Effects of gabapentin on slow-wave sleep period in critically ill adult patients: A randomized controlled trial.

Sleep deprivation is a prevalent problem in critically ill patients, which leads to delayed recovery and delirium. Slow-wave sleep (SWS) is essential to energy restoration, tissue repair, and immune system strengthening. This study aimed to investigate the effects of gabapentin on SWS in critically ill patients. We performed a prospective open-label randomized controlled study to compare SWS and the clinical outcomes of gabapentin versus a control intervention in critically ill adult patients admitted to the intensive care unit (ICU) within 24 h. The patients' characteristics and sleep-related outcomes were recorded. The sleep-related outcomes, namely, bispectral analysis (BIS), the Richards-Campbell Sleep Questionnaire (RCSQ), and insulin-like growth factor-1 (IGF-1) levels, were evaluated. Furthermore, clinical outcomes and safety were assessed. Sixty patients from 348 cases were eligible for randomization. On day 3 of the study, patients in the gabapentin group had significantly increased SWS (66.79 vs. 0.00 min; p < 0.001), total sleep time (TST) (331.39 vs. 46.16 min; p = 0.001), RCSQ score (55.05 ± 20.18 vs. 32.80 ± 15.31; p < 0.001), and IGF-1 concentrations (84.33 ± 12.40 vs. 44.00 ± 10.20 ng/mL, p < 0.001) compared with the control group. Improvements in clinical outcomes, such as delirium, ICU-free days, and mechanical ventilator-free days, were observed; however, these differences did not reach statistically significant. Gabapentin at bedtime increased SWS, TST, and IGF-1 concentrations in critically ill patients. This regimen might be beneficial to critically ill patients for improving their sleep quality.

Implementing pain, agitation, delirium, and sleep deprivation protocol in critically ill patients: A pilot study on pharmacological interventions.

Critically ill patients frequently experience pain, agitation, delirium, and sleep deprivation, which have been linked to increased mortality and unfavorable clinical outcomes. To address these challenges, the Pain, Agitation, Delirium, and Sleep Deprivation (PADS) protocol was developed, aiming to mitigate mortality and improve clinical outcomes. This study focuses on assessing the protocol's impact using a robust before-and-after study design in the medical and surgical intensive care units (ICUs) at Ramathibodi Hospital. Using an observational approach, this study compares clinical outcomes before and after implementing the PADS protocol in the ICUs. Two patient cohorts were identified: the "before" group, comprising 254 patients with retrospective data collected between May 2018 and September 2019, and the "after" group, consisting of 255 patients for whom prospective data was collected from May to September 2020. Analysis reveals improvements in the after group. Specifically, there was a significant increase in 14-day ICU-free days (9.95 days vs. 10.40 days, p value = 0.014), a decrease in delirium incidence (18.1% vs. 16.1%, p value < 0.001), and a significant reduction in benzodiazepine usage (38.6% vs. 24.6%, p value = 0.001) within the after group. This study emphasizes the protocol's potential to improve patient care and highlights its significance in the ICU context.

Impact of vitamin D supplementation on the clinical outcomes of COVID-19 pneumonia patients: a single-center randomized controlled trial.

BACKGROUND: Vitamin D supplementation for infectious diseases has been discussed, but its role in COVID-19 is unclear. Therefore, this study examined the clinical outcomes of COVID-19 pneumonia patients who received vitamin D supplementation. METHODS: This prospective, open-label, randomized controlled trial was conducted in a university hospital between July 2020 and March 2022. The inclusion criteria were patients aged ≥ 18 years with COVID-19 pneumonia patients. The patients were randomized into two groups: an intervention group receiving vitamin D supplementation (alfacalcidol, two mcg orally daily) until discharge and a control group. The clinical outcomes were pneumonia treatment duration, length of hospital stay, and change in pneumonia severity index between enrollment and discharge. Subgroup analysis was conducted for supplemental oxygen use, high-dose corticosteroid administration, evidence of lymphopenia, C-reactive protein concentration, and total serum vitamin D concentration. Adverse events were monitored. RESULTS: Two hundred ninety-four patients were recruited (147 per group). The two groups did not differ in pneumonia treatment duration to discharge (p = 0.788) or length of hospital stay (p = 0.614). The reduction in the pneumonia severity index between enrollment and discharge was more significant in the intervention group (p = 0.007); a significant decrease was also observed among patients who had C-reactive protein > 30 mg/L (p < 0.001). No adverse reactions were recorded. CONCLUSIONS: Adding active vitamin D to standard treatment may benefit COVID-19 pneumonia patients who require supplemental oxygen or high-dose corticosteroid therapy or who have high C-reactive protein concentrations (> 30 mg/L) upon treatment initiation. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20210906005 (retrospectively registered, 6 September 2021).

