Low-dose Infusion Research Articles

No benefit from the addition of low-dose ketamine infusion to standard evidence-based care of patients with multiple rib fractures.

Multiple rib fractures from blunt thoracic trauma cause significant morbidity. Optimal current management includes multimodal analgesia, pulmonary hygiene, and early mobilization. Low-dose ketamine infusion (LDKI) has been proposed as an adjunctive analgesic in this setting. A prior study reported decreased pain scores with LDKI in patients with multiple rib fractures. We hypothesized that LDKI would decrease morphine milligram equivalents (MMEs) in patients with multiple rib fractures. A prospective randomized placebo-controlled trial was performed in adult (18 years or older) patients with three or more rib fractures. A prestudy power analysis calculated an 80% chance of identifying a 15% decrease in MMEs with 50 subjects. The study was approved by the institutional review board and informed consent obtained in all subjects. Demographic (age, sex) and injury specific information (Injury Severity Score, number of rib fractures) were obtained. Subjects were randomized 1:1 to receive continuous LDKI (0.1 mg/kg/h) or placebo infusion (0.9% NaCl) for ≤48 hours. All patients received a standard evidence-based multidisciplinary protocol for rib fractures management. Primary outcome measure was MME use or pulmonary complications. Statistical comparison of LDKI versus placebo was performed using the Mann-Whitney U test. All 50 enrolled subjects (placebo, 25; LDKI, 25) received study drug infusion. The two groups were well matched for age, Injury Severity Score, and number of rib fractures. We observed no differences in the Day 1 (p = 0.961), Day 2 (p = 0.373), or total MMEs (p = 0.946) between groups. Similar total MME use was observed when subjects who received ≥40 hours of study drug and were compared (p = 0.924). Use of LDKI did not alter subsequent need for opiate analgesics postinfusion, hospital length of stay, pulmonary complications, or need for readmission. The addition of LDKI to an established multimodal, evidence-based protocol for management of multiple rib fractures did not decrease opiate usage or impact pulmonary complications. Therapeutic/Care Managaement; Level I.

Low-dose dobutamine in acute myocardial infarction with intermediate to high risk of cardiogenic shock development (the DOBERMANN-D trial): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial

BackgroundCardiogenic shock (CS) occurs in 5–10% of patients with acute myocardial infarction (AMI), and the condition is associated with a 30-day mortality rate of up to 50%. Most of the AMI patients are in SCAI SHOCK stage B upon hospital arrival, but some of these patients will progression through the stages to overt shock (SCAI C-E). Around one third of patients who develop CS are not in shock at the time of hospital admission. Pro-B-type natriuretic peptide (proband) is a biomarker closely related to CS development. The aim of this study is to investigate the potential for preventing progression of hemodynamic instability by early inotropic support with low-dose dobutamine infusion administrated after revascularization in AMI patients with intermediate to high risk of in-hospital CS development.MethodsThis investigator-initiated, double-blinded, placebo-controlled, randomized, single-center, clinical trial will include 100 AMI patients (≥ 18 years) without CS at hospital admission and at intermediate-high risk of in-hospital CS development (ORBI risk score ≥ 10). Patients will be randomized in a 1:1 ratio to a 24 h intravenous (IV) infusion of dobutamine (5 μg/kg/min) or placebo (NaCl) administrated after acute percutaneous coronary intervention (PCI) (< 24 h from symptom onset). Blood samples are drawn at time points from study inclusion (before infusion, 12, 24, 36, and 48 h).The primary outcome is peak plasma proBNP within 48 h after infusion as a surrogate-measure for the hemodynamic status. Hemodynamic function will be assessed pulse rate, blood pressure, and lactate within 48 h after infusion and by transthoracic echocardiography (TTE) performed after 24–48 h and at follow-up after 3 months. Markers of cardiac injury (troponin T and creatine kinase MB (CK-MB)) will be assessed.DiscussionEarly inotropic support with low-dose dobutamine infusion in patients with AMI, treated with acute PCI, and at intermediate-high risk of in-hospital CS may serve as an intervention promoting hemodynamic stability and facilitating patient recovery. The effect will be assessed using proBNP as a surrogate marker of CS development, hemodynamic measurements, and TTE within the initial 48 h and repeated at a 3-month follow-up.Trial registrationThe Regional Ethics Committee: H-21045751. EudraCT: 2021–002028-19. ClinicalTrials.gov: NCT05350592, Registration date: 2022-03-08. WHO Universal Trial Number: U1111-1277–8523.

