The study, conducted at Massey University and published in Frontiers in Veterinary Science, set out to answer a question that has divided researchers for years. Does a rapid surge of intravenous fluid damage the endothelial glycocalyx, or does the protective layer simply shrug it off? The answer, at least in healthy cats, appears to be the latter, but with a twist that the researchers did not fully anticipate. Rather than the fluid itself, it was the anesthesia used during the experiment that seemed to leave the most visible mark on this microscopic barrier.

Volume overload, the excessive accumulation of fluid within the blood vessels, is a well-recognized danger in both human and veterinary medicine. It can arise when clinicians administer intravenous fluids too aggressively, particularly in critically ill patients whose bodies have lost the capacity to compensate. The consequences are serious: fluid leaks into surrounding tissues, causing swelling and edema, oxygen delivery to cells becomes impaired, and in severe cases, multiple organs begin to fail. Previous research has suggested a specific mechanism behind this damage. When the heart detects increased blood volume, it releases hormones called natriuretic peptides, which trigger the kidneys to excrete more sodium and water. But these same hormones also appear to increase the permeability of blood vessels, potentially by stripping away or degrading the endothelial glycocalyx, the very layer that normally keeps fluid where it belongs.

Cats were chosen for this study for compelling reasons. Their blood volume is proportionally smaller than that of dogs or humans, making them inherently more vulnerable to fluid overload. They also have a high incidence of silent heart disease, which further limits their ability to cope with sudden volume changes, and they eliminate fluids more slowly than many other species. These factors combine to make cats a particularly sensitive model for studying what happens when the vascular system is pushed beyond its normal capacity.

To peer inside the microscopic world of the glycocalyx, the researchers employed a technique called sidestream dark field videomicroscopy, paired with specialized software known as GlycoCheck. The method works by illuminating the blood vessels of the sublingual mucosa, the thin tissue beneath the tongue, with green light at a wavelength of 540 nanometers. This light is absorbed by the hemoglobin inside red blood cells, causing the vessels to appear as dark channels against a bright background. The software then tracks the movement of red blood cells within these vessels, measuring how far they penetrate toward the vessel wall. The key measurement is called the perfused boundary region, or PBR. It represents the gap between the edge of the red blood cell column and the actual vessel wall, and it serves as an inverse estimate of glycocalyx thickness. A higher PBR means the glycocalyx is thinner and potentially damaged, while a lower PBR indicates a thicker, healthier layer.

Twenty healthy research cats were enrolled in the study, each thoroughly screened for underlying disease through bloodwork, physical examination, and cardiac ultrasound. The cats were randomly assigned to receive either a rapid infusion of Hartmann’s solution, a balanced crystalloid fluid, at a dose of 30 milliliters per kilogram of body weight over just 10 minutes, or no fluids at all. After a seven-day washout period, each cat received the opposite treatment, allowing every animal to serve as its own control. The researchers captured images at four time points: before the intervention, immediately after, three hours later, and again at 24 hours. All measurements were performed while the cats were anesthetized with propofol, a commonly used intravenous anesthetic agent.

The results were unexpected. The perfused boundary region did increase over time in both groups, reaching statistical significance at the three-hour mark for vessels measuring between 5 and 25 micrometers in diameter. But critically, this increase occurred in both the fluid-treated and control groups, meaning it could not be attributed to the volume overload itself. Instead, the researchers concluded that the anesthesia, rather than the fluid bolus, was the most likely culprit behind the transient thinning of the glycocalyx. Propofol, the anesthetic agent used throughout the study, has been shown in previous research to affect microcirculatory function and may have direct effects on the endothelium. Cats are also known to be particularly sensitive to propofol-related oxidative stress, and the drug is metabolized more slowly in this species than in many others.

Perhaps the most surprising finding was that the smallest vessels measured, those between 5 and 9 micrometers in diameter, actually showed lower PBR values in the fluid-treated group at the later time points. This suggests that the intravenous fluids may have partially protected or even restored the glycocalyx in these tiny vessels, possibly by diluting circulating anesthetic agents or by rehydrating the glycocalyx layer itself. The researchers noted that this finding warrants further investigation with studies specifically designed to disentangle the effects of anesthesia from those of fluid administration.

