The impact of sedative and vasopressor agents on cerebrovascular reactivity in severe traumatic brain injury.

BACKGROUND: The aim of this study is to evaluate the impact of commonly administered sedatives (Propofol, Alfentanil, Fentanyl, and Midazolam) and vasopressor (Dobutamine, Ephedrine, Noradrenaline and Vasopressin) agents on cerebrovascular reactivity in moderate/severe TBI patients. Cerebrovascular reactivity, as a surrogate for cerebral autoregulation was assessed using the long pressure reactivity index (LPRx). We evaluated the data in two phases, first we assessed the minute-by-minute data relationships between different dosing amounts of continuous infusion agents and physiological variables using boxplots, multiple linear regression and ANOVA. Next, we assessed the relationship between continuous/bolus infusion agents and physiological variables, assessing pre-/post- dose of medication change in physiology using a Wilcoxon signed-ranked test. Finally, we evaluated sub-groups of data for each individual dose change per medication, focusing on key physiological thresholds and demographics. RESULTS: Of the 475 patients with an average stay of 10 days resulting in over 3000 days of recorded information 367 (77.3%) were male with a median Glasgow coma score of 7 (4-9). The results of this retrospective observational study confirmed that the infusion of most administered agents do not impact cerebrovascular reactivity, which is confirmed by the multiple linear regression components having p value > 0.05. Incremental dose changes or bolus doses in these medications in general do not lead to significant changes in cerebrovascular reactivity (confirm by Wilcoxon signed-ranked p value > 0.05 for nearly all assessed relationships). Within the sub-group analysis that separated the data based on LPRx pre-dose, a significance between pre-/post-drug change in LPRx was seen, however this may be more of a result from patient state than drug impact. CONCLUSIONS: Overall, this study indicates that commonly administered agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity in TBI (nor do they impair cerebrovascular reactivity). Though further investigation in a larger and more diverse TBI patient population is required.

Sustaining Life versus Altering Life-Saving Drugs: Insights to Explain the Paradoxical Effect of Extracorporeal Membrane Oxygenation on Drugs.

There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.

Temporal relationship between vasopressor and sedative administration and cerebrovascular response in traumatic brain injury: a time-series analysis.

BACKGROUND: Although vasopressor and sedative agents are commonly used within the intensive care unit to mediate systemic and cerebral physiology, the full impact such agents have on cerebrovascular reactivity remains unclear. Using a prospectively maintained database of high-resolution critical care and physiology, the time-series relationship between vasopressor/sedative administration, and cerebrovascular reactivity was interrogated. Cerebrovascular reactivity was assessed through intracranial pressure and near infrared spectroscopy measures. Using these derived measures, the relationship between hourly dose of medication and hourly index values could be evaluated. The individual medication dose change and their corresponding physiological response was compared. Given the high number of doses of propofol and norepinephrine, a latent profile analysis was used to identify any underlying demographic or variable relationships. Finally, using time-series methodologies of Granger causality and vector impulse response functions, the relationships between the cerebrovascular reactivity derived variables were compared. RESULTS: From this retrospective observational study of 103 TBI patients, the evaluation between the changes in vasopressor or sedative agent dosing and the previously described cerebral physiologies was completed. The assessment of the physiology pre/post infusion agent change resulted in similar overall values (Wilcoxon signed-ranked p value > 0.05). Time series methodologies demonstrated that the basic physiological relationships were identical before and after an infusion agent was changed (Granger causality demonstrated the same directional impact in over 95% of the moments, with response function being graphically identical). CONCLUSIONS: This study suggests that overall, there was a limited association between the changes in vasopressor or sedative agent dosing and the previously described cerebral physiologies including that of cerebrovascular reactivity. Thus, current regimens of administered sedative and vasopressor agents appear to have little to no impact on cerebrovascular reactivity in TBI.

Feasibility of intelligent drug control in the maintenance phase of general anesthesia based on convolutional neural network.

