Extracellular Fluid Compartment Research Articles

Comparison of Venous Blood Gas and Biochemical Parameters in Sunda Pangolin (Manis javanica) and Chinese Pangolin (Manis pentadactyla) before and after Isoflurane Anesthesia

Venous blood gas analytes are commonly examined in animals, and the results may be important when evaluating the overall health status of an animal. Pangolins are critically endangered mammals, and there is limited information on their physiological reference values in the literature. The aim of this study was to analyze venous blood gas and biochemical parameters before and during isoflurane anesthesia in wild healthy Sunda and Chinese pangolins. The results obtained showed that the blood gas index trends of the two pangolin species before and after isoflurane anesthesia were the same. After anesthesia, the partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), total carbon dioxide (CO2), mean blood bicarbonate (HCO3-), extracellular fluid compartment (BEecf) base excess and the mean blood glucose (Glu) levels of both pangolin species showed a significant increase compared to the pre-anesthesia period. In contrast, the mean blood potassium (K+), lactate (Lac) and mean blood pH levels were significantly lower. No significant differences in the mean blood sodium (Na+) or blood ionized calcium (iCa) levels were observed during anesthesia. This study is important for future comparisons and understanding the health status of this endangered species.

EBNEO commentary: Fluid balance as a critical factor in neonatal outcomes.

With this study, Starr and colleagues add to the growing body of literature recognising the importance of fluid status in neonates.1-3 Utilising the weight-change method for estimating fluid balance, which is the preferred method in neonates,4 they found that fluid balance is independently associated with the need for mechanical ventilation at post-natal day 14 and the composite outcome of severe bronchopulmonary dysplasia (BPD) or death. All neonates undergo a period of adaptation of fluid and electrolyte homeostasis after birth, with a contraction of the extracellular fluid (ECF) compartment, driven by natriuretic diuresis and transepidermal losses in preterm infants. This phase ends with maximum weight loss or negative fluid balance.5 Very low birth weight and extremely low birth weight infants can experience 10%–15% negative fluid balance, with this phase lasting up to 8 days.5, 6 Clinicians should allow for ECF contraction while maintaining intravascular fluid volume, achieving a negative sodium balance, maintaining normal serum electrolyte levels and providing sufficient calories to meet maintenance needs.5, 6 Achieving this requires close monitoring of daily intake and output, weight changes and electrolyte concentrations, while thoughtfully adjusting prescribed fluid intake. In the same patient cohort as the present study, Valentine and colleagues analysed weight loss and fluid administration.7 They found that a maximum weight loss of 5–15% within the first post-natal week was associated with decreased odds of developing necrotising enterocolitis (NEC), while an average total fluid administration of >150 mL/kg BW/day over the first post-natal week was associated with increased risk of NEC and patent ductus arteriosus (PDA) requiring surgery. They suggested cautious limitation of total fluid administration and allowing for moderate weight loss in the first post-natal week.7 A 2014 Cochrane review recommended careful restriction of fluid intake in preterm neonates to meet physiological needs without causing dehydration rather than a practice of liberal fluid intake, citing that restricted fluid intake significantly reduced the risks of PDA and NEC, with trends towards reduced risk of BPD, intra-ventricular haemorrhage and death.8 No discussion about fluid status is complete without addressing electrolytes, specifically sodium. Dysnatremias are common in critically ill patients and are associated with mortality and hospital length of stay.9 Preterm infants are at particular risk for dysnatremias given immature renal tubules, fluid shifts, insensible losses and exposure to parenteral nutrition. In an analysis of a contemporary large neonatal cohort, dysnatremias were common in the first week of life, occurring in half of the cohort.9 In adjusted models, the occurrence of hypernatremia and combined hypo- and hypernatremia in the first week of life was associated with an increased risk of mortality in neonates with normal renal function.9 Weight changes, fluid intake, electrolyte status—this is quite the fine balance. When does physiologic weight loss become pathologic? Clearly, there are many variables and outcomes to consider. Starr and colleagues provide potential targets for this complex problem. In efforts to reduce rates of BPD and other neonatal morbidities, fluid balance is emerging as a critical factor. URL LINK: https://ebneo.org/ebneo-commentary-fluid-balance-and-neonatal-outcomes/ None. None.