D-Aspartate Stimulates Growth Hormone Secretion in Wethers.

Growth hormone (GH) is an essential factor in enhancing the productivity of animals. In ruminants, L-aspartate (L-Asp) stimulates the secretion of GH; however, the effect of D-Asp on GH remains unknown. Here, we examined the effect of D-Asp on GH secretion in wethers. Blood GH, insulin, adrenaline, noradrenaline, non-esterified fatty acid (NEFA), and glucose concentrations were evaluated in response to the intravenous infusion of a high-dose (0.1 mmol/kg/min) of D-Asp for 20min. Further, concentrations of these biomolecules were evaluated when a low-dose (0.05 mmol/kg/min) of D-Asp was continuously infused intravenously for 20min. Finally, the direct effect of D-Asp on GH secretion was determined using cultured sections of the anterior pituitary tissue from wethers. Infusion of the high-dose of D-Asp markedly increased blood GH concentrations (P < 0.05), resulting in an increase in the area under the curve (AUC). Plasma GH concentrations and AUC also increased in response to infusion of a low D-Asp dose. Infusion of a high and low D-Asp dose caused a prolonged reduction in plasma insulin concentrations, and the AUC was lower (P < 0.05). Plasma NEFA concentrations gradually increased after the end of D-Asp infusion, with a low D-Asp dose infusion resulting in significantly higher concentrations at 90min (P < 0.05). Plasma adrenaline, noradrenaline, and glucose concentrations did not show significant changes despite differences in the dose of D-Asp. Although D-Asp treatments stimulated GH secretion in the cultured sections of pituitary tissues, the effect was not significant. These results suggest that D-Asp stimulates the secretion of GH in wethers through not only a direct action on the pituitary gland but also through another pathway of GH stimulation.

Effect of low-dose norepinephrine combined with goal-directed fluid therapy on postoperative pulmonary complications in lung surgery: A prospective randomized controlled trial

Study objectivePostoperative pulmonary complications (PPCs), the predominant complications following lung surgery, are closely associated with intraoperative fluid therapy. This study investigates whether continuous low-dose norepinephrine infusion combined with goal-directed fluid therapy (GDFT) reduced the risk of PPCs after lung surgery relative to either GDFT alone or standard fluid treatment. DesignA prospective, randomized controlled trial. SettingThe First Affiliated Hospital of Anhui Medical University, Anhui, China. PatientsThe study included 184 patients undergoing elective thoracoscopic lung resection surgery. InterventionsPatients were randomized into three groups based on different fluid treatment regimens: Group C received standard fluid treatment, Group G received GDFT, and Group N received continuous low-dose norepinephrine infusion combined with GDFT. MeasurementsThe primary outcome was the incidence of PPCs, including respiratory infection, atelectasis, pneumothorax, pleural empyema, respiratory failure, pulmonary embolism and bronchopleural fistula, during the postoperative hospital stay. Secondary outcomes were hemodynamic variables and arterial blood gases. Additional recorded parameters included other postoperative complications such as bleeding, postoperative re-intubation, re-hospitalization within 30 days, and the length of hospital stay. Main resultsGroup N showed a significantly lower PPCs incidence during hospitalization compared to Group C (11.5 % vs 27.9 %; odds ratio, 2.98; 95 % confidence interval, 1.17–8.31; P = 0.023). No significant difference in PPCs was found between Group N and Group G (11.5 % vs 14.5 %; odds ratio, 1.31; 95 % confidence interval, 0.46–3.91; P = 0.616). Additionally, there were no significant differences among the three groups in the components of PPCs. Group N showed higher mean arterial pressure and stroke volume index intraoperatively compared to Group C. ConclusionsContinuous low-dose norepinephrine infusion combined with GDFT reduced PPCs incidence in elective lung surgery patients compared with standard fluid management, but showed no difference compared to GDFT alone. Clinical trial registrationChiCTR2200064081.