Background: The growth and aging process of the human population has accelerated the increase in surgical procedures. Yet, the demand for increasing operations can be hardly met since the training of anesthesiologists is usually a long-term process. Closed-loop artificial intelligence (AI) model provides the possibility to solve intelligent decision-making for anesthesia auxiliary control and, as such, has allowed breakthroughs in closed-loop control of clinical practices in intensive care units (ICUs). However, applying an open-loop artificial intelligence algorithm to build up personalized medication for anesthesia still needs to be further explored. Currently, anesthesiologists have selected doses of intravenously pumped anesthetic drugs mainly based on the blood pressure and bispectral index (BIS), which can express the depth of anesthesia. Unfortunately, BIS cannot be monitored at some medical centers or operational procedures and only be regulated by blood pressure. As a result, here we aim to inaugurally explore the feasibility of a basic intelligent control system applied to drug delivery in the maintenance phase of general anesthesia, based on a convolutional neural network model with open-loop design, according to AI learning of existing anesthesia protocols. Methods: A convolutional neural network, combined with both sliding window sampling method and residual learning module, was utilized to establish an "AI anesthesiologist" model for intraoperative dosing of personalized anesthetic drugs (propofol and remifentanil). The fitting degree and difference in pumping dose decision, between the AI anesthesiologist and the clinical anesthesiologist, for these personalized anesthetic drugs were examined during the maintenance phase of anesthesia. Results: The medication level established by the "AI anesthesiologist" was comparable to that obtained by the clinical anesthesiologist during the maintenance phase of anesthesia. Conclusion: The application of an open-loop decision-making plan by convolutional neural network showed that intelligent anesthesia control is consistent with the actual anesthesia control, thus providing possibility for further evolution and optimization of auxiliary intelligent control of depth of anesthesia.

Association of sedation and anesthesia on cognitive outcomes in very premature infants: a retrospective observational study.

PURPOSE: Cognitive outcomes in preterm infants may be adversely affected by use of sedation and anesthetic agents. We investigated the associations between anesthetics/sedatives and full-scale intelligence quotient (FSIQ) measured at 36 months corrected age (CA) in very preterm infants (born < 29 weeks gestational age). METHODS: This retrospective cohort study included preterm infants born at < 29 weeks of gestation between 1 January 2006 and 31 December 2012, whose cognitive outcomes were assessed at 36 months CA. Imputed and complete case univariable and adjusted multivariable linear regressions were used to investigate the associations between FSIQ [standardized to mean (standard deviation) 100 (15)] and exposure to volatile anesthetics, propofol, benzodiazepines, barbiturates, and ketamine. These agents were the subject of a 2016 warning from regulatory authorities in the USA recommending caution for administration to children and pregnant women. RESULTS: A total of 731 infants met the inclusion criteria. Unadjusted associations were -7 (95% confidence interval [CI], -10 to -4; P < 0.001) and -6 (95% CI, -10 to -3; P < 0.001) FSIQ points with exposure to warned medications using imputed and complete case analyses, respectively. Imputed and complete case adjusted associations between FSIQ and warned medications were -3 (95% CI, -7 to 0; P = 0.045) and -4 (95% CI, -8 to 0; P = 0.071) FSIQ points, respectively. Adjusted associations between volatile anesthetic exposure only and FSIQ were -3 (95% CI, -6 to 0; P = 0.072) and -5 (95% CI, -9 to -2; P = 0.004) FSIQ points using imputed and complete case data sets, respectively. FSIQ was not associated with opioid exposure. CONCLUSION: Exposure of very preterm infants to anesthetics/sedatives on the United States Food and Drug Administration warning list was associated with a decrease in FSIQ points at 36 months CA. There was no association between opioid exposure and FSIQ.

RéSUMé: OBJECTIF : L'utilization d'agents sédatifs et anesthésiques pourrait avoir une incidence défavorable sur l'évolution cognitive des nourrissons prématurés. Nous avons analysé les associations existantes entre les anesthésiques/sédatifs et le quotient d'intelligence global (QIg) mesuré à 36 mois d'âge corrigé (AC) chez des enfants nés grands prématurés (nés < 29 semaines d'âge gestationnel). MéTHODES: Cette étude de cohorte rétrospective a inclus des nourrissons prématurés nés avant 29 semaines d'âge gestationnel entre le 1er janvier 2006 et le 31 décembre 2012 et dont les critères d'évaluation cognitifs ont été évalués à 36 mois d'AC. Des régressions linéaires à une seule variable et multivariables ajustée, sur les cas imputés et sur les cas complets, ont été utilisées pour rechercher les associations entre le QIg (standardisé à la moyenne 100 [± écart-type] [15]) et l'exposition à des anesthésiques volatils, du propofol, des benzodiazépines, des barbituriques et de la kétamine. Ces molécules ont fait l'objet d'une mise en garde en 2016 par les autorités de réglementation aux États-Unis, recommandant la prudence concernant leur administration à des enfants et à des femmes enceintes. RéSULTATS: Un total de 731 nourrissons présentait les critères d'inclusion. Les associations non ajustées ont été de -7 (intervalle de confiance [IC] à 95 % : -10 à -4; P < 0,001) et -6 (IC à 95 % : -10 à -3; P < 0,001) points de QIg avec l'exposition aux médicaments sous avertissement en utilisant, respectivement, des analyses de cas imputés et de cas complets. Les associations ajustées de cas imputés et complets entre le QIg et les médicaments sous avertissement ont été, respectivement, de -3 (IC à 95 % : -7 à 0; P = 0,045) et -4 (IC à 95 % : -8 à 0; P = 0,071) points de QIg. Les associations ajustées entre l'exposition aux anesthésiques volatiles, uniquement, et le QIg ont été de -3 (IC à 95 % : -6 à 0; P = 0,072) et -5 (IC à 95 % : -9 à 2; P = 0,004) points de QIg en utilisant, respectivement, les ensembles de données des cas imputés et des cas complets. Le QIg n'a pas été associé à une exposition aux opioïdes. CONCLUSION: L'exposition des nourrissons grands prématurés aux anesthésiques/sédatifs figurant sur la liste d'avertissement de la Food and Drug Administration des États-Unis a été associée à une diminution des points de QIg à 36 mois d'AC. Il n'y a pas eu d'association entre l'exposition aux opioïdes et le QIg.

