Delphi Process for Validation of Fluid Treatment Algorithm for Critically Ill Pediatric Trauma Patients.

INTRODUCTION: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases. METHODS: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round. RESULTS: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm. CONCLUSIONS: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population.

Increased Extracellular Water in Normal-Appearing White Matter in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Microcirculatory variations have been observed in the normal-appearing white matter (NAWM) of individuals affected by cerebral small vessel disease (CSVD). These variations collectively possess the potential to trigger neuroinflammation and edema, ultimately leading to an elevation in extracellular fluid (ECF). Nevertheless, the specific alterations in ECF within the NAWM of CSVD patients have remained inadequately understood. METHODS: We reviewed the clinical and imaging characteristics of a cohort comprising 129 patients diagnosed with CSVD to investigate alterations in the ECF within NAWM. The severity of CSVD was assessed by total CSVD magnetic resonance (MR) score according to the four imaging markers, namely perivascular space, lacunar infarction, white matter hyperintensities and cerebral microbleed. ECF was evaluated by the parameter free water (FW), ranging from 0 to 1 generated from diffusion tensor imaging. RESULTS: Significant differences in NAWM FW were observed in relation to the total CSVD MR score (p < 0.05). Patients with a total CSVD MR score of 0 exhibited significantly lower NAWM free water (FW) values compared to those with a score greater than 0 (p < 0.05). Similarly, patients with a total CSVD MR score of 1 also demonstrated notably lower NAWM FW values than those with a score greater than 1 (p < 0.05). After conducting multivariate regression analysis, age and total CSVD MR score was independently associated with FW in NAWM (p < 0.001). Further, the total CSVD MR score served as a partial mediator in the relationship between age and FW in the NAWM among patients with CSVD. CONCLUSIONS: ECF in NAWM is increased in CSVD patients, even during the early course of CSVD.

Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

Epidemiology, Pathophysiology, and Clinical Perspectives of Intradialytic Hypertension.

BACKGROUND: Individuals with end-stage renal disease on chronic hemodialysis (HD) may encounter numerous HD-associated complications, including intradialytic hypertension (IDHYPER). Although blood pressure (BP) follows a predictable course in the post-HD period, BP levels during the session may vary across the individuals. Typically, a decline in BP is noted during HD, but a significant proportion of patients exhibit a paradoxical elevation. SUMMARY: Several studies have been conducted to understand the complexity of IDHYPER, but much remains to be elucidated in the future. This review article aimed to present the current evidence regarding the proposed definitions, the pathophysiologic background, the extent and clinical implications of IDHYPER, as well as the possible therapeutic options that have emerged from clinical studies. KEY MESSAGES: IDHYPER is noted in approximately 15% of individuals undergoing HD. Several definitions have been proposed, with a systolic BP rise >10 mm Hg from pre- to post-dialysis in the hypertensive range in at least four out of six consecutive HD treatments being suggested by the latest Kidney Disease: Improving Global Outcomes. Concerning its pathophysiology, extracellular fluid overload is a crucial determinant, with endothelial dysfunction, sympathetic nervous system overdrive, renin-angiotensin-aldosterone system activation, and electrolyte alterations being important contributors. Although its association with ambulatory BP in the interdialytic period is controversial, IDHYPER is associated with adverse cardiovascular events and mortality. Moving to its management, the antihypertensive drugs of choice should ideally be nondialyzable with proven cardiovascular and mortality benefits. Finally, rigorous clinical and objective assessment of extracellular fluid volume is essential. Volume-overloaded patients should be instructed about the importance of sodium restriction, while physicians ought to alter HD settings toward a greater dry weight reduction. The use of a low-sodium dialysate and isothermic HD could also be considered on a case-by-case basis since no randomized evidence is currently available.

Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange.

