Plasma Concentrations Of Bupivacaine Research Articles

Efficacy and safety of different bupivacaine concentrations in periarticular infiltration combined with adductor canal block for bilateral total knee arthroplasty: a randomized controlled trial

BackgroundPain management for bilateral total knee arthroplasty (BTKA) often combines adductor canal block (ACB) with periarticular infiltration (PAI). However, concerns arise regarding local anesthetic toxicity. This study evaluated the efficacy and safety of different bupivacaine concentrations in simultaneous BTKA.MethodsPatients undergoing simultaneous BTKA under spinal anesthesia were included in the study. They received ACB with 50 mg bupivacaine for each thigh. The patients were then randomized into two groups. Group A was administered a PAI of 100 mg bupivacaine per knee (totaling 300 mg bupivacaine for ACB and PAI). Group B received a PAI with 50 mg bupivacaine per knee (totaling 200 mg bupivacaine for ACB and PAI). Postoperative pain was assessed using a visual analog scale at 4-h intervals for 48 h after surgery. Plasma bupivacaine concentrations were measured at eight specified times. Postsurgery walking ability was also evaluated.ResultsAmong the 57 participants analyzed, visual analog scale pain scores revealed no significant differences between the two groups. An interim analysis of plasma bupivacaine concentrations in both groups indicated no significant disparities. In group B, 93.1% managed to walk with assistance within 48 h, as opposed to group A’s 71.4% (P = 0.041).ConclusionsCombining ACB with 100 mg bupivacaine and PAI with another 100 mg bupivacaine provided effective pain relief. This combination also had a better safety profile and led to more patients walking postsurgery than when combining ACB with 100 mg bupivacaine and PAI with 200 mg bupivacaine. Thus, ACB combined with PAI with a total dose of 200 mg bupivacaine appears suitable for simultaneous BTKA.Trial registration: ClinicalTrials.gov (NCT03249662).

Assessment of the Safety and Efficiency of a Preperitoneal Continuous Infusion Using Bupivacaine after Abdominal Laparotomy in Digestive Carcinology.

The purpose of this paper is to evaluate the safety and efficacy of continuous preperitoneal wound infiltration using bupivacaine after abdominal laparotomy in relation to plasma bupivacaine concentration and visual analog scale. Our study was performed on 60 adult patients with digestive cancer, operated at laparotomy, and randomized into two groups: bupivacaine and saline groups. The wound infiltration was through a multiperforated catheter along the scar. For the bupivacaine group, 0.25% bupivacaine was used; however, for the saline group, only saline (0.9%) was infiltrated. The pain was assessed by using the visual analog scale (VAS) in both groups. Plasma bupivacaine concentration was measured by high-performance liquid chromatography. The bupivacaine group had significantly lower postoperative morphine consumption and lower postoperative pain than the saline group (P < 0.0001). The majority of patients in the bupivacaine group had significant relief with the VAS scores of less than 3/10 cm at rest and 6/10 cm on mobilization. However, for the saline group, the VAS scores were higher than 6/10 cm either at rest or with mobilization. There was no clinical sign of toxicity and no technical complications for the bupivacaine group. Only eleven patients required morphine in this group, but the majority of patients received morphine at different doses in the saline group. Plasma bupivacaine was at very low concentrations. Overall, the current study has confirmed that continuous preperitoneal wound infiltration as postoperative analgesia is a simple, effective, and safe technique. It allows decreasing of morphine consumption and subsequently canceling their side effects.

Pharmacokinetics and efficacy of a novel long-acting bupivacaine formulation for cornual nerve block in calves.

Local anesthetics are commonly used in farm animals to provide analgesia for painful procedures but can cause adverse effects at high systemic concentrations. The pharmacokinetics and efficacy of a long-acting sucrose acetate isobutyrate (SAIB) bupivacaine formulation following cornual nerve block in calves were compared to lidocaine. Fourteen calves were randomly assigned to one of the treatment groups (i) 5% Bupivacaine-SAIB (BUP-SAIB), n = 7; or (ii) 2% lidocaine (LID), n = 7. Cornual nerve block was performed, and duration of effective analgesia was evaluated by nociceptive threshold testing using a hand-held pressure algometer. Blood samples were collected at various time points and plasma concentrations were analyzed by HPLC. Pharmacokinetic parameters were calculated using a non-compartmental model. The mechanical nociceptive thresholds showed that the novel formulation could desensitize the skin around the horn bud for 18.77 ± 8.88 h (range 8-36 h), compared to 0.79 ± 0.34 h (range 0.5-1.5 h) with lidocaine. The mean maximum plasma concentration (Cmax) of bupivacaine was 152.03 (SD 37.34) ng/mL and its Tmax was 0.39 (SD 0.13) h. The half-life of elimination was 32.79 ± 11.00 h and the rate of clearance was 0.12 ± 0.03 L h-1. No toxicity signs were seen after treatment in either group. The novel formulation produced long-lasting analgesia of several times greater duration than that produced by lidocaine. This study showed that the safety and efficacy of the SAIB formulation justifies further studies in a larger population of animals.

