PERSUADE Survey-PERioperative AnestheSia and Intensive Care Management of Left VentricUlar Assist DevicE Implantation in Europe and the United States.

OBJECTIVE: To comprehensively assess relevant institutional variations in anesthesia and intensive care management during left ventricular assist device (LVAD) implantation. DESIGN: The authors used a prospective data analysis. SETTING: This was an online survey. PARTICIPANTS: Participants were from LVAD centers in Europe and the US. INTERVENTIONS: After investigating initial interest, 91 of 202 European and 93 of 195 US centers received a link to the survey targeting institutional organization and experience, perioperative hemodynamic monitoring, medical management, and postoperative intensive care aspects. MEASUREMENTS AND MAIN RESULTS: The survey was completed by 73 (36.1%) European and 60 (30.8%) US centers. Although most LVAD implantations were performed in university hospitals (>5 years of experience), significant differences were observed in the composition of the preoperative multidisciplinary team and provision of intraoperative care. No significant differences in monitoring or induction agents were observed. Propofol was used more often for maintenance in Europe (p < 0.001). The choice for inotropes changed significantly from preoperatively (more levosimendan in Europe) to intraoperatively (more use of epinephrine in both Europe and the US). The use of quantitative methods for defining right ventricular (RV) function was reported more often from European centers than from US centers (p < 0.05). Temporary mechanical circulatory support for the treatment of RV failure was more often used in Europe. Nitric oxide appeared to play a major role only intraoperatively. There were no significant differences in early postoperative complications reported from European versus US centers. CONCLUSIONS: Although the perioperative practice of care for patients undergoing LVAD implantation differs in several aspects between Europe and the US, there were no perceived differences in early postoperative complications.

Can perioperative pCO2 gaps predict complications in patients undergoing major elective abdominal surgery randomized to goal-directed therapy or standard care? A secondary analysis.

The difference between venous and arterial carbon dioxide pressure (pCO2 gap), has been used as a diagnostic and prognostic tool. We aimed to assess whether perioperative pCO2 gaps can predict postoperative complications. This was a secondary analysis of a multicenter RCT comparing goal-directed therapy (GDT) to standard care in which 464 patients undergoing high-risk elective abdominal surgery were included. Arterial and central venous blood samples were simultaneously obtained at four time points: after induction, at the end of surgery, at PACU/ICU admission, and PACU/ICU discharge. Complications within the first 30 days after surgery were recorded. Similar pCO2 gaps were found in patients with and without complications, except for the pCO2 gap at the end of surgery, which was higher in patients with complications (6.0 mmHg [5.0-8.0] vs. 6.0 mmHg [4.1-7.5], p = 0.005). The area under receiver operating characteristics curves for predicting complications from pCO2 gaps at all time points were between 0.5 and 0.6. A weak correlation between ScvO2 and pCO2 gaps was found for all timepoints (ρ was between - 0.40 and - 0.29 for all timepoints, p < 0.001). The pCO2 gap did not differ between GDT and standard care at any of the selected time points. In our study, pCO2 gap was a poor predictor of major postoperative complications at all selected time points. Our research does not support the use of pCO2 gap as a prognostic tool after high-risk abdominal surgery. pCO2 gaps were comparable between GDT and standard care. Clinical trial registration Netherlands Trial Registry NTR3380.

ECPELLA as a bridge-to-decision in refractory cardiogenic shock: a single-centre experience.

