Pharmacokinetics of Haloperidol in Critically Ill Patients:Is There an Association with Inflammation?

Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation

Hemichannel-mediated and pH-based feedback from horizontal cells to cones in the vertebrate retina

Background: Recent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH withinthe synaptic cleft that activates the calcium current (Ca2+-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through ahemichannel-mediated ephaptic mechanism.Methodology/Principal Findings: To distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification ofneurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminatebetween a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synapticcleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cellsynapse.Conclusion: We conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina

Post COVID-19 Pandemic Increased Detection of Mycoplasma Pneumoniae in Adults Admitted to the Intensive Care

Background: Mycoplasma pneumoniae (M. pneumoniae) infections can progress to severe respiratory complications, necessitating intensive care treatment. Recent post COVID-19 pandemic surges underscore the need for timely diagnosis, given potential diagnostic method limitations. Methods: A retrospective case series analysis was conducted on M. pneumonia PCR-positive patients admitted to two Dutch secondary hospitals’ ICUs between January 2023 and February 2024. Clinical presentations, treatments, outcomes, and mechanical ventilation data were assessed. Results: Seventeen ICU-admitted patients were identified, with a median age of 44 years, primarily due to hypoxia. Non-invasive ventilation was effective for most, while five required invasive mechanical ventilation. None of the patients required extracorporeal membrane oxygenation. No fatalities occurred. Post-PCR, treatment was adjusted to doxycycline or azithromycin; seven received steroid treatment. Discussion: Increased ICU admissions for M. pneumoniae infection were observed. Diverse clinical and radiological findings emphasize heightened clinical awareness. Early molecular diagnostics and tailored antibiotic regimens are crucial since beta-lactam antibiotics are ineffective. Conclusion: This study highlights the escalating challenge of severe M. pneumoniae infections in ICUs, necessitating a multifaceted approach involving accurate diagnostics, vigilant monitoring, and adaptable treatment strategies for optimal patient outcomes.</p

Presence of procoagulant peripheral blood mononuclear cells in severe COVID-19 patients relate to ventilation perfusion mismatch and precede pulmonary embolism

PURPOSE: Pulmonary emboli (PE) contribute substantially to coronavirus disease 2019 (COVID-19) related mortality and morbidity. Immune cell-mediated hyperinflammation drives the procoagulant state in COVID-19 patients, resulting in immunothrombosis. To study the role of peripheral blood mononuclear cells (PBMC) in the procoagulant state of COVID-19 patients, we performed a functional bioassay and related outcomes to the occurrence of PE. Secondary aims were to relate this functional assay to plasma D-dimer levels, ventilation perfusion mismatch and TF expression on monocyte subsets. METHODS: PBMC from an ICU biobank were obtained from 20 patients with a computed tomography angiograph (CTA) proven PE and compared to 15 COVID-19 controls without a proven PE. Functional procoagulant properties of PBMC were measured using a modified fibrin generation time (MC-FGT) assay. Tissue factor (TF) expression on monocyte subsets were measured by flow cytometry. Additional clinical data were obtained from patient records including end-tidal to arterial carbon dioxide gradient. RESULTS: MC-FGT levels were highest in the samples taken closest to the PE detection, similar to the end-tidal to arterial carbon dioxide gradient (ETCO2 - PaCO2), a measurement to quantify ventilation-perfusion mismatch. In patients without proven PE, peak MC-FGT relates to an increase in end-tidal to arterial carbon dioxide gradient. We identified non-classical, CD16 positive monocytes as the subset with increased TF expression. CONCLUSION: We show that the procoagulant state of PBMC could aid in early detection of PE in COVID-19 ICU patients. Combined with end-tidal to ETCO2 - PaCO2 gradient, these tests could improve early detection of PE on the ICU.</p

Cost-effectiveness in extracorporeal life support in critically ill adults in the Netherlands

