Twelve years of circulatory extracorporeal life support at the University Medical Centre Utrecht.

INTRODUCTION: Circulatory extracorporeal life support (ECLS) has been performed at the University Medical Centre Utrecht for 12 years. During this time, case mix, indications, ECLS set-ups and outcomes seem to have substantially changed. We set out to describe these characteristics and their evolution over time. METHODS: All patients receiving circulatory ECLS between 2007 and 2018 were retrospectively identified and divided into six groups according to a 2-year period of time corresponding to the date of ECLS initiation. General characteristics plus data pertaining to comorbidities, indications and technical details of ECLS commencement as well as in-hospital, 30-day, 1­year and overall mortality were collected. Temporal trends in these characteristics were examined. RESULTS: A total of 347 circulatory ECLS runs were performed in 289 patients. The number of patients and ECLS runs increased from 8 till a maximum of 40 runs a year. The distribution of circulatory ECLS indications shifted from predominantly postcardiotomy to a wider set of indications. The proportion of peripheral insertions with or without application of left ventricular unloading techniques substantially increased, while in-hospital, 30-day, 1­year and overall mortality decreased over time. CONCLUSION: Circulatory ECLS was increasingly applied at the University Medical Centre Utrecht. Over time, indications as well as treatment goals broadened, and cannulation techniques shifted from central to mainly peripheral approaches. Meanwhile, weaning success increased and mortality rates diminished.

The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study.

PURPOSE: This prospective, observational population-based cohort study was performed to determine overall survival (OS) in multiple myeloma (MM) patients in Friesland, the Netherlands, in the era of novel agents and to analyse the influence of first-line treatment, MM-related end-organ damage and comorbidities at initial presentation on OS. METHODS: Detailed clinical information was obtained from the population-based registry 'HemoBase' during the period January 2005 to January 2013, with a follow-up to January 2014. RESULTS: Overall, the symptomatic MM patients (n = 225) had a median OS of 40 months. In the age categories <65, 65-75 and ≥75 years, 99, 94 and 87% of the patients received treatment, with a median OS of 92, 42 and 31 months, respectively. OS for patients with or without treatment was 43 and 3 months, respectively. In multivariable analysis, risk factors for worse OS were increasing age (<65: reference; 65-75: HRadj. = 2.2 (95% CI 1.3-3.7) and ≥75: HRadj. = 2.8 (95% CI 1.7-4.8); P < 0.001), not receiving initial treatment (HRadj. = 4.0 (95% CI 2.1-7.7); P < 0.001), hypercalcaemia (P < 0.001, HRadj. = 1.7 (95% CI 1.2-2.6), P = 0.006) and impaired renal function (HRadj. = 2.6 (95% CI 1.7-4.0); P < 0.001). CONCLUSIONS: Increasing age, not receiving initial treatment, hypercalcaemia and impaired renal function at initial presentation were independent risk factors for worse OS. Comorbidity according to Charlson comorbidity index score was not an independent variable predicting OS.

Methodology of method comparison studies evaluating the validity of cardiac output monitors: a stepwise approach and checklist.

The validity of each new cardiac output (CO) monitor should be established before implementation in clinical practice. For this purpose, method comparison studies investigate the accuracy and precision against a reference technique. With the emergence of continuous CO monitors, the ability to detect changes in CO, in addition to its absolute value, has gained interest. Therefore, method comparison studies increasingly include assessment of trending ability in the data analysis. A number of methodological challenges arise in method comparison research with respect to the application of Bland-Altman and trending analysis. Failure to face these methodological challenges will lead to misinterpretation and erroneous conclusions. We therefore review the basic principles and pitfalls of Bland-Altman analysis in method comparison studies concerning new CO monitors. In addition, the concept of clinical concordance is introduced to evaluate trending ability from a clinical perspective. The primary scope of this review is to provide a complete overview of the pitfalls in CO method comparison research, whereas other publications focused on a single aspect of the study design or data analysis. This leads to a stepwise approach and checklist for a complete data analysis and data representation.

Diagnostic accuracy of stroke volume variation measured with uncalibrated arterial waveform analysis for the prediction of fluid responsiveness in patients with impaired left ventricular function: a prospective, observational study.

