Reversal of rocuronium-induced intense neuromuscular blockade by sugammadex in Korean children: A pharmacokinetic and pharmacodynamic analysis.

Sugammadex, a selective antagonist of steroidal non-depolarizing neuromuscular blocking agents, has been used in children in limited circumstances. However, neither pharmacokinetics (PKs) nor recovery profile of sugammadex for intense neuromuscular blockade reversal in children have been reported. This prospective study aimed to obtain a PK model of sugammadex and evaluate its efficacy and safety for intense neuromuscular blockade reversal in children. Forty children (age, 2-17 years) who underwent surgery that required early neuromuscular blockade reversal were enrolled. After neuromuscular blockade with 1 mg∙kg-1 of rocuronium, sugammadex (2, 4, and 8 mg∙kg-1 ) or a conventional dose of neostigmine (0.03 mg∙kg-1 ) was administered randomly after confirmation of zero post-tetanic count. The plasma concentrations of rocuronium and sugammadex were measured 2 min after rocuronium injection; immediately before, 2, 5, 15, 60, 120, 240, and 480 min after the study drug injection. Response to train-of-four stimulation was continuously recorded. Noncompartmental analysis and population PK modeling were performed. For pharmacodynamics, the recovery profile was measured. Three-compartment PK model was established for sugammadex. The median (interquartile range [IQR]) time from injection of 8 mg∙kg-1 of sugammadex to recovery of T4 /T1 greater than or equal to 0.9 at train-of-four stimulation was 1.1 (IQR: 0.88-1.8) min. No adverse events related to sugammadex were observed. We present a PK analysis of sugammadex for rocuronium-induced intense neuromuscular blockade reversal in children with its recovery profile. The time to recover T4 /T1 greater than or equal to 0.9 at train-of-four stimulation with 8 mg∙kg-1 of sugammadex was less than 3 min and comparable to that in adults.

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.

PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).

[Effects of sevoflurane and desflurane on pharmacodynamics of rocuronium in children].

Objective: To observe the intraoperative influences on pharmacodynamics of rocuronium in children inhaling sevoflurane and desflurane for 40 min balance. Methods: Ninety children (ASAⅠ-Ⅱ) undergoing elective surgery with general anesthesia in Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University from July 2015 to May 2016 were randomly assigned into six groups (n=15): Sevoflurane group (group S1 and S2), Desflurane group (group D1 and D2) and Propofol group (group P1 and P2). Children in group D1, S1 and P1 were allocated to research the dose-effect relationship of rocuronium, children in group D2, S2 and P2 were allocated to research the time-effect relationship of rocuronium. TOF-Watch SX monitor was used to exert a train-of-four stimulation (TOF) at ulnar nerve in wrist, then the adductor pollicis muscle appeared muscle twitch 4 times in turn which was recorded T(1, )T(2, )T(3) and T(4) respectively. After the success of the muscle relaxant calibration, 1.3 MAC sevoflurane and desflurane were inhaled and maintained for 40 min respectively in children in Sevoflurane group (group S1 and S2) and Desflurane group (group D1 and D2), Plasma target controlled infusion of 3.5-4.0 µg/ml propofol was always administered in Propofol group (group P1 and P2). 75 µg/kg rocuronium was injected each time in group S1, D1 and P1 respectively. Maximum inhibited effect of T(1) was recorded after every injection until inhibition of T(1) more than 95% eventually. The method of cumulative dose four times was used to calculate the efficiency curve of rocuronium[median effective dose (ED(50)), 90% effective dose (ED(90)) and 95% effective dose (ED(95))]. 0.6 mg/kg rocuronium was injected respectively through vein in group S2, D2 and P2. The recovery times of muscle relaxant were recorded which including time of T(1) disappeared (onset time), T(1) from 0% to 5% (peak effect time), T(1) from 0% to 25% (clinical effect time), T(1) from 25% to 75% (recovery index), T(1) from 0% to 70% (internal effect time), T(4)/T(1) (TOFr) from 0% to 70% and 90%. Results: ED(50, )ED(90) and ED(95) in group D1 were 128.73, 212.45 and 245.78 µg/kg respectively. ED(50, )ED(90) and ED(95) in group S1 were 132.46, 218.94 and 252.30 µg/kg respectively. ED(50, )ED(90) and ED(95) in group P1 were 230.56, 381.02 and 439.55 µg/kg respectively. ED(50, )ED(90) and ED(95) in group D1 and S1 were significantly lower than those in group P1 (all P<0.05), but there was no significant difference between D1 and S1 group (P>0.05). Compared with group P2, the shorter onset time, the longer peak effect time and clinical effect time was observed in group D2 and S2, the longer recovery index, internal effect time and TOFr from 0% to 70% and 90% was observed in group S2 (all P<0.01). Conclusions: 1.3 MAC sevoflurane and desflurane inhaling for 40 min significantly reduces ED(50) and ED(95) of rocuronium, prolongs the onset time and action time of rocuronium in children. Sevoflurane can significantly prolong the recovery characteristics of rocuronium.

