Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.

Performance and usability of pre-operative prediction models for 30-day peri-operative mortality risk: a systematic review.

Estimating pre-operative mortality risk may inform clinical decision-making for peri-operative care. However, pre-operative mortality risk prediction models are rarely implemented in routine clinical practice. High predictive accuracy and clinical usability are essential for acceptance and clinical implementation. In this systematic review, we identified and appraised prediction models for 30-day postoperative mortality in non-cardiac surgical cohorts. PubMed and Embase were searched up to December 2022 for studies investigating pre-operative prediction models for 30-day mortality. We assessed predictive performance in terms of discrimination and calibration. Risk of bias was evaluated using a tool to assess the risk of bias and applicability of prediction model studies. To further inform potential adoption, we also assessed clinical usability for selected models. In all, 15 studies evaluating 10 prediction models were included. Discrimination ranged from a c-statistic of 0.82 (MySurgeryRisk) to 0.96 (extreme gradient boosting machine learning model). Calibration was reported in only six studies. Model performance was highest for the surgical outcome risk tool (SORT) and its external validations. Clinical usability was highest for the surgical risk pre-operative assessment system. The SORT and risk quantification index also scored high on clinical usability. We found unclear or high risk of bias in the development of all models. The SORT showed the best combination of predictive performance and clinical usability and has been externally validated in several heterogeneous cohorts. To improve clinical uptake, full integration of reliable models with sufficient face validity within the electronic health record is imperative.

Prospective comparison of three methods for detecting peri-operative neurocognitive disorders in older adults undergoing cardiac and non-cardiac surgery.

Postoperative neurocognitive disorders occur frequently in older adult patients. Neuropsychological assessment is the gold standard for diagnosis, but the resources required for routine use are significant. Instead, it is common for simplified and unvalidated tests to be used for trials and in clinical practice. We undertook a single-centre prospective observational study in elective surgical patients aged ≥ 65 years recruited between September 2019 and January 2021. Patients underwent neuropsychological assessment, the Modified Telephone Interview for Cognitive Status and Montreal Cognitive Assessment before surgery. Tests were repeated at approximately four to eight postoperative weeks. We included 105 patients and 28 (27%) were lost to follow-up. Pre-operative Modified Telephone Interview for Cognitive Status and cognitive domain scores were very weakly to moderately correlated (r = 0.09-0.41). Pre-operative Montreal Cognitive Assessment and cognitive domain scores were very weakly to weakly correlated (r = 0.17-0.37) Postoperative Modified Telephone Interview for Cognitive Status and cognitive domain scores were very weakly to weakly correlated (r = 0.09-0.36). Postoperative Montreal Cognitive Assessment score and cognitive domain scores were very weakly to weakly correlated (r = 0.07-0.36). Overall, there was limited agreement between tests. We conclude that the Modified Telephone Interview for Cognitive Status and Montreal Cognitive Assessment should not be used in isolation to diagnose postoperative neurocognitive disorders. There seems to be little to no pre-operative, postoperative or pre- to postoperative correlation between these tests and the neuropsychological assessment in older adults without pre-operative cognitive impairment.

Effects of surgery and general anaesthesia on sleep-wake timing: CLOCKS observational study.

Surgery and general anaesthesia have the potential to disturb the body's circadian timing system, which may affect postoperative outcomes. Animal studies suggest that anaesthesia could induce diurnal phase shifts, but clinical research is scarce. We hypothesised that surgery and general anaesthesia would result in peri-operative changes in diurnal sleep-wake patterns in patients. In this single-centre prospective cohort study, we recruited patients aged ≥18 years scheduled for elective surgery receiving ≥30 min of general anaesthesia. The Munich Chronotype Questionnaire and Pittsburgh Sleep Quality Index were used to determine baseline chronotype, sleep characteristics and sleep quality. Peri-operative sleeping patterns were logged. Ninety-four patients with a mean (SD) age of 52 (17) years were included; 56 (60%) were female. The midpoint of sleep (SD) three nights before surgery was 03.33 (55 min) and showed a phase advance of 40 minutes to 02.53 (67 min) the night after surgery (p < 0.001). This correlated with the midpoint of sleep three nights before surgery and was not associated with age, sex, duration of general anaesthesia or intra-operative dexamethasone use. Peri-operatively, patients had lower subjective sleep quality and worse sleep efficiency. Disruption started from one night before surgery and did not normalise until 6 days after surgery. We conclude that there is a peri-operative phase advance in midpoint of sleep, confirming our hypothesis that surgery and general anaesthesia disturb the circadian timing system. Patients had decreased subjective sleep quality, worse sleep efficiency and increased daytime fatigue.

