Three Years of the Coronavirus Disease 2019 Pandemic in a European Region: A Population-Based Longitudinal Assessment in Madrid Between 2020 and 2022.

Background: Our objective was to assess the health impact of coronavirus disease 2019 (COVID-19) during 2020-2022 in the Madrid region. Methods: We included all individuals registered in the Madrid Health System Registry as of 31 December 2019, and followed them until 31 December 2022. Using a unique personal identifier, we linked the databases of primary care, hospitals, pharmacies, certified laboratories performing diagnostic tests, vaccines, and mortality. Results: Of 6 833 423 individuals, 21.4% had a confirmed COVID-19 diagnosis, and 1.5% had a COVID-19 hospitalization (primary diagnosis). Thirty-day mortality was 1.6% for confirmed COVID-19 (from 11.4% in first semester 2020 to 0.4% in first semester 2022). Thirty-day mortality was 10.8% for COVID-19 hospitalizations (from 14.0% in first semester 2020 to 6.0% in second semester 2022). There were 24 073 deaths within 30 days of a confirmed COVID-19 diagnosis. Advanced age, male sex, higher socioeconomic deprivation, and comorbidities were associated with higher mortality. Conclusions: By linking administrative and clinical databases, we characterized the burden of the COVID-19 pandemic in Madrid over 3 years. Our analysis proposes a high-level framework for comparisons of the burden of COVID-19 across areas worldwide.

Effect of Hemodynamic Changes in Plasma Propofol Concentrations Associated with Knee-Chest Position in Spinal Surgery: A Prospective Study.

BACKGROUND: Anesthesia induction and maintenance with propofol can be guided by target-controlled infusion (TCI) systems using pharmacokinetic (Pk) models. Physiological variables, such as changes in cardiac output (CO), can influence propofol pharmacokinetics. Knee-chest (KC) surgical positioning can result in CO changes. OBJECTIVES: This study aimed to evaluate the relationship between propofol plasma concentration prediction and CO changes after induction and KC positioning. METHODS: This two-phase prospective cohort study included 20 patients scheduled for spinal surgery. Two different TCI anesthesia protocols were administered after induction. In phase I (n = 9), the loss of consciousness (LOC) concentration was set as the propofol target concentration and CO changes following induction and KC positioning were quantified. In phase II (n = 11), based on data from phase I, two reductions in the propofol target concentration on the pump were applied after LOC and before KC positioning. Propofol plasma concentrations were measured at different moments in both phases: after induction and after KC positioning. RESULTS: Schnider Pk model showed a good performance in predicting propofol concentration after induction; however, after KC positioning, when a significant drop in CO occurred, the measured propofol concentrations were markedly underestimated. Intended reductions in the propofol target concentration did not attenuate HD changes. In the KC position, there was no correlation between the propofol concentration estimated by the Pk model and the measured concentration in plasma, as the latter was much higher (P = 0.013) while CO and BIS decreased significantly (P < 0.001 and P = 0.004, respectively). CONCLUSIONS: Our study showed that the measured propofol plasma concentrations during the KC position were significantly underestimated by the Schnider Pk model and were associated with significant CO decrease. When placing patients in the KC position, anesthesiologists must be aware of pharmacokinetic changes and, in addition to standard monitoring, the use of depth of anesthesia and cardiac output monitors may be considered in high-risk patients.

Analysis of electroencephalogram-derived indexes for anesthetic depth monitoring in pediatric patients with intellectual disability undergoing dental surgery.