Sedative drug-use in Denmark, 2000 to 2019: a nationwide drug utilization study.

AIM: To describe trends in and characteristics of sedative drug use from 2000 through 2019 in relation to the introduction of central regulations and new drugs. METHODS: In this descriptive study, we used individual prescription data on the entire Danish population from the Danish National Prescription Registry to calculate yearly incidence and prevalence of use of benzodiazepines, benzodiazepine-related drugs (Z-drugs), melatonin, olanzapine, low-dose quetiapine, mianserin/mirtazapine, pregabalin, and promethazine from 2000 through 2019. From the Danish National Patient Registry, we obtained data on drug users' psychiatric and somatic comorbidity. RESULTS: The use of benzodiazepines and Z-drugs declined gradually from 2000 through 2019, whereas the newer alternatives, melatonin, low-dose quetiapine, pregabalin and promethazine, increased in use, while the use of olanzapine and mianserin/mirtazapine was relatively stable. This development was seen in both men and women and across all age groups except for hypnotic benzodiazepines which showed a steep increase in the oldest age group from 2010. For all sedative drugs depression, anxiety, alcohol and misuse disorder, pain and cancer were the most prevalent comorbidities. During our study period, the number of individuals without any of the selected diagnoses increased. CONCLUSION: In Denmark different central regulations have influenced prescription practice toward more restrictive use of Z-drugs and benzodiazepines, except for hypnotic benzodiazepine prescriptions increased after the introduction of special palliative care. An increase in use of newer sedative drugs, however, indicates that the regulations do not remove the need for sedative drugs in the population.

The Impact of Vasopressor and Sedative Agents on Cerebrovascular Reactivity and Compensatory Reserve in Traumatic Brain Injury: An Exploratory Analysis.

The impact of vasopressor and sedative drugs on cerebrovascular reactivity in traumatic brain injury (TBI) remains unclear. The aim of this study was to evaluate the impact of changes of doses of commonly administered sedation (i.e., propofol, fentanyl, and ketamine) and vasopressor agents (i.e., norepinephrine [NE], phenylephrine [PE], and vasopressin[VSP]) on cerebrovascular reactivity and compensatory reserve in patients with moderate/severe TBI. Using the Winnipeg Acute TBI Database, we identified 38 patients with more than 1000 distinct changes of infusion rates and more than 500 h of paired drug infusion/physiology data. Cerebrovascular reactivity was assessed using pressure reactivity index (PRx) and cerebral compensatory reserve was assessed using RAP (the correlation [R] between pulse amplitude of intracranial pressure [ICP; A] and ICP [P]). We evaluated the data in two phases. First, we assessed the relationship between mean hourly dose of medication and its relation to both mean hourly index values, and time spent above a given index threshold. Second, we evaluated time-series data for each individual dose change per medication, assessing for a statistically significant change in PRx and RAP metrics. The results of the analysis confirmed that, overall, the mean hourly dose of sedative (propofol, fentanyl, and ketamine) and vasopressor (NE, PE, and VSP) agents does not impact hourly cerebrovascular reactivity or compensatory reserve measures. Similarly, incremental dose changes in these medications in general do not lead to significant changes in cerebrovascular reactivity or compensatory reserve. For propofol with incremental dose increases, in situations where PRx is intact (i.e., PRx <0 prior), a statistically significant increase in PRx was seen. However, this may not indicate deteriorating cerebrovascular reactivity as the final PRx (∼0.05) may still be considered to be intact cerebrovascular reactivity. As such, this finding with regards to propofol remains "weak." This study indicates that commonly administered sedative and vasopressor agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity or compensatory reserve in TBI. These results should be considered preliminary, requiring further investigation.