Pharmacokinetics of Bupivacaine Following Administration by an Ultrasound-Guided Transversus Abdominis Plane Block in Cats Undergoing Ovariohysterectomy.

Bupivacaine is commonly used for peripheral nerve block in veterinary medicine. This study described the pharmacokinetics of two doses of bupivacaine following administration by an ultrasound-guided transversus abdominis plane (TAP) block in cats undergoing ovariohysterectomy. Twelve healthy female adult cats were included in a randomized, prospective, blinded clinical trial. Anaesthetic protocol included acepromazine–buprenorphine–propofol–isoflurane–meloxicam. Each cat received 1 mL/kg of bupivacaine 0.2% or 0.25% (BUPI-2 and BUPI-2.5, respectively) via bilateral two-point TAP block before surgery (n = 6/group). Plasma concentrations of bupivacaine were detected using liquid chromatography-mass spectrometry. A one-compartment model and non-compartmental analysis described the pharmacokinetic parameters. Bupivacaine was detected up to 480 min (335 ± 76 in BUPI-2 and 485 ± 198 ng/mL in BUPI-2.5). For BUPI-2 and BUPI-2.5, maximum plasma concentrations were 1166 ± 511 and 1810 ± 536 ng/mL at 33 ± 14 and 47 ± 22 min, clearance was 5.3 ± 1.8 and 4.9 ± 1.5 mL/min/kg, and elimination half-life were 253 ± 55 and 217 ± 52 min, respectively. The two doses of bupivacaine via TAP block produced concentrations below toxic levels in cats. A dose of 2.5 mg/kg bupivacaine was safe to be administered using this block in healthy cats.

Peak plasma concentration of total and free bupivacaine after erector spinae plane and pectointercostal fascial plane blocks.

Erector spinae plane blocks (ESPB) and pectointercostal fascial (PIFB) plane blocks are novel interfascial blocks for which local anesthetic (LA) doses and concentrations necessary to achieve safe and effective analgesia are unknown. The goal of this prospective observational study was to provide the timing (Tmax) and concentration (Cmax) of maximum total and free plasma bupivacaine after ESPB in breast surgery and after PIFB in cardiac surgery patients. Erector spinae plane blocks or PIFBs (18 patients per block; total, 36 patients) were performed with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 μg⋅mL-1. Our principal outcomes were the mean or median Cmax of total and free plasma bupivacaine measured 10, 20, 30, 45, 60, 90, 180, and 240 min after LA injection using liquid chromatography with tandem mass spectrometry. For ESPB, the mean (standard deviation [SD]) total bupivacaine Cmax was 0.37 (0.12) μg⋅mL-1 (range, 0.19 to 0.64), and the median [interquartile range (IQR)] Tmax was 30 [50] min (range, 10-180). For ESPB, the mean (SD) free bupivacaine Cmax was 0.015 (0.017) μg⋅mL-1 (range, 0.003-0.067), and the median [IQR] Tmax was 30 [20] min (range, 10-120). After PIFB, mean plasma concentrations plateaued at 60-240 min. For PIFB, the mean (SD) total bupivacaine Cmax was 0.32 (0.21) μg⋅mL-1 (range, 0.14-0.95), with a median [IQR] Tmax of 120 [150] min (range, 30-240). For PIFB, the mean (SD) free bupivacaine Cmax was 0.019 (0.010) μg⋅mL-1 (range, 0.005-0.048), and the median [IQR] Tmax was 180 [120] min (range, 30-240). For both ESPB and PIFB, we observed no correlations between pharmacokinetic and demographic parameters. Total and free bupivacaine Cmax observed after ESPB and PIFB with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 μg⋅mL-1 were five to twenty times lower than levels considered toxic in the literature.

