Effect of diltiazem on functional recovery and myocardial metabolism during hypothermic global ischemia and normothermic reperfusion

An isolated working rat heart preparation was used to determine the effect of diltiazem, a calcium antagonist, on the myocardial metabolism and functional recovery in the ischemic and reperfused heart, under conditions of 15 degrees C of topical hypothermia. The hearts were divided into two groups according to the solution injected into aortic root at the onset of ischemia. Group I (25 hearts) were given 3 ml of cold Krebs-Henseleit bicarbonate buffer solution (KHB), and Group II (25 hearts) were given the same dose of KHB containing 300 micrograms of diltiazem. After 30 min of reperfusion following 120 min of ischemia, cardiac output (ml/min) was significantly better in Group II (24.1 +/- 3.2) than in Group I (9.5 +/- 2.5). There were no differences between the groups with regard to tissue levels of creatine phosphate, adenosine triphosphate (ATP), total adenine nucleotide (TAN), glucose-6-phosphate and lactate during the ischemia. However, ATP and TAN levels were significantly higher in Group II after 30 min of reperfusion. These data show that, although diltiazem has little effect in preventing the catabolism of high-energy phosphates during hypothermic ischemia, there was an improvement in myocardial metabolism and an enhanced functional recovery during reperfusion in the diltiazem-treated hearts.     

Myocardial adenine nucleotide metabolism in pediatric patients during hypothermic cardioplegic arrest and normothermic ischemia

Quantitative assessment of high-energy phosphate levels, including degradation or utilization during ischemia, has not previously been performed in infants and children. Animal experiments suggest that high-energy phosphate metabolism varies with maturation. To help answer these questions, 24 patients aged 2 months to 8 years underwent myocardial biopsy immediately after the institution of cardiopulmonary bypass (16 to 20 degrees C). Additional samples were obtained at 16 and 45 minutes after aortic cross-clamping and administration of cardioplegia (St. Thomas's solution) (in vivo ischemia). Seven patients also underwent major myocardial resection. Resected specimens were placed in a 37 degrees C bath and divided into equal-sized samples that were removed at ten-minute intervals (in vitro ischemia). All samples were immersed in liquid nitrogen and analyzed for adenine nucleotide pool metabolites using high-performance liquid chromatography. Levels of adenosine triphosphate were high before cross-clamping but diminished during the period of protected ischemia. Adenosine triphosphate loss was much more pronounced in patients less than 18 months old (p less than 0.05) and was associated with accumulation of adenosine monophosphate and inosine, a finding not seen in patients more than 18 months old (p less than 0.05). The same trends documented during in vivo ischemia were noted during in vitro ischemia. Immaturity of 5'-nucleotidase results in accumulation of adenosine monophosphate during ischemia. It is known that 5'-nucleotidase is present in neonatal myocardial cell membranes and absent from the cytosol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of preliminary normothermic flushing on hypothermic renal preservation.

Flushing of harvested kidneys with hypothermic perfusates is presumed to cause inappropriate circulation due to vasospasm. Effects of initial normothermic flushing prior to hypothermic flushing and cold preservation were tested in canine kidneys. Analysis of the perfusion characteristics revealed that a brief initial flushing with solutions at 37 degrees C. eliminates vasoconstriction and even facilitates subsequent hypothermic flushing. In amounts not exceeding 100 cc. it was not deleterious to transplant function. Larger volumes of normothermic flushing were proved to cause endothelial injury and resulted in poor transplant survival.     

Effects of hypothermic and normothermic cardiopulmonary bypass on brain oxygenation.