Prospective audit of sedation/anesthesia practices for children undergoing computerized tomography in a tertiary care institute.

BACKGROUND AND AIMS: The aim of the study was to enumerate the sedative drugs used, assess the efficacy of sedative drugs, and determine the incidence of adverse events. MATERIAL AND METHODS: A prospective audit of children sedated for computerized tomography (CT) by anesthesiology team was conducted for a period of 4 months. The data included patient demographic variables, fasting period, medications administered, adequacy of sedation, imaging characteristics, adverse events, and requirement for escalated care. RESULTS: A total of 331 children were enrolled for sedation by the anesthesia team. The drugs used for sedation were propofol, ketamine, and midazolam. Twenty-two percent children received one sedative drug, 60% children were administered two drugs, and 5% children required a combination of all three drugs for successful sedation. Sedation was effective for successful conduct of CT scan in 95.8% patients without the requirement of a repeat scan. Twelve (5%) children experienced adverse events during the study period. However, none of the adverse events necessitated prolonged postprocedural hospitalization or resulted in permanent neurologic injury or death. CONCLUSIONS: The current practice of sedation with propofol, ketamine, and midazolam, either single or in combination was efficacious in a high percentage of patients. The incidence of adverse events during the study period was low.

The Impact and Mechanism of a Novel Allosteric AMPA Receptor Modulator LCX001 on Protection Against Respiratory Depression in Rodents.

Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.

Sedative drugs used for mechanically ventilated patients in intensive care units: a systematic review and network meta-analysis.

BACKGROUND: The effects of different sedative drugs on all-cause mortality rate, duration of ICU stay, and risk of delirium in mechanically ventilated ICU patients are unclear. This meta-analysis aimed to compare the effectiveness and safety of individual sedative drugs and drug combinations in mechanically ventilated ICU patients. MATERIALS AND METHODS: Medline, Embase, Cochrane, EBSCOhost, and ISI Web of Science databases were searched for studies that assessed sedation in ICU mechanically ventilated patients. A Bayesian random-effects model was used to combine the direct comparisons and indirect evidence. RESULTS: Thirty-one randomized, controlled trials were included, which consisted of 4491 patients who received one of seven sedative drugs or a combination of drugs. There were no significant differences regarding the all-cause mortality rate. Compared to propofol, inhalation anesthetics (hazard ratio [HR] 0.121; 95% credible interval [CrI] -7.58 to 7.62), alpha agonists (HR 2.2; 95% CrI 0.776 to 5.22), propofol with benzodiazepines (HR 0.306; 95% CrI -6.97 to 7.65), ketamine with benzodiazepines (HR 6.57; 95% CrI -6.05 to 19.1) and placebo (HR 2.4; 95% CrI -5.37 to 10.3), benzodiazepines (HR 3.62; 95% CrI 0.834 to 6.2) may increase the duration of ICU stay. Compared to alpha agonists, propofol (HR 2.4; 95% CrI 0.304 to 21.1) and placebo (HR 6.12; 95% CrI 0.745 to 54.6), benzodiazepines (HR 2.59; 95% CrI 1.08 to 7.4) were associated with incremental risks of delirium. CONCLUSION: Compared to propofol, benzodiazepines may increase the duration of ICU stay. Compared to alpha agonists, benzodiazepines were associated with an increased risk of delirium.

Cortisol evaluation during the acute phase of traumatic brain injury-A prospective study.

BACKGROUND: Biochemical diagnosis of adrenal insufficiency (AI) is difficult in the context of traumatic brain injury (TBI). AIM: To assess the frequency and predictive factors of AI in victims of TBI from Algiers. METHODS: Between November 2009 and December 2013, TBI victims had a single 8-9 am serum cortisol measurement during the acute postinjury period (0-7 days). AI was defined according to basal cortisol levels of 83, 276 and 414 nmol/L. Variables studied were TBI severity according to Glasgow coma scale, duration of intubation and coma, pupillary status, hypotension, anaemia, brain imaging findings, diabetes insipidus and medication. Insulin tolerance test was performed during the recovery phase, defining AI as peak cortisol <500 nmol/L. RESULTS: Cortisol samples were obtained at median 3 (1-7) days from 277 patients (257M: 20F) aged 32 (18-65) years. Acute AI frequency was 8 (2.8%), 20 (21%) and 35 (37%), respectively using the three cortisol cut-offs. Factors predicting AI were diastolic hypotension, sedative medication, diabetes insipidus, skull base fracture and intraparenchymal haematoma. Mortality was highest in patients with acute cortisol <276 nmol/L (44.6% with OR for death 1.64, 95% CI 0.92-3.0, P = .12). During the recovery phase, AI was present in 3 of 3, 12 of 24, 4 of 16 and 20 of 66 patients with week 1 cortisol <83, 83-276, 277-414 and >414 nmol/L. CONCLUSION: Hydrocortisone replacement is advised in TBI patients with morning cortisol <276 nmol/L or those <414 nmol/L with additional risk factors for AI. As acute and subsequent AI are poorly correlated, patients with moderate/severe TBI require adrenal re-evaluation during the recovery phase.

