Constant Infusion Research Articles

Comparison of the Effectiveness of Warmed Versus Room Temperature Intravenous Fluids Administration to Prevent Intraoperative Heat Loss in Anaesthetised Calves Undergoing Umbilical Herniorrhaphy.

Warmed intravenous (IV) fluids administration to prevent hypothermia provide controversial results in humans, cats and dogs, but its effect on calves is unknown. To evaluate the effectiveness of warmed IV fluids administered to prevent intraoperative heat loss in anaesthetised calves undergoing umbilical herniorrhaphy. Thirty Simmental breed calves (aged 10-30days) were randomly divided between two equal groups, wherein the infusion fluid (Ringer's lactate, 5mL/kg/h) was administered either at room temperature (Group RoT) or warmed (Group WF). Pulse rate (PR), respiratory rate (fR), peripheral haemoglobin oxygen saturation (SpO2) and rectal temperature (RT) were recorded immediately after the onset of anaesthesia induction (T0) at T5, T10, T15, T30, T45 and T60. Duration of anaesthesia, surgery time and recovery scores were also noted. The PR, RT and fR values showed no significant difference between groups over time (p>0.05). There was no significant difference in duration of anaesthesia, surgery time or recovery score between groups (p>0.05). The findings of the current study suggest that warmed IV fluid as the warming method did not prevent intraoperative hypothermia in calves. A constant-rate infusion of warmed fluid (5mL/kg/h) is insufficient to prevent intraoperative hypothermia in calves.

Intravenous Lipid Emulsion for the Treatment of Ivermectin Toxicity in a Cat: A Case Report

A two-years-old male cat weighing three kg was presented to the Referral Veterinary Polyclinic of ICAR – Indian Veterinary Research Institute (IVRI), Izatnagar with history of anorexia, no water intake, ataxia, head tilting downward, sudden recumbency and loss of vision. While taking history the owner declared about the use of off-label oral ivermectin preparation @ 2.5 mg/kg total dose (5 times the recommended dose) once only. Cat had high rectal temperature (105° F), normal mucus membrane, tachypnoea (70/min), tachycardia(145/min). At the beginning, the patient received 20% lipid emulsion (Intralipid) at 1.5 mL/kg body weight, Diazepam 0.5 mg/kg b. wt. IV once, dexamethasone 0.5 mg/kg b. wt., and 25 mg/kg b. wt. bid of cefotaxime. The patient also received constant rate infusion therapy at 0.25 ml/kg/h, OD, and isotonic crystalloid solution (0.9% NS) at 30 ml/kg body weight for a total of 10 minutes. After three days, the cat's clinical condition returned to normal state. This case reports helps to readers in managing an emergency condition of ivermectin toxicity.

Meals Containing Equivalent Total Protein from Foods Providing Complete, Complementary, or Incomplete Essential Amino Acid Profiles do not Differentially Affect 24-h Skeletal Muscle Protein Synthesis in Healthy, Middle-Aged Women

BackgroundDietary protein quality can be assessed by skeletal muscle protein synthesis (MPS) stimulation. Limited knowledge exists on how consuming isonitrogenous meals with varied protein qualities affects postprandial and 24-h MPS. ObjectivesWe assessed the effects of protein quality and complementary proteins on MPS. We hypothesized that meals containing a moderate amount of high-quality, complete protein would stimulate postprandial and 24-h MPS. Meals containing 2 complementary, plant-based incomplete proteins would stimulate MPS less, and meals containing plant-based incomplete proteins at each meal, but complementary over 24 h would not stimulate MPS. Methods: This quasi-experimental study included a randomized, crossover design to assess protein quality and a nonrandomized low-protein control. We measured postprandial and 24-h MPS responses of healthy middle-aged women (n = 9, age 56 ± 4 y), to 3 dietary conditions: isonitrogenous meals containing 23 g protein/meal from 1) complete protein (lean beef), 2) 2 incomplete, but complementary protein sources (navy/black beans and whole wheat bread), and 3) single incomplete protein sources (black beans or whole wheat bread at 1 meal), but providing a complete amino acid profile over 24 h. In the low-protein group women (n = 8, 54 y) consumed a single breakfast meal containing 5 g of protein. Venous blood and vastus lateralis samples were obtained during primed, constant infusions of L-[ring-13C6]phenylalanine to measure mixed muscle fractional synthetic rates (FSR). ResultsMeals containing complete, complementary, or incomplete proteins did not differentially influence FSR responses after breakfast (P = 0.90) or 24 h (P = 0.38). At breakfast, the complete (P = 0.030) and complementary (P = 0.031) protein meals, but not the incomplete protein meal (P = 0.38), had greater FSR responses compared with the low-protein control meal. ConclusionsIsonitrogenous meals containing a moderate serving of total protein from foods providing complete, complementary, or incomplete essential amino acid profiles do not differentially stimulate muscle protein synthesis after a meal and daily. Trial registration numberThis clinical trial was registered at clinicaltrials.gov as NCT03816579. URLhttps://www.clinicaltrials.gov/ct2/show/NCT03816579?term=NCT03816579&draw=2&rank=1.