The relationship between amniotic fluid index and accuracy of sonographic estimated fetal weight

Background: Ultrasound is the gold standard in evaluation of amniotic fluid volume and diagnosis of volume disorders as oligohydramnios and polyhydramnios. While the amniotic fluid may be thought of as an expansion of the foetus extracellular fluid compartment during the first two trimesters of pregnancy, most amniotic fluid is actually produced during the third trimester due to foetal micturition. We hypothesised a link between the amniotic fluid indexes (AFI) and estimated foetal weight (EFW), which might suggest that EFW be considered in amniotic fluid evaluation.Methods: This cross-sectional study was conducted on 75 pregnant cases (Age was >18 years) and carrying singleton pregnancy with GA from 18 weeks to 40 weeks (GA evaluation was based on menstrual history & early US assessment) for 1 year. All participants underwent full history taking, abdominal ultrasonography examination and assessment of amniotic fluid index.Results: The majority of included pregnancies showed cephalic presentation of the fetus. The overall AFI ranged from 2 to 30 cm, with a mean value of 17.2 (SD, 7.4) cm and a median value of 18 (IQR, 11) cm. The majority of included pregnancies showed a normal BPP. There was no significant association between AFI and EFW for all categories of gestational age, except in the 27 29 week’s group.Conclusions: The AFI and EFW numbers found in this research fell within a certain range. Nevertheless, these variables showed no statistically meaningful correlation with one another. Inferring from that, it seems unlikely that either measure is worth focusing on when the other is subject to fluctuation.

A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls.

Maintaining normal potassium (K+) concentrations in the extra- and intracellular fluid is critical for cell function. K+ homeostasis is achieved by ensuring proper distribution between extra- and intracellular fluid compartments and by matching K+ excretion with intake. The Na+-K+-ATPase pump facilitates K+ uptake into the skeletal muscle, where most K+ is stored. Na+-K+-ATPase activity is stimulated by insulin and aldosterone. The kidneys regulate long term K+ homeostasis by controlling the amount of K+ excreted through urine. Renal handling of K+ is mediated by a number of regulatory mechanisms, including an aldosterone-mediated feedback control, in which high extracellular K+ concentration stimulates aldosterone secretion, which enhances urine K+ excretion, and a gastrointestinal feedforward control mechanism, in which dietary K+ intake increases K+ excretion. Recently, a muscle-kidney cross talk signal has been hypothesized, where the K+ concentration in skeletal muscle cells directly affects urine K+ excretion without changes in extracellular K+ concentration. To understand how these mechanisms coordinate under different K+ challenges, we have developed a compartmental model of whole-body K+ regulation. The model represents the intra- and extracellular fluid compartments in a human (male) as well as a detailed kidney compartment. We included (i) the gastrointestinal feedforward control mechanism, (ii) the effect of insulin and (iii) aldosterone on Na+-K+-ATPase K+ uptake, and (iv) aldosterone stimulation of renal K+ secretion. We used this model to investigate the impact of regulatory mechanisms on K+ homeostasis. Model predictions showed how the regulatory mechanisms synthesize to ensure that the extra- and intracelluller fluid K+ concentrations remain in normal range in times of K+ loading and fasting. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, the model was unable to predict a return to normal extracellular K+ concentration after a period of high K+ loading or depletion.

Multiscale engineered human skeletal muscles with perfusable vasculature and microvascular network recapitulating the fluid compartments

Creating a vasculature in engineered human skeletal muscle tissues (ehSMTs) enables us to create thick tissues, increase cell survival in implantation, provide models of blood-organ barriers for drug testing, and enhance muscle differentiation through paracrine signaling. Here, contractile ehSMTs with a central perfusable vascular channel and microvascular networks growing from this central vasculature into the surrounding skeletal muscle tissue were newly demonstrated. Because coculturing muscle cells and endothelial cells requires incompatible media, we recapitulated the in vivo extracellular fluid compartments between blood plasma and interstitial fluid by creating an in vitro perfusable vasculature running through skeletal muscle tissue with a physiologic cell density. By using this model, we constructed large vascularized ehSMTs and showed the potential to be utilized for drug testing platforms. Also, we found that coculturing with two separate media from an early stage of muscle differentiation led to increased contractile force, thicker myotubes, and improved muscle differentiation.

