The findings describe the experience of this hospitalized cohort and do not establish that dexmedetomidine caused the observed outcomes or was safer or more effective than another sedative. The analysis included patients admitted between June 1 and December 30, 2022, who received dexmedetomidine while receiving non-invasive respiratory support through either continuous positive airway pressure or high-flow nasal cannula. High-flow oxygen therapy was delivered through a nasal cannula, and continuous positive airway pressure was delivered with a nasal mask.

Dexmedetomidine was administered by infusion at 0.1–0.6 micrograms per kilogram per hour without a loading dose. The study used descriptive statistics and examined variables including age, dexmedetomidine dose, adverse effects, sex, heart rate and respiratory rate. Because the investigation was retrospective and did not include a randomized comparison group, it cannot separate the effects of dexmedetomidine from those associated with respiratory support, changes in illness or other aspects of clinical care.

The cohort included 46% females and 54% males. Patients aged 1–12 months accounted for 55.8% of the group, those aged 13–36 months represented 34.5%, and 9.72% were older than 36 months. Non-invasive respiratory support is frequently used in pediatric patients with moderate to severe acute respiratory failure, but non-compliance can reduce treatment success.

Dexmedetomidine is widely used in adults for its sedative and anxiolytic properties, although its use in pediatric populations has been more limited. The research therefore focused on documenting the clinical feasibility, physiological trends and adverse events associated with its use alongside non-invasive support, rather than directly comparing it with a control treatment. Following initiation of combined non-invasive respiratory support and dexmedetomidine therapy, researchers observed statistically significant reductions in respiratory rate and heart rate, with p-values below 0.001 for both measures.

These were observed changes during treatment, not evidence of a causal effect or a prespecified comparison between groups. The respiratory rate and heart rate findings also applied to the overall cohort, which comprised patients treated for acute respiratory failure and a smaller post-extubation group. Documented adverse effects occurred in five of the 113 children: bradycardia in two, elevated liver enzyme levels in two and hypotension in one.

No adverse events were reported in the remaining 108 patients. The source did not classify these events as serious adverse events, so their frequency should not be interpreted as a formal serious-adverse-event rate. In the stratified analysis, 100 of 102 children, or 98%, in the primary non-invasive support subgroup completed treatment without escalation to invasive ventilation; that subgroup was intended to prevent intubation.

All 11 children in the post-extubation subgroup, intended to prevent re-intubation, also completed non-invasive support without escalation. The post-extubation estimate is based on a particularly small group and therefore has greater uncertainty than the overall cohort result. Overall, the study supports the limited conclusion that dexmedetomidine monotherapy can be administered feasibly in a pediatric intensive care setting alongside non-invasive respiratory support, with lower heart and respiratory rates observed and only a small number of patients experiencing documented adverse effects.

The descriptive results do not show that dexmedetomidine prevents intubation or re-intubation, improves survival, or offers advantages over alternative sedatives. The authors called for prospective comparative trials to investigate the safety and effectiveness of the approach. Until such evidence is available, the reported success rate should be viewed as an observation from one retrospective cohort rather than a treatment-effect estimate.

Subject of Research: Retrospective evaluation of dexmedetomidine sedation during pediatric non-invasive respiratory support

Article Title: Safety and feasibility of dexmedetomidine for sedation in pediatric patients receiving non-invasive respiratory support: a descriptive study

Article References: Yavuz, S., & Avci, A. (2026). Safety and feasibility of dexmedetomidine for sedation in pediatric patients receiving non-invasive respiratory support: a descriptive study. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07603-x

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07603-x

Keywords: dexmedetomidine, pediatric sedation, non-invasive respiratory support, pediatric intensive care, acute respiratory failure, continuous positive airway pressure, high-flow nasal cannula, retrospective study, adverse events, clinical feasibility, Safety, feasibility

The review used a targeted search of PubMed/MEDLINE and reference lists to identify evidence published from January 2006 to 10 August 2026. Of 166 records retrieved, the authors included 14 peer-reviewed paediatric studies and five directly relevant systematic reviews or meta-analyses. Two reviewers screened records independently and resolved disagreements by discussion, but the team did not perform a formal risk-of-bias assessment, certainty grading, publication-bias analysis or quantitative synthesis. It also did not search trial registries, Embase, Web of Science, Scopus, the Cochrane Library or non-English databases, so the conclusions apply to the evidence captured by this strategy rather than to every available study.

Most randomised trials and meta-analyses indicate that esketamine can reduce emergence delirium or emergence agitation, with the clearest evidence emerging from children undergoing adenotonsillectomy under sevoflurane anaesthesia. One four-arm trial assigned 164 children to placebo or intravenous esketamine doses of 0.1, 0.3 or 0.5 mg·kg−1 before induction. Emergence agitation occurred in 62.5%, 56.8%, 25.6% and 18.9% of the respective groups, indicating progressively lower observed incidence as the assigned dose increased within that procedure. The 0.5 mg·kg−1 group had a longer time to tracheal tube removal, but the reduction in agitation did not reverse. Because the trial did not test higher doses or establish a concentration–effect relationship, it supports a dose-related signal up to 0.5 mg·kg−1 without locating an upper efficacy or toxicity boundary.

Other randomised studies reported similar directional findings with a 0.2 mg·kg−1 intravenous bolus given at the end of anaesthesia or during surgery, while pooled analyses generally found fewer emergence outcomes after esketamine. Those pooled results, however, combine studies with different procedures, doses, administration schedules, comparators and assessment tools, making them useful for estimating an average preventive effect rather than defining a precise dose threshold. A prospective observational study of 230 preschool children reached the opposite conclusion, associating esketamine exposure at a mean dose of 0.46 mg·kg−1 with more emergence delirium and a longer stay in the post-anaesthesia care unit. Because treatment was not randomised, clinicians may have selected esketamine for children with different underlying risks, and the study compared no prespecified dose levels, it cannot show that a particular dose caused the excess events or identify a dose–response inflection point.

