Mild hypothermia during cardiopulmonary bypass assisted CABG is associated with improved short- and long-term survival, a 18-year cohort study.

Data substantiating the optimal patient body temperature during cooling procedures in cardiac operations are currently unavailable. To explore the optimal temperature strategy, we examined the association between temperature management and survival among patients during cardiopulmonary bypass assisted coronary artery bypass grafting (CABG) procedures on 30-days and 5-year postoperative survival. Adult patients (n = 5,672, 23.6% female and mean (SD) age of 66 (10) years) operated between 1997 and 2015 were included, with continuous measured intraoperative nasopharyngeal temperatures. The association between mortality and patient characteristics, laboratory parameters, the lowest intraoperative plateau temperature and intraoperative cooling/rewarming rates were examined by multivariate Cox regression analysis. Machine learning-based cluster analysis was used to identify patient subgroups based on pre-cooling parameters and explore whether specific subgroups benefitted from a particular temperature management. Mild hypothermia (32-35°C) was independently associated with improved 30-days and 5-year survival compared to patients in other temperature categories regardless of operation year. 30 days and 5-year survival were 98% and 88% in the mild hypothermia group, whereas it amounted 93% and 80% in the severe hypothermia (<30°C). Normothermia (35-37°C) showed the lowest survival after 30 days and 5 years amounting 93% and 72%, respectively. Cluster analysis identified 8 distinct patient subgroups principally defined by gender, age, kidney function and weight. The full cohort and all patient subgroups displayed the highest survival at a temperature of 32°C. Given these associations, further prospective randomized controlled trials are needed to ascertain optimal patient temperatures during CPB.

Apoptosis during CABG surgery with the use of cardiopulmonary bypass is prominent in ventricular but not in atrial myocardium.

Objectives. We aimed to compare the rate of apoptosis after cardiopulmonary bypass (CPB) and cardioplegic arrest during coronary artery bypass grafting (CABG) surgery between atrial and ventricular tissue.Methods. During CABG surgery with CPB and cardioplegic arrest, sequential biopsies were taken from the right atrial appendage and left ventricular anterior wall before CPB and after aortic cross clamp release. Change in number of apoptotic cells and biochemical markers of myocardial ischaemia and renal dysfunction were assessed.Results. CPB was associated with a transient small, but significant increase in CK (1091+/-374%), CK-MB (128+/-38%), troponin-T (102+/-13%) and NT-proBNP (1308+/-372%) levels (all: p<0.05). A higher number of apoptotic cells as assessed by caspase-3 staining was found in the ventricular biopsies taken after aortic cross clamp release compared with the biopsies taken before CPB (5.3+/-0.6 vs. 14.0+/-1.5 cells/microscopic field, p<0.01). The number of apoptotic cells in the atrial appendage was not altered during CPB. Correlation between the duration of aortic cross clamp time and the change in caspase-3 positive cells in the left ventricular wall was of borderline significance (r of 0.58, p=0.08). Similar results were obtained from TUNEL staining for apoptosis.Conclusion. CABG surgery with CPB and cardioplegic arrest is associated with an elevated rate of apoptosis in ventricular but not in atrial myocardial tissue. Ventricular tissue may be more sensitive to detect changes than atrial tissue, and may be more useful to investigate the protective effects of therapeutic intervention. (Neth Heart J 2010;18:236-42.).

Blood cell dynamics during hibernation in the European Ground Squirrel.

Hibernation is a unique natural model to study large and specific modulation in numbers of leukocytes and thrombocytes, with potential relevance for medical application. Hibernating animals cycle through cold (torpor) and warm (arousal) phases. Previous research demonstrated clearance of leukocytes and thrombocytes from the circulation during torpor, but did not provide information regarding the timing during torpor or the subtype of leukocytes affected. To study the influence of torpor-bout duration on clearance of circulating cells, we measured blood cell dynamics in the European Ground Squirrel. Numbers of leukocytes and thrombocytes decreased within 24h of torpor by 90% and remained unchanged during the remainder of the torpor-bout. Differential counts demonstrated that granulocytes, lymphocytes and monocytes are all affected by torpor. Although a decreased production might explain the reduced number of thrombocytes, granulocytes and monocytes, this cannot explain the observed lymphopenia since lymphocytes have a much lower turnover rate than thrombocytes, granulocytes and monocytes. In conclusion, although underlying biochemical signaling pathways need to be unraveled, our data show that the leukocyte count drops dramatically after entrance into torpor and that euthermic cell counts are restored within 1.5h after onset of arousal, even before body temperature is fully normalized.

