Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans.

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.

Pulmonary Vasodilator Response of Combined Inhaled Epoprostenol and Inhaled Milrinone in Cardiac Surgical Patients.

BACKGROUND: Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are major complications in cardiac surgery. Intraoperative management of patients at high risk of RV failure should aim to reduce RV afterload and optimize RV filling pressures, while avoiding systemic hypotension, to facilitate weaning from cardiopulmonary bypass (CPB). Inhaled epoprostenol and inhaled milrinone (iE&iM) administered in combination before CPB may represent an effective strategy to facilitate separation from CPB and reduce requirements for intravenous inotropes during cardiac surgery. Our primary objective was to report the rate of positive pulmonary vasodilator response to iE&iM and, second, how it relates to perioperative outcomes in cardiac surgery. METHODS: This is a retrospective cohort study of consecutive patients with PH or RV dysfunction undergoing on-pump cardiac surgery at the Montreal Heart Institute from July 2013 to December 2018 (n = 128). iE&iM treatment was administered using an ultrasonic mesh nebulizer before the initiation of CPB. Demographic and baseline clinical data, as well as hemodynamic, intraoperative, and echocardiographic data, were collected using electronic records. An increase of 20% in the mean arterial pressure (MAP) to mean pulmonary artery pressure (MPAP) ratio was used to indicate a positive response to iE&iM. RESULTS: In this cohort, 77.3% of patients were responders to iE&iM treatment. Baseline systolic pulmonary artery pressure (SPAP) (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.16 per 5 mm Hg; P = .0006) was found to be a predictor of pulmonary vasodilator response, while a European System for Cardiac Operative Risk Evaluation (EuroSCORE II) score >6.5% was a predictor of nonresponse to treatment (≤6.5% vs >6.5% [reference]: OR, 5.19; 95% CI, 1.84-14.66; P = .002). Severity of PH was associated with a positive response to treatment, where a higher proportion of responders had MPAP values >30 mm Hg (42.4% responders vs 24.1% nonresponders; P = .0237) and SPAP values >55 mm Hg (17.2% vs 3.4%; P = .0037). Easier separation from CPB was also associated with response to iE&iM treatment (69.7% vs 58.6%; P = .0181). A higher proportion of nonresponders had a very difficult separation from CPB and required intravenous inotropic drug support compared to responders, for whom easy separation from CPB was more frequent. Use of intravenous inotropes after CPB was lower in responders to treatment (8.1% vs 27.6%; P = .0052). CONCLUSIONS: A positive pulmonary vasodilator response to treatment with a combination of iE&iM before initiation of CPB was observed in 77% of patients. Higher baseline SPAP was an independent predictor of pulmonary vasodilator response, while EuroSCORE II >6.5% was a predictor of nonresponse to treatment.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Comparison of carbetocin as a bolus or an infusion with prophylactic phenylephrine on maternal heart rate during Cesarean delivery under spinal anesthesia: a double-blinded randomized controlled trial.

PURPOSE: Carbetocin, an oxytocin analog, given as a postpartum hemorrhage prophylaxis in elective Cesarean deliveries, frequently causes tachycardia and hypotension. Phenylephrine infusion has been shown to prevent spinal anesthesia-induced hypotension. The goal of this study was to evaluate if a slow infusion of carbetocin would reduce maternal heart rate variation and hemodynamic disturbances compared with a rapid bolus in parturients receiving a prophylactic phenylephrine infusion during elective Cesarean delivery. METHODS: In this double-blinded randomized controlled trial, 70 healthy parturients were allocated to either a bolus group or an infusion group. At cord clamping, participants in the bolus group received carbetocin 100 µg as a rapid intravenous bolus, while participants in the infusion group received carbetocin 100 µg over 10 min. The primary outcome was the variation in maternal heart rate from baseline during the 20 min following cord clamping. Secondary outcomes included blood pressure, cardiac output, and stroke volume variations during the study period, measured with the ClearSight™ hemodynamic monitor. RESULTS: Maximum heart rate variation was not different between the groups: bolus group, mean (standard deviation) 29.8 (25.2)% vs infusion group, 27.2 (23.3)%; P = 0.67. The increase in heart rate occurred significantly earlier in the bolus group than in the infusion group (median [interquartile range] time, 105 [69-570] sec vs 485 [255-762] sec; P = 0.02; group × time interaction: two-way repeated measures ANOVA, P = 0.04). There was no significant difference in maximum variations for the other hemodynamic parameters between the groups. CONCLUSION: Carbetocin infused over ten minutes did not reduce the magnitude of maternal heart rate variation but delayed its occurrence. This finding could be relevant to the anesthesiologist caring for parturients in whom a slight increase in maternal heart rate is clinically undesirable. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT03404544); registered 19 January 2018.