Suspected local anaesthetic systemic toxicity (LAST) after several bupivacaine injections through an epidural catheter in a cat

AbstractA 9‐year‐old male neutered domestic short hair cat was referred to our practice after a road traffic accident. On presentation, the cat was obtunded, with bilateral hindlimb fractures. The fractures were surgically repaired, and an epidural catheter was placed for perioperative pain management. Postoperative analgesia consisted of bupivacaine administered intermittently through the epidural catheter. In the days after surgery, the cat became duller and more obtunded, and marked bilateral mydriasis with absence of a pupillary reflex was noted. After ruling out different causes for mydriasis and weaning the cat from systemic opioids, local anaesthetic systemic toxicity (LAST) emerged the primary differential diagnosis. Bupivacaine plasma concentrations were measured and found a fourfold increase in concentration over that reported after a perineural block. Mydriasis and absent pupillary light reflex, among other clinical signs, could be early indicators of LAST secondary to accumulation of the local anaesthetic in patients with an epidural catheter.

A multicenter study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years (PLAY)

Study objectiveTo evaluate the pharmacokinetics and safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery. DesignMulticenter, open-label, phase 3, randomized trial (PLAY; NCT03682302). SettingOperating room. PatientsTwo separate age groups were evaluated (age group 1: patients 12 to <17 years undergoing spine surgery; age group 2: patients 6 to <12 years undergoing spine or cardiac surgery). InterventionRandomized allocation of liposomal bupivacaine 4 mg/kg or bupivacaine hydrochloride (HCl) 2 mg/kg via local infiltration at the end of spine surgery (age group 1); liposomal bupivacaine 4 mg/kg via local infiltration at the end of spine or cardiac surgery (age group 2). MeasurementsThe primary and secondary objectives were to evaluate the pharmacokinetics (eg, maximum plasma bupivacaine concentrations [Cmax], time to Cmax) and safety of liposomal bupivacaine, respectively. Main resultsBaseline characteristics were comparable across groups. Mean Cmax after liposomal bupivacaine administration was lower versus bupivacaine HCl in age group 1 (357 vs 564 ng/mL); mean Cmax in age group 2 was 320 and 447 ng/mL for spine and cardiac surgery, respectively. Median time to Cmax of liposomal bupivacaine occurred later with cardiac surgery versus spine surgery (22.7 vs 7.4 h). In age group 1, the incidence of adverse events (AEs) was comparable between liposomal bupivacaine (61% [19/31]) and bupivacaine HCl (73% [22/30]). In age group 2, 100% (5/5) and 31% (9/29) of patients undergoing spine and cardiac surgery experienced AEs, respectively. AEs were generally mild or moderate, with no discontinuations due to AEs or deaths. ConclusionsPlasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults (~2000–4000 ng/mL) across age groups and procedures. AEs were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery.Clinical trial number and registry URL: ClinicalTrials.gov identifier: NCT03682302

Pharmacokinetics and safety of liposomal bupivacaine after local infiltration in healthy Chinese adults: a phase 1 study

BackgroundLiposomal bupivacaine (LB) is a long-acting formulation of bupivacaine. The safety and efficacy of LB has been demonstrated across surgical procedures. However, pharmacokinetic (PK) parameters and safety of LB in the Chinese population have not been assessed.MethodsIn this single-arm, single center, phase 1, open-label study, PK and safety of local infiltration with LB 266 mg were assessed in healthy Chinese adults. Eligible participants were aged 18 to 55 years with biologic parents and grandparents of Chinese ethnicity, in generally good health (i.e., no clinically significant abnormalities), and with a body mass index (BMI) 19.0 to 24.0 kg/m2 (inclusive) and body weight ≥ 50 kg.ResultsParticipants (N = 20) were predominantly men (80 %); mean age was 32 years; and mean BMI was 21.8 kg/m2. After LB administration, mean plasma levels of bupivacaine rapidly increased during the first hour and continued to increase through 24 h; plasma levels then gradually decreased through 108 h followed by a monoexponential decrease through 312 h. Geometric mean maximum plasma concentration was 170.9 ng/mL; the highest plasma bupivacaine concentration detected in any participant was 374.0 ng/mL. Twenty-two treatment-emergent adverse events were reported (mild, n = 21; moderate, n = 1).ConclusionsAfter single-dose administration of LB, PK measures were similar to a previously reported profile in US adults. The highest observed peak plasma concentration of bupivacaine was several-fold below the plasma concentration threshold accepted as being associated with neurotoxicity or cardiotoxicity (2000–4000 ng/mL). These data support that LB is well tolerated and safe in individuals of Chinese descent.Trial registrationNCT04158102 (ClinicalTrials.gov identifier), Date of registration: November 5, 2019.

