Teaching Medical Students Rapid Ultrasound for shock and hypotension (RUSH): learning outcomes and clinical performance in a proof-of-concept study.

BACKGROUND: Point-of-care ultrasound (POCUS) is a critical diagnostic tool in various medical settings, yet its instruction in medical education is inconsistent. The Rapid Ultrasound for Shock and Hypotension (RUSH) protocol is a comprehensive diagnostic tool, but its complexity poses challenges for teaching and learning. This study evaluates the effectiveness of a single-day training in RUSH for medical students by assessing their performance in clinical scenarios. METHODS: In this prospective single-center observational proof-of-concept study, 16 medical students from Saarland University Medical Center underwent a single-day training in RUSH, followed by evaluations in clinical settings and on a high-fidelity simulator. Performance was assessed using a standardized scoring tool and time to complete the RUSH exam. Knowledge gain was measured with pre- and post-training written exams, and diagnostic performance was evaluated with an objective structured clinical examination (OSCE). RESULTS: Students demonstrated high performance in RUSH exam views across patients (median performance: 85-87%) and improved scanning times, although not statistically significant. They performed better on simulators than on live patients. Written exam scores significantly improved post-training, suggesting a gain in theoretical knowledge. However, more than a third of students could not complete the RUSH exam within five minutes on live patients. CONCLUSIONS: Single-day RUSH training improved medical students' theoretical knowledge and simulator performance but translating these skills to clinical settings proved challenging. The findings suggest that while short-term training can be beneficial, it may not suffice for clinical proficiency. This study underscores the need for structured and possibly longitudinal training programs to ensure skill retention and clinical applicability.

Neuropsychological follow-up of isoflurane sedated intensive care patients: a substudy of a randomized trial.

BACKGROUND: Inhaled sedation of intensive care unit (ICU) patients ventilated >24 hours may have long term effects. We hypothesized that isoflurane has a better neuropsychological outcome in a one-year follow-up compared to propofol sedation. METHODS: All 66 patients included by the coordinating center of the ISOCONDA study (EudraCT#: 2016-004551-67) took part in this substudy (DRKS00020240). A delirium test (CAM-ICU) was performed 24 hours after end of sedation. Sedation-, ventilator-, ICU- and delirium-free days within 30 days were calculated. Patients were sent five questionnaires one, three and twelve months after ICU discharge: ICU-Memory-tool (ICU-MT), Short-Form-36-Health-survey (SF-36), Posttraumatic-Stress-Scale-14 (PTSS-14), WHO-Five-Well-Being-Index (WHO-5) and Hospital-Anxiety-Depression-Scale (HADS). RESULTS: CAM-ICU was positive in 17% of patients, however 68% showed signs of delirium during the ICU stay (no group differences). Mortality was lower after isoflurane (30-days: 1/33 versus 7/33, P=0.024; One-year: 9/33 versus 14/33, P=0.156). Isoflurane led to significantly more sedation- (median [IQR]: 28[25-29] versus 24[21-29], P=0.016), ventilator- (28[24-29] versus 22[4-28], P=0.011), ICU- (23[13-26] versus 11[0-25], P=0.044) and delirium-free days (25[21-29] versus 20[12-28], P=0.031). Return rate of questionnaires was high (87/128). In the ICU-MT, isoflurane patients recalled significantly more factual memories after one year. Generally, the psychological tests suggested a poor quality of life (SF-36), high rates of post-traumatic-stress-disorder (PTSS-14: 38%) and depression (WHO-5: 54%, HADS: 43%), without significant group differences. CONCLUSIONS: Isoflurane sedation leads to more delirium free days during the ICU treatment and more factual memories of the ICU stay one year after the ICU stay. However long-term outcome of ventilated ICU patients is poor, and there were no differences between isoflurane and propofol sedation.

Rapid and Effective Elimination of Myoglobin with CytoSorb® Hemoadsorber in Patients with Severe Rhabdomyolysis.