RéSUMé: OBJECTIF: Lorsque la carbétocine, un analogue de l'ocytocine, est administrée à titre de prophylaxie pour les hémorragies du post-partum dans les accouchements par césarienne programmée, cet agent provoque fréquemment une tachycardie et une hypotension. Il a été démontré qu'une perfusion de phényléphrine prévenait l'hypotension induite par la rachianesthésie. L'objectif de cette étude était d'évaluer si une perfusion lente de carbétocine réduirait la variation de fréquence cardiaque maternelle et les perturbations hémodynamiques par rapport à un bolus rapide chez les parturientes recevant une perfusion prophylactique de phényléphrine pendant un accouchement par césarienne programmée. MéTHODE: Dans cette étude randomisée contrôlée à double insu, 70 parturientes en bonne santé ont été allouées à un groupe bolus ou à un groupe perfusion. Lors du clampage du cordon, les participantes du groupe bolus ont reçu 100 µg de carbétocine sous forme de bolus intraveineux rapide, tandis que les participantes du groupe perfusion ont reçu 100 µg de carbétocine sur dix minutes. Le critère d'évaluation principal était la variation de la fréquence cardiaque maternelle par rapport aux valeurs de base au cours des 20 minutes suivant le clampage du cordon. Les critères secondaires comprenaient la tension artérielle, le débit cardiaque et les variations du volume d'éjection au cours de la période d'étude, tels que mesurés avec le moniteur hémodynamique ClearSight™. RéSULTATS: La variation maximale de fréquence cardiaque n'était pas différente entre les groupes : groupe bolus, moyenne (écart type) 29,8 (25,2) % vs groupe perfusion, 27,2 (23,3) %; P = 0,67. L'augmentation de la fréquence cardiaque s'est produite significativement plus tôt dans le groupe bolus que dans le groupe perfusion (temps médian [écart interquartile], 105 [69-570] sec vs 485 [255-762] sec; P = 0,02;× interaction groupe x temps : ANOVA bidirectionnelle à mesures répétées, P = 0,04). Il n'y avait pas de différence significative dans les variations maximales pour les autres paramètres hémodynamiques entre les groupes. CONCLUSION: La carbétocine perfusée pendant dix minutes n'a pas réduit l'ampleur de la variation de la fréquence cardiaque maternelle, mais a retardé son apparition. Cette découverte pourrait être pertinente pour l'anesthésiologiste qui prend soin de parturientes chez qui une légère augmentation de la fréquence cardiaque maternelle serait cliniquement indésirable. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03404544); enregistrée le 19 janvier 2018.

Intrapandemic regional anesthesia as practice: a historical cohort study in patients undergoing breast cancer surgery.

BACKGROUND: The COVID-19 pandemic has markedly increased delays in oncologic surgeries because of the virus's impact on traditional anesthetic management. Novel protocols, developed to protect patients and medical professionals, have altered the ways and instances in which general anesthesia (GA) can be safely performed. To reduce virus exposure related to aerosol-generating procedures, it is now recommended to avoid GA when feasible and promote regional anesthesia instead. At our institution, we observed faster postoperative recovery in patients who received paravertebral blocks for breast cancer surgery instead of GA. This led us to formally evaluate whether regional anesthesia instead of GA helped improve time to hospital discharge. METHODS: We conducted a historical cohort study to retrospectively analyze two cohorts of patients: prepandemic vs intrapandemic. We obtained approval from our institutional ethics committee to review files of consecutive patients who underwent breast cancer surgery between 30 March 2020 and 30 June 2020 (intrapandemic group; N = 106) and consecutive patients-moving backwards-from 28 February 2020 to 6 December 2019 (prepandemic group; N = 104). The primary outcome was the length of time between the end of surgery to readiness for hospital discharge. Secondary outcomes included the incidence of postoperative nausea and vomiting (PONV), the need for postoperative analgesia, and the duration of stay in the postanesthesia care unit (PACU). RESULTS: The median [interquartile range (IQR)] time to readiness for hospital discharge was significantly lower in patients who received paravertebral blocks for breast cancer surgery compared with GA (intrapandemic group, 119 [99-170] min vs prepandemic group, 191 [164-234] min; P < 0.001) as was the incidence of PONV (3% vs 11%; P = 0.03) and median [IQR] PACU durations of stay (29 [21-39] min vs 46 [37-63] min; P < 0.001). CONCLUSIONS: Patients who received paravertebral blocks for breast cancer surgery in the intrapandemic group were ready for hospital discharge earlier, spent less time in the PACU, and experienced less PONV than those who received GA in the prepandemic group. With growing surgical wait times, concerns related to aerosol-generating procedures, and recommendations to avoid GA when feasible, paravertebral blocks as the principal anesthetic modality for breast cancer surgery offered benefits for patients and medical teams.

