Antinociceptive and analgesic effect of continuous intravenous infusion of maropitant, lidocaine and ketamine alone or in combination in cats undergoing ovariohysterectomy

Background Multimodal analgesia consists of the combination of analgesic drugs at low doses to act in different places along the path of pain. Studies with continuous infusion of analgesic drugs in cats are not common. This study aimed to evaluate the analgesic effect of maropitant, lidocaine and ketamine alone or in combination (intravenous bolus + subsequent continuous intravenous infusion) in the management of acute postoperative pain in cats undergoing ovariohysterectomy. Seventy healthy cats undergoing an ovariohysterectomy received a standard anesthetic protocol consisting of acepromazine and morphine, propofol (anesthesia induction), and isoflurane (anesthesia maintenance). The animals were stratified into seven groups (n = 10 in each group): control (CG), maropitant (MG), lidocaine (LG), ketamine (KG), maropitant + lidocaine (LMG), maropitant + ketamine (KMG), and maropitant + lidocaine + ketamine (LKMG). All drugs were injected first as an intravenous bolus and then by continuous intravenous infusion. During surgery, esophageal temperature, respiratory rate, heart rate, oxygen saturation, expired isoflurane concentration, and partial pressure of carbon dioxide at the end of expiration were evaluated at 7 time points. Postoperative pain was evaluated for 6 h after extubation using the visual analogue scale and the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in cats. Results Adverse effects related to maropitant, lidocaine and ketamine infusion were not observed. Pain scores were lower in the MG, KG and LG groups when compared to the CG group using both scales. Although pain scores were also lower in all combination groups than CG, more animals in these groups required rescue analgesia compared to MG. This indicates that the postoperative analgesic effect of all drugs, either alone or in combination, confers analgesia, although the combinations did not promote greater analgesia. Conclusions Continuous intravenous infusion of maropitant, lidocaine, and ketamine alone induces postoperative analgesic effect in cats undergoing ovariohysterectomy, but combinations of these drugs did not increase the analgesic effect. No adverse effect was observed with any drug or their combination.

1106. Evaluation of Penetration of Cefiderocol into Cerebrospinal Fluid Using a Rat Meningitis Model

Background Central nervous system (CNS) infections caused by Gram-negative bacteria (GNB) are sometimes hard to treat due to antibiotic resistance and difficulty with penetration into cerebrospinal fluid (CSF). Cefiderocol (CFDC) which was approved by the FDA and the EMA in 2019 to 2020 is a siderophore cephalosporin with potent activity against various GNB including carbapenem-resistant strains. In this study, we evaluated the penetration of CFDC into CSF using a rat meningitis model. Methods To induce meningitis, the anesthetized immunocompetent rats were infected by intracisternal inoculation of a bacterial suspension of 8.7×101 CFU of E. coli SR200138. 200 mg/kg or 50 mg/kg of CFDC was administered via tail vein bolus injection to uninfected rats (n=4/sampling point) and rats with meningitis (n=4/sampling point) 24 hours after infection. CSF was collected by cisternal puncture and blood was collected from heart. The samplings were performed 0.25, 0.5, 1, 3, and 5 hours after dosing. The concentrations of CFDC in plasma and CSF for individuals were determined by LC/MS/MS. PK parameters for the average values in plasma and CSF were calculated. Results CFDC concentration and the PK parameters are shown in Figure and Table, respectively. The penetration of CFDC from plasma to CSF was observed in both uninfected and meningitis groups, and the penetration rates increased in the rats withs meningitis (AUCCSF/AUCplasma: 0.149-0.183) compared with the uninfected rats (AUCCSF/AUCplasma: 0.0508-0.0588). The penetration rates of CFDC in the meningitis were comparable to those of piperacillin, cefepime, and meropenem in human (0.32, 0.103, and 0.39 in strongly inflamed meninges, respectively) [1]. In both groups, elimination of CFDC from CSF was slower compared with that from plasma as seen with other β-lactam antibiotics such as meropenem, suggesting that T> MIC, an indicator that correlates with the efficacy of β-lactams, may be higher in CSF [2]. Table. PK Parameters of Cefiderocol after Intravenous Bolus Administration in Uninfected Rats and Rats with Meningitis Figure. Concentrations of Cefiderocol after Intravenous Bolus Administration in Uninfected Rats and Rats with Meningitis Conclusion It was confirmed that CFDC penetrates into CSF from plasma in a rat model and the penetration rate was increased 3-fold in meningitis. References 1. Nau, R. et al. Clin Microbiol Rev. 2010 Oct;23(4):858–883. 2. Nau, R. et al. Antimicrob Agents Chemother. 1998 Aug;42(8):2012–2016. Disclosures Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Sachi Kanazawa, PhD, Shionogi & Co., Ltd. (Employee) Naoki Kohira, PhD, Shionogi & Co., Ltd. (Employee) Yuki Aoe, BS, Shionogi TechnoAdvance Research Co., Ltd. (Employee) Atsushi Morimoto, n/a, Shionogi TechnoAdvance Research Co., Ltd. (Employee) Kana Horiuchi, MPharm, Shionogi & Co., Ltd. (Employee) Yuji Inoue, MPharm, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee)

