Increased red cell distribution width predicts mortality in COVID-19 patients admitted to a Dutch intensive care unit.

BACKGROUND: Abnormal red blood cell distribution width (RDW) is associated with poor cardiovascular, respiratory, and coronavirus disease 2019 (COVID-19) outcomes. However, whether RDW provides prognostic insights regarding COVID-19 patients admitted to the intensive care unit (ICU) was unknown. Here, we retrospectively investigated the association of RDW with 30-day and 90- day mortalities, duration of mechanical ventilation, and length of ICU and hospital stay in patients with COVID-19. METHODS: This study included 321 patients with COVID-19 aged >18 years who were admitted to the ICU between March 2020 and July 2022. The outcomes were mortality, duration of mechanical ventilation, and length of stay. RDW >14.5% was assessed in blood samples within 24 hours of admission. RESULTS: The mortality rate was 30.5%. Multivariable Cox regression analysis showed an association between increased RDW and 30-day mortality (hazard ratio [HR], 3.64; 95% CI, 1.54-8.65), 90-day mortality (HR, 3.66; 95% CI, 1.59-8.40), and shorter duration of invasive ventilation (2.7 ventilator-free days, P=0.033). CONCLUSIONS: Increased RDW in COVID-19 patients at ICU admission was associated with increased 30-day and 90-day mortalities, and shorter duration of invasive ventilation. Thus, RDW can be used as a surrogate biomarker for clinical outcomes in COVID-19 patients admitted to the ICU.

Ghrelin for Neuroprotection in Post-Cardiac Arrest Coma: A Randomized Clinical Trial.

Importance: Out-of-hospital cardiac arrest survival rates have markedly risen in the last decades, but neurological outcome only improved marginally. Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have demonstrated unequivocal evidence of efficacy; however, treatment with acyl-ghrelin has shown improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations. Objective: To determine safety and potential efficacy of intravenous acyl-ghrelin to improve neurological outcome in patients in a coma after cardiac arrest. Design, Setting, and Participants: A phase 2, double-blind, placebo-controlled, multicenter, randomized clinical trial, Ghrelin Treatment of Comatose Patients After Cardiac Arrest: A Clinical Trial to Promote Cerebral Recovery (GRECO), was conducted between January 18, 2019, and October 17, 2022. Adult patients 18 years or older who were in a comatose state after cardiac arrest were assessed for eligibility; patients were from 3 intensive care units in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria. Interventions: Patients were randomized to receive intravenous acyl-ghrelin, 600 µg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for 7 days, twice daily, in addition to standard care. Main Outcomes and Measures: Primary outcome was the score on the Cerebral Performance Categories (CPC) scale at 6 months. Safety outcomes included any serious adverse events. Secondary outcomes were mortality and neuron-specific enolase (NSE) levels on days 1 and 3. Results: A total of 783 adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median [IQR] age, 68 [57-75] years; 120 male [75%]) were enrolled. A total of 81 patients (51%) were assigned to the intervention group, and 79 (49%) were assigned to the control group. The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). This was consistent over all CPC categories. Mean (SD) NSE levels on day 1 after cardiac arrest were significantly lower in the intervention group (34 [6] µg/L vs 56 [13] µg/L; P = .04) and on day 3 (28 [6] µg/L vs 52 [14] µg/L; P = .08). Serious adverse events were comparable in incidence and type between the groups. Mortality was 37% (30 of 81) in the intervention group vs 51% (40 of 79) in the control group (absolute risk reduction, 14%; 95% CI, -2% to 29%; P = .08). Conclusions and Relevance: In patients in a coma after cardiac arrest, intravenous treatment with acyl-ghrelin was safe and potentially effective to improve neurological outcome. Phase 3 trials are needed for conclusive evidence. Trial Registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL.

Sub-therapeutic trimethoprim and sulfamethoxazole plasma concentrations during continuous venovenous hemofiltration in a patient with COVID-19 and pulmonary Pneumocystis jirovecii co-infection: A case report.

