Glycemic Variability As a Prognostic Factor for Mortality in Patients With Critical Illness: A Systematic Review and Meta-Analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to evaluate the association of various measures of glycemic variability, including time-domain and complexity-domain, with short-term mortality in patients with critical illness. DATA SOURCES: We searched Embase Classic +, MEDLINE, and the Cochrane Database of Systematic Reviews from inception to November 3, 2023. STUDY SELECTION: We included English language studies that assessed metrics of glycemic variation or complexity and short-term mortality in patients admitted to the ICU. DATA EXTRACTION: Two authors performed independent data abstraction and risk-of-bias assessments. We used a random-effects model to pool binary and continuous data and summarized estimates of effect using odds ratios and mean difference. We used the Quality in Prognosis Studies tool to assess risk of bias and the Grading of Recommendations, Assessment, Development and Evaluations to assess certainty of pooled estimates. DATA SYNTHESIS: We included 41 studies (n = 162,259). We demonstrate that increased sd, coefficient of variance, glycemic lability index, and decreased time in range are probably associated with increased mortality in critically ill patients (moderate certainty) and that increased mean absolute glucose, mean amplitude of glycemic excursion, and detrended fluctuation analysis may be associated with increased mortality (low certainty). CONCLUSIONS: We found a consistent association between increased measures of glycemic variability and higher short-term mortality in patient with critical illness. Further research should focus on standardized measurements of glycemic variation and complexity, along with their utility as therapeutic targets and prognostic markers.

Doctor-patient interactions in the age of AI: navigating innovation and expertise.

The integration of artificial intelligence (AI) in healthcare has the capacity to transform medical practice. Despite its revolutionary potential, the influence of AI may affect the physician-patient interaction and presents ethical challenges that will need to be carefully considered. This article discusses how patients may interact with this technology, considers how emerging technologies may alter the dynamics of the physician-patient relationship, and reviews some of the limitations that continue to exist. We identify potential challenges that may arise with the integration of AI into medical settings and propose solutions to help mitigate these issues.

A systematic review and meta-analysis of sample size methodology for traumatic hemorrhage trials.

BACKGROUND: Trauma hemorrhage remains the most common cause of preventable mortality in trauma. To guide clinical practice, RCTs provide high-quality evidence to inform clinical decision making. The clinical relevance and inferences made by RCTs are dependent on assumptions made during sample size calculation. METHODS: To describe the quality of methodology for sample size determination, we conducted a systemic review RCTs evaluating interventions that aim to improve survival in adults with trauma-related hemorrhage. Estimated and actual outcome data are compared, including components of sample size determination. RESULTS: A total of 13 RCTs were included. We noted a high rate of negative trial results (11 of 13 studies). Most studies were multi-center and conducted in North America, evaluating patients with blunt and penetrating injuries. The criteria for hemorrhagic shock varied across studies. All studies did not accurately estimate the mortality rate during sample size calculation. All but one study overestimated the mortality reduction during sample size calculation; the median absolute mortality reduction was 3%, compared with a target of 10%. Only the CRASH-2 study used a minimal clinically important different for treatment effect target. No RCTs employed prognostic enrichment. Most studies were terminated (8 of 13), mainly for futility. CONCLUSION: Taken together, this review highlights that current clinical trial methodology is limited by imprecise control group risk estimates, overly optimistic treatment effect estimates, and lack of transparent justification for such targets. These limitations result in studies at high risk for futility and potentially premature abandonment of promising therapies. Given the high morbidity and mortality of trauma-related hemorrhage, we recommend that future conduct of trauma RCTs incorporate (1) prognostic enrichment to inform baseline risk, (2) justify target treatment differences based on clinical importance and realistic estimates of feasibility, and (3) be transparent and provide justification for the assumptions made. LEVEL OF EVIDENCE: Systematic Review/Meta-Analysis; Level III.

Presence of Macrotroponin for Over 2 Years in a Young Woman.

We present the case of a 28-year-old woman who presented with nonspecific symptoms with a high-sensitivity troponin I level > 10,000 ng/L, which led to extensive investigations and a hospital stay. Follow-up testing using an alternate troponin assay yielded undetectable levels. Two years later, the patient had a high-sensitivity troponin I level > 1500 ng/L, with experiments confirming the presence of a macrocomplex. We advocate for communication with laboratory professionals to expedite identification of macrotroponin complexes, so that patients and clinicians can reduce the number of unwarranted investigations. Novel teaching points include the importance of identifying macrocomplexes as a source of persistent false elevations and ensuring that a process is instituted to investigate troponin-level elevations when false-positive results are suspected.

