Continuous Intravenous Infusion Research Articles

Co-administration of dexmedetomidine with total intravenous anaesthesia in carotid endarterectomy reduces requirements for propofol and improves haemodynamic stability: A single-centre, prospective, randomised controlled trial.

Total intravenous anaesthesia guided by electroencephalography and neurophysiological monitoring may be used for carotid endarterectomy. Reduction of brain metabolic demand during cross-clamping of the internal carotid artery with propofol titrated to burst suppression requires effect-site concentrations that may delay emergence and interfere with intraoperative neurophysiological monitoring. To test the hypothesis that dexmedetomidine decreases the effect-site concentration of propofol required for burst-suppression in patients undergoing carotid endarterectomy. Randomised controlled trial. Patients undergoing carotid endarterectomy. University Hospital of Berne, Switzerland, from October 2018 to September 2024. Patients were randomised into a control (n = 23) and a dexmedetomidine groups (n = 22). Total intravenous anaesthesia was administered to both groups. Patients in the dexmedetomidine group received an intravenous bolus of dexmedetomidine (0.4 μg kg-1 over 10 min) before induction, followed by a continuous intravenous infusion (0.4 μg kg-1 h-1). The effect-site concentrations of propofol were titrated against frontal electroencephalography parameters. Burst suppression was induced with propofol during cross-clamping of the internal carotid artery. The primary outcome was the effect-site concentration of propofol required for burst-suppression. The secondary outcomes were the requirement for vasoactive substances, neurophysiological monitoring parameters, and postoperative delirium. The effect-site concentration of propofol required for burst suppression was 4.0 μg ml-1 [3.50 to 4.90] (median [interquartile range]) in the dexmedetomidine group compared with 6.0 μg ml-1 [5.5 to 7.3] in the control group (P < 0.001). Less norepinephrine was required in the dexmedetomidine group (total 454 μg [246 to 818] compared with 1000 μg [444 to 1326] (P = 0.015) in the control group). Dexmedetomidine did not affect intraoperative neurophysiological monitoring. Co-administration of dexmedetomidine to total intravenous anaesthesia for carotid endarterectomy decreased the effect-site concentrations of propofol required for burst suppression by 33%. The propofol-sparing effect and peripheral alpha-agonism of dexmedetomidine may explain the reduced requirement for vasopressors. Clinicaltrials.gov identifier: NCT04662177.

The Effects of Intra-Operative Lidocaine Infusion on Post Operative Pain and Morphine Consumption Following Major Gynaecological Surgeries Under General Anaesthesia

&amp;lt;i&amp;gt;Introduction&amp;lt;/i&amp;gt;: Major gynaecological surgeries are associated with considerable postoperative pain, which remains a challenge for many practitioners. Multimodal forms of analgesia significantly reduce the requirement of opioids for pain management. Despite its local anaesthetic effects, lidocaine infusion improves postoperative pain and morphine consumption following gynaecological surgeries. &amp;lt;i&amp;gt;Materials and methods&amp;lt;/i&amp;gt;: Sixty patients were assigned randomly into 2 groups (A and B) with 30 patients per group. Group A received intravenous lidocaine 1.5 mg/kg at induction via a bolus injection and 1.5 mg/kg/hr in normal saline infusion from onset of surgery to the end of surgery, while the control group (Group B) received equal volume of normal saline at the same timelines. Pain scores were assessed postoperatively using the numerical rating scale and the cumulative morphine consumed postoperatively were also measured. &amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: The mean pain scores were significantly higher in the Saline Group than in the Lidocaine group. The cumulative morphine consumption after 48 hours was significantly reduced in the study group 4.87 ± 1.80 mg vs 14.13 ± 4.10 mg (P&amp;lt;0.0001). Conclusion: The administration of a bolus dose (1.5 mg/kg) of intravenous lidocaine at induction and a continuous intravenous infusion of 1.5 mg/kg/hr from onset of surgery till skin closure reduced the postoperative pain intensity and morphine consumption in patients undergoing major gynaecological surgeries under general anaesthesia.

