Rethink analgo-sedation in digestive endoscopy: the role of scientific societies in tracing training path.

OBJECTIVE: The Italian Society of Anesthesia, Analgesia, Reanimation and Intensive Care Medicine (SIAARTI) and the Italian Society of Digestive Endoscopy (SIED) worked together to produce a joint Good Clinical Practice (GCP) on analgo-sedation in digestive endoscopy and launched a survey to support the document. The aim was to identify and describe the actual clinical practice of sedation in Italian digestive endoscopy units and offer material for a wider and more widespread discussion among anesthetists and endoscopists. SUBJECTS AND METHODS: A national survey was planned, in order to support the statements of the GCP. Twelve thousand and five hundred questionnaires were sent to the members of SIAARTI and SIED in June 2020. RESULTS: A total of 662 forms (5.3%) returned completed. Highly complex procedures are performed according to 70% of respondents; daily anesthesiologist's assistance is guaranteed in 26%, for scheduled sessions in 14.5% and as needed in 8%. 69% of respondents declared not to have a dedicated team of anesthesiologists, while just 5% reported an anesthesiologist in charge. A complete monitoring system was assured by 70% of respondents. Dedicated pathways for COVID-19-positive patients were confirmed in <40% of the answers. With regard to moderate/deep sedation, 90% of respondents stated that an anesthetist decides timing and doses. Propofol was exclusively administered by anesthetists according to 94% of answers, and for 6% of respondents the endoscopist is allowed to administer propofol in presence of a dedicated nurse, but with a readily available anesthetist. Only 32.8% of respondents reported institutional training courses on procedural analgo-sedation. CONCLUSIONS: The need to provide patients scheduled for endoscopy procedures with an adequate analgo-sedation is becoming an increasing concern, well-known in almost all countries, but many factors compromise the quality of patient care. Results of a national survey would give strength to the need for a shared GCP in gastrointestinal endoscopy. Training and certification of non-anesthetist professionals should be one of the main ways to center the objective.

Refractory atrial fibrillation with rapid ventricular response as a heralding sign of propofol infusion syndrome in a patient with COVID-19.

A woman in her 40s was transferred to the medical intensive care unit due to severe COVID-19 infection causing respiratory failure. Her respiratory failure worsened rapidly, requiring intubation and continuous sedation with fentanyl and propofol infusions. She required progressive increases in the rates of the propofol infusion, as well as addition of midazolam and cisatracurium due to ventilator dyssynchrony. To support the high sedative doses, norepinephrine was administered as a continuous infusion. She developed atrial fibrillation with rapid ventricular response, with rates ranging between 180 and 200 s which did not respond to intravenous adenosine, metoprolol, synchronised cardioversion or amiodarone. A blood draw revealed lipaemia, and triglyceride levels were noted to be elevated to 2018. The patient developed high-grade fevers up to 105.3 and acute renal failure with severe mixed respiratory and metabolic acidosis, indicating propofol-related infusion syndrome. Propofol was promptly discontinued. An insulin-dextrose infusion was initiated which improved patient's fevers and hypertriglyceridaemia.

Development of a compounded propofol nanoemulsion using multiple non-invasive process analytical technologies.

Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak of the COVID-19 pandemic, regular supply chains could not keep up with the sudden increase in global demand, causing drug shortages. Propofol is formulated as an oil-in-water emulsion which is administered intravenously. This study explores the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment to temporally alleviate such shortages. A commercially available lipid emulsion (IVLE, SMOFlipid 20 %), intended for parenteral nutrition, was used to create a propofol loaded nanoemulsion via addition of liquid propofol drug substance and subsequent mixing. Critical quality attributes such as mean droplet size and the volume-weighted percentage of large-diameter (>5µm) droplets were studied. The evolution of droplet size and propofol distribution was monitored in situ and non-destructively, maintaining sterility, using Spatially Resolved Dynamic Light Scattering and Near Infrared Spectroscopy, respectively. Using response surface methodology, an optimum was found for a 4 % w/v propofol formulation with a ∼15 min mixing time in a flask shaker at a 40° shaking angle. This study shows that extemporaneous compounding is a viable option for emergency supply of propofol drug product during global drug shortages.

Unusual case of propofol-related infusion syndrome complicating severe COVID-19 ARDS.

