randomized clinical trials. Circulation. 2006;114(suppl):I331YI338. 11. Misfeld M, Davierwala P. Crystalloid-based cardioplegia for minimally invasive cardiac surgery. Semin Thorac Cardiovasc Surg. 2012;24:305Y307. 12. Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Warm versus cold cardioplegia for heart surgery: a meta-analysis. Eur J Cardiothorac Surg. 2010;37:912Y919. 13. Jacob S, Kallikourdis A, Sellke F, Dunning J. Is blood cardioplegia superior to crystalloid cardioplegia? Interact Cardiovasc Thorac Surg. 2008;7:491Y498. 14. Savini C, Camurri N, Castelli A, et al. Myocardial protection using HTK solution in minimally invasive mitral valve surgery. Heart Surg Forum. 2005;8:E25YE27. 15. Braathen B, Jeppsson A, Scherste´n H, et al. One single dose of histidinetryptophan-ketoglutarate solution gives equally good myocardial protection in elective mitral valve surgery as repetitive cold blood cardioplegia: a prospective randomized study. J Thorac Cardiovasc Surg. 2011;141: 995Y1001. 16. Liu J, Feng Z, Zhao J, Li B, Long C. The myocardial protection of HTK cardioplegic solution on the long-term ischemic period in pediatric heart surgery. ASAIO J. 2008;54:470Y473. 17. Lindner G, Zapletal B, Schwarz C, Wisser W, Hiesmayr M, Lassnigg A. Acute hyponatremia after cardioplegia by histidine-tryptophane-ketoglutarateVa retrospective study. J Cardiothorac Surg. 2012;7:52. 18. Lueck S, Preusse CJ, Welz A. Clinical relevance of HTK-induced hyponatremia. Ann Thorac Surg. 2013;95:1844Y1845.
CLINICAL PERSPECTIVE This case series examined the results of 49 consecutive patients undergoing minimally invasive mitral valve surgery using a single dose of histidine-tryptophan-ketoglutarate solution (HTK-Custodiol). The authors had excellent results in this small series, in which 90% of the patients underwent mitral valve repair. There were no operative deaths or major postoperative complications. They saw no ischemic electrocardiographic changes or significant increases in myocardial cytonecrosis enzymes postoperatively. This study establishes the feasibility of single-dose HTK-Custodiol solution in a selected group of low-risk, uncomplicated patients. This is a cohort of patients in whom you would not expect any mortality or complications. All patients had normal ventricular function, and the mean patient age was only 57 years. This report does not establish efficacy or safety, particularly in higher-risk patients. Whether it is equivalent to standard repetitive-dose blood cardioplegia would require further study.
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Safety of Single-Dose Histidine-Tryptophan-Ketoglutarate Cardioplegia During Minimally Invasive Mitral Valve Surgery Carlo Savini, MD,* Giacomo Murana, MD,* Marco Di Eusanio, MD, PhD,* Sofia Martin Suarez, MD, PhD,* Giuliano Jafrancesco, MD,* Sebastiano Castrovinci, MD,* Andrea Castelli, MD,Þ and Roberto Di Bartolomeo, MD*
Objective: Minimally invasive mitral valve surgery may require a prolonged period of myocardial ischemia. Cardioplegic solutions that necessitate a single dose for adequate myocardial protection are evoked to simplify surgery and result to be appealing in this setting. The aim of this study was to assess early outcomes after minimally invasive mitral valve surgery using one single dose of histidine-tryptophanketoglutarate solution (HTK; Custodiol) for myocardial protection. Methods: Between February 2003 and October 2012, a total of 49 consecutive patients underwent minimally invasive mitral valve surgery using a single dose of HTK solution for myocardial protection. The patients’ mean (SD) age was 57 (14) years; the preoperative ejection fraction was normal in all cases. The mean (SD) CPB time and aortic cross-clamp time were 148 (45) minutes and 97 (45) minutes, respectively. Results: The heart spontaneously restarted after cross-clamp removal in 37 patients (75.5%). Five patients (10.2%) required prolonged inotropic drug support. Postoperatively, no significant increase in myocardial cytonecrosis enzymes was found [mean (SD) creatine kinase isoenzyme MB, 77.14 (53.67) Kg/L at 3 hours, 71.2 (55.67) Kg/L at 12 hours, and 42.53 (38.38) Kg/L at 24 hours)], and no ischemic electrocardiogram modifications were observed before discharge. Conclusions: During minimally invasive mitral valve surgery, HTK solution