Effect of immediate initiation of invasive ventilation on mortality in acute hypoxemic respiratory failure: a target trial emulation.

PURPOSE: Invasive ventilation is a fundamental treatment in intensive care but its precise timing is difficult to determine. This study aims at assessing the effect of initiating invasive ventilation versus waiting, in patients with hypoxemic respiratory failure without immediate reason for intubation on one-year mortality. METHODS: Emulation of a target trial to estimate the benefit of immediately initiating invasive ventilation in hypoxemic respiratory failure, versus waiting, among patients within the first 48-h of hypoxemia. The eligible population included non-intubated patients with SpO2/FiO2 ≤ 200 and SpO2 ≤ 97%. The target trial was emulated using a single-center database (MIMIC-IV) which contains granular information about clinical status. The hourly probability to receive mechanical ventilation was continuously estimated. The hazard ratios for the primary outcome, one-year mortality, and the secondary outcome, 30-day mortality, were estimated using weighted Cox models with stabilized inverse probability weights used to adjust for measured confounding. RESULTS: 2996 Patients fulfilled the inclusion criteria of whom 792 were intubated within 48 h. Among the non-invasive support devices, the use of oxygen through facemask was the most common (75%). Compared to patients with the same probability of intubation but who were not intubated, intubation decreased the hazard of dying for the first year after ICU admission HR 0.81 (95% CI 0.68-0.96, p = 0.018). Intubation was associated with a 30-day mortality HR of 0.80 (95% CI 0.64-0.99, p = 0.046). CONCLUSION: The initiation of mechanical ventilation in patients with acute hypoxemic respiratory failure reduced the hazard of dying in this emulation of a target trial.

Deep embedded clustering generalisability and adaptation for integrating mixed datatypes: two critical care cohorts.

We validated a Deep Embedded Clustering (DEC) model and its adaptation for integrating mixed datatypes (in this study, numerical and categorical variables). Deep Embedded Clustering (DEC) is a promising technique capable of managing extensive sets of variables and non-linear relationships. Nevertheless, DEC cannot adequately handle mixed datatypes. Therefore, we adapted DEC by replacing the autoencoder with an X-shaped variational autoencoder (XVAE) and optimising hyperparameters for cluster stability. We call this model "X-DEC". We compared DEC and X-DEC by reproducing a previous study that used DEC to identify clusters in a population of intensive care patients. We assessed internal validity based on cluster stability on the development dataset. Since generalisability of clustering models has insufficiently been validated on external populations, we assessed external validity by investigating cluster generalisability onto an external validation dataset. We concluded that both DEC and X-DEC resulted in clinically recognisable and generalisable clusters, but X-DEC produced much more stable clusters.

A guide to sharing open healthcare data under the General Data Protection Regulation.

Sharing healthcare data is increasingly essential for developing data-driven improvements in patient care at the Intensive Care Unit (ICU). However, it is also very challenging under the strict privacy legislation of the European Union (EU). Therefore, we explored four successful open ICU healthcare databases to determine how open healthcare data can be shared appropriately in the EU. A questionnaire was constructed based on the Delphi method. Then, follow-up questions were discussed with experts from the four databases. These experts encountered similar challenges and regarded ethical and legal aspects to be the most challenging. Based on the approaches of the databases, expert opinion, and literature research, we outline four distinct approaches to openly sharing healthcare data, each with varying implications regarding data security, ease of use, sustainability, and implementability. Ultimately, we formulate seven recommendations for sharing open healthcare data to guide future initiatives in sharing open healthcare data to improve patient care and advance healthcare.

Computerized tests to evaluate recovery of cognitive function after deep sedation with propofol and remifentanil for colonoscopy.

