Efficacy comparison of intraperitoneal anaesthesia and post-operative analgesia regimens in laboratory rats.

INTRODUCTION: Effective and safe anesthesia for rodents has long been a leading concern among biomedical researchers. Intraperitoneal injection constitutes an alternative to inhalant anesthesia. PURPOSE: The aim of this study was to identify a safe, reliable, and effective anesthesia and postoperative analgesia protocol for laboratory rats exposed to painful procedures. MATERIAL AND METHODS: Twenty-seven female Wistar rats in an ongoing study that required surgery were randomized into groups for three different intraperitoneal anesthesia protocols and three different analgesia regimens. The anesthesia groups were (1) medetomidine + ketamine (MK), (2) ketamine + xylacine (KX), and (3) fentanyl + medetomidine (FM). Three analgesia groups were equally distributed among the anesthesia groups: (1) local mepivacaine + oral ibuprofen (MI), (2) oral tramadol + oral ibuprofen (TI), and (3) local tramadol + oral tramadol + + oral ibuprofen (TTI). A core was assigned to measure anesthesia (0-3) and analgesia (0-2) effectiveness; the lower the score, the more effective the treatment. RESULTS: The mean MK score was 0.44 versus 2.00 for FM and 2.33 for KX. Mean score for analgesia on the first postoperative day was TTI (4.66) TI (9.13), and MI (10.14). Mean score 48 hours after surgery was TTI (3.4), TI (6.71), and MI (9.5). These differences were statistically significant. CONCLUSION: MK was shown to be a reliable, safe, and effective method of anesthesia. The TTI analgesia regimen is strongly recommended in light of these results.

Impact of ketamine as an adjunct sedative in acute respiratory distress syndrome due to COVID-19 Pneumonia.

PURPOSE: Deep sedation is sometimes needed in acute respiratory distress syndrome. Ketamine is a sedative that has been shown to have analgesic and sedating properties without having a detrimental impact on hemodynamics. This pharmacological profile makes ketamine an attractive sedative, potentially reducing the necessity for other sedatives and vasopressors, but there are no studies evaluating its effect on these medications in patients requiring deep sedation for acute respiratory distress syndrome. MATERIALS AND METHODS: This is a retrospective, observational study in a single center, quaternary care hospital in southeast Texas. We looked at adults with COVID-19 requiring mechanical ventilation from March 2020 to September 2020. RESULTS: We found that patients had less propofol requirements at 72 h after ketamine initiation when compared to 24 h (median 34.2 vs 54.7 mg/kg, p = 0.003). Norepinephrine equivalents were also significantly lower at 48 h than 24 h after ketamine initiation (median 38 vs 62.8 mcg/kg, p = 0.028). There was an increase in hydromorphone infusion rates at all three time points after ketamine was introduced. CONCLUSIONS: In this cohort of patients with COVID-19 ARDS who required mechanical ventilation receiving ketamine we found propofol sparing effects and vasopressor requirements were reduced, while opioid infusions were not.

Feasibility of sit training for patients with severe COVID-19 pneumonia during deep sedation: A case report.

RATIONALE: There have been a few reports on the early rehabilitation of patients with coronavirus disease (COVID-19), and none on the effectiveness and adverse events of early mobilization for mechanical ventilation patients (other than COVID-19) during deep sedation. This report indicates that sitting without adverse events is possible in patients with severe COVID-19 pneumonia during deep sedation with muscle relaxation. PATIENT CONCERNS: A 65-year-old man with a history of diabetes mellitus, lacunar infarction, and Parkinson's disease was admitted to a local hospital for pneumonia due to COVID-19. After admission, the patient was managed on a ventilator under deep sedation with muscle relaxants and sedatives. Twelve days after admission, the patient was transferred to our hospital due to his worsening respiratory status. DIAGNOSIS: Pneumonia due to COVID-19 was diagnosed using a polymerase chain reaction-dependent method. INTERVENTIONS: The day following transfer, a physical therapist started passive range of motion training and sitting. OUTCOMES: The period spanning his initial rehabilitation to muscle relaxant medication interruption was 9 days, and he underwent 7 rehabilitation sessions. The patient was unable to sit during only one of the 7 sessions due to pre-rehabilitation hypoxemia. In 5 of the 6 sitting sessions, PaO2/FiO2 transiently decreased but recovered by the time of subsequent blood sampling. The patient's PaCO2 decreased during all sessions. His blood pressure did not drastically decrease in any sitting session, except the first. Sputum excretion via sputum suction increased during sitting, and peak inspiratory pressure did not change. LESSONS: The patient eventually died of pneumonia due to COVID-19. However, sitting during deep sedation with muscle relaxants did not cause any serious adverse events nor did it appear to cause obvious negative respiratory effects.