BACKGROUND: In refractory cardiogenic shock, temporary mechanical support (tMCS) may be crucial for maintaining tissue perfusion and oxygen delivery. tMCS can serve as a bridge-to-decision to assess eligibility for left ventricular assist device (LVAD) implantation or heart transplantation, or as a bridge-to-recovery. ECPELLA is a novel tMCS configuration combining venoarterial extracorporeal membrane oxygenation with Impella. The present study presents the clinical parameters, outcomes, and complications of patients supported with ECPELLA. METHODS: All patients supported with ECPELLA at University Medical Centre Utrecht between December 2020 and August 2023 were included. The primary outcome was 30-day mortality, and secondary outcomes were LVAD implantation/heart transplantation and safety outcomes. RESULTS: Twenty patients with an average age of 51 years, and of whom 70% were males, were included. Causes of cardiogenic shock were acute heart failure (due to acute coronary syndrome, myocarditis, or after cardiac surgery) or chronic heart failure, respectively 70 and 30% of cases. The median duration of ECPELLA support was 164 h (interquartile range 98-210). In 50% of cases, a permanent LVAD was implanted. Cardiac recovery within 30 days was seen in 30% of cases and 30-day mortality rate was 20%. ECPELLA support was associated with major bleeding (40%), haemolysis (25%), vascular complications (30%), kidney failure requiring replacement therapy (50%), and Impella failure requiring extraction (15%). CONCLUSION: ECPELLA can be successfully used as a bridge to LVAD implantation or as a bridge-to-recovery in patients with refractory cardiogenic shock. Despite a significant number of complications, 30-day mortality was lower than observed in previous cohorts.

Postoperative vasoplegia in lung transplantation: incidence and relation to outcome in a single-centre retrospective study.

BACKGROUND: The incidence and clinical importance of vasoplegia after lung transplantation remains poorly studied. We describe the incidence of vasoplegia and its association with complications after lung transplantation. METHODS: Perioperative data of 279 lung transplant recipients operated on from 2015 to 2020 in a UK hospital were analysed retrospectively. RESULTS: Vasoplegia occurred in 41.6% of patients after lung transplantation (mild, 31.0%; moderate, 55.2%; severe, 13.8%). Compared with non-vasoplegic patients, vasoplegic patients had a higher incidence of any acute kidney injury, defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria (78.5% vs 65%, P=0.015), renal replacement therapy (47.4% vs 24.5%, P<0.001), and delayed chest closure (18.4% vs 9.2%, P=0.025); were ventilated longer (70 [32-368] vs 34 [19-105] h, P<0.001); and stayed longer in the ICU (12.9 [5-30] vs 6.8 [3-20] days, P<0.001). Mortality at 30 days and 1 yr was higher in patients with vasoplegia (11.2% vs 5.5% and 20.7% vs 11.7%, P=0.039, respectively). Severe vasoplegia represented a predictor of longer-term mortality (hazard ratio=1.65, P=0.008). Underlying infectious disease, increased BMI, higher preoperative pulmonary artery systolic pressure and bilirubin levels, lower glomerular filtration rate, and increased fresh frozen plasma transfusion were predictors of vasoplegia severity. Neutrophilia, leucocytosis, and increased C-reactive protein were associated with vasoplegia, but release of the neutrophil activation markers myeloperoxidase and heparin-binding protein was similar between groups. CONCLUSIONS: Influenced by preoperative status as well as procedural factors and inflammatory response, vasoplegia is a common and critical condition after lung transplantation with worse short-term outcomes and long-term survival.

Effects of dobutamine and phenylephrine on cerebral perfusion in patients undergoing cerebral bypass surgery: a randomised crossover trial.

BACKGROUND: Patients undergoing cerebral bypass surgery are prone to cerebral hypoperfusion. Currently, arterial blood pressure is often increased with vasopressors to prevent cerebral ischaemia. However, this might cause vasoconstriction of the graft and cerebral vasculature and decrease perfusion. We hypothesised that cardiac output, rather than arterial blood pressure, is essential for adequate perfusion and aimed to determine whether dobutamine administration resulted in greater graft perfusion than phenylephrine administration. METHODS: This randomised crossover study included 10 adult patients undergoing cerebral bypass surgery. Intraoperatively, patients randomly and sequentially received dobutamine to increase cardiac index or phenylephrine to increase mean arterial pressure (MAP). An increase of >10% in cardiac index or >10% in MAP was targeted, respectively. Before both interventions, a reference phase was implemented. The primary outcome was the absolute difference in graft flow between the reference and intervention phase. We compared the absolute flow difference between each intervention and constructed a random-effect linear regression model to explore treatment and carry-over effects. RESULTS: Graft flow increased with a median of 4.1 (inter-quartile range [IQR], 1.7-12.0] ml min-1) after dobutamine administration and 3.6 [IQR, 1.3-7.8] ml min-1 after phenylephrine administration (difference -0.6 ml min-1; 95% confidence interval [CI], -14.5 to 5.3; P=0.441). There was no treatment effect (0.9 ml min-1; 95% CI, 0.0-20.1; P=0.944) and no carry-over effect. CONCLUSIONS: Both dobutamine and phenylephrine increased graft flow during cerebral bypass surgery, without a preference for one method over the other. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register, NL7077 (https://www.trialregister.nl/trial/7077).