Uncalibrated arterial waveform analysis enables dynamic preload assessment in a minimally invasive fashion. Evidence about the validity of the technique in patients with impaired left ventricular function is scarce, while adequate cardiac preload assessment would be of great value in these patients. The aim of this study was to investigate the diagnostic accuracy of stroke volume variation (SVV) measured with the FloTrac/Vigileo™ system in patients with impaired left ventricular function. In this prospective, observational study, 22 patients with a left ventricular ejection fraction of 40 % or less undergoing elective coronary artery bypass grafting were included. Patients were considered fluid responsive if cardiac output increased with 15 % or more after volume loading (7 ml kg(-1) ideal body weight). The following variables were calculated: area under the receiver operating characteristics (ROC) curve, ideal cut-off value for SVV, sensitivity, specificity, positive and negative predictive values, and overall accuracy. In addition, SVV cut-off points to obtain 90 % true positive and 90 % true negative predictions were determined. ROC analysis revealed an area under the curve of 0.70 [0.47; 0.92]. The ideal SVV cut-off value was 10 %, with a corresponding sensitivity and specificity of 56 and 69 % respectively. Overall accuracy was 64 %, positive and negative predictive values were 69 and 56 % respectively. SVV values to obtain more than 90 % true positive and negative predictions were 16 and 6 % respectively. The ability of uncalibrated arterial waveform analysis SVV to predict fluid responsiveness in patients with impaired LVF was low.

The effects of intraoperative dexamethasone on left atrial function and postoperative atrial fibrillation in cardiac surgical patients.

Postoperative new-onset atrial fibrillation (PNAF) is very common after cardiac surgery and postoperative inflammation may contribute to PNAF by inducing atrial dysfunction. Corticosteroids reduce inflammation and may thus reduce atrial dysfunction and PNAF development. This study aimed to determine whether dexamethasone protects against left atrial dysfunction and PNAF in cardiac surgical patients. Cardiac surgical patients were randomised to a single dose of dexamethasone (1 mg.kg(-1)) or placebo after inducing anaesthesia. Transoesophageal echocardiography was performed in patients before and after surgery. Primary outcome was left atrial total ejection fraction (LA-TEF) after sternal closure; secondary outcomes included left atrial diameter and PNAF. 62 patients were included. Baseline characteristics were well balanced. Postoperative LA-TEF was 36.4 % in the dexamethasone group and 40.2 % in the placebo group (difference -3.8 %; 95 % confidence interval (CI) -9.0 to 1.4 %; P = 0.15). Postoperative left atrial diameter was 4.6 and 4.3 cm, respectively (difference 0.3; 95 % CI -0.2 to 0.7; P = 0.19). The incidence of PNAF was 30 % in the dexamethasone group and 39 % in the placebo group (P = 0.47). Intraoperative high-dose dexamethasone did not protect against postoperative left atrial dysfunction and did not reduce the risk of PNAF in cardiac surgical patients.

Diagnostic accuracy of modified transoesophageal echocardiography for pre-incision assessment of aortic atherosclerosis in cardiac surgery patients.

BACKGROUND: Epiaortic ultrasound scanning (EUS) is regarded as the reference standard for detecting atherosclerosis in the ascending aorta (AA). Combined with appropriate surgical modifications, EUS use can significantly reduce the incidence of postoperative stroke when detecting severe AA atherosclerosis. A recently introduced modification of conventional transoesophageal echocardiography (TOE), known as the A-View method, has proven capable of inspecting the distal AA. The objective of this study was to quantify the diagnostic accuracy of modified TOE in assessing atherosclerosis of the distal AA. METHODS: After approval by the institutional medical ethical committee and after obtaining written informed consent, 465 consecutive patients above 65 yr old, undergoing elective cardiac surgery with a median sternotomy, were included. The study followed a cross-sectional diagnostic design. All consecutive patients underwent modified TOE followed by EUS (reference standard) to assess the severity of distal AA atherosclerosis. We constructed contingency tables to compare the presence (and severity) of atherosclerosis, detected by the two techniques. RESULTS: The positive predictive value of modified TOE for the detection of clinically significant atherosclerosis was 67%, and the negative predictive value was 97%. The sensitivity was 95% and the specificity was 79%. One patient suffered a pulmonary haemorrhage, although he recovered without further sequelae. We did not observe any clinical significant haemodynamic or ventilatory effects. CONCLUSIONS: The high negative predictive value and sensitivity show that modified TOE yields adequate diagnostic accuracy for excluding clinically relevant aorta atherosclerosis without significant cardiopulmonary side-effects, provided that the A-View catheter is introduced carefully.

