Slow Bolus Research Articles

Comparison of the Preemptive/Preventive Effect of Dexmedetomidine and Ketorolac on Post-operative Pain of Appendectomy Patients: A Randomized Clinical Trial

Objectives: The primary objective was to test the hypothesis that the preemptive/preventive effect of Dexmedetomidine would attenuate the post-operative pain more effectively compared to ketorolac and control groups. Methods: This study was conducted in Shahid Mohamadi Hospital. Sixty patients undergoing appendectomy operations were randomized in 3 groups. Group A received intravenous Dexmedetomidine bolus (1 μg/kg) and infusion (0.5 μg/kg/h). Group B received slow intravenous bolus ketorolac 30 mg. Group C was the control group. Post-operatively fentanyl (5µg/mL) as patient control analgesia (PCA) was provided only on demand. The primary outcome was the Visual Analogue Scale (VAS) pain scores recorded at 1, 3, 6, 12 and 24 hours postoperatively. The secondary outcome was the 24-hour cumulative fentanyl PCA dose. Tertiary outcomes; changes in blood pressure, heart rate, body temperature, SpO2 perioperatively. Quaternary outcomes were PONV, shivering. Results: In the Dexmedetomidine group the mean ± SD pain VAS scores 1.15 ± 1.98 and 0.95 ± 1.76 were significantly lower at 12 and 24 hours after operation (P = 0.004 and P = 0.003) compared to the other two (ketorolac and control) groups. The cumulative volume dose of fentanyl PCA 21.35 ± 11.77 mL was less in the Dexmedetomidine group compared to ketorolac (28.35 ± 9.82 mL, P = 0.629) and control (40.35 ± 12.90 mL, P = 0.003) groups. Conclusions: Preemptive/preventive effects of Dexmedetomidine were greatest after operation compared to the ketorolac and control groups in the terms of pain scores and amount of analgesia needed postoperatively.

Clinical impact of perfusion balloon for ST-segment elevated myocardial infarction: RYUSEI study

Abstract Background Drug-eluting stents have significantly contributed to reducing mortality in patients with ST-segment elevation myocardial infarctions (STEMIs), but slow flow/no-reflow phenomenon and in-stent restenosis are still clinical problems. On the other hand, perfusion balloons (PBs) can compress thrombi and ruptured plaque for long inflation without ischemia and can be used as a delivery device for infusion of nitroprusside to distal risk area during ballooning. Purpose We conducted RYUSEI (Reduction of risk bY perfUsion balloon for ST-segment Elevated myocardial Infarction) study to evaluate whether PBs before stenting are more effective than conventional stenting for STEMIs. Methods We divided consecutive patients with STEMIs who underwent optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) into PB group who were treated with PBs before stenting and the conventional PCI (CP) group. In PB group, we inflated PB at the culprit lesion for five minutes to compress thrombi and ruptured plaque as a pre-stent lesion modification. In addition, an intra-coronary injection of nitroprusside (total dose: 120 µg; slow bolus injection of 24 µg/5mL every minute [5 times]) into the distal vascular bed to the culprit lesion through the PB was performed during a 5-minute PB ballooning. We compared clinical results including slow flow/no-reflow phenomenon, OCT findings, and one-year clinical events including cardiac death, target vessel-related myocardial infarctions, target lesion revascularization and stent thromboses between the two groups. Results We finally analyzed 34 patients in PB group and 90 in CP group. After propensity score matching, PB and CP groups consisted of 23 patients, respectively. In the propensity score-matched cohort, there were no significant differences of the patients’ backgrounds and lesion and procedural characteristics between the two groups. In the cohort, regarding post PCI angiographic and OCT findings, the incidence of slow flow/no-reflow phenomenon and maximum protrusion area detected by OCT were significantly lower (P=0.047 and P=0.019, respectively) and TIMI flow grade 3 was significantly higher (P=0.022) in the PB group than CP group while the other parameters were similar (Table). Kaplan-Meier analysis revealed a significantly better one-year clinical outcome in PB group than CP group (p=0.038) (Figure). Conclusions The RYUSEI study revealed a pre-stent lesion modification in addition to nitroprusside infusion using PB is useful to achieve better clinical course in STEMI patients.Post PCI Angiographic and OCT FindingsComparison of One-year Clinical Outcome

Comparison of remimazolam tosilate and propofol during induction and maintenance of general anesthesia in patients undergoing laparoscopic cholecystectomy: a prospective, single center, randomized controlled trial