BACKGROUND: In this study, we assessed the effects of normothermia and hypothermia during cardiopulmonary bypass (CPB) both on internal jugular venous oxygen saturation (SjvO2) and the regional cerebral oxygenation state (rSO2) estimated by near infrared spectroscopy (NIRS). METHODS: Thirty patients scheduled for elective coronary artery bypass graft surgery (CABG) were randomly divided into two groups. Group 1 (n = 15) underwent surgery for normothermic (> 35 degrees C) CPB, and group 2 (n = 15) underwent surgery for hypothermic (30 degrees C) CPB, and alpha-stat regulation was applied. A 4.0-French fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to continuously monitor the SjvO2 value. To estimate the rSO2 state, a spectrophotometer probe was attached to the mid-forehead. SjvO2 and rSO2 values were then collected simultaneously using a computer. RESULTS: Neither the cerebral desaturation time (duration during SjvO2 value below 50%), nor the ratio of the cerebral desaturation time to the total CPB time significantly differed (normothermic group: 18+/-6 min, 15+/-6%; hypothermic group: 17+/-6 min, 13+/-6%, respectively). The rSO2 value in the normothermic group decreased during the CPB period compared with the pre-CPB period. The rSO2 value in the hypothermic group did not change throughout the perioperative period. CONCLUSIONS: These findings suggest that near infrared spectroscopy might be sensitive enough to detect subtle changes in regional cerebral oxygenation.     

Preservation of myocardial high-energy phosphates with vagal stimulation and hypothermic cardioplegia

We examined three methods of inducing hypothermic cardioplegic arrest and related each to preservation of high-energy phosphates. Levels of adenosine triphosphate (ATP) and creatine phosphate (CP) in baseline rat hearts were compared with levels found after vagal stimulation combined with cardioplegia containing 15 mEq of potassium chloride (KCl) per liter, cardioplegia with 15 mEq of KCl per liter alone, and cardioplegia with 30 mEq of KCl per liter alone. Vagal stimulation produced complete electromechanical arrest in a shorter time than either 15 or 30 mEq of KCl alone (p less than 0.001 for both cardioplegic solutions compared with vagal stimulation), with fewer ventricular beats after ischemia than cardioplegic solution containing 15 or 30 mEq of KCl (p less than 0.001 and less than 0.01, respectively). Levels of ATP and CP, although less than baseline levels (p less than 0.01 and less than 0.001, respectively), were greater with vagal stimulation than with either 15 or 30 mEq of KCl (p less than 0.001 and less than 0.05, respectively, for ATP and p less than 0.001 for both CP levels). Furthermore, when all groups were combined, ATP and CP levels were found to correlate negatively with arrest time (r = -0.851 and -0.788, respectively; both r values significant at p less than 0.01) and with the number of ventricular beats after ischemia (r = -0.927 and -0.851, respectively; both r values significant at p less than 0.01). We conclude that electromechanical work quantified as time to arrest after aortic cross-clamping and as number of ventricular beats after ischemia correlates negatively with ATP and CP levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial high-energy phosphates, lactate and pyruvate during moderate or severe normothermic ischemia in rat hearts perfused with phosphoenolpyruvate and ATP in cardioplegic solution

Rat hearts were subjected to normothermic ischemia for 15 min (group I) or 30 min (group II). During the ischemic period the hearts were perfused twice with cardioplegic solution supplemented with 14.4 mM phosphoenolpyruvate (PEP) and/or 0.067 mM adenosine triphosphate (ATP), and at the end of ischemia they were freeze-clamped. The myocardial ATP content in group I fell to about 55% of normal values except in hearts supplemented with only PEP, which showed greater reduction. In group II the ATP fell to only about 5% of normal values, without significant differences between the subgroups Hearts supplemented with PEP alone or with combined PEP-ATP showed significantly higher levels of pyruvate than in hearts with only ATP supplementation or control hearts. The study thus demonstrated clear difference in ATP content between moderate and severe ischemic trauma. The high pyruvate levels after PEP supplementation indicate formation of pyruvate without concomitant lactate increase.     