OBJECTIVE: To investigate drug concentration of trimethoprim-sulfamethoxazole (TMP-SMX) using therapeutic drug monitoring (TDM) for severe Pneumocystis jirovecii (PJP) infection in a critically ill patient with COVID-19 receiving continuous venovenous hemofiltration treatment and regional citrate anticoagulation (RCA-CCVH). MATERIALS AND METHODS: A 72-year-old man with hypoxemic respiratory failure due to COVID-19 infection was admitted to the intensive care unit for invasive mechanical ventilation. The patient developed acute renal failure that required RCA-CVVH. Pulmonary co-infection with PJP was diagnosed, and a high TMP-SMX dose was initiated according to (inter)national guidelines with dose reduction after 3 days because of renal failure. Population pharmacokinetics were assessed for TMP and SMX as well as clearance by RCA-CVVH, volume of distribution, and time above threshold levels for measured plasma concentrations. RESULTS: During renal failure requiring RCA-CVVH, a corresponding dose reduction of TMP-SMX to 320/1,600 mg twice a day, according to current Dutch SWAB and Dutch Association of Hospital Pharmacists guidelines, resulted in unintended under-dosing with sub-therapeutic TMP-SMX concentrations. Pharmacokinetic modeling and dose adjustment of TMP-SMX to 640/3,200 mg 3 times daily resulted in steady-state TMP-SMX peak concentrations associated with efficacy against PJP. Hence, the patient was successfully weaned from the ventilator and discharged. CONCLUSION: We hypothesize that our new dose recommendation of 640/3,200 mg TMP-SMX 3 times daily is associated with an increased probability of critical patients being successfully liberated from mechanical weaning following PJP pneumonia and COVID-19 infection.

Cognition, emotional state, and quality of life of survivors after cardiac arrest with rhythmic and periodic EEG patterns.

AIM: Rhythmic and periodic patterns (RPPs) on the electroencephalogram (EEG) in comatose patients after cardiac arrest have been associated with high case fatality rates. A good neurological outcome according to the Cerebral Performance Categories (CPC) has been reported in up to 10% of cases. Data on cognitive, emotional, and quality of life outcomes are lacking. We aimed to provide insight into these outcomes at one-year follow-up. METHODS: We assessed outcome of surviving comatose patients after cardiac arrest with RPPs included in the 'treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation' (TELSTAR) trial at one-year follow-up, including the CPC for functional neurological outcome, a cognitive assessment, the hospital anxiety and depression scale (HADS) for emotional outcomes, and the 36-item short-form health survey (SF-36) for quality of life. Cognitive impairment was defined as a score of more than 1.5 SD below the mean on ≥ 2 (sub)tests within a cognitive domain. RESULTS: Fourteen patients were included (median age 58 years, 21% female), of whom 13 had a cognitive impairment. Eleven of 14 were impaired in memory, 9/14 in executive functioning, and 7/14 in attention. The median scores on the HADS and SF-36 were all worse than expected. Based on the CPC alone, 8/14 had a good outcome (CPC 1-2). CONCLUSION: Nearly all cardiac arrest survivors with RPPs during the comatose state have cognitive impairments at one-year follow-up. The incidence of anxiety and depression symptoms seem relatively high and quality of life relatively poor, despite 'good' outcomes according to the CPC.

Target attainment and population pharmacokinetics of flucloxacillin in critically ill patients: a multicenter study.

PURPOSE: Insufficient antimicrobial exposure has been associated with worse clinical outcomes. Reportedly, flucloxacillin target attainment in critically ill patients was heterogeneous considering the study population selection and reported target attainment percentages. Therefore, we assessed flucloxacillin population pharmacokinetics (PK) and target attainment in critically ill patients. METHODS: This prospective, multicenter, observational study was conducted from May 2017 to October 2019 and included adult, critically ill patients administered flucloxacillin intravenously. Patients with renal replacement therapy or liver cirrhosis were excluded. We developed and qualified an integrated PK model for total and unbound serum flucloxacillin concentrations. Monte Carlo dosing simulations were performed to assess target attainment. The unbound target serum concentration was four times the minimum inhibitory concentration (MIC) for ≥ 50% of the dosing interval (ƒT>4xMIC ≥ 50%). RESULTS: We analyzed 163 blood samples from 31 patients. A one-compartment model with linear plasma protein binding was selected as most appropriate. Dosing simulations revealed 26% ƒT>2 mg/L ≥ 50% following continuous infusion of 12 g flucloxacillin and 51% ƒT>2 mg/L ≥ 50% for 24 g. CONCLUSION: Based on our dosing simulations, standard flucloxacillin daily doses of up to 12 g may substantially enhance the risk of underdosing in critically ill patients. Prospective validation of these model predictions is needed.