The study also revealed an important methodological consideration. Packed cell volume, a measure of the proportion of blood made up by red blood cells, was significantly associated with several GlycoCheck parameters. When packed cell volume decreased, the perfused boundary region tended to increase, even though the underlying glycocalyx may not have changed at all. This makes sense when one considers how the technology works: the software relies on detecting red blood cells against a contrasting background, and fewer red blood cells in the bloodstream could artificially widen the apparent gap between the cell column and the vessel wall. The researchers emphasized that this finding should be explored further, as it may require adjustments to how PBR measurements are interpreted in clinical settings.

The implications of this research extend beyond feline medicine. The endothelial glycocalyx is increasingly recognized as a critical player in human health, with damage to this layer implicated in sepsis, trauma, diabetes, and cardiovascular disease. Understanding how intravenous fluids interact with the glycocalyx in a controlled experimental setting provides valuable insight into the broader question of whether aggressive fluid resuscitation helps or harms the microcirculation. The answer, at least for now, appears to be nuanced: in healthy individuals, a transient fluid surge may not be the glycocalyx-destroying event that some earlier studies suggested, but the full picture remains far from complete. The researchers call for further studies designed with a deeper understanding of feline volume kinetics, acknowledging that the current findings represent an exploratory step rather than a definitive answer.

Subject of Research: Effects of transient intravascular volume overload on endothelial glycocalyx thickness in healthy anesthetized cats

Article Title: Effects of transient intravascular volume overload on endothelial glycocalyx thickness in healthy anesthetized cats

Article References: Yozova, I. D., Thomson, N., Irie, M., Owen, R., & Munday, J. S. (2026). Effects of transient intravascular volume overload on endothelial glycocalyx thickness in healthy anesthetized cats. Frontiers in Veterinary Science, 13, Article 1742967. https://doi.org/10.3389/fvets.2026.1742967

Image Credits: AI Generated

DOI: 10.3389/fvets.2026.1742967

Keywords: endothelial glycocalyx, volume overload, intravenous fluids, cats, sidestream dark field videomicroscopy, GlycoCheck, perfused boundary region, propofol anesthesia, microcirculation, packed cell volume, veterinary medicine, fluid therapy

The research, led by Gürkan Tarçın of Kocaeli University Medical Faculty together with colleagues from pediatric endocrinology, emergency, and critical care units across ten institutions, examined 139 children treated for diabetic ketoacidosis between June 2021 and August 2023 in five tertiary centers. Rather than imposing a single protocol, the investigators took advantage of natural variation in routine practice: each center managed DKA according to its own established fluid regimen. This real-world design allowed the team to compare three distinct maintenance and deficit fluid protocols as they were actually delivered at the bedside, capturing the consequences of everyday clinical decisions rather than the idealized conditions of a controlled trial.

All three protocols shared a common opening move. Every child received an initial bolus of isotonic saline to restore circulating volume, the universally accepted first step in DKA resuscitation. The protocols then diverged in the composition of the fluids given over the following hours. Protocol 1 used a solution of 0.6 percent sodium chloride containing 3.3 percent dextrose throughout the entire treatment course. Protocol 2 began with 5 percent dextrose in 0.9 percent sodium chloride for the first six hours, then switched to 0.6 percent sodium chloride with 5 percent dextrose. Protocol 3 continued with 5 percent dextrose in 0.9 percent normal saline for the duration of therapy. The critical chemical difference lay in the chloride load: Protocol 1 delivered roughly 100 milliequivalents of chloride per liter, the lowest of the three, while the protocols built on normal saline carried a substantially heavier chloride burden.

The most striking finding emerged among newly diagnosed children presenting with severe acidosis. In this subgroup, the low-chloride Protocol 1 was associated with a shorter treatment duration and lower peak chloride levels compared with Protocols 2 and 3. In other words, children whose fluids spared them the excess chloride came out of the ketoacidotic state faster and avoided one of the well-recognized side effects of aggressive saline-based regimens: hyperchloremia, an abnormally high blood chloride concentration that can itself produce a non-anion-gap metabolic acidosis and muddy the biochemical picture clinicians rely on to judge recovery.