476 Induced hindgut acidosis in sheep affected gut permeability and ruminal fermentation

Abstract Leaky gut may be caused by acidotic conditions in the hindgut and lead to systemic inflammation and negative effects on the gastrointestinal tract. The objective was to determine the effects of induced hindgut acidosis in sheep on cecal pH, ruminal fermentation, and gut permeability. Ruminally and cecally cannulated ewes [n = 11; body weight (BW) = 49 ± 4 kg] were assigned to one of two treatments: control (CON; n = 5) or induced hindgut acidosis (HGA; n = 6). To induce hindgut acidosis, 3 g wheat starch/kg BW per 24 h was continuously infused via the cecal cannula for 4 d. Control ewes received a constant infusion of deionized water. The diet contained 40% grass hay pellets, 35% whole shelled corn, 15% dried distillers grains, and 10% alfalfa cubes. Chromium EDTA was dosed once daily via the cecal cannula as a marker of gut permeability. Rumen, cecal, and fecal samples were collected to determine pH and volatile fatty acids (VFA). Rumen fluid was collected on d 4 for an ex vivo fermentation. Flasks were incubated for 24 h to determine pH, VFA, ammonia and in vitro dry matter digestibility. Tissue samples from the ileum, cecum, and colon were mounted in Ussing chambers to measure transepithelial electrical resistance (TEER). There was a treatment × time effect (P = 0.05) for cecal pH with HGA ewes having lesser cecal pH after d 1. By d 4, cecal pH had declined to 5.07 for HGA ewes compared with CON ewes which remained above 6.40 throughout the experiment. A treatment × time interaction was also observed (P < 0.01) for fecal pH and followed the same trend as cecal pH. Rumen pH was not affected (P = 0.87) by the interaction of treatment and time but was affected (P < 0.01) by treatment as ewes on the HGA treatment had a lesser rumen pH than CON ewes. Control ewes had lesser ruminal VFA and ammonia concentrations than HGA ewes (P < 0.01). Urinary Cr recovery was not affected by the interaction of treatment and time, or treatment (P ≥ 0.13). In vitro dry matter disappearance was not affected by cecal infusion treatment (P = 0.60). There was no effect (P = 0.78) of treatment on ex vivo pH. There were no effects (P ≥ 0.11) of treatment, time, or their interaction on ex vivo ammonia or total VFA concentration. In cecal tissue, TEER tended (P = 0.09) to be greater in CON ewes than HGA ewes. In contrast, TEER was not different (P ≥ 0.83) in ileal or colonic tissues between treatments. Induced hindgut acidosis in sheep altered rumen fermentation and tended to increase ex vivo measures of cecal permeability, but did not affect ex vivo rumen fermentation.

Hepato-splanchnic fluxes during exercise in patients with cirrhosis-a pilot study.

