Anne H. Epema

Immediate Postoperative Renal Function Deterioration in Cardiac Surgical Patients Predicts In-Hospital Mortality and Long-Term Survival

Postoperative renal function deterioration is a serious complication after cardiac surgery with cardiopulmonary bypass and is associated with increased in-hospital mortality. However, the long-term prognosis of patients with postoperative renal deterioration is not fully determined yet. Therefore, both in-hospital mortality and long-term survival were studied in patients with postoperative renal function deterioration. Included were 843 patients who underwent cardiac surgery with cardiopulmonary bypass in 1991. Postoperative renal function deterioration (increase in serum creatinine in the first postoperative week of at least 25%) occurred in 145 (17.2%) patients. In these patients, in-hospital mortality was 14.5%, versus 1.1% in patients without renal function deterioration (P < 0.001). Multivariate analysis significantly associated in-hospital mortality with postoperative renal function deterioration, re-exploration, postoperative cerebral stroke, duration of operation, age, and diabetes. In patients who were discharged alive, during long-term follow-up (100 mo), mortality was significantly increased in the patients with renal function deterioration (n = 124) as compared with those without renal function deterioration (hazard ratio 1.83; 95% confidence interval 1.38 to 3.20). Also after adjustment for other independently associated factors, the risk for mortality in patients with postoperative renal function deterioration remained elevated (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32). The elevated risk for long-term mortality was independent of whether renal function had recovered at discharge from hospital. It is concluded that postoperative renal function deterioration in cardiac surgical patients not only results in increased in-hospital mortality but also adversely affects long-term survival.

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 sup -6 to 10 sup -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 IC50 S (mean +/-SEM; micro Meter) 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.

Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate

Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism (‘torpor’) with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2–10 °C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1-phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P1), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at ∼8 °C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4 °C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at ± 25 °C), during forced hypothermia in anesthetized (summer-active) hamsters (at ± 9 °C), and in a nonhibernator (rat at ∼19 °C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients.

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, perioperative 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.

Clinical Effectiveness of Centrifugal Pump to Produce Pulsatile Flow During Cardiopulmonary Bypass in Patients Undergoing Cardiac Surgery

Although the centrifugal pump has been widely used as a nonpulsatile pump for cardiopulmonary bypass (CPB), little is known about its performance as a pulsatile pump for CPB, especially on its efficacy in producing hemodynamic energy and its clinical effectiveness. We performed a study to evaluate whether the Rotaflow centrifugal pump produces effective pulsatile flow during CPB and whether the pulsatile flow in this setting is clinically effective in adult patients undergoing cardiac surgery. Thirty-two patients undergoing CPB for elective coronary artery bypass grafting were randomly allocated to a pulsatile perfusion group (n = 16) or a nonpulsatile perfusion group (n = 16). All patients were perfused with the Rotaflow centrifugal pump. In the pulsatile group, the centrifugal pump was adjusted to the pulsatile mode (60 cycles/min) during aortic cross-clamping, whereas in the nonpulsatile group, the pump was kept in its nonpulsatile mode during the same period of time. Compared with the nonpulsatile group, the pulsatile group had a higher pulse pressure (P < 0.01) and a fraction higher energy equivalent pressure (EEP, P = 0.058). The net gain of pulsatile flow, represented by the surplus hemodynamic energy (SHE), was found much higher in the CPB circuit than in patients (P < 0.01). Clinically, there was no difference between the pulsatile and nonpulsatile groups with regard to postoperative acute kidney injury, endothelial activation, or inflammatory response. Postoperative organ function and the duration of hospital stay were similar in the two patient groups. In conclusion, pulsatile CPB with the Rotaflow centrifugal pump is associated with a small gain of EEP and SHE, which does not seem to be clinically effective in adult cardiac surgical patients.

The effect of midazolam at two plasma concentrations on 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.

Adjunct Nitrous Oxide Normalizes Vascular Reactivity Changes after Hemorrhagic Shock in Mice under Isoflurane Anesthesia

