Effect of induction and reperfusion with warm substrate-enriched cardioplegia on ventricular function.

BACKGROUND: This study tested the hypothesis that induction and reperfusion with warm substrate-enriched (IRWSE) blood cardioplegia improves postoperative left ventricular (LV) function in patients undergoing elective coronary bypass surgery (CABG). METHODS: After giving informed consent, 67 patients scheduled for CABG surgery were randomized to either IRWSE + cold blood (CB) or CB alone. IRWSE cardioplegia consisted of 37 degrees C substrate-enriched (glutamate, aspartate, hyperkalemic) anterograde and retrograde blood cardioplegic solution followed by non-substrate-enriched cardioplegic solution given at 4 degrees C to 8 degrees C. LV function was measured with ventriculograms, volume conductance catheters, echocardiography, and multiple gated (image) acquisition. RESULTS: The end-systolic pressure-volume relationship was improved postbypass in the IRWSE + CB group (CB, 1.5 +/- 0.74 mm Hg/mL vs IRWSE + CB, 2.1 +/- 1.2 mm Hg/mL; p = 0.042). The postoperative ejection fraction (EF%) was better preserved in the CB group (CB, 65 +/- 11.53% vs IRWSE + CB, 58.62 +/- 11.75%; p < 0.04). CONCLUSIONS: Our results demonstrate a transient improvement in LV systolic function in the immediate postbypass period in CABG patients in the IRWSE + CB group. The intraoperative benefits of the IRWSE + CB technique did not persist in the postoperative period.

Effects of dobutamine on hemodynamics and left ventricular performance after cardiopulmonary bypass in cardiac surgical patients.

BACKGROUND: Dobutamine is commonly used to improve ventricular performance after cardiopulmonary bypass. The authors determined the effect of dobutamine on hemodynamics and left ventricular performance immediately after cardiopulmonary bypass in patients undergoing coronary artery bypass graft surgery. METHODS: One hundred patients received sequential 3-min infusions of dobutamine at 0-40 microg x kg(-1) x min(-1) immediately after cardiopulmonary bypass. Ten additional patients who received no dobutamine served as controls. Hemodynamics and left ventricular performance (fractional area change by transesophageal echocardiography, stroke volume index, and thermodilution cardiac index) were measured. Mixed-effects modeling accounted for repeated-measures data and interindividual differences and allowed for potential effects of covariates. RESULTS: Heart rate increased in a dose-dependent manner. The slope of HR versus dobutamine dose was steeper in individuals in whom peak dobutamine dose was not reached compared with that in the remaining individuals; slope decreased 2.71 +/- 0.68% per year of age. Dobutamine affected blood pressure minimally, but slightly decreased pulmonary capillary wedge pressure and central venous pressure. Systemic vascular resistance initially increased with dobutamine 10 microg x kg(-1) x min(-1) and remained constant with larger doses. Dobutamine produced a dose-dependent increase in left ventricular performance, primarily by increasing heart rate, because stroke volume index decreased with dobutamine dose. CONCLUSION: Our results suggest that the response to graded dobutamine infusion in the post-cardiopulmonary bypass period differs from that previously reported. After cardiopulmonary bypass, the dominant mechanism by which dobutamine improves left ventricular performance is by increasing heart rate. Dobutamine affects blood pressure minimally.

Cutaneous histiocytosis with Langerhans cell features induced by scabies: a case report.

An infant with biopsy-proven scabies developed nodular lesions. Histopathology revealed atypical histiocytes with Langerhans cell features. Within six months after treatment all skin lesions gradually disappeared. We suggest that the nodules in scabies can be due to Langerhans cell proliferation.

Importance of acid-base strategy in reducing myocardial and whole body oxygen consumption during perfusion hypothermia.

During induced hypothermia with cardiopulmonary bypass, acid-base management usually follows one of two strategies: the so-called ectothermic or alpha-stat strategy, in which the pH of the arterial blood increases 0.015 pH units for every degree Celsius decrease in body temperature, or the pH-stat strategy, in which pH remains 7.4 at all temperatures. It has been assumed that oxygen consumption decreases approximately equally during hypothermia with either strategy, although there are biochemical reasons to hypothesize that oxygen consumption would be better maintained with the alpha-stat strategy. We also hypothesized that venous oxygen tension would be lower with the more alkaline alpha-stat strategy than with the pH-stat acid-base strategy, because of the Bohr effect. We tested these hypotheses by placing 10 anesthetized immature domestic pigs on cardiopulmonary bypass. We measured whole body oxygen consumption and myocardial oxygen consumption. Control measurements were made at 37 degrees C. Then the animals were cooled to 27 degrees C and the measurements were repeated. The alpha-stat strategy (pH 7.554 +/- 0.020 at 27 degrees C) was used in five animals and five animals received pH-stat management (pH 7.409 +/- 0.012 at 27 degrees C). Whole body and myocardial oxygen consumption rate decreased in both groups, but more so in the alpha-stat animals than in the pH-stat animals. The unexpectedly high oxygen consumption in the pH-stat animals also resulted in a lower than expected venous oxygen tension. Thus the effect of hypothermia in reducing oxygen consumption was less pronounced with pH-stat acid-base management.