Long-term outcomes of delirium in critically ill surgical patients: A multicenter prospective cohort study.

OBJECTIVE: To identify the mortality rates and dependency rate (functional outcomes) of delirious patients at 12-months after surgical intensive care unit (SICU) admission and to determine the independent risk factors of 12-months mortality and dependency rate in a cohort of SICU patients. METHODS: A prospective, multi-center study was conducted in 3 university-based hospitals. Critically-ill surgical patients who were admitted to SICU and followed-up at 12-months after ICU admission were enrolled. RESULTS: A total of 630 eligible patients were recruited. 170 patients (27%) had postoperative delirium (POD). The overall 12-months mortality rate in this cohort was 25.2%. Delirium group showed significantly higher mortality rates than non-delirium group at 12-months after ICU admission (44.1% vs 18.3%, P < 0.001). Independent risk factors of 12-months mortality were age, diabetes mellitus, preoperative dementia, high Sequential Organ Failure Assessment (SOFA) score and POD. POD was associated with 12-months mortality (adjusted hazard ratio, 1.49; 95% confidence interval 1.04-2.15; P = 0.032). The dependency rate defined as the Basic Activities Daily Living (B-ADL) ≤70 was 52%. Independent risk factors of B-ADL were age ≥ 75 years, cardiac disease, preoperative dementia, intraoperative hypotension, on mechanical ventilator and POD. POD was associated with dependency rate at 12-months. (adjusted risk ratio, 1.26; 95%CI 1.04-1.53; P = 0.018). CONCLUSIONS: Postoperative delirium was an independent risk factor of death and was also associated with dependent state at 12 months after a surgical intensive care unit admission in critically ill surgical patients.

Validation of a delirium predictive model in patients admitted to surgical intensive care units: a multicentre prospective observational cohort study.

OBJECTIVE: To internally and externally validate a delirium predictive model for adult patients admitted to intensive care units (ICUs) following surgery. DESIGN: A prospective, observational, multicentre study. SETTING: Three university-affiliated teaching hospitals in Thailand. PARTICIPANTS: Adults aged over 18 years were enrolled if they were admitted to a surgical ICU (SICU) and had the surgery within 7 days before SICU admission. MAIN OUTCOME MEASURES: Postoperative delirium was assessed using the Thai version of the Confusion Assessment Method for the ICU. The assessments commenced on the first day after the patient's operation and continued for 7 days, or until either discharge from the ICU or the death of the patient. Validation was performed of the previously developed delirium predictive model: age+(5×SOFA)+(15×benzodiazepine use)+(20×DM)+(20×mechanical ventilation)+(20×modified IQCODE>3.42). RESULTS: In all, 380 SICU patients were recruited. Internal validation on 150 patients with the mean age of 75±7.5 years resulted in an area under a receiver operating characteristic curve (AUROC) of 0.76 (0.683 to 0.837). External validation on 230 patients with the mean age of 57±17.3 years resulted in an AUROC of 0.85 (0.789 to 0.906). The AUROC of all validation cohorts was 0.83 (0.785 to 0.872). The optimum cut-off value to discriminate between a high and low probability of postoperative delirium in SICU patients was 115. This cut-off offered the highest value for Youden's index (0.50), the best AUROC, and the optimum values for sensitivity (78.9%) and specificity (70.9%). CONCLUSIONS: The model developed by the previous study was able to predict the occurrence of postoperative delirium in critically ill surgical patients admitted to SICUs. TRIAL REGISTRATION NUMBER: Thai Clinical Trail Registry (TCTR20180105001).

Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure.

BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.

Incidence and clinical manifestation of iatrogenic opioid withdrawal syndrome in mechanically ventilated patients.