The apparent contradictions are better understood as differences between endpoints than as evidence for a single reversal in drug response. Esketamine is also evaluated for procedural sedation, attenuation of propofol injection pain and postoperative analgesia, each of which may require a different depth and duration of drug action. A dose that suppresses a brief response during gastroscope insertion, for example, cannot define the lower threshold for sustained postoperative analgesia. Likewise, a regimen producing procedural sedation cannot establish the upper limit for emergence prophylaxis. The review therefore treats the emergence results, injection-pain dose estimates and analgesic studies as separate bodies of evidence rather than evidence for one common effect.

Measurement also contributes to the apparent variability. Emergence delirium and emergence agitation overlap but are not interchangeable: the Pediatric Anesthesia Emergence Delirium scale was designed to assess delirium, whereas the Watcha and Cravero instruments place more emphasis on agitation. Pain, fear, residual sedation and dissociative behaviour can influence scores, and studies differ in their thresholds and assessment times. These differences limit direct comparison of incidence and treatment effects. Anaesthetic context may matter as well. Sevoflurane exposure, preschool age, preoperative anxiety and postoperative pain are established correlates of emergence delirium, while procedures such as endoscopy, bronchoscopy, strabismus surgery, hypospadias repair and neurosurgery have different baseline risks and anaesthetic conditions. Results from one setting therefore cannot be assumed to estimate the same effect in another.

Route of administration creates another unresolved layer. Adult studies estimate that intranasal esketamine has an absolute bioavailability of approximately 50%–54%, but that figure alone cannot establish that 1.0 mg·kg−1 intranasally is equivalent to 0.5 mg·kg−1 intravenally. Intranasal delivery produces variable absorption, a swallowed fraction, first-pass metabolism and different timing of peak concentration, while an intravenous bolus creates a more immediate systemic peak. The cited adult nasal-spray models were developed in healthy volunteers and adults with depression, not perioperative children, and the targeted search found no validated paediatric perioperative population pharmacokinetic model. Intravenous and intranasal regimens consequently remain distinct evidence categories rather than being converted through a simple bioavailability calculation.

Developmental pharmacology adds uncertainty but does not supply a solution. Maturation of body composition, hepatic metabolic capacity and the formation of active metabolites such as noresketamine may alter distribution and clearance, while developmental changes in N-methyl-D-aspartate receptor expression provide biological plausibility for age-dependent responses. None of these factors has yet been quantified in a paediatric perioperative exposure model, however, and apparent age effects may instead reflect baseline emergence risk, communication ability, vascular access or procedure mix. Adult data, racemic ketamine models and animal studies can therefore generate hypotheses but cannot justify empirical age-based dose escalation or reduction. Likewise, high-dose neonatal mouse studies and prolonged exposure in developing non-human primates do not define a neurotoxicity threshold for a single low-dose perioperative bolus in children, although they support the need for longer clinical surveillance.

Clinical studies have generally concentrated on short-term outcomes such as heart-rate and blood-pressure changes, respiratory events, oxygen desaturation, nausea and vomiting, abnormal behaviour, salivation, recovery time, tracheal tube removal and post-anaesthesia care unit stay. In the four-dose adenotonsillectomy trial, heart rate and mean arterial pressure differed among groups, and 0.5 mg·kg−1 prolonged tube removal, although post-anaesthesia care unit duration and postoperative complications did not differ significantly. Most trials were designed to test efficacy rather than detect uncommon harms, so the absence of a statistically significant safety difference does not demonstrate an upper boundary. Reviews combining dexmedetomidine and esketamine are also encouraging in some settings, but current comparisons do not include factorial designs or prespecified interaction tests; they therefore do not establish pharmacological synergy, a uniform half-dose strategy or a higher safety ceiling.

The review’s central conclusion is that evidence supports context-specific studied ranges rather than a validated universal therapeutic window. The 0.2–0.5 mg·kg−1 intravenous interval is best supported for selected emergence-prevention settings and should not be extrapolated automatically to analgesia, procedural sedation, intranasal administration or other operations. Future trials should randomise prespecified doses and timing within the same procedure and anaesthetic protocol, report emergence delirium, emergence agitation, pain, extubation time, recovery duration and adverse effects separately, and preserve the thresholds and terminology of validated assessment instruments. Population models should link weight, maturation, route, timing, co-medication and metabolite exposure to both efficacy and safety, while follow-up should extend beyond the behavioural assessments commonly limited to 30 days. Until that work is available, the evidence neither validates a universal dose nor shows that doses above 0.5 mg·kg−1 are safe.

Subject of Research: Endpoint- and dose-dependent evidence for perioperative esketamine in children

Article Title: Dose- and endpoint-dependent effects of perioperative esketamine in children: evidence from a targeted review

Article References: Yang, Y., He, T., Mao, W., & Wang, X. (2026). Dose- and endpoint-dependent effects of perioperative esketamine in children: evidence from a targeted review. Frontiers in Pediatrics, 14, Article 1963881. https://doi.org/10.3389/fped.2026.1963881

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DOI: 10.3389/fped.2026.1963881

Keywords: paediatric anaesthesia, esketamine, emergence delirium, emergence agitation, dose response, analgesia, procedural sedation, dexmedetomidine, pharmacokinetics, drug safety, Dose-, endpoint-dependent

The research team, led by Chloe R. Dupleix with colleagues Jacob P. Rastas, Qianqian Zhao, Robert Young, and Rebecca A. Johnson, set out to answer a deceptively simple question: can a sensor stuck to the skin over a major blood vessel track the core temperature of an anesthetized dog as accurately as a rectal probe? The answer, according to their preliminary data, is a qualified yes, with performance depending on both the sedative drug used before anesthesia and whether the fur at the sensor site has been clipped away.

Core body temperature monitoring is a vital part of physiological evaluation during anesthesia. Depending on the type of procedure and the position in which the patient is placed, obtaining consistent core temperature measurements can be surprisingly difficult. Long surgical drapes, limited access to the patient, and the practical challenges of keeping a rectal probe in place all complicate continuous monitoring. Anesthetized animals cannot regulate their own body temperature effectively, and sedative drugs themselves interfere with the body’s thermoregulatory mechanisms, making accurate and frequent measurement essential for patient safety.