Comparing early liver graft function from heart beating and living-donors: A pilot study aiming to identify new biomarkers of liver injury.

The liver and kidney functions of recipients of liver transplantation (LT) surgery with heart beating (HBD, n = 13) or living donors (LD, n = 9) with different cold ischemia times were examined during the neohepatic phase for the elimination of rocuronium bromide (ROC, cleared by liver and kidney) and tranexamic acid (TXA, cleared by kidney). Solid phase micro-extraction and LC-MS/MS was applied to determine the plasma concentrations of ROC and TXA, and creatinine was determined by standard laboratory methods. Metabolomics and the relative expressions of miR-122, miR-148a and γ-glutamyltranspeptidase (GGT), liver injury biomarkers, were also measured. The ROC clearance for HBD was significantly lower than that for LD (0.147 ± 0.052 vs. 0.265 ± 0.148 ml·min-1 ·g-1 liver) after intravenous injection (0.6 mg·kg-1 ). The clearance of TXA, a compound cleared by glomerular filtration, given as a 1 g bolus followed by infusion (10 mg·kg-1 ·h-1 ), was similar between HBD and LD groups (~ 1 ml·min-1 ·kg-1 ). The TXA clearance in both groups was lower than the GFR, showing a small extent of hepatorenal coupling. The miR-122 and miR-148a expressions were similar for the HBD and LD groups, whereas GGT expression was significantly increased for HBD. The lower ROC clearance and the higher GGT levels in the HBD group of longer cold ischemia times performed worse than the LD group during the neophase. Metabololmics further showed clusters of bile acids, phospholipids and lipid ω-oxidation products for the LD and HBD groups. In conclusion, ROC CL and GGT expression, and metabolomics could serve as sensitive indices of early graft function. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery.

OBJECTIVE: To evaluate the impact of advanced age on rocuronium kinetic disposition in ASA I-III patients undergoing elective surgeries. METHODS: Young adult (20-50 years, n = 15) and elderly patients (65-85 years, n = 14) submitted to surgery under general anaesthesia were investigated. All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. Rocuronium-induced neuromuscular block was monitored by train of four stimulations of the adductor muscle of the thumb on the ulnar nerve. The pharmacokinetic parameters were calculated by non-compartmental analysis. The relationship between rocuronium plasma concentration and the neuromuscular blockade was described by a sigmoidal Emax model. KEY-FINDINGS: Elderly patients presented decreased Cl (2.1 ml/kg per min vs 2.8 ml/kg per min; P = 0.0123); increased AUC/dose (507.8 µg min/ml (mg/kg) vs 392.2 µg min/ml/(mg/kg); P = 0.0168) and reduced volume of distribution (285.4 ml/kg vs 435.6 ml/kg, P = 0.0434) compared to young adults. The concentrations required to achieve 50% of maximum neuromuscular block (EC50) were similar for young adult (338.8 ng/ml) and elderly (462.7 ng/ml) patients (P > 0.05). CONCLUSIONS: Elderly patients showed increased AUC/D and reduced total Cl compared to young adult patients due to the age-related reduced renal function. Differences in the PK-PD properties of rocuronium in elderly population are due to changes in drug disposition rather than to alterations in the sensitivity to the drug.

Comparison of distributed and compartmental models of drug disposition: assessment of tissue uptake kinetics.

The utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function. With a deviation in the estimate of the permeability-surface area product (PS) of about 18 %, the compartmental approach appears as a useful alternative on condition that a priori knowledge of cardiac output is included. It is also shown that the distribution clearance calculated from the parameters of a mammillary compartment model changes proportional to PS and can be used as an indirect measure of permeability-limited tissue uptake of drugs.

Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy for at least Three Months.

Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non-depolarizing neuromuscular-blocking agent in patients in long-term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long-term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non-statin users were included in the non-statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9 mg/kg (3ED95 ) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T1 and 25% T1 of rocuronium were recorded. Blood samples were obtained before induction and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non-statin group (p = 0.02), while the duration 10% T1 and duration 25% T1 of the statin group were significantly longer than those of the non-statin group (p = 0.006; p = 0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non-statin group just at 24 hr (p = 0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long-term statin therapy.

The predictive ability of six pharmacokinetic models of rocuronium developed using a single bolus: evaluation with bolus and continuous infusion regimen.

PURPOSE: Rocuronium concentration prediction using pharmacokinetic (PK) models would be useful for controlling rocuronium effects because neuromuscular monitoring throughout anesthesia can be difficult. This study assessed whether six different compartmental PK models developed from data obtained after bolus administration only could predict the measured plasma concentration (Cp) values of rocuronium delivered by bolus followed by continuous infusion. METHODS: Rocuronium Cp values from 19 healthy subjects who received a bolus dose followed by continuous infusion in a phase III multicenter trial in Japan were used retrospectively as evaluation datasets. Six different compartmental PK models of rocuronium were used to simulate rocuronium Cp time course values, which were compared with measured Cp values. Prediction error (PE) derivatives of median absolute PE (MDAPE), median PE (MDPE), wobble, divergence absolute PE, and divergence PE were used to assess inaccuracy, bias, intra-individual variability, and time-related trends in APE and PE values. RESULTS: MDAPE and MDPE values were acceptable only for the Magorian and Kleijn models. The divergence PE value for the Kleijn model was lower than -10 %/h, indicating unstable prediction over time. The Szenohradszky model had the lowest divergence PE (-2.7 %/h) and wobble (5.4 %) values with negative bias (MDPE = -25.9 %). These three models were developed using the mixed-effects modeling approach. The Magorian model showed the best PE derivatives among the models assessed. CONCLUSIONS: A PK model developed from data obtained after single-bolus dosing can predict Cp values during bolus and continuous infusion. Thus, a mixed-effects modeling approach may be preferable in extrapolating such data.

Rocuronium pharmacokinetics and pharmacodynamics in the adductor pollicis and masseter muscles.

BACKGROUND: The aim of this study was to characterize the dose-effect relationship of rocuronium at the adductor pollicis and masseter muscles. METHODS: Ten, ASA I, adult patients, received a bolus dose of rocuronium 0.3 mg/kg during propofol based anesthesia. Train-of-four (TOF) was simultaneously monitored at the masseter and the adductor pollicis muscles until recovery. Rocuronium arterial serum concentrations were measured during 120 min. The first twitch of the TOF response was used to characterize the time-effect profile of both muscles using pharmacokinetic-pharmacodynamic analysis in NONMEM. A decrease in NONMEM objective function (∆OFV) of 3.84 points for an added parameter was considered significant at the 0.05 level. RESULTS: Onset time at the masseter (mean ± SD, 1.5 ± 0.9 min) was faster than at the adductor pollicis (2.7 ± 1.4 min, P < 0.05). Recovery, measured as the time to TOF ratio = 0.9 was similar between muscles 29.9 ± 6.7 (adductor pollicis) vs. 29.3 ± 8.1 (masseter). (P = 0.77). The estimated pharmacodynamic parameters [mean (95% CI)] of the adductor pollicis muscle and the masseter muscle were; plasma effect-site equilibration half-time (teq) 3.25 (2.34, 3.69) min vs. 2.86 (1.83, 3.29) min, (∆OFV 383.665); Ce50 of 1.24 (1.13, 1.56) mg/l vs. 1.19 (1.00, 1.21) mg/l, (∆OFV 184.284); Hill coefficient of 3.97 (3.82, 5.62) vs. 4.68 (3.83, 5.71), (∆OFV 78.906). CONCLUSIONS: We found that the masseter muscle has faster onset of blockade and similar recovery profile than adductor pollicis muscle. These findings were best, explained by a faster plasma effect-site equilibration of the masseter muscle to rocuronium.