In cirrhotic patients, compromised hepatocyte function combined with disturbed hepatic blood flow could affect hepato-splanchnic substrate and metabolite fluxes and exacerbate fatigue during exercise. Eight cirrhotic patients performed incremental cycling trials (3 × 10 min; at light (28 [19-37] W; median with range), moderate (55 [41-69] W), and vigorous (76 [50-102] W) intensity). Heart rate increased from 68 (62-74) at rest to 95 (90-100), 114 (108-120), and 140 (134-146) beats/min (P < 0.05), respectively. The hepatic blood flow, as determined by constant infusion of indocyanine green with arterial and hepatic venous sampling, declined from 1.01 (0.75-1.27) to 0.69 (0.47-0.91) L/min (P < 0.05). Hepatic glucose output increased from 0.6 (0.5-0.7) to 1.5 (1.3-1.7) mmol/min, while arterial lactate increased from 0.8 (0.7-0.9) to 9.0 (8.1-9.9) mmol/L (P < 0.05) despite a rise in hepatic lactate uptake. Arterial ammonia increased in parallel to lactate from 47.3 (40.1-54.5) to 144.4 (120.5-168.3) μmol/L (P < 0.05), although hepatic ammonia uptake increased from 19.5 (12.4-26.6) to 69.5 (46.5-92.5) μmol/min (P < 0.05). Among the 14 amino acids measured, glutamate was released in the liver, while the uptake of free fatty acids decreased. During exercise at relatively low workloads, arterial lactate and ammonia levels were comparable to those seen in healthy subjects at higher workloads, while euglycemia was maintained due to sufficient hepatic glucose production. The accumulation of lactate and ammonia may contribute to exercise intolerance in patients with cirrhosis.

Pain related syndrome of inappropriate antidiuretic hormone secretion in a kitten

A 2-month-old domestic shorthair kitten was presented for evaluation of weakness, gait abnormalities, and signs of pain after trauma. On admission, the patient was found laterally recumbent with obvious gait abnormalities: difficulty rising from sitting and marked unilateral left hind limb lameness. On orthopedic examination, severe pain, crepitations, and swelling of the left hind limb were detected. Results of the first diagnostic work-up were all consistent with hyponatremia, hypochloremia and a Salter-Harris type I fracture.The kitten initially received isotonic fluids, analgesia, and antiemetic treatment. Twelve hours after admission, the analgesic plan was considered insufficient, and the general patient's condition worsened, showing severe mental depression. Blood and urine samples were collected for a more in-depth diagnostic evaluation; the patient showed worsening hyponatremia (113 mmol/L; [RR: 146,2-156,2]), severe plasma hypoosmolality (218.2 mOsm/kg; [RR: 287-307 mOsm/kg]), high natriuresis (Na: 74.9 mmol/L; [RR: <40 mmol/L]), and urinary hyperosmolality (630 mOsm/kg; [RR: <150 mOsm/kg]). Based on these new clinical findings syndrome of inappropriate antidiuretic hormone (SIADH) secretion was diagnosed.Emergency treatment with hypertonic saline was then instituted, a constant rate infusion of 3% hypertonic saline infusion to increase plasma sodium was initiated and a loop diuretic, furosemide (1 mg/kg/IV), was administered at 12-hour intervals to induce diuresis. Discharge occurred 4 days after admission as the patient was clinically stable and the hyponatremia progressively resolved. To the author's knowledge this is the first report of a kitten developing pain related SIADH associated to orthopedic trauma.

The effect of intravenous magnesium sulphate infusion on total intravenous anesthesia with propofol in adult dogs: A randomized, blinded trial

ObjectiveTo evaluate cardiopulmonary, arterial blood gas and propofol-sparing effects of magnesium sulfate (MgSO4) constant rate infusion (CRI) in mechanically ventilated dogs maintained under total intravenous anesthesia with propofol. Study designBlinded, randomized, clinical trial. AnimalsA total of 24 healthy adult dogs. MethodsDogs were premedicated with intramuscular acepromazine (0.05 mg kg–1) and morphine (0.5 mg kg–1), followed by an intravenous (IV) bolus of saline or MgSO4 (50 mg kg–1 over 15 minutes) and propofol (given to effect to induce anesthesia). Anesthesia was maintained with an IV propofol infusion (beginning at 0.3 mg kg–1 minute–1, adjusted as necessary). Concurrently, one of three IV infusions were administered: GS (0.9% NaCl), GM30 (MgSO4, 30 mg kg–1 hour–1) or GM80 (MgSO4, 80 mg kg–1 hour–1). Propofol induction and maintenance doses were recorded. The following variables were recorded at baseline (T0), after bolus treatment (T1), after beginning mechanical ventilation (T5) and every 15 minutes until the end of the procedure (T15–T120): mean arterial pressure, heart rate, peripheral oxygen saturation, end-tidal partial pressure of CO2, temperature, blood gas variables, indirect calorimetry and extubation time. Values of p < 0.05 were considered significant. ResultsPropofol induction bolus dose was lower in GM30 (31.2%, p = 0.04) and GM80 (38.9%, p = 0.003) than in GS. The maintenance propofol infusion rate in GM80 was 16.9% lower (p = 0.03), resulting in fewer propofol CRI rescues during the perioperative period. GM30 and GM80 exhibited faster extubation times than GS (46.2%, p = 0.002 and 48.9%, p = 0.001, respectively). Conclusions and clinical relevanceInfusion of a 50 mg kg–1 bolus, followed by CRI of MgSO4 (30 and 80 mg kg–1 hour–1), reduces the propofol induction and maintenance (CRI) requirement, maintaining cardiorespiratory stability and reducing the time required to extubation.