RATIONALE: The sarcolemma of cardiomyocytes contains many proteins that are essential for electromechanical function in general, and excitation-contraction coupling in particular. The distribution of these proteins is nonuniform between the bulk sarcolemmal surface and membrane invaginations known as transverse tubules (TT). TT form an intricate network of fluid-filled conduits that support electromechanical synchronicity within cardiomyocytes. Although continuous with the extracellular space, the narrow lumen and the tortuous structure of TT can form domains of restricted diffusion. As a result of unequal ion fluxes across cell surface and TT membranes, limited diffusion may generate ion gradients within TT, especially deep within the TT network and at high pacing rates. OBJECTIVE: We postulate that there may be an advective component to TT content exchange, wherein cyclic deformation of TT during diastolic stretch and systolic shortening serves to mix TT luminal content and assists equilibration with bulk extracellular fluid. METHODS AND RESULTS: Using electron tomography, we explore the 3-dimensional nanostructure of TT in rabbit ventricular myocytes, preserved at different stages of the dynamic cycle of cell contraction and relaxation. We show that cellular deformation affects TT shape in a sarcomere length-dependent manner and on a beat-by-beat time-scale. Using fluorescence recovery after photobleaching microscopy, we show that apparent speed of diffusion is affected by the mechanical state of cardiomyocytes, and that cyclic contractile activity of cardiomyocytes accelerates TT diffusion dynamics. CONCLUSIONS: Our data confirm the existence of an advective component to TT content exchange. This points toward a novel mechanism of cardiac autoregulation, whereby the previously implied increased propensity for TT luminal concentration imbalances at high electrical stimulation rates would be countered by elevated advection-assisted diffusion at high mechanical beating rates. The relevance of this mechanism in health and during pathological remodeling (eg, cardiac hypertrophy or failure) forms an exciting target for further research.

Effect of indexed glomerular filtration rate according to age.

BACKGROUND: To find out up to what age there is dispersion in glomerular filtration rate (GFR) values when normalised by body surface area (BSA) and extracellular fluid volume (ECFV), based on the hypothesis that these values differ in childhood age. METHODS: A retrospective study was performed on patients aged 0-85 years, with renal pathology, who were administered i.v. 51Cr-EDTA. GFR was obtained using the Ham and Piepsz (children) or Christensen and Groth (adults) formula. Results were normalised by BSA and ECFV. RESULTS: The cut-off point is defined as the age that discriminates between values ± 10 points apart. Using a ROC curve analysis, this age was set at 11.96 years with a sensitivity of 0.83 and a specificity of 0.85. The area obtained was 0.902 (95%CI 0.880-0.923). The results were corroborated by linear regression stratifying by age. For children under 12 years of age, the Pearson correlation was 0.883 (95% CI 0.860-0.902). For those aged 12 years or older, this coefficient was 0.963 (95%CI 0.957-0.968). According to our results, when normalising GFR by BSA and by ECFV there are different behaviours according to age. CONCLUSION: For children older than 12 years both normalisation methods can be used, but for children younger than 12 years there are differences. We believe that in children under 12 years of age, GFR should be normalised by ECFV.

Impact of Decreased Visibility of Deep Medullary Veins on White Matter Integrity in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. METHODS: We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0-18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). RESULTS: DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [ß (95% confidence interval (CI)): -0.219 (-0.375, -0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. CONCLUSIONS: DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.

Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022.

Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It is characterized by the primary elevation of serum bicarbonate and arterial pH, along with a compensatory increase in Pco2 consequent to adaptive hypoventilation. The pathogenesis of metabolic alkalosis involves either a loss of fixed acid or a net accumulation of bicarbonate within the extracellular fluid. The loss of acid may be via the gastrointestinal tract or the kidney, whereas the sources of excess alkali may be via oral or parenteral alkali intake. Severe metabolic alkalosis in critically ill patients-arterial blood pH of 7.55 or higher-is associated with significantly increased mortality rate. The kidney is equipped with sophisticated mechanisms to avert the generation or the persistence (maintenance) of metabolic alkalosis by enhancing bicarbonate excretion. These mechanisms include increased filtration as well as decreased absorption and enhanced secretion of bicarbonate by specialized transporters in specific nephron segments. Factors that interfere with these mechanisms will impair the ability of the kidney to eliminate excess bicarbonate, therefore promoting the generation or impairing the correction of metabolic alkalosis. These factors include volume contraction, low glomerular filtration rate, potassium deficiency, hypochloremia, aldosterone excess, and elevated arterial carbon dioxide. Major clinical states are associated with metabolic alkalosis, including vomiting, aldosterone or cortisol excess, licorice ingestion, chloruretic diuretics, excess calcium alkali ingestion, and genetic diseases such as Bartter syndrome, Gitelman syndrome, and cystic fibrosis. In this installment in the AJKD Core Curriculum in Nephrology, we will review the pathogenesis of metabolic alkalosis; appraise the precipitating events; and discuss clinical presentations, diagnoses, and treatments of metabolic alkalosis.