Dexmedetomidine elevates the lethal dose threshold of bupivacaine in rats: A dosing study.

Dexmedetomidine (DMED), an alpha-2 adrenoreceptor agonist, has been widely used in regional anesthesia procedures. However, the effect of DMED on local anesthetic cardiotoxicity has not been well delineated. This study consisted of two experiments. In experiment A, 42 Sprague-Dawley (SD) rats were randomly divided into 6 groups (n = 7), each group was pretreated with DMED 0 μg kg-1 (D0 group), 1 μg kg-1 (D1 group), 3 μg kg-1 (D3 group), 6 μg kg-1 (D6 group), 12 μg kg-1 (D12 group), and 24 μg kg-1 (D24 group), administered through the right femoral vein. In experiment B, 20 SD rats were randomly divided into 4 groups (n = 5), such as control group, DMED group, yohimbine (YOH) group, and DMED + YOH group. Each subgroup in experiment B was also pretreated similarly as in experiment A. After pretreatment of rats as described above (in experiments A and B), bupivacaine 2.5 mg kg-1 min-1 was infused to induce cardiac arrest. In experiment A, the lethal dose threshold of bupivacaine and plasma bupivacaine concentration in D3 and D6 group were higher than the other groups. In experiment B, there was no interaction between DMED and YOH in lethal dose threshold, arrhythmia time, plasma concentration of bupivacaine, and myocardial content of bupivacaine. DMED doses of 3-6 μg kg-1 elevated the lethal dose threshold of bupivacaine without involvement of the alpha-2 adrenoceptors.

Matrix effect-free on-line pass-through cleanup procedure for the fast determination of local anesthetic drug by LC-MS/MS

A novel nano-titania modified covalent organic frameworks (NTM-COFs) has been synthesized and characterized by transmission electron microscopy (TEM) and scanning electron micrographs (SEM). Besides, NTM-COFs, as efficient sorbent, has also been evaluated in the on-line pass-through cleanup procedure prior to the analysis of local anesthetic drugs (lidocaine, bupivacaine and tetracaine) in human plasma by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). Under optimum conditions, the level of matrix effects can be dramatically reduced by the NTM-COFs based on-line pass-through cleanup procedure, with acceptable recoveries ranging from 88.8% to 103%. Satisfactory trueness and precision of the proposed method were also obtained, with the within- and between-run RSDs less than 7.0% and relative error (REs) less than 12%. The limits of detections (LODs) of lidocaine, bupivacaine and tetracaine were 0.029 μg·L−1, 0.027 μg·L−1 and 0.016 μg·L−1, respectively. The analytical method has been successfully applied for the determination of the plasma concentrations of bupivacaine in five parturients who received an epidural administration of bupivacaine hydrochloride during vaginal delivery. Results demonstrate the applicability of the developed NTM-COFs on-line pass-through cleanup procedure coupled with LC-MS/MS method to clinical studies.

The block of the crural nerve as a technique of analgesia postoperative knee surgery

Ten ASA patients 1 and 2 are being studied, aged 18 to 54 years (mean ± SD: 37 ± 17 years) and undergoing knee surgery. At the end of the surgical procedure under general anesthesia, an epidural catheter is placed in the colorectal cavity. After radiological monitoring, a large dose of bupivacaine 0.5% epinephrine 2.5 mg • kg-1 was injected. A 0.125% non-adrenaline bupivacaine was maintained for 48 hours at a dose of 0.25 mg • kg-1 • h-1. The pain score measured using a visual analog scale before occlusion was 5.0 ± 1.9. From the 6th hour to the 48th hour, it decreased significantly. The plasma concentrations of bupivacaine obtained at 24, 36, and 48 hours were significantly higher than those at 30 minutes, and 1, 6, and 12 hours. The steady-state concentration of bupivacaine was 1.78 ± 0.59 μg • ml-1. The clearance rate of bupivacaine was 2.59 ± 0.91 ml • min-1 • kg-1. No neurological complications were observed.