Effect of dexmedetomidine constant rate infusion on the analgesic duration of peripheral nerve blocks in dogs: a randomized clinical study

The aim of this study was to evaluate whether a constant rate infusion of dexmedetomidine could prolong the analgesic effect of peripheral nerve blocks. Twenty client-owned dogs were enrolled and randomly divided into 2 groups. The DEX group received dexmedetomidine infusion at 1 mcg kg−1 h−1, and the NaCl group received an equivalent volume infusion of saline. Infusions were started after securing vascular access and continued for 10 min, after which intravenous (IV) methadone at 0.2 mg kg−1 and propofol to effect were administered. All animals were maintained with isoflurane in 70% oxygen. Sciatic, saphenous and obturator nerve blocks were performed using 0.1 mL kg−1 0.5% ropivacaine/block. Intraoperative fentanyl was administered if the heart rate and/or mean arterial pressure (MAP) increased > 15% from the previous measurement, and vasopressors were administered if MAP was ≤ 70 mmHg. Postoperative pain was assessed every hour using the Glasgow Composite Pain Scale (GCPS) until the first rescue analgesia administration. Postoperative rescue analgesia (methadone (0.2 mg kg−1 IV) and carprofen (2 mg kg−1 IV)) was administered if the pain score was higher than 6/24 or 5/20. Duration of analgesia was defined as the time between the nerve block procedure and initial postoperative rescue analgesia. Ambulation, proprioception, and skin sensitivity were evaluated to assess the duration of the motor and sensory block. A Student T and chi-square test were used to compare groups for duration of postoperative analgesia and intraoperative fentanyl and vasopressor use, respectively (p values ≤ 0.5 considered significant). A greater number of dogs in the NaCl group required fentanyl (5/10 p = 0.03) and vasopressors (8/10, p = 0.02) than did those in the DEX group (0/10 and 2/10, respectively). The duration of postoperative analgesia was significantly longer (604 ± 130 min) in the DEX group than in the NaCl group (400 ± 81 min, p = 0.0005).Dexmedetomidine infusion at 1 mcg kg−1 h−1 delays the time to first administration of rescue analgesia and reduces intraoperative analgesic and vasopressor requirements during Tibial Tuberosity Advancement surgery.

Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives.

One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia.

Addition of a metoclopramide constant rate infusion to prevent ptyalism, regurgitation and vomiting in brachycephalic dogs undergoing spinal surgery

ObjectiveTo assess whether adding metoclopramide to a protocol of maropitant and pantoprazole would reduce incidence of ptyalism, vomiting and regurgitation in brachycephalic dogs undergoing thoracolumbar spinal surgery. Study designRandomized blinded controlled trial. AnimalsA total of 43 brachycephalic dogs undergoing thoracolumbar spinal surgery. MethodsIn addition to a standardized anaesthetic regimen, dogs were randomized to be administered either a 2 mg kg–1 day–1 metoclopramide constant rate infusion (CRI) or a saline solution at an equivalent infusion rate, started after anaesthetic induction and discontinued 5 hours after tracheal extubation. The presence of vomiting, regurgitation and pytalism, and short form of the Glasgow Composite Pain Scale pain scores were assessed by a blinded observer hourly for 4 hours, starting 1 hour postextubation. ResultsRegurgitation occurred in six dogs postoperatively; three dogs were in the placebo group and three in the metoclopramide group. The odds ratio (OR) of regurgitation after surgery did not differ between groups [OR: 0.76, 95% confidence interval (CI): 0.13–4.3, p = 0.76]. The odds of observing ptyalism at 3 and 4 hours was approximately 15 times less than 1 hour postoperatively (both OR: 15.4, 95% CI: 1.8–130.7, p = 0.012) and did not differ based on the addition of metoclopramide (OR: 0.73, 95% CI: 0.07–8.0, p = 0.79). The odds of observing pain did not change over time and did not differ based on the addition of metoclopramide (OR: 0.71, 95% CI: 0.12–4.2, p = 0.71). Vomiting did not occur during the study (0.0%, 95% CI: 0.0–8.2%). No adverse effects were observed during the study period in either group. Conclusions and clinical relevanceThe addition of a metoclopramide CRI to maropitant and pantoprazole did not result in a significant reduction in ptyalism or regurgitation in brachycephalic dogs undergoing thoracolumbar spinal surgery.