The study enrolled three healthy beagle dogs in a pilot design. Before anesthesia was induced, each dog received a premedication of either dexmedetomidine, a potent alpha-2 adrenergic agonist known to cause significant drops in body temperature, or acepromazine, a commonly used phenothiazine tranquilizer. Anesthesia was then induced with intravenous propofol and maintained with isoflurane, a typical inhalant anesthetic regimen in veterinary practice. Throughout the procedures, the dogs were monitored every five minutes with pulse oximetry, non-invasive blood pressure measurement, electrocardiography, and capnometry, providing a full picture of their anesthetic status.

Temperature data were collected every three minutes for up to 120 minutes following induction. The researchers compared three measurement approaches: conventional rectal thermometry, the CORE sensor placed on clipped skin over the jugular veins, and the same sensor placed on unclipped skin at the same location. Testing the sensor both with and without fur removal was a key design choice, because clipping is time-consuming and may not always be desirable in clinical cases, particularly in patients presenting for non-surgical procedures where an owner may object to shaving a patch of fur.

The CORE sensor works on a heat flux principle. Instead of assuming that skin temperature reflects core temperature, which it often does not, the device measures the actual flow of heat through the skin and uses that measurement to calculate a deeper body temperature estimate. This approach has gained attention in human sports and health monitoring, where athletes and researchers use the sensor to track core temperature during exercise without invasive probes. Applying the same physics to a furry, four-legged patient is far from trivial, because fur adds a variable insulating layer that alters heat flux in unpredictable ways.

To evaluate agreement between the wearable and the rectal reference, the team used two complementary statistical tools. The correlation coefficient for repeated measures, denoted r_rm, captures the strength of the association between two measurement methods when multiple readings are taken from the same subjects over time. The Shrout-Fleiss intraclass correlation coefficient, or ICC, goes further by assessing not just whether two methods move together, but whether they agree closely enough to be used interchangeably in practice. Values approaching 1.0 indicate excellent reliability, while values below roughly 0.5 suggest that agreement is too weak for confident clinical use.

In dogs premedicated with acepromazine, the results were encouraging across the board. There was good, statistically significant correlation and reliability between rectal temperatures and CORE readings on clipped skin, with r_rm equal to 0.81 and a P value below 0.0001, paired with an ICC of 0.78. Performance on unclipped skin was equally strong, showing r_rm of 0.79 with P below 0.0001 and an ICC of 0.85. These findings indicate that when acepromazine is the premedication, the sensor can track rectal temperature closely whether or not the fur is clipped, which is a meaningful practical advantage in a busy clinic.

The picture changed under dexmedetomidine. Although the clipped-skin CORE readings were still statistically correlated with rectal measurements, with r_rm of 0.30 and P below 0.0001, the reliability was poor, at an ICC of only 0.28. Dexmedetomidine produces pronounced peripheral vasoconstriction and alters heat distribution in the body, which likely changes the heat flux signal the sensor depends on. Notably, reliability improved substantially when the sensor was placed on unclipped skin in these same dogs, with r_rm rising to 0.48 and the ICC climbing to 0.88, suggesting that the insulating effect of intact fur may in some circumstances stabilize the heat flux measurement rather than disrupt it.

Beyond the correlation statistics, the researchers also assessed clinical agreement using Bland-Altman analysis, which plots the difference between two methods against their average to reveal systematic bias and limits of agreement. Clinically acceptable Bland-Altman agreement was found between the rectal method and the unclipped CORE method, meaning the wearable’s readings fell within a range veterinarians would consider acceptable for guiding patient care. Taken together, these preliminary results suggest that the CORE sensor may provide a viable alternative method for assessing core body temperature in unclipped, anesthetized dogs. As a pilot study involving three animals, the work cannot yet support universal clinical recommendations, and the authors’ findings will need validation in larger and more diverse patient populations. But the prospect of continuous, wireless, non-invasive core temperature monitoring that does not require shaving or a rectal probe represents an appealing step forward for veterinary anesthesia, where every practical improvement in monitoring translates directly into safer procedures for patients.

Subject of Research: Validation of a wearable heat flux body temperature sensor against rectal thermometry in anesthetized dogs

Article Title: Evaluation of a novel body temperature sensor (CORE) in dogs under general anesthesia following premedication with dexmedetomidine or acepromazine: A pilot study

Article References: Dupleix, C. R., Rastas, J. P., Zhao, Q., Young, R., & Johnson, R. A. (2026). Evaluation of a novel body temperature sensor (CORE) in dogs under general anesthesia following premedication with dexmedetomidine or acepromazine: A pilot study. PLOS One, 21(10), e0360808. https://doi.org/10.1371/journal.pone.0360808

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DOI: 10.1371/journal.pone.0360808

Keywords: veterinary anesthesia, dogs, core body temperature, wearable sensor, heat flux thermometry, dexmedetomidine, acepromazine, hypothermia, rectal thermometry, Bland-Altman analysis, intraclass correlation, PLOS One

The team, led by corresponding author Michael D. Hambuchen, had previously shown that dexmedetomidine, a non-scheduled alpha-2 adrenergic agonist sedative, could be safely co-administered with naloxone in rats co-intoxicated with methamphetamine and fentanyl. Dexmedetomidine reverses fentanyl-induced sedation with naloxone while potently attenuating the agitation that naloxone unmasks, and it does so without potentiating opioid-induced respiratory depression, a property that makes it uniquely suited to polysubstance cases. But dexmedetomidine has a pharmacological quirk: its sedation is uniquely arousable, more like natural sleep than anaesthesia, and patients can typically respond to simple commands. That arousability is clinically useful for milder cases, allowing clinicians to monitor patients without deep sedation and its associated prolonged hospital stays. For severely agitated patients, or when clinicians need to perform intricate procedures such as placing an intravenous line, however, arousable sedation may simply not be enough.