Comparison of myocardial temperatures with multidose cardioplegia versus single-dose cardioplegia and myocardial surface cooling during coronary artery bypass grafting.

Myocardial hypothermia with multidose cardioplegia has not been compared with single-dose cardioplegia and myocardial surface cooling with a cooling jacket in patients having coronary artery bypass grafting. In this study, 20 patients with three-vessel disease undergoing coronary bypass at 28 degrees C with bicaval cannulation, caval tapes, and pulmonary artery venting (4.9 +/- 0.7 grafts per patient) were prospectively randomized equally into group I (multidose cardioplegia) and group II (single-dose cardioplegia with a cooling jacket). The initial dose of cardioplegic solution was 1000 ml. Group I then received 500 ml of cardioplegic solution every 20 minutes, delivered into the aortic root and available grafts. In group II, after the cardioplegic solution had been administered, a cooling jacket covering the right and left ventricles was applied. In both groups temperatures were recorded every 30 seconds at five ventricular sites: (1) right ventricular epicardium; (2) right ventricular myocardium or cavity, 7 mm; (3) left ventricular epicardium; (4) left ventricular myocardium or cavity, 15 mm; and (5) septum, 20 mm. Group mean temperatures at each site at various times were compared within each group and between the two groups by analysis of variance. Aortic crossclamp time was 60.3 +/- 12.1 minutes in group I and 52.8 +/- 7.3 minutes in group II (p = 0.12); cardiopulmonary bypass time was 103.7 +/- 11.1 minutes in group I versus 87.7 +/- 12.7 minutes in group II (p less than 0.01). One minute after the cardioplegic solution was initially given, temperatures between groups at each site were not statistically different, but left ventricular epicardial temperatures within both groups were significantly higher than in the other four sites. Nineteen minutes after administration of the cardioplegic solution, temperatures in group I at all sites were higher than in group II. Similarly, throughout the entire period of aortic crossclamping, mean temperatures (except left ventricular myocardial site), maximum temperatures, and percentage of time all temperatures were 15 degrees C or higher were greater in group I than in group II. The following conclusions can be reached: 1. Initial myocardial cooling with 1000 ml of cardioplegic solution is not significantly limited by coronary artery disease but is suboptimal (16 degrees or 17 degrees C) in the inferior left ventricular epicardium because of continual warming from the aorta and subdiaphragmatic viscera. 2. Without myocardial surface cooling, excessive external myocardial rewarming to 18 degrees to 22 degrees C occurs within 20 minutes at all sites after delivery of the cardioplegic solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical comparisons of methods of myocardial protection.

Currently, numerous methods are in use for myocardial hypothermia as a myocardial preservation modality for cardiac operations. During cardiac ischemia we have compared myocardial surface cooling with topical cold saline (Group I, N = 9), crystalloid cardioplegia plus topical cold saline (Group II, N = 8) and cardioplegia with a specially designed cooling jacket (Group III, N = 8) in patients undergoing aortic or mitral valve replacement, or both. Temperatures were assessed and recorded continuously in standardized locations for the right and left ventricular epicardium and endocardium. In Group I the rate of cooling was significantly slower than in the other two groups. Also, excessive gradients were developed across the left and right ventricular walls. In Group II the rate and depth of cooling were adequate and initial temperature gradients were eliminated. However, over the period of ischemia, significant rewarming occurred. In Group III temperatures were reduced rapidly and uniformly and maintained at or below 10 degrees C for the duration of the ischemic period. These differences are statistically significant (p less than 0.05). For optimal myocardial hypothermia, we recommend the following: separate cannulation of the superior and inferior venae cavae with caval snares; venting of the pulmonary artery (if inadequate, pulmonary vein occlusion or direct left atrial venting); induction of myocardial hypothermia with crystalloid or cold blood cardioplegia; and maintenance of hypothermia by the cooling jacket described herein. It is also desirable to continuously monitor temperatures of the right and left ventricular endocardial and epicardial surfaces.