Remote wireless vital signs monitoring on the ward for early detection of deteriorating patients: A case series.

INTRODUCTION: Remote wireless monitoring is a new technology that allows the continuous recording of ward patients' vital signs, supporting nurses by measuring vital signs frequently and accurately. A case series is presented to illustrate how these systems might contribute to improved patient surveillance. METHODS AND RESULTS: Five hospitals in three European countries installed a remote wireless vital signs monitoring system on medical or surgical wards. Heart rate, respiratory rate and temperature were measured by the system every 2 min. Four cases of (paroxysmal) atrial fibrillation are presented, two cases of sepsis and one case each of pyrexia, cardiogenic pulmonary edema and pulmonary embolisms. All cases show that the remote monitoring system revealed the first signs of ventilatory and circulatory deterioration before a change in the trends of the respective values became obvious by manual vital signs measurement. DISCUSSION: This case series illustrates that a wireless remote vital signs monitoring system on medical and surgical wards has the potential to reduce time to detect deteriorating patients.

[Postoperative remote monitoring]. / Postoperatives "remote monitoring".

During the course of surgical interventions, complications mostly occur in the postoperative period. Slight clinical indications can be observed, which precede a significant deterioration of the patient's condition. On the general ward vital parameters, such as heart and breathing frequencies are measured every 4-8 h. Even if the monitoring of critically ill patients is increased to every 2 h and the measurement of vital functions takes 10 min, the patient is only monitored for 120 min in a 24 h period and remains postoperatively on the general ward without monitoring for 22 out of 24 h. New wireless monitoring systems are available to continuously register some vital functions with the aid of wearable sensors. These systems can alert and alarm ward personnel if the patient's condition deteriorates. Although the optimal monitoring system does not yet exist and implementation of these new wireless monitoring systems might involve some risks, these new methods offer a great opportunity to optimize surveillance of postoperative patients on the general ward.

Adverse side-effects of dexamethasone in surgical patients - an abridged Cochrane systematic review.

In the peri-operative period, dexamethasone is widely and effectively used for prophylaxis of postoperative nausea and vomiting. The objective of this meta-analysis was to assess the adverse effects of an incidental steroid load of dexamethasone in adult surgical patients. We searched in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science for randomised controlled trials comparing an incidental steroid load of dexamethasone with a control intervention in adult patients undergoing surgery. Two review authors independently screened studies for eligibility, extracted data and assessed all included studies for bias. Our primary outcomes were postoperative systemic or wound infection, delayed wound healing and glycaemic response within 24 h. We included 37 studies in this meta-analysis. The pooled results found no evidence that dexamethasone increased the risk of a postoperative wound infection, Peto OR (95%CI) 1.01 (0.80-1.27); 4603 participants, 26 studies; I² = 32%; moderate-quality evidence. Whether dexamethasone influenced wound healing was unclear due to the large confidence intervals, Peto OR (95%CI) 0.99 (0.28-3.43); 1072 participants, 8 studies; I² = 0%; low-quality evidence. Dexamethasone produced a mild increase in glucose levels among participants without diabetes during the first 12 h after surgery, mean difference (95%CI) 0.7 mmol.l-1 (0.3-1.2) 10 studies; 595 participants; I² = 50%; low-quality evidence. This article is an abridged version of a Cochrane Review.

Sevoflurane based anaesthesia does not affect already impaired cerebral autoregulation in patients with type 2 diabetes mellitus.