BackgroundRemimazolam tosilate (RT) is a new, ultrashort-acting benzodiazepine. Here, we investigated the efficacy and safety of RT for general anesthesia in patients undergoing Laparoscopic Cholecystectomy (LC).MethodsIn this study, 122 patients undergoing laparoscopic cholecystectomy were randomly allocated to receive either remimazolam tosilate (Group RT) or propofol group (Group P). RT was administered as a slow bolus of 0.3 mg kg− 1 for induction, followed by 1.0–2.0 mg kg− 1 h− 1 for maintenance of general anesthesia. Propofol was started at 2 mg kg− 1 and followed by 4–10 mg kg− 1 h− 1 until the end of surgery. The primary outcome was the time to bispectral index (BIS) ≤ 60. The secondary outcome included the time to loss of consciousness (LoC), and the time to extubation. Adverse events were also assessed.ResultsA total of 112 patients were recruited for study participation. Among them, the time to BIS ≤ 60 in Group RT was longer than that in Group P (Group RT: 89.3 ± 10.7 s; Group P: 85.9 ± 9.7 s, P > 0.05). While the time to LoC comparing remimazolam and propofol showed no statistical significance (Group RT: 74.4 ± 10.3 s; Group P: 74.7 ± 9.3 s, P > 0.05). The time to extubation in Group RT was significantly longer than that in Group P (Group RT: 16.0 ± 2.6 min; Group P: 8.8 ± 4.3 min, P < 0.001). Remimazolam tosilate had more stable hemodynamics and a lower incidence of hypotension during general anesthesia.ConclusionsRemimazolam tosilate can be safely and effectively used for general anesthesia in patients undergoing Laparoscopic Cholecystectomy. It maintains stable hemodynamics during induction and maintenance of general anesthesia compared with propofol. Further studies are needed to validate the findings.Trial registrationChictr.org.cn ChiCTR2300071256 (date of registration: 09/05/2023).

Splenic hematoma and hemoperitoneum in a Thoroughbred racehorse after racing.

To describe the clinical presentation of a Thoroughbred filly with acute hemoperitoneum from a splenic source immediately after racing. A 3-year-old Thoroughbred filly used for racing and that had raced shortly before presentation to the hospital. On presentation, the filly was quiet, alert, and responsive with a heart rate of 76 beats/min, pale mucous membranes, and absent borborygmi. All other physical examination parameters were within normal limits. Abdominal ultrasound was performed and revealed echogenic free abdominal fluid and a splenic hematoma. Abdominocentesis yielded sanguinous fluid with a PCV of 35%. The next day, repeat ultrasound revealed the splenic hematoma with capsular separation. The filly was treated overnight with isotonic crystalloid fluids and aminocaproic acid (40 mg/kg, IV, slow bolus over 30 minutes followed by 20 mg/kg, IV, q 6 h), potassium penicillin (22,000 IU/kg, IV, q 6 h), gentamicin (6.6 mg/kg, IV, q 24 h), and omeprazole (4 mg/kg, PO, q 24 h). The lowest PCV obtained from the filly was 36 hours after presentation. The filly stabilized with medical treatment and was discharged to a farm for further recuperation. There are no published reports detailing hemoperitoneum of splenic origin in Thoroughbreds immediately after racing. Hemoperitoneum of splenic origin is not common in horses, with most cases of hemoperitoneum being secondary to acute trauma, neoplasia, parturition, or postoperative complications. While uncommon, this case raises awareness to another differential for a colicky horse immediately after racing.

Treatment of lidocaine-refractory ventricular tachycardia using procainamide in an anesthetized horse.

To highlight the use of procainamide as a potential alternative treatment modality in cases of ventricular tachycardia that are refractory to lidocaine and magnesium sulfate. 1 adult horse weighing 380 kg. A 25-year-old Arabian gelding presented with severe colic signs. Due to persistent pain, it was elected to carry out an exploratory laparotomy. During the procedure a diagnosis of severe, unstable ventricular tachycardia was made based on the ECG findings, with an initial heart rate of 195 beats per minute and severe hypotension. Initial treatment consisted of discontinuing dobutamine and the administration of a 2 mg/kg IV lidocaine bolus followed by a continuous rate infusion at 50 μg/kg/min. Twenty grams magnesium sulfate (5 mg/kg) was administered IV in 1 L of lactated Ringer solution as a slow bolus over 30 minutes. Ventricular tachycardia persisted with poor peripheral pulses, a severely dampened arterial waveform, and a MAP of 30 to 45 mm Hg. Two milligrams/kg IV procainamide was administered over 3 minutes, 3 separate times, at 5-minute intervals. Immediately following the third dose sinus rhythm was detected on the ECG, the arterial waveform improved, and MAP increased to 85 mm Hg. Ventricular tachycardia is a rare but potentially life-threatening complication in horses undergoing general anesthesia. The potential of this arrhythmia to progress to ventricular fibrillation is of grave concern, as the option to attempt to externally defibrillate horses back to normal sinus rhythm does not exist. This case highlights procainamide as a potential option for cases of ventricular tachycardia that are refractory to more standard treatment modalities.