RéSUMé: CONTEXTE: La pandémie de COVID-19 a considérablement augmenté les retards dans les chirurgies oncologiques en raison de l'impact du virus sur la prise en charge anesthésique traditionnelle. De nouveaux protocoles, mis au point pour protéger les patients et les professionnels de la santé, ont modifié les façons et les cas dans lesquels une anesthésie générale (AG) peut être réalisée en toute sécurité. Afin de réduire l'exposition au virus liée aux interventions génératrices d'aérosols, il est maintenant recommandé d'éviter l'AG lorsque possible et de privilégier l'anesthésie régionale. Dans notre établissement, nous avons observé une récupération postopératoire plus rapide chez les patientes ayant reçu des blocs paravertébraux pour une chirurgie de cancer du sein au lieu d'une AG. Cela nous a menés à évaluer de façon formelle si l'anesthésie régionale au lieu de l'AG avait contribué à réduire les délais jusqu'au congé de l'hôpital. MéTHODE: Nous avons réalisé une étude de cohorte historique afin d'analyser rétrospectivement deux cohortes de patientes : prépandémie vs intrapandémie. Nous avons obtenu l'approbation de notre comité d'éthique institutionnel pour examiner les dossiers de patientes consécutives ayant bénéficié d'une chirurgie de cancer du sein entre le 30 mars 2020 et le 30 juin 2020 (groupe intrapandémie; n = 106) et des patientes consécutives ­ en reculant ­ du 28 février 2020 au 6 décembre 2019 (groupe prépandémie; n = 104). Le critère d'évaluation principal était le délai entre la fin de la chirurgie et le moment où les patientes étaient prêtes à recevoir leur congé de l'hôpital. Les critères d'évaluation secondaires comprenaient l'incidence de nausées et vomissements postopératoires (NVPO), la nécessité d'une analgésie postopératoire et la durée de séjour en salle de réveil (SDR). RéSULTATS: Le délai médian [écart interquartile (ÉIQ)] jusqu'à la disposition au congé de l'hôpital était significativement plus court chez les patientes ayant reçu des blocs paravertébraux pour une chirurgie de cancer du sein plutôt qu'une AG (groupe intrapandémie, 119 [99-170] min vs groupe prépandémie, 191 [164­234] min; P < 0,001), tout comme l'incidence de NVPO (3 % vs 11 %; P = 0,03) et les durées médianes [ÉIQ] de séjour en salle de réveil (29 [21­39] min vs 46 [37­63] min; P < 0,001). CONCLUSION: Les patientes qui ont reçu des blocs paravertébraux pour une chirurgie de cancer du sein dans le groupe intrapandémie étaient prêtes à quitter l'hôpital plus tôt, ont passé moins de temps en salle de réveil et ont ressenti moins de NVPO que celles qui ont reçu une AG dans le groupe prépandémie. Avec des temps d'attente pour accès à la chirurgie de plus en plus longs, des préoccupations liées aux interventions génératrices d'aérosols et les recommandations d'éviter l'AG lorsque possible, les blocs paravertébraux ont offert des avantages aux patientes et aux équipes médicales en tant que principale modalité anesthésique pour la chirurgie de cancer du sein.

Impact of chronic treatment by ß1-adrenergic antagonists on Nociceptive-Level (NOL) index variation after a standardized noxious stimulus under general anesthesia: a cohort study.

During the perioperative period, nociception control is certainly one of the anesthesiologist's main objectives when assuming care of a patient. There exists some literature demonstrating that the nociceptive stimuli experienced during surgery are responsible for peripheral and central sensitization phenomena, which can in turn lead to persistent postsurgical pain. An individualized approach to the evaluation and treatment of perioperative nociception is beneficial in order to avoid the sensitization phenomena that leads to prolonged postoperative pain and to minimize the consumption of opiates and their adverse effects. In terms of sensitivity, specificity, and positive/negative predictive values when compared to heart rate (HR) and mean arterial pressure (MAP), recent literature has shown that the NOL variation (ΔNOL) is the best index to distinguish noxious from non-noxious stimuli. Chronic treatment with ß1-adrenergic antagonists may constitute a limitation to the use of the NOL index. ß1-adrenergic antagonists induce a depressive action on the heart rate, which results in a limitation of its variability after a noxious stimulus. Since heart rate and heart rate variability are two parameters integrated into the NOL index, the validity of the NOL index in a population of patients receiving ß1-adrenergic antagonists has not yet been determined. Our study sought to explore the NOL index, the BIS, and the heart rate variation in a group of patients under chronic treatment with ß1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia. We then compared those results to a control group of patients from our previous study (CJA group) that received no ß1-adrenergic antagonist chronic treatment. The patients in this study were subjected to a standardized anesthetic protocol from induction up to 3 min after a standardized tetanic stimulus to the ulnar nerve at a frequency of 100 Hz and an amperage of 70 mA, for a duration of 30 s. Data were electronically recorded to obtain NOL, BIS, and heart rate values every 5 s for the duration of the protocol. The NOL maximal mean value reached after noxious stimulation was not different between our two cohorts (CJA: 30(14) versus BETANOL: 36(14) (p = 0.12)). There was no statistically significant difference between our cohorts in regards of the NOL AUC representing the variation of the NOL over a 180 s period (CJA: 595(356) versus BETANOL: 634(301) (p = 0.30)). However, a repeated measurement ANCOVA identified slight statistically significant differences between our cohorts in the peak of variation of the NOL index between 20 and 65 s after noxious stimulation, the NOL index of the cohort of beta-blocked patients being higher than the CJA patients. Moreover, the time to reach the maximum value was not different (CJA: 73(37) versus BETANOL: 63(41) (p = 0.35)). NOL sensitivity and specificity to detect a noxious stimulus under general anesthesia were similar in patients taking beta-blockers or not, and were better than those of heart rate and Bispectral index (AUC NOL 0.97, CI(0.92-1), versus AUC BIS 0.78, CI(0.64-0.89) and AUC HR 0.66, CI(0.5-0.8)). In conclusion, the NOL index is a reliable monitor to assess nociception in a population of patients under chronic beta-blocker therapy. Patients under such therapy achieve similar maximal NOL values over a 180 s period after a standardized noxious stimulus and the NOL variation over time, represented by the AUC is not significantly different from a cohort of non-beta-blocked patients. Whether the patient takes beta-blockers or not, sensitivity of the NOL index is greater than that seen for BIS index or heart rate to detect an experimental noxious stimulus under general anesthesia.