Tailored Pharmacokinetic model to predict drug trapping in long-term anesthesia.

Introduction: In long-term induced general anesthesia cases such as those uniquely defined by the ongoing Covid-19 pandemic context, the clearance of hypnotic and analgesic drugs from the body follows anomalous diffusion with afferent drug trapping and escape rates in heterogeneous tissues. Evidence exists that drug molecules have a preference to accumulate in slow acting compartments such as muscle and fat mass volumes. Currently used patient dependent pharmacokinetic models do not take into account anomalous diffusion resulted from heterogeneous drug distribution in the body with time varying clearance rates. Objectives: This paper proposes a mathematical framework for drug trapping estimation in PK models for estimating optimal drug infusion rates to maintain long-term anesthesia in Covid-19 patients. We also propose a protocol for measuring and calibrating PK models, along with a methodology to minimize blood sample collection. Methods: We propose a framework enabling calibration of the models during the follow up of Covid-19 patients undergoing anesthesia during their treatment and recovery period in ICU. The proposed model can be easily updated with incoming information from clinical protocols on blood plasma drug concentration profiles. Already available pharmacokinetic and pharmacodynamic models can be then calibrated based on blood plasma concentration measurements. Results: The proposed calibration methodology allow to minimize risk for potential over-dosing as clearance rates are updated based on direct measurements from the patient. Conclusions: The proposed methodology will reduce the adverse effects related to over-dosing, which allow further increase of the success rate during the recovery period.

Association of Sedation, Coma, and In-Hospital Mortality in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Acute Respiratory Distress Syndrome: A Retrospective Cohort Study.

OBJECTIVES: In patients with coronavirus disease 2019-associated acute respiratory distress syndrome, sedatives and opioids are commonly administered which may lead to increased vulnerability to neurologic dysfunction. We tested the hypothesis that patients with coronavirus disease 2019-associated acute respiratory distress syndrome are at higher risk of in-hospital mortality due to prolonged coma compared with other patients with acute respiratory distress syndrome matched for disease severity. DESIGN: Propensity-matched cohort study. SETTING: Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA). PATIENTS: All mechanically ventilated coronavirus disease 2019 patients between March and May 2020 were identified and matched with patients with acute respiratory distress syndrome of other etiology. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using clinical data obtained from a hospital registry, we matched 114 coronavirus disease 2019 patients to 228 noncoronavirus disease 2019-related acute respiratory distress syndrome patients based on baseline disease severity. Coma was identified using the Richmond Agitation Sedation Scale less than or equal to -3. Multivariable logistic regression and mediation analyses were used to assess the percentage of comatose days, sedative medications used, and the association between coronavirus disease 2019 and in-hospital mortality. In-hospital mortality (48.3% vs 31.6%, adjusted odds ratio, 2.15; 95% CI, 1.34-3.44; p = 0.002), the percentage of comatose days (66.0% ± 31.3% vs 36.0% ± 36.9%, adjusted difference, 29.35; 95% CI, 21.45-37.24; p < 0.001), and the hypnotic agent dose (51.3% vs 17.1% of maximum hypnotic agent dose given in the cohort; p < 0.001) were higher among patients with coronavirus disease 2019. Brain imaging did not show a higher frequency of structural brain lesions in patients with coronavirus disease 2019 (6.1% vs 7.0%; p = 0.76). Hypnotic agent dose was associated with coma (adjusted coefficient, 0.61; 95% CI, 0.45-0.78; p < 0.001) and mediated (p = 0.001) coma. Coma was associated with in-hospital mortality (adjusted odds ratio, 5.84; 95% CI, 3.58-9.58; p < 0.001) and mediated 59% of in-hospital mortality (p < 0.001). CONCLUSIONS: Compared with matched patients with acute respiratory distress syndrome of other etiology, patients with coronavirus disease 2019 received higher doses of hypnotics, which was associated with prolonged coma and higher mortality.

Use of volatile agents for sedation in the intensive care unit: A national survey in France.