INTRODUCTION: Rhabdomyolysis is characterized by destruction of muscle fibers by various causes and is diagnosed by increased creatine kinase concentrations in the blood. Myoglobin released into the blood may cause acute kidney injury. In this randomized controlled study, we hypothesized that myoglobin elimination would be faster when a hemoadsorber was added to a continuous veno-venous hemodialysis (CVVHD). METHODS: Four patients in the control group received CVVHD with a high cut-off hemofilter using high blood and dialysate flows for 48 h. Four patients in the CytoSorb group received the same treatment, but in addition, the hemoadsorber CytoSorb® was inserted in front of the hemofilter and replaced once after 24 h. Blood samples were drawn simultaneously before (pre) and after (post) the hemofilter or else the hemoadsorber, after 5 and 30 min, as well as after 2, 4, 8, and 24 h. All measurements were repeated the next day after the hemoadsorber had been renewed in the CytoSorb group. Primary outcome was the area under the curve (AUC) of the relative myoglobin concentrations as percent of baseline. To evaluate the efficacy of myoglobin removal, relative reductions in myoglobin concentrations during one passage through each device at each time point were calculated. RESULTS: Patients in the CytoSorb group had a significantly lower AUC during the first 24 h (42 ± 10% vs. 63 ± 6%, p = 0.029) as well as during the observation period of 48 h (26 ± 7% vs. 51 ± 12%, p = 0.029). The relative reductions for myoglobin were considerably higher in the CytoSorb group compared to the control group during the first 8 h. CONCLUSION: Myoglobin concentrations declined considerably faster when CytoSorb was added to a CVVHD. When compared to a high-cut-off hemofilter, efficacy of CytoSorb in myoglobin elimination was much better. Because of saturation after 8-12 h an exchange may be necessary.

Population pharmacokinetic modeling of multiple-dose intravenous fosfomycin in critically ill patients during continuous venovenous hemodialysis.

The aim of this study was to investigate the pharmacokinetics of multiple-dose intravenous (i.v.) fosfomycin in critically ill patients during continuous venovenous hemodialysis (CVVHD). Non-compartmental analysis and population pharmacokinetic modeling were used to simulate different dosing regimens. We evaluated 15 critically ill patients with renal insufficiency and CVVHD undergoing anti-infective treatment with fosfomycin in our ICU. Five grams of fosfomycin were administered for 120 min every 6 h. Plasma concentrations were determined with and without CVVHD. Pharmacokinetic analysis and simulations were performed using non-linear mixed effects modelling (NONMEM). A two-compartment model with renal and dialysis clearance was most accurate in describing the pharmacokinetics of i.v. fosfomycin during CVVHD. Population parameter estimates were 18.20 L and 20.80 L for the central and peripheral compartment volumes, and 0.26 L/h and 5.08 L/h for renal and intercompartmental clearance, respectively. Urinary creatinine clearance (CLCR) represented a considerable component of renal clearance. Central compartment volume increased over time after the first dose. For patients with CLCR > 50 (90) mL/min and CVVHD, dosage should be increased to ≥ 15 (16) grams of i.v. fosfomycin across three (four) daily doses. Individual CLCR must be considered when dosing i.v. fosfomycin in critically ill patients during CVVHD.

ICU- and ventilator-free days with isoflurane or propofol as a primary sedative - A post- hoc analysis of a randomized controlled trial.

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.

Ventilatory Effects of Isoflurane Sedation via the Sedaconda ACD-S versus ACD-L: A Substudy of a Randomized Trial.