The use of sedation for diagnostic procedures including gastrointestinal endoscopy is rapidly growing. Recovery of cognitive function after sedation is important because it would be important for most patients to resume safe, normal life soon after the procedure. Computerized tests have shown being accurate descriptors of cognitive function. The purpose of the present study was to evaluate the time course of cognitive function recovery after sedation with propofol and remifentanil. A prospective observational double blind clinical study conducted in 34 young healthy adults undergoing elective outpatient colonoscopy under sedation with the combination of propofol and remifentanil using a target controlled infusion system. Cognitive function was measured using a validated battery of computerized cognitive tests (Cogstate™, Melbourne, Australia) at different predefined times: prior to starting sedation (Tbaseline), and then 10 min (T10), 40 min (T40) and 120 min (T120) after the end of colonoscopy. Tests included the assessment of psychomotor function, attention, visual memory and working memory. All colonoscopies were completed (median time: 26 min) without significant adverse events. Patients received a median total dose of propofol and remifentanil of 149 mg and 98 µg, respectively. Psychomotor function and attention declined at T10 but were back to baseline values at T40 for all patients. The magnitude of psychomotor task reduction was large (d = 0.81) however 100% of patients were recovered at T40. Memory related tasks were not affected 10 min after ending sedation. Cognitive impairment in attention and psychomotor function after propofol and remifentanil sedation was significant and large and could be easily detected by computerized cognitive tests. Even though, patients were fully recovered 40 min after ending the procedure. From a cognitive recovery point of view, larger studies should be undertaken to propose adequate criteria for discharge after sedation.

Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2.

Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. Participants randomly received infusions of propofol and remifentanil. Predicted plasma concentrations, outputted by infusion pumps, were available. Transcutaneous arterial pressure of carbon dioxide (pCO2) was measured. Data were analyzed using nonlinear mixed-effects modeling methods. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion), and A118G genotype for the µ-opioid receptor (OPRM1). Participants had a median (range) age of 64.0 (25.0-88.0) years, weight of 70.0 (35.0-98.0) kg, and height of 164.0 (147.0-190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. An indirect-effect model with a "modulator" compartment best described pCO2 data (P < 0.001) over a direct-effect model. Remifentanil inhibited pCO2 removal with an IC50 of 1.13 ng/ml and first-order rate constant (ke 0) of 0.28 minute(-1). Propofol affected the modulator compartment with an IC50 of 4.97 µg/ml (no effect-site compartment). Propofol IC50 and remifentanil ke 0 were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.

Sedation-analgesia with propofol and remifentanil: concentrations required to avoid gag reflex in upper gastrointestinal endoscopy.

BACKGROUND: The purpose of this study was to identify optimal target propofol and remifentanil concentrations to avoid a gag reflex in response to insertion of an upper gastrointestinal endoscope. METHODS: Patients presenting for endoscopy received target-controlled infusions (TCI) of both propofol and remifentanil for sedation-analgesia. Patients were randomized to 4 groups of fixed target effect-site concentrations: remifentanil 1 ng•mL (REMI 1) or 2 ng•mL (REMI 2) and propofol 2 µg•mL (PROP 2) or 3 µg•mL (PROP 3). For each group, the other drug (propofol for the REMI groups and vice versa) was increased or decreased using the "up-down" method based on the presence or absence of a gag response in the previous patient. A modified isotonic regression method was used to estimate the median effective Ce,50 from the up-down method in each group. A concentration-effect (sigmoid Emax) model was built to estimate the corresponding Ce,90 for each group. These data were used to estimate propofol bolus doses and remifentanil infusion rates that would achieve effect-site concentrations between Ce,50 and Ce,90 when a TCI system is not available for use. RESULTS: One hundred twenty-four patients were analyzed. To achieve between a 50% and 90% probability of no gag response, propofol TCIs were between 2.40 and 4.23 µg•mL (that could be achieved with a bolus of 1 mg•kg) when remifentanil TCI was fixed at 1 ng•mL, and target propofol TCIs were between 2.15 and 2.88 µg•mL (that could be achieved with a bolus of 0.75 mg•kg) when remifentanil TCI was fixed at 2 ng•mL. Remifentanil ranges were 1.00 to 4.79 ng•mL and 0.72 to 3.19 ng•mL when propofol was fixed at 2 and 3 µg•mL, respectively. CONCLUSIONS: We identified a set of propofol and remifentanil TCIs that blocked the gag response to endoscope insertion in patients undergoing endoscopy. Propofol bolus doses and remifentanil infusion rates designed to achieve similar effect-site concentrations can be used to prevent gag response when TCI is not available.

Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies.

The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands.

Modeling the influence of the A118G polymorphism in the OPRM1 gene and of noxious stimulation on the synergistic relation between propofol and remifentanil: sedation and analgesia in endoscopic procedures.

BACKGROUND: The presence of the A118G single nucleotide polymorphism in the OPRM1 gene as well as noxious stimulation might affect the requirements of remifentanil for patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil. Bispectral index (BIS) was used as a surrogate measure of effect. METHOD: A total of 207 patients were screened for A118G and randomly received different combinations of propofol and remifentanil, changed depending on the nausea response to endoscopy tube introduction. Nonlinear mixed effects modelling was used to establish the relation between propofol and remifentanil with respect to BIS and to investigate the influence of A118G or noxious stimulation. The value of k e0 for propofol and remifentanil was estimated to avoid the hysteresis between predicted effect site concentration (Ce) and BIS. RESULTS: Data from 176 patients were analysed. Eleven were recessive homozygous for A118G (OPRM = 1). A total of 165 patients were either dominant homozygous or heterozygous and considered normal (OPRM = 0). The estimated values of k e0 for propofol and remifentanil were 0.122 and 0.148 min(-1). Propofol and remifentanil were synergistic with respect to the BIS (α = 1.85). EC50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326 ng/ml in OPRM = 1 patients. BIS increases around 4% for the same effect site concentrations with noxious stimulation. CONCLUSIONS: Predicted effect site concentration of remifentanil ranging 1-5 ng/ml synergistically potentiates the effects of propofol on the BIS but has no effect in A118G patients. Noxious stimulation increases BIS values by 4% at the same concentrations of propofol and remifentanil.

Effect of intra-abdominal pressure on hepatic microcirculation: implications of the endothelin-1 receptor.

OBJECTIVE: To investigate the effect of endothelin receptor A (ET(A)) and endothelin receptor B (ET(B)) blockade on liver microcirculation and oxygenation during intra-abdominal pressure (IAP) increase. METHODS: Fifteen anesthetized pigs were randomized to receive either nonselective endothelin-1 (ET-1) blocker tezosentan (TG, n = 7) or saline (CG, n = 8). Helium was insufflated to increase IAP from 0 to 25 mmHg. Stroke volume variability was maintained ≤ 12% with colloid infusion. Total liver blood flow (TLBF), hepatic microcirculatory blood flow (MBF), hepatic tissue oxygenation (HpO(2)), hyaluronic acid and plasma disappearance rate (PDR) of indocyanine green (ICG) were recorded. RESULTS: TLBF remained mostly unaltered in both groups at low IAP and decreased only in CG at the IAP of 25 mmHg. As IAP increased, a significant decline in MBF was observed without correlation with cardiac output or TLBF. In CG, HpO(2) decreased as early as IAP of 10 mmHg to high levels of pressure. However, in TG the decrease was significant only at the IAP of 25 mmHg. PDR of ICG decreased in both groups at IAP of 25 mmHg (P = 0.046 and P = 0.009 in TG and CG, respectively). These changes correlated with MBF (r = 0.793). CONCLUSION: Blocking ET(A) and ET(B) receptors partially protects sinusoidal circulation and tissue oxygenation against stress induced by high IAP.

Failed tracheal intubation with the LMA-CTrach in two patients with lingual tonsil hyperplasia.

The LMA-CTrach combines the features of the Intubating Laryngeal Mask Airway with a fiberoptic system and a screen for visualization of the airway. Local pathology, such as lingual tonsillar hyperplasia, may obstruct the view of the airway leading to unanticipated difficult intubation. We present two cases of failed intubation with the LMA-CTrach in patients with lingual tonsillar hyperplasia. In both cases, the LMA-CTrach maintained adequate ventilation, giving time to prepare alternative strategies.