BACKGROUND: The baroreflex regulates arterial blood pressure (BP). During periods when blood pressure changes, cerebral blood flow (CBF) is kept constant by cerebral autoregulation (CA). In patients with diabetes mellitus (DM), low baroreflex sensitivity (BRS) is associated with impaired CA. As sevoflurane-based anaesthesia obliterates BRS, we hypothesised that this could aggravate the already impaired CA in patients with DM resulting in a 'double-hit' on cerebral perfusion leading to increased fluctuations in blood pressure and cerebral perfusion. METHODS: On the day before surgery, we measured CBF velocity (CBFV), heart rate, and BP to determine BRS and CA efficacy (CBFVmean-to-BPmean-phase lead) in 25 patients with DM and in 14 controls. During the operation, BRS and CA efficacy were determined during sevoflurane-based anaesthesia. Patients with DM were divided into a group with high BRS (DMBRS↑) and a group with low BRS (DMBRS↓). Values presented are median (inter-quartile range). RESULTS: Preoperative vs intraoperative BRS was 6.2 (4.5-8.5) vs 1.9 (1.1-2.5, P<0.001) ms mm Hg-1 for controls, 5.8 (4.9-7.6) vs 2.7 (1.5-3.9, P<0.001) ms mm Hg-1 for patients with DMBRS↑, and 1.9 (1.5-2.8) vs 1.1 (0.6-2.5, P=0.31) ms mm Hg-1 for patients with DMBRS↓. Preoperative vs intraoperative CA efficacy was 43° (38-46) vs 43° (38-51, P=0.30), 44° (36-49) vs 41° (32-49, P=0.52), and 34° (28-40) vs 30° (27-38, P=0.64) for controls, DMBRS↑, and DMBRS↓ patients, respectively. CONCLUSIONS: In diabetic patients with low preoperative BRS, preoperative CA efficacy was also impaired. In controls and diabetic patients, CA was unaffected by sevoflurane-based anaesthesia. We therefore conclude that sevoflurane-based anaesthesia does not contribute to a 'double-hit' phenomenon on cerebral perfusion. CLINICAL TRIAL REGISTRATION: NCT 03071432.

Newer propofol, ketamine, and etomidate derivatives and delivery systems relevant to anesthesia practice.

Drug discovery is the cornerstone of developments in the field of anesthesia. Each year, new drugs enter the market and possibly change clinical practice. The development of new anesthetics can be divided into two groups. One strategy is the discovery of a new type of drug with unique molecular structure, better clinical properties, and lesser side effects than the already existing drugs. Another strategy is changing the molecular structure of current clinically available anesthetics to create new drugs with better pharmacokinetic and pharmacodynamic properties. In this review, we describe the current developments of frequently used anesthetics, namely, propofol, etomidate, and ketamine. Alfaxalone is an old anesthetic with favorable properties such as hemodynamic and respiratory stability but lacks appropriate vehicle. New formulations with recently developed solvents together with this old anesthetic are created. Next to drug development, there is also a constant search for better delivery systems for the already available anesthetics. Following open-loop systems like TIVA, new closed-loop systems have entered the market. We also discuss about SEDASYS®-Computer-Assisted Personalized Sedation System, an automatic closed-loop delivery system that provides propofol sedation for endoscopic procedures.

The effect of haemodynamic and peripheral vascular variability on cardiac output monitoring: thermodilution and non-invasive pulse contour cardiac output during cardiothoracic surgery.

While haemodynamic variability interferes with the assumption of constant flow underlying thermodilution cardiac output calculation, variability in (peripheral) arterial vascular physiology may affect pulse contour cardiac output methods. We compared non-invasive finger arterial pressure-derived continuous cardiac output measurements (Nexfin® ) with cardiac output measured using thermodilution during cardiothoracic surgery and determined the impact of cardiovascular variability on either method. We compared cardiac output derived from non-invasive finger arterial pressure with cardiac output measured by thermodilution at four grades (A-D) of cardiovascular variability. We defined Grade A data as heart rate and mean arterial pressure variability < 5% and the absence of arrhythmias (implying stable flow) and Physiocal® interval (as measure of variability in finger arterial physiology) > 30 beats. Grade B included all levels of heart rate/mean arterial pressure variability and arrhythmias (Physiocal < 30 excluded). Grade C included all Physiocal intervals (heart rate/mean arterial pressure variability > 5% and arrhythmias excluded). Grade D included all data. Comparison results were quantified as percentage errors. We analysed measurements in 27 patients undergoing coronary artery bypass surgery. Before extracorporeal circulation, the percentage error was 23% (n = 14 patients) in grade A, 28% (n = 20) in grade B, 32% (n = 22) in grade C and 37% (n = 26) in grade D, with a significant increase in variance (p = 0.035). Bias did not differ between grades. After extracorporeal circulation (n = 27), percentage errors became larger, but were not different between grades. Variability during cardiothoracic surgery affected the comparison between thermodilution and non-invasive finger arterial pressure-derived cardiac output. When the main sources of variability were included, percentage errors were large. Future cardiac output methodology comparison studies should report haemodynamic variability.