BACKGROUND: Current intensive care unit (ICU) sedation guidelines recommend strategies using non-benzodiazepine sedatives. This survey was undertaken to explore inhaled ICU sedation practice in France. METHODS: In this national survey, medical directors of French adult ICUs were contacted by phone or email between July and August 2019. ICU medical directors were questioned about the characteristics of their department, their knowledge on inhaled sedation, and practical aspects of inhaled sedation use in their department. RESULTS: Among the 374 ICUs contacted, 187 provided responses (50%). Most ICU directors (73%) knew about the use of inhaled ICU sedation and 21% used inhaled sedation in their unit, mostly with the Anaesthetic Conserving Device (AnaConDa, Sedana Medical). Most respondents had used volatile agents for sedation for <5 years (63%) and in <20 patients per year (75%), with their main indications being: failure of intravenous sedation, severe asthma or bronchial obstruction, and acute respiratory distress syndrome. Sevoflurane and isoflurane were mainly used (88% and 20%, respectively). The main reasons for not using inhaled ICU sedation were: "device not available" (40%), "lack of medical interest" (37%), "lack of familiarity or knowledge about the technique" (35%) and "elevated cost" (21%). Most respondents (80%) were overall satisfied with the use of inhaled sedation. Almost 75% stated that inhaled sedation was a seducing alternative to intravenous sedation. CONCLUSION: This survey highlights the widespread knowledge about inhaled ICU sedation in France but shows its limited use to date. Differences in education and knowledge, as well as the recent and relatively scarce literature on the use of volatile agents in the ICU, might explain the diverse practices that were observed. The low rate of mild adverse effects, as perceived by respondents, and the users' satisfaction, are promising for this potentially important tool for ICU sedation.

A Case Report of Sedation Strategy for a Patient With Coronavirus Disease 2019 Supported by Extracorporeal Membrane Oxygenation After Cesarean Section.

Pneumonia caused by coronavirus disease 2019 (COVID-19) is a highly contagious disease. Unfortunately, research on extracorporeal membrane oxygenation (ECMO) assisted treatments for patients with COVID-19 infection is limited. In this case study, a patient who was in late pregnancy (35+2 weeks of pregnancy) and suffering from severe COVID-19 was extremely irritable during ECMO-assisted treatment after she underwent a cesarean section. Her Richmond Agitation Sedation Scale (RASS) score reached +3. Nevertheless, the patient successfully was treated with a continuous single/combined application of propofol, midazolam, dexmedetomidine, hibernation mixture, and other drugs for several days (maintaining RASS -2 to -4) and provided with anti-infection, mechanical ventilation, nutritional support, fluid balance under hemodynamic monitoring, liver support, and other organ function support treatments. ECMO-assisted sedation strategy for patients was introduced and discussed in this case to provide a certain reference for the clinical diagnosis and treatment of such patients.

Frontotemporal EEG to guide sedation in COVID-19 related acute respiratory distress syndrome.

OBJECTIVE: To study if limited frontotemporal electroencephalogram (EEG) can guide sedation changes in highly infectious novel coronavirus disease 2019 (COVID-19) patients receiving neuromuscular blocking agent. METHODS: 98 days of continuous frontotemporal EEG from 11 consecutive patients was evaluated daily by an epileptologist to recommend reduction or maintenance of the sedative level. We evaluated the need to increase sedation in the 6 h following this recommendation. Post-hoc analysis of the quantitative EEG was correlated with the level of sedation using a machine learning algorithm. RESULTS: Eleven patients were studied for a total of ninety-eight sedation days. EEG was consistent with excessive sedation on 57 (58%) and adequate sedation on 41 days (42%). Recommendations were followed by the team on 59% (N = 58; 19 to reduce and 39 to keep the sedation level). In the 6 h following reduction in sedation, increases of sedation were needed in 7 (12%). Automatized classification of EEG sedation levels reached 80% (±17%) accuracy. CONCLUSIONS: Visual inspection of a limited EEG helped sedation depth guidance. In a secondary analysis, our data supported that this determination may be automated using quantitative EEG analysis. SIGNIFICANCE: Our results support the use of frontotemporal EEG for guiding sedation in patients with COVID-19.

Optimal Sedation and Pain Management: A Patient- and Symptom-Oriented Paradigm.

In the critically ill patient, optimal pain and sedation management remains the cornerstone of achieving comfort, safety, and to facilitate complex life support interventions. Pain relief, using multimodal analgesia, is an integral component of any orchestrated approach to achieve clinically appropriate goals in critically ill patients. Sedative management, however, remains a significant challenge. Subsequent studies including most recent randomized trials have failed to provide strong evidence in favor of a sedative agent, a mode of sedation or ancillary protocols such as sedative interruption and sedative minimization. In addition, clinical practice guidelines, despite a comprehensive evaluation of relevant literature, have limitations when applied to individual patients. These limitations have been most apparent during the coronavirus disease 2019 pandemic. As such, there is a need for a mindset shift to a practical and achievable sedation strategy, driven by patients' characteristics and individual patient needs, rather than one cocktail for all patients. In this review, we present key principles to achieve patient-and symptom-oriented optimal analgesia and sedation in the critically ill patients. Sedative intensity should be proportionate to care complexity with due consideration to an individual patient's modifiers. The use of multimodal analgesics, sedatives, and antipsychotics agents-that are easily titratable-reduces the overall quantum of sedatives and opioids, and reduces the risk of adverse events while maximizing clinical benefits. In addition, critical considerations regarding the choice of sedative agents should be given to factors such as age, medical versus operative diagnosis, and cardiovascular status. Specific populations such as trauma, neurological injury, and pregnancy should also be taken into account to maximize efficacy and reduce adverse events.

Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages.

The rapid spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global pandemic. The 2019 coronavirus disease (COVID-19) presents with a spectrum of symptoms ranging from mild to critical illness requiring intensive care unit (ICU) admission. Acute respiratory distress syndrome is a major complication in patients with severe COVID-19 disease. Currently, there are no recognized pharmacological therapies for COVID-19. However, a large number of COVID-19 patients require respiratory support, with a high percentage requiring invasive ventilation. The rapid spread of the infection has led to a surge in the rate of hospitalizations and ICU admissions, which created a challenge to public health, research, and medical communities. The high demand for several therapies, including sedatives, analgesics, and paralytics, that are often utilized in the care of COVID-19 patients requiring mechanical ventilation, has created pressure on the supply chain resulting in shortages in these critical medications. This has led clinicians to develop conservation strategies and explore alternative therapies for sedation, analgesia, and paralysis in COVID-19 patients. Several of these alternative approaches have demonstrated acceptable levels of sedation, analgesia, and paralysis in different settings but they are not commonly used in the ICU. Additionally, they have unique pharmaceutical properties, limitations, and adverse effects. This narrative review summarizes the literature on alternative drug therapies for the management of sedation, analgesia, and paralysis in COVID-19 patients. Also, this document serves as a resource for clinicians in current and future respiratory illness pandemics in the setting of drug shortages.

Inhalational volatile-based sedation for COVID-19 pneumonia and ARDS.

Hospitals worldwide are experiencing a shortage in essential intravenous sedative medications. This is attributable to high number and high sedative needs of COVID-19 critical care patients with disruption of drug supply chains. Inhaled volatile anesthetic agents are an abundant resource and readily implementable solution for providing ICU sedation. Inhaled volatile agents may also provide important pulmonary benefits for COVID-19 patients with ARDS that could improve gas exchange and reduce time spent on a ventilator. We review the use of volatile agents, and provide a technical overview and algorithm for administering inhaled volatile-based sedation in ICUs.

Anticipatory prescribing in community end-of-life care in the UK and Ireland during the COVID-19 pandemic: online survey.

BACKGROUND: Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing guidelines and practice have been reported during the COVID-19 pandemic. AIMS AND OBJECTIVES: To investigate UK and Ireland clinicians' experiences concerning changes in AP during the COVID-19 pandemic and their recommendations for change. METHODS: Online survey of participants at previous AP national workshops, members of the Association for Palliative Medicine of Great Britain and Ireland and other professional organisations, with snowball sampling. RESULTS: Two hundred and sixty-one replies were received between 9 and 19 April 2020 from clinicians in community, hospice and hospital settings across all areas of the UK and Ireland. Changes to AP local guidance and practice were reported: route of administration (47%), drugs prescribed (38%), total quantities prescribed (35%), doses and ranges (29%). Concerns over shortages of nurses and doctors to administer subcutaneous injections led 37% to consider drug administration by family or social caregivers, often by buccal, sublingual and transdermal routes. Clinical contact and patient assessment were more often remote via telephone or video (63%). Recommendations for regulatory changes to permit drug repurposing and easier community access were made. CONCLUSIONS: The challenges of the COVID-19 pandemic for UK community palliative care has stimulated rapid innovation in AP. The extent to which these are implemented and their clinical efficacy need further examination.

Dexmedetomidine and worsening hypoxemia in the setting of COVID-19: A case report.

Emergency department management of hypoxemia in the setting of COVID-19 is riddled with uncertainty. The lack of high-quality research has translated to an absence of clarity at the bedside. With disease spread outpacing treatment consensus, provider discretion has taken on a heightened role. Here, we report a case of dexmedetomidine use in the setting of worsening hypoxemia, whereby oxygenation improved and intubation was avoided. Well known pharmacologic properties of the drug, namely the lack of respiratory depression and its anti-delirium effects, as well as other possible physiologic effects, suggest potential benefit for patients being managed with a delayed intubation approach. If dexmedetomidine can improve compliance with non-invasive oxygen support (the current recommended first-line therapy) while promoting better oxygenation, it may also decrease the need for mechanical ventilation and thus improve mortality.