The effect of using low dose norepinephrine before hypotensive resuscitation in hemorrhagic shock; a randomized controlled trial

Background &amp; Objectives: Hemorrhagic shock is not a very rare occurrence in big hospitals. It might be encountered in the emergency room (ER) or in the operating rooms (OR). A rapid response and systematic management will save the life of the victim. The objective of this research was to investigate the impact of a low dose of norepinephrine (NE) administered prior to the initiation of hypotensive resuscitation in patients with hemorrhagic shock. Methodology: This randomized controlled trial was conducted on 200 participants, at least 18 years old, classified as severely traumatized and had significant hemorrhage with mean arterial pressure ranging from 65 to 75 mmHg. We divided the patients into two equal groups. Group I received a low dose of NE (&lt; 0.3 µg/kg/min) concurrently with resuscitation fluids. Group II received resuscitative fluids only. If the resuscitative fluids failed to keep mean arterial pressure (MAP) &gt; 65 mmHg, the patient was progressively administered NE even with high doses (0.05 to more than 0.3 µg/kg/min). The primary outcome was 24-hour mortality. In-hospital mortality, incidence of acute kidney injury (AKI), and duration of hospital and intensive care unit (ICU) stay constituted the secondary outcomes. Results: Group I had lower 24-hour mortality compared to Group II (3% vs 13%; P &lt; 0.05). Compared to Group II, Group I needed reduced amount of fluid resuscitation within 24 h, had lower serum lactate levels at 6 and 12 h, and lower serum creatinine at 6, 12, and 18 h (P &lt; 0.001). Group I had a lower incidence of mechanical ventilation (13% vs 27%), hospital and ICU stays, and in-hospital mortality (9% vs 21%) (P &lt; 0.05). There was a lack of disparity seen in the incidence of AKI and duration of mechanical ventilation. Conclusion: Low-dose norepinephrine infusion during the early period of hypotensive resuscitation reduces resuscitative fluid requirement, improves tissue perfusion, preserves renal function, and lowers mortality in hemorrhagic shock patients. Abbreviations: AKI - acute kidney injury; APACHE III - Acute Physiology And Chronic Health Evaluation III; HS - hemorrhagic shock; ICU - intensive care unit; MAP - mean arterial pressure; NE - Norepinephrine Keywords: Hemorrhagic Shock; Hypotensive Resuscitation; Norepinephrine; Fluid Therapy; Renal Protection; Mortality; Low Dose Citation: Mohamed RM, Anwar AG, Eid AA. The effect of using low dose norepinephrine before hypotensive resuscitation in hemorrhagic shock; a randomized controlled trial. Anaesth. pain intensive care 2024;28(5):914−921; DOI: 10.35975/apic.v28i5.2560 Received: April 17, 2024; Reviewed: August 03, 2024; Accepted: September 04, 2024

8281 Continuous Low-Dose Etomidate Infusion For The Management Of Severe Hypercortisolism In Metastatic Adrenocortical Carcinoma