provided excellent myocardial protection even after prolonged periods of cardioplegic arrest. The avoidance of repetitive infusions may reduce the risk for coronary malperfusion due to dislodgement of the endoaortic clamp (if used) and increase the surgeon’s comfort during the procedure. Key Words: Minimally invasive mitral valve surgery, Myocardial protection, HTK-Custodiol, Cardioplegia. (Innovations 2014;9:416Y420) Accepted for publication January 18, 2014. From the Departments of *Cardiac Surgery, and †Anesthesia and Resuscitation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. Presented at the Annual Scientific Meeting of the International Society for Minimally Invasive Cardiothoracic Surgery, June 12Y15, 2013, Prague, Czech Republic. Disclosure: The authors declare no conflicts of interest. Address correspondence and reprint requests to Carlo Savini, MD, Department of Cardiac Surgery, Ospedale S.Orsola-Malpighi, Via Massarenti 9, 40124 Bologna, Italy. E-mail: [email protected]. Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery ISSN: 1556-9845/14/0906-0416
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erfusion strategies and operative techniques for minimally invasive mitral valve repair have evolved over time, and adequate myocardial protection represents a key requirement in this setting. The histidine-tryptophan-ketoglutarate (HTK), or the Bretschneider cardioplegic solution (CPS) (Custodiol; Koehler Chemie, Alsbach-Haenlein, Germany), offers myocardial protection for a period longer than 3 hours when administered in a single dose.1Y4 This characteristic makes HTK highly appreciated during minimally invasive cardiac procedures. During the years, some concerns have emerged about the adequacy of myocardial protection offered by only a single dose of cardioplegia and about the hyponatraemia that follows the rapid administration of this low-sodium CPS.5,6 In the present study, we retrospectively assessed our results with Custodiol during minimally invasive mitral valve surgery.
MATERIALS AND METHODS Clinical Characteristics From February 2003 to October 2012, a total of 49 consecutive patients underwent minimally invasive mitral valve surgery with a single dose of HTK solution for myocardial protection, using either the Chitwood clamp (Scanlan International, Inc., Minneapolis, MN USA) or the endoclamp system. Twenty-five patients were men (71.8%), and the mean (SD) age was 61.1 (9.3) years. The preoperative ejection fraction was normal in all patients [63.7 (8.4)], two patients had peripheral vascular disease, two had chronic obstructive pulmonary disease, and two had cerebrovascular disease. Mitral valve insufficiency (83.67%), rheumatic mitral valve stenosis disease (4.08%), and functional mitral regurgitation (2.04%) represented the main indications to surgery (Table 1). All patients underwent preoperative and predischarge transthoracic echocardiography (TTE) and intraoperative transesophageal echocardiography (TEE) (Table 1). Left ventricle (LV) end-diastolic and end-systolic volumes were estimated using the Simpson biplane method, and LV ejection fraction was derived. Regional wall motion was analyzed using a 17-segment model as well as the scoring system recommended by the American Society of Echocardiography and the European Association for Echocardiography. Innovations & Volume 9, Number 6, November/December 2014
Copyright © 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery. Unauthorized reproduction of this article is prohibited.
Innovations & Volume 9, Number 6, November/December 2014
Surgical Techniques
TABLE 1. Baseline Characteristics Age, mean (SD), y Male sex, n (%) BSA, mean (SD) Hypertension, n (%) COPD, n (%) Diabetes, n (%) PAD, n (%) Stroke, n (%) NYHA III/IV, n (%) Valve pathology, n (%) Stenosis Regurgitation Mixed lesion History of AF, n (%) Creatinine, mean (SD), mg/dL Hct, mean (SD), % LVEF, mean (SD), %
HTK Cardioplegia in Minimally Invasive Surgery
57.3 (14.1) 25 (71.8) 1.77 (0.19) 12 (24.49) 2 (4.08) 3 (6.12) 2 (4.08) 2 (4.08) 7 (14.28) 2 (4.08) 41 (83.67) 6 (12.24) 5 (10.2) 1.5 (0.71) 37.3 (4.4) 63.7 (8.4)
AF indicates atrial fibrillation; BSA, body surface area; COPD, chronic obstructive pulmonary disease; Hct, hematocrit; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PAD, peripheral arterial disease.