Spiritual Care in the Intensive Care Unit: Experiences of Dutch Intensive Care Unit Patients and Relatives.

BACKGROUND/OBJECTIVE: To gain insight into both patients' and relatives' experiences with spiritual care (SC) in the intensive care unit (ICU). METHODS: Method used was qualitative interviewing. This was a thematic, topic-centered, biographical, and narrative approach, using semistructured interviews with thematic analysis. A purposive sampling method was used to select a sample of ICU patients and ICU patients' relatives. An interview guide facilitated individual, semistructured interviews. The interview data were recorded by means of note-taking and audio-recording. Verbatim transcripts were compiled for analysis and interpretation. RESULTS: All 12 participants-7 ICU patients and 5 family members of 5 other ICU patients-experienced ICU admission as an existential crisis. Participants would appreciate the signaling of their spiritual needs by ICU health care professionals (HCPs) at an early stage of ICU admission and subsequent SC provision by a spiritual caregiver. They regarded the spiritual caregiver as the preferred professional to address spiritual needs, navigate during their search for meaning and understanding, and provide SC training in signaling spiritual needs to ICU HCPs. DISCUSSION: Early detection of existential crisis signals with ICU patients and relatives contributes to the mapping of spiritual and religious needs. Spiritual care training of ICU HCPs in signaling spiritual needs by ICU patients and relatives is recommended. Effective SC contributes to creating room for processing emotions, spiritual well-being, and satisfaction with integrated SC as part of daily ICU care.

Population pharmacokinetics of unbound ceftriaxone in a critically ill population.

OBJECTIVE: To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen. MATERIALS AND METHODS: This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT>4xMIC ≥ 60%). RESULTS: 91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85m2, the unbound renal clearance of ceftriaxone divided by the creatinine clearance 0.61 ± 0.24, lean body mass corrected volume of distribution of the central compartment 0.82 ± 0.21 L/kg, and intercompartmental distribution rate constant from central to peripheral compartment 0.18 ± 0.08 h-1. Dosing simulations predicted ƒT>4 mg/L of 88% (95% CI: 69 - 100%) for 2,000 mg ceftriaxone once daily and ƒT>4 mg/L of 100% (95% CI: 100 - 100%) both for 1,000 mg twice daily and continuous infusion of 2,000 mg daily. CONCLUSION: We developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT>4 mg/L ≥ 60% for 1,000 mg twice daily and 2,000 mg once daily or by continuous infusion.

Prognostic value of the shock index and modified shock index in survivors of out-of-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND: There is a lack of rapid, non-invasive tools that aid early prognostication in patients with return of spontaneous circulation (ROSC) after Out-of-Hospital Cardiac Arrest (OHCA). The shock index (SI) and modified shock index (MSI) have shown to be useful in several medical conditions, including myocardial infarction. In this study, we assessed the prognostic value of SI and MSI at Emergency Department (ED) triage on survival to discharge of OHCA patients. METHODS: A single-center retrospective observational cohort study. All OHCA patients with a period of ROSC between 2014 and 2019 were included. Data collection was based on the Utstein criteria. The SI and MSI at ED triage were calculated by dividing heart rate by systolic blood pressure or mean arterial pressure. Survival rates were compared between patients with a high and low SI and MSI. Subsequent Cox regression analysis was performed. MAIN RESULTS: A total of 403 patients were included, of which 46% survived until hospital discharge. An elevated SI and MSI was defined by SI ≥ 1.00 and MSI ≥ 1.30. Survival to discharge, 30-day- and one-year survival were significantly lower in patients with an elevated SI and MSI (p < 0.001). An elevated SI and MSI was also associated with a higher rate of recurrent loss of circulation in the ED (p < 0.001). The 30-day survival hazard ratio was 2.24 (1.56-3.22) for SI and 2.46 (1.71-3.53) for MSI; the one-year survival hazard ratio was 2.20 (1.54-3.15) for SI and 2.38 (1.66-3.40) for MSI. CONCLUSION: Survival to discharge and 30-day survival are lower in OHCA patients with an elevated SI and MSI at ED triage. Further studies are warranted to elucidate the causational mechanisms underlying the association between elevated SI or MSI and worse outcomes.