Changes in high-energy phosphates in the myocardium before and after ischemia

Assessment of the level of high-energy phosphates in the myocardium before, during and after ischemia was performed in 19 consecutive patients who underwent cardiac operation. The following results were obtained. 1) The levels of total nucleotides (ATP, ADP, AMP, CP) determined before, during and after aortic cross clamp were 14.94 +/- 4.12, 5.59 +/- 2.16 and 3.58 +/- 1.14 micrograms/mg. protein in the right atrial appendage. Those in the left ventricular myocardium were 18.22 +/- 4.90, 6.99 +/- 1.52 and 4.35 +/- 1.06 micrograms/mg. protein. The latter levels were higher than the former. 2) Rapidly decreasing after aortic cross clamp, the nucleotides dropped to 37-38% of preischemic level during aortic cross clamp and to 23% of preischemic level 30 minutes after reperfusion. At the termination of extracorporeal circulation, when circulatory dynamics stabilized, the nucleotides were only recovered to 50-53% of preischemic level. 3) Negative correlation was observed between the length of aortic cross clamp time and the content of nucleotides in the atrial muscle. (p less than 0.05) 4) Fluctuations in the nucleotide level indicated that the current method of myocardial protection using GIK solution produced unsatisfactory recover from ischemic damage and reperfusion injury.     

Effects of delta-opioid agonist SNC80 on white matter injury following spinal cord ischemia in normothermic and mildly hypothermic rats

Purpose Although the delta-opioid agonist SNC80 has been shown to attenuate hind-limb motor function and gray matter injury in normothermic rats subjected to spinal cord ischemia (SCI), its effects on white matter injury remain undetermined. In the present study, we investigated whether SNC80 could attenuate white matter injury in normothermic and mildly hypothermic rats. Methods Forty rats were randomly allocated to one of following five groups: vehicle or SNC80 with 10 min of SCI at 38°C (V-38-10m or SNC-38-10m, respectively), vehicle or SNC80 with 22 min of SCI at 35°C (V-35-22m or SNC-35-22m, respectively), or sham. SNC80 or vehicle was intrathecally administered 15 min before SCI. Forty-eight hours after reperfusion, the white matter injury was evaluated by the extent of vacuolation. Results The percent area of vacuolation in the ventral white matter was significantly lower in the SNC-38-10m and SNC-35-22m groups compared with that in the V-38-10m and V-35-22m groups, respectively (P < 0.05). Conclusion The results indicate that intrathecal treatment with the delta-opioid agonist SNC80 can attenuate the ventral white matter injury following SCI in rats under normothermic and mildly hypothermic conditions.     

常温与低温心肺转流心肌损伤的比较

目的比较常温和低温心肺转流（CPB）中的心肌损伤。方法成年健康杂种犬11只，随机分为低温组（H组，n=5）和常温组（N组，n=6）。H组采用4℃改良托马氏停搏液间断灌注，最低鼻咽温度28～30℃，N组采用氧合温血持续灌注，最低鼻咽温度35．3～37．1℃。主动脉阻断60min，CPB90min。分别测定CPB前、CPB30、90min、CPB后60min时静脉血心肌相关酶含量；CPB中心脏停跳时间和复跳时间；CPB后60min心肌含水量。结果两组天门冬氨酸氨基转移酶（AST）、乳酸脱氢酶（LDH）、羟丁酸脱氢酶（HBDH）、肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）在CPB中和CPB后均较CPB前升高；且H组AST、HBDH、CK、CK-MB在CPB30、90min，CPB后60min均较N组升高；H组LDH在CPB90min、CPB后60min较N组高。主动脉夹闭后，H组的心脏停跳所需时间明显短于N组；主动脉开放后，H组的心脏复跳所需时间明显长于N组。CPB后60min心肌含水量H组高于N组。结论常温和低温CPB都可引起心肌组织损伤，尤以低温CPB为著。     

Changes in serum myoglobin levels caused by tourniquet ischemia under normothermic and hypothermic conditions

Serum myoglobin levels have been found to be elevated for a few hours after removal of a tourniquet. In the present study, levels of serum myoglobin were measured by radioimmunoassay from local blood samples in patients who were treated with surgery of the hand in a bloodless field. After removal of the tourniquet blood samples were obtained from the antecubital vein of each patient immediately after release, five minutes, one hour, and 24 hours later. In these samples the serum myoglobin levels were not influenced by the mode of anesthesia, tourniquet time, or specific type of surgery. When the upper extremity was cooled with ice water before application of the tourniquet, however, the increase of serum myoglobin was statistically significantly inhibited when compared with the normothermic condition. Muscle injury due to tourniquet ischemia may be decreased by cooling of the upper extremity prior to tourniquet application.     