Efficacy and safety of alfaxalone compared to propofol in canine refractory status epilepticus: a pilot study.

Refractory status epilepticus (RSE) is defined as seizure activity that is minimally responsive to first- or second-line antiseizure medications. Constant rate infusion (CRI) intravenous propofol (PPF) is commonly used to treat RSE in dogs and cats. The antiseizure activity of alfaxalone (ALF) in RSE has been demonstrated in various experimental studies. This study compared the clinical efficacy and safety of intramuscular administration followed by CRI infusion of ALF with intravenous administration followed by CRI infusion of PPF to treat canine RSE. This was a multicenter, prospective, randomized clinical trial of client-owned dogs referred for status epilepticus that did not respond to first- and second-line drugs. Animals with suspected or confirmed idiopathic or structural epilepsy were included. The dogs were randomly assigned to either the PPF or ALF treatment groups and each group received drug CRI infusions for 6 h. Drug dosages were progressively reduced by 25% every hour from the third hour until suspension after 6 h. Patients were classified as responders or non-responders based on the relapse of epileptic seizures during the 24 h therapy infusion or within 24 h of drug suspension. Univariate statistical analyses were performed. Twenty dogs were enrolled in the study. Ten (10/20) dogs were randomly allocated to the PPF group and 10 (10/20) to the ALF group. Successful outcomes were obtained in six (6/10) patients in the PPF group and five (5/10) patients in the ALF group. Adverse effects were recorded in six (6/10) and three (3/10) animals in the PPF and ALF groups, respectively. No statistically significant differences in outcomes or the presence of adverse effects were observed between the groups. The results of this preliminary study suggest that ALF can be considered a valid and safe alternative to PPF for the treatment of RSE in dogs, with the additional advantage of intramuscular administration. However, caution should be exercised when using these drugs to provide airway and hemodynamic support.

Therapeutic Insulin Analogue Concentrations at Infusion Sites Enhanced the Pro-Inflammatory Response and Apoptosis in an In Vitro Macrophage-Material Interaction Model.

Continuous subcutaneous insulin infusion for Type 1 diabetes relies upon insulin infusion sets (IIS) to reliably deliver insulin to a subcutaneous depot, where it is absorbed into systemic circulation. However, IIS are plagued by short wear times and high failure rates, due in part to inconsistent insulin absorption that can arise over time. While emerging evidence suggests that the local inflammatory response to the IIS cannula may impact both wear times and unreliable insulin adsorption, the mechanisms are poorly understood. Here, we investigated the effects of local infused insulin concentrations on the biomaterial host response to better understand the underlying factors that limit the IIS performance. We first modeled the insulin concentration for a constant basal infusion rate to select a relevant insulin concentration range of 0.1-10 U/mL within the infusion site. We then examined the influence of a commercial insulin analogue (Humulin-N) using an in vitro macrophage-material model, which uses adsorbed fibroblast lysate (containing damage-associated molecular patterns) to activate macrophages and recapitulates macrophage responses on implanted biomaterials. RAW-Blue macrophages cultured on lysate-adsorbed surfaces had increased nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) activity and intracellular reactive oxygen species (ROS) accumulation compared to control surfaces. Humulin-N concentration (0.5-10 U/mL) enhanced the NF-κB/AP-1 activity and ROS accumulation in macrophages on lysate-adsorbed surfaces. However, Humulin-N had no effect on NF-κB/AP-1 or ROS in the absence of the inflammatory stimulus. Additionally, high insulin concentrations arising from therapeutic doses induced macrophage apoptosis with and without adsorbed lysate. This study contributes to emerging evidence that infused insulin affects the tissue response to IIS.

Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses.