Advances in the use of dexmedetomidine during the perioperative period to improve postoperative sleep quality in patients undergoing surgery.

There is a high incidence of postoperative sleep and sleep architecture disorders in patients undergoing surgery, and dexmedetomidine (DEX) is commonly used to improve postoperative sleep quality and ameliorate the adverse effects of poor sleep on various organ systems. The continuous intraoperative intravenous infusion of DEX, the addition of DEX to postoperative intravenous analgesia pumps, and the continuous infusion of DEX after admission to the intensive care unit are often used clinically to improve postoperative sleep quality at doses of 0.1 to 0.7 μg/kg/hour, but the effects of DEX on sleep quality and structure identified in these studies have been inconsistent. Thus, it is unclear whether DEX improves postoperative sleep quality. The various methods of administering DEX to improve postoperative sleep quality have differing effects, the route used modifies the effect of DEX on sleep structure, and the intrinsic mechanism whereby DEX improves sleep quality remains to be fully investigated. In the present review, we describe new directions for future research into the effects of DEX on postoperative sleep quality and the mechanisms involved, which should help guide the design of further studies. This narrative review was completed according to the Scale for the Assessment of Narrative Review Articles (SANRA).

Selenoprotein P as a prognostic biomarker of burn sepsis: A prospective cohort study

IntroductionSeverely burned patients exhibit increased nutritional requirements and are at high risk of developing sepsis. Selenium is an essential trace element supporting antioxidant and anti-inflammatory pathways, mediated by incorporation into selenoproteins. The selenium status may affect sepsis risk in burn injury. MethodsThis prospective cohort study included 90 adult patients admitted to Zurich Burn Center, Switzerland. All patients received a continuous intravenous infusion of 1000μg sodium selenite per day during the first week as part of local standard of care. Three complementary biomarkers of serum selenium status were determined at nine time-points up to six months postburn, namely total selenium, selenoprotein P, and glutathione peroxidase 3. The resulting data were correlated to clinical parameters and outcomes, with sepsis as primary end point. ResultsA high fraction of the patients displayed selenium deficiency already at admission, and developed sepsis during hospitalization (n = 55; 61%). Selenium status at admission was inversely related to burn severity. Low baseline selenoprotein P was associated with sepsis incidence, irrespective of trauma severity (adjusted HR, 1.94; 95% CI, 1.05–3.63; p = 0.035). Burn severity and baseline concentrations of selenoprotein P and white blood cells corporately predicted sepsis with an area under the curve of 0.84 (95% CI, 0.75–0.93; p < 0.0001). Supplemental selenium was associated with a transient normalization of selenium status. ConclusionConsidering its rapid decline following severe burn injury, the assessment of serum selenoprotein P upon admission may contribute to an early prediction of sepsis risk.

Use of esketamine for tracheoscopic drug injection: a randomized controlled trial.

Sufentanil may induce hypotensive bradycardia and other adverse reactions in elderly patients during anesthesia, while esketamine exhibits sedative and analgesic effects with minimal impact on respiration and circulation. The objective of this study was to investigate the impact of these two anesthetics on vital signs in patients undergoing bronchoscopy and lavage under general anesthesia. This study was a randomized controlled trial with a parallel design. A total of 100 patients aged ≥60 years with ASAI or II who were undergoing bronchoscopy and lavage were randomly assigned to two groups: group A (esketamine, n = 50) and group B (sufentanil, n = 50). During anesthesia induction, both groups received intravenous infusion of propofol at a dose of 1.5 mL/kg and atracurium. In group A, esketamine at a dose of 0.3 mg/kg was injected; in group B, sufentanil at a dose of 0.2 μg/kg was injected intravenously. Subsequently, a laryngeal mask was inserted and connected to an anesthesia machine for mechanical ventilation. Anesthesia maintenance involved continuous intravenous infusion of propofol at a dose of 3 mL/kg. The mean arterial pressure (MAP), heart rate (HR), and blood oxygen saturation (SpO2) were recorded at various time points: before anesthesia injection (T0), after laryngeal mask insertion (T1), 5 min after the operation started (T2), 15 min after the operation started (T3), and before the end of the operation (T4). Additionally, the recovery time was recorded. The blood pressure of patients in the esketamine group exhibited higher levels compared to those in the sufentanil group at multiple time points during the operation, while maintaining a more stable intraoperative blood pressure and shorter postoperative recovery time than that observed in the sufentanil group. The blood pressure and heart rate of patients in the esketamine group exhibited significant fluctuations after laryngeal mask implantation compared to pre-anesthesia induction, with a statistically significant increase observed. Conversely, no significant changes were observed in the sufentanil group. The heart rate and oxygen saturation showed no significant differences between the two groups, nor did the amount of propofol administered during the procedure. The utilization of esketamine during the induction phase of bronchoscopy and lavage under general anesthesia can enhance hemodynamic stability and reduce the occurrence of hypotension, thereby facilitating postoperative anesthetic recovery.