Devices used to deliver inhaled sedation increase dead space ventilation. We therefore compared ventilatory effects among isoflurane sedation via the Sedaconda ACD-S (internal volume: 50 mL), isoflurane sedation via the Sedaconda ACD-L (100 mL), and propofol sedation with standard mechanical ventilation with heat and moisture exchangers (HME). This is a substudy of a randomized trial that compared inhaled isoflurane sedation via the ACD-S or ACD-L to intravenous propofol sedation in 301 intensive care patients. Data from the first 24 h after study inclusion were analyzed using linear mixed models. Primary outcome was minute ventilation. Secondary outcomes were tidal volume, respiratory rate, arterial carbon dioxide pressure, and isoflurane consumption. In total, 151 patients were randomized to propofol and 150 to isoflurane sedation; 64 patients received isoflurane via the ACD-S and 86 patients via the ACD-L. While use of the ACD-L was associated with higher minute ventilation (average difference (95% confidence interval): 1.3 (0.7, 1.8) L/min, p < 0.001), higher tidal volumes (44 (16, 72) mL, p = 0.002), higher respiratory rates (1.2 (0.1, 2.2) breaths/min, p = 0.025), and higher arterial carbon dioxide pressures (3.4 (1.2, 5.6) mmHg, p = 0.002), use of the ACD-S did not significantly affect ventilation compared to standard mechanical ventilation and sedation. Isoflurane consumption was slightly less with the ACD-L compared to the ACD-S (-0.7 (-1.3, 0.1) mL/h, p = 0.022). The Sedaconda ACD-S compared to the ACD-L is associated with reduced minute ventilation and does not significantly affect ventilation compared to a standard mechanical ventilation and sedation setting. The smaller ACD-S is therefore the device of choice to minimize impact on ventilation, especially in patients with a limited ability to compensate (e.g., COPD patients). Volatile anesthetic consumption is slightly higher with the ACD-S compared to the ACD-L.

Increasing the reflection efficiency of the Sedaconda ACD-S by heating and cooling the anaesthetic reflector: a bench study using a test lung.

BACKGROUND: As volatile anaesthetic gases contribute to global warming, improving the efficiency of their delivery can reduce their environmental impact. This can be achieved by rebreathing from a circle system, but also by anaesthetic reflection with an open intensive care ventilator. We investigated whether the efficiency of such a reflection system could be increased by warming the reflector during inspiration and cooling it during expiration (thermocycling). METHODS: The Sedaconda-ACD-S (Sedana Medical, Danderyd, Sweden) was connected between an intensive care ventilator and a test lung. Liquid isoflurane was infused into the device at 0.5, 1.0, 2.0 and 5.0 mL/h; ventilator settings were 500 mL tidal volume, 12 bpm, 21% oxygen. Isoflurane concentrations were measured inside the test lung after equilibration. Thermocycling was achieved by heating the breathing gas in the inspiratory hose to 37 °C via a heated humidifier without water. Breathing gas expired from the test lung was cooled to 14 °C before reaching the ACD-S. In the test lung, body temperature pressure saturated conditions prevailed. Isoflurane concentrations and reflective efficiency were compared between thermocycling and control conditions. RESULTS: With thermocycling higher isoflurane concentrations in the test lung were measured for all infusion rates studied. Interpolation of data showed that for achieving 0.4 (0.6) Vol% isoflurane, the infusion rate can be reduced from 1.2 to 0.7 (2.0 to 1.2) mL/h or else to 56% (58%) of control. CONCLUSION: Thermocycling of the anaesthetic gas considerably increases the efficiency of the anaesthetic reflector and reduces anaesthetic consumption by almost half in a test lung model. Given that cooling can be miniaturized, this method carries a potential for further saving anaesthetics in clinical practice in the operating theatre as well as for inhaled sedation in the ICU.

Isoflurane vs. propofol for sedation in invasively ventilated patients with acute hypoxemic respiratory failure: an a priori hypothesis substudy of a randomized controlled trial.