Inhaled iloprost to control pulmonary artery hypertension in patients undergoing mitral valve surgery: a prospective, randomized-controlled trial.

BACKGROUND: Pulmonary hypertension (PHT) is common in patients undergoing mitral valve surgery and is an independent risk factor for the development of acute right ventricular (RV) failure. Inhaled iloprost was shown to improve RV function and decrease RV afterload in patients with primary PHT. However, no randomized-controlled trials on the intraoperative use of iloprost in cardiac surgical patients are available. We therefore compared the effects of inhaled iloprost vs. intravenous standard therapy in cardiac surgical patients with chronic PHT. METHODS: Twenty patients with chronic PHT undergoing mitral valve repair were randomized to receive inhaled iloprost (25 microg) or intravenous nitroglycerine. Iloprost was administered during weaning from cardiopulmonary bypass (CPB). Systemic and pulmonary haemodynamics were assessed with pulmonary artery catheterization and transoesophageal echocardiography. Milrinone and/or inhaled nitric oxide were available as rescue medication in case of failure to wean from CPB. RESULTS: Inhaled iloprost selectively decreased the pulmonary vascular resistance index after weaning from CPB (208 +/- 108 vs. 422 +/- 62 dyn.s/cm(5)/m(2), P<0.05), increased the RV-ejection fraction (29 +/- 3% vs. 22 +/- 5%, P<0.05), improved the stroke volume index (27 +/- 7 vs. 18 +/- 6 ml/m(2), P<0.05) and reduced the transpulmonary gradient (10 +/- 4 vs. 16 +/- 3 mmHg, P<0.05). In all patients receiving inhaled iloprost, weaning from CPB was successful during the first attempt. In contrast, three patients in the control group required re-institution of CPB and had to be weaned from CPB using rescue medication. CONCLUSIONS: In patients with pre-existing PHT undergoing mitral valve surgery, inhaled iloprost is superior to intravenous nitrogylycerine by acting as a selective pulmonary vasodilator, reducing RV afterload and moderately improving RV-pump performance.

Limitations of arterial pulse pressure variation and left ventricular stroke volume variation in estimating cardiac pre-load during open heart surgery.

BACKGROUND: In addition to their well-known ability to predict fluid responsiveness, functional pre-load parameters, such as the left ventricular stroke volume variation (SVV) and pulse pressure variation (PPV), have been proposed to allow real-time monitoring of cardiac pre-load. SVV and PPV result from complex heart-lung interactions during mechanical ventilation. It was hypothesized that, under open-chest conditions, when cyclic changes in pleural pressures during positive-pressure ventilation are less pronounced, functional pre-load indicators may be deceptive in the estimation of ventricular pre-load. METHODS: Forty-five patients undergoing coronary artery bypass grafting participated in this prospective, observational study. PPV and SVV were assessed by pulse contour analysis. The thermodilution technique was used to measure the stroke volume index and global and right ventricular end-diastolic volume index. Trans-oesophageal echocardiography was used to determine the left ventricular end-diastolic area index. All parameters were assessed before and after sternotomy, and, in addition, after weaning from cardiopulmonary bypass before and after chest closure (pericardium left open). Patients were ventilated with constant tidal volumes (8 +/- 2 ml/kg) throughout the study period using pressure control. RESULTS: SVV and PPV decreased after sternotomy and increased after chest closure. However, these changes could not be related to concomitant changes in the ventricular pre-load. The stroke volume index was correlated with SVV and PPV in closed-chest conditions only, whereas volumetric indices reflected cardiac pre-load in both closed- and open-chest conditions. SVV and PPV were correlated with left and right ventricular pre-load in closed-chest-closed-pericardium conditions only (with the best correlation found for the right ventricular end-diastolic volume index). CONCLUSIONS: SVV and PPV may be misleading when estimating cardiac pre-load during open heart surgery.