Postoperative renal dysfunction and preoperative left ventricular dysfunction predispose patients to increased long-term mortality after coronary artery bypass graft surgery.

BACKGROUND: Both preoperative left ventricular dysfunction and postoperative renal function deterioration are associated with increased long-term mortality after cardiac surgery. The influence of preoperative left ventricular dysfunction on postoperative renal dysfunction and long-term mortality is not defined. METHODS: We collected data from 641 consecutive patients undergoing coronary bypass surgery with cardiopulmonary bypass in 1991 at our institution. Prospective follow-up was through to July 2004. RESULTS: In-hospital mortality was 2.7% (17 of 641). During follow-up, 248 (40%) patients discharged alive died (5 and 10 yr survival 90% and 70%, respectively). On univariate analysis, preoperative left ventricular dysfunction (ejection fraction <50%) and an increase in serum creatinine > or =25% in the first postoperative week were associated with long-term mortality. The associated mortality risk was additive in predominantly non-overlapping patients groups: the hazard ratio (HR) for renal function deterioration only was 1.41 [95% confidence interval (CI) 0.95-2.32, P=0.083; n=64] and for left ventricular dysfunction only 1.71 (95% CI 1.26-2.95, P=0.0026; n=73). In patients in whom both were present, HR was 3.23 (95% CI 2.52-20.28, P<0.0001; n=20). Although postoperative renal dysfunction was associated with left ventricular dysfunction (P=0.008), both left ventricular dysfunction and postoperative renal function deterioration were independently associated with long-term mortality on multivariate analysis, as were age and the use of venous conduits. CONCLUSIONS: Both postoperative renal function deterioration and preoperative left ventricular dysfunction independently identify largely non-overlapping groups of patients with increased long-term mortality after coronary bypass surgery. In the group of patients with both factors present, the mortality risks appear additive.

Changes in glomerular filtration rate after cardiac surgery with cardiopulmonary bypass in patients with mild preoperative renal dysfunction.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is commonly perceived as a risk factor for decline in renal function, especially in patients with preoperative renal dysfunction. There are few data on the effects of CPB on renal function in patients with mild preoperative renal dysfunction. The purpose of this study was to evaluate renal function in patients with pre-existing mild renal dysfunction undergoing cardiac surgery with CPB. METHODS: In a multicentre study cohort we measured prospectively the glomerular filtration rate (GFR) by radioactive markers both before operation and on the 7th postoperative day in cardiac surgical patients with preoperative serum creatinine >120 micromol l(-1) (n=56). In a subgroup of patients (n=14) in addition to the GFR, the effective renal plasma flow (ERPF) and the filtration fraction (FF) were measured. RESULTS: While preoperative GFR [77.9 (25.5) ml min(-1)] increased to 84.4 (23.7) ml min(-1) (P=0.005) 1 week after surgery, ERPF did not change [295.8 (75.2) ml min(-1) and 295.9 (75.9) ml min(-1), respectively; P=0.8]. In accordance, the FF increased from 0.27 (0.05) (before operation) to 0.30 (0.04) (Day 7, P=0.01). CONCLUSION: Our results oppose the view that cardiac surgery with CPB adversely affects renal function in patients with preoperative mild renal dysfunction and an uncomplicated clinical course.

Effect of dexamethasone on perioperative renal function impairment during cardiac surgery with cardiopulmonary bypass.