BACKGROUND: Acute hypoxemic respiratory failure (AHRF) is a leading concern in critically ill patients. Experimental and clinical data suggest that early sedation with volatile anesthestics may improve arterial oxygenation and reduce the plasma and alveolar levels of markers of alveolar epithelial injury and of proinflammatory cytokines. METHODS: An a priori hypothesis substudy of a multicenter randomized controlled trial (The Sedaconda trial, EUDRA CT Number 2016-004551-67). In the Sedaconda trial, 301 patients on invasive mechanical ventilation were randomized to 48 h of sedation with isoflurane or propofol in a 1:1 ratio. For the present substudy, patients with a ratio of arterial pressure of oxygen (PaO2) to inspired fraction of oxygen (FiO2), PaO2/FiO2, of ≤ 300 mmHg at baseline were included (n = 162). The primary endpoint was the change in PaO2/FiO2 between baseline and the end of study sedation. A subgroup analysis in patients with PaO2/FiO2 ≤ 200 mmHg was performed (n = 82). RESULTS: Between baseline and the end of study sedation (48 h), oxygenation improved to a similar extent in the isoflurane vs. the propofol group (isoflurane: 199 ± 58 to 219 ± 76 mmHg (n = 70), propofol: 202 ± 62 to 236 ± 77 mmHg (n = 89); p = 0.185). On day seven after randomization, PaO2/FiO2 was 210 ± 79 mmHg in the isoflurane group (n = 41) and 185 ± 87 mmHg in the propofol group (n = 44; p = 0.411). In the subgroup of patients with PaO2/FiO2 ≤ 200 mmHg, PaO2/FiO2 increase between baseline and end of study sedation was 152 ± 33 to 186 ± 54 mmHg for isoflurane (n = 37), and 150 ± 38 to 214 ± 85 mmHg for propofol (n = 45; p = 0.029). On day seven, PaO2/FiO2 was 198 ± 69 mmHg in patients randomized to isoflurane (n = 20) and 174 ± 106 mmHg in patients randomized to propofol (n = 20; p = 0.933). Both for the whole study population and for the subgroup with PaO2/FiO2 ≤ 200 mmHg, no significant between-group differences were observed for PaCO2, pH and tidal volume as well as 30-day mortality and ventilator-free days alive. CONCLUSIONS: In patients with AHRF, inhaled sedation with isoflurane for a duration of up to 48 h did not lead to improved oxygenation in comparison to intravenous sedation with propofol. Trial registration The main study was registered in the European Medicines Agency's EU Clinical Trial register (EudraCT), 2016-004551-67, before including the first patient. The present substudy was registered at German Clinical Trials Register (DRKS, ID: DRKS00018959) on January 7th, 2020, before opening the main study data base and obtaining access to study results.

Increased Respiratory Drive after Prolonged Isoflurane Sedation: A Retrospective Cohort Study.

Low-dose isoflurane stimulates spontaneous breathing. We, therefore, tested the hypothesis that isoflurane compared to propofol sedation for at least 48 h is associated with increased respiratory drive in intensive care patients after sedation stop. All patients in our intensive care unit receiving at least 48 h of isoflurane or propofol sedation in 2019 were included. The primary outcome was increased respiratory drive over 72 h after sedation stop, defined as an arterial carbon dioxide pressure below 35 mmHg and a base excess more than -2 mmol/L. Secondary outcomes were acid-base balance and ventilatory parameters. We analyzed 64 patients, 23 patients sedated with isoflurane and 41 patients sedated with propofol. Patients sedated with isoflurane were about three times as likely to show increased respiratory drive after sedation stop than those sedated with propofol: adjusted risk ratio [95% confidence interval]: 2.9 [1.3, 6.5], p = 0.010. After sedation stop, tidal volumes were significantly greater and arterial carbon dioxide partial pressures were significantly lower, while respiratory rates did not differ in isoflurane versus propofol-sedated patients. In conclusion, prolonged isoflurane use in intensive care patients is associated with increased respiratory drive after sedation stop. Beneficial effects of isoflurane sedation on respiratory drive may, thus, extend beyond the actual period of sedation.

Anesthetic gas consumption with target-controlled administration versus a semi-closed circle system with automatic end-tidal concentration control in an artificial lung model.

The use of volatile anesthetics as sedatives in the intensive care unit is relevant to the patient's outcome. We compared anesthetic gas consumption of the conventional semi-closed Aisys CSTM with the MIRUSTM system, which is the first anesthetic gas reflector system that can administer desflurane in addition to isoflurane and sevoflurane. We connected an artificial lung model to either a MIRUSTM system and a Puritan BennettTM 840 ventilator or an Aisys CSTM anesthesia machine. We found that consumption of 0.5% isoflurane, which corresponds to the target concentration 0.5 MAC, was averaged to 2 mL/h in the MIRUSTM system, which is identical to the Aisys CSTM at a fresh gas flow (FGF) of 1.0 L/min. MIRUSTM consumption of 1% sevoflurane was averaged to 10 mL/h, which corresponds to 8.4 mL/h at FGF 2.5 L/min. The MIRUSTM system consumed 3% or 4% desflurane at an average of 13.0 mL/h or 21.3 mL/h, which is between the consumption at 1.0 L/min and 2.5 L/min FGF. Thus, the MIRUSTM system can effectively deliver volatile anesthetics in clinically relevant concentrations in a similar rate as a conventional circular breathing system at FGFs between 1.0 L/min and 2.5 L/min.

