Single Bolus Dose Research Articles

Perioperative Precedex: Whole New Ball Game or Whole New Ball of Wax?

Perioperative Precedex: Whole New Ball Game or Whole New Ball of Wax?

Intravenous dexmedetomidine enhances the experience of visceral pain in parturients during cesarean delivery under spinal anesthesia

Background and hypothesis Visceral pain is a common incidence in cesarean delivery under spinal anesthesia. Dexmedetomidine (DEX) has analgesic, sedative, anxiolytic effect, as it is an α 2-receptor agonist. Intraoperative visceral pain resulting from manipulation of the uterus and traction of the peritoneum is still a challenge for anesthetists. The present study hypothesized that single intravenous bolus dose of DEX added as a supplement to intrathecal anesthesia for an elective cesarean section could reduce intraoperative visceral pain, lessen blood pressure swings, and produce an acceptable sedative effect, with minimal fetal and maternal consequences. Patients and methods A randomized double-blinded placebo-controlled study was conducted. A total of 70 patients were randomly allocated to receive either intravenous DEX or placebo (saline) before spinal anesthesia. The primary outcomes were decreased intraoperative visceral pain. Secondary outcomes included the stability of hemodynamic parameters (blood pressure and heart rate), sedation score, time to rescue analgesia reduction, neonatal APGAR score, and any adverse effects (nausea and vomiting). Results There was a significant difference between the groups in the incidence of moderate to severe visceral pain (P<0.001), intraoperative fentanyl requirements (P=0.004), and longer time to rescue analgesia (P<0.001). Both groups had comparable mean blood pressure (P>0.005); however, there was a highly significant difference in heart rate (P=0.01). Moreover, a significantly higher sedation score was seen in the DEX group (2.08±0.8) in comparison with the control group (1±0). APGAR score was comparable in the studied groups. Conclusion As a single intravenous bolus, DEX seems to be an excellent supplement to intrathecal anesthesia for an elective cesarean section. It can reduce intraoperative visceral pain and lessen blood pressure swings and produce an acceptable sedative effect with minimal fetal and maternal influence.

Comparison of two different methods for labor analgesia depending on the mode of epidural infusion administration (continuous or intermittent)

Introduction: The use of a local anesthetic solution with opioids as a continuous epidural infusion administration during labor is controversial. It is considered to prolong the second stage of labor and to increase the total delivered dose of anesthetic, without improving the analgesia in comparison with the usage of the same solution in intermittent bolus doses, periodically. This study is designed to compare these two techniques. Materials and methods: In this study, 60 parturient women were included. Labor analgesia started with a single bolus dose of 10 mL ropivacaine 0.1% administered epidurally in both groups. Group A was, subsequently, given epidurally Ropivacaine 0.15% with Fentanyl 2 μgr/mL in continuous infusion with a rate of 10 mL/h throughout labor, while Group B was given the same dose per hour but in two bolus doses of 5 mL administered every 30 min. In both groups, we had the possibility of additional bolus doses of 5 mL of the same solution with a lock out interval of 20 min. The total dosage received, the duration of the 2nd stage of labor, the method of delivery (assisted or not, Cesarean section), the motor activity (using the Bromage scale) and the pain intensity (using the VAS 1–10, every 20 min) were evaluated. Results: No statistically significant differences were observed in the duration of labor (one way ANOVA), in the Bromage score and in the method of delivery between the two groups (x2 test). No differences were also observed in the recordings of pain intensity between the two groups (two-way ANOVA for repeated measurements), but in some specific instances Group A presented higher VAS score, although the total dosage of local anesthetic received was greater in this group compared to group B (180 mL vs. 162 mL, p = 0.04). Conclusions: The use of intermittent epidural bolus doses compared to a continuous infusion technique is associated with lower total consumption and periodically better pain management.