Onset and duration of intravenous and intraosseous rocuronium in hypovolemic swine.

OBJECTIVE: Compare the onset and duration of rocuronium administered via the intravenous (IV), and intraosseous (IO) routes in a hypovolemic swine model. DESIGN: Prospective, between subjects, experimental study. SETTING: Vivarium. SUBJECTS: Yorkshire-cross swine (N = 8). INTERVENTION: Electromyography (EMG) amplitudes were recorded at baseline and for every 15 seconds after administering 1.2 mg/kg of rocuronium via IV or IO routes to hypovolemic swine. EMG amplitudes were measured until termination of EMG activity and then measured every 5 minutes until there was a return to baseline values. Individual data were transformed to percent baseline. MAIN OUTCOME MEASUREMENTS: The time from the end of injection to 90 percent reduction of baseline EMG activity (Onset90), the time to maximum reduction (Onsetpeak), and the maximum reduction of the neuromuscular response (peak effect), as well as, time from the end of injection to the return of 25, 50, 75, and 95 percent of baseline EMG activity was used to characterize onset and recovery of neuromuscular function. RESULTS: Maximum reduction, Onset 90 and Onset peak times were not statistically different between groups. The IV group's mean time to recovery of all benchmarks was faster than the IO group. The IO group took statistically longer than the IV group to return to 25, 50, 75, and 95 percent of baseline activity. CONCLUSION: The IO route is an effective method of administering rocuronium and is comparable to the IV route even under conditions of significant hemorrhage.

In vitro and in vivo metabolism studies of dimethazine.

The use of anabolic steroids is prohibited in sports. Effective control is done by monitoring their metabolites in urine samples collected from athletes. Ethical objections however restrict the use of designer steroids in human administration studies. To overcome these problems alternative in vitro and in vivo models were developed to identify metabolites and to assure a fast response by anti-doping laboratories to evolutions on the steroid market. In this study human liver microsomes and an uPA(+/+) -SCID chimeric mouse model were used to elucidate the metabolism of a steroid product called 'Xtreme DMZ'. This product contains the designer steroid dimethazine (DMZ), which consists of two methasterone molecules linked by an azine group. In the performed stability study, degradation from dimethazine to methasterone was observed. By a combination of LC-High Resolution Mass Spectrometry (HRMS) and GC-MS(/MS) analysis methasterone and six other dimethazine metabolites (M1-M6), which are all methasterone metabolites, could be detected besides the parent compound in both models. The phase II metabolism of dimethazine was also investigated in the mouse urine samples. Only metabolites M1 and M2 were exclusively detected in the glucuro-conjugated fraction; all other compounds were also found in the free fraction. For effective control of DMZ misuse in doping control samples, screening for methasterone and methasterone metabolites should be sufficient. Copyright © 2016 John Wiley & Sons, Ltd.

Preclinical evaluation of investigational radiopharmaceutical RISAD-P intended for use as a diagnostic and molecular radiotherapy agent for prostate cancer.

BACKGROUND: The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17ß-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated. METHODS: Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice. RESULTS: RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy × MBq(-1) × g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed. CONCLUSIONS: Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.

Role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy of rocuronium in Chinese patients.

This study explored the role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy and duration of action of rocuronium in Chinese patients. Two hundred seven unrelated Chinese patients scheduled for elective surgery were recruited, and 200 completed the study. Their ABCB1, SLCO1B1, and CHRNA1 genotypes were determined. Demographic and clinical non-genetic data also were collected. The SLCO1B1, ABCB1, and CHRNA1 variants did not affect the onset time of rocuronium. Clinical duration and recovery time of rocuronium were prolonged in patients with the ABCB1 rs1128503TT and SLCO1B1 rs2306283 AG and GG genotypes. We demonstrate that the SLCO1B1 and ABCB1 gene variants could affect the pharmacodynamics of rocuronium. The ABCB1 rs1128503 C>T genotype was the most important factor on the efficacy of rocuronium.