To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects. Experimental study; randomized, crossover design. Six healthy adult horses. Each horse received metoclopramide via IV CRI (0.04 mg/kg/h for 24 h) and SC bolus (0.08 mg/kg once), with ≥1 week washout period between. Plasma was analyzed by UPLC-MS/MS. Compartmental modeling was used to determine PK parameters for each treatment; nonparametric superposition was used to simulate multiple SC bolus regimens. Gastrointestinal motility and evidence of adverse effects were monitored. Tmax (h) for SC bolus was 0.583 ± 0.204 versus 17.3 ± 6.41 for IV CRI, while Cmax (ng/mL) was 27.7 ± 6.38 versus 43.6 ± 9.97, respectively. AUC (h × ng/mL) was calculated as 902 ± 189 for 24 h IV CRI versus 244 ± 37.4 simulated for 0.08 mg/kg SC bolus every 8 h. Simulations revealed similar exposure between groups with administration of 0.96 mg/kg/day SC bolus, divided into three, four, or six doses. SC bolus bioavailability was estimated as 110 ± 11.5%. No clear trends in motility alteration were identified. No adverse effects were noted. Repeated SC boluses of metoclopramide at 0.08 mg/kg would result in lower total drug exposure and Tmax than IV CRI administration but would be highly bioavailable. Higher and/or more frequent SC bolus doses are needed to achieve a similar AUC to IV CRI. No adverse effects were noted; however, evaluation of alternative dosing strategies is warranted.

Connectivity based on glucose dynamics reveals exaggerated sensorimotor network coupling on subject-level in Parkinson’s disease

PurposeWhile fMRI provides information on the temporal changes in blood oxygenation, 2- [18F]fluoro-2-deoxy-D-glucose ([18F]FDG)-PET has traditionally offered a static snapshot of brain glucose consumption. As a result, studies investigating metabolic brain networks as potential biomarkers for neurodegeneration have primarily been conducted at the group level. However, recent pioneering studies introduced time-resolved [18F]FDG-PET with constant infusion, which enables metabolic connectivity studies at the individual level.MethodsIn the current study, this technique was employed to explore Parkinson’s disease (PD)-related alterations in individual metabolic connectivity, in comparison to inter-subject measures and hemodynamic connectivity. Fifteen PD patients and 14 healthy controls with comparable cognition underwent sequential resting-state dynamic PET with constant infusion and functional MRI. Intrinsic networks were identified by independent component analysis and interregional connectivity calculated for summed static PET images, PET time series and functional MRI.ResultsOur findings revealed an intrinsic sensorimotor network in PD patients that has not been previously observed to this extent. In PD, a significantly higher number of connections in cortical motor areas was observed compared to elderly control subjects, as indicated by both static PET and functional MRI (pBonferroni−Holm = 0.027), as well as constant infusion PET and functional MRI connectomes (pBonferroni−Holm = 0.012). This intensified coupling was associated with disease severity (ρ = 0.56, p = 0.036).ConclusionMetabolic connectivity, as revealed by both static and dynamic PET, provides unique information on metabolic network activity. Subject-level metabolic connectivity based on constant infusion PET may serve as a potential marker for the metabolic network signature in neurodegeneration.

Total intravenous anesthesia with Ketofol in rabbits: a comparison of the effects of constant rate infusion of midazolam, fentanyl or dexmedetomidine