BACKGROUND: In cardiac surgery with cardiopulmonary bypass (CPB), corticosteroids are administered to attenuate the physiological changes caused by the systemic inflammatory response. The effects of corticosteroids on CPB-associated renal damage have not been documented. The purpose of this study was to evaluate the effects of dexamethasone on perioperative renal dysfunction in patients undergoing cardiac surgery with CPB. METHODS: Renal damage was prospectively studied in 20 patients without concomitant morbidity undergoing coronary artery surgery with CPB. Patients were randomized in a double-blind fashion to receive dexamethasone or placebo. Markers of glomerular function (creatinine clearance) and damage (microalbuminuria), and markers of tubular function (fractional excretion of sodium and free water clearance) and damage (N-acetyl-beta-D glucosaminidase (NAG)) were evaluated in addition to plasma and urinary glucose levels. Plasma and urinary specimens were obtained at the following time periods: (1) baseline, during the 12 h before surgery; (2) skin incision before heparinization; (3) from heparinization until the end of CPB; (4) during the 2 h following weaning from CPB; (5) in the intensive care unit from 2 to 6 h after weaning of CBP; (6) and from 36 to 60 h after weaning of CPB. RESULTS: CPB was associated with an increase in markers in the placebo group, which returned to baseline during the second postoperative day, demonstrating a transient impairment of glomerular and tubular renal function. Similar patterns were observed in patients treated with dexamethasone. While postoperative glycosuria was significantly higher in the dexamethasone-treated group, no other differences between groups were observed. CONCLUSION: Dexamethasone administration before CPB has no protective effect on perioperative renal dysfunction in low-risk cardiac surgical patients.

Effects of preoperative treatment with diltiazem on diastolic ventricular function after coronary artery bypass graft surgery.

OBJECTIVE: To examine whether preoperative treatment with diltiazem could ameliorate left ventricular (LV) diastolic dysfunction in patients after coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, nonrandomized clinical study. SETTING: University hospital. PARTICIPANTS: Thirty-four patients with preserved LV function undergoing elective CABG surgery. INTERVENTIONS: According to medical history, patients were divided into 2 groups: patients not receiving diltiazem (n = 17) and patients treated with once-daily oral diltiazem for at least 2 weeks (n = 17). All patients received preoperative beta-blockers. MEASUREMENTS AND MAIN RESULTS: After induction of anesthesia, after sternal closure, and 4 hours after cardiopulmonary bypass (CPB), mitral and pulmonary venous flow velocities were measured with pulsed Doppler. LV short-axis end-diastolic area by Doppler transesophageal echocardiography (TEE) and hemodynamic variables were obtained simultaneously at comparable pulmonary capillary wedge pressures. Postoperatively, increased peak E and A velocities were observed in patients with diltiazem and controls and returned to baseline 4 hours post-CPB in controls. Changes in these velocities did not result in a decreased E/A ratio. Peak A velocity, E/A ratio, and E wave deceleration time were significantly dependent on heart rate, not peak E velocity. End-diastolic area at comparable pulmonary capillary wedge pressure remained unchanged. In relation to diltiazem, only peak A velocity and time velocity integral of the A wave (TVI-A) at 4 hours post-CPB differed from controls. CONCLUSION: Diastolic function is preserved after CABG surgery and is not altered by diltiazem in patients with preserved LV systolic function. The persistence of increased peak A velocity and TVI-A into the postoperative period suggests improved atrial systolic function with diltiazem.

Validation of an ultrasound scanner for determing urinary volumes in surgical patients and volunteers.

OBJECTIVE: As bladder distension related to anaesthesia puts patients at risk for permanent dysfunction, peri-operative determination of bladder volume is of great importance. The aim of this study is to validate an ultrasonic imaging device for determing bladder urine volume. METHOD: To evaluate a broad volume range, ultrasonically scanned volumes were compared to true urinary volumes both in surgical patients and in volunteers. After institutional approval and informed consent 60 healthy volunteers were asked not to void for as long as possible. After ultrasound measurements (BladderScan BVI 2500, Diagnostic Ultrasound, Redmond WA, U.S.A.) they voided and true urinary volumes were measured. Fifty surgical patients scheduled for procedures requiring urinary catheterisation were studied. Pre- and post-induction of anaesthesia ultrasound measurements were recorded, followed by urinary catheterisation and measurement of true urinary volume. Urine volumes were compared using Student t-tests and Wilcoxon Rank Tests (p < 0.05). For validation linear regression was used together with Bland-Altman analyses. RESULTS: Ultrasonic scanning underestimated the true urine volume by about 7% over the whole volume range (17 ml to 970 ml). Underestimation was larger in females than in males (p < 0.02). R2 values for correlation of measured and scanned urinary volumes ranged between 0.92 and 0.95. Bland and Altman analyses showed a bias of 31 ml in volunteers and of 19 ml in patients and a precision of 110 ml and 80 ml, respectively. CONCLUSIONS: The ultrasonic imaging device can be used peri-operatively to establish bladder volume, taking into account the 7% underestimation of the bladder volume.