Effects of preoperatively administered carbamazepine and phenytoin on rocuronium-induced neuromuscular block under sevoflurane anesthesia: a retrospective clinical study.

We examined the effects of preoperatively administered phenytoin and carbamazepine on rocuronium-induced neuromuscular block under sevoflurane anesthesia in this retrospective clinical study. When compared to patients without anticonvulsant therapy (n = 16), the recovery index (i.e., the time required from 25% of spontaneous return of T1 to 75% of spontaneous return of T1) was significantly lower in patients with anticonvulsant therapy using carbamazepine and/ or phenytoin (n = 17); however, no significant dose-dependent effects of carbamazepine as well as phenytoin on the recovery index were detected. Further studies are required to elucidate the mechanisms underlying the modifying effects of carbamazepine and phenytoin on pharmacokinetics and pharmacodynamics of rocuronium.

Automatic control of the NMB level in general anaesthesia with a switching total system mass control strategy.

This paper presents a model based switching control strategy to drive the neuromuscular blockade (NMB) level of patients undergoing general anesthesia to a predefined reference. A single-input single-output Wiener system with only two parameters is used to model the effect of two different muscle relaxants, atracurium and rocuronium, and a switching controller is designed based on a bank of total system mass control laws. Each of such laws is tuned for an individual model from a bank chosen to represent the behavior of the whole population. The control law to be applied at each instant corresponds to the model whose NMB response is closer to the patient's response. Moreover a scheme to improve the reference tracking quality based on the analysis of the patient's response, as well as, a comparison between the switching strategy and the Extended Kalman Kilter (EKF) technique are presented. The results are illustrated by means of several simulations, where switching shows to provide good results, both in theory and in practice, with a desirable reference tracking. The reference tracking improvement technique is able to produce a better reference tracking. Also, this technique showed a better performance than the (EKF). Based on these results, the switching control strategy with a bank of total system mass control laws proved to be robust enough to be used as an automatic control system for the NMB level.

Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics.

Rocuronium (ROC) is a neuromuscular blocking agent used in surgical procedures which is eliminated primarily by biliary excretion. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of ROC in human plasma. Separation of ROC and IS (verapamil) was performed using an endcapped C-18 column and a mixture of water:acetonitrile:trifluoracetic acid (50:50:0.1, v/v) as mobile phase. Aliquots of 100 µL of human plasma were extracted at pH 3, using dichloromethane. The lower limit of quantification of 5 ng/mL shows the high sensitivity of this method. Intra- and inter-assay precision (as relative standard deviation) was all ≤14.2% and accuracy (as relative standard error) did not exceed 10.1%. The validated method was successfully applied to quantify ROC concentrations in patients under surgical procedures up to 6h after the administration of the 0.4-0.9 mg/kg ROC. The pharmacokinetic parameter estimations of ROC showed AUC/dose of 563 µg min/mL, total clearance of 2.5 mL/min/kg, volume of distribution at steady state of 190 mL/kg and mean residence time of 83 min.

Influence of obstructive jaundice on pharmacodynamics of rocuronium.

BACKGROUND: Anesthetics are variable in patients with obstructive jaundice. The minimum alveolar concentration awake of desflurane is reduced in patients with obstructive jaundice, while it has no effect on pharmacodynamics and pharmacokinetics of propofol. In this study, we investigated the influence of obstructive jaundice on the pharmacodynamics and blood concentration of rocuronium. METHODS: Included in this study were 26 control patients and 27 patients with obstructive jaundice. Neuromuscular block of rocuronium was monitored by acceleromyography. Onset time, spontaneous recovery of the height of twitch first (T1) to 25% of the final T1 value (Duration 25%, Dur 25%), recovery index (RI), and spontaneous recovery of train-of-four (TOF) ratios to 70% were measured. The plasma rocuronium concentrations were determined by high performance liquid chromatography using berberine as an internal standard. RESULTS: There was no significant difference in onset time between the two groups. The Dur 25%, the recovery index and the time of recovery of the TOF ratios to 70% were all prolonged in the obstructive jaundice group compared with the control group. The plasma concentration of rocuronium at 60, 90 and 120 min after bolus administration was significantly higher in the obstructive jaundice group. CONCLUSIONS: The neuromuscular blockade by rocuronium is prolonged in obstructive jaundice patients, and therefore precautions should be taken in case of postoperative residual neuromuscular block. The possible reason is impedance of rocuronium excretion due to biliary obstruction and increased plasma unbound rocuronium because of free bilirubin competing with it for albumin binding.