Evaluation of the Effects of Magnesium Sulphate versus Normal Saline on Hemodynamics in Patients Undergoing Laparoscopic Cholecystectomy

Introduction: Numerous studies have shown that giving magnesium sulphate intravenously before carbon dioxide pneumoperitoneum is produced reduces the adverse hemodynamic response in patients undergoing elective laparoscopic cholecystectomy. &#x0D; Objective: To examine the effects on hemodynamics in patients undergoing laparoscopic cholecystectomy between magnesium sulphate and normal saline.&#x0D; Methodology:The Department of Anaesthesia at the Pakistan Institute of Medical Sciences, SZABMU, Islamabad, conducted a Randomised Clinical Trial. The study involved the enrolment of 108 adult patients, regardless of gender, who were admitted for elective laparoscopic cholecystectomy and ranged in age from 18 to 65. Every patient who was enrolled was in ΑSΑ classes I and II. Patients were randomised equally to Group M, which received an IV slow bolus of magnesium sulphate (28 mg/kg) over a 20-minute period, and Group N, which received a 0.9% normal saline solution. The patient was tilted right and up by 15 degrees.&#x0D; Results:Both groups' baseline characteristics were comparable. The mean age of groups M and N was 42.2 years ± 7.6SD and 40.5 years ± 8.4SD, respectively (Ρ-value t-test=0.258). 22 (40.7%) men and 32 (59.3%) women made up group M, while 20 (37.0%) men and 34 (63.0%) women made up group N (Ρ-value chi-square = 0.693). Both groups' baseline and pre-pneumoperitoneum hemodyanamic parameters (HR, Systolic, BΡ, Diastolic BΡ, and MAΡ) were similar (Ρ-value t-test &gt; 0.05).&#x0D; Conclusions:The adverse hemodynamic response caused by pneumoperitoneum was significantly attenuated by pretreatment with intravenous magnesium sulphate. Heart rate, systolic blood pressure, diastolic blood pressure, and MTH were all significantly lower than baseline. Significant hypotension and bradycardia, however, were not seen.

The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69).

An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (AppendixIII). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in AppendixIII. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].

Pharmacology of a CpG-Linked Anti-Mir-126 Oligonucleotide Targeting Acute Myeloid Leukemia (AML) in Rats and Non-Human Primates (NHP)

Introduction: Acute myeloid leukemia (AML) is a lethal hematopoietic malignancy, characterized by the accumulation of clonal myeloid progenitor cells arrested in development. AML patients have dismal outcomes with a 5-year overall survival (2011 - 2017) of 29.5% (SEER). The persistence of leukemia stem cells (LSCs), a treatment-resistant primitive cell population able to inititiate and maintain AML, is thought to underlie relapse. Even newly approved drugs do not target LSCs efficiently. MicroRNA (miR)-126 is a non-coding regulatory RNA that contributes to LSC homeostasis in the bone marrow niche. Several lines of evidence validate miR-126 as a target in AML. Thus, we designed and made a novel anti-miR-126 oligonucleotide (oligo) linked to a CpG moiety, termed miRisten. miRisten incorporates modifications such as 2'-fluoro and phosphorothioate substituting phosphodiester in the sugar moiety of the nucleotide to enhance in vivo stability. miRisten eradicates LSCs in mouse models of AML and synergizes with FDA-approved AML drugs (PMID: 29505034, 34372909). Here, the results of IND-enabling toxicokinetic (TK) studies of miRisten in rats and NHP are presented. Objective: To investigate the pharmacological properties of miRisten to establish a safe dosing strategy to achieve prolonged knockdown of miR-126 for a first-in-human trial. Experimental Plan and Results: Good laboratory practice (GLP) TK studies were carried out in Sprague-Dawley rats. miRisten was given IV b.i.d. for 19 days at human equivalent doses (HED) of 1.6 and 4 mg/kg. miRisten was measured in plasma after the first dose. Plasma miRisten C max average was 3622 ± 335 and 6010 ± 175 nM post first doses of 1.6 and 4mg/kg, respectively. Plasma t 1/2 averaged 20.0 ± 3.8 minutes across both doses. The area under the curve (AUC 0 - ¥) were 638.9 ± 32 nMxhr (1.6 mg/kg) and 1313.5 ± 439 (4 mg/kg). A parallel toxicology study was undertaken documenting cage-side observations and body weight; complement activation, blood chemistries, urine and hematology were also evaluated. There were no unscheduled deaths in the toxicology segment. Four single NHP exploratory studies were also carried out (Fig. 1: Treatment schema). In each study, miRisten was given IV as a slow bolus (~5') b.i.d. and PK parameters evaluated in plasma. Study #1 &amp; #2: 1 wk at 4mg/kg; #3: 1 wk at 5 mg/kg; #4: 18 days at 4 mg/kg. In all studies, miRisten dosage was ramped up (1, 2, 4 mg/kg for all and 5 mg/kg at dose 4 for Study #3). Solumedrol was given as premedication for the first 3 doses in all studies to prevent known phosphorothioate-mediated complement activation and cytokine release syndrome. Blood draws for PK were carried out immediately following doses 3 and 12 (Studies 1 - 3) and after the last dose on Day 18 (Study 4). The average area under the curve AUC was 3860 ± 1189 (4 mg/kg) and 3954 ± 1569 nMxhr (5 mg/kg) which was greater than observed in mice given the equivalent HED in bolus doses (~6x, 465.0). The t 1/2 of plasma miRisten was 11.7 min on Day 3 and 12.0 min on Day 7, comparable to mouse (9.6 min) and rat (20 min). Cage-side observations, body weight, complement activation, blood chemistries, urine and hematology were also evaluated. There was no terminal sacrifice of NHP however, all animals tolerated the treatment without observable adverse events. Conclusion: The dose ramp-up in NHP combined with pre-medication with solumedrol were undertaken to prevent possible acute inflammatory reactivity leading potentially to death. There were no unscheduled deaths in any species studied. These data are consistent with the safety of miRisten given IV with a dose ramping regimen combined with solumedrol. The greater AUC in NHP may predict better potency in humans. In mice, miRisten at 1.6 mg/kg HED q.d. effectively eradicated LSCs [PMID 29505034].