The effect of midazolam at two plasma concentrations of hemodynamics and sufentanil requirement in coronary artery surgery.

OBJECTIVES: In this study, the hemodynamics and sufentanil requirement were compared at two midazolam target plasma concentrations in patients undergoing coronary artery bypass grafting (CABG). DESIGN: Prospective, randomized study. SETTING: University hospital, single institution. PARTICIPANTS: Patients undergoing CABG. INTERVENTIONS: Patients were randomly assigned to receive midazolam at a target plasma concentration of 150 ng/mL (group 1; n = 10) or 300 ng/mL (group 2; n = 10). Sufentanil infusion was titrated to maintain hemodynamic stability, defined as mean arterial pressure within 15% of baseline values. All patients received preoperative beta-blocking agents. Arterial blood samples of midazolam and sufentanil were analyzed by high-performance liquid chromatography and radioimmunoassay, respectively. MEASUREMENTS AND MAIN RESULTS: The mean dose of sufentanil (7.5 +/- 1.7 microgram/kg in group 1 v 7.2 +/- 2.5 micrograms/kg in group 2) did not differ. There were no significant differences in hemodynamics between the groups in the period before or after cardiopulmonary bypass (CPB). Before CPB, in two patients in each group, hypertension was controlled with sufentanil only. One patient in group 1 required a vasodilator in addition to sufentanil. No ischemic events occurred before CPB. After CPB, one patient in group 2 required a vasodilator to control hypertension. Two patients in group 2 required treatment with nitroglycerin for myocardial ischemia. Stable plasma concentrations of sufentanil and midazolam were obtained during and after CPB. The midazolam infusion was continued in both groups at a rate of 1.25 micrograms/kg/min during the first 4 postoperative hours. The time to awakening did not differ between the groups (100 +/- 58 minutes in group 1 v 173 +/- 147 minutes in group 2) nor did the plasma concentrations of midazolam (96 +/- 28 ng/mL v 108 +/- 42 ng/mL) at the time of awakening. Intraoperative awareness was not reported. CONCLUSION: In patients undergoing CABG, good hemodynamic control with a similar incidence of hemodynamic interventions was observed at midazolam target plasma concentrations of 150 and 300 ng/mL when coadministered with sufentanil. The sufentanil requirement was identical in both groups. This study suggests that a midazolam plasma concentration of 150 ng/mL is sufficient to provide satisfactory hemodynamic control and to avoid intraoperative awareness.

Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle.

BACKGROUND: Cardiovascular instability after intravenous induction of anesthesia may be explained partly by direct negative inotropic effects. The direct inotropic influence of etomidate, ketamine, midazolam, propofol, and thiopental on the contractility of isolated human atrial tissue was determined. Effective concentrations were compared with those reported clinically. METHODS: Atrial tissue was obtained from 16 patients undergoing coronary bypass surgery. Each fragment was divided into three strips, and one anesthetic was tested per strip in increasing concentrations (10(-6) to 10(-2) M). Strips were stimulated at 0.5 Hz, and maximum isometric force was measured. Induction agents were studied in two groups, group 1 (n = 7) containing thiopental, midazolam, and propofol, and group 2 (n = 9) consisting of etomidate, ketamine, and propofol. RESULTS: The tested anesthetics caused a concentration-dependent depression of contractility resulting in complete cessation of contractions at the highest concentrations. The IC50s (mean +/- SEM; microM) for inhibition of the contractility were: thiopental 43 +/- 7.6, propofol 235 +/- 48 (group 1), and 246 +/- 42 (group 2), midazolam 145 +/- 54, etomidate 133 +/- 13, and ketamine 303 +/- 54. CONCLUSIONS: This is the first study demonstrating a concentration-dependent negative inotropic effect of intravenous anesthetics in isolated human atrial muscle. No inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong and ketamine showed slight negative inotropic properties. Thus, negative inotropic effects may explain in part the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine cannot be explained by intrinsic cardiac stimulation.