Aggressively increasing the dexmedetomidine dose to achieve deeper sedation carries its own dose-dependent risks. Through alpha-2a receptor-mediated sympatholytic effects, dexmedetomidine initially causes hypotension and bradycardia, and at higher concentrations it further suppresses heart rate while raising blood pressure through alpha-2b receptor-mediated vasoconstriction. It inhibits insulin secretion from pancreatic alpha-2 receptors, potentially causing hyperglycaemia, and it lowers the thermoregulatory thresholds for shivering and vasoconstriction, producing hypothermia in humans. The Marshall team hypothesised that adjunctive ketamine, a dissociative NMDA antagonist anaesthetic with partial mu-opioid receptor agonism, could deepen dexmedetomidine’s sedation without escalating the dose and its attendant adverse effects. Ketamine brings its own advantages to polysubstance cases: like dexmedetomidine, it causes minimal respiratory depression, and its sympathomimetic activation of the cardiovascular system could counteract dexmedetomidine’s bradycardic and hypotensive tendencies. The dexmedetomidine-ketamine combination is increasingly used in human sedation, from paediatric dental patients to opioid-free anaesthesia protocols, but no study had ever tested it against stimulant-induced agitation.

The experimental design was deliberately rigorous. Male Sprague Dawley rats received 1 mg/kg of methamphetamine subcutaneously, a dose chosen because it produces robust locomotor activation with minimal stereotypy, closely mimicking the effect of intravenous methamphetamine. Fifteen minutes later, once the stimulant effect was fully underway, the rats received one of four treatments: saline control, low-dose dexmedetomidine at 0.032 mg/kg, low-dose dexmedetomidine plus 56 mg/kg ketamine, or high-dose dexmedetomidine at 0.18 mg/kg. The fifteen-minute delay was clinically meaningful, simulating the scenario in which naloxone unmasks agitation in a fentanyl-methamphetamine co-intoxicated patient and treatment begins after the opioid reversal is underway. The researchers tracked horizontal locomotor activity as a validated rat model of agitation, quantified arousability with an adapted rat coma scale based on the Glasgow coma scale used in humans, and monitored a battery of alpha-2 agonist class side effects including peripheral oxygen saturation, heart rate, blood glucose, and rectal temperature over four hours.

The locomotor results were striking. Both high-dose dexmedetomidine and the dexmedetomidine-ketamine combination almost completely eliminated methamphetamine-induced locomotor activity during the targeted ninety-minute post-treatment window, which encompassed the most intense phase of the stimulant response. Low-dose dexmedetomidine alone significantly reduced activity but only partially attenuated and shortened the methamphetamine effect. Over the full four-hour trial, the combination produced a smaller overall reduction than high-dose dexmedetomidine because of a post-sedation elevation in locomotor activity, which the authors interpret as ketamine emergence agitation, a well-documented phenomenon upon recovery from ketamine sedation that includes euphoria, vivid dreams, hallucinations, and delirium. The emergence response appeared less severe when rats awakened in the smaller, enclosed diuresis cages used during the sedation trial compared to the large open-field chambers, consistent with clinical evidence that awakening from ketamine in a minimally stimulating environment reduces emergence reactions. The authors suggest this effect could likely be managed by additional low-dose dexmedetomidine administration before patients awaken.

The sedation depth results revealed the combination’s decisive advantage. Despite significantly reducing locomotor activity, low-dose dexmedetomidine alone produced sedation that was almost completely arousable, with rat coma scale scores barely differing from saline controls. Even high-dose dexmedetomidine, which nearly eliminated movement for the entire trial, produced only partially arousable sedation. The low-dose dexmedetomidine-ketamine combination, by contrast, rapidly produced significantly deeper and less arousable sedation than every other group at the twenty-minute time point, precisely when methamphetamine-induced locomotor activity peaked in the control animals. At sixty minutes, the combination-treated rats remained substantially more deeply sedated than those receiving low-dose dexmedetomidine alone, comparable to the deepest sedation produced by high-dose dexmedetomidine, before returning to baseline by two hours. In a secondary qualitative measure, all rats treated with either dose of dexmedetomidine monotherapy required physical restraint for blood glucose and temperature measurements at every time point, while all eight combination-treated rats could be handled without restraint at both the twenty- and sixty-minute marks.

The side effect profile told an equally compelling story. High-dose dexmedetomidine produced minor but significant reductions in peripheral oxygen saturation at three time points, while neither low-dose dexmedetomidine nor the combination produced any significant oxygenation changes, though a subset of combination-treated rats showed early transient dips consistent with those occasionally seen in humans receiving rapid intravenous ketamine. All treatments reduced heart rate, as expected from dexmedetomidine’s sympatholytic effects, but high-dose dexmedetomidine produced the most intense bradycardia, persisting throughout the entire four-hour trial. The combination actually improved cardiovascular safety compared to low-dose dexmedetomidine alone: heart rate was significantly higher in the combination group between twenty and one hundred twenty minutes, and it returned to baseline by two hours rather than three, an effect the authors attribute to ketamine’s sympathomimetic activation opposing dexmedetomidine’s cardiosuppression. Blood glucose rose substantially in all treatment groups, largely recovering in the low-dose groups but remaining highly elevated after high-dose dexmedetomidine. Temperature dropped in all groups, but fully recovered in the low-dose groups by the trial’s end while remaining significantly depressed after high-dose dexmedetomidine. Overnight weight loss of roughly five percent occurred only in the high-dose dexmedetomidine group, further evidence of the combination’s superior tolerability.