Effects of adenosine infusion on the pig heart during normothermic ischemia and reperfusion.

Possible enhancement of myocardial protection during ischemia and reperfusion by administration of adenosine was evaluated in a pig heart model. Adenosine (100 micrograms/kg/min) was infused into the aortic root during ischemia in group AI (n = 5) and into the right atrium during reperfusion in group AR (n = 6). Group C (n = 6) served as controls. During cardiopulmonary bypass the hearts were subjected to 30 min of normothermic ischemia and 15 min of reperfusion before weaning. In group AI the stroke work index 30 and 90 min after ischemia and the mean arterial pressure 30 min after ischemia were significantly higher than in group C. These parameters did not differ significantly between groups AR and C. All groups showed decrease in myocardial adenosine triphosphate (ATP) and adenylate charge potential (ACP) during ischemia and partial (ATP) or complete (ACP) restoration after ischemia. Adenosine infusion into the aortic root during ischemia (adenosine cardioplegia) thus resulted in improved postischemic heart function, although biochemical correlates in ATP and ACP were not apparent.     

Continuous measurement of intramyocardial pH: correlation to functional recovery following normothermic and hypothermic global ischemia

The continuous measurement of intramyocardial pH was used to follow the progression of ischemia and was correlated to the recovery of left ventricular function following normothermic (38 degrees C) and hypothermic (25 degrees C) global ischemia. New miniature myocardial transducers, which incorporate fiberoptic technology and dual pH- and temperature-sensing capability, were placed into the left ventricular free wall and septum of 52 sheep undergoing cardiopulmonary bypass. Left ventricular stroke work as a function of mean left atrial pressure curves were generated before and after cardiopulmonary bypass by volume loading with whole blood. Functional recovery was determined by the ratio of the integrals of the preischemic and postischemic function curves. Control sheep (N = 11) did not undergo ischemia. Three groups (N = 41) underwent aortic cross-clamping until pH reached 7.0, 6.8, or 6.6. The preischemic myocardial pH averaged 7.42 +/- 0.01. Following both normothermic and hypothermic global ischemia, no significant difference was demonstrated in recovery of function between control (pH 7.4) and pH 7.0 groups at either temperature. However, recovery of function of the pH 6.8 and pH 6.6 groups was significantly decreased (p less than 0.01) versus control and pH 7.0 groups at both temperatures. No significant difference in recovery of function was demonstrated at any pH level when normothermic versus hypothermic groups were compared. However, hypothermia provided increased time (p less than 0.001) before each level of function was reached with a slower rate of change of pH (p less than 0.01) compared with the corresponding same pH group in sheep undergoing normothermic (38 degrees C) cardiopulmonary bypass.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and hormonal responses to hypothermic and normothermic cardiopulmonary bypass.