A randomized controlled trial comparing nociception level (NOL) index, blood pressure, and heart rate responses to direct laryngoscopy versus videolaryngoscopy for intubation: the NOLint project.

PURPOSE: The effect of direct laryngoscopy using a Macintosh blade (MAC) vs GlideScope™ videolaryngoscopy using a Spectrum LoPro blade (GVL) on nociceptive stimulation has not been quantitatively studied. This study used the new nociception level (NOL) index to compare the nociceptive response induced by GVL or MAC during laryngoscopy with or without intubation. METHODS: Patients underwent two laryngoscopies at four-minute intervals (L1, L2), one with GVL and the other with MAC (first randomization). A third laryngoscopy (L3) followed by tracheal intubation was performed four minutes after L2 (GVL or MAC, second randomization). Nociception was quantitatively assessed by NOL and standard hemodynamic parameters (heart rate [HR] and mean arterial pressure). For the crossover design, blade comparisons accounted for sequence and blade type. A possible carryover effect between laryngoscopies was assessed. RESULTS: In the 50 patients randomized, there was no carryover effect from one laryngoscopy to the next for all analyzed parameters. Nociception level index peak values were higher with MAC than GVL. Analysis of ΔNOL showed a lower nociceptive response with GVL for L1+L2 combined. Mean peak NOL values were significantly higher after L3+intubation than after L1+L2, for both GVL and MAC groups. Analysis of ΔHR values did not show a significant difference between GVL and MAC for any laryngoscopy. CONCLUSION: Laryngoscopy alone with GVL induces less nociception than with MAC. The NOL was more sensitive than HR at detecting nociceptive responses to MAC vs GVL. Additionally, and irrespective of which technique/blade was used, the combination of laryngoscopy + tracheal intubation produced a much greater nociceptive response than the laryngoscopy alone. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03277872); registered 29 August 2017.

RéSUMé: OBJECTIF: L'effet de la laryngoscopie directe avec une lame Macintosh (MAC) par rapport à la vidéolaryngoscopie à l'aide d'un GlideScope™ avec lame Spectrum LoPro (GVL) sur la stimulation nociceptive n'a pas été quantitativement étudié. Cette étude a utilisé le nouvel indice de niveau de nociception (NOL) pour comparer la réponse nociceptive induite par une laryngoscopie avec GVL ou MAC avec ou sans intubation. MéTHODE: Les patients ont subi deux laryngoscopies à des intervalles de quatre minutes (L1, L2), l'une par GVL et l'autre par MAC (première randomisation). Une troisième laryngoscopie (L3) suivie d'une intubation trachéale a été effectuée quatre minutes après L2 (GVL ou MAC, deuxième randomisation). La nociception a été quantitativement évaluée à l'aide de l'indice NOL, et les paramètres hémodynamiques standard (fréquence cardiaque [FC] et pression artérielle moyenne) ont été mesurés. Dans le volet croisé de l'étude, les comparaisons de lames ont tenu compte de la séquence et du type de lame. La possibilité d'un effet de persistance entre les laryngoscopies a été évaluée. RéSULTATS: Chez les 50 patients randomisés, il n'y a eu aucun effet de persistance d'une laryngoscopie à la suivante pour tous les paramètres analysés. Les valeurs maximales de l'indice de nociception étaient plus élevées avec les lames MAC qu'avec la vidéolaryngoscopie GVL. L'analyse de ΔNOL a montré une réponse nociceptive inférieure avec la vidéolaryngoscopie GVL pour L1+L2 combinés. Les valeurs maximales moyennes de NOL étaient significativement plus élevées après L3+intubation qu'après L1+L2, tant pour les groupes GVL que MAC. L'analyse des valeurs ΔFC n'a pas montré de différence significative entre les techniques GVL et MAC pour quelque laryngoscopie que ce soit. CONCLUSION: La laryngoscopie seule avec le GlideScope induit moins de nociception qu'avec une lame MAC. L'indice NOL était plus sensible que les FC pour détecter les réponses nociceptives à la laryngoscopie MAC vs GVL. En outre, et indépendamment de la technique/lame utilisée, la combinaison de laryngoscopie + intubation trachéale a produit une réponse nociceptive beaucoup plus importante que la laryngoscopie seule. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03277872); enregistrée le 29 août 2017.

