The effect of immunosuppressive therapies on the endothelial host response in critically ill COVID-19 patients.

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0-1, day 2-4 and day 6-8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54-70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002-0.064] and 0.041 [0.013-0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034-0.107], 0.060 [0.030-0.091] and 0.043 [0.001-0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006-0.071] and 0.023 [0.000-0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments.

Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial.

Importance: An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. Objective: To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. Design, Setting, and Participants: Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. Interventions: Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H2O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H2O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. Main Outcomes and Measures: The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with Spo2 ≤92% for >1 minute). Results: Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, -2.3% [95% CI, -5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, -8.6% [95% CI, -11.1% to 6.1%]; P < .001). Conclusions and Relevance: Among obese patients undergoing surgery under general anesthesia, an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers, compared with a strategy with a lower level of PEEP, did not reduce postoperative pulmonary complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02148692.

[The use of dexmedetomidine in extreme agitation]. / Het gebruik van dexmedetomidine bij extreme agitatie.

BACKGROUND: In clinical practice antipsychotics, benzodiazepines and/or antihistamines are used to calm agitated patients. If agitation persists and patients have contraindications for these substances, then anesthetics, such as propofol, can also be used as well, to serve as a sedative. Our attention was drawn to a particular case in which dexmedetomidine was used as a sedative.
AIM: To study the literature on the use of α2-agonists, such as dexmedetomidine, in the treatment of extreme agitation.
METHOD: We reviewed the relevant scientific literature.
RESULTS: α2-agonists, such as dexmedetomidine, are new anesthetic agents that have analgetic and sympatholytic effects without suppressing respiration. These agents are used frequently in intensive care because their sedative effect are short-lived and do not cause amnesia, sleep deprivation or cognitive disturbance. Excited delirium syndrome (eds) is a type of extreme agitation for which dexmedetomidine can be used.
CONCLUSION: There may well be a place for dexmedetomidine in the treatment of extreme agitation when standard treatments have failed. Further research is needed in order to ascertain whether dexmedetomidine should play a role in such treatment.

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial.

BACKGROUND: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. METHODS/DESIGN: The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. DISCUSSION: To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016.

A review of the interest of sugammadex for deep neuromuscular blockade management in Belgium.

Oro-tracheal intubation and selected surgical conditions are facilitated by a deep neuromuscular block (NMB), but patient's security can be jeopardized by its residual effects at the time of tracheal extubation. Although neostigmine remains the reference reversal agent in many situations, the limitations of its efficacy must be well understood (ceiling effect, delay of action, side effects). It is best administered after re-emergence of the 3rd or 4th train-of-four (TOF) response. Sugammadex causes more predictable and more rapid recoveries from much deeper rocuronium-induced NMB. Therefore, maintaining deep NMB during surgery is no longer incompatible with rapid recovery and safe extubation. In Belgium, the use of sugammadex and its reimbursement depend on specific conditions. The excellent clinical tolerance of sugammadex benefits to patients at risk of developing complications related to residual NMB or to the undesirable effects of neostigmine. In all cases, neuromuscular transmission monitoring is the key to adequate NMB management.

Ideal versus corrected body weight for dosage of sugammadex in morbidly obese patients.

To date, the dosing of sugammadex is based on real body weight without taking fat content into account. We compared the reversal of profound rocuronium-induced neuromuscular blockade in morbidly obese patients using doses of sugammadex based on four different weight corrections. One hundred morbidly obese patients, scheduled for laparoscopic bariatric surgery under propofol-sufentanil anaesthesia, were randomly assigned four groups: ideal body weight; ideal body weight + 20%; ideal body weight + 40%; and real body weight. Patients received sugammadex 2 mg.kg(-1), when adductor pollicis monitoring showed two responses. The primary endpoint was full decurarisation. Secondary endpoints were the ability to get into bed independently on arrival to the post-anaesthetic care unit and clinical signs of residual paralysis. There was no residual paralysis in any patient. Morbidly obese patients can safely be decurarised from rocuronium-induced neuromuscular blockade T1-T2 with sugammadex dosed at 2 mg.kg(-1) ideal body weight + 40% (p < 0.0001).

A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery.

A randomised study of 414 patients undergoing coronary artery surgery with cardiopulmonary bypass was conducted to compare the effects of a volatile anaesthetic regimen with either deesflurane or sevoflurane, and a total intravenous anaesthesia (TIVA) regimen on postoperative troponin T release. The primary outcome variable was postoperative troponin T release, secondary outcome variables were hospital length of stay and 1-year mortality. Maximal postoperative troponin T values did not differ between groups (TIVA: 0.30 [0.00-4.79] ng x ml(-1) (median [range]), sevoflurane: 0.33 [0.02-3.68] ng x ml(-1), and desflurane: 0.39 [0.08-3.74] ng x ml(-1)). The independent predictors of hospital length of stay were the EuroSCORE (p < 0.001), female gender (p = 0.042) and the group assignment (p < 0.001). The one-year mortality was 12.3% in the TIVA group, 3.3% in the sevoflurane group, and 6.7% in the desflurane group. The EuroSCORE (p = 0.003) was the only significant independent predictor of 1-year mortality.