The Role of Dexmedetomidine and Pethidine in Controlling Intraoperative Shivering During Spinal Anesthesia

Spinal anesthesia is a safe and widely used anesthetic procedure, practiced for both elective and emergency surgeries. The present study compares the efficacy of Dexmedetomidine and Pethidine to control intraoperative shivering during spinal anesthesia. The study was conducted from January 2020 - July 2020 in a tertiary care centre including 60 patients aged between 20-60 years, belonging to ASA grade I/II, who developed grade 2-3 shivering following spinal anesthesia. These patients were randomized into two groups: Group I received a single intravenous bolus dose of 0.5 mcg/kg of Dexmedetomidine over 5 minutes and Group II received a single intravenous bolus dose of 0.5 mg/kg Pethidine over 5 minutes. Patients were monitored for drug failure, recurrence of shivering, and side effects. Preoperative temperature in Group I and Group II was 37.1 degrees Celsius and 37.2 degrees Celsius, respectively. The temperature in both groups during shivering was 36.2 and 36.4 degrees Celsius in Group I and Group II, respectively. Preoperative heart rate in Group I and Group II was 84.2 beats/minute and 75.4 beats/minute, respectively. Heart rate in both groups during shivering was 83.6 and 73.5 beats/minute in Group I and Group II, respectively. Grade 3 shivering was observed in 14 patients of Group I and in 19 patients of Group II (p< 0.05). Sixteen and eleven patients in Group I and Group II, respectively were found to have Grade 4 shivering (p< 0.05). Five patients of Group I and four patients of Group II experience recurrent shivering (P< 0.05). Nausea was reported by 2 patients in Group I and 1 patient in Group II (P< 0.05). Dexmedetomidine has better intraoperative shivering control during spinal anesthesia.

Minimum Alveolar Concentration of Sevoflurane as a Single Hypnotic Agent to Maintain BIS Below 50 in Patients During Normothermic Cardiopulmonary Bypass

Minimum alveolar concentration (MAC) of volatile anesthetic agents to maintain bispectral index (BIS) below 50 in 50% of patients was defined as MACBIS50. The primary objective of this study was to determine the minimum alveolar concentration of sevoflurane as a single hypnotic agent to maintain BIS below 50 in patients during normothermic cardiopulmonary bypass. Prospective and observational study. Dante Pazzanese Institute of Cardiology, Brazil. Eighteen consecutive patients scheduled for elective coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) under general anesthesia, American Society of Anesthesiologists physical status classes III and IV, between the ages of 40 and 70, were included in the study. All patients underwent inhalation induction with facial mask using sevoflurane (Cristália) in 100% oxygen, pancuronium (Cristália) 0.1 mg/kg, and sufentanil (Cristália) 0.5 µg/kg intravenously (IV) administered. A single bolus dose of sufentanil, 1.0 µg/kg IV, was administered before surgical incision. MACBIS50 was calculated using the midpoint concentration of patients involving a crossover (BIS < or ≥50) according to Dixon's Up-and-Down method. The Up-and-Down sequence also was analyzed by probit test that enabled the authors to obtain the effective dose 50 (ED50) and effective dose 95 (ED95) of sevoflurane to maintain a BIS value <50, with a 95% confidence interval (95% CI) of the mean. A total of 15 patients were analyzed in this study. MACBIS50 of sevoflurane as a single hypnotic agent was 0.82% (95% CI 0.47-1.16) in patients aged 40 to 70 undergoing CABG during normothermic CPB. The ED50 and ED95 of sevoflurane to maintain a BIS value <50 for the same context were 0.73% (95% CI 0.45-1.00) and 1.39 (95% CI 0.42-2.37) by means of probit analysis, respectively. MACBIS50 of sevoflurane as a single hypnotic agent was 0.82% in patients undergoing CABG during normothermic CPB.

AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia.

Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL-mediated thrombocytopenia. We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-xL-dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2-selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.

Comparison of intraoperative bleeding and surgical fields with and without tranexamic acid in Functional endoscopic sinus surgery

Functional endoscopic sinus surgery (FESS) requires good intraoperative surgical field visualization for better identification of structures. Among the many modalities for improving visibility, antifibrinolytic agent like Tranexamic acid has shown good results in many other surgeries. In this study, we have evaluated the effect of a single bolus dose of 15mg/kg intravenous Tranexamic acid when used as an adjunct. Materials and Methods: We have studied group T (n=30), who received Inj. Tranexamic acid against group C (n=30) i.e. control group. They were compared for surgical field using Boezaart scale, surgical duration and blood loss. Statistical analysis was done by unpaired t test and chi square test as was appropriate. Results: T group showed significantly lower values of Boezaart scale score i.e. better visualisation for surgical field (p Conclusion: We found that Tranexamic acid has a beneficial role in functional endoscopic sinus surgeries by improving the quality of surgical field when used as an adjunct. Keywords: Tranexamic acid, surgical field, functional endoscopic sinus surgery.