Factors affecting time to recovery from diabetic ketoacidosis in adult diabetic patients in Alexandria Main University Hospital

BackgroundDiabetic ketoacidosis (DKA) is a life-threatening condition as a complication of diabetes and represents a significant healthcare global burden. The current study goal was to determine factors affecting time to recovery from DKA in Alexandria Main University Hospital.Patients and methodsOne hundred fifty patients who had been admitted with DKA were included in this study. All patients were managed with hospitalization for IV fluids, continuous intravenous insulin infusion, electrolyte correction, as well as detection and treatment of the predisposing factor until the full resolution of DKA.ResultsMales contributed to 58.7% of the total patients in this study with a mean age of 32.16 ± 15.06 years. DKA mean time of resolution was 18.76 ± 14.07 h. The majority of patients were with T1DM (86%), while T2DM were 14%. Missed insulin dose was the leading precipitating factor (60.7%) followed by infections (38.7%). There was a statistically significant relationship between DKA resolution time with age, time of presentation, type of diabetes, initial pH, initial serum K+ level, initial HCO3− level, initial anion gap, initial base excess, and initial RBS (p value < 0.001).ConclusionDelayed time of resolution from DKA was associated with initial lower pH, initial lower HCO3− level, initial lower base excess level, initial higher anion gap level, type 2 diabetes mellitus, patients on pre-mixed insulin regimen, old patients, delayed time for seeking medical care, and abnormal serum K+ level.

Glycemic Management in Patients with COVID-19 Admitted to the Intensive Care Unit: Evaluation of Glycemic Control and Drug Therapy.

Emerging evidence describes the high incidence and strong impact of hyperglycemia on the outcomes of critically ill patients with a diagnosis of COVID-19. Given resource limitations during the COVID-19 pandemic, clinicians moved away from using continuous IV infusions of insulin to manage hyperglycemia. To evaluate glycemic control in critically ill patients receiving various medication regimens to manage their hyperglycemia. This retrospective cohort study involved 120 mechanically ventilated adult patients (> 18 years) with COVID-19 who were admitted to the intensive care unit (ICU) between February 2020 and December 2021. The following data were collected for the first 14 days of the ICU admission: blood glucose values (up to 4 times daily), hypoglycemia events, and antihyperglycemic medication regimens. The use of IV insulin infusions maintained glucose measurements within the target range of 4 to 10 mmol/L more often than any other medication regimen, with 60% of measured values falling within the target range. The use of a sliding-scale insulin regimen maintained 52% of glucose measurements within the target range. Oral hypoglycemic agents performed relatively poorly, with only 12% to 29% of glucose measurements within range. The coadministration of corticosteroids led to worse glycemic control across all medication regimens. This study confirmed that ICUs should continue using the standard protocol of IV insulin infusion to achieve recommended blood glucose targets in critically ill patients with COVID-19, particularly those receiving corticosteroids.