Supraventricular tachycardia in pregnancy: a rare case series and dilemmatic antiarrhythmic drug choices in the rural area

Background: The prevalence of cardiovascular disease in pregnancy is reported to be increasing and becoming a major cause of maternal morbidity and mortality. The incidence of arrhythmia during pregnancy has been linked to increased fetal mortality and complications. Arrhythmias can develop de novo during pregnancy or be exacerbated by pregnancy. Case Description: A 35-year-old (third trimester) and a 25-year-old (second trimester) woman complained of shortness of breath and palpitations. The first patient was in her sixth pregnancy, with three live births and two miscarriages. Meanwhile, the second patient was in her first pregnancy and had never miscarried. The first and second patients' pulse rates were 180 and 160 beats per minute, respectively. In both cases, 12-lead electrocardiography revealed an atrioventricular nodal re-entrant tachycardia rhythm. Initially, both patients were given carotid artery massages. The first patient's rhythm returned to normal sinus, but carotid artery massage failed in the second patient. Then, the second patient received a slow bolus of 0.5 mg digoxin IV. The heart rate returned to normal sinus rhythm following the observation. Both patients were admitted to the intensive care unit. Conclusion: Atrioventricular nodal re-entrant tachycardia is a type of paroxysmal supraventricular tachycardia. Effective management highly depends on both clinical presentation and the trimester of pregnancy. This arrhythmia can be treated with vagal maneuvers in mild cases. When vagal maneuvers fail, medical management is preferred. The main concern with using antiarrhythmic drugs during pregnancy is the risk of fetal harm and the decision should be tailored based.

Image-guided focused ultrasound-mediated molecular delivery to breast cancer in an animal model

Tumors become inoperable due to their size or location, making neoadjuvant chemotherapy the primary treatment. However, target tissue accumulation of anticancer agents is limited by the physical barriers of the tumor microenvironment. Low-intensity focused ultrasound (FUS) in combination with microbubble (MB) contrast agents can increase microvascular permeability and improve drug delivery to the target tissue after systemic administration. The goal of this research was to investigate image-guided FUS-mediated molecular delivery in volume space. Three-dimensional (3-D) FUS therapy functionality was implemented on a programmable ultrasound scanner (Vantage 256, Verasonics Inc.) equipped with a linear array for image guidance and a 128-element therapy transducer (HIFUPlex-06, Sonic Concepts). FUS treatment was performed on breast cancer-bearing female mice (N = 25). Animals were randomly divided into three groups, namely, 3-D FUS therapy, two-dimensional (2-D) FUS therapy, or sham (control) therapy. Immediately prior to the application of FUS therapy, animals received a slow bolus injection of MBs (Definity, Lantheus Medical Imaging Inc.) and near-infrared dye (IR-780, surrogate drug) for optical reporting and quantification of molecular delivery. Dye accumulation was monitored via in vivo optical imaging at 0, 1, 24, and 48 h (Pearl Trilogy, LI-COR). Following the 48 h time point, animals were humanely euthanized and tumors excised for ex vivo analyzes. Optical imaging results revealed that 3-D FUS therapy improved delivery of the IR-780 dye by 66.4% and 168.1% at 48 h compared to 2-D FUS (p = 0.18) and sham (p = 0.047) therapeutic strategies, respectively. Ex vivo analysis revealed similar trends. Overall, 3-D FUS therapy can improve accumulation of a surrogate drug throughout the entire target tumor burden after systemic administration.