Analgesic efficacy of ketamine and magnesium after laparoscopic sleeve gastrectomy: A randomized, double-blind, placebo-controlled trial

BackgroundKetamine and magnesium are antagonists of the N-methyl-d-aspartate receptor, and are valuable adjuvants for multimodal analgesia and opioid sparing. Data are limited regarding the opioid sparing efficacy of the combined intraoperative application of these agents in laparoscopic bariatric surgery. The objective of this study was to compare the postoperative opioid sparing properties of a single intraoperative dose of ketamine versus a combination of single doses of ketamine and magnesium after laparoscopic gastric sleeve resection in bariatric patients.MethodsOne hundred and twenty- six patients were randomly assigned to receive single boluses of ketamine alone 0.5 mg kg−1 IV (ketamine group); combined ketamine bolus of 0.5 mg kg−1 IV and magnesium 2 g IV (ketamine and magnesium group); or placebo. Opioid consumption at 24 h (in morphine equivalents); pain at rest; postoperative nausea and vomiting impact score; sedation scores; and trends of transcutaneous carbon-di-oxide values were analysed.ResultsThe median (inter-quartile range [range]) morphine consumption at 24 h were 32 (24–47 [4.8–91]) mg in the ketamine group, 37 (18–53 [1–144]) mg in the ketamine and magnesium group, and 26 (21–36 [5–89]) mg in the control group and were not significantly different between the groups. There were no differences for all other outcomes examined.ConclusionCombined single intraoperative bolus doses of ketamine and magnesium did not result in postoperative opioid sparing after laparoscopic gastric sleeve resection.

Dexmedetomidine as a Single Bolus Dose in Laparoscopic Cholecystectomy under General Anesthesia – A Comparison of Different Doses

Introduction: Dexmedetomidine has an ideal pharmacodynamic profile for attenuation of stress response during general anesthesia for laparoscopic cholecystectomy. Since, the value of dexmedetomidine as a single premedication dose remains largely unexplored, this study compared dexmedetomidine in 0.5μg/kg and 1μg/kg dose for laparoscopic cholecystectomy under general anesthesia. &#x0D; Objectives: The primary objective of this study was to compare dexmedetomidine in a single premedication dose of 0.5μg/kg and 1μg/kg in terms of hemodynamic (heart rate and mean arterial pressure) changes to critical incidences such as laryngoscopy, endotracheal intubation, pneumoperitoneum and extubation. The secondary objectives were to compare induction dose of propofol required, sedation scores in the immediate post anesthesia period and adverse events such as bradycardia and hypotension. &#x0D; Methodology: This was a prospective double blind study. Ninety-two patients aged 18-55 years of either gender of American Society of Anesthesiologists physical status I-II were randomly allocated into two groups to receive either Dexmedetomidine 1μg/kg or 0.5μg/kg slowly IV over 10 minutes as a premedication before induction. Heart rate, Mean arterial pressure, induction dose of propofol, sedation scores, and adverse events were compared. &#x0D; Results: The patient characteristics, Fentanyl consumption, duration of surgery and anesthesia in both groups were comparable. There was comparable attenuation of hemodynamics in both groups during laryngoscopy and intubation. Dexmedetomidine in 1μg/kg compared to 0.5μg/kg had significantly better attenuation of hemodynamics from 1 minute to 40 minutes of pneumoperitoneum. After 40 minutes, there was no attenuation in either group. The post anesthesia sedation scores were comparable. The induction dose of propofol was significantly less and the incidence of bradycardia was significantly higher with dexmedetomidine 1μg/kg. &#x0D; Conclusion This study demonstrates that a premedication dose of Dexmedetomidine in 1μg/kg compared to 0.5μg/kg has significantly betier attenuation of hemodynamics from 1 minute to 40 minutes of pneumoperitoneum.

Semi-Mechanistic Pharmacokinetic Modeling of Lipid Core Nanocapsules: Understanding Quetiapine Plasma and Brain Disposition in a Neurodevelopmental Animal Model of Schizophrenia.

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous bolus dose of FQ or QLNC to naive and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bidirectional drug transport across the blood-brain barrier (CLin and CLout). SCZ-like rats' significant decrease in brain exposure with FQ (decrease in CLin) was reverted by QLNC, showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LNC for brain delivery. SIGNIFICANCE STATEMENT: A population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of the drug's brain distribution following administration of both free drug in solution or as nanoformulation to naive and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment-limited response rates.