BACKGROUND: Patients with intellectual disability (ID) often require general anesthesia during oral procedures. Anesthetic depth monitoring in these patients can be difficult due to their already altered mental state prior to anesthesia. In this study, the utility of electroencephalographic indexes to reflect anesthetic depth was evaluated in pediatric patients with ID. METHODS: Seventeen patients (mean age, 9.6 ± 2.9 years) scheduled for dental procedures were enrolled in this study. After anesthesia induction with propofol or sevoflurane, a bilateral sensor was placed on the patient's forehead and the bispectral index (BIS) was recorded. Anesthesia was maintained with sevoflurane, which was adjusted according to the clinical signs by an anesthesiologist blinded to the BIS value. The index performance was accessed by correlation (with the end-tidal sevoflurane [EtSevo] concentration) and prediction probability (with a clinical scale of anesthesia). The asymmetry of the electroencephalogram between the left and right sides was also analyzed. RESULTS: The BIS had good correlation and prediction probabilities (above 0.5) in the majority of patients; however, BIS was not correlated with EtSevo or the clinical scale of anesthesia in patients with Lennox-Gastaut, West syndrome, cerebral palsy, and epilepsy. BIS showed better correlations than SEF95 and TP. No significant differences were observed between the left- and right-side indexes. CONCLUSION: BIS may be able to reflect sevoflurane anesthetic depth in patients with some types of ID; however, more research is required to better define the neurological conditions and/or degrees of disability that may allow anesthesiologists to use the BIS.

Evaluation of renal injury caused by acute volume replacement with hydroxyethyl starch 130/0.4 or Ringer's lactate solution in pigs.

This work aimed to evaluate the effects on renal tissue integrity after hydroxyethyl starch (HES) 130/0.4 and Ringer's lactate (RL) administration in pigs under general anesthesia after acute bleeding. A total of 30 mL/kg of blood were passively removed from the femoral artery in two groups of Large White pigs, under total intravenous anesthesia with propofol and remifentanil. After bleeding, Group 1 (n = 11) received RL solution (25 mL/kg) and Group 2 (n = 11) received HES 130/0.4 solution (20 mL/kg). Additionally, Group 3 (n = 6) was not submitted to bleeding or volume replacement. Pigs were euthanized and kidneys were processed for histopathological and immunohistochemical analyses. Minimal to moderate glomerular, tubular, and interstitial changes, as well as papillary necrosis, were observed in all experimental groups. Pre-apoptosis and apoptosis indicators were higher in pigs that received HES 130/0.4, indicating a higher renal insult. Both HES 130/0.4 and RL administration may cause renal injury, although renal injury may be more significant in pigs receiving HES 13/0.4. Results also suggest that total intravenous anesthesia with propofol and remifentanil may cause renal injury, and this effect can be dose related.

The influence of Ringer's lactate or HES 130/0.4 administration on the integrity of the small intestinal mucosa in a pig hemorrhagic shock model under general anesthesia.

OBJECTIVE: To determine the effect of fluid resuscitation with 2 different physiological solutions, Ringer's lactate (RL) and hydroxyethyl starch (HES) 130/0.4, on histological lesions of the small intestinal mucosa in anesthetized pigs subjected to severe acute bleeding. DESIGN: Prospective experimental study. SETTING: University teaching hospital. ANIMALS: Twenty-eight healthy Large White pigs, 3 months of age. INTERVENTIONS: Pigs were subjected to severe acute bleeding (30 mL/kg) under total intravenous anesthesia with propofol and remifentanil. Pigs were randomly allocated to 3 groups: Group 1 (n = 11) received RL solution (25 mL/kg) after bleeding; Group 2 (n = 11) received HES 130/0.4 solution (20 mL/kg) after bleeding; and Group 3 (n = 6) volume replacement nor induced bleeding. Pigs were euthanized and the small intestine was harvested for histopathological analysis. MEASUREMENTS AND MAIN RESULTS: The small intestine was histologically evaluated and the presence of the following lesions were characterized: edema, congestion, hyperemia, hemorrhage, inflammatory infiltration, cellular degeneration, necrosis, and epithelial detachment. Mucosal loss percentage (%ML) and crypt:interstitium ratio (C:I) were also assessed. In the duodenum, jejunum, and ileum, and the entire small intestine, the %ML was significantly higher in Group 1, than in Groups 2 and 3. Hyperemia in the small intestine was significantly higher in pigs resuscitated with HES 130/0.4 compared to pigs resuscitated with RL. CONCLUSIONS AND CLINICAL RELEVANCE: In a setting of controlled hemorrhage, resuscitation with HES 130/0.4 was associated with a lower percentage of mucosal loss on the small intestine, compared with resuscitation with RL solution. Our study also suggests that the duodenum may be more sensitive to hypovolemia induced by severe hemorrhage.

