Matthias Heringlake

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery

BACKGROUND Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. METHODS We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. RESULTS A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. CONCLUSIONS Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).

Preoperative Cerebral Oxygen Saturation and Clinical Outcomes in Cardiac Surgery

Background: The current study was designed to determine the relation between preoperative cerebral oxygen saturation (Sco2), variables of cardiopulmonary function, mortality, and morbidity in a heterogeneous cohort of cardiac surgery patients. Methods: In this study, 1,178 consecutive patients scheduled for on-pump surgery were prospectively studied. Preoperative Sco2, demographics, N-terminal pro-B-type natriuretic peptide, high-sensitive troponin T, clinical outcomes, and 30-day and 1-yr mortality were recorded. Results: Median additive EuroSCORE was 5 (range: 0–19). Thirty-day and 1-yr mortality and major morbidity (at least two major complications and/or a high-dependency unit stay of at least 10 days) were 3.5%, 7.7%, and 13.3%, respectively. Median minimal preoperative oxygen supplemented Sco2 (Sco2min-ox) was 64% (range: 15–92%). Sco2min-ox was correlated (all: P value <0.0001) with N-terminal pro-B-type natriuretic peptide (&rgr;: −0.35), high-sensitive troponin T (&rgr;: −0.28), hematocrit (&rgr;: 0.34), glomerular filtration rate (&rgr;: 0.19), EuroSCORE (&tgr;: 0.20), and left ventricular ejection fraction class (&tgr;: 0.12). Thirty-day nonsurvivors had a lower Sco2min-ox than survivors (median 58% [95% CI, 50.7–62%] vs. 64% [95% CI, 64–65%]; P < 0.0001). Receiver-operating curve analysis of Sco2min-ox and 30-day mortality revealed an area-under-the-curve of 0.71 (95% CI, 0.68–0.73%; P < 0.0001) in the total cohort and an area-under-the-curve of 0.77 (95% CI, 0.69–0.86%; P < 0.0001) in patients with a EuroSCORE more than 10. Logistic regression based on different EuroSCORE categories (0–2; 3–5, 6–10, >10), Sco2min-ox, and duration of cardiopulmonary bypass showed that a Sco2min-ox equal or less than 50% is an independent risk factor for 30-day and 1-yr mortality. Conclusions: Preoperative Sco2 levels are reflective of the severity of cardiopulmonary dysfunction, associated with short- and long-term mortality and morbidity, and may add to preoperative risk stratification in patients undergoing cardiac surgery.

Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery: a randomized controlled trial

BACKGROUND Cognitive dysfunction is a frequent complication after cardiac surgery and has been found to be associated with decreases in cerebral oxygen saturation measured with near-infrared spectroscopy. Sevoflurane has neuroprotective properties in vitro and in animal models. This study was designed to determine cognitive and clinical outcomes after sevoflurane- compared with propofol-based anaesthesia for on-pump cardiac surgery and the impact of decreases in under different anaesthesia regimens. METHODS One hundred and twenty-eight patients were randomly assigned to either i.v. anaesthesia with propofol- (PROP) or sevoflurane-based anaesthesia (SEVO). An intraoperative was defined as desaturation. The Abbreviated Mental Test, Stroop Test, Trail-Making Test, Word Lists, and mood-assessment tests were performed before, 2, 4, and 6 days after cardiac surgery. Markers of general outcome were obtained. RESULTS The analysis groups had differences in baseline cognitive performance. Analysis of variance for repeated measures (incorporating covariance of baseline scores) showed that in three of four cognitive tests, patients with cerebral desaturation showed worse results than patients without desaturation. Patients assigned to sevoflurane-based anaesthesia showed better results in all cognitive tests than patients after propofol. Interactions between the anaesthetic regimen and desaturation were found in all four cognitive tests. There were no differences in markers of organ dysfunction or general clinical outcome. CONCLUSIONS Patients with impaired cognitive performance before operation may be at particular risk for intraoperative cerebral insult. A sevoflurane-based anaesthesia was associated with better short-term postoperative cognitive performance than propofol.

Preoperative regional cerebral oxygen saturation is a predictor of postoperative delirium in on-pump cardiac surgery patients: a prospective observational trial

IntroductionPostoperative delirium is an important problem in patients undergoing major surgery. Cerebral oximetry is a non-invasive method to detect imbalances in the cerebral oxygen supply/demand-ratio. Low preoperative cerebral oxygen saturation (ScO2) levels have been associated with postoperative delirium in non-cardiac surgery patients. The present prospective observational study determines the relationship between pre- and intra-operative ScO2 levels and postoperative delirium in patients undergoing on-pump cardiac surgery.MethodsAfter approval of the local ethical committee and written informed consent, N = 231 patients scheduled for elective/urgent cardiac surgery were enrolled. Delirium was assessed by the confusion-assessment-method for the intensive care unit (CAM-ICU) on the first three days after surgery. ScO2 was obtained on the day before surgery, immediately before surgery and throughout the surgical procedure. Preoperative cognitive function, demographic, surgery related, and intra- and post-operative physiological data were registered.ResultsPatients with delirium had lower pre- and intra-operative ScO2 readings, were older, had lower mini-mental-status-examination(MMSE) scores, higher additive EuroScore and lower preoperative haemoglobin-levels. The binary logistic regression identified older age, lower MMSE, neurological or psychiatric disease and lower preoperative ScO2 as independent predictors of postoperative delirium.ConclusionsThe presented study shows that a low preoperative ScO2 is associated with postoperative delirium after on-pump cardiac surgery.