An elderly man presenting with shortness of breath and hypoxaemia was admitted with acute hypoxic respiratory failure secondary to COVID-19 pneumonia. Due to worsening hypoxaemia, he was transferred to the intensive care unit and required mechanical ventilation. Propofol was infused at 1.5-4 mg/kg/hour. Within 48 hours of initiation, we noticed worsening metabolic acidosis, acute kidney injury, hyperkalaemia, hyperphosphataemia, hypertriglyceridaemia, elevated creatine kinase and elevated myoglobin levels. Suspecting propofol-related infusion syndrome (PRIS), we discontinued his propofol infusion immediately and initiated supportive measures. In 48 hours, there was a significant improvement in metabolic acidosis, hypertriglyceridaemia, rhabdomyolysis and renal function. The propofol infusion rate and cumulative propofol dosage (under 140 mg/kg) were well below levels associated with PRIS. COVID-19's pathogenesis, still under investigation, may have contributed to this presentation. It is imperative for clinicians to maintain a high degree of suspicion once propofol is initiated, regardless of the cumulative dose or rate of infusion.

Tracheotomy in ventilator-dependent patients with COVID-19: a cross-sectional study of analgesia and sedative requirements.

OBJECTIVE: During March 2020 in the United States, demand for sedatives increased by 91%, that for analgesics rose by 79%, and demand for neuromuscular blockers increased by 105%, all owing to the number of COVID-19 cases requiring invasive mechanical ventilation (MV). We hypothesize that analgesic and sedative requirements decrease following tracheotomy in this patient population. METHODS: In this cross-sectional study, we conducted a retrospective chart review to identify patients with COVID-19 who underwent tracheotomy (T) at an academic medical center between March 2020 and January 2021. We used a paired Student t-test to compare total oral morphine equivalents (OMEs), total lorazepam equivalents, 24-hour average dexmedetomidine dosage in µg/kg/hour, and 24-hour average propofol dosage in µg/kg/minute on days T-1 and T+2 for each patient. RESULTS: Of 50 patients, 46 required opioids before and after tracheotomy (mean decrease of 49.4 mg OMEs). Eight patients required benzodiazepine infusion (mean decrease of 45.1 mg lorazepam equivalents. Fifteen patients required dexmedetomidine infusion (mean decrease 0.34 µg/kg/hour). Seventeen patients required propofol (mean decrease 20.5 µg/kg/minute). CONCLUSIONS: When appropriate personal protective equipment is available, use of tracheotomy in patients with COVID-19 who require MV may help to conserve medication supplies in times of extreme shortages.

The Emergency Medicine Pharmacotherapy Literature of 2021.

This article highlights the most relevant emergency medicine (EM) pharmacotherapy publications indexed in 2021. A modified Delphi approach was utilized for selected journals to identify the most impactful EM pharmacotherapy studies via the GRADE system. After review of journal table of contents GRADE 1A and 1B articles were reviewed by authors. Twenty articles, 2 guidelines, 2 position papers, and 2 meta-analysis were selected for full summary. Articles included in this review highlight acute agitation management, acute appendicitis treatment, sexually transmitted infection updates, optimizing sepsis management and treatment, updates for the ideal thrombolytic agent in acute ischemic stroke and endovascular therapy candidates, indications for tranexamic acid, calicium for out of hospital cardiac arrest, optimial inotrope for cardiogenic shock, awareness during rapid sequence intubation paralysis, comparison of propofol or dexmedetomidine for sedation, treatment of cannabis hyperemsis syndrome, and prophylactic use of diphenhydramine to reduce neuroleptic side effects. Selected articles are summarized to include design, results, limitations, conclusions and impact.

Propofol directly binds to and inhibits TLR7.

Sedatives/anesthetics are important medical tools to facilitate medical care and increase patients' comfort. Increasingly, there is recognition that sedatives/anesthetics can modulate immune functions. Toll-like receptors (TLRs) are major pattern recognition receptors involved in the recognition of microbial components. TLR7 recognizes single-strand RNA virus such as influenza and SARS-CoV2 viruses and initiates interferon (IFN) responses. IFN production triggered by TLR7 stimulation is a critical anti-viral response. For example, patients with TLR7 variants including loss-of- function variants were associated with severe COVID-19. Taken together, it is important to determine if sedatives/anesthetics mitigate TLR7 function. We have previously showed that TLR7-mediated activation was not affected by volatile anesthetics. However, we found that propofol attenuated TLR7 activation among intravenous sedatives in the reporter assay. TLR7 agonist R837 stimulation increased TNF-α, IL-1ß, IL-6, IL-10, and IFN-ß mRNA levels in bone marrow-derived dendritic cells, while these levels were attenuated by propofol. Our murine lung slice experiments showed that propofol attenuated IFN production. R837 increased IFN-ß expression in the lungs, and propofol attenuated IFN-ß expression in an in vivo model of R837 intranasal instillation. We also found that propofol directly bound to and hindered its association of TLR7 with MyD88. Our analysis using fropofol, propofol derivative showed that the hydroxyl group in propofol was important for propofol-TLR7 interaction.