Blood concentration of bupivacaine and duration of sensory and motor block following ultrasound-guided femoral and sciatic nerve blocks in dogs.

Peripheral nerve blocks are becoming increasingly popular for perioperative use as anesthetics and analgesics in small animals. This prospective study was performed to investigate the duration of motor and sensory blockade following use of bupivacaine for ultrasound-guided femoral and sciatic nerve blocks in dogs and to measure the plasma concentrations of bupivacaine that result from these procedures. Six dogs were anesthetized twice using a randomized cross-over design. At the first anesthetic, dogs were assigned to receive either an ultrasound-guided femoral nerve block or sciatic nerve block with 0.15 mL kg-1 of bupivacaine 0.5%. Two months later, the other nerve block was performed during a second anesthetic. At 5, 10, 15, 20, 30 and 60 minutes after injection, arterial blood samples were collected for laboratory measurement of bupivacaine. After 60 minutes, dogs were recovered from anesthesia. Starting at two hours post-injection, video-recordings of the dogs were made every two hours for 24 hours. The videos were randomized and the degree of motor and sensory blockade was evaluated using a three-point scoring system (0 = no effect, 1 = mild effect, 2 = complete blockade) by two blinded assessors. The median (range) times to full recovery from motor blockade were 11 (6–14) hours (femoral) and 12 (4–18) hours (sciatic), and 15 (10–18) hours (femoral) and 10 (4–12) hours (sciatic) for sensory blockade. There were no differences in the median times to functional recovery for the two techniques. Plasma concentrations of bupivacaine were no different following the blocks and were less than 0.78 μg mL-1 at all times. These results suggest that these ultrasound-guided nerve blocks do not result in potentially toxic systemic levels of local anesthetic and that their duration of action is useful for providing anesthesia and analgesia for pelvic limb procedures.

Analgesic efficacy and safety of epidural oxycodone in patients undergoing total hip arthroplasty: a pilot study.

Background and objectivesOxycodone is poorly studied as an adjuvant to central blockades. The aim of this pilot study was to assess the efficacy and safety of oxycodone hydrochloride in epidural blockade among patients undergoing total hip arthroplasty (THA).Patients and methodsIn 11 patients (American Society of Anesthesiologists physical status classification system II/III, age range: 59–82 years), THA was conducted with an epidural blockade using 15 mL 0.25% bupivacaine (37.5 mg) with 5 mg oxycodone hydrochloride and sedation with propofol infusion at a dose of 3–5 mg/kg/h. After the surgery, patients received ketoprofen at a dose of 100 mg twice daily. In the first 24 hours postoperative period, pain was assessed by numerical rating scale at rest and on movement; adverse effects (AEs) were recorded; and plasma concentrations of oxycodone, noroxycodone, and bupivacaine were measured.ResultsThe administration of epidural oxycodone at a dose of 5 mg in patients undergoing THA provided analgesia for a mean time of 10.3±4.89 h. In one patient, mild pruritus was observed. Oxycodone did not evoke other AEs. Plasma concentrations of oxycodone while preserving analgesia were >2.9 ng/mL. Noroxycodone concentrations in plasma did not guarantee analgesic effect.ConclusionThe administration of epidural oxycodone at a dose of 5 mg prolongs the analgesia period to ~10 hours in patients after THA. Oxycodone may evoke pruritus. A 5 mg dose of oxycodone hydrochloride used in an epidural blockade seems to be a safe drug in patients after THA.

Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis plane block following cesarean delivery under spinal anesthesia