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery

BACKGROUND Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS In a multicenter, randomized, placebo‐controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four‐component composite of death through day 30, renal‐replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two‐component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention‐to‐treat population. The four‐component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two‐component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS Prophylactic levosimendan did not result in a rate of the short‐term composite end point of death, renal‐replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO‐CTS ClinicalTrials.gov number, NCT02025621.)

The relationship between urotensin II plasma immunoreactivity and left ventricular filling pressures in coronary artery disease

The role of urotensin II (U-II)--a vasoactive, mitogenic, and inotropic, peptide--in the pathophysiology of heart failure is controversial. The present study explores the relationship between plasma U-II immunoreactivity (U-IIIR) and hemodynamics in patients with coronary artery disease (CAD). Thirty-six patients with CAD-3 undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) and 36 medical patients (MED group) with CAD-1 to CAD-3 during right heart catheterization were studied. Significant correlations were observed between pulmonary capillary wedge pressure (PCWP) and U-IIIR--determined by enzyme immunoassay (EIA)--before (rho = 0.83) and after (rho = 0.6) cardiopulmonary bypass in the CABG group. With the exception of the CPB period, CABG patients with increased PCWP before CPB had higher U-II(IR) concentrations throughout the procedure. Significant correlations were observed between U-IIIR, proANP, proBNP, and mean right ventricular pressure (RVPM) in MED patients. No correlation was detectable between U-IIIR and PCWP. However, MED patients with CAD-3 (n = 13) had higher levels of U-IIIR, NTproANPIR (RIA), NTproBNPIR (EIA) and higher cardiac filling pressures than patients with CAD-1 (n = 13). These findings support an association between plasma U-IIIR levels and diastolic myocardial dysfunction in ischemic heart failure. The discrepancies regarding left and right cardiac filling pressures and U-IIIR levels in CABG and MED patients require further evaluation.

Choice of hospital after out-of-hospital cardiac arrest - a decision with far-reaching consequences: a study in a large German city

IntroductionBetween 1 and 31% of patients suffering out-of-hospital cardiac arrest (OHCA) survive to discharge from hospital. International studies have shown that the level of care provided by the admitting hospital determines survival for patients suffering from OHCA. These data may only be partially transferable to the German medical system where responders are in-field emergency medical physicians. The present study determines the influence of the emergency physicians choice of admitting hospital on patient outcome after OHCA in a large urban setting.MethodsAll data for patients collected in the German Resuscitation Registry for the city of Dortmund during 2007 and 2008 were analyzed. Patients under 18 years of age, with traumatic mechanism, and with incomplete charts were excluded. Admitting hospitals were divided into two groups: those without the capability for percutaneous coronary intervention (PCI), and those with PCI capability. Data were analyzed by multivariate statistics, taking into account the effects of mild therapeutic hypothermia treatment and PCI capability of the admitting hospital with respect to the neurological status upon hospital discharge.ResultsBetween 2007 and 2008 a total of 1,109 cardiopulmonary resuscitation attempts were registered for the city of Dortmund, of which 889 could be included in our study. Return of spontaneous circulation was achieved in 360 of 889 patients (40.5%). In total, 282 of 889 patients displayed return of spontaneous circulation during transport to the hospital (31.7%); 152 were transported with ongoing cardiopulmonary resuscitation (17.1%). Of the total 434 patients admitted to hospital, 264 were admitted to hospitals without PCI capability and 170 to hospitals with PCI capability. Multivariate analysis demonstrated a significant influence on patient discharge with good neurological status for those admitted to PCI hospitals (odds ratio 3.14 (95% confidence interval 1.51 to 6.56)), independent of receiving mild therapeutic hypothermia and/or PCI. Compared with patients admitted to hospitals without PCI capability, significantly more patients in PCI hospitals were discharged alive (41% vs. 13%, P < 0.001) and remained alive 1 year after the event (28% vs. 6%, P < 0.001).ConclusionsThe choice of admitting hospital for patients suffering OHCA significantly influences treatment and outcome. This influence is independent of PCI performance and of mild therapeutic hypothermia. Further analysis is required to determine the possible parameters determining patient outcome.

Variations in arterial blood pressure are associated with parallel changes in FlowTrac/Vigileo-derived cardiac output measurements: a prospective comparison study.