All procedures were performed through a small anterolateral right thoracotomy using Port-Access technology (HeartPort Inc., Redwood City, CA USA), as previously described.7 The Chitwood clamp was used in 37 patients (75.5%), and in the remaining patients, the aorta was occluded from the inside with the endoaortic balloon (n = 12, 24.5%). The endoclamp was adequately positioned using TEE, and the balloon was inflated. Adenosine (0.25 mg/kg) was injected at the tip of the balloon to achieve a brief cardiac arrest before complete balloon inflation and to prevent the balloon from migrating toward the brachiocephalic trunk during inflation. The use of adenosine is particularly useful at the beginning of the cross-clamping to fasten the plegic power of the HTK solution. After aortic occlusion, one single dose of Custodiol solution was delivered for a period of 6 to 8 minutes (20Y25 mL/kg) at the balloon tip via a roller pump into the aortic root with a perfusion pressure (aortic root pressure) of 40 to 60 mm Hg. No additional cardioplegic doses were delivered. The left atrium was contemporarily opened parallel to the interatrial septum. Subsequently, mitral valve surgery was performed, as indicated. All patients underwent a complete TEE examination intraoperatively after the surgical procedure and a TTE examination before hospital discharge.
Biochemical Analysis Primary outcomes included hospital mortality, low cardiac output syndrome (LCOS) (defined by the need for inotropic and/or intra-aortic balloon pump support), myocardial infarction (MI) [which includes both electrocardiogram-defined (ECG-defined) and/or enzyme-defined MI], and rhythm disturbances [ventricular fibrillation (VF) after cross-clamp release and new postoperative atrial fibrillation (AF)].
Venous blood samples were collected before the operation as well as 6, 12, 24, and 48 hours postoperatively. Laboratory measurements of serum enzymes indicative of myocardial cell damage were creatine kinase (CK) and its MB fraction. Diagnostic criteria for perioperative MI or ischemia were ECG abnormalities according to European Society of Cardiology/American Heart Association guidelines and CK-MB
FIGURE 1. Creatine kinase isoenzyme MB at 3, 12, and 24 hours postoperatively according to the cross-clamp time (G100 minutes or Q100 minutes). P values were less than 0.4 at 3 hours, P G 0.5 at 12 hours, and P G 0.3 at 24 hours between the groups. CK-MB, Creatine kinase isoenzyme MB. Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery
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TABLE 2. Operative Data CPB time Cross-clamp time Amount of cardioplegic solution, mL Ultrafiltration in CPB, mL Diuresis in CPB Lowest Hct in CPB Hct end of CPB Mitral valve repair Mitral valve replacement Internal defibrillation after X-clamp removal
148.6 (45) 97.9 (45) 1769.4 (461.5) 936.95 (498.2) 652.85 (461.9) 29.95 (3.37) 34.36 (2.24) 41 (83.67%) 8 (16.32%) 12 (24.49%)
Values are presented as mean (SD) or number (percentage). CPB indicates cardiopulmonary bypass; Hct, hematocrit.
levels 910% than total CK.8 Arterial blood gas analysis, which was taken approximately every 30 minutes intraoperatively and every 3 hours during the first day after operation, was gathered for each patient.
Electrocardiogram A 12-lead ECG was recorded before surgery; at 1 hour and 6 hours postoperatively; as well as on the first, the second, and the seventh day after the operation. Diagnostic criteria for perioperative MI or ischemia, in the absence of LV hypertrophy or left bundle branch block, were new STelevation at the J point in at least two contiguous leads of 2 mm or greater in men or 1.5 mm or greater in women in leads V2 to V3 and/or of 1 mm or greater in other contiguous chest leads or the limb leads as well as new horizontal or downsloping ST depression of 0.05 mV or greater in two contiguous leads or T inversion of 0.1 mV or greater in two contiguous leads with prominent R wave or R/S ratio of greater than 1.6
Data Analysis Descriptive statistics, correlations, and paired t tests are reported as mean (SD) for continuous variables and as frequencies and percentages for categorical variables, unless otherwise noted. Variables were analyzed with IBM SPSS 20 software (SPSS Inc, Chicago, IL USA).