12391 When Pressure Drops, Consequences Rise: A Case Of Pituitary Apoplexy And Watershed Infarcts

Abstract Disclosure: D. Moreno Watashi: None. H.R. Alkaissi: None. M.B. Sharma: None. Introduction: Pituitary apoplexy (PA) results from sudden hemorrhaging and infarction of the pituitary gland, typically within a pituitary adenoma. The primary symptom is a sudden, severe headache, often followed by acute endocrine dysfunction, ophthalmoplegia and visual or neurological disturbances. Case Description: A 68-year-old male with a past medical history of hypertension presented to the emergency department with acute chest and upper back pain, beginning one day prior. No history of smoking, alcohol intake or drug use. Blood pressure (BP) on arrival was 180/95 mmHg. Initial labs revealed mild electrolyte abnormalities. Troponins were normal, but ECG showed diffuse T wave inversion and ST depression. CT angiography revealed a type B aortic dissection. He was managed in the critical care unit with continuous esmolol intravenous (IV) infusion and planned for endovascular repair. During his stay, he became disoriented and hypotensive. MRI from the brain incidentally discovered a pituitary macroadenoma measuring 2.9x2.2x3cm and recent infarcts, with a distribution concerning for hypoperfusion. Fundoscopy concerning for optic chiasm compression. Labs indicated secondary hypothyroidism and hypogonadism (TSH 0.3 uUI/ml, free T4 0.88 ng/dL, total testosterone 56.3 ng/dL). Neurosurgical intervention was deferred until after aortic repair. Endovascular aortic repair was performed with episodes of hypotension. Post-procedure, the patient developed fever (39.5°C) and worsening mental status. Head CT revealed an increased suprasellar extension of the pituitary macroadenoma and vasogenic edema, consistent with hemorrhage of the lesion. He was started on stress doses of hydrocortisone, levothyroxine 125mcg and managed conservatively due to a high surgical risk. Discussion: PA's extrinsic risk factors include angiographic procedures, endocrinological dynamic tests, anticoagulation therapy, exogenous estrogen administration, orthopedic and cardiac surgeries (due to BP fluctuations). The intrinsic risk factors are non-functioning adenomas, macroadenomas and suprasellar extension. Treatment is focused on immediate correction of endocrine derangements and relieving local compression. Stress dosage of corticosteroids should be administered IV as soon as the diagnosis is confirmed to prevent life-threatening corticotropic deficiency. Neurosurgical decompression via a transsphenoidal approach is the definitive therapy to relieve local compression with severe visual loss, obtundation or rapidly progressive course. The potential outcomes are based on the extent of hemorrhage, necrosis, and edema. PA should be treated as a medical emergency in the setting of hemodynamic changes from acute corticotropic deficiency and irreversible neurological damage from acute intracranial compression. The risk factors for PA should be known to assist in early diagnosis. Presentation: 6/1/2024

