Jonathan A. Silversides

Background: Hypernatremia is frequent in the intensive care unit (ICU) and is associated with adverse outcomes. Despite its prevalence, robust evidence to guide treatment is lacking, and global practice patterns are largely unknown. We investigated global treatment preferences and clinicians' willingness to enroll patients in a randomized trial to inform its feasibility. Methods: This international cross‐sectional online survey comprised 20 primarily closed‐ended questions, using five‐point Likert‐scale responses, across four themes: treatment method, threshold, correction rate, and opinion on a proposed trial. Respondents considered a clinical vignette of hypernatremia developing before or during ICU admission, excluding dehydration and chronic causes. It was distributed to ICU physicians worldwide. Results: The survey was sent to 3053 ICU physicians in 17 countries, with 1051 respondents, yielding a response rate of 34%. Of respondents, 74% were consultants, and 26% were residents. The mean ICU experience was 14 years. Increasing free water intake via enteral route was the most frequently reported treatment strategy (80% reporting “often” or “always”). Moderate hypernatremia (plasma sodium 151–156 mmol/L) was the most frequently reported threshold for initiating correction (533/892, 60%). 45% (396/888) preferred a correction rate of 8–12 mmol/L/day, and 41% (366/888) of < 8 mmol/L/day, with the remainder having no correction rate target or correction rate target of > 12 mmol/L/day. 74% (654/882) reported no barriers to enrolling eligible patients in the proposed trial. Conclusion: Among ICU physicians, correction of hypernatremia is mostly achieved by increasing free water intake using hypotonic fluids, predominantly via the enteral route. Most clinicians initiate treatment once hypernatremia reaches a moderate level, aiming for a correction rate of < 12 mmol/L/day. Most clinicians expressed willingness to enroll eligible patients in the proposed trial. Editorial Comment: This survey study aimed to sample physician preferences for treatment of hypernatremia when on their way to or in the ICU. This study sampled respondents in many countries, and based on different phases of treatment and assessment, as well as participant willingness for a future treatment trial.

OBJECTIVES: Among precision medicine approaches in critical care, protein biomarker quantification offers a timely and reproducible route to patient subtyping, but the landscape of automated platforms suitable for near-patient deployment remains unclear. This review aimed to identify available automated platforms for quantitative measurement of human protein biomarkers in blood, serum, or plasma, in order to support planning for precision medicine trials. DATA SOURCES: PubMed, Embase, and Espacenet were searched for eligible sources. Relevant company correspondence was also included where available. STUDY SELECTION: Publication reports, patent reports, and company correspondence were eligible if they described commercially available platforms meeting a prespecified definition of automation for quantitative measurement of one or more human protein biomarkers in blood, serum, or plasma. DATA EXTRACTION: Data were extracted on device model, manufacturer, and analytes measured. Eligible devices were extracted as separate device records, including multiple devices reported within a single source. DATA SYNTHESIS: Overall, 228 sources were included, comprising 211 publication reports, 14 patent reports, and three company correspondence reports. Publications contributed 256 publication-derived device records representing 74 distinct automated device models from 34 manufacturers. The most frequently represented devices were Ella ( n = 48), LUMIPULSE G1200 ( n = 25), LUMIPULSE G600II ( n = 17), cobas e 411 ( n = 13), and Simoa HD-X ( n = 12). Multiplex capability was identified for eight devices in included publications, with two additional multiplex-capable platforms identified through company correspondence. Across publication-derived device records, inflammatory and neurologic biomarkers predominated. The most frequently reported inflammatory biomarkers were procalcitonin ( n = 36), interleukin (IL)-6 ( n = 35), tumor necrosis factor (TNF)-α ( n = 22), and IL-10 ( n = 14). The most frequently reported neurologic biomarkers were neurofilament light chain ( n = 34), p-tau217 ( n = 31), Aβ42 ( n = 29), Aβ40 ( n = 27), and p-tau181 ( n = 27). CONCLUSIONS: Automated platforms for quantitative protein biomarker measurement span numerous devices and manufacturers, but multiplex capability remains limited. More standardized device-level reporting would strengthen platform selection for biomarker-enabled trials and future clinical implementation.