Nous décrivons le cas d'une femme de 28 ans qui présentait des symptômes non spécifiques et un taux de troponine I mesuré par dosage ultrasensible s'élevant à plus de 10 000 ng/l, ce qui a mené à des investigations poussées et à une hospitalisation. Lors d'analyses de suivi avec une mesure alternative de la troponine, les taux étaient indétectables. Deux ans plus tard, le taux de troponine I mesuré par dosage ultrasensible était supérieur à 1500 ng/l chez cette patiente, et des analyses ont confirmé la présence d'un macrocomplexe. Nous préconisons une communication avec les professionnels de laboratoire pour accélérer la détection de complexes de macrotroponine, afin de permettre aux cliniciens de diminuer le nombre d'investigations qui ne sont pas nécessaires chez les patients. Les points d'enseignements les plus récents insistent sur l'importance de détecter les macrocomplexes qui pourraient être à l'origine des taux de troponine faussement élevés persistants et de s'assurer qu'un processus soit mis en place pour investiguer les élévations du taux de troponine lorsque des résultats faussement positifs sont suspectés.

Continuous EEG in a Pediatric Intensive Care Unit: Adherence to Monitoring Criteria and Barriers to Adequate Implementation.

BACKGROUND: Subclinical seizures are common in critically ill children and are best detected by continuous EEG (cEEG) monitoring. Timely detection of seizures requires pediatric intensive care unit (PICU) physicians to identify patients at risk of seizures and request cEEG monitoring. A recent consensus statement from the American Clinical Neurophysiology Society (ACNS) outlines the indications for cEEG monitoring in critically ill patients. However, adherence to these cEEG monitoring criteria among PICU physicians is unknown. Our project had two goals: 1. To assess adherence to cEEG monitoring indications and barriers toward their implementation; 2. To improve compliance with the ACNS cEEG monitoring criteria in our PICU. METHODS: This is a single-institution study. A total of 234 PICU admissions (183 unique patients) were studied. A 6-month retrospective chart review identified PICU patients meeting ACNS criteria for cEEG monitoring, and patients for whom monitoring was requested. This was followed by an 8-week quality improvement project. During this mentorship period, a didactic 15-min lecture and summary handouts regarding the ACNS indications for cEEG monitoring were provided to all PICU physicians. Requests for cEEG monitoring during the mentorship period were compared to baseline adherence to cEEG monitoring recommendations, and barriers toward timely cEEG monitoring were assessed. RESULTS: Nearly every fifth PICU patient met cEEG monitoring indications, and prevalences of patients meeting those indications were similar in the retrospective and the prospective mentorship period (18% vs. 19%). Almost all patients (98%) requiring cEEG as per ACNS criteria met the indication for monitoring already at the time of their PICU admission. During the retrospective period, 23% of patients meeting ACNS criteria had a request for cEEG monitoring, which increased to 83% during the mentorship period. The median delay to cEEG initiation was 16.7 h during the mentorship period, largely due to limited hours of EEG technician availability. Electrographic seizures were identified in 36% of patients monitored, all within the first 120 min of cEEG recording. The majority (79%) of cEEGs informed clinical management. CONCLUSIONS: A brief teaching intervention supplemented by pictographic handouts significantly increased adherence to cEEG monitoring recommendations, and cEEGs guided clinical management. However, there were long delays to cEEG initiation. In order to promptly recognize subclinical seizures in critically ill children, we strongly advocate for a routine screening for cEEG monitoring indications as part of the PICU admission process, and a care model allowing for cEEG initiation around-the-clock.

Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice.

Prostaglandin E2 receptor EP1 (PGE2/EP1) promotes diabetic renal injury, and EP1 receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP1 receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP1 receptors to HKD. EP1 null (EP1-/-) mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 weeks. EP1 deletion had no effect on elevation of systolic blood pressure in Htn mice (HtnEP1-/-) but resulted in pronounced albuminuria and reduced FITC-inulin clearance, compared with Htn or wild-type (WT) mice. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP1-/- mice; including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from basement membrane, with focal subendothelial cell debris. Cortex COX2 mRNA was increased by EP1 deletion. Glomerular EP3 mRNA was reduced by EP1 deletion, and EP4 by Htn and EP1 deletion. In WT mice, PGE2 increased chloride reabsorption via EP1 in isolated perfused thick ascending limb (TAL), but PGE2 or EP1 deletion did not affect vasopressin-mediated chloride reabsorption. In WT and Htn mouse inner medullary collecting duct (IMCD), PGE2 inhibited vasopressin-water transport, but not in EP1-/- or HtnEP1-/- mice. Overall, EP1 mediated TAL and IMCD transport in response to PGE2 is unaltered in Htn, and EP1 is protective in HKD.