8255 Munchausen Syndrome After Partial Pancreatectomy for Insulinoma: A Case Report

Abstract Disclosure: C.R. de Macedo: None. T.D. Bertolacini da Silva: None. I.P. de Magalhães: None. M.A. Pereira: None. I.C. Marques: None. J.L. Pinheiro Filho: None. G.F. Darce: None. D.M. Lourenço Junior: None. Background: Insulinoma is a rare, insulin-secreting pancreatic neuroendocrine tumor, most commonly benign, solitary, sporadic, well differentiated and with a slight female predominance. The investigation of hypoglycemia requires a fasting test to exclude, among other causes, factitious hypoglycemia. Clinical Case: A 27-year-old woman was admitted to the emergency room after seizure by hypoglycemic crisis (capillary blood glucose &amp;lt; 55 mg/dL). She had recurrent episodes of adrenergic/neuroglycopenic symptoms since the age of 14, occurring during fasting, mainly in the morning, with improvement after eating. After confirming Whipple's triad, a fasting test showed hyperinsulinemic hypoglycemia (glycemia 53 mg/dL, normal value &amp;gt;55 mg/dL; insulin 11.5 mcU/mL, nv &amp;lt;3mcU/mL) and increased C-peptide (3.83 ng/mL, nv &amp;lt;0,6 ng/mL). Abdominal magnetic resonance showed a 1.4 cm nodule in the pancreas tail. During hospitalization, she experienced Raynaud's phenomenon, leading to the diagnosis of Raynaud's disease (RD). Distal pancreatectomy was performed, confirming the diagnosis of insulinoma by immunohistochemistry. There was brief remission of the hypoglycemic episodes once they recurred two weeks later. As imaging tests did not show new pancreatic lesions, somatostatin analogue was begun, resulting in improvement for a few more weeks. Due to recurrent hypoglycemia and new seizures, she required continuous intravenous infusion of glucose during hospitalization. A new fasting test revealed hyperinsulinemic hypoglycemia (glycemia 42 mg/dL, insulin 43.3 mcU/mL), low C-peptide (0.5 ng/mL) and normal proinsulin (2.39 pmol/L, nv &amp;lt;5 pmol/L) values. Due RD, auto-immune hypoglycemia was excluded by negative anti-insulin antibodies. Insulinomatosis was also considered, as potential etiology, but review of surgical specimen excluded this hypothesis. After 4 months of hospitalization, due suspicious behavior, a review of her personal belongings revealed insulin vials and needles for injection. The patient confessed to applying insulin to simulate the symptoms, also revealing a history of childhood trauma and previous suicide attempts. After psychiatric evaluation, borderline personality disorder was identified, and Munchausen syndrome was considered. Since then, the patient did not require intravenous glucose with no recurrence of hypoglycemia. Conclusion: The investigation of hypoglycemia can be challenging, requiring appropriate diagnostic protocols. Even in patients who appear to have a well-defined diagnosis, as in our case with anatomopathological confirmation of insulinoma, it is always important to rule out factitious hypoglycemia. The incorrect diagnosis can lead to inappropriate invasive and surgical procedures with definitive consequences, such as exogenous pancreatic insufficiency and insulin-dependent diabetes mellitus. Presentation: 6/1/2024

L-carnitine for valproic acid-induced toxicity.

Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.

Intermittent versus continuous intravenous epoprostenol for the treatment of digital ischemia

Digital ischemia can be a painful complication of Raynaud’s phenomenon or systemic sclerosis, which is caused by narrowing of blood vessels in the toes and hands. Epoprostenol is a potent vasodilator that may be used to treat digital ischemia in this patient population. Our institution provides epoprostenol infusion using two different administration techniques: a 30-h continuous infusion option and a 5-day intermittent 6-h infusion. In this retrospective chart review, we compared two administration techniques of intravenous epoprostenol administered to patients with digital ischemia. The primary outcome was to compare the efficacy of intravenous epoprostenol 30-h continuous infusion versus 5-day intermittent infusion, as defined by the presence of treatment failure. Between June 2019 and June 2020, 72 adult patient encounters met the inclusion criteria (intermittent: n = 20; continuous: n = 52). The primary outcome did not achieve a statistically significant difference between the two groups: intermittent 20% versus continuous 33.3% p = 0.390, odds ratio = 0.57 (95% confidence interval = 0.17–1.90). Adverse reactions were documented in 28% of patients across both treatment groups, and there was no difference detected when treatment groups were compared (25% vs 28.8%). Patients who received the 5-day infusion experienced a significantly longer average length of stay, with a mean of 8.9 days versus 3 days for those treated with the continuous 30-h infusion ( p &lt; 0.05; 95% confidence interval = 2.15–9.47). This study determined that the efficacy and safety profiles of the two administration techniques may not be comparable. Each protocol offers advantages over the other, and selection should be guided by patient history and risk factors to optimize management.

Angiotensin-(1–7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1–2 randomized clinical trial

BackgroundThe coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host’s cells via the angiotensin-converting enzyme 2 (ACE2).MethodsThis investigator-initiated, seamless phase 1–2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1–7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1–7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2.ResultsBetween August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0–21] vs. 14 [0–18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1–2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0–21] vs. 14 [0–18] days; absolute difference −5 days, 95% CI [0–7] p = 0.04).ConclusionsThe main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1–7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups.Trial Registration ClinicalTrials.gov Identifier: NCT04633772—Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.