OBJECTIVE: The incidence of iatrogenic opioid withdrawal syndrome (IOWS) in mechanically ventilated adults has been questioned in settings driven by analgosedation strategies. This study aimed to describe the incidence, risk factors and clinical impact of IOWS in mechanically ventilated adults. METHODS: This prospective, observational study was performed between 1 January and 31 August 2018. IOWS was identified based on the presence of at least three signs or symptoms according to the Diagnostic and Statistical Manual 5th edition (DSM-5) criteria after opioid discontinuation or rate reduction. Incidence of IOWS, patient characteristics, opioid administration, and the impact of IOWS on the duration of mechanical ventilator and length of stay in the intensive care unit (ICU) were collected. RESULTS: Thirteen out of 55 patients (23.6%) manifested withdrawal symptoms. Two patients in the non-withdrawal group also developed hypertensive urgency after opioid discontinuation. Patients who received rapid once-daily weaning, especially rate reduction more than 50 µg as fentanyl equivalent per hour, were associated with IOWS. However, there was no statistically significant difference in ventilator-free days and ICU-free days. CONCLUSIONS: These findings showed that approximately one-fourth of mechanically ventilated patients who received opioid infusion experienced IOWS. Monitoring for IOWS is recommended especially in patients who received rapid weaning rate of opioids. Future studies to develop IOWS assessment tools with the change of hemodynamic parameters should be performed. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov: identifier NCT03374722, date of registration 15 December 2018.

Clinical outcomes of empirical high-dose meropenem in critically ill patients with sepsis and septic shock: a randomized controlled trial.

BACKGROUND: Appropriate antimicrobial dosing is challenging because of changes in pharmacokinetics (PK) parameters and an increase in multidrug-resistant (MDR) organisms in critically ill patients. This study aimed to evaluate the effects of an empirical therapy of high-dose versus standard-dose meropenem in sepsis and septic shock patients. METHODS: We performed a prospective randomized open-label study to compare the changes of modified sequential organ failure assessment (mSOFA) score and other clinical outcomes of the high-dose meropenem (2-g infusion over 3 h every 8 h) versus the standard-dose meropenem (1-g infusion over 3 h every 8 h) in sepsis and septic shock patients. Patients' characteristics, clinical and microbiological outcomes, 14 and 28-day mortality, vasopressor- and ventilator-free days, intensive care unit (ICU) and hospital-free days, percent of the time of antibiotic concentrations above the minimum inhibitory concentration (%T>MIC), and safety were assessed. RESULTS: Seventy-eight patients were enrolled. Median delta mSOFA was comparable between two groups (- 1 in the high-dose group vs. - 1 in the standard-dose group; P value = 0.75). There was no difference between the two groups regarding clinical and microbiological cure, 14- and 28-day mortality, vasopressor- and ventilator-free days, and ICU- and hospital-free days. In patients admitted from the emergency department (ED) with a mSOFA score ≥ 7, the high-dose group demonstrated significantly better microbiological cure compared with the standard-dose group (75% (9/12 patients) vs. 20% (2/10 patients); P value = 0.03). Likewise, the high-dose group presented higher microbiological cure rate in patients admitted from ED who had either APACHE II score > 20 (83.3% (10/12) vs. 28.6% (2/7); P value = 0.045) or on mechanical ventilator (87.5% (7/8) vs. 23.1% (3/13); P value = 0.008) than the standard-dose group. Adverse events were comparable between the two groups. CONCLUSIONS: Empirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients. Besides, subgroup analysis manifested superior microbiological cure rate in sepsis or septic shock patients admitted from ED. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03344627, registered on November 17, 2017.

Impact of pharmaceutical care on pain and agitation in a medical intensive care unit in Thailand.