Isoflurane promotes early spontaneous breathing in ventilated intensive care patients: A post hoc subgroup analysis of a randomized trial.

BACKGROUND: Spontaneous breathing is desirable in most ventilated patients. We therefore studied the influence of isoflurane versus propofol sedation on early spontaneous breathing in ventilated surgical intensive care patients and evaluated potential mediation by opioids and arterial carbon dioxide during the first 20 h of study sedation. METHODS: We included a single-center subgroup of 66 patients, who participated in a large multi-center trial assessing efficacy and safety of isoflurane sedation, with 33 patients each randomized to isoflurane or propofol sedation. Both sedatives were titrated to a sedation depth of -4 to -1 on the Richmond Agitation Sedation Scale. The primary outcome was the fraction of time during which patients breathed spontaneously. RESULTS: Baseline characteristics of isoflurane and propofol-sedated patients were well balanced. There were no substantive differences in management or treatment aside from sedation, and isoflurane and propofol provided nearly identical sedation depths. The mean fraction of time spent spontaneously breathing was 82% [95% CI: 69, 90] in patients sedated with isoflurane compared to 35% [95% CI: 22, 51] in those assigned to propofol: median difference: 61% [95% CI: 14, 89], p < .001. After adjustments for sufentanil dose and arterial carbon dioxide partial pressure, patients sedated with isoflurane were twice as likely to breathe spontaneously than those sedated with propofol: adjusted risk ratio: 2.2 [95%CI: 1.4, 3.3], p < .001. CONCLUSIONS: Isoflurane compared to propofol sedation promotes early spontaneous breathing in deeply sedated ventilated intensive care patients. The benefit appears to be a direct effect isoflurane rather than being mediated by opioids or arterial carbon dioxide.

In vitro performance evaluation of AnaConDaTM-100 and AnaConDaTM-50 compared to a circle breathing system for control and consumption of volatile anaesthetics.

To identify the better volatile anaesthetic delivery system in an intensive care setting, we compared the circle breathing system and two models of reflection systems (AnaConDa™ with a dead space of 100 ml (ACD-100) or 50 ml (ACD-50)). These systems were analysed for the parameters like wash-in, consumption, and wash-out of isoflurane and sevoflurane utilising a test lung model. The test lung was connected to a respirator (circle breathing system: Aisys CS™; ACD-100/50: Puriton Bennett 840). Set parameters were volume-controlled mode, tidal volume-500 ml, respiratory rate-10/min, inspiration time-2 sec, PEEP-5 mbar, and oxygen-21%. Wash-in, consumption, and wash-out were investigated at fresh gas flows of 0.5, 1.0, 2.5, and 5.0 l/min. Anaesthetic target concentrations were 0.5, 1.0, 1.5, 2.0, and 2.5%.  Wash-in was slower in ACD-100/-50 compared to the circle breathing system, except for fresh gas flows of 0.5 and 1.0 l/min. The consumption of isoflurane and sevoflurane in ACD-100 and ACD-50 corresponded to the fresh gas flow of 0.5-1.0 l/min in the circle breathing system. Consumption with ACD-50 was higher in comparison to ACD-100, especially at gas concentrations > 1.5%. Wash-out was quicker in ACD-100/-50 than in the circle breathing system at a fresh gas flow of 0.5 l/min, however, it was longer at all the other flow rates. Wash-out was comparable in ACD-100 and ACD-50. Wash-in and wash-out were generally quicker with the circle breathing system than in ACD-100/-50. However, consumption at 0.5 minimum alveolar concentration was comparable at flows of 0.5 and 1.0 l/min.

Sonographic Evaluation of Gastric Residual Volume during Enteral Nutrition in Critically Ill Patients Using a Miniaturized Ultrasound Device.