‘NOPAIN-ROP’ trial: Intravenous fentanyl and intravenous ketamine for pain relief during laser photocoagulation for retinopathy of prematurity (ROP) in preterm infants: A randomised trial

ObjectivesTo investigate if intravenous fentanyl or intravenous ketamine can provide adequate analgesia in preterm infants undergoing laser photocoagulation for retinopathy of prematurity (ROP).DesignOpen-label randomised trial.SettingTertiary care institution.ParticipantsPreterm infants who underwent laser photocoagulation for ROP.InterventionsInfants were randomised to receive fentanyl as intravenous bolus dose of 2 µg/kg, followed by an intravenous infusion of 1 µg/kg/hour increased to a maximum of 3 µg/kg/hour or intravenous ketamine as bolus dose of 0.5 mg/kg, followed by further intermittent intravenous bolus doses of 0.5 mg/kg to a maximum of 2 mg/kg in the initial phase and intravenous fentanyl (bolus of 2 µg/kg followed by infusion of 2 µg/kg/hour to a maximum of 5 µg/kg/hour) or intravenous ketamine (bolus dose of 1 mg/kg followed by intermittent bolus doses of 0.5 mg/kg to a maximum of 4 mg/kg) in the revised regimen phase.Main outcome measuresProportion of infants with adequate analgesia defined as the presence of both: (1) all the Premature Infant Pain Profile-Revised scores measured every 15 min less than seven and (2) proportion of the procedure time the infant spent crying less than 5%.Secondary outcomes included apnoea, cardiorespiratory or haemodynamic instability, feed intolerance and urinary retention requiring catheterisation during and within 24 hours following the procedure.ResultsA total of 97 infants were randomised (fentanyl=51, ketamine=46). The proportions of infants with adequate analgesia were 16.3% (95% CI 8.5% to 29%) with fentanyl and 4.5% (95% CI 1.3% to 15.1%) with ketamine. Ten infants (19.6%) in the fentanyl group and seven infants (15.2%) in the ketamine group had one or more side effects. In view of inadequate analgesia with both the regimens, the study steering committee recommended using a higher dose of intravenous fentanyl and intravenous ketamine. Consequently, we enrolled 27 infants (fentanyl=13, ketamine=14). With revised regimens, the proportions of infants with adequate analgesia were higher: 23.1% (95% CI 8.2% to 50.2%) with fentanyl and 7.1% (95% CI 1.3% to 31.5%) with ketamine. However, higher proportions of infants developed apnoea (n=4; 30.7%), need for supplemental oxygen (n=5, 38.4%) and change in cardiorespiratory scores (n=7; 53.8%) with fentanyl but none with ketamine.ConclusionsFentanyl-based and ketamine-based drug regimens provided adequate analgesia only in a minority of infants undergoing laser photocoagulation for ROP. More research is needed to find safe and effective regimens that can be employed in resource constrained settings.Trial registration numberCTRI/2018/03/012878.

Effects of Intermittent Bolus Paravertebral Block On Analgesia and Recovery in Open Hepatectomy: A Retrospective, Cohort Study.

