Pharmacology of Commonly Used Analgesics and Sedatives in the ICU: Benzodiazepines, Propofol, and Opioids

To evaluate the feasibility of conducting a prospective randomised controlled trial (pRCT) comparing remifentanil and fentanyl as adjuncts to sedate mechanically ventilated patients.

Single-center, open-labelled, pRCT with blinded analysis.

Australian tertiary intensive care unit (ICU).

Consecutive adults between June 2020 and August 2021 expected to receive invasive ventilation beyond the next day and requiring opioid infusion were included. Exclusion criteria were pregnant/lactating women, intubation >12 h, or study-drug hypersensitivity.

Open-label fentanyl and remifentanil infusions per existing ICU protocols.

Primary outcomes were feasibility of recruiting ≥1 patient/week and >90 % compliance, namely no other opioid infusion used during the study period. Secondary outcomes included complications, ICU-, ventilator- and hospital-free days, and mortality (ICU, hospital). Blinded intention-to-treat analysis was performed concealing the allocation group.

208 patients were enrolled (mean 3.7 patients/week). Compliance was 80.6 %. More patients developed complications with fentanyl than remifentanil: bradycardia (n = 44 versus n = 21; p < 0.001); hypotension (n = 78 versus n = 53; p < 0.01); delirium (n = 28 versus n = 15; p = 0.001). No differences were seen in ICU (24.3 % versus 27.6 %,p = 0.60) and hospital mortalities (26.2 % versus 30.5 %; p = 0.50). Ventilator-free days were higher with remifentanil (p = 0.01).

We demonstrated the feasibility of enrolling patients for a pRCT comparing remifentanil and fentanyl as sedation adjuncts in mechanically ventilated patients. We failed to attain the study-opioid compliance target, likely because of patients with complex sedative/analgesic requirements. Secondary outcomes suggest that remifentanil may reduce mechanical ventilation duration and decrease the incidence of complications. An adequately powered multicentric phase 2 study is required to evaluate these results.

Clinically significant post-traumatic stress symptoms (PTSS) have been reported in up to a quarter of paediatric intensive care unit (PICU) survivors. Ongoing PTSS negatively impacts children's psychological development and physical recovery. However, few data regarding associations between potentially modifiable PICU treatment factors, such as analgosedatives and invasive procedures, and children's PTSS have been reported.

We sought to investigate the medical treatment factors associated with children's PTSS after PICU discharge.

A prospective longitudinal cohort study was conducted in two Australian tertiary referral PICUs. Children aged 2-16 y admitted to the PICU between June 2008 and January 2011 for >8 h and <28 d were eligible for participation. Biometric and clinical data were obtained from medical records. Parents reported their child's PTSS using the Trauma Symptom Checklist for Young Children at 1, 3, 6, and 12 months after discharge. Logistic regression was used to assess potential associations between medical treatment and PTSS.

A total of 265 children and their parents participated in the study. In the 12-month period following PICU discharge, 24% of children exhibited clinically elevated PTSS. Median risk of death (Paediatric Index of Mortality 2 [PIM2]) score was significantly higher in the PTSS group (0.31 [IQR 0.14–1.09] v 0.67 [IQR 0.20–1.18]; p = 0.014). Intubation and PICU and hospital length of stay were also significantly associated with PTSS at 1 month, as were midazolam, propofol, and morphine. After controlling for gender, reason for admission, and PIM2 score, only midazolam was significantly and independently associated with PTSS and only at 1 month (adjusted odds ration (aOR) 3.63, 95% CI 1.18, 11.12, p = 0.024). No significant relationship was observed between the use of medications and PTSS after 1 month.

Elevated PTSS were evident in one quarter (24%) of children during the 12 months after PICU discharge. One month after discharge, elevated PTSS were most likely to occur in children who had received midazolam therapy.

Extracellular vesicles (EVs) are effective mediators of intercellular communications between enterocytes and immune cells. The current study showed that EVs isolated from mouse and human intestinal organoids modulated inflammatory responses of various immune cells including mouse bone-marrow derived-macrophages, dendritic cells, microglia cells, and human monocytes. EVs suppressed LPS-elicited cytokine production in these cells while morphine abolished EVs' immune modulatory effects. Microarray analysis showed that various microRNAs, especially Let-7, contributed to EV-mediated immune modulation. Using murine models, we showed that injection of EVs derived from intestinal organoids reduced endotoxin-induced systemic inflammation and alleviated the symptoms of DSS-induced colitis. EVs derived from morphine-treated organoids failed to suppress the immune response in both these models. Our study suggests that EVs derived from intestinal crypt cells play crucial roles in maintaining host homeostasis and opioid use is a risk factor for exacerbating inflammation in patients with inflammatory diseases such as sepsis and colitis.