The earth-star basidiomycetous mushroom Astraeus odoratus produces polyhydroxyalkanoates during cultivation on malt extract.

Polyhydroxyalkanoates (PHAs) including poly-3-hydroxybutyrate (P3HB) as secondary metabolisms were in vitro produced by the edible basidiomycetous mushroom Astraeus odoratus during its growth on malt agar extract. Various carbon and nitrogen sources containing cellulose, glucose, glycerol, rice straw powder, soybean meal and peptone were investigated for the growth of basidiomycetous mushrooms. During cultivation, the A. odoratus culture exudated the considerably extracellular fluid up to approx. 2.3 ml on 2% malt extract agar plate within 7 days. The chemical compounds of the exudated fluid were further investigated by Fourier-transform infrared spectroscopy (FTIR) and gas chromatography/mass spectrometry (GC/MS); and its morphology of the lyophilized sample was observed by scanning electron microscope (SEM). FTIR results showed the characteristic bands of OH at 3445 cm-1, CH/CH2/symmetric CH3 (stretch) at 2923 and 2852 cm-1, C=O at 1730 cm-1, asymmetric CH3 (bend) at 1454 and 1414 cm-1, C-O of COO- at 1396 cm-1 and C-O-C at 1223, 1160, 1116, 1058 and 1019 cm-1 which were similar to the absorptive characteristics of P3HB. Methyl ester derivatives of GC/MS results identified 7 compounds including: 3-hydroxybutanoic (monomer of PHB), aminobenzoic, salicylic, hexadecenoic, octadecadienoic, octadecenoic and octadecanoic acids. SEM images revealed a fibriform and porous materials. Hence, the occurrence of PHAs was first described in a basidiomycetous mushroom A. odoratus. Thus, PHAs could be found not only in bacteria and but also in basidiomycetous mushroom, which can be promising target for bioplastics and green environmental studies.

Clinical assessment of liver metabolism during hypothermic oxygenated machine perfusion using microdialysis.

BACKGROUND: While growing evidence supports the use of hypothermic oxygenated machine perfusion (HOPE) in liver transplantation, its effects on liver metabolism are still incompletely understood. METHODS: To assess liver metabolism during HOPE using microdialysis (MD), we conducted an open-label, observational pilot study on 10 consecutive grafts treated with dual-HOPE (D-HOPE). Microdialysate and perfusate levels of glucose, lactate, pyruvate, glutamate, and flavin mononucleotide (FMN) were measured during back table preparation and D-HOPE and correlated to graft function and patient outcome. RESULTS: Median (IQR) MD and D-HOPE time was 228 (210, 245) and 116 (103, 143) min. Three grafts developed early allograft dysfunction (EAD), with one requiring retransplantation. During D-HOPE, MD glucose and lactate levels increased (ANOVA = 9.88 [p = 0.01] and 3.71 [p = 0.08]). Their 2nd-hour levels were higher in EAD group and positively correlated with L-GrAFT score. 2nd-hour MD glucose and lactate were also positively correlated with cold ischemia time, macrovesicular steatosis, weight gain during D-HOPE, and perfusate FMN. These correlations were not apparent when perfusate levels were considered. In contrast, MD FMN levels invariably dropped steeply after D-HOPE start, whereas perfusate FMN was higher in dysfunctioning grafts. CONCLUSION: MD glucose and lactate during D-HOPE are markers of hepatocellular injury and could represent additional elements of the viability assessment.

Brain Distribution of Drugs: Brain Morphology, Delivery Routes, and Species Differences.