Effects of acute bleeding followed by hydroxyethyl starch 130/0.4 or a crystalloid on propofol concentrations, cerebral oxygenation, and electroencephalographic and haemodynamic variables in pigs.

Bleeding changes the haemodynamics, compromising organ perfusion. In this study, the effects of bleeding followed by replacement with hydroxyethyl starch 130/0.4 (HES) or lactated Ringer's (LR) on cerebral oxygenation and electroencephalogram-derived parameters were investigated. Twelve young pigs under propofol-remifentanil anaesthesia were bled 30 mL/kg and, after a 20-minute waiting period, volume replacement was performed with HES (GHES; N = 6) or LR (GRL; N = 6). Bleeding caused a decrease of more than 50% in mean arterial pressure (P < 0.01) and a decrease in cerebral oximetry (P = 0.039), bispectral index, and electroencephalogram total power (P = 0.04 and P < 0.01, resp.), while propofol plasma concentrations increased (P < 0.01). Both solutions restored the haemodynamics and cerebral oxygenation similarly and were accompanied by an increase in electroencephalogram total power. No differences between groups were found. However, one hour after the end of the volume replacement, the cardiac output (P = 0.03) and the cerebral oxygenation (P = 0.008) decreased in the GLR and were significantly lower than in GHES (P = 0.02). Volume replacement with HES 130/0.4 was capable of maintaining the cardiac output and cerebral oxygenation during a longer period than LR and caused a decrease in the propofol plasma concentrations.

Evaluation of the Cerebral State Index in Cats under Isoflurane Anaesthesia: Dose-Effect Relationship and Prediction of Clinical Signs.

The performance of the cerebral state index (CSI) in reflecting different levels of isoflurane anaesthesia was evaluated in ten cats subjected to four end-tidal isoflurane concentrations (EtIso), each maintained for 15 minutes (0.8%, 1.2%, 1.6%, or 2.0% EtIso). The CSI, hemodynamic data, ocular reflexes, and eye position were recorded for each EtIso concentration. Pharmacodynamic analysis of CSI with EtIso was performed, as well as prediction probability analysis with a clinical scale based on the eye reflexes. The CSI values showed great variability. Between all parameters, burst suppression ratio showed the better fitting with the sigmoidal concentration-effect model (R (2) = 0.93) followed by CSI (R (2) = 0.82) and electromyographic activity (R (2) = 0.79). EtIso was the variable with better prediction of the clinical scale of anaesthesia (prediction probability value of 0.94). Although the CSI values decrease with increasing isoflurane concentrations, the huge variability in CSI values may be a strong limitation for its use in cats and it seems to be no better than EtIso as a predictor of clinical signs.

The effect of high doses of remifentanil in brain near-infrared spectroscopy and in electroencephalographic parameters in pigs.

OBJECTIVE: To study the effects of a high remifentanil bolus dose on pig's electroencephalographic indices and on brain regional and global oxygenation. STUDY DESIGN: Prospective experimental study. ANIMALS: Twelve healthy Large-White male pigs, age 3 months and weight 26.2 ± 3.6 kg. METHODS: Anaesthesia was induced with intravenous propofol 4 mg kg⁻¹, then maintained with constant rate infusions of propofol (15 mg kg⁻¹ hour⁻¹) and remifentanil (0.3 µg kg⁻¹ minute⁻¹). Following instrumentation, all pigs received a 5 µg kg⁻¹ remifentanil bolus. The responses of jugular venous oxygen saturation, cardiac output and cerebral oxygen saturation to the remifentanil bolus were studied. The Bispectral index, spectral edge frequency 95%, total power, approximate entropy and permutation entropy were also studied. Repeated measures anova and Pearson correlation were used to analyze the effect of remifentanil bolus on these variables until 5 minutes after the bolus. RESULTS: Cardiac output and cerebral oxygen saturation decreased significantly after the remifentanil bolus from 4.6 ± 0.9 to 3.8 ± 1.0 L minute⁻¹ and from 65 ± 6 to 62 ± 1% (p < 0.05), respectively. No significant changes were observed in the jugular venous oxygen saturation (p > 0.05) nor in any of the electroencephalogram derived indices (p > 0.05). Correlation analysis revealed strong positive significant correlations between cerebral oxygen saturation and cardiac output (r = 0.82, p < 0.001) and between cerebral oxygen saturation and approximate entropy (r = 0.65, p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The effect caused by the remifentanil bolus on the brain oxygenation seems to be better reflected by the cerebral oxygen saturation than the jugular venous oxygen saturation. The effect of remifentanil on the electroencephalogram may not be reflected in indices derived from the electroencephalogram, but the potential of the approximate entropy in reflecting changes caused by opioids on the electroencephalogram should be further investigated.