Background: Extracorporeal life support (ECLS) is used to support the cardiorespiratory function in case of severe cardiac and/or respiratory failure in critically ill patients. According to the ELSO guidelines ECLS should be considered when estimated mortality risk approximates 80%. ECLS seems an efficient therapy in terms of survival benefit, but no undisputed evidence is delivered yet. The aim of the study is to assess the health-related quality of life after ECLS treatment and its cost effectiveness. Methods: We will perform a prospective observational cohort study. All adult patients who receive ECLS in the participating centers will be included. Exclusion criteria are patients in whom the ECLS is only used to bridge a procedure (like a high risk percutaneous coronary intervention or surgery) or the absence of informed consent. Data collection includes patient characteristics and data specific for ECLS treatment. Severity of illness and mortality risk is measured as precisely as possible using measurements for the appropriate age group and organ failure. For analyses on survival patients will act as their own control as we compare the actual survival with the estimated mortality on initiation of ECLS if conservative treatment would have been continued. Survivors are asked to complete validated questionnaires on health related quality of life (EQ5D-5 L) and on medical consumption and productivity losses (iMTA/iPCQ) at 6 and 12 months. Also the health related quality of life 1 month prior to ECLS initiation will be obtained by a questionnaire, if needed provided by relatives. With an estimated overall survival of 62% 210 patients need to be recruited to make a statement on cost effectiveness for all ECLS indications. Discussion: If our hypothesis that ECLS treatment is cost-effective is confirmed by this prospective study this could lead to an even broader use of ECLS treatment

Spontaneous perforation of the cystic duct in streptococcal toxic shock syndrome: a case report

Introduction: Streptococcal toxic shock syndrome is a complication of group A streptococcal infection, most often originating from the skin. The syndrome is characterized by fever, hypotension and multiple organ failure. Mortality rate may be as high as 80%. Case presentation: A 25-year-old man of Indian origin presented with abdominal complaints, rash and fever after an episode of pharyngitis. The patient was operated and a biliary peritonitis was found caused by perforation of the cystic duct in the absence of calculi. Cholecystectomy was performed, but after the operation, the patient's condition worsened and multi-organ failure developed. Group A streptococci were cultured in blood taken at admission and streptococcal toxic shock syndrome was diagnosed. Treatment consisted of antibiotics, corticosteroids, immunoglobulin and supportive treatment for haemodynamic, respiratory and renal failure. Conclusion: This is a patient with streptococcal toxic shock syndrome complicated by spontaneous perforation of the cystic duct. Spontaneous perforation of the cystic duct is a rare finding, most often reported in children and secondary to anatomic defects. We found only one similar adult case in the literature. Perforation may be due to microthrombosis and ischaemia, and so be a part of the multi-organ failure often found in streptococcal toxic shock syndrome

Cost-effectiveness of extracorporeal cardiopulmonary resuscitation after in-hospital cardiac arrest

Background: This study aimed to estimate the cost-effectiveness of extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital cardiac arrest treatment. Methods: A decision tree and Markov model were constructed based on current literature. The model was conditional on age, Charlson Comorbidity Index (CCI) and sex. Three treatment strategies were considered: ECPR for patients with an Age-Combined Charlson Comorbidity Index (ACCI) below different thresholds (2–4), ECPR for everyone (EALL), and ECPR for no one (NE). Cost-effectiveness was assessed with costs per quality-of-life adjusted life years (QALY). Measurements and main results: Treating eligible patients with an ACCI below 2 points costs 8394 (95% CI: 4922–14,911) euro per extra QALY per IHCA patient; treating eligible patients with an ACCI below 3 costs 8825 (95% CI: 5192–15,777) euro per extra QALY per IHCA patient; treating eligible patients with an ACCI below 4 costs 9311 (95% CI: 5478–16,690) euro per extra QALY per IHCA patient; treating every eligible patient with ECPR costs 10,818 (95% CI: 6357–19,400) euro per extra QALY per IHCA patient. For WTP thresholds of 0–9500 euro, NE has the highest probability of being the most cost-effective strategy. For WTP thresholds between 9500 and 12,500, treating eligible patients with an ACCI below 4 has the highest probability of being the most cost-effective strategy. For WTP thresholds of 12,500 or higher, EALL was found to have the highest probability of being the most cost-effective strategy. Conclusions: Given that conventional WTP thresholds in Europe and North-America lie between 50,000–100,000 euro or U.S. dollars, ECPR can be considered a cost-effective treatment after in-hospital cardiac arrest from a healthcare perspective. More research is necessary to validate the effectiveness of ECPR, with a focus on the long-term effects of complications of ECPR

A cross-sectional investigation of communication in Do-Not-Resuscitate orders in Dutch hospitals

Background: The decision to attempt or refrain from resuscitation is preferably based on prognostic factors for outcome and subsequently communicated with patients. Both patients and physicians consider good communication important, however little is known about patient involvement in and understanding of cardiopulmonary resuscitation (CPR) directives. Aim: To determine the prevalence of Do No