Multiple-Vessel-Based Blood Gas Profiles Analysis Revealed the Potential of Blood Oxygen in Mammary Vein as Indicator of Mammary Gland Health Risk of High-Yielding Dairy Cows.

Simple SummaryThe objective of the study was to realize the function of blood gas parameter in relation to the health of high-yielding dairy cows. The study showed that most blood gas parameters differ across the three vessels (coccygeal artery, coccygeal vein, and mammary vein). The associations of oxygen-related variables in the mammary vein are negatively correlated with the levels of malondialdehyde, lactate dehydrogenase, and plasmin in the milk. In the present study, we used blood gas profile to identify the mammary gland health condition in lactating dairy cows.The blood gas profile is a routine method in the rapid disease diagnosis of farm animals, yet its potential in evaluating mammary health status of dairy cows remains to be investigated. This study was conducted to learn the potential of the blood gas parameter regarding the mammary gland health status in lactating dairy cows. Twenty animals were divided into two groups, the H-SCC group (milk SCC > 122 k/mL) and L-SCC group (milk SCC < 73.8 k/mL), to compare blood gas profiles from different blood vessels and to identify the key parameters associated with milk somatic cell count. H-SCC cows are higher in malondialdehyde content, but lower in SOD and T-AOC activities in the milk, compared to the L-SCC group. In terms of blood gas parameters, most differ across the three vessels, including K+, CO2 pressure, O2 pressure, HCO3−, base excess in the extracellular fluid compartment, and saturation of O2. The Pearson correlation analysis showed that oxygen-related variables in the mammary vein, including oxygen concentrations, O2 pressure, and saturation of O2, are negatively correlated with levels of malondialdehyde, lactate dehydrogenase, and plasmin in the milk. Our study revealed that oxygen-related variables in the mammary vein can be a marker in suggesting mammary-gland health status in high-yielding cows.

The Wright Variation of the Darrow‐Yannet Diagram: A New Tool to Teach Water Homeostasis

PurposeTo introduce an expanded version of the Darrow‐Yannet (D‐Y) diagram that can both improve basic understanding of water balance homeostasis and be more specifically applied to specific organ system topics (e.g., gastrointestinal secretion) than can the basic diagram.Introduction and hypothesisSince 1935, the Darrow‐Yannet diagram has been used to teach both water balance and homeostasis. Six models of ECF volume expansion or contraction of hypertonic, isotonic, or hypotonic fluid with subsequent water transfer to or from ICF show how ECF and ICF remain in balance. Yet when osmosis is used later in both gastrointestinal and renal physiology to describe movement of water from spaces that are technically outside the body into or out of part of the extracellular fluid compartment, students sometimes struggle with the concept of osmosis (water diffusion between compartments) not from ECF to ICF but from ECF to OB and back. They must also consider that through both structural characteristics of the epithelium and the autonomic and hormonal control of epithelium function, this water transfer can be considerably modified or even prevented. Because the classic D‐Y has no OB in its illustrations, it cannot be used to show either of these aspects of water balance. The question therefore arose, is there some way to expand the D‐Y diagram to show both, and emphasize other aspects of homeostasis too? The author hypothesized that it could be done.ResultIn the Wright variation of the D‐Y diagram, two changes are made to expand the D‐Y diagram and increase its usefulness. First, an OB compartment of open volume is introduced on the one side of the ECF while keeping ICF on the other side as usual. Second, the epithelial layer between OB and ECF is artificially widened so that it is both more easily visualized and potentially drawn with two cell populations (e.g., secretory vs. absorptive cells lining the duodenal lumen). Though volume is undefined in the OB compartment, osmolarity is defined, ranging from zero (pure water) to immeasurably high (dry), so osmotic OB‐to‐ECF gradients can be seen. Using control of the epithelium to determine whether fluid flows through or not regardless of gradient, nervous and hormonal control of water homeostasis can be shown. Finally, not just water movement but hormonal‐ or autonomic‐controlled ion movement across the epithelium can be graphically shown, showing off an important aspect of homeostasis. Loss of control of these ion movements (e.g., in GI secretory cells in cholera) can also be demonstrated, along with its pathophysiological effect.ConclusionAn expanded D‐Y diagram with an artificially emphasized epithelial layer between an outside‐the‐body (OB) compartment and the extracellular fluid (ECF) has the potential to better illustrate the epithelium’s possible control in expanding or contracting ECF volume prior to ICF change than can a D‐Y diagram alone, both in health and disease.