The renal pharmacokinetic findings added an unexpected dimension. Dexmedetomidine dose-dependently increased urine production, a known effect mediated through reduced vasopressin release, and unexpectedly reduced urine pH. More acidic urine can ion-trap methamphetamine and related compounds in the renal tubule, enhancing elimination, and the researchers observed a moderate, significant positive correlation between urine volume and the percentage of unchanged methamphetamine excreted, along with a moderate, significant negative correlation between urine pH and methamphetamine excretion. While the trend toward enhanced renal methamphetamine elimination after high-dose dexmedetomidine did not reach statistical significance in the main study, partly due to polyuria-induced urine loss during transport between measurements, the authors suspect this pharmacokinetic bonus could prove clinically meaningful and plan dedicated pharmacokinetic studies with serum measurements to evaluate any potential beneficial effects on systemic methamphetamine exposure.

The Marshall team is careful to frame these findings as preclinical proof-of-concept rather than a clinical recommendation. Future studies will test the intervention in a methamphetamine-fentanyl polysubstance scenario with naloxone reversal, mirroring their earlier dexmedetomidine-naloxone work, and a rigorous preclinical comparison with the benzodiazepine standard of care is needed to demonstrate superiority. Sex comparisons are also critical, as female rats and female humans are more sensitive to methamphetamine’s stimulant effects and dexmedetomidine’s sedative effects than males, while the sex-dependent effects of ketamine remain less consistently established across species. The study’s design was facilitated by a research team spanning clinical and preclinical research, pharmacy, veterinary medicine, and clinical toxicology, reflecting a strategy of clinically guided preclinical work designed to inform future human trials. If the combination survives those tests, clinicians could initially exploit dexmedetomidine’s uniquely arousable sedation for milder agitation, then administer adjunctive ketamine to deepen sedation only when necessary, offering a pharmacologically tailored alternative to a one-size-fits-all benzodiazepine approach in an era when methamphetamine rarely travels alone.

Subject of Research: Ketamine enhancement of dexmedetomidine attenuation of methamphetamine-induced agitation in rats

Article Title: Ketamine enhancement of dexmedetomidine attenuation of methamphetamine-induced agitation in rats

Article References: Budamkayala, M., Yalakala, J., Skeen, M. B., Karuturi, S., McPhillen, C., Bailey, K., Davies, T. H., & Hambuchen, M. D. (2026). Ketamine enhancement of dexmedetomidine attenuation of methamphetamine-induced agitation in rats. Journal of Pharmacy & Pharmaceutical Sciences, 29, Article 16294. https://doi.org/10.3389/jpps.2026.16294

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DOI: 10.3389/jpps.2026.16294

Keywords: methamphetamine, dexmedetomidine, ketamine, agitation, preclinical, sedation, polysubstance, rat study, enhancement, attenuation, methamphetamine-induced, rats

The author, veterinary anesthesiologist Shotaro Nagahama of Gifu University in Japan, proposes a working model in which general anesthesia and alpha2-agonists shift the apparent set-point of fluid homeostasis along a wet-to-dry axis. In the awake state, intake and excretion are tightly coupled: drink too much water and free-water clearance rises rapidly to defend osmolality and volume around a neutral operating point. Under anesthesia, that coupling weakens — and the entire curve relating filling state to urine output appears displaced toward conservation.

The mechanistic case for this wet-biased state is convergent. Anesthetic drugs reduce arterial pressure and cardiac output, pushing renal perfusion toward the limits of autoregulation and lowering glomerular filtration. But perfusion mechanics alone cannot explain the oliguria. In a randomized clinical study, sevoflurane anesthesia reduced urine output and sodium excretion while raising plasma renin compared with propofol, and population volume-kinetic analyses show that general anesthesia can strongly suppress the urinary excretion of infused crystalloid. The neuroendocrine milieu amplifies the effect: surgical stress and nociceptive input drive non-osmotic arginine vasopressin (AVP) secretion, peritoneal opening and visceral manipulation during abdominal surgery can further augment AVP release, and renal sympathetic nerve activity together with renin-angiotensin-aldosterone signaling promotes tubular sodium and water reabsorption.

Translational work adds a crucial autonomic layer. In a series spanning pediatric anesthesia and large-animal models, sevoflurane was associated with renal sodium and water retention, reduced renal blood flow, and increased renal sympathetic nerve activity. When the kidney was surgically denervated, excretory function normalized and renal blood flow improved during sevoflurane anesthesia — implicating renal sympathetic pathways as a key mediator of the retention-biased phenotype. From the set-point perspective, intraoperative oliguria is a physiologically plausible output of a regulated, conservation-biased state. The author is careful, however, to note that this interpretation is not clinically reassuring: the same low-output phenotype may coexist with impaired perfusion, insufficient effective circulating volume, or evolving kidney injury, so contextual assessment remains essential.

Alpha2-agonists appear to push the system in the opposite direction. Dexmedetomidine’s clinical pharmacology is dominated by central sympatholysis, and mechanistic studies show it inhibits hypothalamic paraventricular nucleus neurons involved in autonomic regulation and AVP-related pathways — providing a plausible central substrate for suppressing antidiuretic signaling. By reducing sympathetic outflow, including to the kidney, alpha2-agonists may also diminish renal sympathetic-driven tubular reabsorptive tone. The hemodynamic profile, with an early pressor phase followed by sympatholytic hypotension, can contribute transiently to pressure natriuresis, but the clinically salient pattern is often a sustained, dilute, high-output diuresis that is difficult to attribute to a one-off pressure effect alone.

Human evidence, though dominated by case reports and small series, is remarkably stereotyped: urine output rises abruptly to high volumes, urine becomes dilute, serum sodium may rise if replacement lags, and the phenotype resolves with dose reduction or discontinuation. Most reports exclude obvious osmotic drivers such as glucose or mannitol and do not suggest structural renal injury. Comparative veterinary physiology provides the most direct support, because controlled studies can measure urine indices and hormones systematically. In dogs, medetomidine produces dose-dependent increases in urine output with decreased urine osmolality and specific gravity, alongside decreases in plasma AVP at higher doses and increases in atrial natriuretic peptide. Alpha2-antagonists such as atipamezole and yohimbine can attenuate the diuresis and reverse the AVP-related changes, supporting receptor-mediated mechanisms rather than nonspecific nephrotoxicity. Similar diuresis occurs in cats, and rat studies using the peripherally restricted alpha2-antagonist vatinoxan suggest that peripheral alpha2-dependent processes may also contribute to the urinary phenotype.

