Small Bolus Doses Research Articles

Levosimendan and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials.

Atrial fibrillation (AF) is a prevalent complication associated with levosimendan; however, it remains uncertain whether there are any disparities in the effects of levosimendan on non-postoperative and postoperative AF. This study aimed to evaluate the levosimendan effect on non-postoperative and postoperative AF by conducting a meta-analysis of randomized control trials (RCTs). PubMed, Embase, Cochrane Library, and other databases were searched. Pairs of reviewers identified RCTs that compared levosimendan and placebo or other therapies, and the results reported AF events data. Random effects models were used (at a significance level of 5%). Twenty-nine eligible trials comprising 6550 participants were included, eleven of which evaluated the non-postoperative AF incidence, and 18 included postoperative AF. The analysis revealed that levosimendan elevated the AF risk significantly in the non-postoperative group (OR, 1.62; 95% CI: 1.19-2.20; p=0.002) and reduced the AF incidence in the postoperative group (OR, 0.65; 95% CI: 0.44-0.96; p=0.03). AF occurrence decreased more significantly in patients who used levosimendan after cardiac surgery (OR, 0.53; 95% CI: 0.32-0.88; p=0.02) than in patients who used levosimendan before cardiac surgery (OR, 0.67; 95% CI: 0.42-1.06; p=0.09). Moreover, The AF risk was significantly elevated by levosimendan large bolus dose (bolus dose≥12 μg/kg) (OR, 1.44; 95% CI: 1.10-1.88; p=0.004) and decreased by small bolus dose of levosimendan (bolus dose<12 μg/kg) (OR, 0.64; 95% CI: 0.34-1.20; p=0.16). Levosimendan was linked to an increased non-postoperative AF incidence. The employment of levosimendan was effective in preventing postoperative AF.

Levosimendana e Fibrilação Atrial: Uma Metanálise de Ensaios Clínicos Randomizados

Abstract Background Atrial fibrillation (AF) is a prevalent complication associated with levosimendan; however, it remains uncertain whether there are any disparities in the effects of levosimendan on non-postoperative and postoperative AF. Objectives This study aimed to evaluate the levosimendan effect on non-postoperative and postoperative AF by conducting a meta-analysis of randomized control trials (RCTs). Methods PubMed, Embase, Cochrane Library, and other databases were searched. Pairs of reviewers identified RCTs that compared levosimendan and placebo or other therapies, and the results reported AF events data. Random effects models were used (at a significance level of 5%). Results Twenty-nine eligible trials comprising 6550 participants were included, eleven of which evaluated the non-postoperative AF incidence, and 18 included postoperative AF. The analysis revealed that levosimendan elevated the AF risk significantly in the non-postoperative group (OR, 1.62; 95% CI: 1.19-2.20; p=0.002) and reduced the AF incidence in the postoperative group (OR, 0.65; 95% CI: 0.44-0.96; p=0.03). AF occurrence decreased more significantly in patients who used levosimendan after cardiac surgery (OR, 0.53; 95% CI: 0.32-0.88; p=0.02) than in patients who used levosimendan before cardiac surgery (OR, 0.67; 95% CI: 0.42-1.06; p=0.09). Moreover, The AF risk was significantly elevated by levosimendan large bolus dose (bolus dose≥12 μg/kg) (OR, 1.44; 95% CI: 1.10-1.88; p=0.004) and decreased by small bolus dose of levosimendan (bolus dose&lt;12 μg/kg) (OR, 0.64; 95% CI: 0.34-1.20; p=0.16). Conclusion Levosimendan was linked to an increased non-postoperative AF incidence. The employment of levosimendan was effective in preventing postoperative AF.

P–671 Dual Trigger(low adjuvant HCG4h after GnRHagonist trigger)have positive impact of overall embryo’s quality, implantation ,clinical pregnancy and live birth rates in high-risk patients for OHSS