Conservation of a flagship species: Health assessment of the pink land iguana, Conolophus marthae.

The pink land iguana, Conolophus marthae, is one of four species of iguanas (three terrestrial and one marine) in the Galápagos Islands, and the only one listed as critically endangered by the IUCN. The species can only be found on the north-west slopes of the highest volcano on Isabela Island and was first described to science in 2009. As part of a population telemetry study, a health assessment was authorized by the Galápagos National Park. Wild adult iguanas were captured on Wolf Volcano in September 2019 and April 2021 to record morphological and physiological parameters including body temperature, heart rate, intraocular pressures, tear formation, and infrared iris images. Blood samples were also collected and analyzed. An i-STAT portable blood analyzer was used to obtain values for base excess in the extracellular fluid compartment (BEecf), glucose (Glu), hematocrit (HctPCV), hemoglobin (Hb), ionized calcium (iCa), partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), percent oxygen saturation (sO2%), pH, potassium (K), and sodium (Na). When possible, data were compared to previously published and available data for the other Galápagos iguanas. The results reported here provide baseline values that will be useful in detecting changes in health status among pink land iguanas affected by climate change, invasive species, anthropogenic threats, or natural disturbances. The collected data also provide an invaluable resource for conservation scientists planning to implement conservation strategies, like translocations, that may temporarily alter these baseline values.

Skin Sodium and Blood Pressure Regulation.

Hypertension is a major public health concern due to its high prevalence and increased risk of cardiovascular disease and mortality. Complex traits resulting from both genetic and environmental factors affect the development of hypertension. Among environmental factors, a high salt diet is an important cause for hypertension. Humans show a heterogeneous blood pressure (BP) response to sodium intake. Although the precise mechanisms for the association between salt sensitivity and hypertension have not been fully elucidated, renal sodium handling has been considered to play a pivotal role. However, this conventional view has recently been challenged in that a third compartment, namely, skin may have a role in the regulation of sodium homeostasis. Skin is comprised of a significant portion of interstitium, which is a major extracellular fluid compartment, and its complex capillary network regulates body temperature and skin perfusion. Growing evidence indicates that local regulatory action of cutaneous blood flow as well as salt and water metabolism is associated with systemic BP control. Previous experimental studies have shown that dietary salt loading resulted in nonosmotic sodium accumulation via glycosaminoglycans and lymphatics embedded in the skin that were mediated by several endogenous factors and attenuated an increase in BP. Studies in humans have also suggested that the skin serves as a buffer system for sodium storage and that skin sodium contributes to salt sensitivity and hypertension. Thus, skin sodium storage provides the possibility of being an additional buffering system in response to salt loading and concomitant BP changes in humans.

Use of cardiac troponin I (cTnI) levels to diagnose severe hypoxia and myocardial injury induced by perinatal asphyxia in neonatal dogs