[Pulmonary artery catheter in anaesthesiology and intensive care medicine]. / Pulmonalarterienkatheter: Einsatz in Anästhesie und Intensivmedizin.

The indication for the use of the pulmonary artery catheter (PAC) in high-risk patients is still a matter of discussion. Observational studies suggested that the use of the PAC did not result in decreased mortality but may even lead to increased mortality and morbidity. Therefore, a number of randomized controlled trials have been performed throughout recent years in patients suffering from sepsis/ARDS, congestive heart failure, multi-organ failure and those undergoing high-risk non-cardiac surgery. The majority of recent randomized studies failed to demonstrate any benefit of the PAC with respect to mortality and morbidity. However, the use of the PAC was also regularly not associated with an increase in morbidity and/or mortality. This review gives an overview of measurement parameters obtained by the current generation of PACs, alternatives to the PAC and recent studies on the use of the PAC in clinical practice.

Solid state protein monolayers: morphological, conformational, and functional properties.

We have studied the morphological, conformational, and electron-transfer (ET) function of the metalloprotein azurin in the solid state, by a combination of physical investigation methods, namely atomic force microscopy, intrinsic fluorescence spectroscopy, and scanning tunneling microscopy. We demonstrate that a "solid state protein film" maintains its nativelike conformation and ET function, even after removal of the aqueous solvent.

Haemodynamic changes during low-pressure carbon dioxide pneumoperitoneum in young children.

BACKGROUND: Both mechanical and pharmacological effects may contribute to the haemodynamic consequences of carbon dioxide (CO2) pneumoperitoneum. The aim of the present study was to evaluate the haemodynamic effects of low-pressure pneumoperitoneum [intra-abdominal pressure (IAP) 5 mmHg] in young children (< 3 years). METHODS: Thirteen children, aged 6-36 months, ASA physical status I-III, who were scheduled for laparoscopic fundoplication for gastro-oesophageal reflux were investigated in the head-up position (10 degrees ). Noninvasive thoracic electrical bioimpedance cardiac index (CI), stroke volume index (SVI), heart rate (HR), mean arterial pressure (MAP) and peak inspiratory pressure (PIP) were recorded, together with PetCO2 and PaCO2 at five time points: before insufflation, 20, 35 and 70 min after start of CO2 insufflation and 12 min after desufflation. During insufflation, minute ventilation was not adjusted and the IAP was maintained at 5 mmHg. RESULTS: During insufflation, PetCO2 increased from 29 +/- 4 to 37 +/- 5 mmHg (P < 0.001) and PaCO2 increased from 31 +/- 4 to 39 +/- 5 mmHg (P < 0.01). CI increased from 2.39 +/- 0.86 to 2.92 +/- 0.94 l x min-1 x m2 (P < 0.01), HR increased from 108 +/- 10 to 126 +/- 22 b x min-1 (P < 0.01), MAP increased from 52 +/- 10 to 63 +/- 9 (P < 0.05) and PIP increased from 16 +/- 3 to 18 +/- 3 cm H2O (P < 0.001). There were no changes in SVI and arterial oxygen saturation. CONCLUSIONS: We conclude that low-pressure CO2 pneumoperitoneum (with IAPs not exceeding 5 mmHg) for laparoscopic fundoplication in infants and children does not decrease their cardiac index.

Enthalpic and entropic contributions to the mutational changes in the reduction potential of azurin.

The changes in the reduction potential of Pseudomonas aeruginosa and Alcaligenes denitrificans azurins following point mutations and residue ionizations were factorized into the enthalpic and entropic contributions through variable temperature direct electrochemistry experiments. The effects on the reduction enthalpy due to changes in the first coordination sphere of the copper ion, as in the Met121Gln and Met121His variants of A. denitrificans azurin, insertion of a net charge and alteration in the solvation properties and electrostatic potential in proximity of the metal site, as in the Met44Lys and His35Leu variants of P. aeruginosa azurin, respectively, and proton uptake/release in wild-type and mutated species could invariably be accounted for on the basis of simple coordination chemistry and/or electrostatic considerations. The concomitant changes in reduction entropy were found in general to contribute to the E degrees ' variation to a lesser extent as compared to the enthalpy changes. However, their effects were by no means negligible and in some instances were found to heavily contribute to (or even become the main determinant of) the observed change in reduction potential. Several lines of evidence indicate that the entropic effects are notably influenced by reduction-induced solvent reorganization effects. In particular, protein reduction tends to be favored on entropic grounds with increasing exposure of the copper site to the solvent. Moreover, enthalpy-entropy compensation phenomena are invariably observed when residue mutation or pH-induced conformational changes modify the solvent accessibility of the metal site or alter the H-bonding network in the hydration shell of the molecule. Therefore, in these cases, caution must be used in making predictions of E degrees ' changes simply based on Coulombic or coordination chemistry arguments.