A comparison of cardiac output derived from the arterial pressure wave against thermodilution in cardiac surgery patients.

In three clinical centres, we compared a new method for measuring cardiac output with conventional thermodilution. The new method computes beat-to-beat cardiac output from radial artery pressure by simulating a three-element model of aortic input impedance, and includes non-linear aortic mechanical properties and a self-adapting systemic vascular resistance. We compared cardiac output by continuous model simulation (MF) with thermodilution cardiac output (TD) in 54 patients (18 female, 36 male) undergoing coronary artery bypass surgery. We made three or four conventional thermodilution estimates spread equally over the ventilatory cycle. In 490 series of measurements, thermodilution cardiac output ranged from 2.1 to 9.3, mean 5.0 litre min(-1). MF differed +0.32 (1.0) litre min(-1) on average with limits of agreement of -1.68 and +2.32 litre min(-1). Differences decreased when the first series of measurements in a patient was used to calibrate the model. In 436 remaining series, the mean difference became -0.13 (0.47) litre min(-1) with limits of agreement of -1.05 and +0.79 litre min(-1). When consecutive measurements were made, the change was greater than 0.5 litre min(-1), on 204 occasions. The direction of change was the same with both methods in 199. The difference between the methods remained near zero during surgery suggesting that a single calibration per patient was adequate. Aortic model simulation with radial artery pressure as input reliably monitors changes in cardiac output in cardiac surgery patients. Before calibration, the model cannot replace thermodilution, but after calibration the model method can quantitatively replace further thermodilution estimates.

The left ventricular ejection effect.

A recently developed model of the left ventricle, based on experimental data, has been shown to exhibit the main features of the heart's ability to pump. Two special cases during blood ejection, termed pressure deactivation and hyperactivation, were identified. This study proposes an 'ejection effect' correction to the model that addresses deactivation, hyperactivation and adjusts the shape of the computed ventricular ejection curve in late systole. Also, a new approach based on new animal experiments is proposed to identify the ejection effect mechanism(s).

A comparison of anaesthesia using remifentanil combined with either isoflurane, enflurane or propofol in patients undergoing gynaecological laparoscopy, varicose vein or arthroscopic surgery.

BACKGROUND: Anaesthesia comprising remifentanil plus isoflurane, enflurane or propofol was randomly evaluated in 285, 285 and 284 patients, respectively, undergoing short-procedure surgery. METHODS: Anaesthesia was induced with propofol (0.5 mg x kg(-1) and 10 mg x 10 s(-1)), and a remifentanil bolus (1 microg x kg(-1)) and infusion at 0.5 microg x g(-1) x min(-1). Five minutes after intubation, remifentanil infusion was halved and 0.5 MAC of isoflurane or enflurane, or propofol at 100 microg x kg(-1) x min(-1) were started and titrated for maintenance. RESULTS: Patient demography and anaesthesia duration were similar between the groups. Surgery was performed as daycases (52%) or inpatients (48%). The median times (5-7 min) to extubation and postoperative recovery were similar between the groups. Responses to tracheal intubation (15% vs 8%) and skin incision (13% vs 7%) were significantly greater in the total intravenous anaesthesia (TIVA) group (P<0.05). Fewer patients given remifentanil and isoflurane (21%) or enflurane (19%) experienced > or =1 intraoperative stress response compared to the TIVA group (28%) (P<0.05). Median times to qualification for and actual recovery room discharge were 0.5-0.6 h and 1.1-1.2 h, respectively. The most common remifentanil-related symptoms were muscle rigidity (6-7%) at induction, hypotension (3-5%) and bradycardia (1-4%) intraoperatively and, shivering (6-7%), nausea and vomiting postoperatively. Nausea (7%) and vomiting (3%) were significantly lower with TIVA compared with inhaled anaesthetic groups (14-15% and 6-8%, respectively; P<0.05). CONCLUSION: Anaesthesia combining remifentanil with volatile hypnotics or TIVA with propofol was effective and well tolerated. Times of extubation, postanaesthesia recovery and recovery room discharge were rapid, consistent and similar for all three regimens.

Comparison of the cardiovascular effects of cisatracurium and vecuronium in patients with coronary artery disease.