Neuropharmacokinetics considers cerebral drug distribution as a critical process for central nervous system drug action as well as for drug penetration through the CNS barriers. Brain distribution of small molecules obeys classical rules of drug partition, permeability, binding to fluid proteins or tissue components, and tissue perfusion. The biodistribution of all drugs, including both small molecules and biologics, may also be influenced by specific brain properties related to brain anatomy and physiological barriers, fluid dynamics, and cellular and biochemical composition, each of which can exhibit significant interspecies differences. All of these properties contribute to select optimal dosing paradigms and routes of drug delivery to reach brain targets for classical small molecule drugs as well as for biologics. The importance of these properties for brain delivery and exposure also highlights the need for efficient new analytical technologies to more comprehensively investigate drug distribution in the CNS, a complex multi-compartmentalized organ system.

Monitoring of Indoor Farming of Lettuce Leaves for 16 Hours Using Electrical Impedance Spectroscopy (EIS) and Double-Shell Model (DSM).

An electrical impedance spectroscopy (EIS) experiment was performed using a double-shell electrical model to investigate the feasibility of detecting physiological changes in lettuce leaves over 16 h. Four lettuce plants were used, and the impedance spectra of the leaves were measured five times per plant every hour at frequencies of 500 Hz and 300 kHz. Estimated R-C parameters were computed, and the results show that the lettuce leaves closely fit the double-shell model (DSM). The average resistance ratios of R1 = 10.66R4 and R1 = 3.34R2 show high resistance in the extracellular fluid (ECF). A rapid increase in resistance (R1, R2, and R4) and a decrease in capacitance (C3 and C5) during water uptake were observed. In contrast, a gradual decrease in resistance and an increase in capacitance were observed while the LED light was on. Comparative studies of leaf physiology and electrical value changes support the idea that EIS is a great technique for the early monitoring of plant growth for crop production.

[Epidural photobiomodulation accelerates the drainage of brain interstitial fluid and its mechanism].

OBJECTIVE: To evaluate the effect of photobiomodulation (PBM) on the drainage of brain interstitial fluid (ISF) and to investigate the possible mechanism of the positive effect of PBM on Alzheimer's disease (AD). METHODS: Twenty-four SD male rats were randomly divided into PBM group (n=12), sham PBM group (n=6), and negative control group (n=6). According to the injection site of tracer, the PBM group was further divided into PBM-ipsilateral traced group (n=6) and PBM-contralateral traced group (n=6). Rats in the PBM group and the sham PBM group were exposed to the dura minimally invasively on the skull corresponding to the frontal cortical area reached by ISF drainage from caudate nucleus region. The PBM group was irradiated by using 630 nm red light (5-6 mW/cm2), following an irradiation of 5 min with a 2 min pause, and a total of 5 times; the sham PBM group was kept in the same position for the same time using the light without power. The negative control group was kept without any measure. After PBM, tracer was injected into caudate nucleus of each group. The changes of ISF drainage in caudate nucleus were observed according to the diffusion and distribution of tracer molecule by tracer-based magnetic resonance imaging, and the structural changes of brain extracellular space (ECS) were analyzed by diffusion rate in ECS-mapping (DECS-mapping) technique. Finally, parameters reflecting the structure of brain ECS and the drainage of ISF were obtained: volume fraction (α), tortuo-sity (λ), half-life (T1/2), and DECS. The differences of parameters among different groups were compared to analyze the effect of PBM on brain ECS and ISF. One-Way ANOVA post hoc tests and independent sample t test were used for statistical analysis. RESULTS: The parameters including T1/2, DECS, and λ were significantly different among the PBM-ipsilateral traced group, the PBM-contralateral traced group, and the sham PBM group (F=79.286, P < 0.001; F=13.458, P < 0.001; F=10.948, P=0.001), while there was no difference in the parameter α of brain ECS among the three groups (F=1.217, P=0.324). Compared with the sham PBM group and the PBM-contralateral traced group, the PBM-ipsilateral traced group had a significant decrease in the parameter T1/2 [(45.45±6.76) min vs. (76.01±3.44) min, P < 0.001; (45.45±6.76) min vs. (78.07±4.27) min, P < 0.001], representing a significant acceleration of ISF drainage; the PBM-ipsilateral traced group had a significant increase in the parameter DECS [(4.51±0.77)×10-4 mm2/s vs. (3.15±0.44)×10-4 mm2/s, P < 0.001; (4.51±0.77)×10-4 mm2/s vs. (3.01±0.38)×10-4 mm2/s, P < 0.001], representing a significantly increased molecular diffusion rate of in the brain ECS; the PBM-ipsilateral traced group had a significant decrease in the parameter λ (1.51±0.21 vs. 1.85±0.12, P=0.001; 1.51±0.21 vs. 1.89±0.11, P=0.001), representing a significant decrease in the degree of tortuosity in the brain ECS. CONCLUSION: PBM can regulate the brain ISF drainage actively, which may be one of the potential mechanisms of the effect of PBM therapy on AD. This study provides a new method for enhancing the brain function via ECS pathway.