Median effective dose (ED50) of esketamine combined with propofol for children to inhibit response of gastroscope insertion

BackgroundPropofol is the most commonly used drug for procedural sedation during gastroscopy. However, independent use of propofol can lead to increased dosage and additional side effects. Esketamine was found to be exceptional in combination with propofol for painless gastroscopy. No studies have calculated the median effective dose (ED50) of esketamine combined with propofol in pediatric painless gastroscopy. Here, we designed a research to study the ED50 of esketamine combined with propofol using the Dixon and Massey up-and-down sequential method for inhibiting the response of gastroscope insertion.MethodsChildren who met the inclusion and exclusion criteria were included in this study. Propofol and esketamine were used as anesthetics for painless gastroscopy in children. To explore the ED50, the initial propofol dose was set at 3 mg/kg in all children. The first child was given an esketamine dose of 0.1 mg/kg, followed by 30 s of slow bolus injection propofol. If anesthesia induction failed (coughing or body movement of children during gastroscope insertion), the esketamine dose was elevated in the next child, with a interval difference of 0.05 mg/kg. Otherwise, if the anesthesia induction was successful, the next dosage was reduced by 0.05 mg/kg. The study was stopped if nine crossover inflection points were reached. The ED50 of esketamine was calculated using probit regression, and the blood pressure, pulse oxygen saturation, heart rate, recovery time, and side effects were recorded in all children.ResultsA total of 26 children were included in this study. The ED50 of esketamine combined with 3 mg/kg propofol was 0.143 mg/kg (95% CI 0.047–0.398 mg/kg). The total consumption of propofol was 16.04 ± 5.37 mg. The recovery time was 16.38 ± 8.70 min. Adverse effects recorded were delayed awakening in two cases and increased oral secretions of another child during the examination inducing cough and hypoxemia (86% was the lowest).DiscussionThe ED50 of esketamine was 0.143 mg/kg when combined with 3 mg/kg propofol for successful sedation in pediatric gastroscope insertion. This sub-anaesthetic dose of esketamine was safe and efficacious with few complications in pediatric painless gastroscopy.Trial registrationThe study was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; registration number: ChiCTR2100052830 on 06/11/2021).

Enhancing Oil Solubility of BCS Class II Drug Phenytoin Through Hydrophobic Ion Pairing to Enable High Drug Load in Injectable Nanoemulsion to Prevent Precipitation at Physiological pH With a Potential to Prevent Phlebitis

This work investigates the micellar titration of phenytoin (a weakly acidic drug) with cetyltrimethylammonium hydroxide (CTAH) to form a hydrophobic ion-pair to enhance oil solubility of phenytoin, followed by an effort to formulate nanoemulsion that could potentially prevent precipitation of phenytoin at physiological pH. The ion-pair formulated in nanoemulsion was evaluated for in vitro precipitation during serial dilution at physiological pH. The formation of ion-pair during titration was explained in context of pH-solubility data. The mathematical model successfully integrated ionization and micellization equilibria to reflect on dominant mechanisms for solubilization. The micellar phenomenon during titration was confirmed using Dynamic Light Scattering (DLS). The phase changes of the excess undissolved solids during titration were evident from X-Ray Powder Diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR). This analysis confirmed the conversion of phenytoin into ionized state and its subsequent ionic interaction with CTAH forming hydrophobic ion-pair complex (HIP). The complete ion pair formation was evident at pHmax (8.8 to 9.2), and its 1:1 stoichiometry was confirmed using HPLC (Phenytoin and CTAH) and H1 NMR, hence could also be called as a lipophilic salt. The ion-pair (salt) was insoluble in water and showed remarkably high partition coefficient (log P) in octanol/water. As characterized by Hot Stage Microscopy (HSM), the melting point of the ion-pair complex was lowered to 150.8⁰C compared to the free acid (> 300οC), this was even further lowered to 81.1 °C when evaluated in castor oil. This led to approximately eight-fold higher solubility of hydrophobic ion pair (HIP) in castor oil compared to the free acid form. The high miscibility in castor oil was suitable to formulate a high drug load injectable dispersed system. This was successfully achieved with lecithin and polysorbate as emulsifiers without leaching drug into continuous phase at pH 7.4. This nanoemulsion (<300 nm, and > +30 mV zeta potential) remain stable when evaluated over a period of one month. A serial dilution study of the nanoemulsion was performed in PBS buffer, microscopic observations suggested no birefringence despite incubation at 25°C for several hours. This result indicated that Phenytoin remained strongly partitioned within dispersed oily phase with a higher drug loading when ion-paired phenytoin was used. The higher drug load could enable a small volume slow bolus injection to meet 50 mg/min or lower delivery rate criteria for Phenytoin in the clinical set up. This provided a pathway to further explore potential injectable nano-emulsion formulations that could alleviate typical phlebitis issue associated with the injectable phenytoin solution administration at physiological pH.