Abstract Study question Study aim is to compare implantation,clinical pregnancy and livebirth rates between giving1500IU of hCG4hours after GnRHagonist,on trigger day or GnRHagonist as alone trigger with luteal support withHCG1500IU.35h later on OPUday. Summary answer Adjuvant doze of1500IUhCG4h after bolus of GnRHagonist on trigger day significantly improve quality of blastocyst,implantation,clinical pregnancy and live birth rates without increasing the risk ofOHSS. What is known already The use of GnRHagonist for final oocyte maturation in antagonist cycle significantly decrease the incidence of OHSS,but there have been studies showing lower pregnancy rates in patients triggered with GnRHagonist compared with hCG in autologous cycles,attributed to a defective luteal phase, especially in high–risk patients despite intensive luteal phase support.To improve the results of IVF,an alternative approach is adding a small bolus dose of hCG(1500IU)35h later,on the OPU day after GnRHagonist trigger which provides more sustained support for the corpus luteum.The question is does low doses of hCGgiven on the same day with GnRHagonist trigger is making better quality oocytes. Study design, size, duration Single center prospective longitudinal cohort study fromJanuary2017 to Decembar2019.The initial inclusion criteria were:women age≥18and≤39years,AMH≥3,3ng/ml and ≥12 antral follicles on basal ultrasound.Patients with history of OHSS and PCO are also included in the study.Patients with applied “freeze-all” technique with peak estradiol≥4000pg/ml on trigger day&amp;gt;18oocytes on the OPU day,and recognized significant risk for developing OHSS were also included.The cumulative implantation,clinical pregnancy and live birth rates were analyzed,only in embryos from the same COS protocol in every patient. Participants/materials, setting, methods A total of 231 patients were entered for final analysis,who underwent a flexible antagonist protocol,ICSI and fresh or thawed ET on 3th(38.53%) or 5th( 61.47%)day in women’s autologous cycles.Patients were randomized in one of two groups: GroupA-Dual trigger group 1500IUof hCG 4h after GnRH agonist application on trigger day and GroupB –1500IU of HCG 35h later,on the OPU day.We used nonparametric and parametric statistical tests.Significant differences were considered all values ​​of p &amp;lt; 0.05 Main results and the role of chance Both groups are homogenous regarding several variables:age,BMI,type of sterility,smoking status,AMH,PCO, spermogram.There is no significant difference between the two(AvsB)groups according to average number of retrieved oocytes(13.6 vs 14.6 p &amp;gt; 0,05),M II oocytes(11.03 vs 11.99 p &amp;gt; 0.05).The dual trigger group(A)had a higher fertility rate(69.99% vs 64.11% p &amp;lt; 0,05)compared with GnRHagonist trigger group(B).There are no significant difference between groups(AvsB)according to cumulative average number of:transferred embryos(2.4vs2.5 p &amp;gt; 0.05)TQE transfered on 3th day(1.5.vs 1.3.p&amp;gt;0.05);transferred blastocyst(2.6 vs2.7 &amp;gt;0.05);cryo embryos(2.5vs1.9 p &amp;gt; 0.05),but there are significant difference according to cumulative implantation rate of transferred blastocyst in favor of group A(48.18% vs 33.89%p&amp;lt;0.05).Analyzes of morphological characteristics of transferred blastocyst depicted in the order of degree of blastocyst expansion,inner cellular mass(ICM)and trofoectoderm(TE) and ranking overall blastocysts quality from“excellent”,“good”,“average” and “pore” ,shows that there are significantly more percentage of patient with embryo transfer of “excellent” or even one “excellent” blastocyst in group A (30.56%,31.94% vs 21.54%,23.08% p &amp;lt; 0.05) in opposite of percentage of patients with embryo transfer with “poore “” blastocyst in group B (37.5% vs 46.15.%p&amp;lt;0.05). Clinical pregnanacy rate (71.68% vs 50.84% p &amp;lt; 0.05) , and live birth rate (60,18% vs 42,58% ), were significantly higher in group A. There were no cases of moderate or severe OHSS in both groups. Limitations, reasons for caution Dual trigger in GnRH antagonist protocols should be advocated as a safe approach but undetected high risk patients are reasons for caution for developing clinically significant OHSS. Wider implications of the findings: Adjuvant low dose of hCG on GnRHagonist trigger day improve clinical pregnancy and live birth rates without increasing the risk of clinically significant OHSS.Protocol of dual trigger and freezing all oocytes or embryos in patients with high risk of developing OHSS is promising technique in everyday practice. Trial registration number 8698

Feasibility of Patient-Controlled Sleep with Dexmedetomidine in Treating Chronic Intractable Insomnia.