To move beyond simple group comparisons, the researchers performed a multivariable linear regression analysis, a statistical technique that isolates the independent contribution of each factor while holding the others constant. Three variables independently predicted a longer course of treatment: a lower initial blood pH at presentation, reflecting more profound acidosis on arrival; a higher peak chloride level reached during therapy; and new-onset diabetes, meaning the DKA episode was the child’s first manifestation of the disease. The chloride finding is particularly consequential because it is the one variable clinicians can directly control through fluid selection. A lower starting pH is fixed at the moment of arrival, and whether diabetes is newly diagnosed is a matter of history, but the chloride load delivered through the intravenous line is a protocol choice, and this study suggests it matters.

The biology behind the chloride effect is worth unpacking. Normal saline contains a chloride concentration of about 154 milliequivalents per liter, considerably higher than the roughly 100 to 110 milliequivalents per liter found in human plasma. When large volumes of such fluid are infused, the excess chloride overwhelms renal handling and lowers the strong ion difference in the blood, driving a hyperchloremic acidosis that is physiologically distinct from the ketoacidosis being treated. Clinicians tracking bicarbonate and pH during DKA therapy can then face an ambiguous picture: is the persistent acidosis ongoing ketone production, or is it iatrogenic, manufactured by the resuscitation itself? By keeping the maintenance fluid chloride load near physiological levels, the low-chloride protocol appears to have minimized this confounding, allowing the true resolution of ketoacidosis to show through and, per the study’s results, shortening the time needed to reach treatment endpoints.

Equally notable is what all three protocols had in common: dextrose was included in the initial maintenance and deficit fluids from the outset, regardless of the child’s serum glucose concentration. This runs counter to the instinct, still common in some settings, to withhold glucose until blood sugar falls toward the hypoglycemic range. The authors propose that early dextrose administration may have blunted rapid osmotic shifts, the sudden changes in extracellular tonicity that are thought to contribute to the most feared complication of pediatric DKA: cerebral edema, a swelling of the brain that historically carries significant mortality and neurological morbidity. By providing a steady glucose supply alongside insulin therapy from the first hours, the fluid regimens may have smoothed the osmotic transition as the child’s chemistry normalized.

The safety signal here is remarkable in its own right. Across all 139 children and all three treatment protocols, not a single case of cerebral edema was observed. Given that cerebral edema is rare but devastating, occurring in a small fraction of pediatric DKA episodes, an absence of cases in a cohort of this size cannot prove protection, and the study’s retrospective design limits causal inference. Nevertheless, the combination of early dextrose and controlled osmotic shifts offers a plausible physiological account, and the zero-case outcome is consistent with the hypothesis that gentler fluid chemistry, applied early, may contribute to a safer treatment course. The authors themselves frame it cautiously, suggesting that early dextrose may have minimized rapid osmotic shifts and potentially contributed to the absence of cerebral edema across all groups.

The study’s design deserves both credit and scrutiny. Its multicenter scope, spanning five tertiary hospitals and ten institutional affiliations across Türkiye, lends ecological validity that single-center studies often lack, and the ethics approval from the Istanbul University-Cerrahpaşa ethics committee, with written informed consent obtained from participants and guardians, anchors the work in standard research protections. At the same time, the retrospective cohort structure means the investigators depended on chart documentation, and the assignment of children to protocols reflected where they happened to be treated rather than randomization. Centers may differ in ways beyond fluid recipes, including insulin dosing practices, monitoring frequency, and patient demographics, and although multivariable regression adjusted for key predictors such as initial pH and diabetes status, unmeasured confounding cannot be excluded. A randomized controlled trial would be needed to confirm that the low-chloride, early-dextrose approach itself, rather than the environment in which it was used, drives the faster recovery.