The impact of bolus versus continuous infusion of intravenous ketamine on bispectral index variations and desflurane administration during major surgery: The KETABIS study.

BACKGROUND: Although ketamine, a NMDA-receptor antagonist, tends to increase the bispectral index (BIS), it remains a widely used analgesic whenever administered in low doses during major surgery. OBJECTIVE: The objective of this study was to compare the impact of intravenous ketamine (given either as a continuous infusion or as a bolus) on BIS and to compare desflurane administration and postoperative outcomes between the groups. DESIGN: Prospective, randomised, parallel-group, open-label study. SETTING: University hospital, operating room. PARTICIPANTS: Fifty patients, scheduled for major abdominal surgery. INTERVENTIONS AND MAIN OUTCOMES MEASURES: Patients were randomised into two groups: ketamine by intravenous continuous infusion - group (KI) and ketamine by i.v. bolus - group (KB). In the KI group, ketamine at a rate of 0.25 mg kg-1 h-1 was commenced at skin incision (T0) and maintained at this rate for the duration of surgery. In group KB, a ketamine bolus of 0.25 mg kg-1was administered at T0 and repeated every hour. The difference in BIS between the groups was compared from T0 onwards. The amount of desflurane administered to keep BIS within the usual recommended range (40-60) was compared, as were the doses of phenylephrine and remifentanil. Postoperative pain and recovery outcomes were also assessed. RESULTS: After T0, the BIS increased significantly from baseline in group KB compared with group KI: the rise in BIS was 20 ±â€Š8 vs. 11 ±â€Š6, respectively (P = 0.0001). The between-group mean difference (95% confidence interval (CI), was 9 (5 to 13). In group KB, desflurane administration significantly increased for the first 15 min after T0: 6.3 ±â€Š1.8 vs. 3.8 ±â€Š1.3 ml (P < 0.0001) with a mean intergroup group difference (95% CI) of 2.4 (1.5 to 3.4) ml. There was no difference in desflurane administration when considering the full hour from T0 to T60 min: 16 ±â€Š9 vs. 15 ±â€Š5 ml (P = 0.63) with a mean intergroup difference (95% CI) of 1 (-3 to 5) ml. After surgery, pain scores, opioid consumption, incidence of nausea and vomiting and recovery scores were similar between groups. CONCLUSION: Compared with a continuous ketamine infusion, a ketamine bolus significantly increased the BIS after T0. In order to keep the BIS below 60, significantly more desflurane was administered from T0 to T15 min in group KB. To prevent such higher desflurane administration and its related atmospheric pollution, our results suggest administering intra-operative intravenous ketamine as an infusion rather than a bolus. TRIAL REGISTRATION: Clinicaltrials.gov registration identifier: NCT03781635.

In Vivo Protamine Titration Using Activated Coagulation Time to Neutralize Heparin Anticoagulation in Cardiac Surgery: Proof of Concept.

OBJECTIVE: In vivo protamine titration (IVPT) is based on the observation of a plateau on the decay curve of the celite activated clotting times (ACTs) during protamine infusion for heparin reversal. The aim of the present study was to determine the optimal protamine/heparin ratio to reverse anticoagulation using IVPT curves. DESIGN: Prospective, randomized study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 138 patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: The control group was given a protamine infusion of 1.3 mg per 1 mg (100 U) of heparin over 21 minutes. ACT was measured every 3 minutes. In the test group, the protamine dose was prepared using the same ratio as for the control group, and ACT values were measured every 3 minutes until a plateau was reached (2 consecutive ACT values <160 s), at which time the protamine infusion was stopped. The protamine/heparin ratio, blood losses, transfusions, and heparin concentrations were recorded. RESULTS: The protamine dose was lower in the test group (456.00 ± 105.66 mg [control group] v 295.25 ± 100.60 mg [test group]; p < 0.0001). The mean protamine/heparin ratios were 1.30 ± 0.10 (control group) and 0.81 ± 0.22 (test group) (p < 0.0001). Heparin concentrations were greater in the test group 15 minutes (0.10 [0-0.2] U/mL v 0 [0-0.1] U/mL; p = < 0.0001) and 3 hours (0 [0-0.1] U/mL v 0 [0-0] U/mL; p = 0.0002) after protamine infusion. There was no difference in the blood losses and transfusion requirements. CONCLUSIONS: IVPT is safe and efficient in this low-risk population.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Myocardial Protection in Minimally Invasive Mitral Valve Surgery: Retrograde Cardioplegia Alone Using Endovascular Coronary Sinus Catheter Compared With Combined Antegrade and Retrograde Cardioplegia.