BackgroundPatient-controlled analgesia (PCA) is an “on-demand” system which allows patients to self-administer intravenous medications in small bolus doses. Based on the principles of PCA, we developed Patient-Controlled Sleep (PCSL) for chronic intractable insomnia where the traditional analgesics in PCA were replaced with dexmedetomidine (Dex), an alpha-2 agonist widely used for premedication, sedation, anxiolysis and analgesia. The purpose of this study was to assess the feasibility of the new method for the treatment of chronic intractable insomnia.Patients and MethodsPatients with chronic intractable insomnia undergoing PCSL (n=20) were evaluated with the Pittsburgh Sleep Quality Index (PSQI), Symptom Checklist 90 (SCL-90), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) before and after the treatment. The patient characteristics, overall outcomes and related side effects were also assessed.ResultsFifteen patients completed the treatment protocol. The duration of PCSL varied from a few days to four months, and the dosage of Dex gradually decreased without eliciting signs or symptoms of tolerance or physical dependence. The sleep quality improvement occurred immediately after the therapy in 12/15 patients, and of which, 7/12 patients achieved continuously improved sleep quality in follow-up.ConclusionPCSL with Dex might be a potential treatment for patients with chronic intractable insomnia. However, it is an off-label use, and the potential side effects of dexmedetomidine with long-term use needs further evaluation.

International consensus statement on the use of uterotonic agents during caesarean section.

It is routine to give a uterotonic drug following delivery of the neonate during caesarean section. However, there is much heterogeneity in the relevant research, which has largely been performed in low-risk elective cases or women with uncomplicated labour. This is reflected in considerable variation in clinical practice. There are significant differences between dose requirements during elective and intrapartum caesarean section. Standard recommended doses are higher than required, with the potential for acute cardiovascular adverse effects. We recommend a small initial bolus dose of oxytocin, followed by a titrated infusion. The recommended doses of oxytocin may have to be increased in women with risk factors for uterine atony. Carbetocin at equipotent doses to oxytocin has similar actions, while avoiding the requirement for a continuous infusion after the initial dose and reducing the need for additional uterotonics. As with oxytocin, carbetocin dose requirements are higher for intrapartum caesarean sections. A second-line agent should be considered early if oxytocin/carbetocin fails to produce good uterine tone. Women with cardiac disease may be very sensitive to the adverse effects of oxytocin and other uterotonics, and their management needs to be individualised.

Human Errors and Adverse Hemodynamic Events Related to "Push Dose Pressors" in the Emergency Department.

Though the use of small bolus doses of vasopressors, termed "push dose pressors," has become common in emergency medicine, data examining this practice are scant. Push dose pressors frequently involve bedside dilution, which may result in errors and adverse events. The objective of this study was to assess for instances of human error and adverse hemodynamic events during push dose pressor use in the emergency department. This was a structured chart and video review of all patients age ≥ 16years undergoing resuscitation and receiving push dose pressors from a single center from January 2010 to November 2017. Push dose pressors were defined as intended intravenous boluses of phenylephrine (any dose) or epinephrine (≤ 100mcg). A total of 249 patients were analyzed. Median age was 60years (range, 16-97), 58% were male, 49% survived to discharge. Median initial epinephrine dose was 20mcg (n = 139, IQR 10-100, range 1-100); median phenylephrine dose was 100mcg (n = 110, IQR 100-100, range 25-10,000). Adverse hemodynamic events occurred in 98 patients (39%); 30 in the phenylephrine group (27%; 95% CI, 19-36%), and 68 in the epinephrine group (50%; 95% CI, 41-58%). Human errors were observed in 47 patients (19%), including 7 patients (3%) experiencing dosing errors (all overdoses; range, 2.5- to 100-fold) and 43 patients (17%) with a documentation error. Only one dosing error occurred when a pharmacist was present. Human errors and adverse hemodynamic events were common with the use of push dose pressors in the emergency department. Adverse hemodynamic events were more common than in previous studies. Future research should determine if push dose pressors improve outcomes and if so, how to safely implement them into practice.

Feasibility of Patient-Controlled Sleep with Dexmedetomidine in Treating Chronic Intractable Insomnia