Decreased critical mixed venous oxygen tension and critical oxygen transport during induced hypothermia in pigs.

The effects of hypothermia on oxygen delivery and tolerance to hypoxia were studied in 8 normothermic (36.8 degrees C) and 10 hypothermic (29.3 degrees C) pigs that had been anesthetized and surgically implanted with instruments. Cardiac output (QT), VO2 [oxygen consumption, or QT X C(a-v)O2, where C(a-v)O2 is arteriovenous oxygen content difference], arterial and mixed venous blood gas values, and lactate concentrations were measured as the animals were made progressively hypoxic. Under control, normoxic conditions, mixed venous oxygen tension (PvO2) was 41.4 +/- 2.1 mm Hg (mean +/- SE) in the normothermic animals and 26.1 +/- 1.6 mm Hg in the hypothermic animals; these values are close to those predicted in our previous theoretical analysis. To study tolerance to hypoxia during hypothermia, critical PvO2 and critical total oxygen transport (TOT = QT X CaO2, where CaO2 is oxygen content of arterial blood) were determined by decreasing the inspired oxygen concentration (FIO2) in steps and measuring the point where VO2 and blood lactate levels became PO2 or TOT dependent. Again as predicted, the critical PVO2 was lower in the hypothermic animals (15.5 +/- 1.0 mm Hg at 29.3 degrees C compared with 22.0 +/- 1.4 mm Hg at 36.8 degrees C), but critical venous oxyhemoglobin saturation values were not statistically different at the two temperatures. Critical TOT was also decreased during hypothermia, as was the margin of reserve in both PVO2 and TOT (the difference between the normoxic and the critical values).

Temporary extracorporeal support of the right ventricle.

Six patients having severe right ventricular failure after cardiac surgical procedures were treated temporarily with an extracorporeal pump to bypass the right ventricle. The initial operative procedures included coronary artery bypass procedures with and without concomitant valvular and aortic replacement. A Biomedicus centrifugal pump was used as the right ventricular assist device in most cases. The assist period ranged from 3 to 96 hours, and an intra-aortic balloon pump was used in five of the six patients. All patients initially responded to the right ventricular assist device, four were successfully weaned, and one patient is a long-term survivor. The use of a right ventricular assist device is not difficult or complicated and can be lifesaving for those patients having potentially reversible profound right ventricular failure.

Theoretical analysis of oxygen transport during hypothermia.

Oxygen transport and delivery to peripheral tissues during hypothermia are analyzed theoretically, taking into consideration various conditions observed both in nature and clinically. With decreasing temperature, P50 (the oxygen tension [PO2] at 50% hemoglobin saturation with oxygen) decreases, thereby leading to low mixed venous oxygen tension (PvO2) and thus low tissue PO2 values. On cooling from 37 degrees C to 25 degrees C at pH 7.4, the P50 decreases from a normal 26.8 mm Hg to 13.2 mm Hg. In the intact animal, as well as in a patient on cardiopulmonary bypass, oxygen consumption (Vo2) and cardiac output (QT, or recommended pump flow rate) decrease. If the ratio of Vo2/QT remains constant, then the arteriovenous O2 content difference, C(a-v)O2, must remain constant. If C(a-v)O2 is 5 ml/dl, we calculate that the PvO2 must decrease from a normal 40 mm Hg to 26.8 mm Hg at 25 degrees C. Clinically induced hypothermia is usually accompanied by hemodilution of the patient's blood to 50% normal hematocrit, which would reduce PvO2 to 13.7 mm Hg. Use of constant relative alkalinity (pH = 7.58 at 25 degrees C) further reduces the P50 to 10.8 mm Hg and the PvO2 to 10.9 mm Hg. Other clinical situations are also discussed. Sensitivity analysis predicts that during hypothermia PvO2 (and thus tissue PO2) is very dependent on P50, hemoglobin concentration, and QT, and less dependent on oxygen solubility and arterial PO2. We conclude that monitoring of mixed venous or tissue PO2 might be advisable, and that blood flow is the component of oxygen transport most amenable to manipulation by the clinician to ensure adequate tissue oxygenation during induced hypothermia.

Quantitative evaluation of the myocardial preservative characteristics of nifedipine during hypothermic myocardial ischemia.