In vitro transepithelial drug transport by on-line measurement: cellular control of paracellular and transcellular transport.

Studies on transcellular transport across epithelial cell layers are performed mostly by discontinuous sampling of the transported compound. This has several drawbacks, e.g., it gives disturbances in volume, it limits the time-resolution, and is often laborious. In this report we introduce a method to measure transepithelial transport of fluorescent compounds continuously. The time-resolution is at the (sub)minute scale, allowing the measurement of the change in transport rate before and after transport modulation. We will describe how we used the method to measure transcellular and paracellular transport. For highly membrane-impermeable compounds, the paracellular transport and the regulation of the tight junctions was studied in wild-type and MDR1 cDNA transfected epithelial canine kidney cells (MDCKII). The effect of the multidrug transporter P-glycoprotein (Pgp) on the transepithelial transport was studied. Addition of the Pgp inhibitor SDZ PSC 833 showed a modulation of the idarubicin (IDA) and daunorubicin (DNR) transport, which was larger during transport from the basolateral to the apical side than in the reverse direction. By modeling the transepithelial transport, we found that in these cells Pgp had more effect on the basolateral to apical transport than vice versa, which can be attributed to a relatively large passive permeation coefficient for the cellular basolateral plasma membrane.

Effects of salmeterol on host resistance to Trichinella spiralis in rats.

Salmeterol is a long-acting beta2-adrenoreceptor agonist. The compound has previously been screened for immunotoxic potential in a repeated dose toxicity study in rats for 28 days. The total serum IgG levels were increased at dose levels of 2 and 10 mg/kg/day. Presently, salmeterol was studied in an immune function assay addressing the host resistance to Trichinella spiralis parasites. Rats were daily treated with salmeterol for 28 days at dose levels of 0, 2, 6 and 10 mg/kg/day. On day 29, the animals were infected with T. spiralis parasites. After six weeks, host resistance was examined. The numbers of T. spiralis muscle larvae in the tongue nor the inflammatory reactions around the encapsulated larvae were affected by salmeterol treatment. The yield of muscle larvae in the whole carcass was not changed either. The IgM, IgA and IgE antibody responses to T. spiralis were unaffected. Only at the highest dose level tested, the anti-T. spiralis IgG antibody response was decreased significantly. However, salmeterol's interference with the generation of anti-T. spiralis antibodies of the IgG subclass apparently did not adversely affect the resistance to infection.

Effects of prolonged exposure to morphine and methadone on in vivo parameters of immune function in rats.

In rats, two 6-week repeated dose oral toxicity studies were performed with morphine (250 and 500 mg/kg food) and methadone (200 and 400 mg/kg food), respectively. Alterations in immune function were studied by assessing primary and secondary immune responses to sheep red blood cells. In addition, the ability to resist challenge with infectious agents was measured in host resistance models employing the parasite Trichinella spiralis and the bacterium Listeria monocytogenes. The primary and secondary antibody responses to sheep red blood cells were not affected by treatment with either morphine or methadone. The clearance of L. monocytogenes bacteria in the spleen was not affected either. Prolonged treatment with morphine, however, resulted in a decrease in host resistance to T. spiralis infection, as indicated by a 1.5-fold increase in numbers of muscle larvae counted in the carcass, but did not affect the T. spiralis-specific IgM, IgG and IgE antibody responses. In contrast to morphine, the methadone-treated animals did not show a significant change in host resistance to T. spiralis. Total serum IgG levels, however, were increased in high-dose methadone-treated animals. Apparently, prolonged administration of morphine to rats resulted in immune suppression, mediating a slight, though biologically relevant, exacerbation of the T. spiralis infection, whereas methadone did not.