Prolonged perinatal asphyxia and subsequent severe hypoxia are the main causes of mortality in neonatal dogs in the first days of life. In medicine, specific cardiac biochemical markers, such as troponin I, are used to diagnose ischemic and nonischemic myocardial injury in asphyxiated newborns after birth. Thus, the objectives of this study were to compare the levels of cardiac troponin I (cTnI) between asphyxiated and nonasphyxiated newborn dogs and evaluate the correlations of cTnI levels with the modified Apgar score, the levels of oxygen saturation, blood glucose, and lactatemia, and blood gas parameters. This study aimed to determine the possible use of cTnI as a marker of severe hypoxia and myocardial ischemic injury in neonatal dogs. Fifteen animals in a eutocic vaginal delivery group (VG), 15 animals in a cesarean section group (CG), and 13 animals in a hypoxia (asphyxiated) group (HG) were evaluated. The animals in the asphyxiated group were from dystocic deliveries and born by vaginal delivery or cesarean section. All groups were evaluated at birth and after 60 min. The newborns in the VG and CG exhibited mixed acidosis (respiratory acidosis due to increased partial pressure of CO2 (pCO2) and metabolic acidosis due to reduced pH and bicarbonate (HCO3) levels, base excess/deficit in the extracellular fluid compartment (BEecf), and increased lactate levels) due to transient physiological hypoxemia at birth. The cTnI levels in the VG and CG were within the reference standards for healthy dogs. No correlations between cTnI level and the other parameters were observed in the VG and CG. Newborns in the HG exhibited prominent mixed acidosis (p < 0.05) due to severe hypoxemia. The Apgar score and blood gas parameters showed that these dogs were born asphyxiated, and they presented low vitality and the need for resuscitation maneuvers. The cTnI levels in the HG were significantly higher than those in the VG and CG (p < 0.05) and above the reference standards for healthy dogs, which indicated ischemic myocardial injury. The cTnI level was negatively correlated (p < 0.05) with the parameters Apgar score, heart rate, peripheral oxygen saturation (sO2) level, reflex score, and total carbon dioxide (TCO2) level and positively correlated (p < 0.01) with lactate level. This study showed that asphyxiated newborn dogs have higher serum cTnI levels than nonasphyxiated newborn dogs; thus, the cTnI can be used as a marker of severe hypoxia and ischemic myocardial damage in newborn dogs.

Стан водних секторів у жінок із прееклампсією в перипартальному періоді

Актуальність. Прееклампсія у вагітних є загрозливим станом, що зумовлює значні порушення водного балансу, формує гіпергідратацію позаклітинного сектора. Це обумовлено основними патогенетичними ланками — ендотеліальною дисфункцією та подальшим розвитком гіпопротеїнемії. Підтвердити дані зміни можливо методом визначення показників об’ємів водних секторів організму. Мета: дослідити вплив стандартної інтенсивної терапії на показники водних секторів організму в породіль із прееклампсією середнього та тяжкого ступенів. Матеріали та методи. Обстежені 90 жінок, включених у три групи: здорові невагітні жінки, вагітні жінки з неускладненим перебігом вагітності та жінки з прееклампсією середнього та тяжкого ступенів. Методом неінвазивної біоімпедансометрії визначали показники водних секторів організму. Результати. Вагітність, ускладнена прееклампсією, у терміні 34–40 тижнів супроводжується зростанням загального об’єму рідини за рахунок збільшення як позаклітинного, так і внутрішньоклітинного водних секторів організму, але з перевагою позаклітинного сектора. До 7-ї доби післяпологового періоду формується тенденція до зниження загального об’єму рідини, але зберігаються набряк інтерстицію та внутрішньоклітинний набряк. Висновки. Результати біоімпедансного аналізу водних секторів свідчать про необхідність залучення додаткових методів лікування для корекції водних секторів організму в породіль із прееклампсією.

CGRP outflow into jugular blood and cerebrospinal fluid and permeance for CGRP of rat dura mater

BackgroundCalcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks. Increased CGRP levels have been observed in different extracellular fluid compartments during primary headaches such as migraine but it is not entirely clear how CGRP is drained from the meninges.MethodsWe have used an in vivo preparation of the rat to examine after which time and at which concentration CGRP applied onto the exposed parietal dura mater appears in the jugular venous blood and the cerebrospinal fluid (CSF) collected from the cisterna magna. Recordings of meningeal (dural) and cortical (pial) blood flow were used to monitor the vasodilatory effect of CGRP. In a new ex vivo preparation we examined how much of a defined CGRP concentration applied to the arachnoidal side penetrates the dura. CGRP concentrations were determined with an approved enzyme immunoassay.ResultsCGRP levels in the jugular plasma in vivo were slightly elevated compared to baseline values 5-20 min after dural application of CGRP (10 μM), in the CSF a significant three-fold increase was seen after 35 min. Meningeal but not cortical blood flow showed significant increases. The spontaneous CGRP release from the dura mater ex vivo was above the applied low concentration of 1 pM. CGRP at 1 nM did only partly penetrate the dura.ConclusionsWe conclude that only a small fraction of CGRP applied onto the dura mater reaches the jugular blood and, in a delayed manner, also the CSF. The dura mater may constitute a barrier for CGRP and limits diffusion into the CSF of the subarachnoidal space, where the CGRP concentration is too low to cause vasodilatation.