Interaction between hydroxyethyl starch and propofol: computational and laboratorial study.

BACKGROUND: Hydroxyethyl starch (HES) is one of the most used colloids for intravascular volume replacement during anesthesia. AIM: To investigate the existence of a chemical interaction between HES and the anesthetic propofol by in vitro propofol dosing, computational docking, and examination of a complex between propofol and HES by infrared (IR), ultraviolet (UV), and (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy. METHODS: Ten samples with human plasma mixed with HES or lactated Ringers (n = 5 for each fluid) were prepared, and the propofol free fraction was quantified until 50 min, using gas chromatography-mass spectrometry. The docking study was performed between HES and propofol and compared with controls. The binding affinities between HES and the small molecules were evaluated by binding free energy approximation (ΔGb, kJ mol(-1)). The IR, UV, and NMR spectra were measured for propofol, HES, and a mixture of both obtained by the kneading method. RESULTS: Propofol concentrations were significantly lower in the HES samples than in the LR samples (p = .021). The spectroscopic characterization of propofol combined with HES revealed differences in spectra and docking studies reinforced a potential interaction between propofol and HES. CONCLUSIONS: Propofol and HES form a complex with different physical-bio-chemical behavior than the single drugs, which may be an important drug interaction. Further studies should evaluate its clinical effects.

Electroencephalogram-based anaesthetic depth monitoring in laboratory animals.

Objective measurements of physiological parameters controlled by the autonomic nervous system such as blood pressure, heart rate and respiration are easily obtained nowadays during anaesthesia by the use of monitors: oscillometers, pulseoximeters, electrocardiograms and capnographs are available for laboratory animals. However, the effect-site of hypnotic drugs that cause general anaesthesia is the central nervous system (the brain). In the present, the adjustment of hypnotic drugs in veterinary anaesthesia is performed according to subjective evaluation of clinical signs which are not direct reflexes of anaesthetic effects on the brain, making depth of anaesthesia (DoA) assessment a complicated task. The difficulties in assessing the real anaesthetic state of a laboratory animal may not only result in welfare-threatening situations, such as awareness and pain sensation during surgery, but also in a lack of standardization of experimental conditions, as it is not easy to keep all animals from an experiment in the same DoA without a measure of anaesthetic effect. A direct measure of this dose-effect relationship, although highly necessary, is still missing in the veterinary market. Meanwhile, research has been intense in this subject and methods based on the brain electrical activity (electroencephalogram) have been explored in laboratory animal species. The objective of this review is to explain the achievements made in this topic and clarify how far we are from an objective measure of DoA for animals.

Performance of anesthetic depth indexes in rabbits under propofol anesthesia: prediction probabilities and concentration-effect relations.

BACKGROUND: The permutation entropy, the approximate entropy, and the index of consciousness are some of the most recently studied electroencephalogram-derived indexes. In this work, a thorough comparison of these indexes was performed using propofol anesthesia in a rabbit model. METHODS: Six rabbits were anesthetized with three propofol infusion rates: 70, 100, and 130 mg · kg⁻¹ · h⁻¹, each maintained for 30 min, in a random order for each animal. Data recording was performed in the awake animals 20, 25, and 30 min after each infusion rate was begun in the recovered animals and consisted of electroencephalogram recordings, evaluation of depth of anesthesia according to a clinical scale, and arterial blood samples for plasma propofol determination. Median and spectral edge frequencies were analyzed for single-scale permutation entropy and composite multiscale permutation entropy, approximate entropy, index of consciousness, and the spectral parameters. The spectral parameters and single-scale and multiscale permutation entropies were corrected for the presence of burst suppression. Performance of the indexes was compared by prediction probability and pharmacodynamic analysis. RESULTS: The single-scale and composite multiscale permutation entropies with a burst suppression correction showed better prediction probabilities than did the other electroencephalogram-derived parameters but not better than the electromyographic activity. CONCLUSION: Single-scale and multiscale permutation entropies may be promising measures of propofol anesthetic depth when corrected for burst suppression. Additional studies should investigate the information measured by electromyography algorithms from commercial monitors of anesthetic depth. The rabbit may be a promising animal model for electroencephalographic studies because it provides a good-quality signal.