Assessment of the anti-allodynic efficacy of a glycine transporter 2 inhibitor relative to pregabalin and duloxetine in a rat model of prostate cancer-induced bone pain.

The pathobiology of prostate cancer-induced bone pain (PCIBP) is underpinned by both inflammatory and neuropathic components. Here, we used a rat model of PCIBP to assess the analgesic efficacy of a glycine transporter 2 (GlyT2) inhibitor (N-(6-((1,3-dihydroxypropan-2-yl)amino)-2-(dimethylamino)pyridin-3-yl)-3,5-dimethoxy-4-(4-(trifluoromethyl)phenoxy) benzamide) relative to two clinically available adjuvant drugs that are recommended for the relief of neuropathic pain, viz, pregabalin and duloxetine. PCIBP was induced in male Wistar Han rats following intra-tibial injection (ITI) of rat prostate cancer (AT3B) cells into the left tibia. Sham-rats received an ITI of heat-killed AT3B cells. PCIBP rats with fully developed mechanical allodynia in the ipsilateral hindpaws as assessed using von Frey filaments, received single oral (p.o.) bolus doses of the GlyT2 inhibitor (3-30mg/kg), pregabalin (3-100mg/kg), duloxetine (3-100mg/kg), or vehicle. Baseline paw withdrawal thresholds (PWTs) were determined in the ipsilateral (injured side) and contralateral hindpaws immediately prior to dosing and at scheduled times for 3h post dosing in individual animals. Single oral bolus doses of the GlyT2 inhibitor (3-30mg/kg) evoked partial pain relief at the doses tested in the ipsilateral hindpaws of PCIBP rats without any discernible behavioural side effects. By contrast, single oral bolus doses of pregabalin at 10-100mg/kg evoked dose-dependent and complete alleviation of mechanical allodynia. By comparison, single oral bolus doses of duloxetine at doses up to 100mg/kg lacked efficacy. Oral administration of this GlyT2 inhibitor evoked partial pain relief in PCIBP rats and did not evoke central nervous system side effects in contrast to GlyT2 inhibitors reported by others.

Evaluation of the Effect of Single Bolus Dose of Intravenous Dexmedetomidine in Spinal Anaesthesia for Lower Limb Surgeries

Introduction: The use of intrathecal adjuvants in spinal anaesthesia in enhancing and prolonging it’s action has been well established and is widely used for surgery below the umbilicus. Dexmedetomidine, a selective α2A receptor agonist is a suitable adjuvant due to its selective activity.&#x0D; Objectives: To evaluate the effect of a single bolus dose of intravenous dexmedetomidine as an adjuvant in cases undergoing lower limb surgeries under spinal anaesthesia.&#x0D; Methodology: One hundred patients posted for lower limb surgery under spinal anaesthesia with hyperbaric bupivacaine, were equally divided into two groups. In group D, in addition to spinal, intravenous dexmedetomidine 0.5mcg/kg over 10 min was given whereas group C patients received spinal and intravenous normal saline .&#x0D; Results: The onset of sensory and motor block was faster in group D (2.09 ± 0.71 min, 3.18 ± 1min)compared to group C (3.5 ± 0.82 min, 6.19 ± 1.87 min) which was statistically significant . The duration of sensory and motor block was also significantly prolonged in Group D (174.5 ± 14.04 min, 133.4 ± 10.42 min) as compared to Group C(138.2 ± 11.51 min, 120.4 ± 8.8 min).The duration of analgesia in Group D (225.3 ±20.11 min)was prolonged when compared to Group C (168.3 ± 15.11).&#x0D; Conclusion: Intravenous dexmedetomidine as a single bolus dose before spinal anaesthesia can fasten the onset of sensory and motor block, prolongs the duration of sensory and motor block and also increased the duration of analgesia.

Simultaneous Measurement of Glomerular Filtration Rate, Effective Renal Plasma Flow and Tubular Secretion in Different Poultry Species by Single Intravenous Bolus of Iohexol and Para-Aminohippuric Acid.