Abstract Disclosure: A. Jamil: None. N. Mohammad: None. S. Narayana: None. Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal glands with a poor prognosis that often presents with excess hormone secretion. Approximately, 45% of cases present with hypercortisolism.1 A key component of management is achieving control of hypercortisolism. Though there are multiple enteral therapies that can inhibit cortisol production, few treatment options are available for use in critically ill patients who are not surgical candidates and cannot take oral medications. Though primarily known as a short-acting intravenous anesthetic agent used for sedation, etomidate also inhibits 11-β-hydroxylase, a key enzyme involved in corticosteroid biosynthesis.2 Clinical Case: A 28-year-old woman with metastatic adrenocortical carcinoma with associated hypercortisolism was initially admitted for anemia and thrombocytopenia, with an initial cortisol on admission of 29.3 μg/dl (normal range: 2.3-19.4 ug/dl). Due to her large tumor burden with metastasis to the liver and invasion into the inferior vena cava, she was deemed a poor surgical candidate with a poor overall prognosis. Her hospital course was complicated by acute hypoxemic respiratory failure requiring intubation, and thus her enteral steroidogenesis inhibitors (mitotane, ketoconazole, and metyrapone) were discontinued as none were administrable via nasogastric tube. Consequently, her hypercortisolism worsened rapidly with a cortisol level of 351.3 μg/dl , prompting initiation of continuous low-dose etomidate infusion, which resulted in significant improvements in her cortisol levels. After eight days of etomidate treatment, her cortisol levels reached a goal value of 25.0 μg/dl. However, she then suffered an ischemic cerebrovascular event and multiorgan failure, and was subsequently transitioned to hospice care. Conclusion: Low-dose etomidate infusion is an effective therapeutic agent for hypercortisolism in patients with ACC that are unable to take oral medications.

Investigation of Sonication Parameters for Large-Volume Focused Ultrasound-Mediated Blood-Brain Barrier Permeability Enhancement Using a Clinical-Prototype Hemispherical Phased Array.

Background/Objectives: Focused ultrasound (FUS) and microbubble (MB) exposure is a promising technique for targeted drug delivery to the brain; however, refinement of protocols suitable for large-volume treatments in a clinical setting remains underexplored. Methods: Here, the impacts of various sonication parameters on blood-brain barrier (BBB) permeability enhancement and tissue damage were explored in rabbits using a clinical-prototype hemispherical phased array developed in-house, with real-time 3D MB cavitation imaging for exposure calibration. Initial experiments revealed that continuous manual agitation of MBs during infusion resulted in greater gadolinium (Gd) extravasation compared to gravity drip infusion. Subsequent experiments used low-dose MB infusion with continuous agitation and a low burst repetition frequency (0.2 Hz) to mimic conditions amenable to long-duration clinical treatments. Results: Key sonication parameters-target level (proportional to peak negative pressure), number of bursts, and burst length-significantly affected BBB permeability enhancement, with all parameters displaying a positive relationship with relative Gd contrast enhancement (p < 0.01). Even at high levels of BBB permeability enhancement, tissue damage was minimal, with low occurrences of hypointensities on T2*-weighted MRI. When accounting for relative Gd contrast enhancement, burst length had a significant impact on red blood cell extravasation detected in histological sections, with 1 ms bursts producing significantly greater levels compared to 10 ms bursts (p = 0.03), potentially due to the higher pressure levels required to generate equal levels of BBB permeability enhancement. Additionally, albumin and IgG extravasation correlated strongly with relative Gd contrast enhancement across sonication parameters, suggesting that protein extravasation can be predicted from non-invasive imaging. Conclusions: These findings contribute to the development of safer and more effective clinical protocols for FUS + MB exposure, potentially improving the efficacy of the approach.

A Comparative Study of Infusion of Ephedrine and Phenylephrine on Hemodynamic Stability After Spinal Anesthesia in Elderly Patients Undergoing Lower Limb Orthopedic Surgeries.