Effects of combined helium pre/post-conditioning on the brain and heart in a rat resuscitation model.

BACKGROUND: The noble gas helium induces cardio- and neuroprotection by pre- and post-conditioning. We investigated the effects of helium pre- and post-conditioning on the brain and heart in a rat resuscitation model. METHODS: After approval by the Animal Care Committee, 96 Wistar rats underwent cardiac arrest for 6 min induced by ventricular fibrillation. Animals received 70% helium and 30% oxygen for 5 min before cardiac arrest and for 30 min after restoration of spontaneous circulation (ROSC). Control animals received 70% nitrogen and 30% oxygen. Hearts and brains were excised after 2, 4 h or 7 days. Neurological degeneration was evaluated using TUNEL and Nissl staining in the hippocampal CA-1 sector. Cognitive function after 7 days was detected with the tape removal test. Molecular targets were measured by infrared western blot. Data are shown as median [Interquartile range]. RESULTS: Helium treatment resulted in significantly less apoptosis (TUNEL positive cells/100 pixel 73.5 [60.3-78.6] vs.78.2 [70.4-92.9] P = 0.023). Changes in Caveolin-3 expression in the membrane fraction and Hexokinase-II in the mitochondrial fraction were observed in the heart. Caveolin-1 expression of treated animals significantly differed from control animals in the membrane fraction of the heart and brain after ROSC. CONCLUSION: Treatment with helium reduced apoptosis in our resuscitation model. Differential expression levels of Caveolin-1, Caveolin-3 and Hexokinase II in the heart were found after helium pre- and post-conditioning. No beneficial effects were seen on neurofunctional outcome.

Peri-operative continuation of metformin does not improve glycaemic control in patients with type 2 diabetes: A randomized controlled trial.

Historically, metformin was withheld before surgery for fear of metformin-associated lactic acidosis. Currently, however, this risk is deemed to be low and guidelines have moved towards the continuation of metformin. We hypothesized that continuing metformin peri-operatively would lower postoperative serum glucose level without an effect on plasma lactate levels. We performed a single-blind multicentre randomized controlled trial in people with type 2 diabetes mellitus scheduled for non-cardiac surgery and continued (MF+ group) or withheld (MF- group) metformin before surgery. The main outcome measures were the differences in peri-operative plasma glucose and lactate levels. We randomized 70 patients (37 MF+ group and 33 MF- group) with type 2 diabetes mellitus. Postoperative glucose levels were similar in the MF+ and the MF- groups (8.2 ± 1.8 vs 8.3 ± 2.3 mmol/L P = .95) Although preoperative lactate levels were slightly higher in the MF+ group compared with the MF- group (1.5 vs 1.2 mmol/L; P = .02), the postoperative lactate levels were not significantly different (1.2 vs 1.0 mmol/L; P = .18). In conclusion, continuation of metformin during elective non-cardiac surgery does not improve glucose control or raise lactate levels to a clinically relevant degree.

Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose-insulin-potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial.

In this open-label multicentre randomised controlled trial, we investigated three peri-operative treatment strategies to lower glucose and reduce the need for rescue insulin in patients aged 18-75 years with type-2 diabetes mellitus undergoing non-cardiac surgery. Patients were randomly allocated using a web-based randomisation program to premedication with liraglutide (liraglutide group), glucose-insulin-potassium infusion (insulin infusion group) or insulin bolus regimen (insulin bolus group), targeting a glucose < 8.0 mmol.l-1 . The primary outcome was the between group difference in median glucose levels 1 h after surgery. We analysed 150 patients (liraglutide group n = 44, insulin infusion group n = 53, insulin bolus group n = 53) according to the intention-to-treat principle. Median (IQR [range]) plasma glucose 1 h postoperatively was lower in the liraglutide group compared with the insulin infusion and insulin bolus groups (6.6 (5.6-7.7 [4.2-13.5]) mmol.l-1 vs. 7.5 (6.4-8.3 [3.9-16.6]) mmol.l-1 (p = 0.026) and 7.6 (6.4-8.9 [4.7-13.2]) mmol.l-1 ) p = 0.006, respectively). The incidence of hypoglycaemia and postoperative complications did not differ between the groups. Six patients had pre-operative nausea in the liraglutide group, of which two had severe nausea, compared with no patients in the insulin infusion and insulin bolus groups (p = 0.007). The pre-operative administration of liraglutide stabilised peri-operative plasma glucose levels and reduced peri-operative insulin requirements, at the expense of increased pre-operative nausea rates.