Pre-loading large volume oral electrolytes: tracing fluid and ion fluxes in horses during rest, exercise and recovery.

KEY POINTS: Exercise results in rapid and large extracellular to intracellular fluid shifts, as well as significant sweating losses of water and ions. It is unknown whether ions within oral electrolyte supplements are taken up by muscle (and other soft tissues) and whether oral supplementation can effectively offset sweating losses. Pre-loading with 8 L of a balanced hypotonic electrolyte supplement attenuated extracellular fluid losses, increased exercise duration and increased sweating fluid and ion losses during submaximal exercise. Supplemented electrolytes appear in skeletal muscle within 1 h after administration. Electrolyte supplementation increased exercise performance, improved maintenance of extracellular fluid volumes, and attenuated body fluid losses while maintaining sweating rates. ABSTRACT: This study used radioactive sodium (24 Na) and potassium (42 K) in a balanced, hypotonic electrolyte supplement to trace their appearance in skeletal muscle, and also quantified extracellular and whole-body fluid and ion changes during electrolyte supplementation, exercise and recovery. In a randomized crossover design, 1 h after administration of 1 to 3 L of water or electrolyte supplement with 24 Na, horses were exercised at 35% VO2max to voluntary fatigue or, after administration of 8 L of water or electrolyte supplement with 42 K were exercised at 50% peak VO2 for 45 min (n = 4 in each trial). Pre-exercise electrolyte supplementation was associated with decreased loss of fluid and electrolytes from the extracellular fluid compartments during exercise and recovery compared with water alone. The improved fluid and ion balance during prolonged exercise was associated with increased exercise duration, despite continuing sweating losses of fluid and ions. Nasogastric administration of radiotracer 24 Na+ and 42 K+ showed rapid absorption into the blood with plasma levels peaking 45 min after administration, followed by distribution into the extracellular space and intracellular fluid of muscle within 1 h. Following exercise, virtually all Na+ remained within the extracellular compartment, while the majority of K+ underwent intracellular uptake by 2 h of recovery. It is concluded that pre-loading with a large volume, balanced electrolyte supplement helps maintain whole-body fluid and ion balance and support muscle function during periods of prolonged sweat ion losses.

Salt sensitivity of volume and blood pressure in a mouse with globally reduced ENaC γ-subunit expression.

The epithelial Na+ channel (ENaC) promotes the absorption of Na+ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding subunits of ENaC results in early postnatal mortality. Here, we present the initial characterization of a mouse with dramatically suppressed expression of the ENaC γ-subunit. We used this hypomorphic (γmt) allele to explore the importance of this subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ-subunit expression in γmt/mt mice was markedly suppressed in the kidney and lung, whereas electrolytes resembled those of littermate controls. Aldosterone levels in γmt/mt mice exceeded those seen in littermate controls. Quantitative magnetic resonance measurement of body composition revealed similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mt mice and controls. γmt/mt mice exhibited a more rapid decline in body water and lean tissue mass in response to a low-Na+ diet than the controls. Replacement of drinking water with 2% saline selectively and transiently increased body water and lean tissue mass in γmt/mt mice relative to the controls. Lower blood pressures were variably observed in γmt/mt mice on a high-salt diet compared with the controls. γmt/mt also exhibited reduced diurnal blood pressure variation, a "nondipping" phenotype, on a high-Na+ diet. Although ENaC in the renal tubules and colon works to prevent extracellular fluid volume depletion, our observations suggest that ENaC in other tissues may participate in regulating extracellular fluid volume and blood pressure.NEW & NOTEWORTHY A mouse with globally suppressed expression of the epithelial Na+ channel γ-subunit showed enhanced sensitivity to dietary salt, including a transient increase in total body fluid, reduced blood pressure, and reduced diurnal blood pressure variation when given a dietary NaCl challenge. These results point to a role for the epithelial Na+ channel in regulating body fluid and blood pressure beyond classical transepithelial Na+ transport mechanisms.

Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study.

BACKGROUND: Extracellular fluid volume (ECF) is independently associated with chronic kidney disease (CKD) progression and mortality in patients with CKD, but the prognostic value of the trajectory of ECF over time beyond that of baseline value is unknown. OBJECTIVES: To characterize ECF trajectory and evaluate its association with the risks of end-stage kidney disease (ESKD) and mortality. METHODS: From the prospective tricentric NephroTest cohort, we included 1588 patients with baseline measured glomerular filtration rate (mGFR) ≥15 mL min-1 /1.73 m2 and ECF measurement. ECF and GFR were measured repeatedly using the distribution volume and clearance of 51 Cr-EDTA, respectively. ESKD and mortality were traced through record linkage with the national registries. Adjusted shared random-effect joint models were used to analyse the association between the trajectory of ECF over time and the two competing outcomes. RESULTS: Patients were mean age 58.7 years, 66.7% men, mean mGFR of 43.6 ± 18.6 mL min-1 /1.73 m2 and mean ECF of 16.1 ± 3.6 L. Over a median follow-up of 5.3 [IQR: 3.0;7.4] years, ECF increased by 136 [95%CI 106;167] mL per year on average, whilst diuretic prescription and 24-hour urinary sodium excretion remained stable. ESKD occurred in 324 (20.4%) patients, and 185 (11.6%) patients died before ESKD. A higher current value of ECF was associated with increased hazards of ESKD (adjusted hazard ratio [aHR]: 1.12 [95%CI 1.06;1.18]; P < 0.001 per 1 L increase in ECF), and death before ESKD (aHR: 1.10 [95%CI 1.04;1.17]; P = 0.002). CONCLUSIONS: The current value of ECF was associated with the risks of ESKD and mortality, independent of multiple potential confounders, including kidney function decline. This highlights the need for a close monitoring and adjustment of treatment to avoid fluid overload in CKD patients.

Differential assessment of fluid compartments by bioimpedance in pediatric patients with kidney diseases.

BACKGROUND: The kidney is central for maintaining water balance. As a corollary, patients with impaired kidney function are prone to pathological fluid volumes. Total body water (TBW) is distributed between the extracellular (ECW) and intracellular fluid compartments (ICW). In clinical practice, the judgment of hydration status does not allow to distinguish between ECW and ICW. Here, we evaluate the hydration status in children with chronic kidney disease by analyzing TBW, ECW, and ICW. METHODS: Hydration was quantified using whole-body bioimpedance spectroscopy (BCM) in 128 outpatients (1-25 years, 52 girls). Forty-two were transplanted (TPL), 43 suffered from chronic kidney disease without kidney replacement therapy (CKD), 21 were on peritoneal dialysis (PD), and 22 on hemodialysis (HD). HD patients were investigated before, after, and sequentially during dialysis. RESULTS: The ECW and ICW values obtained by BCM were of the same magnitude as those from the literature using isotope dilution. When compared with a healthy control group, TBW was increased in 9 TPL, 9 CKD, 1 PD, and 11 HD patients before but in none after dialysis. The decline of overhydration during dialysis (p < 0.001, n = 22) correlated with the change in body weight (R2 = 0.62). The kinetics of fluid compartment changes assessed twice in six HD patients revealed a reproducible linear decay of the ECW/ICW ratio due to an increase of ICW and a decrease of ECW. CONCLUSION: BCM quantifies TBW and acute changes of ECW and ICW in children with chronic kidney failure. The clinical utility of measuring TBW, ECW, and ICW should be defined in the future.