OBJECTIVE: To compare myocardial protection with retrograde cardioplegia alone with antegrade and retrograde cardioplegia in minimally invasive mitral valve surgery (MIMS). DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: The authors studied 97 MIMS patients using retrograde cardioplegia alone and 118 MIMS patients using antegrade and retrograde cardioplegia. INTERVENTIONS: The data from patients admitted for MIMS using retrograde cardioplegia (MIMS retro) between 2009 to 2012 were compared with the data from patients undergoing MIMS with antegrade and retrograde cardioplegia (MIMS ante-retro) between 2006 and 2010 (control group). Cardioplegia in the MIMS retro group was delivered solely through an endovascular coronary sinus (CS) catheter positioned under echographic and fluoroscopic guidance. Antegrade and retrograde cardioplegia was used in the MIMS ante-retro group. Data regarding myocardial infarction (MI; creatine kinase Mb, troponin T, electrocardiogram), myocardial function, and hemodynamic stability were collected for comparison. MEASUREMENTS AND MAIN RESULTS: Adequate cardioplegia administration (CS pressure >30 mmHg and asystole) was attained in 74.2% of the patients with retrograde cardioplegia alone. In 23.7% of the patients, the addition of an antegrade cardioplegia was necessary. No difference was observed in the incidence of MI (0 MIMS retro v 1 for MIMS ante-retro, p = 0.3623), difficult separation from cardiopulmonary bypass, and postoperative malignant arrhythmia. No difference was found for maximal creatine kinase Mb (39.1 [28.0-49.1] v 37.9 [28.6-50.9]; p = 0.8299) and for maximal troponin T levels (0.39 [0.27-0.70] v 0.47 [0.32-0.79]; p = 0.1231) for MIMS retro and MIMS ante-retro, respectively. However, lactate levels in the MIMS retro group were significantly lower than in the MIMS ante-retro group (2.1 [1.4-3.05] v 2.4 [1.8-3.3], respectively; p = 0.0453). No difference was observed in duration of intensive care unit stay and death. MIMS retro patients had a shorter hospital stay (7.0 [6.0-8.0] v 8.0 [7.0-9.0] days; p = 0.0003). CONCLUSION: Retrograde cardioplegia administration alone provided comparable myocardial protection to antegrade and retrograde cardioplegia during MIMS, but was not sufficient to achieve asystole in one-fifth of patients.

A Simplified Approach to Extravascular Lung Water Assessment Using Point-of-Care Ultrasound in Patients with End-Stage Chronic Renal Failure Undergoing Hemodialysis.

BACKGROUND: Fluid overload leading to pulmonary congestion is an important issue in patients undergoing hemodialysis. This study aimed to determine if a simplified method of extravascular lung water assessment using ultrasound provided clinically relevant information. METHODS: This prospective study recruited 47 patients from a single hemodialysis center. Pulmonary ultrasound was performed before and after 2 hemodialysis sessions in 28 regions on the thorax. The B-line score was defined as the percentage regions where B-lines were present. RESULTS: When B-lines were detected before hemodialysis, a significant relationship was found between fluid removal and the change in B-line score. Patients with a B-line score of ≥21.4% (4th quartile) after the second hemodialysis session were more likely to be hospitalized for pulmonary edema or acute coronary syndrome. CONCLUSIONS: A simplified pulmonary assessment using ultrasound provides relevant information about pulmonary congestion in hemodialysis patients and identifies patients at risk of hospitalization for heart-related problems.

The Association Between Pulsatile Portal Flow and Acute Kidney Injury after Cardiac Surgery: A Retrospective Cohort Study.