Vasoplegia after implantation of a continuous flow left ventricular assist device: incidence, outcomes and predictors.

BACKGROUND: Vasoplegia after routine cardiac surgery is associated with severe postoperative complications and increased mortality. It is also prevalent in patients undergoing implantation of pulsatile flow left ventricular assist devices (LVAD). However, less is known regarding vasoplegia after implantation of newer generations of continuous flow LVADs (cfLVAD). We aim to report the incidence, impact on outcome and predictors of vasoplegia in these patients. METHODS: Adult patients scheduled for primary cfLVAD implantation were enrolled into a derivation cohort (n = 118, 2006-2013) and a temporal validation cohort (n = 73, 2014-2016). Vasoplegia was defined taking into consideration low mean arterial pressure and/or low systemic vascular resistance, preserved cardiac index and high vasopressor support. Vasoplegia was considered after bypass and the first 48 h of ICU stay lasting at least three consecutive hours. This concept of vasoplegia was compared to older definitions reported in the literature in terms of the incidence of postoperative vasoplegia and its association with adverse outcomes. Logistic regression was used to identify independent predictors. Their ability to discriminate patients with vasoplegia was quantified by the area under the receiver operating characteristic curve (AUC). RESULTS: The incidence of vasoplegia was 33.1% using the unified definition of vasoplegia. Vasoplegia was associated with increased ICU length-of-stay (10.5 [6.9-20.8] vs 6.1 [4.6-10.4] p = 0.002), increased ICU-mortality (OR 5.8, 95% CI 1.9-18.2) and one-year-mortality (OR 3.9, 95% CI 1.5-10.2), and a higher incidence of renal failure (OR 4.3, 95% CI 1.8-10.4). Multivariable analysis identified previous cardiothoracic surgery, preoperative dopamine administration, preoperative bilirubin levels and preoperative creatinine clearance as independent preoperative predictors of vasoplegia. The resultant prediction model exhibited a good discriminative ability (AUC 0.80, 95% CI 0.71-0.89, p <  0.01). Temporal validation resulted in an AUC of 0.74 (95% CI 0.61-0.87, p <  0.01). CONCLUSIONS: In the era of the new generation of cfLVADs, vasoplegia remains a prevalent (33%) and critical condition with worse short-term outcomes and survival. We identified previous cardiothoracic surgery, preoperative treatment with dopamine, preoperative bilirubin levels and preoperative creatinine clearance as independent predictors.

The cumulative effect of assisted reproduction procedures on placental development and epigenetic perturbations in a mouse model.

Assisted reproductive technologies (ART) are associated with several complications including low birth weight, abnormal placentation and increased risk for rare imprinting disorders. Indeed, experimental studies demonstrate ART procedures independent of existing infertility induce epigenetic perturbations in the embryo and extraembryonic tissues. To test the hypothesis that these epigenetic perturbations persist and result in adverse outcomes at term, we assessed placental morphology and methylation profiles in E18.5 mouse concepti generated by in vitro fertilization (IVF) in two different genetic backgrounds. We also examined embryo transfer (ET) and superovulation procedures to ascertain if they contribute to developmental and epigenetic effects. Increased placental weight and reduced fetal-to-placental weight ratio were observed in all ART groups when compared with naturally conceived controls, demonstrating that non-surgical embryo transfer alone can impact placental development. Furthermore, superovulation further induced overgrowth of the placental junctional zone. Embryo transfer and superovulation defects were limited to these morphological changes, as we did not observe any differences in epigenetic profiles. IVF placentae, however, displayed hypomethylation of imprinting control regions of select imprinted genes and a global reduction in DNA methylation levels. Although we did not detect significant differences in DNA methylation in fetal brain or liver samples, rare IVF concepti displayed very low methylation and abnormal gene expression from the normally repressed allele. Our findings suggest that individual ART procedures cumulatively increase placental morphological abnormalities and epigenetic perturbations, potentially causing adverse neonatal and long-term health outcomes in offspring.