The unified model has a distinctive feature: it does not assume a fixed urine-output curve on which patients merely move as volume changes. Instead, anesthesia and alpha2-agonists are proposed to shift the curve itself, so the same observed filling condition maps to different urine-output phenotypes. Operationally, movement along a curve would be inferred when transient changes in filling or fluid loading alter urine output without changing the underlying volume-diuresis relationship; a curve shift would be supported when the threshold or slope of that relationship differs between drug states under otherwise comparable hemodynamic, osmotic, and drug-exposure conditions. The author emphasizes that set-point is used operationally here — describing a testable shift in the relation between filling state and urine-output phenotype — not to imply that a new defended reference value has already been experimentally demonstrated.

One of the most striking predictions concerns breakthrough diuresis during ordinary anesthesia. Even in anesthetized preparations, diuresis and urine dilution can be gated by central volume or atrial-pressure signals linked to AVP suppression. Increasing left atrial pressure in anesthetized dogs provokes a reversible water diuresis with a fall in circulating AVP, and this response is abolished when AVP is clamped exogenously. Conversely, in anesthetized rats, acute volume expansion fails to elicit volume diuresis or natriuresis when right atrial pressure is prevented from rising — despite similar cardiac output and mean arterial pressure. This provides a mechanistic backbone for a key prediction: under a wet-biased anesthetic set-point, escalating fluid may remain clinically silent until central filling, venous or atrial pressure, or related neuroendocrine permissive signals cross a threshold, after which urine output rises nonlinearly. The same framework explains why some patients without overt hypovolemia become oliguric soon after induction, yet later begin producing urine as time under anesthesia and cumulative fluid administration increase — even when arterial pressure appears stable.

The model yields several falsifiable predictions. Greater alpha2-agonist exposure — through a higher loading dose, higher infusion rate, longer duration, or greater cumulative exposure — should increase the probability, earlier emergence, and persistence of dilute polyuria, while dose reduction or pharmacologic antagonism should shift the phenotype back toward lower output and greater concentration. If alpha2-associated polyuria reflects a dry-biased state, urine osmolality should fall before or during the rise in output, and serum sodium and osmolality should remain stable only if free-water losses are replaced adequately — otherwise they should increase progressively. Direct AVP or copeptin measurement would test whether the trajectory is accompanied by inappropriately low antidiuretic signaling relative to plasma tonicity. Definitive experiments should compare graded volume-diuresis curves across awake, anesthetized, and alpha2-exposed states while measuring arterial pressure, cardiac output, venous or atrial filling indices, AVP or copeptin, urine osmolality, sodium excretion, and serum sodium.

Clinically, the framework does not replace individualized goal-directed fluid therapy, which uses dynamic cardiovascular variables to guide fluid and vasoactive treatment. It addresses a different question: why urine output may decouple from those hemodynamic targets when renal excretion is governed by a shifted peri-anesthetic regulatory state. A low urine output is neither automatically benign nor automatically a marker of renal injury — in a wet-biased state it may reflect neuroendocrine conservation, while in other contexts it may signal hypoperfusion or evolving kidney injury. Escalating crystalloid purely to normalize urine output can contribute to fluid overload. Conversely, under a dry-biased set-point during alpha2-agonist infusion, the key hazard is progressive intravascular depletion if urinary losses are not matched — particularly when clinicians interpret high output as reassuring renal competence. If replacement lags, hypernatremia becomes a predictable risk. The author also situates the model within a familiar theme in anesthesia physiology: anesthetic drugs do not merely perturb measured variables, they shift thresholds and operating points that govern compensatory responses — as seen in thermoregulation, ventilatory control, and baroreflex function. The fluid set-point axis proposed here fits naturally into this broader idea: anesthesia as the management of drug-modifiable regulated states, rather than isolated numeric abnormalities to be corrected reflexively.

Subject of Research: Set-point shifts in peri-anesthetic fluid homeostasis: a conceptual framework informed by α2-agonist diuresis

Article Title: Set-point shifts in peri-anesthetic fluid homeostasis: a conceptual framework informed by α2-agonist diuresis

Article References: Nagahama, S. (2026). Set-point shifts in peri-anesthetic fluid homeostasis: a conceptual framework informed by α2-agonist diuresis. Frontiers in Anesthesiology, 5, Article 1873909. https://doi.org/10.3389/fanes.2026.1873909

Image Credits: AI Generated

DOI: 10.3389/fanes.2026.1873909

Keywords: anesthesia, dexmedetomidine, fluid homeostasis, oliguria, polyuria, vasopressin, set-point, perioperative medicine, shifts, peri-anesthetic, fluid, homeostasis

The clinical stakes are considerable. Propofol is a widely used anesthetic and sedative agent prized for its rapid onset and quick recovery profile, but questions have been raised about its safety when given repeatedly to young children. In pediatric oncology, patients with acute lymphoblastic leukemia, the most common childhood cancer, typically require numerous sedated procedures over two to three years of treatment, including diagnostic lumbar punctures with intrathecal chemotherapy and bone marrow aspirates to assess disease status. The study’s authors note that children exposed to high cumulative doses of propofol may be at increased risk for adverse neurocognitive outcomes, a possibility that has prompted clinicians and researchers to look for ways to minimize the total amount of propofol delivered across a treatment course.

Dexmedetomidine, the other drug at the center of the analysis, is a selective alpha-2 adrenergic agonist that produces sedation through a mechanism distinct from that of propofol. Rather than acting primarily on GABA receptors, dexmedetomidine targets receptors in the brainstem and elsewhere that modulate noradrenergic signaling, producing a sedative state that more closely resembles natural sleep. Beyond its sedative properties, experimental and preclinical studies have suggested that dexmedetomidine may have neuroprotective effects, a property that makes it particularly interesting in a pediatric population where concerns about anesthetic neurotoxicity are most acute. The drug has also shown a consistent propofol-sparing effect in prior work, meaning that when it is co-administered, less propofol is needed to achieve the same depth of sedation.

