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We characterized the volume kinetics of crystalloid solutions (Ringer’s lactate solution and 5% dextrose water) and colloid solutions (6% tetrastarch and 10% pentastarch) by nonlinear mixed-effects modeling in healthy volunteers. We also assessed whether the bioelectrical impedance analysis parameters are significant covariates for volume kinetic parameters. Twelve male volunteers were randomly allocated to four groups, and each group received the four fluid solutions in specified sequences, separated by 1-week intervals to avoid any carryover effects. Volunteers received 40 ml/kg Ringer’s lactate solution, 20 ml/kg 5% dextrose water, 1000 ml 6% tetrastarch, and 1000 ml 10% pentastarch over 1 h. Arterial blood samples were collected to measure the hemoglobin concentration at different time points. Bioelectrical impedance spectroscopy (BIS, INBODY S10, InBody CO., LTD, Seoul, Korea) was also carried out at preset time points. In total, 671 hemoglobin-derived plasma dilution data points were used to determine the volume kinetic characteristics of each fluid. The changes in plasma dilution induced by administration of crystalloid and colloid solutions were well-described by the two-volume and one-volume models, respectively. Extracellular water was a significant covariate for the peripheral volume of distribution at baseline in the volume kinetic model of Ringer’s lactate solution. When the same amount was administered, the colloid solutions had ~4 times more plasma expansion effect than did the crystalloid solutions. Starches with larger molecular weights maintained the volume expansion effect longer than those with smaller molecular weights.

Background Fluid loading with crystalloids is the conventional treatment of major hemorrhage but might tend to create fluid overload. We studied hemodynamic profiles of fluid replacement therapies during major surgical hemorrhage and compared the ability of pulse pressure variation (PPV), plethysmographic variation index (PVI), cardiac output (CO) and Guyton´s approach to detect hypovolemia. Methods In this single center randomized controlled trial, fluid replacement therapy to treat hemorrhage in 42 patients was randomized to consist of either 5% albumin (12 mL/kg) or 20% albumin (3 mL/kg) over 30 min, both completed by Ringer lactate replacing blood loss in a 1:1 ratio, or Ringer solution alone in a 3:1 ratio. Measurements included CO, PPV, PVI, arterial and central venous pressures, heart rate (HR) and subsequent calculation of Guyton´s physiological parameters. CO was measured by an esophageal Doppler probe. Results The Ringer-only fluid program resulted in slight hypovolemia (mean, 313 mL), decreased mean arterial pressure (MAP), increased HR, PPV values and vasopressor requirement. The 5% and 20% albumin programs were more effective in filling the vascular system, as evidenced by higher mean circulatory filling pressure and unchanged or decreased PPV over the 5 h observation period. The 20% albumin increased the systemic vascular resistance and the resistance to venous return. Receiver operating characteristics curves indicated that hypovolemia > 500 mL could only be accurately detected by PPV when 5% albumin was used, that PVI was reliable when Ringer was infused, and that CO indicated the hypovolemia when 20% albumin was administered. Conclusions The trends in PPV, PVI, and CO reflected the changes in intravascular volume, but how well they indicated hypovolemia > 500 mL may differ depending on the choice of infusion fluid. Identifying hypovolemia using non-invasive hemodynamic monitors remains challenging and associated with low predictive values. Trial registration number: NCT05391607, May 26, 2022.

ObjectiveTo determine if very low dose (VLD, 0.5% phenylephrine, 0.1% cyclopentolate) mydriatic microdrop (approximately 7 μL) administration (up to three doses) is non-inferior to low dose (LD, 1% phenylephrine, 0.2% cyclopentolate) mydriatic microdrop administration for ophthalmologist-determined successful retinopathy of prematurity eye examination (ROPEE).DesignMulticentre, prospective, randomised controlled, non-inferiority clinical trial.SettingFour neonatal intensive care units in Aotearoa, New Zealand from October 2019 to September 2021.PatientsInfants with a birth weight less than 1250 g or gestational age less than 30+6 weeks and who required a ROPEE.InterventionsThe intervention: microdrop (approximately 7 μL) of VLD (0.5% phenylephrine and 0.1% cyclopentolate) to both eyes, or the comparison: microdrop of LD (1% phenylephrine and 0.2% cyclopentolate) to both eyes. Up to three doses could be administered.Main outcome measuresThe primary outcome measure was an ophthalmologist-determined successful ROPEE.ResultsOne hundred and fifty preterm infants (LD mean GA=27.4±1.8 weeks, mean birth weight=1011±290 g, VLD mean GA=27.5±1.9 weeks, mean birth weight=1049±281 g,) were randomised. Non-inferiority for successful ROPEE was demonstrated for the VLD group compared with the LD group (VLD successful ROPEE=100%, LD successful ROPEE=100%, 95% CI no continuity correction −0.05 to 0.05) and for Māori (95% CI no continuity correction −0.02 to 0.19).ConclusionVLD microdrops enable safe and effective screening for ROPEE in both Māori and non-Māori preterm infants.Trial registration numberACTRN12619000795190.