Normothermic cardiopulmonary bypass (CPB) is used in cardiac surgery at some institutions. To compare hemodynamic and hormonal responses to hypothermic (29 degrees C) and normothermic nonpulsatile CPB, 20 adults undergoing coronary artery bypass graft and/or aortic valve replacement were studied. Hemodynamic measurements and plasma hormone concentrations were obtained from preinduction to the third postoperative hour. The two groups were given similar amounts of anesthetics and vasodilators. Systemic vascular resistance increased only during hypothermic CPB, and heart rate was higher at the end of hypothermic CPB. Postoperative central venous pressure and pulmonary capillary wedge pressure were lower after hypothermic CPB. Oxygen consumption decreased by 45% during hypothermic CPB, did not change during normothermic CPB, but increased similarly in the two groups after surgery; mixed venous oxygen saturation (SvO2) was significantly lower during normothermic CPB. Urine output and composition were similar in the two groups. In both groups, plasma epinephrine, norepinephrine, renin activity, and arginine vasopressin concentrations increased during and after CPB. However, epinephrine, norepinephrine, and dopamine were 200%, 202%, and 165% higher during normothermic CPB than during hypothermic CPB, respectively. Dopamine and prolactin increased significantly during normothermic but not hypothermic CPB. Atrial natriuretic peptide increased at the end of CPB and total thyroxine decreased during and after CPB, with no difference between groups. This study suggests that higher systemic vascular resistance during hypothermic CPB is not caused by hormonal changes, but might be caused by other factors such as greater blood viscosity. A higher perfusion index during normothermic CPB might have allowed higher SvO2.     

热缺血后低温保存对供心的影响

目的　观察常温短暂热缺血后低温保存对供心的影响。方法　建立猪原位心脏移植模型 ,随机分为对照组 (C组 )和热缺血组 (H组 )。H组供心切取前常温缺血 5min。供心 4℃保存4h测定含水率、MDA、ATP含量 ,原位末端标记法检测心肌细胞凋亡 ;两组供心行原位心脏移植各8例 ,观察移植后血浆肌钙蛋白I(cTnI)水平、心排量 (CO )和再灌注 2h的心肌超微结构和凋亡。结果　与C组比较 ,H组供心低温保存后含水率、MDA高于C组 ,而ATP明显降低 ,差异均有显著性 (P <0 .0 5 ) ;C组cTnI漏出少 ,CO高于H组 (P <0 .0 5 ) ;H组心肌细胞结构改变明显 ,凋亡水平高于C组 (P <0 .0 1)。结论　热缺血使供心能量消耗 ,诱导再灌注后心肌细胞凋亡 ,一定程度上导致了供心移植后早期功能异常。     

Experimental models of temporary normothermic liver ischemia.

Hepatic ischemia/reperfusion injury has so far been investigated in various experimental models. A clinical transfer of experimental results is, however, problematic because of anatomical and physiological differences and also the inevitable simplification of experimental work. The choice of model must therefore be adapted to the clinical question to be answered. The simplest procedure for inducing normothermic ischemia is to clamp the hepatoduodenal ligament. Models that do not avert portal congestion are regarded as unsuitable. Our current understanding of the pathogenesis of ischemia/reperfusion injury depends mainly on studies whose authors have investigated either global liver ischemia with a portocaval shunt, spleen transposition and in the isolated perfused system, or partial ischemia. This review is a critical examination of various approaches to the study of normothermic hepatic ischemia in experimental animals.     

吡那地尔预处理对缺血心肌的保护效果

目的观察心肺转流(cardiopulmonory bypass,CPB)下,ATP敏感性钾通道开放剂(KCOs)吡那地尔(pinacidil)预处理分别对常温和低温高钾停跳心肌的保护作用.方法18只犬均分为三组,CPB心脏高钾停跳,全心缺血60 min,恢复灌注30 min.常温吡那地尔组(NP组)、低温吡那地尔组(HP组)CPB前主动脉根部灌注浓度为10 μmol/L的吡那地尔5 min.对比观察阻断主动脉前、后心肌超微结构、丙二醛(MDA)含量、血清心肌酶含量以及血液动力学的变化.结果(1)电镜:HP组除阻断60min外的其他时点心肌的正常线粒体及糖原含量均接近缺血前水平,明显高于C组和NP组;(2)心肌MDA的含量:HP组阻断30 min和开放20 min以及NP组开放20 min与C组有显著性差异;(3)血清心肌酶:HP组,除阻断30 min,CK-MB均明显低于同期C组;(4)血液动力学变化:HP组开放循环后心输出量(CO)、左室搏出功(LVSW)恢复比C组迅速.结论吡那地尔明显增强低温CPB心肌缺血-再灌注期超微结构的保护效果.     