Simple SummaryThe aim of this study was to investigate the simultaneous measurement of two different renal markers (iohexol and p-aminohippuric acid) in the plasma of different poultry species as the gold standard method. The two markers reflect three different renal processes: glomerular filtration, effective renal plasma flow, and tubular secretion. The rate at which the kidneys filter blood is called the glomerular filtration rate. The effective renal plasma flow is the volume of plasma that reaches the kidney per time unit. Tubular secretion can be defined as active transport from the peritubular capillaries to the renal tubules. A moderate correlation was observed between tubular secretion and the glomerular filtration rate. A good correlation was demonstrated between the effective renal plasma flow and the glomerular filtration rate. This might be useful to model both renal processes. This approach could support the further development and validation of clinical renal biomarkers. These markers can be useful in the case of a chronic renal disease or renal failure, for which repeated evaluations of the renal function are required.The aim of the current study was to investigate the simultaneous measurement of plasma p-aminohippuric acid (PAH) clearance as a potential marker to assess effective renal plasma flow (eRPF) and tubular secretion (TS), and the plasma clearance of iohexol (IOH) as a marker of the glomerular filtration rate in poultry species. The PAH was administered intravenously (IV) to broiler chickens, layers, turkeys, Muscovy ducks, and pigeons. Each animal received successively a single bolus dose of 10 mg PAH/kg bodyweight (BW) and 100 mg PAH/kg BW to assess the eRPF and TS, respectively. Simultaneously with both PAH administrations, a single IV bolus of 64.7 mg/kg BW of IOH was administered. A high linear correlation (R2 = 0.79) between eRPF, based on the clearance of the low dose of PAH, and BW was observed for the poultry species. The correlation between TS, based on the clearance of the high dose of PAH, and BW was moderate (R2 = 0.50). Finally, a moderate correlation (R2 = 0.68) was demonstrated between GFR and eRPF and between GFR and TS (R2 = 0.56). This presented pharmacokinetic approach of the simultaneous administration of IOH and PAH enabled a simultaneous evaluation of eRPF/TS and GFR, respectively, in different poultry species.

Abstract D052: Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy

Abstract Introduction: The 5-year survival rate for Pancreatic Ductal Adenocarcinoma (PDAC) remains 7%. An emerging treatment strategy involves the combination of vitamin D receptor (VDR) ligands with chemotherapeutic agents to re-program the activated cancer-associated fibroblast (CAFs). Calcipotriol (CAP), a synthetic analogue of vitamin D can reprogram CAFs, but is toxic with side effects including cachexia and edema. Due to the abundance of the VDR in the body, diminished plasma exposure and elimination of calcipotriol together with enhanced accumulation in the tumor are desirable to reduce toxicity and increase efficacy. We propose to achieve this with a slow-releasing micellar nanoformulation with a well-controlled size to take advantage of the leaky tumor fenestrations and enhance delivery. Method: 8-week old male C57BL/6 mice were administered with either formulated or non-formulated single IV bolus dose of CAP and paclitaxel (PTX). Drugs from blood samples were extracted, and simultaneously quantified using validated LC-MS/MS assay. Pharmacokinetic modeling was performed with Phoenix® WinNonlin (8.0) using 2-compartment model. Results: Our co-formulation of CAP and PTX resulted in &amp;gt;2-fold decrease in plasma exposure (AUC) and 5-fold reduction of peak concentration (Cmax) of CAP. Similarly, PTX AUC and Cmax were halved in mice administered with the formulated drugs. The PTX total clearance (CL) was similar between both groups, but CAP CL was 5-fold lower in formulation-administered mice. Further, CAP elimination (k10) from central compartment and from central to peripheral compartments (k12) were 2 and &amp;gt;3-fold slower, respectively, in the formulation group. The reverse elimination (k21) are similar. Similarly, the k10 of PTX was almost halved, while the k12 was 44-fold slower in mice receiving formulated drugs. The reverse elimination from the peripheral to the central compartment (k21) for formulated PTX is almost 10 times slower than in the mice receiving non-formulated PTX. Conclusion: Our micellar co-formulation of CAP and PTX is able to reduce total clearance of these agents from the systemic circulation. Further, rate constants derived show that PTX elimination from the systemic circulation to tissues is very slow and we expect this to correlate with an extended duration of action of this drug. Finally, our formulation halved the systemic exposure and peak concentrations of CAP that should lead to a more favorable safety profile of this agent. Ongoing work will focus on studying the pharmacokinetics of co-formulated CAP and PTX in a larger cohort of animals and we eventually hope to demonstrate the therapeutic merits of our nanoformulation strategy in pancreatic tumor-bearing mice. Citation Format: Victor R Lincha, Jun Zhao, Chun Li, Diana S-L Chow. Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D052.