Nifedipine, a slow calcium-channel blocker, has been used to preserve myocardial function in the ischemic heart. To quantitatively evaluate the effectiveness of nifedipine as a cardioplegic agent during moderate hypothermia (28 degrees C), 15 pigs were evaluated on total and right heart bypass with measurement at normothermia and after 1 hour of hypothermic ischemia of stroke volume, coronary blood flow, myocardial oxygen consumption, and lactate extraction. Myocardial tissue gases (oxygen and carbon dioxide) were continuously monitored. Animals were divided into three groups: hypothermic ischemia, hypothermic ischemia with infusion of nifedipine carrier without nifedipine, and hypothermic ischemia with nifedipine and its carrier. A significant decrease in stroke volume was seen in all three groups; however, the depression was significantly greater following hypothermic ischemia than following cardioplegia with either nifedipine or its carrier. The mean recovery value of stroke volume was highest in the nifedipine group, but this difference between nifedipine and its carrier alone did not reach statistical significance. Coronary blood flow, myocardial oxygen consumption, lactate extraction, and tissue gases failed to substantiate a significant benefit when nifedipine was compared with its carrier alone. We conclude that under these hypothermic conditions, no proven statistically significant advantage was noted in the nifedipine group when compared with the nifedipine carrier group in swine. However, both nifedipine and the carrier were superior as a myocardial preservative when compared with hypothermic ischemic arrest alone.

Effects of tifluadom on food consumption compared with chlordiazepoxide and kappa agonists in the rat.

Tifluadom (0.625-10.0 mg kg-1) was administered to non-deprived male rats which had been accustomed to eating a highly palatable diet in a 30 min test period. This compound, an opioid benzodiazepine, produced a significant increase in consumption of food when administered by the subcutaneous route, but not after intraperitoneal injection. Both chlordiazepoxide (1.25-20.0 mg kg-1) and the selective kappa opiate receptor agonist U-50,488 (0.3125-2.5 mg kg-1) also produced significant hyperphagic effects in the same feeding situation. In contrast, the two kappa opiate receptor agonists, ethylketocyclazocine (0.1-3.0 mg kg-1) and bremazocine (0.078-1.25 mg kg-1) brought about a dose-related suppression of food intake. Hence, the effects of kappa opiate receptor agonists in the feeding situation described here were not uniform. Furthermore, tifluadom could be likened either to a benzodiazepine or to a selective kappa receptor agonist. The hyperphagia induced by tifluadom was antagonized by naloxone, suggesting that the effect was mediated by an action at opiate receptors. It was not antagonized however by Ro15-1788 (10.0 and 20.0 mg kg-1), a selective benzodiazepine receptor antagonist, ruling out possible mediation by benzodiazepine receptors. The benzodiazepine receptor antagonist, CGS 8216, exhibited intrinsic activity when administered alone, and significantly reduced food consumption in tifluadom-treated and control animals.

Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital.

Nondeprived male rats were familiarized with 30 min daily access to a highly palatable diet. Clonazepam, midazolam and chlordiazepoxide each produced significant dose-dependent increases in food consumption. Clonazepam was the most potent, and a significant hyperphagic effect was detected following 0.078 mg/kg (IP). Amongst novel non-benzodiazepine anxiolytics, zopiclone and CL 218,872 also produced significant increases in food intake. The smallest doses to produce significant hyperphagia for these two drugs were 10.0 and 2.5 mg/kg (IP) respectively. In contrast, tracazolate caused only a reduction in feeding, evident at 20 and 40 mg/kg (IP). Previous reports indicate that although benzodiazepines, zopiclone and CL 218,872 displace [3H] flunitrazepam binding in rat cerebral cortex preparations, tracazolate enhances the binding. Our results are consistent with the drug-induced hyperphagia depending upon agonist actions at high-affinity benzodiazepine sites. They also provide pharmacological evidence for a dissociation between hyperphagic and anxiolytic drug effects. Phenobarbital (2.5-40.0 mg/kg), like the benzodiazepines, produced a strong stimulation of food intake, indicating that drug action at an alternative site in the benzodiazepine receptor-GABA receptor-chloride channel complex can also lead to hyperphagia.

Chlordiazepoxide-induced hyperphagia in non-food-deprived rats: effects of Ro15-1788, CGS 8216 and ZK 93 426.

Chlordiazepoxide (1.25-20.0 mg/kg i.p.) was administered to non-food-deprived male rats given 30 min access to a highly palatable, familiar diet, and produced a potent stimulation of food consumption. At the maximum dose effect, the rats consumed about 24 g food in the 30 min test. The benzodiazepine receptor antagonist, Ro15-1788 (2.5-40.0 mg/kg i.p.) had no effect on food intake when given alone, but did dose-dependently attenuate chlordiazepoxide's hyperphagic effect. The antagonist CGS 8216 (5.0-20.0 mg/kg i.p.) completely abolished the hyperphagic effect, and in doses of 10.0 and 20.0 mg/kg produced significant suppression of feeding when administered by itself. ZK 93 426, in doses (0.625-10.0 mg/kg i.p.) which have previously been shown to antagonize the discriminative cue of chlordiazepoxide produced no significant change in chlordiazepoxide's hyperphagic effect. These data point to an interesting and important distinction between ZK 93426 and the other two benzodiazepine receptor antagonists when given in combination with chlordiazepoxide in the palatable food consumption test.