Zonal organization of the flocculovestibular nucleus projection in the rabbit: a combined axonal tracing and acetylcholinesterase histochemical study.

With the use of retrograde transport of horseradish peroxidase we confirmed the observation of Yamamoto and Shimoyama ([1977] Neurosci Lett. 5:279-283) that Purkinje cells of the rabbit flocculus projecting to the medial vestibular nucleus are located in two discrete zones, FZII and FZIV, that alternate with two other Purkinje cell zones, FZI and FZIII, projecting to the superior vestibular nucleus. The retrogradely labeled axons of these Purkinje cells collect in four bundles that occupy the corresponding floccular white matter compartments, FC1-4, that can be delineated with acetylcholinesterase histochemistry (Tan et al. [1995a] J. Comp. Neurol., this issue). Anterograde tracing from small injections of wheat germ agglutin-horseradish peroxidase in single Purkinje cell zones of the flocculus showed that Purkinje cell axons of FZII travel in FC2 to terminate in the medial vestibular nucleus. Purkinje cell axons from FZI and FZIII occupy the FC1 and FC3 compartments, respectively, and terminate in the superior vestibular nucleus. Purkinje cell axons from all three compartments pass through the floccular peduncle and dorsal group y. In addition, some fibers from FZI and FZII, but not from FZIII, arch through the cerebellar nuclei to join the floccular peduncle more medially. No anterograde tracing experiments were available to determine the projections of the FZIV and C2 zones. The functional implications of these results are discussed.

Cerebello-vestibular connections of the anterior vermis. A retrograde tracer study in different mammals including primates.

Purkinje cells were retrogradely labelled from large injections of wheatgerm-coupled horseradish peroxidase in the vestibular nuclei, including Deiters' nucleus. The labelled Purkinje cells were located in two parallel strips in the anterior vermis; the medial strip is located within the A-zone, the lateral strip corresponds to the B-zone. In the ventral part of the anterior lobe the two strips fuse into a single band, in the dorsal part of the anterior lobe they are separated by a wedge-shaped area, corresponding to the X-zone. The B-zone proceeds in the simple lobule, where it deviates laterally and where it terminates at the centre of the ansoparamedian lobule. Identical zonal patterns were observed in cat, rabbit, rat and monkey. The demarcation of the anterior vermis by the lateral border of the B-zone, and the differences in the projection of the A and B-zone are briefly discussed.

Secondary vestibulocerebellar projections to the flocculus and uvulo-nodular lobule of the rabbit: a study using HRP and double fluorescent tracer techniques.

The distribution of vestibular neurons projecting to the flocculus and the nodulus and uvula of the caudal vermis (Larsell's lobules X and IX) was investigated with retrograde axonal transport of horseradish peroxidase and the fluorescent tracers Fast Blue, Nuclear Yellow and Diamindino Yellow. The presence of collateral axons innervating the flocculus on one hand and the nodulus and uvula on the other was studied with simultaneous injection of the different fluorescent racers. The distribution of vestibular neurons projecting to either flocculus or caudal vermis is rather similar and has a bilateral symmetry. The projection from the magnocellular medial vestibular nucleus is very sparse, while that from the lateral vestibular nucleus is absent. The majority of labeled neurons was found in the medial, superior, and descending vestibular nuclei, in that order. Double labeled neurons were distributed in a similar way as the single labeled ones. Labeled neurons project to the nodulus and uvula, the flocculus, and to both parts of the cerebellum simultaneously in a ratio of 12:4:1. Five different populations of vestibulocerebellar neurons can be distinguished on the basis of their projection to the: (1) ipsilateral flocculus, (2) contralateral flocculus, (3) ipsilateral flocculus and nodulus/uvula, (4) contralateral flocculus and nodulus/uvula, and (5) nodulus/uvula.