BACKGROUND: To assess the risk of aspiration, nutrient tolerance, and gastric emptying of patients in ICUs, gastric ultrasound can provide information about the gastric contents. Using established formulas, the gastric residual volume (GRV) can be calculated in a standardized way by measuring the gastric antrum. The purpose of this study was to determine the GRV in a cohort of enterally fed patients using a miniaturized ultrasound device to achieve knowledge about feasibility and the GRV over time during the ICU stay. The findings could contribute to the optimization of enteral nutrition (EN) therapy. METHODS: A total of 217 ultrasound examinations with 3 measurements each (651 measurements in total) were performed twice daily (morning and evening) in a longitudinal observational study on 18 patients with EN in the interdisciplinary surgical ICU of Saarland University Medical Center. The measured values of the GRV were analyzed in relation to the clinical course, the nutrition, and other parameters. RESULTS: Measurements could be performed without interrupting the flow of clinical care and without pausing EN. The GRV was significantly larger with sparsely auscultated bowel sounds than with normal and excited bowel sounds (p < 0.01). Furthermore, a significantly larger GRV was present when using a high-caloric/low-protein nutritional product compared to an isocaloric product (p = 0.02). The GRV at the morning and evening measurements showed no circadian rhythm. When comparing the first and last ultrasound examination of each patient, there was a tendency towards an increased GRV (p = 0.07). CONCLUSION: The GRV measured by miniaturized ultrasound devices can provide important information about ICU patients without restricting treatment procedures in the ICU. Measurements are possible while EN therapy is ongoing. Further studies are needed to establish gastric ultrasound as a management tool in nutrition therapy.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.

Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial.

BACKGROUND: Previous studies indicate that isoflurane could be useful for the sedation of patients in the intensive care unit (ICU), but prospective studies evaluating isoflurane's efficacy have been small. The aim of this study was to test whether the sedation with isoflurane was non-inferior to sedation with propofol. METHODS: This phase 3, randomised, controlled, open-label non-inferiority trial evaluated the efficacy and safety of up to 54 h of isoflurane compared with propofol in adults (aged ≥18 years) who were invasively ventilated in ICUs in Germany (21 sites) and Slovenia (three sites). Patients were randomly assigned (1:1) to isoflurane inhalation via the Sedaconda anaesthetic conserving device (ACD; Sedana Medical AB, Danderyd, Sweden; ACD-L [dead space 100 mL] or ACD-S [dead space 50 mL]) or intravenous propofol infusion (20 mg/mL) for 48 h (range 42-54) using permuted block randomisation with a centralised electronic randomisation system. The primary endpoint was percentage of time in Richmond Agitation-Sedation Scale (RASS) range -1 to -4, assessed in eligible participants with at least 12 h sedation (the per-protocol population), five or more RASS measurements, and no major protocol violations, with a non-inferiority margin of 15%. Key secondary endpoints were opioid requirements, spontaneous breathing, time to wake-up and extubation, and adverse events. Safety was assessed in all patients who received at least one dose. The trial is complete and registered with EudraCT, 2016-004551-67. FINDINGS: Between July 2, 2017, and Jan 12, 2020, 338 patients were enrolled and 301 (89%) were randomly assigned to isoflurane (n=150) or propofol (n=151). 146 patients (97%) in each group completed the 24-h follow-up. 146 (97%) patients in the isoflurane group and 148 (98%) of patients in the propofol group were included in the per-protocol analysis of the primary endpoint. Least-squares mean percentage of time in RASS target range was 90·7% (95% CI 86·8-94·6) for isoflurane and 91·1% (87·2-95·1) for propofol. With isoflurane sedation, opioid dose intensity was 29% lower than with propofol for the overall sedation period (0·22 [0·12-0·34] vs 0·32 [0·21-0·42] mg/kg per h morphine equivalent dose, p=0·0036) and spontaneous breathing was more frequent on day 1 (odds ratio [OR] 1·72 [1·12-2·64], generalised mixed linear model p=0·013, with estimated rates of 50% of observations with isoflurane vs 37% with propofol). Extubation times were short and median wake-up was significantly faster after isoflurane on day 2 (20 min [IQR 10-30] vs 30 min [11-120]; Cox regression p=0·0011). The most common adverse events by treatment group (isoflurane vs propofol) were: hypertension (ten [7%] of 150 vs two [1%] of 151), delirium (eight [5%] vs seven [5%]), oliguria (seven [5%] vs six [4%]), and atrial fibrillation (five [3%] vs four [3%]). INTERPRETATION: These results support the use of isoflurane in invasively ventilated patients who have a clinical need for sedation. FUNDING: Sedana Medical AB.