Even with those caveats, the findings arrive at a practical moment. Pediatric DKA remains one of the most common pediatric endocrine emergencies, and international guidance, including that of the International Society for Pediatric and Adolescent Diabetes, continues to evolve on fluid composition. The message emerging from this cohort is twofold. First, the chloride content of maintenance and deficit fluids is not a trivial detail: a regimen delivering roughly 100 milliequivalents per liter was linked to quicker acidosis resolution and less treatment-related hyperchloremia in the sickest children. Second, adding dextrose early, rather than waiting for glucose to fall, appears compatible with, and possibly protective against, the osmotic turbulence that complicates therapy. For emergency physicians and pediatric intensivists, the study reframes a routine order set as an active therapeutic lever, one that could shorten hospital courses and, perhaps, keep children with diabetic ketoacidosis on the safer side of one of medicine’s most feared complications.

Subject of Research: Intravenous fluid composition in the treatment of pediatric diabetic ketoacidosis

Article Title: Early dextrose and lower-chloride fluids in pediatric diabetic ketoacidosis: a faster and safer approach? – A multicenter cohort study

Article References: Tarçın, G., Özer, E., Küçükali, G. K., Yaşar, A., Çakır, A. D., Karakaş, H., Emeksiz, S., Karacan, C. D., Uçar, A., Kırmızıbekmez, H., Çetinkaya, S., Boyraz, M., Cebeci, S. O., Turan, H., Bayramoğlu, E., Aygün, F., & Evliyaoğlu, O. (2026). Early dextrose and lower-chloride fluids in pediatric diabetic ketoacidosis: a faster and safer approach? – A multicenter cohort study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02555-w

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02555-w

Keywords: diabetic ketoacidosis, pediatrics, type 1 diabetes, intravenous fluids, hyperchloremia, dextrose, cerebral edema, acidosis, emergency medicine, fluid therapy, ISPAD, multicenter cohort study

Acute gastroenteritis remains one of the most common reasons young children end up in emergency departments worldwide. The illness, usually viral, produces vomiting and diarrhea that can rapidly dehydrate a small body. The cornerstone of treatment is oral rehydration therapy, a carefully balanced solution of salts and sugars. The problem is that persistent vomiting often defeats oral rehydration before it can work, forcing clinicians toward intravenous lines, hospital admission, and prolonged distress. Ondansetron, a selective serotonin 5-HT3 receptor antagonist originally developed for chemotherapy-induced nausea, blocks the signaling pathway that triggers the vomiting reflex at the level of the gut and the brain’s vomiting center. Its adoption in pediatric emergency care has grown steadily, but the evidence base has needed updating.

The previous comprehensive meta-analysis on the question was published in 2020, and the research team identified three specific gaps it left open. It could not incorporate a subsequently published trial of multidose ondansetron given after hospital discharge, it did not evaluate the volume of oral rehydration solution children actually tolerated, and it did not formally explore sources of statistical heterogeneity through meta-regression. The new analysis, conducted and reported according to the PRISMA 2020 statement and guided by the AMSTAR 2 appraisal tool, set out to close those gaps. The researchers searched PubMed, CENTRAL, ScienceDirect, Google Scholar, and ClinicalTrials.gov through June 2026, and assessed risk of bias with the Cochrane RoB 2 tool and certainty of evidence with GRADE.

The headline results are striking in their consistency across measures of vomiting morbidity. Compared with placebo, ondansetron reduced the risk of ongoing vomiting by more than half, with a pooled risk ratio of 0.48. Children given the drug experienced on average 0.73 fewer vomiting episodes. Failure of oral rehydration therapy fell dramatically, with a risk ratio of 0.39, and the use of intravenous fluids dropped to 0.57 times the rate seen with placebo. Perhaps most tellingly for frontline practice, children who received ondansetron tolerated significantly more oral rehydration solution, a mean difference of nearly 48 milliliters more than placebo recipients. For a therapy whose entire purpose is to keep fluids going in by mouth rather than through a needle, that volume difference is clinically meaningful.

The picture darkens somewhat around the outcomes that matter most for health systems and families over longer horizons. The analysis found no significant difference between ondansetron and placebo in hospitalization rates, repeat healthcare visits, ongoing diarrhea, diarrheal episodes, or adverse events. Moreover, the hospitalization result proved fragile: it reached statistical significance only when a single large trial was omitted from the pooling, a sensitivity finding that undermines confidence in any true effect on admissions. Reassuringly for safety, the drug did not appear to worsen diarrhea, a concern sometimes raised because intestinal motility is partly serotonin-mediated. But the authors emphasize that the safety comparison rests on very few estimable comparisons and very few adverse events, meaning the analysis simply cannot rule out uncommon or delayed harms.