Naloxone: ineffective in improving cardiac performance after hypoperfusion in swine.

A study was done to measure beta-endorphin immunoreactivity (beta-EI) in swine subjected to cardiopulmonary bypass at normal aortic perfusion pressures and during low-flow states such as can occur with shock. Fifteen pigs, divided into three groups of five each, were placed on total and right heart bypass and perfused as follows: group I, normal blood pressure (80 mmHg); group II, low blood pressure (45 mmHg); and group III, low flows (25 ml/kg/hr). beta-endorphin immunoreactivity was assayed six times during the procedure. Ventricular performance was evaluated by measuring stroke volume (SV) while controlling preload, afterload, and heart rate. Determinations of SV were made at the beginning of bypass, after a 1-hr pump run, and after administration of naloxone (1.1 mg/kg). There were no significant changes in beta-EI in any of the groups during the study. The initial SV in group III (23 +/- 6 ml) decreased significantly (p less than 0.05) after 1 hr of decreased cardiac perfusion (8.0 +/- 7 ml) and was not improved by naloxone (5.0 +/- 7 ml). Ventricular performance was not improved in any group following naloxone administration. In our study, naloxone administered to swine following inadequate myocardial perfusion did not effect a significant cardiac hemodynamic response.

Benzodiazepine receptor ligands and the consumption of a highly palatable diet in non-deprived male rats.

Non-deprived rats were familiarized with a highly palatable diet until baseline consumption in a 60-min daily access period had stabilised. The benzodiazepine receptor agonist midazolam (1.25-10.0 mg/kg, IP) produced a large, dose-related increase in food consumption during the first 30 min of access. It also produced significant, short-term hyperphagia in animals which had been partially pre-satiated on the diet before drug administration, an effect which was reversible by the benzodiazepine receptor antagonist Ro15-1788. Administered alone, Ro15-1788 (1.25-10.0 mg/kg, IP) had no intrinsic activity in the food consumption test. In contrast, CGS 8216 (2.5-40.0 mg/kg, IP) produced a marked dose-related suppression of food intake. This anorectic effect was shared by two benzodiazepine receptor inverse agonists, FG 7142 and DMCM, which also produced dose-dependent reductions in consumption. The effects on feeding produced by FG 7142 (20 mg/kg, IP) and DMCM (1.25 mg/kg, IP) were reversed by either Ro15-1788 (2.5 and 5.0 mg/kg) or midazolam (5.0 and 10.0 mg/kg). A matched anorectic effect produced by CGS 8216 (40 mg/kg) was not, however, reversed by either Ro15-1788 or midazolam. This suggests that at a high dose CGS 8216 may act by a mechanism different from that of the two inverse agonists. The feeding test described in the report proved sensitive to both hyperphagic and anorectic effects of drugs active at benzodiazepine receptors, pointing to a possible bi-directional control of palatable food consumption.

Sonomicrometry: its application as a routine monitoring technique in cardiac surgery.

We utilized ultrasonic-dimension crystals in approximately 50 patients during a three-year period to evaluate clinical sonomicrometry as a routine monitoring tool in patients undergoing cardiac operations. Standard research piezoelectric pulse transit ultrasonic transducers were modified with a hooked attachment in a tethered configuration to facilitate accurate alignment and quick insertion for the measurement of myocardial segment length changes. These segment crystals were used both intraoperatively and postoperatively to evaluate the left ventricular pressure-geometry relationships and to serve as a continuous monitor of myocardial function. The left ventricular pressure-volume relationship was varied by temporarily reapproximating the pericardium (pericardial closure resulted in a 12% reduction in fractional shortening, a 5% decrease in end-diastolic segment length, and an 8% increase in pulmonary artery diastolic pressure). During both the intraoperative and postoperative periods, we found good correlation between thermodilution, stroke volume, and myocardial dimensions; no correlation was noted between pulmonary artery diastolic pressure and stroke volume. No bleeding or major complications resulted from the use of these sonomicrometry transducers. Our initial clinical experience with sonomicrometry seems to support its use as a potentially valuable monitoring tool.