Background Recent evidence suggests that acetate-buffered infusions result in better hemodynamic stabilization than 0.9% saline in patients undergoing major surgery. The choice of buffer in balanced crystalloid solutions may modify their hemodynamic effects. We therefore compared the inopressor requirements of Ringer’s acetate and lactate for perioperative fluid management in patients undergoing cardiac surgery. Methods Using a randomized controlled double-blind design, we compared Ringer’s acetate (RA) to Ringer’s lactate (RL) with respect to the average rate of inopressor administered until postoperative hemodynamic stabilization was achieved. Secondary outcomes were the cumulative dose of inopressors, the duration of inopressor administration, the total fluid volume administered, and the changes in acid-base homeostasis. Patients undergoing elective valvular cardiac surgery were included. Patients with severe cardiac, renal, or liver disease were excluded from the study. Results Seventy-five patients were randomly allocated to the RA arm, 73 to the RL. The hemodynamic profiles were comparable between the groups. The groups did not differ with respect to the average rate of inopressors (RA 2.1 mcg/kg/h, IQR 0.5–8.1 vs. RL 1.7 mcg/kg/h, IQR 0.7–8.2, p  = 0.989). Cumulative doses of inopressors and time on individual and combined inopressors did not differ between the groups. No differences were found in acid-base parameters and their evolution over time. Conclusion In this study, hemodynamic profiles of patients receiving Ringer’s lactate and Ringer’s acetate were comparable, and the evolution of acid-base parameters was similar. These study findings should be evaluated in larger, multi-center studies. Trial registration Clinicaltrials.gov NCT02895659 . Registered 16 September 2016.

AimsTo demonstrate non-inferiority of a hydroxypropyl guar/polyethylene glycol/propylene glycol lubricating eye-drop (HPG/PEG/PG) compared with an osmoprotective carboxymethylcellulose/glycerine eye-drop (O/CMC) for ocular surface staining.MethodsThis was a multicentre, randomised, observer-masked, parallel-group study. Adults with dry eye instilled HPG/PEG/PG/ or O/CMC 4 times daily for 35 days and then as needed through day 90. Total ocular surface staining (TOSS) score changes from baseline and Impact of Dry Eye on Everyday Life (IDEEL) treatment satisfaction module scores were assessed. Non-inferiority, based on TOSS score change from baseline, was concluded if the upper limit of the 2-sided CI was <2 units.ResultsMean±SD patient age was 64.4±13.7 years; 94 patients were randomised to treatment (HPG/PEG/PG, n=46; O/CMC, n=48). Mean±SE TOSS score change from baseline to day 35 was −2.2±0.33 with HPG/PEG/PG and −1.7±0.47 with O/CMC (treatment difference, −0.47±0.47; p=0.38), and the non-inferiority criterion was met. IDEEL treatment satisfaction scores were similar between groups at day 35 and day 90. The most frequently reported adverse event was eye irritation (HPG/PEG/PG, n=2; O/CMC, n=3).ConclusionsHPG/PEG/PG and O/CMC reduced ocular surface damage, and HPG/PEG/PG was non-inferior to O/CMC. Both treatments were effective, convenient and well tolerated.Trial registration numberNCT01863368, Results.

Oral rehydration solutions (ORSs) is the key treatment of acute diarrhea in children, as it restores the electrolyte balance by stimulating the intestinal sodium/glucose transporter SGLT1 to induce fluid absorption. The World Health Organization (WHO) and The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) proposed ORSs with different chemical compositions. The main agent of childhood acute gastroenteritis is rotavirus (RV). We evaluate the effects of ORS with different concentration of glucose and sodium on RV induced secretion. Ussing chambers technique was used for electophysiology experiments to evaluate ion fluid flux. ESPGHAN ORS (sodium 60 mmol/L and glucose 111 mmol/L) induced a more potent proabsorptive effect in Caco-2 cells than WHO ORS, and this effect depended on the sodium/glucose ratio. Titration experiments showed that RV-induced fluid secretion can be reverted to a proabsorptive direction when sodium and glucose concentration fall in specific ranges, specifically 45–60 mEq/L and 80–110 mM respectively. The results were confirmed by testing commercial ORSs. These findings indicated that ORS proabsorptive potency depends on sodium and glucose concentrations. Optimal ORS composition should be tailored to reduce RV-induced ion secretion by also considering palatability. These in vitro data should be confirmed by clinical trials.

The effect of intravenous (IV) fluid administration type on cerebral perfusion pressure (CePP) during cardiopulmonary resuscitation (CPR) is controversial. The purpose of this study was to evaluate the association between IV fluid type and CePP in a porcine cardiac arrest model. We randomly assigned 12 pigs to the hypertonic crystalloid, isotonic crystalloid and no-fluid groups. After 4 min of untreated ventricular fibrillation (VF), chest compression was conducted for 2 cycles (CC only). Chest compression with IV fluid infusion (CC + IV) was followed for 2 cycles. Advanced life support, including defibrillation and epinephrine, was added for 8 cycles (ALS phase). Mean arterial pressure (MAP), intracranial pressure (ICP) and CePP were measured. A paired t-test was used to measure the mean difference in CePP. Twelve pigs underwent the experiment. The hypertonic crystalloid group showed higher CePP values than those demonstrated by the isotonic crystalloid group from ALS cycles 2 to 8. The MAP values in the hypertonic group were higher than those in the isotonic group starting at ALS cycle 2. The ICP values in the hypertonic group were lower than those in the isotonic group starting at ALS cycle 4. From ALS cycles 2 to 8, the reduction in the mean difference in the isotonic group was larger than that in the other groups. In a VF cardiac arrest porcine study, the hypertonic crystalloid group showed higher CePP values by maintaining higher MAP values and lower ICP values than those of the isotonic crystalloid group.