Continuous Intravenous Lidocaine for Acute Pain Management Post Laparotomy Surgery: A Case Series

Introduction: Acute post-operative pain can lead to prolonged use of opioids and progress to chronic pain. Multimodal analgesic approaches have replaced the use of opioid monotherapy, but opioid use continues and contributes to inadequate acute pain management. Intravenous lidocaine has analgesic, anti-hyperalgesic, and anti-inflammatory effects. This study aims to describe post-operative pain management using intravenous lidocaine.&#x0D; Case presentation: There were two cases. The first was a 32-year-old female patient with suspected interrupted ectopic pregnancy who underwent emergency laparotomy under spinal anesthesia and, after 2 hours, was converted to general anesthesia. Postoperatively, the analgesic lidocaine was given as a 52 mg intravenous bolus followed by a continuous 36 mg/hour/syringe pump. The patient's VAS scale was initially 2/10, and on the third day, 1/10 continued treatment. In the second case, an 18-year-old male patient with suspected acute appendicitis underwent a midline incision laparotomy appendectomy with spinal anesthesia. Postoperatively, lidocaine was given a slow bolus of 75 mg intravenously, finished in 5 minutes, then 50 mg/hour/intravenously. The patient's VAS scale was initially 2-3/10 until on the third day. He was transferred to a room with a VAS of 1-2/10.&#x0D; Conclusion: Lidocaine is an effective intravenous analgesic to treat acute pain after laparotomy surgery. Administration of relatively low doses can achieve post-operative analgesia without concern for toxicity.

Awake videolaryngoscopic orotracheal intubation in patients with laryngeal tumour using the C-MAC D-Blade.

ABSTRACTBackground and Aims:This study assessed the applicability of C-MAC videolaryngoscope (VL) D-blade for awake intubation in patients with laryngeal tumour. The primary study objective was to determine the rate of successful intubation in the first attempt. The other parameters recorded were number of attempts required for intubation, duration of different stages of intubation, haemodynamics, ease of intubation and patient comfort on visual analogue scale (VAS) postoperatively.Methods:Thirty patients were studied. Patients were sedated with dexmedetomidine and fentanyl as a slow bolus (over 20 min) and Ramsay sedation score was assessed. Topicalisation of the oropharynx, tonsillar pillars and base of the tongue was done with lignocaine 10% spray. Four ml of 4% lignocaine using MADgic atomiser was used for anaesthetising the glottis and the tracheal lumen.Results:Successful intubation was achieved in 86.6% patients in first attempt and 13.3% in two attempts. Total time for all intubations was less than 30 seconds. Fremantle score was F-1-C-MAC D-blade (easy intubation with full view) in 60% patients, while 23.3% had F-2-C-MAC D-blade (full view and either required more than one attempt or a modified technique), 13.3% had P-1-C-MAC D-blade (partial view with easy intubation) and 3.3% had P-2-C-MAC D-blade (partial view and required more than one attempt or a modified technique). The VAS score for anaesthesiologist’s ease and for patient’s experience was 85.83 ± 7.20 and 86.66 ± 14.46, respectively.Conclusion:C-MAC VL D-blade-assisted awake intubation is an effective and safe method to manage the airway of patients with laryngeal tumour once adequate topicalisation is ensured before the procedure.

Systemic TLR7/8 micelles trigger a novel and potent anti-tumor response by strong recruitment of neutrophils leading to massive tumor cell killing.