Novel method for intraoperative assessment of cerebral autoregulation by paced breathing.

Background: Cerebral autoregulation (CA) is the mechanism that maintains constancy of cerebral blood flow (CBF) despite variations in blood pressure (BP). Patients with attenuated CA have been shown to have an increased incidence of peri-operative stroke. Studies of CA in anaesthetized subjects are rare, because a simple and non-invasive method to quantify the integrity of CA is not available. In this study, we set out to improve non-invasive quantification of CA during surgery. For this purpose, we introduce a novel method to amplify spontaneous BP fluctuations during surgery by imposing mechanical positive pressure ventilation at three different frequencies and quantify CA from the resulting BP oscillations. Methods: Fourteen patients undergoing sevoflurane anaesthesia were included in the study. Continuous non-invasive BP and transcranial Doppler-derived CBF velocity (CBF V ) were obtained before surgery during 3 min of paced breathing at 6, 10, and 15 bpm and during surgery from mechanical positive pressure ventilation at identical frequencies. Data were analysed using frequency domain analysis to obtain CBF V -to-BP phase lead as a continuous measure of CA efficacy. Group averages were calculated. Values are means ( sd ), and P <0.05 was used to indicate statistical significance. Results: Preoperative vs intraoperative CBF V -to-BP phase lead was 43 (9) vs 45 (8)°, 25 (8) vs 24 (10)°, and 4 (6) vs -2 (12)° during 6, 10, and 15 bpm, respectively (all P =NS). Conclusions: During surgery, cerebral autoregulation indices were similar to values determined before surgery. This indicates that CA can be quantified reliably and non-invasively using this novel method and confirms earlier evidence that CA is unaffected by sevoflurane anaesthesia. Clinical trial registration: NCT03071432.

Cerebral oxygenation during changes in vascular resistance and flow in patients on cardiopulmonary bypass - a physiological proof of concept study.

Despite a rise in blood pressure, cerebral oxygenation decreases following phenylephrine administration, and we hypothesised that phenylephrine reduces cerebral oxygenation by activating cerebral α1 receptors. We studied patients on cardiopulmonary bypass during constant flow. Phenylephrine raised mean arterial pressure (α1 -mediated) from mean (SD) 69 (8) mmHg to 79 (8) mmHg; p = 0.001, and vasopressin raised mean arterial pressure (V1 mediated) from 69 (8) mmHg to 83 (6) mmHg; p = 0.001. Both drugs elicited a comparable decrease in cerebral oxygenation from 61 (7)% to 60 (7)%; p = 0.023 and 61 (8)% to 59 (8)%; p = 0.022, respectively. This implies that after phenylephrine or vasopressin administration, cerebral oxygenation declines as a result of cerebral vasoconstriction, due to either both cerebral α1 and V1 receptors being equipotentially activated or to an intrinsic myogenic mechanism of cerebral vasculature in reaction to blood pressure elevation.

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency and Perioperative Management in Adult Patients.

Surgery and anesthesia pose a threat to patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), because prolonged fasting, stress, and pain are known risk factors for the induction of metabolic derangement. The optimal perioperative management in these patients is unknown and the use of volatile agents and agents dissolved in fatty acids has been related to postoperative metabolic complications. However, the occurrence of metabolic derangement is multifactorial and depends, amongst others, on the severity of the mutation and residual enzyme activity. Current guidelines suggest avoiding both volatile anesthetics as well as propofol, which seriously limits the options for providing safe anesthesia. Therefore, we reviewed the available literature on the perioperative management of patients with VLCADD. We concluded that the use of some medications, such as volatile anesthetics, in patients with VLCADD might be wrongfully avoided and could in fact prevent metabolic derangement by the adequate suppression of pain and stress during surgery. We will illustrate this with a case report of an adult VLCADD patient undergoing minor surgery. Besides the use of remifentanil, anesthesia was uneventfully maintained with the use of sevoflurane, a volatile agent, and continuous glucose infusion. The patient was monitored with a continuous glucose meter and creatinine kinase measurements.