BackgroundTransversus abdominis plane block is an effective method of post-cesarean analgesia. There are no data available about plasma bupivacaine levels after this block in adults. This study aimed to assess bupivacaine pharmacokinetic parameters after ultrasound-guided transversus abdominis plane blocks following cesarean delivery under spinal anesthesia. MethodsA prospective observational study in parturients undergoing elective cesarean delivery under hyperbaric bupivacaine spinal anesthesia was conducted. After surgery, patients received bilateral transversus abdominis plane block (50mg bupivacaine each side). Venous blood samples were collected immediately before performing the block and at 10, 20, 30, 45, 60, 90, 120, 180, 240, 720 and 1440minutes. High performance liquid chromatography was used to measure total plasma bupivacaine concentrations. Mean bupivacaine area under the curve (AUC) was calculated from 0 to 24hours. ResultsData were collected from 17 parturients. Mean age and body mass index were 31±6y and 30±4kg/m2 respectively. Mean plasma bupivacaine concentration before the block was 171ng/mL. Mean peak concentration was 802.36ng/mL (range 231.8 to 3504.5ng/mL). Mean time to peak concentration was 30min and mean area-under-the-curve (0–24h) was 4505.4h.ng/mL. Mean elimination half-life was 8.75h. Three subjects had concentrations above the quoted toxic threshold and mild symptoms suggestive of neurotoxicity were reported by two subjects, but no treatment was required. ConclusionSingle-dose bilateral transversus abdominis plane block using 100mg of bupivacaine, after spinal anesthesia for cesarean delivery, can result in toxic plasma bupivacaine concentrations.

Plasma bupivacaine concentrations following orbital injections in cats

ObjectiveTo determine plasma bupivacaine concentrations after retrobulbar or peribulbar injection of bupivacaine in cats. Study designRandomized, crossover, experimental trial with a 2 week washout period. AnimalsSix adult healthy cats, aged 1–2 years, weighing 4.6 ± 0.7 kg. MethodsCats were sedated by intramuscular injection of dexmedetomidine (36–56 μg kg−1) and were administered a retrobulbar injection of bupivacaine (0.75 mL, 0.5%; 3.75 mg) and iopamidol (0.25 mL), or a peribulbar injection of bupivacaine (1.5 mL, 0.5%; 7.5 mg), iopamidol (0.5 mL) and 0.9% saline (1 mL) via a dorsomedial approach. Blood (2 mL) was collected before and at 5, 10, 15, 22, 30, 45, 60, 120, 240 and 480 minutes after bupivacaine injection. Atipamezole was administered approximately 30 minutes after bupivacaine injection. Plasma bupivacaine and 3-hydroxybupivacaine concentrations were determined using liquid chromatography–mass spectrometry. Bupivacaine maximum plasma concentration (Cmax) and time to Cmax (Tmax) were determined from the data. ResultsThe bupivacaine median (range) Cmax and Tmax were 1.4 (0.9–2.5) μg mL−1 and 17 (4–60) minutes, and 1.7 (1.0–2.4) μg mL−1, and 28 (8–49) minutes, for retrobulbar and peribulbar injections, respectively. In both treatments the 3-hydroxybupivacaine peak concentration was 0.05–0.21 μg mL−1. Conclusions and clinical relevanceIn healthy cats, at doses up to 2 mg kg−1, bupivacaine peak plasma concentrations were approximately half that reported to cause arrhythmias or convulsive electroencephalogram (EEG) activity in cats, and about one-sixth of that required to produce hypotension.

The effects of intravenous lipid emulsion on hemodynamic recovery and myocardial cell mitochondrial function after bupivacaine toxicity in anesthetized pigs.

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® ( n = 7) with Ringer's acetate ( n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration ( p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid ( p < 0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer's acetate (88.1 (7.1) mg·min/L) ( p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine ( p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.

Local anaesthetic systemic toxicity

Access the CPD MCQs for this issue online here ### Key points Well-placed local anaesthetics (LAs) can yield great clinical benefits. But systemic toxicity related to their use can be devastating. The highly publicized case in 2004 of Mayra Cabrera, a theatre nurse who died shortly after delivery of her baby boy when her epidural infusion of bupivacaine was mistakenly connected to her i.v. line, reminds us to be vigilant and to learn from such rare events. While prevention is clearly the most important element in avoiding morbidity and mortality associated with local anaesthetic systemic toxicity (LAST), such cases still occur despite best practice. Knowing how to manage these uncommon events is vital. In this review, we cover LA toxicity, its incidence, clinical features, risk factors, prevention, and management and examine i.v. lipid emulsion (ILE) therapy in more detail. LAST has been recognized for more than a hundred years, but the precise incidence is currently unknown. In 1928, the American Medical Association reported 40 deaths attributable to LAs.1 Cocaine was responsible for half of these deaths, but procaine was also implicated. These findings prompted the search for less toxic agents. Lidocaine, first synthesized in 1944, was the first amide LA to be used clinically. However, in 1979, the potentially fatal toxicity of amide LAs was highlighted by Albright.2 More recently, studies from 1993 …

Is the pharmacokinetics of bupivacaine equivalent after lumbar epidural administration through a needle or a catheter in male and female adults?