Accuracy, Precision, and Trending Ability of Uncalibrated Arterial Pressure Waveform Analysis of Cardiac Output in Patients With Impaired Left Ventricular Function: A Prospective, Observational Study.

OBJECTIVES: Uncalibrated arterial waveform analysis provides minimally invasive and continuous measurement of cardiac output (CO). This technique could be of great value in patients with impaired left ventricular function, but the validity in these patients is not well established. The aim of this study was to investigate the accuracy, precision, and trending ability of uncalibrated arterial waveform analysis of cardiac output in patients with impaired left ventricular function. DESIGN: Prospective, observational, method-comparison study. SETTING: Nonuniversity teaching hospital, single center. PARTICIPANTS: The study included 22 patients with a left ventricular ejection fraction of 40% or less undergoing elective coronary artery bypass grafting. INTERVENTIONS: In the period between induction of anesthesia and sternotomy, CO was measured using the FloTrac/Vigileo system (third-generation software) and intermittent pulmonary artery thermodilution before and after volume loading. MEASUREMENTS AND MAIN RESULTS: Accuracy and precision as determined using Bland-Altman analysis revealed a bias of -0.7 L/min, limits of agreement of -2.9 to 1.5 L/min, and a mean error of 55% for pooled data. Proportional bias and spread were present, indicating that bias and limits of agreement were underestimated for high CO values. Trending ability was assessed using 4-quadrant analysis, which revealed a concordance of 86%. Concordance from a clinical perspective was 36%. Polar plot analysis showed an angular bias of 13° degrees, with radial limits of agreement of -55° to 51°. Polar concordance at±30° was 50%. CONCLUSIONS: Arterial waveform analysis of cardiac output and pulmonary artery thermodilution cardiac output were not interchangeable in patients with impaired left ventricular function.

Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming.

The use of assisted reproductive technologies (ART) has become increasingly common worldwide and is now responsible for 2-3% of children born in developed countries. Multiple reports have suggested that ART-conceived children are more likely to develop rare epigenetic disorders such as Beckwith-Wiedemann Syndrome or Angelman Syndrome, both of which involve dysregulation of imprinted genes. Anecdotal reports suggest that animals produced with ART that manifest apparent epigenetic defects typically do not transmit these epimutations to subsequent generations when allowed to breed naturally, but this hypothesis has not been directly studied. We analyzed allele-specific DNA methylation and expression at three imprinted genes, H19, Snrpn, and Peg3, in somatic cells from adult mice generated with the use of intracytoplasmic sperm injection (ICSI), a type of ART. Epimutations were detected in most of the ICSI-derived mice, but not in somatic cells of their offspring produced by natural mating. We examined germ cells from the ICSI mice that exhibited epimutations in their somatic cells and confirmed normal epigenetic reprogramming of the three imprinted genes analyzed. Collectively, these results confirm that ART procedures can lead to the formation of primary epimutations, but while such epimutations are likely to be maintained indefinitely in somatic cells of the ART-derived individuals, they are normally corrected in the germ line by epigenetic reprogramming and thus, not propagated to subsequent generations.

Arterial pressure waveform analysis versus thermodilution cardiac output measurement during open abdominal aortic aneurysm repair: a prospective observational study.