Comparison of Pethidine and Dexmedetomidine for the Control of Intraoperative Shivering Under Spinal Anesthesia

Background: Spinal anesthesia significantly impairs the thermoregulation system by inhibiting tonic vasoconstriction, which plays a significant role in temperature regulation. Various non-pharmacological and pharmacological methods are available for the control of shivering during anesthesia. The present study was done with an aim to compare the two drugs Pethidine and Dexmedetomidine for the control of intraoperative shivering under spinal anesthesia.Subjects and Methods:A prospective randomized study was carried out in the Department of Anaesthesiology, on 100 patients who developed intra-operative shivering following spinal anesthesia for numerous surgical procedures. When patients developed shivering of higher than mentioned grades, they were randomly assigned to one of the 2 study groups: Group D- Dexmedetomidine group receiving single intravenous bolus dose of 0.5mcg/kg over 5 min. Group P: Pethidine group patients receiving 0.5mg/kg Pethidine IV over 5 min. Patients were intently monitored for the failure of the drug, Recurrence of shivering and side effects like nausea, vomiting, bradycardia (&lt; 50/min), hypotension (&gt;20% of baseline), giddiness and sedation score were recorded.Results:We found the Pethidine group had 62.5% and Dexmedetomidine had 67.5% of grade 3 shivering. The grades of shivering were comparable between the two groups with no statistical difference. We found the dexmedetomidine group had a significant reduction in time required to control shivering and vanishing of shivering after drug.Conclusion:Both dexmedetomidine (0.5mcg/kg) and Pethidine (0.5mg/kg) are effective in treating patients with post-spinal anesthesia shivering but the time taken for control of shivering was shorter with Dexmedetomidine as compared to Pethidine.

Randomized open-label trial of intravenous brivaracetam versus lorazepam for acute treatment of increased seizure activity

ObjectiveThe objective of the present trial was to assess efficacy and safety of intravenous (IV) brivaracetam (BRV) vs. lorazepam (LZP) in patients with epilepsy undergoing evaluation in an epilepsy monitoring unit (EMU) who experienced seizures requiring acute treatment. MethodsThis was a phase 2, open-label, randomized, active-control, proof-of-concept trial (EP0087; NCT03021018). Patients (18–70 years) admitted to EMU were randomized 1:1:1 to single-dose bolus IV LZP (dose per investigator's practice), IV BRV 100 mg, or IV BRV 200 mg. Trial medication had to be administered within 30 min of qualifying seizure. Primary efficacy outcome was time to next seizure (clinical observation with electroencephalogram [EEG] confirmation) or to rescue medication use within 12 h of trial medication administration. Secondary outcomes included seizure freedom and rescue medication use within 12 h of trial medication administration. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). ResultsOverall, 46 patients were randomized, and 45 received trial medication for a qualifying seizure. Patients in the LZP arm had doses from 1 to 4 mg (median: 1 mg). Eleven of 45 patients had a seizure within 12 h of trial medication administration (LZP 5/15 [median time to next seizure: 5.55 h], BRV 100 mg 3/15 [5.97 h], BRV 200 mg 3/15 [3.60 h]). No patients received additional rescue medication to control their qualifying seizure. Most patients were seizure-free over 12 h (LZP 9/15 [60.0%], BRV 100 mg 12/15 [80.0%], BRV 200 mg 12/15 [80.0%]). Rescue medication use within 12 h was numerically higher for LZP (6/15 [40.0%]) vs. BRV 100 mg (1/15 [6.7%]) and vs. BRV 200 mg (2/15 [13.3%]). Treatment-emergent adverse events were reported by 5/16 (31.3%), 6/15 (40.0%), and 3/15 (20.0%) of LZP, BRV 100 mg, and BRV 200 mg patients; one LZP patient had a serious TEAE (seizure cluster). Most common TEAEs (≥10% of patients) were sedation and somnolence with LZP, and dizziness, headache, and nausea with BRV. SignificanceIntravenous LZP, IV BRV 100 mg, and IV BRV 200 mg showed similar efficacy in controlling acute seizure activity in the EMU. Treatment-emergent adverse events were as expected for each medication. Although this trial should be interpreted with caution because of small patient numbers, it suggests a possible role of BRV in the acute treatment of increased seizure activity.