We assessed possible pharmacokinetic modifications due to different epidural injection techniques using either a needle or a catheter. Adult patients (n=23) undergoing lower abdominal or lower extremity surgery were randomly assigned a single bupivacaine epidural injection anesthesia (0.5%, 15mL, 0.3mL/s) through needle or catheter device. Plasma bupivacaine concentration was quantified using a validated HPLC method and non-compartmental pharmacokinetic parameters estimated. CMAX and TMAX were similar in both groups: 952±346 ng/mL, 0.65±0.51h in the needle group; 810±307 ng/mL, 0.43±0.29h in the catheter group respectively. Plasma AUC0→∞ was also similar in both groups: 3868±1687 ngh/mL for needle versus 4096±1748 ngh/mL using catheter. The catheter group showed slower disposition than the needle group: t1/2=3.9±2.3h, MRT=6.0±3.1h versus 2.7±1.03h and 4.5±1.2h with needle administration respectively though it did not reach statistical significance, Cl/F and V/F were also similar. Lastly, female patients showed significant longer t1/2 after administration through catheter (5.7±2.0h) than needle (2.7±0.6h) group (P=0.0279). The device type does not affect the pharmacokinetics which is similar in both groups although sex-based differences might exist.

The analgesic efficacy of continuous presternal bupivacaine infusion through a single catheter after cardiac surgery.

Background:Median sternotomy, sternal spreading, and sternal wiring are the main causes of pain during the early recovery phase following cardiac surgery.Aim:This study was designed to evaluate the analgesic efficacy of continuous presternal bupivacaine infusion through a single catheter after parasternal block following cardiac surgery.Materials and Methods:The total of 40 patients (American Society of Anesthesiologist status II, III), 45–60 years old, undergoing coronary – artery bypass grafting were enrolled in this prospective, randomized, double-blind study. A presternal catheter was inserted with continuous infusion of 5 mL/h bupivacaine 0.25% (Group B) or normal saline (Group C) during the first 48 postoperative hrs. Primary outcomes were postoperative morphine requirements and pain scores, secondary outcomes were extubation time, postoperative respiratory parameters, incidence of wound infection, Intensive Care Unit (ICU) and hospital stay duration, and bupivacaine level in blood.Statistical Methods:Student's t-test was used to analyze the parametric data and Chi-square test for categorical variables.Results:During the postoperative 48 h, there was marked reduction in morphine requirements in Group B compared to Group C, (8.6 ± 0.94 mg vs. 18.83 ± 3.4 mg respectively, P = 0.2), lower postoperative pain scores, shorter extubation time (117 ± 10 min vs. 195 ± 19 min, respectively, P = 0.03), better respiratory parameters (PaO2/FiO2, PaCO2 and pH), with no incidence of wound infection, no differences in ICU or hospital stay duration. The plasma concentration of bupivacaine remained below the toxic threshold (at T24, 1.2 ug/ml ± 0.3 and T48 h 1.7 ± 0.3 ug/ml).Conclusion:Continuous presternal bupivacaine infusion has resulted in better postoperative analgesia, reduction in morphine requirements, shorter time to extubation, and better postoperative respiratory parameters than the control group.

Population pharmacokinetic analysis of bupivacaïne used in regional anaesthesia

Introduction The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight, sex and drugs co medication (Clonidine and Propofol) on pharmacokinetic parameters. Materials and method A total of 59 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. This pharmacokinetic model was validated using npde package for statistic software R. The simulations confirm that our final model was valid. Results and discussion Two compartment model with first order absorption, two input compartments, a central elimination and peripheral compartment was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model ( P = 0.837) showed this as a valid model. The description of the quality of the estimate by the graphic diagnostic suggests a good fitting of the final model. The selected model predicts a population clearance of 503 mL/min (residual standard error [RSE] = 16.5%, 95% CI = [534.9–866.9]) with between subject variability of 93.16%. The central and peripheral volumes of distribution were respectively 6850 L and 120 L. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00073/min for the lumbar site and 0.0037/min for the sciatic site. Within subject variability WSV% was 30, 3%. Drug Co medication, age, body weight and sex, have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.