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

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 8L 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 1h after administration. Electrolyte supplementation increased exercise performance, improved maintenance of extracellular fluid volumes, and attenuated body fluid losses while maintaining sweating rates. 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, 1h after administration of 1 to 3L of water or electrolyte supplement with 24 Na, horses were exercised at 35% VO2max to voluntary fatigue or, after administration of 8L 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 45min after administration, followed by distribution into the extracellular space and intracellular fluid of muscle within 1h. Following exercise, virtually all Na+ remained within the extracellular compartment, while the majority of K+ underwent intracellular uptake by 2h 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.

Combination of DXA and BIS Predicts Jump Power Better Than Traditional Measures of Sarcopenia.

ABSTRACTTraditional diagnostic criteria for sarcopenia use dual‐energy X‐ray absorptiometry (DXA)‐measured appendicular lean mass (ALM), normalized to height (ALM/ht2) or body mass index (ALM/BMI) to define low muscle mass. However, muscle function declines with aging before the loss of muscle mass is detected by ALM. This is likely due, in part, to qualitative muscle changes such as extracellular and intracellular fluid compartment shifts uncaptured by DXA. We propose combining bioimpedance spectroscopy (BIS), which estimates extracellular and intracellular compartment volume, with DXA to more accurately predict muscle function. This combination may help incorporate muscle quality, thereby improving sarcopenia diagnosis. We cross‐sectionally analyzed data from 248 Black and White participants aged 25 to 75 years from the Midlife in the United States Refresher Cohort. We proposed two novel muscle measures: ALM corrected by the BIS‐derived whole‐body extracellular to intracellular fluid ratio (E/I) and leg lean mass (LLM) corrected by leg‐specific E/I, creating (ALM/(E/I)W) and (LLM/(E/I)L), respectively. We compared the associations of traditional muscle measures, ALM/(E/I)W, and LLM/(E/I)L, with grip strength and lower limb power using jumping mechanography. LLM/(E/I)L explained jump power best at R 2 = 0.803 compared with ALM/(E/I)W (p < 0.0001) and all other measures. ALM/(E/I)W explained jump power second best (R 2 = 0.759) but not significantly better than traditional muscle measures. No muscle measure performed better than covariates when predicting handgrip strength. LLM/(E/I)L outperformed ALM/ht2 and ALM/BMI when predicting jump power. We propose LLM/(E/I)L is a powerful and clinically relevant method that accounts for muscle quality. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug’s physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.

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

BackgroundThe 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.MethodsHydration 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.ResultsThe 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.ConclusionBCM 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.

Mechanisms of Acid-Base Kinetics During Hemodialysis: a Mathematical-Model Study.

This study contrasts the abilities and mechanisms of two physicochemical, mathematical models to predict experimental bicarbonate kinetics, hence, buffer transport, during a hemodialysis (HD) treatment in chronic renal failure patients. The existing Sargent model assumes that the body fluids can be described as a single, homogeneous extracellular fluid (EC) compartment whose volume decreases because of a constant ultrafiltration rate during HD. Bicarbonate and acetate transport between HD fluid and the EC compartment are by convection and diffusion with acetate metabolized in that compartment. The new model formulated in this study assumes the same conditions as Sargent et al., but constrains ion concentrations in the EC to be electrically neutral at all times. This constraint requires inclusion in the EC of other transportable small ions, Na+, K+, Cl- and unidentified, anionic organic acids in addition to an electrical charge on impermeable albumin. The findings are that the new electroneutrality model predicts plasma bicarbonate-concentration kinetics as closely as the Sargent model, but bicarbonate transport is an unlikely mechanism. Rather, the findings are better explained by rapid interconversion of CO2 and bicarbonate in this simplified EC compartment model. The results of this study bring into question the ability of the Sargent et al. hypothesized H+-mobilization model to explain buffer-transport kinetics during HD.