Background Hypotension during spinal anesthesia occurs due to sympathetic nervous system blockade, resulting in decreased systemic vascular resistance and reduced cardiac output. Due to reduced sympathetic tone, peripheral arterial vasodilatation and blood pooling in lower limbs due to venodilatation occur, reducing preload to the heart and stroke volume. The elderly patients have reduced cardiovascular compensatory mechanisms, increasing the frequency and severity of hypotension due to sympathetic blockade after spinal anesthesia significantly. Vasopressors correct hypotension during the intraoperative period to maintain organ perfusion. Fluids can be administered, and if given excessively, can cause fluid overload and urinary retention. This study aimed to compare the effectiveness of vasopressors, phenylephrine, and ephedrine in maintaining hemodynamic stability intraoperatively through prophylactic infusion after spinal anesthesia in elderly patients for lower limb orthopedic surgeries. Methodology A total of 174 elderly patients aged 60 years and above with American Society of Anesthesiologists (ASA) Classification I and II, undergoing lower limb orthopedic surgeries, enrolled in a randomized comparative study, were allocated into three groups: Group P (phenylephrine, n=58) received 250 mcg phenylephrine in 30 ml normal saline using infusion syringe pump, Group E (ephedrine, n=58) received 30 mg ephedrine in 30 ml normal saline using infusion syringe pump, and Group C (control group, n=58) received mephentermine I/V (6 mg bolus) when the fall in blood pressure was below 30% of baseline without any placebo infusion. Hemodynamic parameters (systolic and diastolic blood pressure, mean arterial pressure (MAP), heart rate) at 15, 10, and 5-minute intervals before spinal anesthesia, and at 3, 6, 9, 12, 15, 20, 25, and 30-minute intervals after spinal anesthesia. The need for rescue doses to treat hypotension after spinal anesthesia was recorded. Result At all time intervals following spinal anesthesia, Group E reported heart rate and systolic blood pressure better than Groups P and C, significantly. At 3, 6, 9, 12, 15, and 25-minute intervals following spinal anesthesia, the diastolic blood pressure in Group E was enhanced significantlythan Groups P and C. The MAP in Group E was substantially higher than in other groups at 3, 6, 15, and 20-minute intervals following spinal anesthesia, which was statistically significant. Compared to Groups P and C, Group E required lesser rescue doses to treat intraoperative fall in hypotension 30% below baseline and lesser events of bradycardia. Conclusion Following spinal anesthesia, the preload to the heart is to be maintained with intravenous (crystalloid or colloidal) solutions to maintain cardiac output adequately. Intraoperative use of phenylephrine and ephedrine as a low-dose prophylactic infusion can be used, as it increases both systemic vascular resistance and preload without cardiac stimulation along with intravenous solutions to maintain hemodynamic parameters such as systolic and diastolic blood pressure, MAP, heart rate effectively but preferably ephedrine in elderly patients.

Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial

PurposeDexmedetomidine increases sleep and reduces delirium in postoperative patients, but it is expensive and requires a monitored environment. Clonidine, another α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\alpha$$\\end{document}2-agonist, is cheaper and is used safely for other purposes in wards. We assessed whether clonidine would improve sleep in postoperative high-dependency unit (HDU) patients.MethodsThe Clonidine at Low dosage postoperatively to Nocturnally Enhance Sleep (CLONES) study was a double-blind, placebo-controlled, parallel-group pilot effectiveness randomised trial involving adult elective surgery HDU patients in a single academic hospital. Patients received clonidine 0.3 μg/kg/h or saline placebo on the night of surgery. The primary outcome was total sleep time measured using a consumer actigraphy/photoplethysmography device.ResultsOf the 83 randomised patients, three had no data available, leaving 80 (39 clonidine, 41 placebo) in the intention-to-treat analysis, modified for missing data. Median patient ages of the groups were similar (61 and 59 years), as were other baseline characteristics. Clonidine patients had a mean of 100.8 (95% confidence interval [CI] 38.2–163.4) minutes (p = 0.002) longer total sleep time (mean 497.2 vs. 396.4 min) and reported better sleep overall. Delirium was only observed in one patient prior to study drug infusion, and none at the end of the study. Safety outcomes were not different. Four clonidine patients had their medication ceased due to bradycardia and hypotension that required no additional treatment.ConclusionAmong postoperative elective surgical patients admitted to HDU, low-dose non-titrated clonidine, compared to placebo, was associated with longer and subjectively better-quality sleep.