Development of modified laser Doppler flowmetry device for real-time monitoring of esophageal mucosal blood flow: a preclinical assessment with an animal model.

This study aimed to modify a laser Doppler flowmeter designed and assembled at our institute. After measuring sensitivity evaluation in ex vivo experiments, we confirmed the efficacy of this new device for monitoring real-time esophageal mucosal blood flow changes after thoracic stent graft implantation by simulating various clinical situations in an animal model. Thoracic stent graft implantation was performed in a swine model (n = 8). Esophageal mucosal blood flow decreased significantly from baseline (34.1 ± 18.8ml/min/100g vs. 16.7 ± 6.6ml/min/100g, P < 0.05) in the lower esophagus (Th6-Th8) where the stent graft covered the aorta. In the hemorrhagic shock model (shock index ≥ 1.0), esophageal mucosal blood flow showed a remarkable change from baseline in the upper esophagus (Th1-Th3), where the stent graft did not cover the aorta (20.8 ± 9.8ml/min/100g vs. 12.9 ± 8.6ml/min/100g, P < 0.01); however, it returned to the baseline value within a 30-min period. Mucosal blood flow remained stable in the esophagus, where the stent graft did not cover the aorta. After elevating the mean blood pressure to > 70mmHg with continuous intravenous noradrenaline infusion, esophageal mucosal blood flow increased significantly in both regions; however, the reaction was different between the two regions. Our newly developed laser Doppler flowmeter could measure real-time esophageal mucosal blood flow changes in various clinical situations during thoracic stent graft implantation in a swine model. Hence, this device can be applied in many medical fields by downsizing it.

The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150mg/kg, SC) for 36h and continuous intravenous infusion of vehicle (20μL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) for the full 36h. NLX elicited pronounced withdrawal signs in rats treated for 48h with morphine (150mg/kg, SC), plus continuous infusion of vehicle (20μL/h, IV) that began at the 36h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12h infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) that began at the 36h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.

Retrospective comparison of the effects of remimazolam and dexmedetomidine on postoperative delirium in elderly patients undergoing orthopedic surgery of the lower extremities under spinal anesthesia.

Remimazolam is often used for perioperative sedation due to its rapid onset and offset. However, the possible association between remimazolam and postoperative delirium (POD) remains undetermined. The present study evaluated whether remimazolam increased the incidence of POD compared with dexmedetomidine in elderly patients undergoing orthopedic surgery of the lower extremities. This retrospective study included patients aged ≥ 65years who had undergone orthopedic surgery of the lower extremities under spinal anesthesia from January 2020 to November 2022 and were sedated with continuous intravenous infusion of dexmedetomidine or remimazolam. The incidence of POD was assessed through a validated comprehensive review process of each patient's medical records. The effect of remimazolam on the occurrence of POD compared with dexmedetomidine was evaluated by propensity score weighted multivariable logistic models. A total of 447 patients were included in the final analysis. The crude incidence of POD within 3days after surgery was 7.5% (17/226) in the dexmedetomidine group and 11.8% (26/221) in the remimazolam group, increasing to 9.7% (22/226) and 15.8% (35/221), respectively (p = 0.073), within 5days. The multivariable models showed that, compared with dexmedetomidine, intraoperative sedation with remimazolam significantly increased the occurrence of POD within 3days (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.31 to 3.82, p = 0.003) and 5days (OR 2.10, 95% CI 1.32 to 3.40, p = 0.002). Compared with dexmedetomidine, remimazolam infusion may be associated with a higher risk of POD in elderly patients undergoing orthopedic surgery of the lower extremities under spinal anesthesia.

Adrenaline intravenous therapy persistence grade I severe allergic reaction: A case report and literature review.