What remained incompletely characterized, however, was the shape of that relationship: how much propofol is actually saved per unit increase in dexmedetomidine dose, and whether the effect follows a dose-response pattern within the range of doses used in routine clinical practice. Answering that question was the central aim of the new study, which was conducted at the Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and supported by the Italian Ministry of Health in Rome. The research team, led by Julia Cavasin and Vittorio Greco of the University of Trieste together with colleagues at the institute, set out to evaluate the association between dexmedetomidine dose and propofol requirements during pediatric procedural sedation.

To do so, the investigators turned to their institution’s clinical records, identifying children with acute lymphoblastic leukemia who had undergone lumbar puncture or bone marrow aspiration under combined sedation with dexmedetomidine and propofol. The retrospective observational design allowed the team to analyze sedations that had already taken place as part of standard care, drawing on documented drug dosages, vital parameters, and adverse events. In total, the study encompassed 212 procedural sedations performed in 36 patients, a dataset that provided multiple observations per child and allowed the researchers to account for the fact that sedations within the same patient are not independent of one another.

The statistical approach was central to the study’s rigor. Because each child contributed several sedations, the team used a linear mixed-effects model, a technique that can simultaneously estimate the effect of interest while adjusting for repeated measures within individuals and for other factors that influence propofol requirements. The model adjusted for body weight, procedure type, and procedure duration, all of which could plausibly affect how much propofol a given sedation demands. Weight adjustment was particularly important because drug doses in pediatric practice are typically calculated per kilogram of body weight, and body size can independently alter anesthetic requirements.

The results revealed a statistically robust dose-response relationship. After adjustment for body weight, procedure type, and procedure duration, each 1 microgram per kilogram increase in dexmedetomidine dose was associated with a reduction of 0.87 milligrams per kilogram in propofol requirements, with a 95 percent confidence interval ranging from 1.50 to 0.24 milligrams per kilogram lower and a p-value of 0.0074. Translated into clinically relevant terms, the model estimated that moving from a dexmedetomidine dose of 1.0 to 1.5 micrograms per kilogram, a contrast relevant to the institution’s sedation protocol, would correspond to approximately 0.44 milligrams per kilogram less propofol, with a confidence interval of 0.75 to 0.12 milligrams per kilogram lower. The confidence intervals exclude zero, indicating that the association is unlikely to be a statistical artifact.

The analysis also identified other determinants of propofol need. Higher body weight was associated with lower weight-adjusted propofol requirements, a pattern consistent with known scaling relationships in anesthetic pharmacology, where per-kilogram dosing requirements tend to decline as children grow. Conversely, longer procedure duration and bone marrow aspiration were both associated with higher propofol requirements, which makes intuitive sense: longer sedations require more drug to maintain the desired depth, and bone marrow aspiration is among the more stimulating and painful procedures performed in this population, demanding deeper sedation than a lumbar puncture alone. These covariate findings reinforce the plausibility of the model and suggest that the dexmedetomidine effect was estimated against a backdrop of expected clinical variation.

The authors conclude that higher dexmedetomidine doses were associated with lower propofol requirements during procedural sedation in children with acute lymphoblastic leukemia, indicating an inverse dose-response association within the evaluated dose range. They frame the finding as real-world evidence, distinguishing it from the controlled conditions of randomized trials and laboratory experiments. Because the data come from routine clinical practice at a single pediatric oncology center, they reflect how these drugs are actually used together at the bedside, including the variability in patients, procedures, and clinical judgment that characterizes everyday care. That ecological validity is part of what makes the result useful for clinicians weighing sedation protocols.

Several caveats nonetheless temper the interpretation. As a retrospective observational study, the analysis can establish association but not causation; unmeasured factors that influenced both dexmedetomidine dosing decisions and propofol use could in principle contribute to the observed relationship. The single-center design and the relatively small number of patients, even though the number of sedations was substantial, may limit generalizability to other institutions and populations. The study also did not report long-term neurocognitive outcomes in the children themselves, so the clinical benefit of propofol sparing in terms of brain development remains a hypothesis grounded in preclinical evidence rather than a demonstrated outcome. Still, the dose-response gradient, the statistical adjustment for key confounders, and the consistency with prior experimental findings together make a compelling case that escalating dexmedetomidine within the studied range meaningfully reduces propofol exposure. For the growing number of children worldwide who require repeated sedated procedures during leukemia treatment, the finding suggests a practical lever for reducing cumulative propofol doses, one that future prospective studies can now test against the outcomes that matter most: the long-term cognitive health and quality of life of childhood cancer survivors.

Subject of Research: Dexmedetomidine dose-dependent propofol sparing during procedural sedation in pediatric oncology patients

Article Title: A retrospective evaluation of the relationship between dexmedetomidine dosage and propofol sparing in pediatric oncology sedation

Article References: Cavasin, J., Greco, V., Console, K., Lucafò, M., Rabusin, M., Verzegnassi, F., Franzelli, B., Barbi, E., & Dalena, P. (2026). A retrospective evaluation of the relationship between dexmedetomidine dosage and propofol sparing in pediatric oncology sedation. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07802-6

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07802-6

Keywords: dexmedetomidine, propofol, pediatric sedation, acute lymphoblastic leukemia, procedural sedation, dose-response, neuroprotection, anesthetic neurotoxicity, lumbar puncture, bone marrow aspiration, linear mixed-effects model, pediatric oncology

The research team, led by Xiaoyu Yang and Xiaoning Jiang with corresponding author Fan Wang, drew on trials conducted in patients aged 60 and older undergoing major orthopedic procedures such as hip and knee surgery. These operations are among the most common reasons older adults end up in the operating room, and they carry a substantial risk of delirium. The condition is not a minor side effect. Postoperative delirium is associated with longer hospital stays, increased rates of institutional discharge, accelerated cognitive decline, and higher mortality. For decades, clinicians have relied mainly on non-drug prevention strategies, such as reorientation protocols, sleep hygiene, early mobilization, and vision and hearing aids, because no pharmacological approach had been clearly validated.