OBJECTIVE: Venous congestion is a possible mechanism leading to acute kidney injury (AKI) following cardiac surgery. Portal vein flow pulsatility is an echographic marker of cardiogenic portal hypertension and might identify clinically significant organ congestion. This exploratory study aims to assess if the presence of portal flow pulsatility measured by transthoracic echography in the postsurgical intensive care unit is associated with AKI after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Specialized care university hospital. PARTICIPANTS: Patients who underwent cardiac surgery between May 2015 and February 2016 and had at least 1 Doppler assessment of portal flow performed by the attending critical care physician during the week following cardiac surgery. INTERVENTIONS: The association between portal flow pulsatility defined as a pulsatility fraction ≥50% and the risk of subsequent AKI was assessed using univariate and multivariate logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: The files of 132 consecutive patients were reviewed and 102 patients were included in the analysis. Significant portal flow pulsatility was detected in 38 patients (37.3%) in the week following surgery. During this period, 60.8% developed AKI and 13.7% progressed to severe AKI. The detection of portal flow pulsatility was associated with an increased risk for the development of AKI (odds ration [OR] 4.31, confidence interval [CI] 1.50-12.35, p = 0.007). After adjustment, portal flow pulsatility and AKI were independently associated (OR 4.88, CI 1.54-15.47, p = 0.007). CONCLUSIONS: Assessment of portal flow using Doppler ultrasound at the bedside might be a promising tool to detect patients at risk for AKI due to cardiogenic venous congestion.

Myocardial Protection in Mitral Valve Surgery: Comparison Between Minimally Invasive Approach and Standard Sternotomy.

OBJECTIVE: To compare antegrade and retrograde cardioplegia administration in minimally invasive mitral valve surgery (MIMS) and open mitral valve surgery (OMS) for myocardial protection. DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 118 patients undergoing MIMS and 118 patients undergoing OMS. INTERVENTIONS: The data of patients admitted for MIMS from 2006 to 2010 were reviewed. Patients undergoing isolated elective OMS from 2004 to 2006 were used as a control group. Cardioplegia in the MIMS group was delivered via the distal port of the endoaortic clamp and an endovascular coronary sinus catheter positioned using echographic and fluoroscopic guidance. Antegrade and retrograde cardioplegia were used in OMS. Data regarding myocardial infarction (MI) (creatine kinase [CK]-MB, troponin T, electrocardiography); myocardial function; and hemodynamic stability were collected. MEASUREMENTS AND MAIN RESULTS: There was no difference in the perioperative MI incidence between both groups (1 in each group, p = 0.96). No statistically significant difference was found for maximal CK-MB (35.9 µg/L [25.1-50.1] v 37.9 µg/L [28.6-50.9]; p = 0.31) or the number of patients with CK-MB levels >50 µg/L (29 v 33; p = 0.55) or CK-MB >100 µg/L (3 v 4; p = 0.70) between the OMS and MIMS groups. However, maximum troponin T levels in the MIMS group were significantly lower (0.47 µg/L [0.32-0.79] v 0.65 µg/L [0.45-0.94]; p = 0.0007). No difference in the incidence of difficult weaning from bypass and intra-aortic balloon pump use between the MIMS and OMS groups was found. CONCLUSIONS: Antegrade and retrograde cardioplegia administration during MIMS and OMS provided comparable myocardial protection.

Preliminary Experience in Combined Somatic and Cerebral Oximetry Monitoring in Liver Transplantation.

OBJECTIVE: The use of cerebral near-infrared spectroscopy (NIRS) has become widespread in cardiac surgery after research demonstrated an association between perioperative cerebral desaturations and postoperative complications. Somatic NIRS desaturation also is associated with an increased risk of postoperative complications and mortality. The objective of this study was to explore the trends of both somatic and cerebral NIRS during liver transplantation. DESIGN: A prospective, single-site, observational case series. SETTING: Tertiary care center. PARTICIPANTS: The study comprised 10 patients undergoing liver transplantation. INTERVENTIONS: NIRS sensors were placed on the forehead (cerebral regional oxygen saturation [rSO2]) and on the right arm and right leg (somatic rSO2) to measure tissue perfusion. Desaturation was defined as a 20% decrease of baseline values for 15 seconds. MEASUREMENTS AND MAIN RESULTS: In all patients, parallel changes in both cerebral and somatic rSO2 values were observed during phlebotomy, bleeding, transfusion, portal vein clamping, and the use of vasoactive agents. Induction of anesthesia increased cerebral rSO2 more than it did somatic values. However, ascites removal, abdominal manipulation, and clamping of the inferior vena cava (IVC) were associated with nonparallel changes in cerebral and somatic rSO2. Ascites removal was associated with increased somatic leg rSO2, and IVC clamping and abdominal hypertension were associated with a significant reduction in somatic leg rSO2. Somatic leg desaturation instead of arm or cerebral desaturation was associated with more postoperative complications. CONCLUSIONS: The use of combined NIRS monitoring allows for the identification of the source of somatic or cerebral desaturation. Compromised venous flow from the IVC from clamping or abdominal compartment syndrome typically is associated with the appearance of more pronounced leg than arm desaturation.

Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond.

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial ß-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/.

Prognostic impact of the residual SYNTAX score on in-hospital outcomes in patients undergoing primary percutaneous coronary intervention.