Background:Hemorrhagic shock is associated with changes in vascular responsiveness that may lead to organ dysfunction and, ultimately, multiple organ dysfunction syndrome. Volatile anesthetics interfere with vasoresponsiveness, which may contribute to organ hypoperfusion. In this study, the authors examined the influence of adjunct nitrous oxide on the vascular responsiveness after short-term hemorrhagic shock under isoflurane anesthesia. Methods:Spontaneously breathing mice (n = 31, 27.6 ± 0.31 g) were anesthetized with isoflurane (1.4%) or with isoflurane (1.4%) and adjunct nitrous oxide (66%). Both groups were divided into Sham, Shock, and Resuscitated groups. Vascular reactivity to phenylephrine and acetylcholine and expression of cyclooxygenases were studied in the aorta. Results:In the isoflurane-anesthetized groups, the contractile response to phenylephrine was increased in the Shock as compared with the Sham and Resuscitated groups (Emax = 3.2 ± 0.4, 1.2 ± 0.4, and 2.5 ± 0.5 mN, respectively). Adjunct nitrous oxide increased phenylephrine contraction to a similar level in all three groups. In the Sham isoflurane group, acetylcholine caused a biphasic response: An initial relaxation followed by a contractile response sensitive to cyclooxygenases inhibition by indomethacine. The contractile response was abrogated in the isoflurane-anesthetized groups that underwent shock. In all groups, adjunct nitrous oxide preserved the contractile phase. Shock induced a down-regulation of cyclooxygenases-1, which was normalized by adjunct nitrous oxide. Conclusion:Adjunct nitrous oxide attenuates shock-induced changes in vascular reactivity and cyclooxygenases expression of mice under isoflurane anesthesia. This implies that vascular reactive properties during anesthesia in hemorrhagic shock conditions may be influenced by the choice of anesthetics.

Dopamine treatment attenuates acute kidney injury in a rat model of deep hypothermia and rewarming – The role of renal H2S-producing enzymes

Hypothermia and rewarming produces organ injury through the production of reactive oxygen species. We previously found that dopamine prevents hypothermia and rewarming-induced apoptosis in cultured cells through increased expression of the H2S-producing enzyme cystathionine β-Synthase (CBS). Here, we investigate whether dopamine protects the kidney in deep body cooling and explore the role of H2S-producing enzymes in an in vivo rat model of deep hypothermia and rewarming. In anesthetized Wistar rats, body temperature was decreased to 15°C for 3h, followed by rewarming for 1h. Rats (n≥5 per group) were treated throughout the procedure with vehicle or dopamine infusion, and in the presence or absence of a non-specific inhibitor of H2S-producing enzymes, amino-oxyacetic acid (AOAA). Kidney damage and renal expression of three H2S-producing enzymes (CBS, CSE and 3-MST) was quantified and serum H2S level measured. Hypothermia and rewarming induced renal damage, evidenced by increased serum creatinine, renal reactive oxygen species production, KIM-1 expression and influx of immune cells, which was accompanied by substantially lowered renal expression of CBS, CSE, and 3-MST and lowered serum H2S levels. Infusion of dopamine fully attenuated renal damage and maintained expression of H2S-producing enzymes, while normalizing serum H2S. AOAA further decreased the expression of H2S-producing enzymes and serum H2S level, and aggravated renal damage. Hence, dopamine preserves renal integrity during deep hypothermia and rewarming likely by maintaining the expression of renal H2S-producing enzymes and serum H2S.

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.

Normalization of aortic function during arousal episodes in the hibernating ground squirrel

Hypothermia is commonly used to restrict organ damage during preservation of tissue, but does not offer complete protection. Organ damage after reperfusion/rewarming is amongst others caused by an impairment of vascular properties, particularly endothelium-dependent vasodilatation. We hypothesized that hibernating small animals, which frequently cycle through periods of deep cooling (torpor) and full rewarming (arousal), employ specific mechanisms to preserve vascular function after cooling and reperfusion. Therefore we measured contraction of aortic tissue of hibernating European ground squirrels after 24 h and 7 days of torpor, arousal (1.5 h) and in non-hibernating animals. To assess the role of nitric oxide (NO), experiments were performed in the absence and presence of the NO-synthesis inhibitor, L-NMMA (10(-4) M). Maximum contraction to phenylephrine and angiotensin II was doubled in 7-days torpid animals without a shift in EC50, compared to the other 3 groups. Maximum contraction to KCl was doubled in 7-days torpid animals compared to the arousal group and non-hibernating animals. Relaxation to acetylcholine (ACh) and sodium nitrite in phenylephrine precontracted rings did not differ between groups. In the presence of L-NMMA, the maximum of concentration-response curves for all three vasoconstrictors was increased by about 30% in the arousal group, but unaffected in other groups. L-NMMA completely inhibited ACh-induced relaxation in 24-h torpid animals and non-hibernating animals, but only partially in 7-days torpid animals and in the arousal group. From this we conclude that vascular adaptation proceeds during torpor. Further, increased contractility of aortic tissue during long torpor returns to normal within 1.5 hours of arousal, which is associated with an increased basal NO synthesis. In addition, involvement of NO in agonist-mediated relaxation differs between the various stages of hibernation.Thus, hibernating animals have effectively developed mechanisms to preserve vascular function after cooling and rewarming.