RESULTS Intraoperatively, the mitral valve was repaired in 44 cases (89.8%) and replaced in 5 cases (10.2%). Two patients required
a second cardiopulmonary bypass (CPB) run with aortic clamping and reinfusion of CPS because of an inadequate valve repair with a significant residual mitral regurgitation. Overall, the mean (SD) CPB time was 148.6 (45) minutes, and aortic cross-clamp duration was 97.9 (45) minutes. The heart, after removal of the cross-clamp, restarted spontaneously in 37 cases (75.5%), and ventricular arrhythmias requiring electrical cardioversion to sinus rhythm occurred in the remaining 12 cases (24.5%). The incidence of AF in the postoperative period occurred in 12 patients (24.49%). There were no operative/ hospital deaths or major postoperative complications. At 3, 12, and 24 hours after surgery, no significant modifications in myocardial cytonecrosis enzymes were found, regardless of cross-clamp time duration (9100 or G 100 minutes) (Fig. 1). Consistently, no ischemic ECG modifications were observed before discharge. None of the patients developed LCOS postoperatively, and only five patients (10.2%) needed mild-to-moderate postoperative inotropic support. The overall frequency of postoperative neurologic events and acute renal dysfunction was 2% (n = 1) and 0%, respectively. The amount of units of blood transfused during either the perioperative period or the postoperative course was 0.14 (0.35) [minimum (min), 0; maximum (max), 4] (Table 3). The mean (SD) assisted ventilation time was 9.3 (15.9) hours (min, 4; max, 18), and the mean (SD) intensive care unit stay was 1.69 (1.44) days (min, 1; max, 4) (Table 2). Predischarge TTE showed a preserved LV ejection fraction [61.2 (6.8)], with no significant differences compared with the preoperative status [63.7 (8.4)].
DISCUSSION Perfusion strategies and operative techniques for minimally invasive mitral valve repair have evolved over time.9 Ideally, every surgical technique should allow a practicing surgeon to continue to use familiar tools and approaches to cardiac operations. Of course, this is not always possible in minimally invasive cardiac surgery (MICS) because of different instruments and approaches that are often necessary. Surgeons performing MICS most frequently protect the myocardium through standard intermittent blood or crystalloid cardioplegia. Data available in the literature have shown blood and crystalloid cardioplegia solutions to be associated with similar results in terms of postoperative MI and death.10Y13 However, these solutions often require intermittent multiple
FIGURE 2. Lines showing the trend of creatine kinase isoenzyme MB (CK-mB) 3, 12, 24, and 48 hours postoperatively (A) and lactate 1, 6, 12, and 24 hours postoperatively (B).
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Innovations & Volume 9, Number 6, November/December 2014
TABLE 3. Clinical Outcomes In-hospital mortality ICU stay, d MAV, h CK-MB 3 h CK-MB 12 h CK-MB 24 h Lactic acid 6 h Lactic acid 24 h Inotropic support 9 24 h Reoperation for bleeding Periopertive MI Neurologic complications Postoperative red blood cell transfusion Fresh frozen plasma Creatinine 48 h Postoperative AF LVEF at discharge, %
0 (0%) 1.69 (1.44) 9.3 (15.9) 77.14 (53.67) 71.20 (55.67) 42.53 (38.38) 1.2 (0.45) 1.1 (0.35) 5 (10.2%) 2 (4.08%) 0 (0%) 1 (2.04%) 0.14 (0.35) 0.04 (0.2) 0.60 (0.52) 12 (24.49%) 61.2 (6.8)
Values are presented as mean (SD) or number (percentage). AF indicates atrial fibrillation; CK-MB, creatine kinase isoenzyme MB; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MAV, mechanical-assisted ventilation; MI, myocardial infarction.