BACKGROUND: Arterial pressure waveform analysis enables continuous, minimally invasive measurement of cardiac output. Haemodynamic instability compromises the reliability of the technique and a means of maintaining accurate measurement in this circumstance would be useful. OBJECTIVES: To investigate the accuracy, precision and trending ability of arterial pressure waveform cardiac output obtained with FloTrac/Vigileo, versus pulmonary artery thermodilution in patients undergoing elective open abdominal aortic aneurysm repair. DESIGN: A prospective observational study. SETTING: Operating room in a university hospital. PATIENTS: Twenty-two patients scheduled for elective, open abdominal aortic aneurysm repair. MAIN OUTCOME MEASURES: Bias, limits of agreement and mean error as determined with Bland-Altman analysis between arterial waveform and thermodilution cardiac output assessment at four time points: after induction of anaesthesia (t1); after aortic cross-clamping (t2); after clamp release (t3); and after skin closure (t4). Trending ability from t1 to t2, t2 to t3 and t3 to t4, determined with four-quadrant and polar plot methodology. Clinically acceptable boundaries were defined in advance. RESULTS: Bland-Altman analysis revealed a bias of 0.54 l min (thermodilution minus arterial waveform cardiac output) for pooled data, and 0.51 (t1), -0.42 (t2), 0.98 (t3) and 0.98 (t4) l min at the different time points. Limits of agreement (LOA) were [-3.0 to 4.0] (pooled), [-2.0 to 3.0] (t1), [-3.1 to 2.3] (t2), [-2.5 to 4.4] (t3) and [-1.7 to 3.7] (t4) l min, resulting in mean errors of 58% (pooled), 45% (t1), 53% (t2), 52% (t3) and 41% (t4). Four-quadrant concordance was 65%. Polar plot analysis resulted in an angular bias of -12°, with radial LOA of -60° to 36°. CONCLUSION: Bias between arterial waveform and thermodilution cardiac output was within a predefined acceptable range, but the mean error was above the accepted range of 30%. Trending ability was poor. Arterial waveform and thermodilution cardiac outputs are, therefore, not interchangeable in patients undergoing open abdominal aortic aneurysm repair.

Gonadotropin stimulation contributes to an increased incidence of epimutations in ICSI-derived mice.

We previously demonstrated that intracytoplasmic sperm injection (ICSI), a type of assisted reproductive technology (ART), can induce epimutations and/or epimutant phenotypes in somatic tissues of adult mice produced by this method. In the present study, we compared the occurrence of epimutations in mice produced by natural conception, ICSI and somatic cell nuclear transfer. Surprisingly, we observed the highest frequency of epimutations in somatic tissues from ICSI-derived mice. We also observed a delay in reprogramming of the maternal allele of the imprinted H19 gene in spermatogonia from juvenile ICSI-derived male mice. These observations led us to hypothesize that the exposure of the maternal gametic genome to exogenous gonadotropins during the endocrine stimulation of folliculogenesis (superovulation) may contribute to the disruption of the normal epigenetic programming of imprinted loci in somatic tissues and/or epigenetic reprogramming in the germ line of ensuing offspring. To test this hypothesis, we uncoupled superovulation from ICSI by subjecting female mice to gonadotropin stimulation and then allowing them to produce offspring by natural mating. We found that mice produced in this way also exhibited epimutations and/or epimutant phenotypes in somatic tissues and delayed epigenetic reprogramming in spermatogenic cells, providing evidence that gonadotropin stimulation contributes to the induction of epimutations during ART procedures. Our results suggest that gonadotropin stimulation protocols used in conjunction with ART procedures should be optimized to minimize the occurrence of epimutations in offspring produced by these methods.

In vitro culture increases the frequency of stochastic epigenetic errors at imprinted genes in placental tissues from mouse concepti produced through assisted reproductive technologies.

Assisted reproductive technologies (ART) have enabled millions of couples with compromised fertility to conceive children. Nevertheless, there is a growing concern regarding the safety of these procedures due to an increased incidence of imprinting disorders, premature birth, and low birth weight in ART-conceived offspring. An integral aspect of ART is the oxygen concentration used during in vitro development of mammalian embryos, which is typically either atmospheric (~20%) or reduced (5%). Both oxygen tension levels have been widely used, but 5% oxygen improves preimplantation development in several mammalian species, including that of humans. To determine whether a high oxygen tension increases the frequency of epigenetic abnormalities in mouse embryos subjected to ART, we measured DNA methylation and expression of several imprinted genes in both embryonic and placental tissues from concepti generated by in vitro fertilization (IVF) and exposed to 5% or 20% oxygen during culture. We found that placentae from IVF embryos exhibit an increased frequency of abnormal methylation and expression profiles of several imprinted genes, compared to embryonic tissues. Moreover, IVF-derived placentae exhibit a variety of epigenetic profiles at the assayed imprinted genes, suggesting that these epigenetic defects arise by a stochastic process. Although culturing embryos in both of the oxygen concentrations resulted in a significant increase of epigenetic defects in placental tissues compared to naturally conceived controls, we did not detect significant differences between embryos cultured in 5% and those cultured in 20% oxygen. Thus, further optimization of ART should be considered to minimize the occurrence of epigenetic errors in the placenta.