Comparison of intravenous dexmedetomidine versus ketamine-dexmedetomidine combination on spinal block characteristics in patients undergoing lower limb orthopaedic surgery - A randomised clinical trial.

One major limitation of the spinal block remains the inability to extend the duration of the block intraoperatively unless planned before with spinal or epidural catheters and/or intrathecal additives. This study was designed to compare the effects of intravenous dexmedetomidine versus low-dose ketamine-dexmedetomidine combination infusion on spinal anaesthesia in lower limb orthopaedic surgeries. This randomised study was conducted in 60 patients scheduled for unilateral lower limb surgeries under spinal anaesthesia. Patients were randomised into Group D (n = 30) (0.5 µg/kg of intravenous (IV) dexmedetomidine bolus followed by maintenance infusion at 0.5 µg/kg/h) and Group LKD (n = 30) (IV bolus of 0.5 µg/kg of dexmedetomidine and 0.2 mg/kg of ketamine, followed by maintenance infusions of dexmedetomidine and ketamine at 0.5 µg/kg/h and 0.2 mg/kg/h, respectively). Ramsay Sedation Scale score of 3-4 was maintained. The t-test or the Wilcoxon-Mann-Whitney U test was used to compare the parameters between groups. The mean sacral segment 1 (S1) regression time was 390.3 [standard deviation (SD):84.38] [95% confidence interval (CI): 360.13, 420.53] versus 393.23 (SD: 93.01) (95% CI: 363.04, 423.43) min in Group D versus Group LKD respectively ((P = 0.701). The number of episodes of hypotension was significantly higher in Group D (19 patients) compared to Group LKD (nine patients) (P = 0.001). Pre- and postoperative stress markers (24 h) and the incidence of postoperative nausea and shivering were comparable between the two groups (P > 0.05). Tramadol requirement in the postoperative period was significantly less in Group LKD compared to Group D (P = 0.003). The duration of S1 regression was similar between group dexmedetomidine (Group D) and group low-dose ketamine and dexmedetomidine (Group LKD).

The Effect of Low-Dose Dexmedetomidine on Perioperative Neurocognitive Dysfunction in Elderly Patients Undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP): A Randomized, Controlled, Double-Blind Trial.

This study investigates the effect of low-dose dexmedetomidine infusion on perioperative neurocognitive function in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). This double-blind trial enrolled 80 elderly ERCP patients randomized to receive dexmedetomidine (Group D) or placebo (Group S). Group D received dexmedetomidine at 0.4 μg·kg-1·h-1 starting 15 minutes before surgery until completion, along with propofol at 1.5 mg/kg for anesthesia. Group S received saline and propofol in a similar manner. Anesthesia was maintained with dexmedetomidine at 0.4 μg·kg-1·h-1 and propofol at 1-2 mg/kg during surgery. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and on postoperative days 1, 3, and 5. Primary outcome was perioperative neurocognitive disorder (PND) incidence on day 5; secondary outcomes included changes in perioperative IL-6, cortisol, S100-β, hemodynamics, anesthesia parameters, postoperative pain, agitation scores, and adverse events. All 80 patients completed the trial. On postoperative day 5, the cumulative probability of PND incidence was significantly lower in Group D than in Group S (12.5% vs 35%, P=0.018). Group D also had lower levels of IL-6 (F=199.472, P<0.001), S100-β (F=2681.964, P<0.001), and cortisol (F=137.637, P<0.001). Propofol doses were lower in Group D (706.1 ± 202.4 vs 1003.3 ± 203.7, P<0.001), and bradycardia rates were higher (45% vs 15%, P=0.003), though atropine use did not significantly differ between groups. Group D showed greater stability in mean arterial pressure. Postoperative complications and adverse reactions were similar across groups. Perioperative low-dose dexmedetomidine infusion with propofol in elderly ERCP patients ensures safe and effective monitored anesthesia care (MAC), reducing PND incidence by mitigating peripheral inflammation and stress responses. Long-term follow-up is needed to fully evaluate PND incidence.