Outcome Prediction of Postanoxic Coma: A Comparison of Automated Electroencephalography Analysis Methods.

BACKGROUND: To compare three computer-assisted quantitative electroencephalography (EEG) prediction models for the outcome prediction of comatose patients after cardiac arrest regarding predictive performance and robustness to artifacts. METHODS: A total of 871 continuous EEGs recorded up to 3 days after cardiac arrest in intensive care units of five teaching hospitals in the Netherlands were retrospectively analyzed. Outcome at 6 months was dichotomized as "good" (Cerebral Performance Category 1-2) or "poor" (Cerebral Performance Category 3-5). Three prediction models were implemented: a logistic regression model using two quantitative features, a random forest model with nine features, and a deep learning model based on a convolutional neural network. Data from two centers were used for training and fivefold cross-validation (n = 663), and data from three other centers were used for external validation (n = 208). Model output was the probability of good outcome. Predictive performances were evaluated by using receiver operating characteristic analysis and the calculation of predictive values. Robustness to artifacts was evaluated by using an artifact rejection algorithm, manually added noise, and randomly flattened channels in the EEG. RESULTS: The deep learning network showed the best overall predictive performance. On the external test set, poor outcome could be predicted by the deep learning network at 24 h with a sensitivity of 54% (95% confidence interval [CI] 44-64%) at a false positive rate (FPR) of 0% (95% CI 0-2%), significantly higher than the logistic regression (sensitivity 33%, FPR 0%) and random forest models (sensitivity 13%, FPR, 0%) (p < 0.05). Good outcome at 12 h could be predicted by the deep learning network with a sensitivity of 78% (95% CI 52-100%) at a FPR of 12% (95% CI 0-24%) and by the logistic regression model with a sensitivity of 83% (95% CI 83-83%) at a FPR of 3% (95% CI 3-3%), both significantly higher than the random forest model (sensitivity 1%, FPR 0%) (p < 0.05). The results of the deep learning network were the least affected by the presence of artifacts, added white noise, and flat EEG channels. CONCLUSIONS: A deep learning model outperformed logistic regression and random forest models for reliable, robust, EEG-based outcome prediction of comatose patients after cardiac arrest.

Effects of targeted temperature management at 33 °C vs. 36 °C on comatose patients after cardiac arrest stratified by the severity of encephalopathy.

OBJECTIVES: To assess neurological outcome after targeted temperature management (TTM) at 33 °C vs. 36 °C, stratified by the severity of encephalopathy based on EEG-patterns at 12 and 24 h. DESIGN: Post hoc analysis of prospective cohort study. SETTING: Five Dutch Intensive Care units. PATIENTS: 479 adult comatose post-cardiac arrest patients. INTERVENTIONS: TTM at 33 °C (n = 270) or 36 °C (n = 209) and continuous EEG monitoring. MEASUREMENTS AND MAIN RESULTS: Outcome according to the cerebral performance category (CPC) score at 6 months post-cardiac arrest was similar after 33 °C and 36 °C. However, when stratified by the severity of encephalopathy based on EEG-patterns at 12 and 24 h after cardiac arrest, the proportion of good outcome (CPC 1-2) in patients with moderate encephalopathy was significantly larger after TTM at 33 °C (66% vs. 45%; Odds Ratios 2.38, 95% CI = 1.32-4.30; p = 0.004). In contrast, with mild encephalopathy, there was no statistically significant difference in the proportion of patients with good outcome between 33 °C and 36 °C (88% vs. 81%; OR 1.68, 95% CI = 0.65-4.38; p = 0.282). Ordinal regression analysis showed a shift towards higher CPC scores when treated with TTM 33 °C as compared with 36 °C in moderate encephalopathy (cOR 2.39; 95% CI = 1.40-4.08; p = 0.001), but not in mild encephalopathy (cOR 0.81 95% CI = 0.41-1.59; p = 0.537). Adjustment for initial cardiac rhythm and cause of arrest did not change this relationship. CONCLUSIONS: Effects of TTM probably depend on the severity of encephalopathy in comatose patients after cardiac arrest. These results support inclusion of predefined subgroup analyses based on EEG measures of the severity of encephalopathy in future clinical trials.

Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest.

BACKGROUND: Whether the treatment of rhythmic and periodic electroencephalographic (EEG) patterns in comatose survivors of cardiac arrest improves outcomes is uncertain. METHODS: We conducted an open-label trial of suppressing rhythmic and periodic EEG patterns detected on continuous EEG monitoring in comatose survivors of cardiac arrest. Patients were randomly assigned in a 1:1 ratio to a stepwise strategy of antiseizure medications to suppress this activity for at least 48 consecutive hours plus standard care (antiseizure-treatment group) or to standard care alone (control group); standard care included targeted temperature management in both groups. The primary outcome was neurologic outcome according to the score on the Cerebral Performance Category (CPC) scale at 3 months, dichotomized as a good outcome (CPC score indicating no, mild, or moderate disability) or a poor outcome (CPC score indicating severe disability, coma, or death). Secondary outcomes were mortality, length of stay in the intensive care unit (ICU), and duration of mechanical ventilation. RESULTS: We enrolled 172 patients, with 88 assigned to the antiseizure-treatment group and 84 to the control group. Rhythmic or periodic EEG activity was detected a median of 35 hours after cardiac arrest; 98 of 157 patients (62%) with available data had myoclonus. Complete suppression of rhythmic and periodic EEG activity for 48 consecutive hours occurred in 49 of 88 patients (56%) in the antiseizure-treatment group and in 2 of 83 patients (2%) in the control group. At 3 months, 79 of 88 patients (90%) in the antiseizure-treatment group and 77 of 84 patients (92%) in the control group had a poor outcome (difference, 2 percentage points; 95% confidence interval, -7 to 11; P = 0.68). Mortality at 3 months was 80% in the antiseizure-treatment group and 82% in the control group. The mean length of stay in the ICU and mean duration of mechanical ventilation were slightly longer in the antiseizure-treatment group than in the control group. CONCLUSIONS: In comatose survivors of cardiac arrest, the incidence of a poor neurologic outcome at 3 months did not differ significantly between a strategy of suppressing rhythmic and periodic EEG activity with the use of antiseizure medication for at least 48 hours plus standard care and standard care alone. (Funded by the Dutch Epilepsy Foundation; TELSTAR ClinicalTrials.gov number, NCT02056236.).

Heart-rate-variability (HRV), predicts outcomes in COVID-19.

BACKGROUND: Patients with COVID-19 present with a variety of clinical manifestations, ranging from mild or asymptomatic disease to severe illness and death. Whilst previous studies have clarified these and several other aspects of COVID-19, one of the ongoing challenges regarding COVID-19 is to determine which patients are at risk of adverse outcomes of COVID-19 infection. It is hypothesized that this is the result of insufficient inhibition of the immune response, with the vagus nerve being an important neuro-immuno-modulator of inflammation. Vagus nerve activity can be non-invasively indexed by heart-rate-variability (HRV). Therefore, we aimed to assess the prognostic value of HRV, as a surrogate marker for vagus nerve activity, in predicting mortality and intensive care unit (ICU) referral, in patients hospitalized with COVID-19. METHODS: A retrospective cohort study including all consecutive patients (n = 271) diagnosed and hospitalized with COVID-19 between March 2020 and May 2020, without a history of cardiac arrhythmias (including atrial and ventricular premature contractions), pacemaker, or current bradycardia (heart rate <50 bpm) or tachycardia (heart rate >110 bpm). HRV was based on one 10s ECG recorded at admission. 3-week survival and ICU referral were examined. RESULTS: HRV indexed as standard deviation of normal to normal heartbeat intervals (SDNN) predicted survival (H.R. = 0.53 95%CI: 0.31-0.92). This protective role was observed only in patients aged 70 years and older, not in younger patients. HRV below median value also predicted ICU referral within the first week of hospitalization (H.R = 0.51, 95%CI: 0.29-0.90, P = 0.021). CONCLUSION: Higher HRV predicts greater chances of survival, especially in patients aged 70 years and older with COVID-19, independent of major prognostic factors. Low HRV predicts ICU indication and admission in the first week after hospitalization.

Iatrogenic topiramate poisoning in an ICU patient: Focus on topiramate peak time prolongation.