IntroductionThe reliability of autocalibrated pressure waveform analysis by the FloTrac-Vigileo® (FTV) system for the determination of cardiac output in comparison with intermittent pulmonary arterial thermodilution (IPATD) is controversial. The present prospective comparison study was designed to determine the effects of variations in arterial blood pressure on the reliability of the FTV system in patients undergoing coronary artery bypass grafting (CABG).MethodsComparative measurements of cardiac output by FTV (derived from a femoral arterial line; software version 1.14) and IPATD were performed in 16 patients undergoing elective CABG in the period before institution of cardiopulmonary bypass. Measurements were performed after induction of anesthesia, after sternotomy, and during five time points during graft preparation. During graft preparation, arterial blood pressure was increased stepwise in intervals of 10 to 15 minutes by infusion of noradrenaline and lowered thereafter to baseline levels.ResultsMean arterial blood pressure was varied between 85 mmHg and 115 mmHg. IPATD cardiac output did not show significant changes during periods with increased arterial pressure either during sternotomy or after pharmacological manipulation. In contrast, FTV cardiac output paralleled changes in arterial blood pressure; i.e. increased significantly if blood pressure was raised and decreased upon return to baseline levels. Mean arterial blood pressure (MAP) and FTV cardiac output were closely correlated (r = 0.63 (95% confidence interval [CI]: 0.49 - 0.74), P < 0.0001) while no correlation between MAP and IPATD cardiac output was observed. Bland-Altman analyses for FTV versus IPATD cardiac output measurements revealed a bias of 0.4 l/min (8.5%) and limits of agreement from 2.1 to -1.3 l/min (42.2 to -25.3%).ConclusionsAcute variations in arterial blood pressure alter the reliability of the FlowTrac/Vigileo® device with the second-generation software. This finding may help to explain the variable results of studies comparing the FTV system with other cardiac output monitoring techniques, questions the usefulness of this device for hemodynamic monitoring of patients undergoing rapid changes in arterial blood pressure, and should be kept in mind when using vasopressors during FTV-guided hemodynamic optimization.

The metabolic and renal effects of adrenaline and milrinone in patients with myocardial dysfunction after coronary artery bypass grafting

IntroductionMyocardial dysfunction necessitating inotropic support is a typical complication after on-pump cardiac surgery. This prospective, randomized pilot study analyzes the metabolic and renal effects of the inotropes adrenaline and milrinone in patients needing inotropic support after coronary artery bypass grafting (CABG).MethodsDuring an 18-month period, 251 patients were screened for low cardiac output upon intensive care unit (ICU) admission after elective, isolated CABG surgery. Patients presenting with a cardiac index (CI) of less than 2.2 liters/minute per square meter upon ICU admission – despite adequate mean arterial (titrated with noradrenaline or sodium nitroprusside) and filling pressures – were randomly assigned to 14-hour treatment with adrenaline (n = 7) or milrinone (n = 11) to achieve a CI of greater than 3.0 liters/minute per square meter. Twenty patients not needing inotropes served as controls. Hemodynamics, plasma lactate, pyruvate, glucose, acid-base status, insulin requirements, the urinary excretion of alpha-1-microglobuline, and creatinine clearance were determined during the treatment period, and cystatin-C levels were determined up to 48 hours after surgery (follow-up period).ResultsAfter two to four hours after ICU admission, the target CI was achieved in both intervention groups and maintained during the observation period. Plasma lactate, pyruvate, the lactate/pyruvate ratio, plasma glucose, and insulin doses were higher (p < 0.05) in the adrenaline-treated patients than during milrinone or control conditions. The urinary excretion of alpha-1-microglobuline was higher in the adrenaline than in the control group 6 to 14 hours after admission (p < 0.05). No between-group differences were observed in creatinine clearance, whereas plasma cystatin-C levels were significantly higher in the adrenaline than in the milrinone or the control group after 48 hours (p < 0.05).ConclusionThis suggests that the use of adrenaline for the treatment of postoperative myocardial dysfunction – in contrast to treatment with the PDE-III inhibitor milrinone – is associated with unwarranted metabolic and renal effects.Clinical trials registration: ClinicalTrials.gov NCT00446017.

Lack of agreement between pulmonary arterial thermodilution cardiac output and the pressure recording analytical method in postoperative cardiac surgery patients

BACKGROUND Pulse-contour analysis method (PCM) cardiac output (CO) monitors are increasingly used for CO monitoring during anaesthesia and in the critically ill. Very recently, several systems have been introduced that do not need calibration; among them the pressure recording analytical method (PRAM). Sparse data comparing the accuracy of the PRAM-CO with conventional thermodilution CO (ThD-CO) in cardiac surgery patients are available. METHODS In this prospective comparison study, paired CO measurements with a pulmonary artery catheter and a PRAM monitoring set were obtained 20-30 min apart (t1, t2) in 23 extubated patients on the first postoperative day after cardiac surgery. Data were analysed by the Bland-Altman method. RESULTS A total of 46 paired CO measurements (23 for each interval) were collected. The Bland-Altman analysis showed a mean difference (bias) of 0.0 litre min(-1) and limits of agreement (1.96 sd) of 4.53 to -4.54 litre min(-1) [upper 95% confidence interval (CI), 3.26-5.80; lower 95% CI, -5.8 to -3.27]. The percentage error (1.96 sd/mean of the reference method) was 87%. CONCLUSIONS These results question the reliability of the PRAM technology for the determination of CO in postoperative cardiac surgery patients.