The incidence of propofol infusion syndrome in critically-ill patients.

PURPOSE: PRIS is a potentially fatal syndrome characterized by various clinical symptoms and abnormalities. Experts suggest that propofol treatment duration ≥48 h or dose ≥83 µg/kg/min is associated with developing PRIS. We hypothesized PRIS might be underdiagnosed due to the overlap of PRIS clinical manifestations with critical illnesses. MATERIALS AND METHODS: Multihospital, retrospective study of adult patients who received continuous propofol infusion ≥48 h or dose ≥60µg/kg/min for >24 h since admission were assessed for the development of PRIS. RESULTS: The incidence of PRIS was 2.9% with a PRIS-associated mortality rate of 36.8%. In PRIS patients, propofol was administered at a median dose of 36.4 µg/kg/min and over a median duration of 147.0 h. The development of PRIS was observed at a median of 125.0 h post-propofol initiation and a cumulative dose of 276.5 mg/kg. The development of metabolic acidosis (78.9%), cardiac dysfunction (52.6%), hypertriglyceridemia (100%), and rhabdomyolysis (26.3%) were observed in our PRIS patients. CONCLUSION: PRIS can often be overlooked and underdiagnosed. It is important to monitor for early signs of PRIS in patients who are on prolonged propofol infusion. Prompt recognition and interventions can minimize the dangers resulting from PRIS.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome.

BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels. METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels. RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01). CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Resolution of status epilepticus after ketamine administration.

BACKGROUND: Status Epilepticus is the most common non-traumatic neurologic emergency in childhood. Current algorithms prioritize the use of benzodiazepines as first line treatment followed by Levetiracetam or Valproic Acid, possibly Fosphenytoin and eventually high dose Propofol and intubation. CASE REPORT: A 9-month old girl was brought to the emergency department with a continuous seizure involving the right upper and lower extremity for 45 min prior to arrival. Patient received a dose of rectal Diazepam, intramuscular Midazolam, 2 doses of Lorazepam, Levetiracetam, Fosphenytoin and 2 additional doses of Lorazepam. The seizure remained refractory and generalized. In anticipation of intubation, and because of its action on the NMDA receptor, Ketamine (1 mg/kg IV) was administered. The clonic movements and eye deviations stopped. Patient was intubated for airway protection, sedated with Propofol, then admitted to the PICU. EEG showed no evidence of a seizure pattern. Labs (CBC, CMP, COVID) were unremarkable except for WBC 24.5, blood glucose of 346 and CO2 of 17 with normal anion gap. Urinalysis showed a urinary tract infection. Patient was at her baseline on 1 week post-discharge re-evaluation. Ketamine theoretically may abort seizures through blockade of NMDA receptors which are unregulated in status epilepticus. To date, no randomized controlled trials have been reported. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ketamine may have a role in treating status epilepticus. It may be considered for induction for rapid sequence intubation and possibly as a third or fourth line agent in refractory cases.

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.

Comparison of Postoperative Recovery after Manual and Target-Controlled Infusion of Remifentanil in Bariatric Surgery.

Background and Objectives: Early postoperative recovery after surgery is a key point for patients' safety and comfort. Moreover, operating room turnover depends on recovery time. Our aim was to assess which method of remifentanil administration, manual (MI) or target-controlled infusion (TCI), could reduce patient time in recovery room. In this study, patients' recovery times were registered and compared among the groups. Materials and Methods: We enrolled 31 morbidly obese patients in this prospective study. All of them had undergone bariatric surgery at the Hospital of Lithuanian University of Health Sciences Kauno Klinikos in 2020. Sevoflurane/remifentanil anaesthesia was performed for all patients. The patients were randomly assigned to the manual infusion (MI) (control group) or target-controlled infusion (TCI) group for the method of the administration of remifentanil. While the patients were waking up after the surgery, we recorded spontaneous breathing and airway reflexes recovery time, time of extubation, eye opening, recovery of orientation and beginning of the following oral command. For the TCI group, we also documented remifentanil concentrations in the blood (automatic infusion pump). Results: Patients did not differ in demographic values and duration of remifentanil infusion. We found that remifentanil consumption in the TCI group was lower, p = 0.02. Despite lower remifentanil consumption in the TCI group patients, they demonstrated longer total recovery time than the control group patiens: 14 (12-20) vs. 10 (6-16), p = 0.001. Conclusions: The study showed that, upon comparing the TCI method with MI, manual infusion produced better results in postoperative patient recovery. Additionally, higher doses of remifentanil were consumed using MI. In conclusion, the dosage recommended by highly qualified anaesthesiologists is favourable for morbidly obesity patients when compared to the TCI method.