At present, there is still insufficient understanding of the progression from persistent allergic reactions to severe reactions. Adrenaline remains the preferred medication for severe allergic reactions, and intramuscular injection of adrenaline can also be considered for patients with grade I reactions that are difficult to alleviate gastrointestinal symptoms. It is worth further discussing whether it is possible to break the conventional intramuscular injection recommended by the guidelines when the effect of intramuscular injection is not ideal for persistent grade I severe allergic reactions. A young male, 20 years of age, was admitted to emergency department because of repeated rash for 3 days and abdominal pain for 6 hours after taking traditional Chinese medicine. After hormone therapy, the rash continued to recur and secondary gastrointestinal symptoms occurred on the 3th day. Adrenaline intramuscular injection was given to temporarily relieve the rash and abdominal pain, but symptoms still persisted. The patient was diagnosed with persistent severe allergic reaction (grade I). Continuous intravenous infusion of low-dose adrenaline under electrocardiographic monitoring, real-time monitoring of heart rate and blood pressure, and routine treatment with methylprednisolone, diphenhydramine, calcium gluconate, and cetirizine. During this period, adrenaline intramuscular injection is temporarily added when abdominal pain symptoms are obvious. The entire treatment process used a total of 6.8 mg of adrenaline. During the entire period of adrenaline intervention, the patient did not experience any new discomfort, and there were no abnormal fluctuations in heart rate, rhythm, or blood pressure. The symptoms of rash and abdominal pain gradually improved. For patients with persistent grade I severe allergic reactions, intravenous administration of low-dose adrenaline under close vital sign monitoring is safe, feasible, and highly effective in preventing biphasic, persistent, or worsening allergic reactions.

Efficacy and Safety of Terlipressin Infusion in Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Retrospective Observational Study.

Background Hepatorenal syndrome-acute kidney injury (HRS-AKI) is an event that occurs in chronic liver disease (CLD) and is associated with high morbidity and mortality. Terlipressin, a vasopressin analog, is used for the treatment of portal hypertension-related gastrointestinal (GI) bleeding and is found to be effective in the management of HRS-AKI. Continuous infusion of terlipressin maintains a high mean arterial pressure while reducing adverse events. It is better tolerated and equally effective at lower doses than intravenous boluses in patients with HRS-AKI. Aim of the study This study aimed to evaluate the safety and efficacy of terlipressin infusion at the rate of 4 mg/day in the treatment of HRS-AKI. Methods This retrospective study included patients who had HRS-AKI according to the modified International Club of Ascites (ICA) definition. Patients were started on a continuous intravenous infusion. The included patients received terlipressin 1 mg stat followed by a 4 mg infusion over 24 hours, and the infusion was continued until specific response criteria were met or for a maximum of seven days. Results In total, 136 patients were included in this study. The mean age of the study group was 45 years, the mean Child-Turcotte-Pugh (CTP) score was 11, the mean model for end-stage liver disease (MELD) score was 30, and the mean serum creatinine was 2.46 mg/dl. A response to treatment in the form of reduction of serum creatinine was observed in 94 (69.1%) patients, 30 (22%) patients showed no response, and worsening of creatinine was seen in 12 (8.8%) patients. The mean duration of hospital stay was 7.6 days, the mean serum creatinine was 1.17 mg/dl at the end of treatment, and the mean CTP and MELD scores in treatment responders were nine and 27, respectively. A total of 29 (21.3%) of 136 patients had adverse events during the terlipressin infusion therapy. Conclusion Terlipressin infusion has sustained effects on splanchnic hemodynamics with fewer and less severe adverse events than intravenous bolus doses. Terlipressin infusion at a dose of 4 mg/day appeared to be well tolerated, with similar outcomes to that of 2 mg/day with a significantly lower albumin dose. These findings emphasize the importance of optimizing treatment protocols, particularly those favoring infusion methods, to enhance efficacy and minimize adverse effects.

Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75min mid-LAD balloon occlusion followed by reperfusion. After 4w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45µg/kg/day rhPlGF-2 or PBS (CON) for 2w using osmotic pumps. We evaluated the treatment effect at 8w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study.

There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment. Participants (≥ 65years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89mL/min for mild and 30-59mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75mg/h continuous intravenous (IV) infusion over 24h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15mg every 6h. There were four treatment periods of 24h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored. Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred. NTM-001 was considered safe and well tolerated in this population of participants ≥ 65years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects.

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.

Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion. Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]). Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.