administrations, every 20 to 40 minutes. If this does not represent a concern during conventional surgery, in MICS, it can increase the difficulties of an already demanding approach, especially if we consider the limited surgical field and the use of an aortic endoclamp, which exposes to a high risk for dislodgement during the reinfusion. In our institution, the HTK solution is routinely used in all conventional cardiac interventions with anticipated prolonged period of myocardial ischemia. The main advantage of this solution is that it allows, after a single dose, a safe cardioplegic arrest up to 2 hours, which represents a period in which almost every cardiac operation can be carried out. Given our favorable
HTK Cardioplegia in Minimally Invasive Surgery
results in conventional cardiac surgery, we have extended the use of HTK solution also to the HeartPort procedures, with satisfactory early results.14 We found that this strategy of myocardial protection translated into a remarkably low incidence of myocardial injury and need for inotropic support (Figs. 1, 2) as well as low postoperative alterations of serum lactate (Fig. 2). All these findings finally support a preserved contractile myocardial function at discharge (Table 3). In addition, we observed that, with the HTK solution, short and long periods of cross-clamp time (9100 minutes) were associated with a similar serum release of myocardial cytonecrosis enzymes (Fig. 1). In our opinion, these data remark the goodness of our approach integrating minimal invasiveness with an appropriate myocardial protection protocol, which is, now, well standardized in our institution. Braathen et al15 recently published a prospective, randomized study comparing the HTK solution with repetitive administration of cold-blood cardioplegia. The authors concluded that, in elective mitral valve surgery, both strategies were equivalent to protect the myocardium. Other studies comparing Custodiol with conventional intermittent cardioplegia have questioned some limits as a consequence of its administration. Increased rate of VF as the first rhythm after reperfusion with Custodiol cardioplegia is documented16 and not clear. Our relatively low occurrence of VF may support a well-established myocardial protection protocol improved over time. Hemodilution after a large volume of cardioplegia infusion is another critical point. To maintain a stable hemoconcentration during the perioperative period, we performed a careful ultrafiltration during extracorporeal circulation as well as a strict use of diuretic drugs in intensive care and ward units (Fig. 3). This approach enabled us to use a minimal amount of blood transfusions during the postoperative course.
FIGURE 3. The line depicts the hematocrit (HTC) trend in the first 3 days postoperatively. Red values represent the mean cardioplegic solution (CPS) and the mean ultrafiltration (UFT) during extracorporeal circulation (ECC). Copyright * 2014 by the International Society for Minimally Invasive Cardiothoracic Surgery
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Innovations & Volume 9, Number 6, November/December 2014
Savini et al
It may also be argued that the HTK solution (which is almost a sodium-free solution) frequently results in acute sodium concentration changes, potentially increasing postoperative incidence of seizure.5 In a series of 25 patients, Lindner et al17 showed no significant change in osmolality after measuring serum sodium and osmolality during the perioperative period. Others have observed hyponatremia without clinical consequence.18 These findings demonstrated that brain complications are possible only in hypotonic hyponatremia, in which a shift of free water from the extracellular to the intracellular space happens, resulting in cerebral edema. However, because the HTK solution is a slightly hypertonic solution, the administration to a patient results in isotonic hyponatremia not requiring hypertonic saline correction. According to this evidence, in this small series, none of our patients experienced serum sodium fluctuation during CPB, and only one patient had a neurologic complication not related to this phenomenon. Furthermore, we reported a very low occurrence of renal complications, low incidence of AF, and excellent clinical outcomes (Table 3). This study carries limitations mainly inherent to its retrospective design and small population size. Larger studies are certainly warranted to demonstrate the effectiveness of HTK crystalloid cardioplegia in minimally invasive surgery compared with the other types of CPSs. In conclusion, a single dose of antegrade HTK crystalloid cardioplegia seems to be a safe and effective strategy to protect the myocardium during minimally invasive mitral valve procedures. Our approach with routinary use of Custodiol gave the advantage to be more flowing during mitral surgery compared with repetitive administration of conventional (blood or crystalloid) cardioplegia.
REFERENCES 1. Arslan A, Sezgin A, Gultekin B, et al. Low-dose histidine-tryptophanketoglutarate solution for myocardial protection. Transplant Proc. 2005; 37:3219Y3222. 2. Careaga G, Salazar D, Te´llez S, Sa´nchez O, Borrayo G, Argu¨ero R. Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients. Arch Med Res. 2001;32:296Y299.