Assessment of the effect of unfractionated heparin administered either by intravenous infusion vs. subcutaneous injection on heparin-binding protein, and plasminogen activator inhibitor-1 in critically ill septic patients: a randomized controlled trial.

The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.

Effectiveness of different doses of dexmedetomidine on intraoperative haemodynamic profiles and postoperative pain in patients undergoing abdominal surgery at Dilla University Referral Hospital, Ethiopia, 2024: a double-blind randomized controlled trial.

Abdominal surgery stands as one of the most frequently conducted procedures across surgical specialties, accounting for up to half of surgery-related expenses. Hemodynamic instability emerges as a significant concern during anaesthesia and surgery, provoked by the stress of intubation, surgical incision, and anaesthetic agents. Following abdominal surgery, pain is an inevitable consequence, typically managed with opioid-based analgesia. However, the adverse effects associated with opioids often overshadow their analgesic benefits, particularly in the context of abdominal surgery. Consequently, there exists a necessity to explore and assess alternative non-opioid pain management options post-abdominal surgery as part of a broader strategy to reduce opioid usage. The primary aim of this investigation is to assess the effectiveness of varying doses of dexmedetomidine in regulating intraoperative hemodynamics and alleviating postoperative pain in patients undergoing abdominal surgery. Ethical clearance and institutional review board were obtained from the ethical clearance committee of Dilla University College of Medicine and Health Sciences with protocol unique number of duirb/008/22-01. Our trial has been prospectively registered on the Pan African Clinical Trial Registry with a unique identification number for the registry PACTR202208813896934. Statistical package and analysis were performed by using SPSS version 25. The distribution of data was checked by using Shapiro-Wilk test and the homogeneity of variance was checked by Levene's test. Analysis of variance (ANOVA) and Kruskal-Wallis H test were used for normally distributed continuous data and non-normally distributed or non-parametric data, respectively. P value less than 0.05 with a power of 90% was considered statistically significant. There was a statistically significant increase in mean SBP in the control group at the different critical time points (P<0.05), as compared to the baseline value, while there was no significant difference in mean systolic blood pressure (SBP) between the baseline and all other levels for group 2 and group 3. A statistically significant increase in mean arterial pressure (MAP) was detected in the control group at immediately after intubation (P=0.009) as compared to the baseline value, while a statistically significant reduction in mean heart rate (HR) was observed in group 3 at 15th min after infusion and at 30th 30 min after induction compared to baseline with a P value of 0.002 and 0.008, respectively.Conclusion:Perioperative low-dose infusion of dexmedetomidine at the rate of 0.4mcg/kg/h is a useful anaesthesia adjuvant to control hemodynamic stress response to critical periods. It is wise to use this infusion dose as part of general anaesthesia to achieve better hemodynamic stability.

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine’s molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

Effectiveness and feasibility of selective intra-arterial low dose of cisplatin infusion and concomitant radiotherapy for patients with advanced laryngeal cancer with impaired renal function: A retrospective cohort study.

Chemoradiation therapy with high-dose cisplatin is the standard regimen against advanced squamous cell carcinoma of the larynx (SCC-L). However, patients with renal dysfunction are ineligible for this regimen. We investigated the effectiveness and feasibility of selective intra-arterial low-dose cisplatin infusion and radiotherapy (modified [m]-RADPLAT) for patients with impaired renal function. We retrospectively reviewed the data of 77 patients with SCC-L who received m-RADPLAT. Fourteen and 63 patients had creatinine clearance (CrCl) values of 30 ≤ CrCl < 60 mL/min and ≥60 mL/min, respectively. The m-RADPLAT regimen led to no significant changes in serum creatinine or CrCl values post-treatment. The 5-year local control, overall survival, and laryngectomy-free survival rates of the CrCl < 60 and ≥60 groups were 90.0% and 90.5%, 100% and 81.8%, and 100% and 79.0%, respectively. Grade 3 or higher toxicity rates were not significantly different between the groups. The m-RADPLAT regimen yielded favorable survival rates and clinical outcomes in patients with impaired renal function.

Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons

BackgroundRecombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients. ObjectivesThe aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers. MethodsEight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry. ResultsBolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants. ConclusionIn conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.

Effects of Low-Dose Ketamine Infusion on the Positive and Negative Domains of Hopelessness and Suicidal Thoughts

Effects of Low-Dose Ketamine Infusion on the Positive and Negative Domains of Hopelessness and Suicidal Thoughts

Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.

Update on targeted treatments for ANCA-associated vasculitis

Targeted therapy has revolutionized the management of ANCA-associated vasculitis (AAV) over the last fifteen years. Rituximab, an approved induction and maintenance agent for severe AAV, is no less effective than cyclophosphamide as induction therapy and particularly useful in relapsing or refractory disease, or in women. In patients with relapsing AAV, granulomatosis with polyangiitis or PR3-ANCA, it is more effective than cyclophosphamide. Rituximab maintenance is superior to the conventional immunosuppressive drugs that it replaces. Low-dose preemptive rituximab infusions are recommended every 6months for 18months, followed by re-evaluation to decide whether 4 additional biannual infusions should be administered, balancing the probability of relapse and the risk of serious infections on rituximab. A growing body of experimental and clinical data shows that C5a pathway inhibition is a promising therapeutic option for AAV, which could reduce glucocorticoids needs. Avacopan is a first approved oral C5A receptor antagonist, used when there is a high risk that glucocorticoids will cause serious adverse events. In eosinophilic granulomatosis with polyangiitis, the importance of IL-5 for eosinophil activation and survival led to evaluation and approval of mepolizumab, a humanized monoclonal antibody directed against IL-5. Mepolizumab showed a steroid-sparing effect. Its effectiveness in active vasculitis remains uncertain and is currently being evaluated. Benralizumab targeting the IL-5 receptor was recently shown to be noninferior to mepolizumab. Rituximab has had disappointing results in non-severe active vasculitis and is being evaluated as maintenance therapy. Plasma exchange is not indicated as first-line treatment but remains recommended when creatinine levels exceed 300μmol/L.

Analgesic Effect and Sleep Quality of Low-Dose Dexmedetomidine in Cardiac Surgical Patients After Ultrafast-Track Extubation: A Randomized Clinical Trial

To compare the analgesic and sleep quality effects of dexmedetomidine infusion versus placebo in patients undergoing cardiac surgery with ultra-fast track extubation. The randomized, double-blind clinical trial study. At a single academic center hospital. We included patients aged 25 to 65 scheduled for elective cardiac surgery under general anesthesia with cardiopulmonary bypass from October 2021 to December 2022. After immediate extubation in the operating room, the patients who were allocated at first after providing their consent to either the dexmedetomidine group (Dex) or the placebo group (Placebo) received continuous infusion of dexmedetomidine (0.2 μg/kg/h) or saline for 12 hours postoperatively. The groups' demographic and perioperative variables were not statistically significant. Total morphine consumption in milligrams at 12 and 24 hours after administered study drug, total sleep time in hours by BIS value ≤85, and sleep quality with the Richard-Campbell Sleep Questionnaire were compared. The analysis included 22 Dex and 23 Placebo patients. The consumption of morphine was not statistically different between the Dex and Placebo groups at 12 and 24 hours (p = 0.707 and p = 0.502, respectively). The Dex group had significantly longer sleep time (8.7 h [7.8, 9.5]) than the Placebo group (5.8 h [2.9, 8.5]; p = 0.007). The Dex group also exhibited better sleep quality (7.9 [6.7, 8.7] vs 6.6 [5.2, 8.0]; p = 0.038). Sedation with low-dose dexmedetomidine infusion for ultra-fast track extubation following cardiac surgery enhances sleep duration and quality.