Index of Microcirculatory Resistance Measured during Intracoronary Adenosine-Induced Hyperemia.

Background The index of microcirculatory resistance is an invasive measure of coronary microvascular function that has to be calculated during maximal hyperemia, classically achieved with intravenous adenosine (IV). The aim of this study was to evaluate the use of intracoronary (IC) adenosine for the calculation of IMR. Methods and Results 31 patients with stable coronary artery disease were included in the study. Coronary pressure and thermodilution measurements were obtained at rest and during maximal hyperemia using a pressure-temperature sensor-tipped coronary guidewire. Duplicate measurements were performed using first IC and then IV adenosine. Dispersion of transit times was comparable for IC and IV adenosine. IMR values based on IC vs IV adenosine showed a high level of agreement and an intraclass correlation coefficient of 0.90. Applying an upper normal limit of 25, misclassification of IMR using IC adenosine was seen in just one patient in whom IC adenosine resulted in a lower value. A simplified procedure based on a single bolus dose of saline did not change the level of agreement or the rate of misclassification. Conclusions We found an excellent agreement between IMR values measured during hyperemia induced by IC as compared to IV adenosine. The use of IC adenosine may facilitate invasive assessment of microvascular function and is potentially time- and cost-saving with less patient discomfort as compared to IV infusion. The trail is registered with NCT03369184.

A Simple, Label-Free, and High-Throughput Method to Evaluate the Epigallocatechin-3-Gallate Impact in Plasma Molecular Profile.

Epigallocatechin-3-gallate (EGCG), the major catechin present in green tea, presents diverse appealing biological activities, such as antioxidative, anti-inflammatory, antimicrobial, and antiviral activities, among others. The present work evaluated the impact in the molecular profile of human plasma from daily consumption of 225 mg of EGCG for 90 days. Plasma from peripheral blood was collected from 30 healthy human volunteers and analyzed by high-throughput Fourier transform infrared spectroscopy. To capture the biochemical information while minimizing the interference of physical phenomena, several combinations of spectra pre-processing methods were evaluated by principal component analysis. The pre-processing method that led to the best class separation, that is, between the plasma spectral data collected at the beginning and after the 90 days, was a combination of atmospheric correction with a second derivative spectra. A hierarchical cluster analysis of second derivative spectra also highlighted the fact that plasma acquired before EGCG consumption presented a distinct molecular profile after the 90 days of EGCG consumption. It was also possible by partial least squares regression discriminant analysis to correctly predict all unlabeled plasma samples (not used for model construction) at both timeframes. We observed that the similarity in composition among the plasma samples was higher in samples collected after EGCG consumption when compared with the samples taken prior to EGCG consumption. Diverse negative peaks of the normalized second derivative spectra, associated with lipid and protein regions, were significantly affected (p < 0.001) by EGCG consumption, according to the impact of EGCG consumption on the patients’ blood, low density and high density lipoproteins ratio. In conclusion, a single bolus dose of 225 mg of EGCG, ingested throughout a period of 90 days, drastically affected plasma molecular composition in all participants, which raises awareness regarding prolonged human exposure to EGCG. Because the analysis was conducted in a high-throughput, label-free, and economic analysis, it could be applied to high-dimension molecular epidemiological studies to further promote the understanding of the effect of bio-compound consumption mode and frequency.

Altered Cisplatin Pharmacokinetics during Nonalcoholic Steatohepatitis Contributes to Reduced Nephrotoxicity