The appeal of drug-based prevention lies in the biology of delirium itself. Scientists believe that surgical trauma triggers a cascade of neuroinflammatory events. Tissue injury releases damage-associated molecular patterns, which activate immune signaling and can drive elevations in inflammatory molecules such as interleukin-6 and tumor necrosis factor-alpha. These signals can disrupt the blood-brain barrier and disturb neurotransmitter systems, particularly acetylcholine and the N-methyl-D-aspartate receptor pathways, tipping the aging brain into the acute disorganization that defines delirium. The drugs tested in the trials reviewed here were chosen precisely because they interact with these pathways, either by damping inflammation or by protecting neurons from stress-related injury.

To compare these strategies fairly, the researchers performed a network meta-analysis, a statistical technique that allows both direct comparisons, from trials that tested two treatments against each other, and indirect comparisons, inferred through shared comparators such as placebo. They systematically searched four electronic databases for randomized controlled trials evaluating perioperative pharmacological strategies for postoperative delirium or postoperative cognitive outcomes in older orthopedic patients. Crucially, for the primary quantitative analysis, delirium had to be diagnosed using a validated instrument, such as the Confusion Assessment Method or the 3-Minute Diagnostic Confusion Assessment Method, rather than by informal clinical impression. This requirement matters because delirium is notoriously under-recognized at the bedside, and screening tools dramatically change detection rates.

Eighteen randomized controlled trials encompassing 4,132 participants made it into the systematic review. Of these, thirteen trials involving 3,466 participants formed the primary network for the delirium analysis, containing nine distinct treatment nodes. The team used a frequentist random-effects model and, importantly, modeled active drug comparisons separately from inert placebo or standard-care controls, a methodological choice designed to avoid distorting effect estimates. They reported odds ratios with 95 percent confidence intervals, which describe the precision of the observed effect, and also 95 percent prediction intervals, which estimate the range of effects one might expect in a future, real-world setting. They ranked treatments using P-scores, built a league table of all pairwise comparisons, mapped how much each trial contributed to the network, and graded the certainty of the evidence using a GRADE and CINeMA-style framework.

The headline findings were striking. Four interventions produced odds ratios whose confidence and prediction intervals both excluded the value of one, the threshold of no effect. An anti-inflammatory bundle showed the largest estimated benefit, with an odds ratio of 0.21, meaning roughly a 79 percent reduction in the odds of delirium compared with control. Dexmedetomidine produced an odds ratio of 0.37, dexamethasone 0.36, and parecoxib 0.46. Among these, dexmedetomidine stood out for a different reason: it was supported by the largest evidence base in the network, making its estimate the most trustworthy of the group. Dexmedetomidine is an alpha-2 adrenergic agonist, a sedative that calms patients without suppressing respiration, and it is already widely used in intensive care and anesthesia settings, which makes a preventive role particularly practical.

Not every candidate drug fared as well. Esketamine, an anesthetic agent acting on the NMDA receptor that had attracted interest for its neuroprotective potential, did not show a statistically significant protective effect against placebo, with an odds ratio of 0.77 and a confidence interval spanning 0.33 to 1.76. The researchers also tested whether the type of surgery modified how well the drugs worked, comparing effects across different orthopedic contexts. It did not. Interaction tests for dexmedetomidine, parecoxib, and propofol all returned non-significant p-values of 0.26, 0.50, and 0.53 respectively, meaning the analysis demonstrated no surgical-stress-dependent treatment hierarchy. In other words, there was no evidence that a particular operation type made one drug strategy clearly superior to another.

The authors were careful to temper enthusiasm with appropriate scientific caution. Certainty of the evidence remains moderate at best, and the network is sparse, with no independent closed loops, meaning the indirect estimates rest on relatively thin connections between trials. Several of the promising effect estimates, including the eye-catching figure for the anti-inflammatory bundle, rest on single small trials that could overstate true benefit. This is a well-known phenomenon in meta-analysis, where early small studies often report larger effects than later, better-powered replications. The prediction intervals, which account for between-study heterogeneity, help guard against false confidence, and the fact that four interventions passed that stricter test is genuinely encouraging, but the authors concluded that adequately powered, standardized head-to-head randomized trials are still needed before any drug can be recommended for routine prophylaxis.

Even so, the implications for perioperative medicine are significant. Hip fracture repair and joint replacement are performed millions of times each year worldwide, and the population undergoing them continues to age. If a low-cost, well-characterized drug such as dexmedetomidine, delivered during and around surgery, can meaningfully cut delirium risk, the potential public health impact is enormous, spanning shorter hospitalizations, fewer nursing home admissions, and preserved cognition for vulnerable patients. The study also delivers a methodological message to the field: future trials should use validated delirium screening instruments, consistent dosing protocols, and direct comparisons between the leading candidates rather than yet another placebo-controlled test of a single agent. Until those head-to-head studies arrive, this analysis provides the clearest map yet of which pharmacological strategies deserve the spotlight, and it places a familiar sedative at the center of one of geriatric surgery’s most urgent unanswered questions.

Subject of Research: Pharmacological prevention of postoperative delirium in older adults undergoing major orthopedic surgery

Article Title: Perioperative pharmacological prophylaxis of postoperative delirium after major orthopedic surgery in older adults: a systematic review and network meta-analysis of randomized controlled trials

Article References: Yang, X., Jiang, X., Xiao, R., Liu, J., Guo, Y., Ji, Y., Zhao, F., & Wang, F. (2026). Perioperative pharmacological prophylaxis of postoperative delirium after major orthopedic surgery in older adults: a systematic review and network meta-analysis of randomized controlled trials. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08430-6

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08430-6

Keywords: postoperative delirium, dexmedetomidine, orthopedic surgery, network meta-analysis, older adults, geriatrics, anesthesia, neuroinflammation, randomized controlled trials, dexamethasone, parecoxib, perioperative medicine