Sugammadex rescue following prolonged rocuronium neuromuscular blockade with 'recurarisation' in a patient with severe renal failure.

We describe our experience of a 71-year-old patient with severe renal failure, who exhibited an unusually prolonged rocuronium-induced neuromuscular blockade (>4 h) and apparent recurarisation, following emergency rapid sequence induction (RSI). At the end of operation, 45 min post induction, train-of-four (TOF) testing had been 4/4 prior to wake up. No respiratory effort was seen 150 min postinduction, despite further neostigmine/glycopyrrolate and repeat TOF 4/4. The patient was resedated and transferred to the intensive care unit (ICU). At 180 min postinduction, fade was evident on TOF, suggestive of rocuronium reblockade. At 285 min, the patient was extubated safely following sugammadex administration and discharged uneventfully from the ICU. An important lesson to recognise is the potential for extremely prolonged neuromuscular blockade following rocuronium in patients with severe renal failure, particularly when using the higher doses (1.2 mg/kg) required for RSI, and that TOF in such cases may not be reliable in detecting residual blockade.

Analysis of rocuronium in human whole blood and tissues using liquid chromatography-tandem mass spectrometry.

A rapid, accurate and sensitive liquid chromatography-tandem mass spectrometry method has been developed for the determination of a quaternary nitrogen muscle relaxant, rocuronium, in human blood. The procedure involves protein precipitation with chloroform and trichloroacetic acid, and purification using methanol. The chromatography was performed using a phenyl-hexyl column (150 × 2.0 mm i.d., 3 µm; Phenomenex) with a mobile phase consisting of 5 mM ammonium formate (pH 3.0) and acetonitrile. Multiple reaction monitoring was used for quantification. The assay was linear over a concentration range of 4-500 ng/mL for rocuronium with R(2) ≥ 0.998. The recoveries for this compound ranged from 96.0 to 109.1%. The intra-day and inter-day precision was less than 10.5% and the accuracy ranged from 106.6 to 114.9%. The validated method was applied to quantify the content of rocuronium in blood and a variety of tissues of a victim suspected of overdose. In conclusion, the method was successfully applied for the analysis of rocuronium in biological samples for forensic toxicology.

Comparison of the variability of the onset and recovery from neuromuscular blockade with cisatracurium versus rocuronium in elderly patients under total intravenous anesthesia

This study was designed to compare the variability of the onset and offset of the effect of two neuromuscular blocking drugs with different elimination pathways in adult and elderly patients during total intravenous anesthesia (TIVA). After Ethics Committee approval and patients’ informed consent, the drugs were compared in 40 adult and 40 elderly patients scheduled for elective surgery under TIVA with tracheal intubation who were randomized to receive a single bolus dose of 0.15 mg/kg cisatracurium or 0.9 mg/kg rocuronium. The time of onset of maximum depression, duration of action, and recovery index time were measured and recorded for each patient and variability is reported as means ± standard deviation. Time of onset was significantly shorter for rocuronium than cisatracurium for the adult and elderly groups (P = 0.000), but the variability of cisatracurium was significantly greater compared with rocuronium for the same age groups (93.25 vs 37.01 s in the adult group and 64.56 vs 33.75 s in the elderly group; P = 0.000). The duration of the effect in the elderly group receiving rocuronium was significantly longer than in the elderly group receiving cisatracurium, and the variability of the duration was significantly greater in the rocuronium group than in the cisatracurium group. Mean time of recovery was significantly longer for the elderly group receiving rocuronium than for the elderly group receiving cisatracurium (P = 0.022), and variability was also greater (P = 0.002). Both drugs favored good intubating conditions. In conclusion, cisatracurium showed less variability in these parameters than rocuronium, especially in the elderly, a fact that may be of particular clinical interest.