The relationship between sedative drug utilization and outcomes in critically ill patients undergoing mechanical ventilation.

OBJECTIVES: The objectives of this study were to describe current sedative drug utilization patterns in critically ill patients undergoing mechanical ventilation (MV) in intensive care units (ICUs) in Japanese hospitals and to elucidate the relationship of these utilization patterns with patient clinical outcomes. METHOD: Analysis of hospital claims data derived from the Quality Indicator/Improvement Project identified 12,395 critically ill adult patients who had undergone MV while hospitalized in the ICUs of 114 Japanese hospitals and had been discharged between April 2008 and March 2010. Descriptive statistics were calculated for the daily utilization of sedative drugs, opioids, and muscle relaxants in this patient sample, and the relationship between drug utilization and patient outcomes using Cox proportional hazards analysis were examined. RESULTS: Of the 12,395 patients included in the analysis, 7300 (58.9 %), 580 (4.7 %), and 671 (5.4 %) received sedative drugs, opioids, and muscle relaxants, respectively, for ≥2 days after intubation. Compared to the other patient groups, there was a higher proportion of males in the group given sedative drugs and the patients were significantly younger (P < 0.001). Propofol was the most frequently used sedative drug, followed by benzodiazepines, barbiturates, and dexmedetomidine. The mortality rate was lower and ventilator weaning was earlier among patients who received only propofol than among those who received only benzodiazepines. Muscle relaxants were associated with increased duration of MV. CONCLUSIONS: This is the first study based on a large-scale analysis in Japan to elucidate sedative drug utilization patterns and their relationship with outcomes in critically ill patients. The most commonly used sedative was propofol, which was associated with favorable patient outcomes. Further prospective research must be conducted to discern effective sedative drug utilization.

EcoDopplercardiografia em coelhos: uso de midazolam e midazolam associado à cetamina / Echocardiographic evaluation in rabbits: association of midazolam and ketamine

O uso de animais como modelos experimentais muitas vezes exige a administração de sedativos ou anestésicos, particularmente quando se trata de avaliação ecoDopplercardiográfica de coelhos. No entanto, existem poucas informações sobre os protocolos e seus efeitos nestes parâmetros. Diante deste contexto, foram utilizados 20 coelhos Nova Zelândia machos, com cinco meses e 3,2kg, distribuídos em dois grupos de 10 animais cada: G1 - maleato de midazolam associado ao cloridrato de cetamina, e G2 - maleato de midazolam. Compararam-se o efeito dos dois protocolos sob os índices funcionais do ventrículo esquerdo e os fluxos valvares, e observaram-se menores valores de frequência cardíaca e da fração de ejeção e maiores valores de diâmetro do ventrículo esquerdo na sístole, de volume sistólico final do ventrículo esquerdo e de diâmetro aórtico no grupo que recebeu apenas maleato de midazolam (G2). Concluiu-se que, o maleato de midazolam apresentou-se mais eficaz, pois causou boa sedação nos animais, permitindo a realização de ecoDopplercardiogramas de qualidade e efeitos limitados no sistema cardiovascular.

The use of animals as experimental models often requires anesthesia, particularly when it comes to echocardiographic evaluation of rabbits. However, there is little information regarding the protocols and their effects on echocardiographic parameters. We used 20 male five month old New Zealand rabbits, weighing 3.2kg, distributed in two groups of 10 animals each: G1 - midazolam maleate associated with ketamine hydrochloride, and G2 - midazolam maleate. We compared the effect of two protocols on functional indicators of the left ventricle and the flow valves and we obtained lower values of heart rate and left ventricular ejection fraction and higher values of left ventricular diameter in systole, end-systolic volume of left ventricle and aortic diameter in the group that received only midazolam. Midazolam maleate was more effective because it promoted good sedation, allowing a good quality examination and limited effects on the cardiovascular system.