The durability of the antiemetic effect emerged as another key nuance. On subgroup analysis by follow-up duration, the benefit for ongoing vomiting was statistically significant through the first twenty-four hours but attenuated at forty-eight hours and beyond. This time-limited effect provides what the authors call a plausible rationale, though not direct evidence from the synthesis itself, for the extended multidose post-discharge regimen evaluated in the largest included trial. That trial, which the 2020 meta-analysis could not include, tested whether continued ondansetron after children left the emergency department could sustain the protection that a single dose evidently cannot. The updated evidence base now incorporates those findings, strengthening the argument that duration of action is a central design question rather than an afterthought.

Beneath the pooled estimates lies a more uncomfortable statistical story. The trials showed substantial heterogeneity, meaning their results varied far more than chance alone would predict. Exploratory meta-regression, introduced during revision and notably not specified in the registered protocol, suggested that the baseline proportion of male participants, baseline vomiting-episode frequency, and baseline diarrheal-episode frequency acted as study-level moderators of the effect on ongoing vomiting, while mean age did not. More concerning, Egger’s test indicated statistically significant funnel-plot asymmetry for both outcomes where publication bias could be assessed: ongoing vomiting, with a p-value of 0.03070, and number of vomiting episodes, with a p-value of 0.04627. Begg and Mazumdar’s rank correlation test was significant for neither, leaving the signal equivocal but sufficient for the authors to rate certainty of evidence as low for ongoing vomiting and very low for the number of vomiting episodes.

What does funnel-plot asymmetry mean in practical terms? Small trials with favorable results tend to be published more readily than small trials with null findings, so when the smaller studies in a meta-analysis cluster at one extreme of the funnel plot, it suggests the literature may be missing negative results. If so, the pooled effect sizes that look so impressive in the forest plots may overstate what a typical child would experience. The authors state this directly: the pooled magnitude of benefit on vomiting may be overstated. This kind of self-critical transparency is increasingly expected of high-quality systematic reviews, and it distinguishes this update from simpler aggregations that report point estimates without interrogating the shape of the evidence behind them.

The research team, which also included authors from Hawassa University in Ethiopia and Ad Diriyah Hospital in Riyadh, concludes that ondansetron significantly reduces vomiting morbidity in children with acute gastroenteritis, with no statistically significant difference versus placebo in adverse events or diarrhea. Their prescription for future research is precise: further randomized trials directly comparing single-dose and multidose regimens, particularly in high-burden, low-resource settings where gastroenteritis still kills, along with individual patient-data analyses that can resolve the heterogeneity that study-level meta-regression only glimpses. The review was registered prospectively on PROSPERO under identifier CRD420261447906, received no extramural funding, and is published open access. For emergency clinicians deciding whether a dose of ondansetron is worth offering a vomiting, dehydrated child, the accumulated evidence now points, with acknowledged caveats, toward yes.

Subject of Research: Efficacy and safety of ondansetron versus placebo for acute gastroenteritis-associated vomiting in children

Article Title: Updated evidence on efficacy and safety of ondansetron compared with placebo for acute gastroenteritis-associated vomiting in children: a systematic review and meta-analysis of randomized controlled trials

Article References: Althunayyan, B. S., Alhoushani, R. A., Alhesayani, L. M., Alsallal, S. A., Aldakhil, L. N., Alharbi, S. J., Alharbi, M. M., Aldaher, Y. J., Aljumah, Y. S., Alharbi, W. A., Yusuf, S. A., & Alrashidi, S. H. (2026). Updated evidence on efficacy and safety of ondansetron compared with placebo for acute gastroenteritis-associated vomiting in children: a systematic review and meta-analysis of randomized controlled trials. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07694-6

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07694-6

Keywords: ondansetron, acute gastroenteritis, vomiting, children, oral rehydration therapy, meta-analysis, randomized controlled trials, pediatrics, emergency care, intravenous fluids, publication bias, GRADE