BackgroundWhen inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain general anesthesia. Total intravenous anesthesia (TIVA) does not require endotracheal intubation, which may be more difficult to achieve in rabbits. A range of different injectable drug combinations have been used as continuous infusion rate in animals. Recently, a combination of ketamine and propofol (ketofol) has been used for TIVA in both human patients and animals. The purpose of this prospective, blinded, randomized, crossover study was to evaluate anesthetic and cardiopulmonary effects of ketofol total intravenous anesthesia (TIVA) in combination with constant rate infusion (CRI) of midazolam, fentanyl or dexmedetomidine in eight New Zealand White rabbits. Following IV induction with ketofol and endotracheal intubation, anesthesia was maintained with ketofol infusion in combination with CRIs of midazolam (loading dose [LD]: 0.3 mg/kg; CRI: 0.3 mg/kg/hr; KPM), fentanyl (LD: 6 µg/kg; CRI: 6 µg/kg/hr; KPF) or dexmedetomidine (LD: 3 µg/kg; CRI: 3 µg/kg/hr; KPD). Rabbits in the control treatment (KPS) were administered the same volume of saline for LD and CRI. Ketofol infusion rate (initially 0.6 mg kg− 1 minute− 1 [0.3 mg kg− 1 minute− 1 of each drug]) was adjusted to suppress the pedal withdrawal reflex. Ketofol dose and physiologic variables were recorded every 5 min.ResultsKetofol induction doses were 14.9 ± 1.8 (KPM), 15.0 ± 1.9 (KPF), 15.5 ± 2.4 (KPD) and 14.7 ± 3.4 (KPS) mg kg− 1 and did not differ among treatments (p > 0.05). Ketofol infusion rate decreased significantly in rabbits in treatments KPM and KPD as compared with saline. Ketofol maintenance dose in rabbits in treatments KPM (1.0 ± 0.1 mg/kg/min) and KPD (1.0 ± 0.1 mg/kg/min) was significantly lower as compared to KPS (1.3 ± 0.1 mg/kg/min) treatment (p < 0.05). Ketofol maintenance dose did not differ significantly between treatments KPF (1.1 ± 0.3 mg/kg/min) and KPS (1.3 ± 0.1 mg/kg/min). Cardiovascular variables remained at clinically acceptable values but ketofol infusion in combination with fentanyl CRI was associated with severe respiratory depression.ConclusionsAt the studied doses, CRIs of midazolam and dexmedetomidine, but not fentanyl, produced ketofol-sparing effect in rabbits. Mechanical ventilation should be considered during ketofol anesthesia, particularly when fentanyl CRI is used.

BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons

BackgroundHigh-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs.MethodsThree-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted.ResultsUsing a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic–euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice.ConclusionThese findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.

e18003 Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Glucagon infusion alters the circulating metabolome and urine amino acid excretion in dogs.

Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes in people associated with glucagon infusions have been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigation. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) - low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90-120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagon's glucose-independent modulation of the canine plasma metabolome and highlight the dog's relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.

Quantifying Diaphragm Blood Flow With Contrast-Enhanced Ultrasound in Humans

Despite the known interplay between blood flow and function, to our knowledge, there is currently no minimally invasive method to monitor diaphragm hemodynamics. We used contrast-enhanced ultrasound to quantify relative diaphragm blood flow (Q˙DIA) in humans and assessed the technique's efficacy and reliability during graded inspiratory pressure threshold loading. We hypothesized that: (1) Q˙DIA would linearly increase with pressure generation, and (2) that there would be good test-retest reliability and interanalyzer reproducibility. Can we validate what is, to our knowledge, the first minimally invasive method to measure relative diaphragm blood flow in humans? Quantitative contrast-enhanced ultrasound of the costal diaphragm was performed in healthy participants (10 male participants, 6 female participants; mean age 28 ± 5 years; BMI 22.8 ± 2.0kg/m) during unloaded breathing and three stages of loaded breathing on two separate days. Gastric and esophageal balloon catheters measured transdiaphragmatic pressure. Ultrasonography was performed during a constant-rate IV infusion of lipid-stabilized microbubbles following each stage. Ultrasound images were acquired after a destruction-replenishment sequence and diaphragm specific time-intensity data were used to determine Q˙DIA by two individuals. Transdiaphragmatic pressure for unloaded and each loading stage were 15.2 ± 0.8, 26.1 ± 0.8, 34.6 ± 0.8, and 40.0 ± 0.8 percentage of the maximum, respectively. Q˙DIA increased with each stage of loading (3.1 ± 3.1, 6.9 ± 3.6, 11.0 ± 4.9, and 13.5 ± 5.4 acoustic units/s; P< .0001). The linear relationship between diaphragmatic flow and pressure was reproducible from day to day. Q˙DIA had good to excellent test-retest reliability (0.86 [0.77, 0.92]; P< .0001) and excellent interanalyzer reproducibility (0.93 [0.90, 0.95]; P< .0001) with minimal bias. Relative Q˙DIA measurements had valid physiological underpinnings, were reliable day-to-day, and were reproducible analyzer-to-analyzer. This study indicated that contrast-enhanced ultrasound is a viable, minimally invasive method for assessing costal Q˙DIA in humans and may provide a tool to monitor diaphragm hemodynamics in clinical settings.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BackgroundUse of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation.MethodsWe measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis.ResultsBoth mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group.ConclusionsOur main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy.Trial registrationclinicaltrials.gov (NCT02752113).