Background Experiences of paravertebral block use in hepatectomy were limited. We aimed to investigate the effects of intermittent bolus paravertebral block on analgesia and recovery in hepatectomy. Methods We selected patients receiving two types of analgesia programs, with matched age, sex and body mass index from a prospective perioperative analgesia and nerve block database: (1) PVB: intermittent bolus paravertebral block (0.5% ropivacaine 25ml before surgery plus 0.125ml•kg− 1 0.2% ropivacaine bolus per hour after surgery) and self-controlled intravenous bolus morphine pump till postoperative 48 hours; (2) control: self-controlled intravenous bolus morphine pump till postoperative 48 hours. The baseline, operation, and postoperative analgsia and recovery data were compared between groups. Results Thirty-eight patients in each group were included in the analysis. Intraoperatively, PVB group used less sevoflurane (difference − 0.1 (-0.2, 0.0) %, P = 0.019), and more ephedrine (U = 986, P = 0.004) and crystalloid (U = 936, P = 0.024) than control group. The mean arterial pressure in PVB group was lower than that in control group (difference − 4mmHg, 95%CI -8 ~ 0mmHg, P = 0.031) but similar to its baseline level (difference 2, 95%CI -1 ~ 5, P = 0.153). Postoperatively, PVB group had lower cumulative morphine consumption at postoperative 2 (U = 371.5, P < 0.001), 4 (U = 349.5, P < 0.001), 12 (U = 342.0, P < 0.001), 24 (U = 338.5, P < 0.001) and 48 (U = 392.5, P = 0.001) hour, lower pain numerical rating scale score at rest at postoperative 0 (U = 299.5, P < 0.001), 2 (U = 355.5, P < 0.001) and 4 (U = 332.0, P < 0.001) hour, and on movement at postoperative 0 (U = 269.5, P < 0.001), 2 (U = 405.0, P = 0.001), 4 (U = 382.5, P < 0.001) and 12 (U = 1179.5, P = 0.003) hour than control group. PVB group also had lower rescue analgesia rates (OR 0.29, 95%CI 0.08 ~ 1.00, P = 0.044), higher emergence satisfaction (5 (4, 5) vs 4 (4, 5), P = 0.018) and lower drowsiness score (0 (0,1) vs 1(0,1), P = 0.007) than control group. Three months postoperatively, PVB group had lower rates of hypoesthesia (OR 0.28 (0.11, 0.75), P = 0.009), numbness (OR 0.26 (0.07, 0.88), P = 0.024) and sleep disorder (OR 0.84 (0.73, 0.97), P = 0.025) than control group. Conclusions Intermittent bolus paravertebral block provided anesthetics- and opioids-sparing effects, and enhanced recovery both in hospital and after discharge in patients receiving hepatectomy.

The Impact of Continuous Infusion Compared to Intravenous Bolus Administration of Pantoprazole on Length of Intensive Care Unit Stay in Critically Ill Patients

Purpose: To determine if intravenous (IV) bolus pantoprazole increases intensive care unit (ICU) length of stay compared to IV infusion pantoprazole for treatment of gastrointestinal (GI) bleeding in critically ill patients. Methods: This retrospective cohort study included adult patients admitted to the ICU with GI bleeds. Patients treated with IV pantoprazole from January 1, 2017 to December 31, 2017 were analyzed in the continuous infusion group, and patients treated from March 1, 2018 to February 28, 2019 were analyzed in the bolus only group. Patients with pregnancy, variceal bleeds, or lower GI bleeds were excluded. Intensive care unit length of stay was compared between the two cohorts using the Mann Whitney U test. Adjusted analysis was conducted using the generalized linear model with gamma log link to estimate the effect of type of infusion on ICU length of stay. Results: A total of 145 patients were included in the analysis, with 72 patients in the continuous infusion group and 73 patients in the bolus only group. The median ICU length of stay was 70.5 hours for continuous infusion and 64 hours for bolus only pantoprazole ( P-value = .577). In the adjusted analysis, there was no difference in ICU length of stay between the continuous infusion and bolus only groups (RR, 1.06; 95% CI, .76–1.47). Conclusion: Intensive care unit length of stay was not prolonged with the use of IV bolus only compared to continuous infusion pantoprazole. Intravenous bolus only pantoprazole may be used in critically ill patients for treatment of upper GI bleeding.

Population Pharmacokinetics Modeling of Levofloxacin In Rabbit By Intravenous Bolus Injection and Peroral Administration

The population-based approach has been widely applied to describe the pharmacokinetic profile of many drugs. The aim of this current research was to study the implementation of the population-based pharmacokinetics of levofloxacin in rabbits administered by intravenous bolus injection and peroral delivery. Modeling analyses were performed using Monolix, one of the alternative tools for the population-based approach. Monolix works based on the Stochastic Approximation Expectation-Maximization (SAEM) method. The analysis was performed based on the population model using one-compartmental and two-compartmental disposition models. The combination error model was used during the analyses. Modeling appropriateness was determined based on the goodness of fit analyses, i.e., 1) the individual fit, 2) the observed versus population prediction values; and 3) the observed versus individual prediction values Plasma concentration profiles of levofloxacin by intravenous bolus injection and oral administration are better described by an appropriate model using a two-compartmental disposition model. All goodness of fit analyses demonstrates the power of the chosen model. However, the estimated disposition parameter values obtained based on the intravenous bolus injection and peroral administration are different for each subject. To confirm this phenomenon, we performed a simultaneous fitting of all intravenous bolus as well as peroral administration data. The goodness of fit analyses indicates an adequate fitting of all data.