Real-Time Evaluation of Optic Nerve Sheath Diameter (ONSD) in Awake, Spontaneously Breathing Patients.

(1) Background: Reliable ultrasonographic measurements of optic nerve sheath diameter (ONSD) to detect increased intracerebral pressure (ICP) has not been established in awake patients with continuous invasive ICP monitoring. Therefore, in this study, we included fully awake patients with and without raised ICP and correlated ONSD with continuously measured ICP values. (2) Methods: In a prospective study, intracranial pressure (ICP) was continuously measured in 25 patients with an intraparenchymatic P-tel probe. Ultrasonic measurements were carried out three times for each optic nerve in vertical and horizontal directions. ONSD measurements and ICP were correlated. Patients with ICP of 2.0-10.0 mmHg were compared with patients suffering from an ICP of 10.1-24.2 mmHg. (3) Results: In all patients, the ONSD vertical and horizontal measurement for both eyes correlated well with the ICP (Pearson R = 0.68-0.80). Both measurements yielded similar results (Bland-Altman: vertical bias: -0.09 mm, accuracy: ±0.66 mm; horizontal bias: -0.06 mm, accuracy: ±0.48 mm). For patients with an ICP of 2.0-10.0 mmHg compared to an ICP of 10.1-24.2, ROC (receiver operating characteristic) analyses showed that ONSD measurement accurately predicts elevated ICP (optimal cut-off value 5.05 mm, AUC of 0.91, sensitivity 92% and specificity 90%, p < 0.001). (4) Conclusions: Ultrasonographic measurement of ONSD in awake, spontaneously breathing patients provides a valuable method to evaluate patients with suspected increased ICP. Additionally, it provides a potential tool for rapid assessment of ICP at the bedside and to identify patients at risk for a poor neurological outcome.

Comparison of isoflurane and propofol sedation in critically ill COVID-19 patients-a retrospective chart review.

PURPOSE: In this retrospective study, we compared inhaled sedation with isoflurane to intravenous propofol in invasively ventilated COVID-19 patients with ARDS (Acute Respiratory Distress Syndrome). METHODS: Charts of all 20 patients with COVID-19 ARDS admitted to the ICU of a German University Hospital during the first wave of the pandemic between 22/03/2020 and 21/04/2020 were reviewed. Among screened 333 days, isoflurane was used in 97 days, while in 187 days, propofol was used for 12 h or more. The effect and dose of these two sedatives were compared. Mixed sedation days were excluded. RESULTS: Patients' age (median [interquartile range]) was 64 (60-68) years. They were invasively ventilated for 36 [21-50] days. End-tidal isoflurane concentrations were high (0.96 ± 0.41 Vol %); multiple linear regression yielded the ratio (isoflurane infusion rate)/(minute ventilation) as the single best predictor. Infusion rates were decreased under ECMO (3.5 ± 1.4 versus 7.1 ± 3.2 ml∙h-1; p < 0.001). In five patients, the maximum recommended dose of propofol of 4 mg∙hour-1∙kg-1ABW was exceeded on several days. On isoflurane compared to propofol days, neuro-muscular blocking agents (NMBAs) were used less frequently (11% versus 21%; p < 0.05), as were co-sedatives (7% versus 31%, p < 0.001); daily opioid doses were lower (720 [720-960] versus 1080 [720-1620] mg morphine equivalents, p < 0.001); and RASS scores indicated deeper levels of sedation (- 4.0 [- 4.0 to - 3.0] versus - 3.0 [- 3.6 to - 2.5]; p < 0.01). CONCLUSION: Isoflurane provided sufficient sedation with less NMBAs, less polypharmacy and lower opioid doses compared to propofol. High doses of both drugs were needed in severely ill COVID-19 patients.