Carbohydrate hastens hypervolemia achieved through ingestion of aqueous sodium solution in resting euhydrated humans.

PURPOSE: Ingesting beverages containing a high concentration of sodium under euhydrated conditions induces hypervolemia. Because carbohydrate can enhance interstitial fluid absorption via the sodium-glucose cotransporter and insulin-dependent renal sodium reabsorption, adding carbohydrate to high-sodium beverages may augment the hypervolemic response. METHODS: To test this hypothesis, we had nine healthy young males ingest 1087 ± 82 mL (16-17 mL per kg body weight) of water or aqueous solution containing 0.7% NaCl, 0.7% NaCl + 6% dextrin, 0.9% NaCl, or 0.9% NaCl + 6% dextrin under euhydrated conditions. Each drink was divided into six equal volumes and ingested at 10-min intervals. During each trial, participants remained resting for 150 min. Measurements were made at baseline and every 30 min thereafter. RESULTS: Plasma osmolality decreased with water ingestion (P ≤ 0.023), which increased urine volume such that there was no elevation in plasma volume from baseline (P ≥ 0.059). The reduction in plasma osmolality did not occur with ingestion of solution containing 0.7% or 0.9% NaCl (P ≥ 0.051). Consequently, urine volume was 176-288 mL smaller than after water ingestion and resulted in plasma volume expansion at 60 min and later times (P ≤ 0.042). In addition, net fluid balance was 211-329 mL greater than after water ingestion (P ≤ 0.028). Adding 6% dextrin to 0.7% or 0.9% NaCl solution resulted in plasma volume expansion within as little as 30 min (P ≤ 0.026), though the magnitudes of the increases in plasma volume were unaffected (P ≥ 0.148). CONCLUSION: Dextrin mediates an earlier hypervolemic response associated with ingestion of high-sodium solution in resting euhydrated young men. (247/250 words).

Relationship of Central Venous Pressure to Body Fluid Volume Status and Its Prognostic Implication in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Although central venous pressure (CVP) is a surrogate measure of preload in patients with acute decompensated heart failure (ADHF), it is a multifactorial index influenced not only by fluid volume status, but also by cardiac pump function and other factors. We aimed to elucidate the individual pathophysiological factors of CVP elevation in patients with ADHF by assessing the relationship between CVP and extracellular fluid volume status (EVS). METHODS AND RESULTS: We quantified EVS in 100 patients with ADHF with the use of bioelectrical impedance analysis. CVP was also measured at the same time point. Subjects were categorized into tertiles according to their CVP-EVS ratios, and patient characteristics and clinical outcomes were compared among these tertiles. The upper-tertile group had a higher incidence of impaired right ventricular pump function, whereas the lower-tertile group had higher incidences of severe inflammation, hypoalbuminemia, and renal dysfunction. Patients in both the upper and lower tertiles had a significantly higher cardiac event rate than those in the middle tertile. CONCLUSIONS: The combined assessment of CVP and EVS provides insight into both the total volume status and distribution of body fluid in ADHF patients, and it may have applications in guiding decongestive therapy and improving prognostic predictions.

The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions.

PURPOSE: We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF). METHODS: The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF. The model includes the distribution of unbound drug within blood plasma, coupled with the distribution of drug within brain ECF and incorporates brain capillaryblood flow, passive paracellular and transcellular BBB transport, active BBB transport, brain ECF diffusion, brain ECF bulk flow, and specific and nonspecific brain tissue binding. All of these processes may change under disease conditions. RESULTS: We show that the simulated disease-induced changes in brain tissue characteristics significantly affect drug concentrations within the brain ECF. CONCLUSIONS: We demonstrate that the 3D brain unit network model is an excellent tool to gain understanding in the interdependencies of the factors governing spatial-temporal drug concentrations within the brain ECF. Additionally, the model helps in predicting the spatial-temporal brain ECF concentrations of existing drugs, under both normal and disease conditions.