Background: Patient-Controlled Analgesia (PCA) is an on-demand system which allows patients to self-administer intravenous medications in small bolus doses. Based on the principles of PCA, we developed Patient-Controlled Sleep (PCSl) for chronic intractable insomnia that the traditional analgesics in PCA was replaced with dexmedetomidine (Dex), an alpha-2 agonist widely used for premedication, sedation, anxiolysis and analgesia. The objective of the study was to establish a system and assess the safety. Methods: Patients with chronic intractable insomnia undergoing PCSl (n=20) between May 2015 and Mar 2019 were evaluated with the Pittsburgh Sleep Quality Index (PSQI), Symptom Check list 90 (SCL-90), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) before and after the treatment. The patient characteristics, overall outcomes and related side effects were also assessed. Results: Fifteen patients completed the treatment. The duration of PCSl varied from days to four months, and the dosage of Dex gradually decreased without eliciting signs or symptoms of tolerance or physical dependence. The sleep quality improvement occurred immediately after the therapy in 12/15 patients, and of which, 7/15 patients achieved continuous improved sleep quality in final follow-up. Conclusions: This study suggests that PCSl with Dex is a feasible and safe treatment for chronic intractable insomnia. Funding Statement: This research was funded by the National Natural Science Foundation of China, grant number 81671076. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The retrospective review was approved by the Institutional Review Board (IRB) of the Aviation General Hospital of China Medical University (HK20090528). All participants provided written informed consent.

Bolus administration of intravenous lidocaine reduces pain after an elective caesarean section: Findings from a randomised, double-blind, placebo-controlled trial

We conducted a randomised double-blind, placebo-controlled trial to assess whether a bolus dose of lidocaine during the induction of general anaesthesia would reduce postoperative pain over 24 h. Level of satisfaction with pain control at 48 h after surgery and Apgar score were also examined. A total of 100 women aged 20–35 years, who were candidates for elective caesarean section (CS) were randomised to receive either 1.5 mg/kg lidocaine or placebo during the induction of general anaesthesia. Results showed that lidocaine decreased pain intensity over 24 h after surgery (p < .001), and decreased postoperative morphine consumption from median (range) of 3.79 (0–9) mg in the placebo group to 0 (0–12) mg and in the lidocaine group (p <.001). Lidocaine was not associated with postoperative nausea and vomiting or any side effects in women and newborn babies. We conclude that a small bolus dose of lidocaine attenuates postoperative pain, thus reducing the requirement for opioid consumption in the postoperative period.Impact statement• With its anti-inflammatory, anti-hyperalgesic and analgesic properties, intravenous perioperative lidocaine infusion (IVLI) has been used for optimal postoperative care in different surgeries. Limited evidence suggests that IVLI may be a useful adjuvant during general anaesthesia. There is a report of a positive effect on several outcomes after surgery including postoperative pain over 24 h after laparoscopic abdominal surgery or open abdominal surgery. However, there was a paucity of information regarding the efficacy of a bolus dose of lidocaine in patients undergoing caesarean section (CS). In this randomized, placebo-controlled trial the use of a bolus dose of 1.5 mg/kg lidocaine 2%, compared with placebo, during the induction of general anaesthesia for elective CS resulted in a significant decrease in postoperative pain score as well as decreased postoperative morphine consumption over 24 h. Lidocaine use was not associated with any side effect in participants and newborns.• This study provides the first evidence that a bolus dose of lidocaine may be a safe and simple alternative therapeutic intervention for enhanced postoperative recovery in terms of pain and postoperative opioid consumption. Future studies are needed to examine pain reducing effect of perioperative bolus dose of lidocaine after CS under spinal or epidural anesthesia.

Development and Application of Simple Pharmacokinetic Models to Study Human Exposure to Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)

In a published controlled dosing experiment, a single individual consumed 5mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models - their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific best-fit intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5μg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.

Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)

In a published controlled dosing experiment, a single individual consumed 5mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models — their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific “best-fit” intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5μg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.

Oxytocin for labour and caesarean delivery: implications for the anaesthesiologist

The implications of the obstetric use of oxytocin for obstetric anaesthesia practice are summarised. The review focuses on recent research on the uterotonic effects of oxytocin for prophylaxis and management of uterine atony during caesarean delivery. Oxytocin remains the first-line agent in the prevention and management of uterine atony. In-vitro and in-vivo studies show that prior exposure to oxytocin induces uterine muscle oxytocin receptor desensitization. This may influence oxytocin dosing for adequate uterine tone following delivery. Oxytocin has important cardiovascular side-effects (hypotension, tachycardia and myocardial ischaemia). Recent studies suggest that the effective dose of oxytocin for prophylaxis against uterine atony during caesarean delivery is significantly lower than the 5-10 IU historically used by anaesthesiologists. Slow administration of small bolus doses of oxytocin minimises maternal haemodynamic disturbance. Continuous oxytocin infusions are recommended for maintaining uterine tone after bolus administration, although ideal infusion rates are still to be established. The efficacy of the long-acting oxytocin analogue carbetocin requires further investigation. Recommendations are presented for oxytocin dosing during caesarean delivery. Oxytocin remains the first-line uterotonic after vaginal and caesarean delivery. Recent research elucidates the therapeutic range of oxytocin during caesarean delivery, as well as receptor desensitization. Evidenced-based protocols for the prevention and treatment of uterine atony during caesarean delivery are recommended.