Dogs mean arterial pressure and heart rate responses during high propofol plasma concentrations estimated by a pharmacokinetic model.

Propofol total intravenous anesthesia should provide stability of the cardiovascular system. In this study, mean arterial pressure and heart rate were evaluated in eight healthy dogs anesthetized with increasing rates of propofol. The cerebral state index (CSI) was studied as an additional parameter. Although the estimated propofol plasma concentration reached a maximal value of 15.3 µg ml(-1), no hypotension or bradycardia were observed. Exploration of each animal's data revealed high inter-individual variability regarding mean arterial pressure and heart rate. Considering the logarithmic of the concentration, a moderate depressant effect of propofol on mean arterial pressure was revealed in five dogs but the effect was not followed on heart rate.

Anesthesia with intraperitoneal propofol, medetomidine, and fentanyl in rats.

A safe and reliable method for anesthetizing rats has long been a leading concern of biomedical researchers. We recently found that the intraperitoneal administration of propofol combined with medetomidine and fentanyl is safe for mouse anesthesia. Here we studied whether the same combination could be used for general anesthesia in rats. We used male Wistar rats to test 10 combinations of propofol, medetomidine, and fentanyl administered intraperitoneally and reversed with intraperitoneal atipamezole 30 min after induction. The depth of anesthesia, induction time, loss of pedal withdrawal reflex, pulse rate, and respiratory rate were evaluated, along with the duration and quality of induction, surgical anesthesia, and recovery. The combination of propofol and medetomidine provided a predictable induction and sufficient hypnosis and muscle relaxation, but surgical anesthesia (loss of pedal withdrawal reflex) was difficult to achieve with this protocol. The addition of fentanyl increased analgesia, making it possible to achieve surgical anesthesia. In conclusion, combination of propofol (100 mg/kg), medetomidine (0.1 mg/kg), and fentanyl (0.1 mg/kg) is a safe and practical technique for intraperitoneal anesthesia in rats, providing a surgical window of 25 min and restraint for 30 min, with rapid recovery after administration of atipamezole.

Comparison of anesthetic depth indexes based on thalamocortical local field potentials in rats.

BACKGROUND: Local field potentials may allow a more precise analysis of the brain electrical activity than the electroencephalogram. In this study, local field potentials were recorded in the thalamocortical axis of rats to (i) compare the performance of several indexes of anesthetic depth and (ii) investigate the existence of thalamocortical correlated or disrupted activity during isoflurane steady-state anesthesia. METHODS: Five rats chronically implanted with microelectrodes were used to record local field potentials in the primary somatosensory cortex and ventroposterolateral thalamic nuclei at six periods: before induction of anesthesia; in the last 5 min of randomized 20-min steady-state end-tidal 0.8, 1.1, 1.4, and 1.7% isoflurane concentrations; and after recovery. The approximate entropy, the index of consciousness, the spectral edge frequency, and the permutation entropy were estimated using epochs of 8 s. A correction factor for burst suppression was applied to the spectral edge frequency and to the permutation entropy. The correlation between the derived indexes and the end-tidal isoflurane was calculated and compared for the two studied brain regions indexes. Coherence analysis was also performed. RESULTS: The burst suppression-corrected permutation entropy showed the highest correlation with the end-tidal isoflurane concentration, and a high coherence was obtained between the two studied areas. CONCLUSIONS: The permutation entropy corrected with the classic burst suppression ratio is a promising alternative to other indexes of anesthetic depth. Furthermore, high coherence level of activity exists between the somatosensory cortical and thalamic regions, even at deep isoflurane stages.