2576 Background: Clinical use of TLR7/8 agonists is currently restricted to topical application of Imiquimod for treatment of superficial basal cell carcinoma since systemic administration is prevented due to dose-limiting toxicity. Here, we present a novel micelle-based drug delivery technology containing a lipid-anchored TLR7/8 agonist for intravenous administration. The MBS8 formulation shows good efficacy in mouse cancer models, is well tolerated in rodents and non-human primates and is currently being tested in clinical studies (NCT04855435). Methods: MBS8 was tested in 12 syngeneic mouse cancer models as monotherapy or in combination anti-PD-1 and anti-PD-L1 antibodies. MBS8 was administered IV as slow bolus. Tumors and spleens were analysed using histology, immunohistochemistry, ELISPOT and flow cytometry. Phenotyping of tumor microenvironment was done using flow cytometry and Nanostring analyses. Safety and tolerability were tested in mice, rats and monkeys. Safety-related and PD biomarkers were identified in monkeys using a multiplex MSD technology and validated in whole human blood stimulated with MBS8 ex-vivo. Results: In several syngeneic mouse tumor models, MBS8 led to complete eradication of established tumors. The complete responders showed tumor rejection upon re-challenge. In these mice, a CD8+-dependent tumor-specific immune memory response was evident. Tumors demonstrated a massive tissue necrosis ( &gt; 80%) within 24-48h after the first drug administration and showed massive neutrophil infiltration 6h after dosing. Antigen specific CD8+ T-cells were detected in tumors 24 hours after treatment with increased CD8+:Treg cell ratio and enhanced antigen presentation in tdLN. MBS8 showed both additive and synergistic effect when combined with anti-PD-1 or anti-PD-L1 antibody treatment. Moreover, in tumors being resistant to anti-PD-1 treatment, co-administration of MBS8 reverted sensitivity to anti-PD-1 treatment in a synergistic manner. A panel of cytokines induced by MBS8 upon repeat dose administration in monkeys was identified in plasma as potential biomarkers. Ten of them were further evaluated in whole human blood treated with MBS8 ex vivo. Currently, these cytokines are being used in Phase I clinical studies. Conclusions: MBS8 showed significant anti-cancer activity in multiple in vivo solid tumor models when administered either as monotherapy or in combination with ICIs. MBS8 demonstrated a novel mode of action with neutrophils playing a central role as primary effector cells causing a rapid killing of tumors. Further, adaptive immune response was initiated including generation of tumor specific CD8+ cells and establishment of the immune memory. MBS8 was well tolerated in rodents and cynomolgus monkeys at the dose levels above therapeutic effective doses identified in mice, thus providing a good therapeutic window.

Oxytocin infusion rates for maintaining uterine tone during non-elective cesarean section in laboring patients: a randomized, controlled trial.

Oxytocin infusions for uterine tone maintenance are recommended following initial low oxytocin doses during cesarean section. Very limited literature is available on the optimal infusion rates in laboring patients who have been earlier exposed to oxytocin. 105 patients, having received oxytocin for induction/augmentation of labor, received oxytocin infusions at rates of 2.5IU/h (Group 2.5), 5IU/h (Group 5) or 10IU/h (Group 10) following 3IU slow bolus. The primary outcome measure was estimated intraoperative blood loss; secondary outcome measures included uterine tone adequacy, requirements for additional uterotonics, and any side effects. Minor postpartum hemorrhage (PPH) was defined as blood loss > 500ml and major/severe hemorrhage as blood loss > 1000ml. Group 10 had minimum blood loss (311.1 ± 44.9ml) and uterotonic requirements compared to other groups (p < 0.001). Group 2.5 had maximum blood loss (549.4 ± 74.3ml) and uterotonic requirements; Group 5 had intermediate values (402.0 ± 49.5ml). Twenty-six patients in group 2.5 had minor PPH against only one in group 5 and none in group 10 (p < 0.001). No patient in either group had major PPH. The incidence of hypotension was higher in group 10 than in group 2.5 (p = 0.004). Nausea and vomiting were also more frequent in group 10 than in the other two groups. Oxytocin infusions at 5IU/h and 10IU/h are more effective in reducing blood loss and preventing PPH than 2.5IU/h. The dose of 10IU/h, although the most efficacious, is associated with a high incidence of side effects. Hence, further studies are needed to find out the optimal maintenance infusion rate of oxytocin during cesarean section in laboring patients who have received oxytocin earlier.