Secondary vestibulocerebellar mossy fiber projection to the caudal vermis in the rabbit.

The vestibulocerebellar projection in the rabbit has been investigated by the anterograde axonal transport of tritiated leucine, wheat germ-agglutinated horseradish peroxidase, and Phaseolus vulgaris leucoagglutinin. Mossy fiber terminals originating from all vestibular nuclei, with the exception of the lateral vestibular nucleus of Deiters, were found bilaterally in the lobules X, IX, and VIII of the caudal vermis, without a clear difference in laterality. Most of the vestibular mossy fiber terminals in the caudal vermis originated in the superior and caudal medial vestibular nuclei. Application of the different tracers led to similar results. The labeled terminals were always most numerous in the lobules X and IXd. Small to moderate numbers of mossy fiber terminals were found in the lobules IXa, b, c, and lobule VIII. The greatest change in the density of terminals occurred in most cases around the apex of lobule IXd and not in the depth of the posterolateral fissure between lobules X and IX. The mossy fiber terminals were not distributed equally over the cortex but showed a preference for the proximal parts of the individual lobules. In all experiments, the terminals exhibited a certain degree of clustering in the mediolateral direction, but the clusters were not arranged in longitudinal zones continuous over successive folia.

The primary vestibulocerebellar projection in the rabbit: absence of primary afferents in the flocculus.

The central projection of vestibular nerve fibers was investigated with anterograde axonal transport of wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine following injection in the vestibular ganglion. Labeled fibers and terminal ramifications were observed throughout the vestibular complex, but absent from the lateral vestibular nucleus. Termination in the cortex was restricted to the vermis. Small numbers of mossy fiber terminals were present bilaterally, close to the midline in lobules I and II, and in the depth of the main fissures separating lobules II-VI. In the posterior vermis labeled mossy fiber terminals were found in lobule X and the ventral aspect of lobule IXd. Here, the entire ipsilateral hemivermis contained a large number of terminals, while contralaterally the medial one-third hemivermis contained fewer terminals. Labeled mossy fibers and terminals were absent in the flocculus and adjacent ventral paraflocculus.

Commissural and intrinsic connections of the vestibular nuclei in the rabbit: a retrograde labeling study.

The intrinsic and commissural projection of the vestibular nuclei were investigated by means of retrograde transport of normal (HRP) and wheat-germ-agglutinated horseradish peroxidase (WGA-HRP). It was found that within each vestibular complex, the superior (SV), medial (MV) and descending (DV) vestibular nuclei are reciprocally connected. A rostrocaudally oriented column of medium-sized and large neurons, comprising the central SV and the magnocellular MV (MVmc) receives input from the surrounding neurons and does not reciprocate this projection. Efferents from group y terminate in the SV, MV and DV. The infracerebellar nucleus (INF) as well as the interstitial nucleus of the VIIIthe nerve (IN) supply fibers to the MV and DV. The neurons that participate in the commissural projection are distributed throughout the vestibular complex with the exception of the lateral vestibular nucleus (LV) and the group x. The largest number of cells was found in the MV. The HRP labeled cells show a tendency to cluster into rostrocaudally oriented groups. Each nucleus projects to more than one contralateral nucleus. Group y shows a more extensive contralateral projection than the bordering INF. It was concluded that quantitative differences in connectivity were present between a core region in the vestibular complex and peripheral parts. This core region comprises the central SV, the LV, the MVmc and extends into the rostral DV. It receives predominantly intrinsic input from the surrounding vestibular neurons and is in contrast to these latter neurons only minimally involved in the commissural projection.

Reciprocal connections between the caudal vermis and the vestibular nuclei in the rabbit.

The termination of secondary vestibulocerebellar mossy fibers and the localization of Purkinje cells giving rise to corticovestibular projections were visualized simultaneously in lobules IX and X after injections of wheat germ agglutinin-horseradish peroxidase in the vestibular nuclei of the rabbit. Vestibulocerebellar mossy fibers from the medial, descending and superior vestibular nuclei terminate in longitudinal strips in the granular layer, which coincide exactly with the localization of the labeled Purkinje cells.