OBJECTIVES: This study sought to assess the impact of residual coronary artery disease (CAD), using the residual SYNTAX score (rSS), on in-hospital outcomes after primary percutaneous intervention (PPCI). The study also aimed to determine independent predictors for high rSS. Residual CAD has been associated with worsened prognosis in patients undergoing PCI for non-ST acute coronary syndromes. The rSS is a systematic angiographic score that measures the extent and complexity of residual CAD after PCI. MATERIALS AND METHODS: Data from 243 consecutive patients undergoing PPCI for ST-elevation myocardial infarction (STEMI) were analyzed. The rSS was derived from post-PPCI angiography. Patients were dichotomized into low (<8) and high rSS (≥8) groups and outcomes were compared between groups. The primary outcome of net adverse cardiovascular events (NACE) consisted of a composite of in-hospital death, congestive heart failure (CHF), recurrent MI and bleeding. RESULTS: The mean rSS was 4.7 (±7.2). A high rSS was associated with the primary outcome (P < 0.0001), in-hospital death (P = 0.0026), periprocedural death (P < 0.0001), CHF (P < 0.0004) and acute kidney injury (P < 0.0019). A high rSS was also an independent predictor of the primary outcome with an OR of 3.82. Independent predictors of a high rSS included a history of diabetes (OR 2.8), previous MI (OR 5.75), 2-vessel disease (VD) (OR 15.48, vs. 1-VD) and 3-VD (OR 57.06, vs. 1-VD). CONCLUSIONS: Residual CAD, as assessed by the rSS, confers a worsened prognosis in patients undergoing PPCI. Diabetes, previous MI and multi-vessel disease were independent predictors of a high rSS. © 2016 Wiley Periodicals, Inc.

Risk Factors Involved in Central-to-Radial Arterial Pressure Gradient During Cardiac Surgery.

BACKGROUND: A central-to-radial arterial pressure gradient may occur after cardiopulmonary bypass (CPB), which, in some patients, may last for a prolonged time after CPB. Whenever there is a pressure gradient, the radial artery pressure measure may underestimate a more centrally measured systemic pressure, which may result in a misguided therapeutic strategy. It is clinically important to identify the risk factors that may predict the appearance of a central-to-radial pressure gradient, because more central sites of measurements might then be considered to monitor systemic arterial pressure in high-risk patients. The objective of this study was to assess preoperative and intraoperative risk factors for central-to-radial pressure gradient. METHODS: Seventy-three patients undergoing cardiac surgery using CPB were included in this prospective observational study. A significant central-to-radial arterial pressure gradient was defined as a difference of 25 mm Hg in systolic pressure or 10 mm Hg in mean arterial pressure for a minimum of 5 minutes. Preoperative data included demographics, presence of comorbidities, and medications. Intraoperative data included type of surgery, CPB and aortic clamping time, use of inotropic drugs, and vasodilators or vasopressors agents. The diameter of the radial and femoral artery was measured before the induction of anesthesia using B-mode ultrasonography. RESULTS: Thirty-three patients developed a central-to-radial arterial pressure gradient (45%). Patients with a significant pressure gradient had a smaller weight (71.0 ± 16.9 vs 79.3 ± 17.3 kg, P = 0.041), a smaller height (162.0 ± 9.6 vs 166.3 ± 8.6 cm, P = 0.047), a smaller radial artery diameter (0.24 ± 0.03 vs 0.29 ± 0.05 cm, P < 0.001), and were at a higher risk as determined by the Parsonnet score (30.3 ± 24.9 vs 17.0 ± 10.9, P = 0.007). In addition, a longer aortic clamping time (85.8 ± 51.0 vs 64.2 ± 29.3 minutes, P = 0.036), mitral and complex surgery (P = 0.007 and P = 0.017, respectively), and administration of vasopressin (P = 0.039) were identified as potential independent predictors of a central-to-radial pressure gradient. By using multivariate logistic regression analysis, the following independent risk factors were identified: Parsonnet score (odds ratio [OR], 1.076; 95% confidence interval [CI], 1.027-1.127, P = 0.002), aortic clamping time >90 minutes (OR, 8.521; 95% CI, 1.917-37.870, P = 0.005), and patient height (OR, 0.933, 95% CI, 0.876-0.993, P = 0.029). The relative risk (RR) estimates remained statistically significant for the Parsonnet score and the aortic clamping time ≥90 minutes (RR, 1.010; 95% CI, 1.003-1.018, P = 0.009 and RR, 2.253; 95% CI, 1.475-3.443, P < 0.001 respectively) while showing a trend for patient height (RR, 0.974; 95% CI, 0.948-1.001, P = 0.058). CONCLUSIONS: Central-to-radial gradients are common in cardiac surgery. The threshold for using a central site for blood pressure monitoring should be low in small, high-risk patients undergoing longer surgical interventions to avoid inappropriate administration of vasopressors and/or inotropic agents.