Comparison of Dexmedetomidine with Midazolam during Monitored Care Anesthesia (MAC) in Patients Undergoing Septoplasty

Objective: To compare the sedative and analgesic outcomes of dexmedetomidine with midazolam for monitored anesthesia care (MAC) in patients undergoing Septoplasty. Methodology:  This comparative study was conducted at Shalamar Medical and Dental College Lahore from March 2019 to August 2020. A total of 150 patients who were planned for Septoplasty under MAC having age 18-45 years, and ASA status I-II in Shalamar Medical and Dental College Lahore. Patients were randomly divided into two equal groups; In group D; IV dexmedetomidine 1 µg.Kg-1 was given over five mins after that IV infusion at the rate of 0.5 µg.Kg-1.hour-1 was started. In group M; midazolam 0.06 mg.Kg-1 was given as slow bolus after that continuous infusion at the rate of 0.01 mg.Kg-1.hour-1 was started. Sedation was monitored according to Ramsay sedation scale and VAS scale was used to measure the intensity of pain. Results: The Mean age was 34.3±5.7 years in group D versus 35.7±6.1 years in group M. There were 49 (65.3%) male patients in group D and 47 (62.7%) in group M. Mean sedation and pain score was significantly less in group D as compared to group M (p-value 0.001 &amp; 0.002 respectively). There were 12 (16.0%) patients in group D who required rescue sedation and 32 (42.7%) in group M required rescue sedation (p-value 0.003). There were 14 (18.7%) patients in group D who required rescue analgesia versus 29 (38.7%) in group M (p-value 0.006). Conclusion: Use of dexmedetomidine for MAC is advantageous as compared to midazolam in-terms of better sedation and analgesia and reduced requirements of rescue doses of sedatives and analgesics.

Системна запальна відповідь після операцій на кульшовому суглобі: порівняння спінальної анестезії та комбінації спінальної анестезії з паравертебральною блокадою

Актуальність. C-реактивний білок (CRP) як біохімічний маркер неспецифічного запалення є об’єктивною мірою інвазивності при протезуванні кульшового суглоба. Мета дослідження. Порівняння рівнів CRP після операцій на кульшовому суглобі в умовах або комбінації спінальної анестезії з паравертебральною блокадою, або однієї лише спінальної анестезії. Матеріали та методи. 22 пацієнти, які мали однобічні операції на кульшовому суглобі, були випадковим чином розподілені на дві групи. У контрольній групі (n = 11) проводилась одноразова спінальна анестезія. У дослідній групі (n = 11) під час операції застосовувалась така сама спінальна анестезія, а після операції — однобічна пролонгована паравертебральна блокада. Результати. У 1, 3 і 7-й післяопераційні дні рівні CRP були статистично значуще (p &lt; 0,05) нижчими у дослідній групі, ніж у контрольній. Висновки. Післяопераційне знеболювання пролонгованою паравертебральною блокадою після інтраопераційної спінальної анестезії для операцій на кульшовому суглобі супроводжується меншим зростанням рівня CRP, ніж після однієї лише спінальної анестезії.

Efficacy and Safety of Remimazolam Tosilate versus Propofol for General Anesthesia in Cirrhotic Patients Undergoing Endoscopic Variceal Ligation.

IntroductionThe best candidate intravenous anesthetic agent for patients with liver cirrhosis undergoing endoscopic variceal ligation (EVL) remains unclear. Remimazolam tosilate (RT) is a new type of benzodiazepine with quick onset, rapid recovery, and no accumulation. Here, we investigated the efficacy and safety of RT for general anesthesia in cirrhotic patients undergoing EVL.MethodsPatients undergoing EVL were randomly classified into the remimazolam tosilate (group R) and the propofol group (group P). RT was administered as a slow bolus of 0.2 mg/kg for induction and followed by 1.0–2.0 mg/kg/h for maintenance of general anesthesia. Propofol was started at 2 mg/kg, followed by 4–10 mg/kg/h until the end of surgery. Flumazenil was routinely administered to group R and the same volume of saline was given to group P immediately after surgery. The efficacy and safety of RT for general anesthesia during EVL were compared with propofol.ResultsAll patients in the two groups had satisfactory anesthetic effects and the efficacy rates were 100%. The time to loss of consciousness (LoC) was longer in group R than in group P (P > 0.05). The return of consciousness (RoC) time, extubation time, and transfer time in group R were significantly shorter than that in group P (P < 0.05). The incidence of intraoperative hypotension and postoperative low SpO2 in group R were lower than that in the group P (P < 0.05). There were no significant differences between the two groups with respect to the satisfaction degree of patients and operators (P > 0.05).ConclusionRemimazolam tosilate can provide satisfactory anesthetic effects for surgery. Group R patients recovered faster and had a shorter PACU stay time than group P patients. Moreover, RT decreased the incidence of hypotension and low SpO2. RT was a safer and more effective alternative for general anesthesia in cirrhotic patients undergoing EVL than propofol.

The effects of prophylactic dexmedetomidine administration on general anesthesia recovery quality in healthy dogs

Introduction: To determine the effects of a dexmedetomidine slow bolus, administered prior to extubation, on recovery from fentanyl and sevoflurane anesthesia in dogs.