Benign spasms of infancy: a mimicker of infantile epileptic disorders.

Benign spasms of infancy (BSI), previously described as benign non-epileptic infantile spasms or benign myoclonus of early infancy, are non-epileptic movements manifesting during the first year of life and spontaneously resolving in the second year of life. BSI are characterized by spasms typically lasting 1-2 seconds, involving, to varying degrees, the head, neck, trunk, shoulders and upper extremities. Ictal and interictal EEG recordings are normal. BSI are not associated with developmental regression and do not require treatment. Distinction between BSI and infantile epileptic disorders, such as epileptic spasms or myoclonic epilepsy of infancy, can be challenging given the clinical similarities. Moreover, interictal EEGs can be normal in all conditions. Epileptic spasms and myoclonic epilepsy require timely treatment to improve neurodevelopmental outcomes. We describe a six-month-old infant presenting with spasm-like movements. His paroxysms as well as a positive family history for epileptic spasms were in keeping with a likely diagnosis of West syndrome. Surprisingly, ictal video-EEG did not reveal epileptiform activity, and suggested a diagnosis of BSI. We emphasize that ictal video-EEG is the gold standard for classification of infantile paroxysms as epileptic or non-epileptic, thereby avoiding over-treatment for BSI and facilitating timely targeted treatment of infantile epilepsies. [Published with video sequences].

PGE2 EP1 receptor inhibits vasopressin-dependent water reabsorption and sodium transport in mouse collecting duct.

PGE2 regulates glomerular hemodynamics, renin secretion, and tubular transport. This study examined the contribution of PGE2 EP1 receptors to sodium and water homeostasis. Male EP1-/- mice were bred with hypertensive TTRhRen mice (Htn) to evaluate blood pressure and kidney function at 8 weeks of age in four groups: wildtype (WT), EP1-/-, Htn, HtnEP1-/-. Blood pressure and water balance were unaffected by EP1 deletion. COX1 and mPGE2 synthase were increased and COX2 was decreased in mice lacking EP1, with increases in EP3 and reductions in EP2 and EP4 mRNA throughout the nephron. Microdissected proximal tubule sglt1, NHE3, and AQP1 were increased in HtnEP1-/-, but sglt2 was increased in EP1-/- mice. Thick ascending limb NKCC2 was reduced in the cortex but increased in the medulla. Inner medullary collecting duct (IMCD) AQP1 and ENaC were increased, but AVP V2 receptors and urea transporter-1 were reduced in all mice compared to WT. In WT and Htn mice, PGE2 inhibited AVP-water transport and increased calcium in the IMCD, and inhibited sodium transport in cortical collecting ducts, but not in EP1-/- or HtnEP1-/- mice. Amiloride (ENaC) and hydrochlorothiazide (pendrin inhibitor) equally attenuated the effect of PGE2 on sodium transport. Taken together, the data suggest that EP1 regulates renal aquaporins and sodium transporters, attenuates AVP-water transport and inhibits sodium transport in the mouse collecting duct, which is mediated by both ENaC and pendrin-dependent pathways.

PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes.

AIMS/HYPOTHESIS: The first clinical manifestation of diabetes is polyuria. The prostaglandin E2 (PGE2) receptor EP3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP3 to diabetic polyuria and renal injury. METHODS: Male Ep 3 (-/-) (also known as Ptger3 (-/-)) mice were treated with streptozotocin (STZ) to generate a mouse model of diabetes and renal function was evaluated after 12 weeks. Isolated collecting ducts (CDs) were microperfused to study the contribution of EP3 to AVP-mediated fluid reabsorption. RESULTS: Ep 3 (-/-)-STZ mice exhibited attenuated polyuria and increased urine osmolality compared with wild-type STZ (WT-STZ) mice, suggesting enhanced water reabsorption. Compared with WT-STZ mice, Ep 3 (-/-)-STZ mice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 (-/-) and WT-STZ CDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZ mice, EP3 activation with sulprostone (PGE2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP3. A major finding of this work is that Ep 3 (-/-)-STZ mice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts. CONCLUSIONS/INTERPRETATION: Taken together, the data suggest that EP3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP3 may prove to be a promising target for more selective management of diabetic kidney disease.