Cisplatin is an alkylating antineoplastic agent that is indicated for the treatment of solid malignancies. Cisplatin is preferentially eliminated from systemic circulation via tubular secretion, whereby it exhibits dose‐limiting nephrotoxicity. Interindividual variability in xenobiotic transporter expression is a known contributor to differential cisplatin toxicity and efficacy, and may be the result of genetic, environmental, and pathological contributions. In this study, we aimed to determine if nonalcoholic steatohepatitis (NASH) alters cisplatin pharmacokinetics and if this change elicits differential nephrotoxicity. Sprague Dawley rats fed a control or methionine and choline deficient (MCD) diet to model NASH were given a single bolus dose of cisplatin and sacrificed after 72 h. The MCD diet resulted in a NASH hepatic phenotype that remained unchanged following cisplatin exposure. Drug‐naïve NASH rats also displayed no evidence of differential renal pathology relative to control rats. However, renal necrosis and inflammation were reduced in NASH by 40 and 63% following cisplatin treatment, respectively, relative to healthy controls. Furthermore, kidney weights of cisplatin‐treated control rats were increased by 31%, compared to an 18% increase in NASH. Plasma cisplatin clearance was reduced from 6.78 (control) to 4.04 mL/min in NASH, and cisplatin plasma AUC was significantly increased by 44% in NASH, relative to control. Cumulative urinary elimination of cisplatin was decreased from 73 to 34% of total dose and renal clearance was reduced from 4.64 to 1.49 mL/min in NASH, compared to control. Subsequently, renal intracellular accumulation of cisplatin after 6 h was reduced by 34% in NASH, relative to control. Supporting these findings, expression of proximal tubule cisplatin uptake transporters, Ctr1 and Ctr2, were reduced by 24 and 64%, respectively compared to healthy control rats, whereas expression of Oct1, Oct2, and Oct3 were unchanged. Interestingly, expression of cisplatin efflux transporters Mate1 and Atp7a were reduced by 52 and 31%, respectively, in NASH compared to control. Taken together, these data suggest that NASH alters renal uptake and efflux transporter expression, thereby attenuating cisplatin uptake and clearance in the kidney with a corresponding reduction in renal cell exposure and nephrotoxicity during NASH. As such, this study demonstrates that NASH can influence pharmacokinetics of drugs cleared by renal elimination, which may contribute to adverse drug reactions.Support or Funding InformationThis work is supported by a NIH grant [R01 ES028668] and the Southwest Environmental Health Sciences Center [P30 ES006694]. JLJ is supported by an institutional training grant [T32 ES007091].

A Single Preoperative Dose of Tranexamic Acid Reduces Perioperative Blood Loss: A Meta-analysis.

To review the efficacy and safety of a single dose of intravenous tranexamic acid (TXA) given preoperatively. TXA is a synthetic antifibrinolytic that has been used in various surgical disciplines to reduce blood loss, blood transfusions, ecchymosis, and hematoma formation. However, there is no universal standard on the most effective dose and route of TXA administration, limiting its routine use in many centers. This study evaluates the current evidence for the efficacy and safety of a single preoperative dose of TXA on surgical blood loss in all surgical disciplines. With the guidance of a research librarian, in accordance with the Cochrane Handbook Medline, Cochrane Central and Embase were searched in November 2018. Search terms included "Tranexamic Acid" AND "Intravenous," with studies limited to randomized controlled trails in adult humans. Two independent reviewers and an arbitrator assessed articles for inclusion. Criteria included a single preoperative bolus dose of intravenous TXA, surgical patients, and intraoperative blood loss measurement or perioperative blood loss up to 24 hours postsurgery. Quality assessment was done using the Cochrane Collaboration risk-of-bias tool by 2 reviewers. Statistical analysis was carried out using Cochrane Review Manager 5.3. The primary outcome was surgical blood loss. Secondary outcomes included venous thromboembolic complications, transfusion requirements, and dosing. A total of 1906 articles were screened, 57 met inclusion criteria. The majority of included studies were orthopedic (27), followed by obstetric and gynecological (16), oral maxillofacial and otolaryngology (10), cardiac (3), and 1 plastic surgery study focusing on acute burn reconstruction. Across all surgical specialties (n = 5698), the perioperative estimated blood loss was lower in patients receiving TXA, with a standard mean difference of -153.33 mL (95% CI = -187.79 to -118.87). Overall, surgical patients with TXA had a 72% reduced odds of transfusion (odds ratio = 0.28 [95% CI = 0.22-0.36]). The most frequently used dose of TXA was 15 mg/kg. There was no difference in the incidence of venous thromboembolic events between TXA and control groups. While there is a growing body of evidence to support benefits of perioperative TXA use, this is the first meta-analysis to identify the efficacy and safety of a single preoperative dose of IV TXA. The potential implications for expanding the use of preoperative TXA for elective day surgery procedures is substantial. Preoperative intravenous TXA reduced perioperative blood loss and transfusion requirements in a variety of surgical disciplines without increasing the risk of thromboembolic events. Therefore, it should be considered for prophylactic use in surgery to reduce operative bleeding.