Probenecid Increases the Concentration of 7-Chlorokynurenic Acid Derived from the Prodrug 4-Chlorokynurenine within the Prefrontal Cortex.

Recent advances in the understanding of depression have led to increasing interest in ketamine and the role that N-methyl-d-aspartate (NMDA) receptor inhibition plays in depression. l-4-Chlorokynurenine (4-Cl-KYN, AV-101), a prodrug, has shown promise as an antidepressant in preclinical studies, but this promise has not been realized in recent clinical trials. We sought to determine if transporters in the CNS could be playing a role in this clinical response. We used radiolabeled uptake assays and microdialysis studies to determine how 4-Cl-KYN and its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA), cross the blood-brain barrier (BBB) to access the brain and its extracellular fluid compartment. Our data indicates that 4-Cl-KYN crosses the blood-brain barrier via the amino acid transporter LAT1 (SLC7A5) after which the 7-Cl-KYNA metabolite leaves the brain extracellular fluid via probenecid-sensitive organic anion transporters OAT1/3 (SLC22A6 and SLC22A8) and MRP4 (ABCC4). Microdialysis studies further validated our in vitro data, indicating that probenecid may be used to boost the bioavailability of 7-Cl-KYNA. Indeed, we found that coadministration of 4-Cl-KYN with probenecid caused a dose-dependent increase by as much as an 885-fold increase in 7-Cl-KYNA concentration in the prefrontal cortex. In summary, our data show that 4-Cl-KYN crosses the BBB using LAT1, while its active metabolite, 7-Cl-KYNA, is rapidly transported out of the brain via OAT1/3 and MRP4. We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect.

Disorders of Acid-Base and Potassium Balance

Water accounts for approximately half of an adult human's body weight. Two thirds of body water is intracellular, and the remaining one third is contained in the extracellular fluid compartment, which includes intravascular (plasma) and interstitial fluid. Small amounts of water are also contained in bone, dense connective tissue, digestive secretions, and cerebrospinal fluid. To maintain stability of the internal milieu, body fluids are processed by the kidney, guided by intricate physiologic control systems that regulate fluid volume and composition. This chapter reviews the principles of body fluid hemostasis and discusses disorders of water excess (hyponatremia), water deficiency (hypernatremia), water conservation (diabetes insipidus), saltwater excess (edematous states), and saltwater deficiency (volume depletion). Figures illustrate the relation between the plasma hydrogen ion concentration and the blood pH, proximal tubular bicarbonate reabsorption, renal secretion of hydrogen ions, renal glutamine metabolism and ammonia diffusion, metabolic alkalosis, and the electrocardiographic changes in and approach to causes of hypokalemia and hyperkalemia. Tables describe causes of metabolic acidosis with a high and a normal ion gap; causes of type 1 renal tubular acidosis; causes of type 4 renal tubular acidosis and aldosterone resistance; causes of metabolic alkalosis, respiratory acidosis, and respiratory alkalosis; evaluation of the renal defect in hyperkalemia; and treatment of hyperkalemia. This chapter contains 10 figures, 12 tables, and 53 references.

Identification of Volume of Distribution for 239Pu in Rats.

The work within identifies the volume of distribution (VD) of plutonium using data from studies in which rats were administered an intravenous bolus injection of 239Pu4+-citrate. The research investigated two separate datasets. Data published by Durbin and colleagues in "Plutonium Deposition Kinetics in Rats" and studies conducted by Lovelace Respiratory Research Institute (LRRI) were examined. The goal of this research was to identify a value of VD consistent with the known biological behavior of plutonium. The identified VD is necessary to develop a physiologically-based pharmacokinetic (PBPK) model. The creation of a PBPK model describing the behavior of plutonium in the body enables the comparison of transfer rates to validate the biokinetic models currently in use for internal dosimetry purposes. The VD of a substance describes the distribution between intracellular and extracellular fluid compartments, providing information such as cellular uptake and protein binding. The VD time profiles and values found using the Durbin data were consistent with known behavior of plutonium. The VD values found using data provided by LRRI were not consistent with known behavior of plutonium; however, the VD time profiles generated may still be of use for PBPK modeling.