Differential responses to JNJ-37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague-Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics.

JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat.

FLAVOUR Study: FLow profiles And postoperative VasOplegia after continUous-flow left ventriculaR assist device implantation.

This study aims to associate the incidence of postoperative vasoplegia and short-term survival to the implantation of various left ventricular assist devices differing in hemocompatibility and flow profiles. The overall incidence of vasoplegia was 25.3% (73/289 patients) and 30.3% (37/122), 25.0% (18/72), and 18.9% (18/95) in the axial flow (AXF), centrifugal flow (CF), and centrifugal flow with artificial pulse (CFAP) group, respectively. Vasoplegia was associated with longer intensive care (ICU) and hospital length of stay (LOS) and mortality. ICU and in-hospital LOS and 1-year mortality were the lowest in the CFAP group. Post hoc analysis resulted in a p-value of 0.43 between AXF and CF; 0.35 between CF and CFAP; and 0.06 between AXF and CFAP. Although there is a trend in diminished incidence of vasoplegia, pooled logistic regression using flow profile and variables that remained after feature selection showed that flow profile was not an independent predictor for postoperative vasoplegia.

Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long-living naked-mole rat: a proteomic approach.

The 'oxidative stress theory of aging' predicts that aging is primarily regulated by progressive accumulation of oxidized macromolecules that cause deleterious effects to cellular homeostasis and induces a decline in physiological function. However, our reports on the detection of higher level of oxidized protein carbonyls in the soluble cellular fractions of long-living rodent naked-mole rats (NMRs, lifespan ~30yrs) compared to short-lived mice (lifespan ~3.5yrs) apparently contradicts a key tenet of the oxidative theory. As oxidation often inactivates enzyme function and induces higher-order soluble oligomers, we performed a comprehensive study to measure global protein carbonyl level in different tissues of age-matched NMRs and mice to determine if the traditional concept of oxidation mediated impairment of function and induction of higher-order structures of proteins are upheld in the NMRs. We made three intriguing observations with NMRs proteins: (1) protein carbonyl is significantly elevated across different tissues despite of its exceptional longevity, (2) enzyme function is restored despite of experiencing higher level of protein carbonylation, and (3) enzymes show lesser sensitivity to form higher-order non-reducible oligomers compared to short-living mouse proteins in response to oxidative stress. These observations were made based on the global analysis of protein carbonyl and identification of two heavily carbonylated proteins in the kidney, triosephosphate isomerase (TPI) and cytosolic peroxiredoxin (Prdx1). These un-expected intriguing observations thus strongly suggest that oxidative modification may not be the only criteria for impairment of protein and enzyme function; cellular environment is likely be the critical determining factor in this process and may be the underlying mechanism for exceptional longevity of NMR.

Arterial waveform analysis in anesthesia and critical care.

PURPOSE OF REVIEW: In this review, we describe the basic principles of arterial waveform analysis (AWA) to assess cardiac output (CO) and cardiac preload. The validity of commercially based hemodynamic monitoring systems is discussed, together with their clinical applications and limitations. RECENT FINDINGS: Currently, three devices (the FloTrac system, PiCCO monitor, and LiDCO system) are available for measurement of AWA-based CO. In addition, dynamic preload parameters such as stroke volume variation (SVV) and pulse pressure variation (PPV) are determined, which may be useful to predict fluid responsiveness in mechanically ventilated patients. SUMMARY: AWA provides a less invasive and easy-to-use alternative for CO measurement. The validity of AWA devices has been verified in a variety of patients and circumstances, but their performance is compromised in the presence of hemodynamic instability, cardiac arrhythmias, or other factors disturbing the arterial pressure waveform. The definitive role of dynamic preload parameters like SVV and PPV is a matter of research. Large trials in which the value of early goal-directed therapy using this technology is studied in relation to outcome are urgently needed.