Background Currently, a lack of pharmaceutical care exists concerning pain and agitation in medical intensive care units (MICU) in Thailand. Pharmaceutical care focusing on analgesics/sedatives would improve clinical outcomes. Objective To investigate the impact of pharmaceutical care of pain and agitation on ICU length of stay (LOS), hospital LOS, ventilator days and mortality. Setting The MICU of a university hospital. Method A before/after study was conducted on mechanically ventilated patients receiving analgesics/sedatives. Medical chart reviews and data collection were conducted in the retrospective group (no pharmacists involved). In the prospective group, pharmacists involved with the critical care team helped select analgesics/sedatives for individual patients. Main outcome measure ICU LOS Results In total, 90 and 66 patients were enrolled in retrospective and prospective groups, respectively. The median duration of ICU LOS was reduced from 10.00 (2.00-72.00) in the retrospective group to 6.50 days (2.00-30.00) in the prospective group (p = 0.002). The median hospital stay was reduced from 30.50 days (2.00-119.00) in the retrospective group to 17.50 days (2.00-110.00) in the prospective group (p < 0.001). Also, the median ventilator days was reduced from 14.00 days (2.00-90.00) to 8.50 days (1.00-45.00), p = 0.008. Mortality was 53.03% in the prospective group and 46.67% in the retrospective group (p = 0.432). Conclusion Pharmacist participation in a critical care team resulted in a significant reduction in the duration of ICU LOS, hospital LOS and ventilator days, but not mortality.

A case report of intravenous posaconazole in hepatic and renal impairment patient with invasive Aspergillus terreus infection: safety and role of therapeutic drug monitoring.

BACKGROUND: Invasive aspergillosis (IA) is a fatal infectious complication among immunocompromised patients. Aspergillus terreus, the fourth common species can be difficult to treat due to a unique resistance pattern. To date, there has been no report on safety and dose adjustment when intravenous posaconazole is selected in hepatic and renal impairment patient. We present a rare case of intravenous posaconazole use in a hepatic and renal impairment patient with invasive A. terreus pulmonary infection. To our knowledge, this is the first report of intravenous posaconazole use in IA due to A. terreus with hepatic and renal impairment focusing on drug safety and role of therapeutic drug monitoring (TDM). CASE PRESENTATION: A 37-year-old previously healthy man with diagnosis of dengue hemorrhagic fever and shock complicated with hepatic and renal impairment proposed to have proven invasive A. terreus pulmonary infection is described. Due to lack of good clinical response and concern of potential adverse effects whilst on intravenous voriconazole, intravenous posaconazole 300 mg every 48 h was chosen with confirmed therapeutic plasma concentrations. Despite the death of the patient and IA deemed uncontrollable, there were no significant side effects attributable to intravenous posaconazole use demonstrated over a period of 34 days. CONCLUSIONS: Intravenous posaconazole use with TDM implementation maybe a safe alternative option to standard therapy. Therapeutic plasma posaconazole level may be reached at lower dosing regimen in renal and hepatic impairment patient. However, explanations of clinical failure on this patient with immunodeficiency state were multifactorial.

A prospective observational study of CYP2C19 polymorphisms and voriconazole plasma level in adult Thai patients with invasive aspergillosis.

The aim of this study was to investigate the association of genetic variants of CYP2C19 (CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles) and voriconazole trough plasma concentrations in Thai patients with invasive fungal infection. A total of 285 samples from patients with invasive fungal infection and treated with voriconazole were prospectively enrolled. At steady state, trough voriconazole concentrations were measured using tandem mass spectrophotometry and high performance liquid chromatography. The genetic variants in the CYP2C19 gene were genotyped for CYP2C19*2 (G681A), CYP2C19*3 (G636A) and CYP2C19*17 (C-806T) on plasma voriconazole level. Voriconazole Ctrough levels were positively associated with CYP2C19*3. The median Ctrough level for patients with the 636GA genotype (2.109, IQR 1.054-4.166 µg/ml) was statistically significantly higher than those with the 636GG genotype (1.596, IQR 0.755-2.980 µg/ml), P = 0.046. The patients with a poor metabolizer (PM; CYP2C19*2/*2, *2/*3) had voriconazole Ctrough level of 1.900 (IQR, 1.130-3.673 µg/ml). This was statistically significantly higher than that seen with the extensive metabolizer phenotype (1.470; IQR, 0.632-2.720 µg/ml), P = 0.039. An association between CYP2C19 variant alleles and high voriconazole plasma level was identified. Therefore, determining the CYP2C19 genotype before initiation of voriconazole treatment may be useful in optimizing the dosing regimen in Thai patients with invasive fungal infections.