PURPOSE: Cisatracurium besylate (Nimbex Injection, Glaxo Wellcome Inc., Research Triangle Park, NC) is an intermediate-acting bis-benzylisoquinolinium neuromuscular blocking drug that is one of the stereoisomers of atracurium. At doses < or = 8 x ED95, it caused no clinically important cardiovascular side effects or histamine release in healthy patients. The purpose of the present study was to investigate the haemodynamic effects of high doses of cisatracurium in patients with coronary artery disease. METHODS: One hundred patients undergoing myocardial revascularization participated in a pilot study (seven patients) and a double-blinded, randomized, controlled trial comparing the haemodynamic effects of cisatracurium with vecuronium at three centres. The patients were anaesthetized using oxygen 100%, with etomidate, fentanyl and a benzodiazepine, and tracheal intubation was facilitated using succinylcholine. After baseline haemodynamic measurements, the study drug was administered over 5-10 sec according to group assignment: Group A (pilot) cisatracurium, 0.20 mg.kg-1 (4 x ED95), (n = 7); Group B-cisatracurium, 0.30 mg.kg-1 (6 x ED95), (n x ED95), (n = 31); Group C-vecuronium, 0.30 mg.kg-1 (6 x ED95), (n = 31); Group D cisatracurium, 0.40 mg.kg-1 (8 x ED95), (n = 21); Group E-vecuronium, 0.30 mg.kg-1 (6 x ED95), (n = 10). The haemodynamic measurements were repeated at 2, 5, and 10 min after cisatracurium or vecuronium. RESULTS: Two patients in Group D had > 20% decreases in MAP, but only one required therapy for hypotension. The haemodynamic changes from pre- to post-injection in the cisatracurium patients were minimal and similar to patients receiving vecuronium. CONCLUSIONS: In patients with coronary artery disease, rapid cisatracurium (4-8 x ED95) boluses and vecuronium (6 x ED95) result in minor, clinically insignificant haemodynamic side effects.

A perspective on myocardial contractility.

Myocardial contractile properties form the cornerstone of the heart's ability to pump blood. Efforts have been made to characterize these properties via classic elasticity theory concepts, which can lead to spurious results, as demonstrated by experiments measuring intramyocardial pressure. Two ways out of these difficulties are identified. One is to start at the cellular level, the other at the chamber level. The latter allows separation of ventricle (source) and arterial (load) effects on measured pressure and flow, distinct from previous definitions of ventricular contractility which tended to lump the two.

Comparison of eltanolone and propofol on a pressure-volume analysis of the heart.

We designed a randomized study to compare the effect of eltanolone and propofol on cardiac contractility. Patients were anesthetized, tracheally intubated and ventilation controlled. Propofol, 1.25 or 2.5 mg/kg, or eltanolone, 0.5 or 1 mg/kg, or a lipid emulsion only was administered in an intravenous (i.v.) bolus dose. Pressure-volume analysis was used based on radial artery pressure and transesophageal left ventricular cross-sectional area. Both propofol and eltanolone have negative inotropic properties in humans. We conclude that equianesthetic doses of these drugs produce similar changes in myocardial contractility.

Comparison between CDI-100 continuous SO2, Hb, and Hct monitoring, intermittent ABL-4 saturation and Hb monitoring, and lab Hb and Hct monitoring.

During extracorporeal circulation (ECC) a continuous monitoring of venous oxygen saturation yields a quantitative impression of the equilibrium of oxygen supply and oxygen consumption in steady state conditions. The aim of the investigation was to study whether the measurements of venous oxygen saturation and haemoglobin of a continuous on-line monitor (CDI-100) agree with those of the ABL-4 bloodgasmonitor or the haemoglobincyanid method in hospital laboratory. The study group consisted of 21 patients, with comparable conditions of anesthesia and ECC set-up. Measurements of saturation and haemoglobin were compared at three moments, resulting in a total of 189 measurements. Analysis was based on the Bland Altman method, using the differences between correspondent measurements, which contain all the information needed to decide whether the methods agree. Bias of saturation measurement (CDI-100 versus ABL-4) is -3.4, 3.0 and -3.5% at times 1,2 and 3. All values are situated within the limits of agreement. Bias of haemoglobin measurement (CDI-100 versus ABL-4) is 0.3, 0.3, and 0.2 gr/dl at times 1, 2 and 3. All values (except one value) are situated within the limits of agreement. Bias of hemoglobin measurement (CDI-100 versus hospital laboratory) is 0.2, 0.0 and 0.1 gr/dl, and all values are situated within the limits of agreement. The results confirm that the CDI-100, in the set-up as described, can be used as a reliable instrument to monitor venous oxygen saturation and haemoglobin during ECC.