Perioperative goal-directed therapy in high-risk abdominal surgery. A multicenter randomized controlled superiority trial.

STUDY OBJECTIVE: The potential of perioperative goal-directed therapy (PGDT) to improve outcome after high-risk abdominal surgery remains subject of debate. In particular, there is a need for large, multicenter trials focusing on relevant patient outcomes to confirm the evidence found in small, single center studies including minor complications in their composite endpoints. The present study therefore aims to investigate the effect of an arterial waveform analysis based PGDT algorithm on the incidence of major complications including mortality after high-risk abdominal surgery. DESIGN: Prospective randomized controlled multicenter trial. SETTING: Operating theatres and Post-Anesthesia/Intensive Care units (PACU/ICU) of four tertiary hospitals in The Netherlands. PATIENTS: A total number of 482 patients undergoing elective, abdominal surgery that is considered high-risk due to the extent of the procedure and/or patient comorbidities. INTERVENTIONS: Hemodynamic therapy using an age-specific PGDT algorithm including cardiac index (CI) and stroke volume variation (SVV) measurements during a 24-h perioperative period starting at induction of anesthesia. MEASUREMENTS: The average number of major complications (including mortality) within 30 days after surgery, the number of minor complications, hospital and PACU/ICU length of stay (LOS), amounts of fluids and vasoactive medications used. Complications were graded using the Accordion severity grading system. RESULTS: The average number of major complications per patient was 0.79 (PGDT group) versus 0.69 (control group) (p = 0.195). There were no statistically significant differences in the number of minor complications, hospital LOS, PACU/ICU LOS, or grading of complications. Patients in the PGDT group received more fluids intraoperatively, more dobutamine intra- and postoperatively, while patients in the control group received more phenylephrine during the operation. CONCLUSIONS: PGDT based on a CI and SVV driven algorithm did not result in improved outcomes after high-risk abdominal surgery. CLINICAL TRIAL REGISTRATION: Netherlands Trial Registry: NTR3380.

Propensity score-based analysis of long-term outcome of patients on HeartWare and HeartMate 3 left ventricular assist device support.

AIMS: Left ventricular assist device therapy has become the cornerstone in the treatment of end-stage heart failure and is increasingly used as destination therapy next to bridge to transplant or recovery. HeartMate 3 (HM3) and HeartWare (HVAD) are centrifugal continuous flow devices implanted intrapericardially and most commonly used worldwide. No randomized controlled trials have been performed yet. Analysis based on large registries may be considered as the best alternative but has the disadvantage of different standard of care between centres and missing data. Bias is introduced, because the decision which device to use was not random, even more so because many centres use only one type of left ventricular assist device. Therefore, we performed a propensity score (PS)-based analysis of long-term clinical outcome of patients that received HM3 or HVAD in a single centre. METHODS AND RESULTS: Between December 2010 and December 2019, 100 patients received HVAD and 81 patients HM3 as primary implantation at the University Medical Centre Utrecht. We performed PS matching with an extensive set of covariates, resulting in 112 matched patients with a median follow-up of 28 months. After PS matching, survival was not significantly different (P = 0.21) but was better for HM3. The cumulative incidences for haemorrhagic stroke (P = 0.01) and pump thrombosis (P = 0.02) were significantly higher for HVAD patients. The cumulative incidences for major bleeding, ischaemic stroke, right heart failure, and driveline infection were not different between the groups. We found no interaction between the surgeon who performed the implantation and survival (P = 0.59, P = 0.78, and P = 0.89). Sensitivity analysis was performed, by PS matching without patients on preoperative temporary support resulting in 74 matched patients. This also resulted in a non-significant difference in survival (P = 0.07). The PS-adjusted Cox regression showed a worse but non-significant (P = 0.10) survival for HVAD patients with hazard ratio 1.71 (95% confidence interval 0.91-3.24). CONCLUSIONS: Survival was not significantly different between both groups after PS matching, but was better for HM3, with a significantly lower incidence of haemorrhagic stroke and pump thrombosis for HM3. These results need to be interpreted carefully, because matching may have introduced greater imbalance on unmeasured covariates. A multicentre approach of carefully selected centres is recommended to enlarge the number of matched patients.