A 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time tmax. According to our modulations, tmax follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.

A multimodal sevoflurane-based sedation regimen in combination with targeted temperature management in post-cardiac arrest patients reduces the incidence of delirium: An observational propensity score-matched study.

BACKGROUND: Recent studies suggest that volatile anaesthetics are safe, efficient, and reliable alternatives to the use of intravenous anaesthetics for out-of-hospital cardiac arrest (OHCA) patients admitted to the intensive care unit (ICU). We hypothesised that volatile anaesthetics may reduce the incidence of delirium rather than intravenous sedatives. This retrospective study aimed to investigate whether sevoflurane combined with higher targeted temperature management could decrease the incidence of delirium when compared with intravenous anaesthetics with lower targeted temperature management. METHODS: Using a propensity score-matched analysis, we retrospectively compared a target temperature management (32-34 °C) method along with intravenous sedation (TTM-33/IV) and a modified target temperature management (34-36 °C) method along with sevoflurane sedation (mTTM-36/sevo). We used the confusion assessment method for the ICU to measure the incidence of delirium. We calculated the time-dependent risk on delirium using the multivariate Cox regression model. RESULTS: The incidence of delirium was significantly lower (p = 0.001) in OHCA patients of the mTTM-36/sevo group (9/56, 16.1%) than in those of the TTM-33/IV group (25/67, 37.3%). Mechanical ventilation and lengths of stay in the ICU (p < 0.001) and hospital stay (p = 0.04) were shorter in the mTTM-36/sevo group. Patients in the TTM-33/IV group required more midazolam, propofol, and fentanyl. We observed no significant difference in mortality. CONCLUSION: A multimodal sevoflurane-based sedation regimen together with targeted temperature management resulted in a lower incidence of delirium and a shorter duration for mechanical ventilation and ICU length of stay than did the treatment with intravenous sedation combined with the classical cooling protocol.

Liquid Chromatography-Tandem Mass Spectrometry to Monitor Unbound and Total Ceftriaxone in Serum of Critically Ill Patients.

BACKGROUND: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic Drug Monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. OBJECTIVE: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. METHODS: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, the limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. RESULTS: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation < 15.0% for concentrations between 0.2 - 400.0 mg/L. Ceftriaxone eluted at 1.94 min and ceftazidime, as internal standard, eluted at 1.42 min. Patients demonstrated a median unbound ceftriaxone fraction of 29.1% (IQR: 15.2 - 52.2). Day 1 of ceftriaxone treatment presented a median PK/PD target attainment of 100.0% (IQR: 81.1 - 100.0) for unbound ceftriaxone in serum, while for calculations based on total concentrations, this figure was 23.9% (IQR: 10.5 - 80.6). CONCLUSION: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

Spiritual care in the intensive care unit: An integrative literature research.

PURPOSE: The aim of this study is to review the literature for three major domains in relation to spiritual care in the ICU, namely Quality of Life (QoL), Quality of Care (QoC), and Education (E). METHOD: An integrative literature research. RESULTS: The 113 selected articles reveal that spirituality is an essential component of QoL and that complementary and effective spiritual care (SC) relieves distress of patients and their relatives. Furthermore, the contribution of SC to quality of care is: 1) diagnosing and addressing spiritual and emotional needs among patients and their relatives; 2) offering spiritual comfort to the patient in distress; 3) increased spiritual well-being of both patients and their relatives; 4) increased family satisfaction in general and by shared decision-making. Finally, the literature reveals the necessity to improve SC knowledge and skills of ICU healthcare professionals (IC HCPs) through relevant training courses. CONCLUSION: SC contributes to QoL and QoC. The literature indicates that IC HCPs acknowledge the need to improve their SC knowledge and skills to enhance complementary, effective SC. Further research on SC as an integrated part of daily ICU care is necessary to improve QoL and QoC of patients and their relatives.

No effect of norepinephrine dose on anti-Xa activity in critically ill patients
.

OBJECTIVE: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. MATERIALS AND METHODS: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 IU subcutaneously once daily and norepinephrine > 0.25 µg/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. RESULTS: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following dalteparin 5,000 IU once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BMI) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity ≥ 0.10 IU/mL in all 5 patients (p = 0.043). CONCLUSION: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-IU administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.