Dexmedetomidine hemodynamics in children after cardiac surgery

Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. A simultaneous pharmacokinetic-pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1-4 mcg.kg(-1) following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. Children had a mean age of 2.67 years (range 4 days-14 years) and a mean weight of 12.34 (range 3.4-48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) was 9.66 (165.23%) min. Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.

Atherosclerotic Peripheral Vascular Disease Symposium II

Percutaneous intervention for peripheral artery disease has evolved from balloon angioplasty for simple focal lesions to multimodality techniques that enable treatment of severe arterial insufficiency. This technological expansion comes without a standard approach or algorithm, which makes the decision-making process more subjective than objective. Nevertheless, clinical tools are available that can have a favorable effect on patient care, and these promote usage. So, when are standard endovascular techniques (such as balloon and stents) good enough, and when are the latest advances (eg, atherectomy, drug-eluting stents) more appropriate? This section will address these questions for acute limb ischemia (ALI) and chronic critical limb ischemia (CLI). It will also delineate the problem of restenosis, particularly of the superficial femoral artery (SFA), and describe treatment alternatives. The discussion will review the role of drug-eluting stents, atherectomy devices, reentry catheters, and brachytherapy, as well as their potential complications and appropriate remedies. Treatment algorithms for aortoiliac and infrainguinal disease are provided in Figures 1 through 3⇓⇓. Figure 1. Treatment algorithm for acute lower-limb ischemia. *Short infusion of thrombolytic therapy proximal to occlusion can be used to facilitate wire traversal. Figure 2. Simplified treatment algorithm for symptomatic aortoiliac disease in patients deemed candidates for revascularization. In patients with multilevel disease, the aortoiliac segment should be addressed first. TASC indicates TransAtlantic Inter-Society Consensus; AI, aortoiliac; PTA, percutaneous transluminal angioplasty; PE, physical examination; ABI, ankle-brachial index; and U/S, ultrasound. Figure 3. Simplified treatment algorithm for symptomatic infrainguinal peripheral arterial disease, assuming concomitant aortoiliac disease has been treated and the patient is an acceptable candidate for revascularization. *Alternative therapies to PTA include cryotherapy, atherectomy (directional, rotational, ablative), and cutting balloon. †Alternative stent options include stent (graft, balloon expanding, and self expanding) and drug-eluting stent. PTA indicates percutaneous transluminal angioplasty; TASC, TransAtlantic Inter-Society Consensus; PE, physical examination; …

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.

The use of Ketamine as Rescue Analgesia in the Recovery Room following Morphine Administration—A Double-Blind Randomised Controlled Trial in Postoperative Patients

In some patients, control of postoperative pain can be difficult with morphine alone. This double-blind randomised controlled trial was designed to evaluate whether a small bolus dose of ketamine could improve pain scores in those patients who had inadequate relief of their postoperative pain after two standard doses of morphine. Forty-one patients with uncontrolled postoperative pain were randomly assigned to receive either morphine (M) alone, or morphine plus 0.25 mg/kg ketamine (K) in the recovery room. No other analgesics were to be given. The study had adequate power to detect a 25% difference in pain scores. There was no statistically significant difference in verbal rating scale pain scores between the two groups either in the recovery room (K = 5.16, M = 6.28, P = 0.065), or at a later time on the ward. There was no apparent difference between groups in sedation, morphine consumption, postoperative nausea and vomiting, quality of recovery or need for rescue analgesia. We could not demonstrate an effective role for ketamine in the management of problematic postoperative pain at the dose studied.