OBJECTIVES: Test the hypothesis that conservative fluid management with active deresuscitation would not adversely affect tissue perfusion or kidney injury and would be associated with reduced vascular injury compared with usual care. DESIGN: Secondary analysis of the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) trial. SETTING: ICUs. PATIENTS OR SUBJECTS: Critically ill patients enrolled in the RADAR-2 trial. INTERVENTIONS: Conservative fluid management with active deresuscitation vs. usual care. MEASUREMENTS AND MAIN RESULTS: Measures of tissue hypoperfusion (whole blood lactate), acute kidney injury (AKIRisk score and urinary cystatin-C), and vascular injury (plasma hyaluronan, syndecan-1, and angiopoietin-2) were compared between groups. For each analyte, change from baseline was compared between groups and the median inter-group difference at each timepoint was estimated with bootstrapped CIs. Exploratory logistic regression examined associations between plasma biomarker levels (including N-terminal pro-B-type natriuretic peptide [NT-proBNP]), 28-day mortality, and treatment allocation. Whole blood lactate levels were similar between groups at all timepoints. Using change from baseline comparisons, no statistically detectable between-group differences were observed in AKIRisk scores or urinary cystatin-C levels. Plasma vascular injury biomarkers showed no statistically detectable between-group differences at any timepoint. High baseline hyaluronan (adjusted odds ratio [aOR], 5.75; 95% CI, 1.94–17.02; p = 0.002), syndecan-1 (aOR, 8.82; 95% CI, 2.67–29.15; p < 0.001), and NT-proBNP greater than 2500 pg/mL (aOR, 21.48; 95% CI, 3.57–129.41; p < 0.001) were independently associated with increased 28-day mortality. There was no evidence of differential treatment response based on these biomarker levels. CONCLUSIONS: Conservative fluid management and active deresuscitation were not associated with worsening tissue perfusion or acute kidney injury. A reduction in vascular injury markers was not observed. Given the modest sample size and resultant imprecision, clinically important effects cannot be excluded.

Proprotein Convertase Subtilisin-Kexin type 9 (PCSK9) is a key regulator of lipid metabolism, binding to the low-density lipoprotein receptor (LDLR) on the cell surface and preventing its recycling, thereby reducing clearance of LDL cholesterol (LDLc) from the circulation. For this reason, it constitutes an alternative therapeutic target for the control of hypercholesterolaemia, with the development of monoclonal antibodies against PCSK9 occurring within 12 years of the protein’s discovery. Recent research has also suggested an inflammatory role played by PCSK9, with elevated plasma levels identified in critical illnesses such as sepsis and Acute Respiratory Distress Syndrome, where PCSK9 is thought to reduce bacterial endotoxin clearance and may exacerbate inflammation. Further work is required in order to clarify the exact role played by PCSK9 in extra-hepatic tissues, and the potential benefits of its pharmacological inhibition.

Background: Post-operative pulmonary complications (PPCs) are an important source of morbidity and mortality after major abdominal and thoracic surgery. The use of neuromuscular blocking drugs in general anaesthesia is an important risk factor for PPCs. The incomplete reversal of this neuromuscular blockade at the end of surgery leads to residual weakness of respiratory muscles and predisposes to aspiration of pharyngeal contents, hypoventilation, and thus to PPCs such as atelectasis and pneumonia. Two reversal drugs for neuromuscular blocking agents are available: neostigmine and sugammadex. Compared with neostigmine, sugammadex use results in more rapid reversal of neuromuscular blockade, and small clinical efficacy studies have suggested an associated lower incidence of PPCs. The comparative clinical effectiveness of the two drugs in reducing length of hospital stay or mortality is uncertain. Moreover, a potential safety concern with sugammadex is the relatively high incidence of life-threatening allergic reactions in countries where this drug has been widely used over the last decade. Methods: SINFONIA is a pragmatic, randomised, open-label, parallel group, superiority trial with an internal pilot which aims to compare the clinical and cost effectiveness of the two available drugs for reversal of neuromuscular blockade, sugammadex and neostigmine, in patients aged 50 years or older undergoing major abdominal or non-cardiac thoracic surgery. The trial will randomise 2500 patients from approximately 40 centres in the UK. The primary outcome will be days alive and out of hospital at 30 days (DAH-30), with key secondary outcomes of PPC incidence, quality of life, and mortality up to 180 days. An embedded observational study will investigate the rate of allergic sensitisation following exposure to sugammadex. Discussion: The SINFONIA trial addresses an important question for anaesthetists and for patients undergoing major abdominal and thoracic surgery. The choice of reversal agent for neuromuscular blockade between sugammadex and neostigmine is currently largely a matter of anaesthetist preference. A growing body of evidence suggests that sugammadex may reduce the incidence of post-operative pulmonary complications relative to neostigmine. This pragmatic clinical effectiveness trial will provide robust evidence as to the effects of the two drugs on patient-centred outcomes such as DAH-30, as well as on cost effectiveness and the incidence of allergic sensitisation. Trial registration: The trial was registered on the ISRCTN database (https://www.isrctn.com) prior to opening to recruitment (registration no 15109717).

OBJECTIVES: Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. DESIGN: An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. SETTING: Two ICUs in the United Kingdom. PATIENTS: Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO₂) and quadriceps muscle tissue saturations (SmtO₂). INTERVENTION: Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo₂) measurements were recorded alongside NIRS data. Arterial Paco₂, Pao₂, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. MEASUREMENTS AND MAIN RESULTS: Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco₂, Spo₂, MAP, and HR were weakly associated with SctO₂ but only explained 7.1% of the total variation. Spo₂ and MAP were associated with SmtO₂, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. CONCLUSIONS: Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.