Hypertriglyceridemia in Critically Ill Patients With SARS-CoV-2 Infection.

BACKGROUND: Patients with SARS-CoV-2 infection could develop severe disease requiring critical care admission. Case reports indicated high incidence of hypertriglyceridemia (HTG) in critically ill patients infected with SARS-CoV-2, which might be related to the drugs. OBJECTIVE: We sought to determine the risk factors associated with HTG in this population and to investigate the relationship between HTG and lipase. METHODS: A retrospective observational study was conducted at our hospital between March 1 and June 30, 2020. Patients were included if they were ≥18 years old, admitted to the intensive care unit (ICU), tested positive for SARS-CoV-2, and had triglycerides (TG) checked during their hospital stay. RESULTS: Of the 111 critically ill patients, 103 patients were included. Males comprised 88.3% of the sample. The median TG at baseline was 197.4 (IQR: 139.8-283) mg/dL. The lipase median level at baseline was 23.00 (IQR: 0.00-69.50) IU/L. The results of the mixed-effects logistic regression analysis indicated that patient-level variables, favipiravir use, blood glucose level, and propofol use were significantly associated with HTG. There was no relationship between lipase and TG levels over time. Furthermore, TG concentrations over time showed a similar trend to inflammatory markers. CONCLUSION AND RELEVANCE: The incidence of clinically significant HTG was high and was associated with propofol and favipiravir use. HTG might reflect the high inflammatory state in these patients. Clinicians should look at the full picture before changing therapies based only on HTG. Our findings need to be replicated in a larger prospective study.

Fetal Bladder Rupture as a Complication of Adjunctive Therapy in Severe Maternal SARS-CoV-2 Pneumonia.

INTRODUCTION: A case of spontaneous fetal bladder rupture occurring in a woman with SARS-CoV-2 pneumonia receiving invasive ventilatory support is reported. CASE: A 33-year-old woman was admitted at 30.6 weeks' gestation with the diagnosis of severe pneumonia due to COVID-19. The patient required invasive mechanical ventilation on day 2. Propofol, fentanyl, midazolam, and dexmedetomidine were administered for sedation, pain relief, and to improve patient-ventilator interaction. A bedside ultrasound on day 3 revealed fetal megacystis. Follow-up scan two days later showed urinary ascites and a collapsed bladder. The diagnosis of fetal bladder rupture was confirmed postpartum. Bladder repair was performed on day 5, with an uneventful recovery. DISCUSSION: Transplacental transfer of opioids during invasive ventilatory support in pregnancy may cause acute fetal bladder atony leading to severe urine retention and, potentially, bladder rupture. This can be a serious complication of adjunctive therapy in women with severe SARS-CoV-2 pneumonia.

Reducing sedated lumbar punctures in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Sedation for lumbar punctures (LPs) in pediatric acute lymphoblastic leukemia (ALL) patients has been the standard for decades to reduce pain and anxiety. Recent studies on the potential long-term neurocognitive effects of cumulative propofol exposure have raised concerns about this practice. The recent pandemic introduced additional burdens to patients, with the requirement of a negative COVID-19 test prior to each sedated procedure. PROCEDURE: These factors prompted a quality improvement intervention at our institution where we aimed to reduce postinduction sedated LPs by 50%. Our intervention included patient and family education, followed by a simulation of the procedure for selected patients. Those converted to unsedated LPs were queried for their preference. Comparative cost, clinical time, and LP success rates were collected for sedated and unsedated LPs. RESULTS: Following the intervention, the percentage of LPs performed with sedation dropped from 100% to 48%. All LPs were successful using both techniques. Most patients who experienced the unsedated LP technique, and their guardians, strongly preferred this approach. Unsedated LPs significantly reduced clinical time (169 vs. 83 minutes) for families, decreased expenditures ($5736 reduction per procedure), and improved institutional opportunity cost due to a decrease in last-minute cancelations. CONCLUSION: We have shown that it is feasible to significantly reduce the use of sedation for LPs in patients with ALL, which has the potential to improve health and patient experience at a lower cost.

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.