Sedation and analgesia are essential in the intensive care unit in order to promote control of pain, anxiety, prevent loss of materials, accidental extubation and improve the synchrony of patients with ventilator. However, excess of these medications leads to an increased morbidity and mortality, and thus demands protocol.

Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Protocol have been used to undertake this review. Pub Med, Cochrane Library, and Google Scholar search engines were used to find up-to-date evidence that helps to draw recommendations and conclusions.

In this Guideline and Systematic Review, we have used 16 Systemic Review and Meta-Analysis, 3 Evidence-Based Guidelines and 10 RCT Meta-Analysis, 6 Systemic Reviews of Non-randomized Studies, 8 Randomized Clinical Trials, 11 Cohort Studies, 5 Cross-Sectional Studies and 1 Case Report with their respective study descriptions.

Analgesia, which as a sedation basement can reduce sedative use, is key aspect of treatment in ICU patients, and we can also conclude that an analgesic sedation regimen can reduce the occurrence of delirium by reducing sedatives. The aim of this guideline and the systematic review is to write up and formulate analgesia-based sedation for limited resource settings.

Analgesia and sedation are effective in critically ill patients; however, too much sedation is associated with longer periods of mechanical ventilation and longer duration of ICU stay. Poorly managed ICU patients have a delirium rate of up to 80%, increased mortality, longer hospital stays, higher hospital costs and bad long-term outcomes.

Sedation and anaesthesia are used universally to facilitate mechanical ventilation – with larger cumulative doses being used in those with prolonged ventilation. Transitioning from an endotracheal to a tracheostomy tube enables the depth of sedation to be reduced. Early use of speaking valves with tracheostomised patients has become routine in some intensive care units (ICU). The return of verbal communication has been observed to improve ease of patient care and increase patient and family engagement, with a perceived reduction in patient agitation.

To investigate the potential impact of speaking valve (SV) use on requirements of sedatives, analgesics and antipsychotics in ICU patients with a tracheostomy.

A retrospective data audit was undertaken for all tracheostomised patients in a cardio-respiratory ICU from 2011 to 2014. Use of sedative, analgesic and antipsychotic drugs was captured for endotracheal tube, tracheostomy and SV periods, including patient demographics, disease specifics and severity. Stratified Cox regression analysis was performed to determine the effects of SV on drug dosage.

Of 257 patients, 144 (56%) received an SV. Use of an SV was associated with reduced risk of being in the upper quartile of daily dosage of analgesics (HR: 0.6; 95% CI: 0.5–0.8; p < 0.001). In the final adjusted multivariable model, analgesic dose was additionally associated with age, and attendance to operating theatre during ICU. Sedative dose was associated with age, gender and SOFA score. Antipsychotic dose was associated with gender (less likely in females: HR 0.6, 95% CI: 0.4–0.8), age and APACHE score.

There was significantly less analgesic used in patients with an SV compared to those without. However, SV use in patients with tracheostomy was not found to be associated with reduced dose of sedatives or antipsychotics, despite the clinical impression. Future prospective studies are needed to more adequately investigate the association between drugs and patients' ability to verbally participate in their care.

Propofol is one of the most widely used agents for anesthetic induction and for sedation in the intensive care unit. Due to its high lipophilicity, propofol has been formulated as an oil in water microemulsion. As an alkyl phenol, it has an irritating effect on skin and mucous membranes which leads to irritation of vein endothelium. Pain on intravenous injection of propofol is a common side effect, which is related to increased concentration of propofol in aqueous phase. Present study was designed to investigate the probable effect of different factors on concentration of propofol in aqueous phase, as follows: (1) type of the osmotic agent, (2) type of the oil used in organic phase, (3) volume of organic phase, and (4) type of surfactant. Water-soluble agents were dissolved in water, and water-insoluble ingredients were dissolved in oil phase. After adding aqueous phase to oil phase, formulations were put in shaker incubator at 150 rate per minute in room temperature for 48 h to reach balance. In order to separate the aqueous phase, each formulation was transferred to a separatory funnel. The HPLC method was used to determine the concentration of propofol in aqueous phase. Our findings show that type of the osmotic agent has not a significant effect on propofol concentration in aqueous phase. Type and amount of the oil phase and type of the surfactant notably affect propofol concentration in aqueous phase. Changing the types of oil or surfactant can lead to a new formulation which has lower concentrations of propofol in aqueous phase. It can result in decrease of pain of injection.