常温和低温心肺转流期间门静脉血流量及氧代谢的变化

目的：研究常温和低温心肺转流（CPB）期间门静脉血流量（PBF）和氧代谢的变化。方法：测定11号杂种犬在常温（N组）或低温（H组）CPB期间PBF和氧代谢指标。结果：CPB中低温组SpO2升高，PDO2、PVO2降低（P＜0．05或P＜0．01）；常温组PpO2、PDO2降低，而PERO2和PBF升高（P＜0．05或P＜0．01）。CPB后两组SaO2、PaO2、SpO2、PpO2、PBF、PDO2均有不同程度的降低（P＜0．05或P＜0．01），而PERO2明显升高（P＜0．01），常温组PVO2减少（P＜0．05）。两组相比，CPB中低温组PaO2、SaO2、SpO2高于常温组，PVO2、PERO2、PBF低于常温组（P＜0．05或P＜0．01）。CPB后低温组SaO2、PDO2、PVO2和PBF都高于常温组（P＜0．05）。结论：常温和低温CPB期间门脉系统都存在氧代谢障碍，但常温CPB期间PBF、门脉组织氧利用明显优于低温CPB，CPB后PBF、门脉组织氧代谢低温组优于常温组。     

An experimental evaluation of continuous normothermic, intermittent hypothermic, and intermittent normothermic coronary perfusion

Hedley Brown, A., Braimbridge, M. V., Darracott, Sally, Chayen, J., and Kasap, H. (1974).Thorax, 29, 38-50. An experimental evaluation of continuous normothermic, intermittent hypothermic, and intermittent normothermic coronary perfusion. Coronary perfusion and hypothermia both have disadvantages, and excellent clinical results are obtained without them, though short operations, spontaneous cooling of unperfused hearts, hyperglycaemia, heparinization, and young and cyanotic subjects may allow more tolerance of ischaemia. Functional, macroscopic, histological, ultrastructural, chemical, and metabolic evidence of the inadvisability of ischaemia, especially of hypertrophied hearts, abounds, though statistical support and histochemical proof are lacking.     

Pharmacokinetics of doxacurium during normothermic and hypothermic cardiopulmonary bypass surgery

Purpose

To compare the pharmacokinetic behaviour of doxacurium in patients undergoing normothermic or hypothermic cardiopulmonary bypass (CPB) for coronary artery bypass graft surgery.

Methods

Twenty patients in two equal groups were studied. Anaesthesia was induced with sufentanil and midazolam after a standard premedication. Doxacurium was administered at 3 × ED₉₅ (80μ·kg^?1), and anaesthesia was maintained with 0.5 μg·kg^?1 hr^?1 sufentanil, 0.05 mg·kg^?1 midazolam and isoflurane 0.5–1%. Systemic temperature for patients in the normothermic and hypothermic groups was maintained at 33–36C and 26–30C respectively. Timed blood and urine samples were collected and pharmacokinetic parameters were estimated using a non-compartmental approach.

Results

For the normothermic and hypothermie groups, terminal elimination half-life (t_1/2B) was 100.1 ± 28 and 183.8 ± 60 min (P < 0.05) respectively, elimination half-life during the CPB phase (T_1/2 CPB) 114.5 ± 10 and 183.8 ± 60 min (P < 0.05), mean residence time 108.8 ± 25 and 164.8 ± 34 min (P < 0.05) and apparent volume of distribution at steady state 0.20 ± 0.03 and 0.26 ± 0.04 L·kg^?1 (P < 0.05). Compared with the hypothermie group, the normothermic group had a higher rate of renal clearance (1.40 ± 0.4 vs 0.93 ± 0.3 ml·min^?1·kg^?1;P < 0.05) and a higher value for renal clearance as a percentage of the total clearance (76.2 ± 10 vs 58.3 ± 20%).

Conclusion

The elimination rate of doxacurium during normothermic CPB is faster than that in hypothermic CPB.