3. Sunderdiek U, Feindt P, Gams E. Aortocoronary bypass grafting: a comparison of HTK cardioplegia vs. intermittent aortic cross-clamping. Eur J Cardiothorac Surg. 2000;18:393Y399. 4. Holper K, Meisner H, Ha¨hnel C, Massoudy P. Technical refinements in myocardial protection: infantsVadults. Thorac Cardiovasc Surg. 1998; 46(suppl 2):292Y295. 5. Kim JT, Park YH, Chang YE, et al. The effect of cardioplegic solutioninduced sodium concentration fluctuation on postoperative seizure in pediatric cardiac patients. Ann Thorac Surg. 2011;91:1943Y1948. 6. Ji B, Liu J, Long C, Yang K, Zheng Z. Potential risk of hyponatremia using histidine-tryptophan-ketoglutarate solution during pediatric cardiopulmonary bypass. Ann Thorac Surg. 2012;93:2120Y2121. 7. Schroeyers P, Wellens F, De Geest R, et al. Minimally invasive videoassisted mitral valve surgery: our lessons after a 4-year experience. Ann Thorac Surg. 2001;72:S1050YS1054. 8. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126:2020Y2035. 9. Grossi EA, Loulmet DF, Schwartz CF, et al. Evolution of operative techniques and perfusion strategies for minimally invasive mitral valve repair. J Thorac Cardiovasc Surg. 2012;143(suppl):S68YS70. 10. Guru V, Omura J, Alghamdi AA, Weisel R, Fremes SE. Is blood superior to crystalloid cardioplegia? A meta-analysis of randomized clinical trials. Circulation. 2006;114(suppl):I331YI338. 11. Misfeld M, Davierwala P. Crystalloid-based cardioplegia for minimally invasive cardiac surgery. Semin Thorac Cardiovasc Surg. 2012;24:305Y307. 12. Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Warm versus cold cardioplegia for heart surgery: a meta-analysis. Eur J Cardiothorac Surg. 2010;37:912Y919. 13. Jacob S, Kallikourdis A, Sellke F, Dunning J. Is blood cardioplegia superior to crystalloid cardioplegia? Interact Cardiovasc Thorac Surg. 2008;7:491Y498. 14. Savini C, Camurri N, Castelli A, et al. Myocardial protection using HTK solution in minimally invasive mitral valve surgery. Heart Surg Forum. 2005;8:E25YE27. 15. Braathen B, Jeppsson A, Scherste´n H, et al. One single dose of histidinetryptophan-ketoglutarate solution gives equally good myocardial protection in elective mitral valve surgery as repetitive cold blood cardioplegia: a prospective randomized study. J Thorac Cardiovasc Surg. 2011;141: 995Y1001. 16. Liu J, Feng Z, Zhao J, Li B, Long C. The myocardial protection of HTK cardioplegic solution on the long-term ischemic period in pediatric heart surgery. ASAIO J. 2008;54:470Y473. 17. Lindner G, Zapletal B, Schwarz C, Wisser W, Hiesmayr M, Lassnigg A. Acute hyponatremia after cardioplegia by histidine-tryptophane-ketoglutarateVa retrospective study. J Cardiothorac Surg. 2012;7:52. 18. Lueck S, Preusse CJ, Welz A. Clinical relevance of HTK-induced hyponatremia. Ann Thorac Surg. 2013;95:1844Y1845.
CLINICAL PERSPECTIVE This case series examined the results of 49 consecutive patients undergoing minimally invasive mitral valve surgery using a single dose of histidine-tryptophan-ketoglutarate solution (HTK-Custodiol). The authors had excellent results in this small series, in which 90% of the patients underwent mitral valve repair. There were no operative deaths or major postoperative complications. They saw no ischemic electrocardiographic changes or significant increases in myocardial cytonecrosis enzymes postoperatively. This study establishes the feasibility of single-dose HTK-Custodiol solution in a selected group of low-risk, uncomplicated patients. This is a cohort of patients in whom you would not expect any mortality or complications. All patients had normal ventricular function, and the mean patient age was only 57 years. This report does not establish efficacy or safety, particularly in higher-risk patients. Whether it is equivalent to standard repetitive-dose blood cardioplegia would require further study.
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