To demonstrate that preoperative treatment for 28 days with topical dorzolamide/timolol is non-inferior (Δ = 4 mm Hg) to oral acetazolamide and topical dexamethasone (standard therapy) in terms of intraocular pressure (IOP) reduction 3 and 6 months after trabeculectomy in glaucoma patients. Sixty-two eyes undergoing trabeculectomy with mitomycin C were included in this monocentric prospective randomized controlled study. IOP change between baseline and 3 months post-op was defined as the primary efficacy variable. Secondary efficacy variables included the number of 5-fluorouracil (5-FU) injections, needlings, suture lyses, preoperative IOP change, hypertension rate and change of conjunctival redness 3 and 6 months post-op. Safety was assessed based on the documentation of adverse events. Preoperative treatment with topical dorzolamide/timolol was non-inferior to oral acetazolamide and topical dexamethasone in terms of IOP reduction 3 months after trabeculectomy (adjusted means -8.12 mmHg versus -8.30 mmHg; Difference: 0.18; 95% CI -1.91 to 2.26, p = 0.8662). Similar results were found 6 months after trabeculectomy (-9.13 mmHg versus -9.06 mmHg; p = 0.9401). Comparable results were also shown for both groups concerning the classification of the filtering bleb, corneal staining, and numbers of treatments with 5-FU, needlings and suture lyses. More patients reported AEs in the acetazolamide/dexamethasone group than in the dorzolamide/timolol group. Preoperative, preservative-free, fixed-dose dorzolamide/timolol seems to be equally effective as preoperative acetazolamide and dexamethasone and has a favourable safety profile.

IntroductionEx vivo normothermic perfusion (EVNP) is a novel technique that reconditions the kidney and restores renal function prior to transplantation. Phase I data from a series of EVNP in extended criteria donor kidneys have established the safety and feasibility of the technique in clinical practice.Methods and analysisThis is a UK-based phase II multicentre randomised controlled trial to assess the efficacy of EVNP compared with the conventional static cold storage technique in donation after circulatory death (DCD) kidney transplantation. 400 patients receiving a kidney from a DCD donor (categories III and IV, controlled) will be recruited into the study. On arrival at the transplant centre, kidneys will be randomised to receive either EVNP (n=200) or remain in static cold storage (n=200). Kidneys undergoing EVNP will be perfused with an oxygenated packed red cell solution at near body temperature for 60 min prior to transplantation. The primary outcome measure will be determined by rates of delayed graft function (DGF) defined as the need for dialysis in the first week post-transplant. Secondary outcome measures include incidences of primary non-function, the duration of DGF, functional DGF defined as <10% fall in serum creatinine for 3 consecutive days in the first week post-transplant, creatinine reduction ratio days 2 and 5, length of hospital stay, rates of biopsy-proven acute rejection, serum creatinine and estimated glomerular filtration rate at 1, 3, 6 and 12 months post-transplant and patient and allograft survival. The EVNP assessment score will be recorded and the level of fibrosis and inflammation will also be measured using tissue, blood and urine samples. Ethics and dissemination. The study has been approved by the National Health Service (NHS) Health Research Authority Research Ethics Committee. The results are expected to be published in 2020.Trial registration numberISRCTN15821205; Pre-results.

We determined the efficacy and safety of 0.1% RGN-259 ophthalmic solution (containing the regenerative protein thymosin ß4) in promoting the healing of persistent epithelial defects in patients with Stages 2 and 3 neurotrophic keratopathy. Complete healing occurred after 4 weeks in 6 of the 10 RGN-259-treated subjects and in 1 of the 8 placebo-treated subjects (p = 0.0656), indicating a strong efficacy trend. Additional efficacy was seen in the significant healing (p = 0.0359) with no recurrent defects observed at day 43, two weeks after cessation of treatment, while the one healed placebo-treated subject at day 28 suffered a recurrence at day 43. The Mackie classification disease stage improved in the RGN-259-treated group at Days 29, 36, and 43 (p = 0.0818, 0.0625, and 0.0467, respectively). Time to complete healing also showed a trend towards efficacy (p = 0.0829, Kaplan–Meier) with 0.1% RGN-259. RGN-259-treated subjects had significant improvements at multiple time points in ocular discomfort, foreign body sensation, and dryness which were not seen in the placebo group. No significant adverse effects were observed. In summary, the use of 0.1% RGN-259 promotes rapid healing of epithelial defects in neurotrophic keratopathy, improves ocular comfort, and is safe for treating this challenging population of patients.