Continuous peripheral nerve blocks: state of the art

This review was performed through a Medline research to evaluate articles published between January 2004 and April 2005. Technical procedures, indications, drugs, infusion regimens, and complications of continuous peripheral nerve blocks were considered. A total of 27 articles were reviewed. With respect to technical procedures, the authors focused on advantages of stimulating catheters or ultrasound guidance. With the help of these techniques, a correct catheter placement as close to the targeted nerve as possible was obtained. The total amount of local anesthetic administered was thereby reduced. Using ultrasound needle guidance, the spread of local anesthetic around the nerve could be visualized. Articles dealing with the choice of local anesthetic showed equianalgesia and equipotency of continuous perineural infusion of levobupivacaine 0.125% and ropivacaine 0.2%. The best infusion regimen for postoperative analgesia appears to be a combination of a preset basal rate administered together with small bolus doses in almost all continuous peripheral nerve blocks. Overall, complications such as infections, local anesthetic toxic plasma levels, hematoma formation, or nerve injury seem to be rare in continuous peripheral nerve blockade. Continuous peripheral nerve blockade is an effective and safe technique for postoperative analgesia, even when administered at home. To optimize this technique, further studies are needed to help minimize the risk of side effects, improve techniques to locate the targeted nerve (stimulating catheters or ultrasound imaging) and choose less toxic drugs (levobupivacaine and ropivacaine) with more effective infusion regimens.

Haemodynamic response to a small intravenous bolus injection of epinephrine in cardiac surgical patients.

The aim was to study the rapid changes in cardiac output and systemic vascular resistance produced by intravenous epinephrine (5 microg) on a beat-by-beat basis. Ten patients were studied during cardiac surgery. Radial or brachial arterial pressure was recorded continuously during intravenous administration of epinephrine (5 microg). Cardiac output and systemic vascular resistance were derived for each beat using arterial pulse contour analysis calibrated by lithium indicator dilution. In each patient a further dose of epinephrine (5 microg) was administered during cardiopulmonary bypass with the blood flow kept constant so that changes in arterial pressure corresponded to changes in systemic vascular resistance. When the patients were not on cardiopulmonary bypass, the epinephrine produced an initial increase in systemic vascular resistance to 129 +/- 15% (mean +/- SD) of control, followed by a more prolonged reduction to 57 +/- 13% of control. Cardiac output showed a small initial reduction coincident with the increase in systemic vascular resistance, followed by an increase to 152 +/- 24% of control. During cardiopulmonary bypass, the changes produced by epinephrine on systemic vascular resistance were qualitatively similar but smaller in amplitude, probably because of a greater volume of dilution in the bypass circuit. Small bolus doses of epinephrine produce an initial increase in systemic vascular resistance followed by a much greater reduction that may cause hypotension.

Feasibility of electromyography (sEMG) in measuring muscular activity during spinal anaesthesia in patients undergoing knee arthroplasty

Bromage scale (0-3) is used to measure the degree of motor block during spinal anaesthesia. However, an estimation of motor block is difficult during surgery. The purpose of this study was to evaluate the feasibility of surface EMG describing spontaneous muscular activity in the lower extremities during spinal anaesthesia. In part I of the study, 13 patients undergoing day case surgery were studied. They received 10 mg hyperbaric bupivacaine at interspace L3-4. EMG, sensory and muscular block were measured at 5-min intervals during the first 30 min and then every 15 min until the patient was able to flex the knee. In part II of the study, 16 patients undergoing knee arthroplasty received 10 mg bupivacaine through spinal catheter at interspace L3-4 (Group CSA). An additional bolus of 2.5 mg was administered using EMG-guidance, if needed. Another group, 15 patients, received a single bolus of bupivacaine (15-20 mg) at L3-4 (Group Bolus). EMG, muscular and sensory block were monitored as described above. The epidural catheter was used as rescue. Part I: EMG compared to modified Bromage scale showed a significant correlation (P < 0.01, Spearman rank correlation). Part II: The amount of bupivacaine was significantly reduced with EMG guidance when compared with the single bolus group (14.0 mg vs. 17.0 mg) (P < 0.05 Mann-Whitney U). Motor block started to recover before the sensory block in 7/15 CSA patients vs. 1/15 Bolus patient. Stable maximal sensory block does not necessarily correlate with adequate motor block in patients receiving spinal anaesthesia induced with small bolus doses. In spite of electrical noise, EMG-guided administration of spinal anaesthesia significantly reduced the amount of bupivacaine compared to the hospital routine. Further studies are needed to develop the method.

The effects of endothelin-1 on ischaemia-induced ventricular arrhythmias in rat isolated hearts

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1–10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K +) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K + (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21–30-min post-occlusion period. Furthermore, in hearts perfused with low K + solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

A review of the use of fentanyl analgesia in the management of acute pain in adults.

A review of the use of fentanyl analgesia in the management of acute pain in adults.