Corrigendum to "Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study" [BJA Open 8 (2023) 100236].

[This corrects the article DOI: 10.1016/j.bjao.2023.100236.].

Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study.

Background: International guidelines recommend quantitative neuromuscular monitoring when administering neuromuscular blocking agents. The train-of-four count is important for determining the depth of block and appropriate reversal agents and doses. However, identifying valid compound motor action potentials (cMAPs) during surgery can be challenging because of low-amplitude signals and an inability to observe motor responses. A convolutional neural network (CNN) to classify cMAPs as valid or not might improve the accuracy of such determinations. Methods: We modified a high-accuracy CNN originally developed to identify handwritten numbers. For training, we used digitised electromyograph waveforms (TetraGraph) from a previous study of 29 patients and tuned the model parameters using leave-one-out cross-validation. External validation used a dataset of 19 patients from another study with the same neuromuscular block monitor but with different patient, surgical, and protocol characteristics. All patients underwent ulnar nerve stimulation at the wrist and the surface electromyogram was recorded from the adductor pollicis muscle. Results: The tuned CNN performed highly on the validation dataset, with an accuracy of 0.9997 (99% confidence interval 0.9994-0.9999) and F1 score=0.9998. Performance was equally good for classifying the four individual responses in the train-of-four sequence. The calibration plot showed excellent agreement between the predicted probabilities and the actual prevalence of valid cMAPs. Ten-fold cross-validation using all data showed similar high performance. Conclusions: The CNN distinguished valid cMAPs from artifacts after ulnar nerve stimulation at the wrist with >99.5% accuracy. Incorporation of such a process within quantitative electromyographic neuromuscular block monitors is feasible.

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision.

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

Ipsilateral and Simultaneous Comparison of Responses from Acceleromyography- and Electromyography-based Neuromuscular Monitors.

BACKGROUND: The paucity of easy-to-use, reliable objective neuromuscular monitors is an obstacle to universal adoption of routine neuromuscular monitoring. Electromyography (EMG) has been proposed as the optimal neuromuscular monitoring technology since it addresses several acceleromyography limitations. This clinical study compared simultaneous neuromuscular responses recorded from induction of neuromuscular block until recovery using the acceleromyography-based TOF-Watch SX and EMG-based TetraGraph. METHODS: Fifty consenting patients participated. The acceleromyography and EMG devices analyzed simultaneous contractions (acceleromyography) and muscle action potentials (EMG) from the adductor pollicis muscle by synchronization via fiber optic cable link. Bland-Altman analysis described the agreement between devices during distinct phases of neuromuscular block. The primary endpoint was agreement of acceleromyography- and EMG-derived normalized train-of-four ratios greater than or equal to 80%. Secondary endpoints were agreement in the recovery train-of-four ratio range less than 80% and agreement of baseline train-of-four ratios between the devices. RESULTS: Acceleromyography showed normalized train-of-four ratio greater than or equal to 80% earlier than EMG. When acceleromyography showed train-of-four ratio greater than or equal to 80% (n = 2,929), the bias was 1.3 toward acceleromyography (limits of agreement, -14.0 to 16.6). When EMG showed train-of-four ratio greater than or equal to 80% (n = 2,284), the bias was -0.5 toward EMG (-14.7 to 13.6). In the acceleromyography range train-of-four ratio less than 80% (n = 2,802), the bias was 2.1 (-16.1 to 20.2), and in the EMG range train-of-four ratio less than 80% (n = 3,447), it was 2.6 (-14.4 to 19.6). Baseline train-of-four ratios were higher and more variable with acceleromyography than with EMG. CONCLUSIONS: Bias was lower than in previous studies. Limits of agreement were wider than expected because acceleromyography readings varied more than EMG both at baseline and during recovery. The EMG-based monitor had higher precision and greater repeatability than acceleromyography. This difference between monitors was even greater when EMG data were compared to raw (nonnormalized) acceleromyography measurements. The EMG monitor is a better indicator of adequate recovery from neuromuscular block and readiness for safe tracheal extubation than the acceleromyography monitor.

Comparison of the TetraGraph and TOFscan for monitoring recovery from neuromuscular blockade in the Post Anesthesia Care Unit.

STUDY OBJECTIVE: Comparison of the TetraGraph (TG) and TOFscan (TS) for monitoring recovery from neuromuscular blockade in the Post Anesthesia Care Unit (PACU). DESIGN: Randomized, multicenter trial. SETTING: PACU in three tertiary care hospitals. PATIENTS: 120 patients (40 per site) receiving neuromuscular blockade during elective surgery. INTERVENTIONS: Patients were enrolled preoperatively and intraoperative neuromuscular blockade management was at the discretion of the anesthesiologist. Upon arrival to the PACU, patients were randomized to have either TG or TS placed on their dominant hand. The alternate device (TS or TG) was placed on the non-dominant hand. Following simultaneous ulnar nerve stimulation on each arm, the response of the adductor pollicis was measured. MEASUREMENTS: Train-of-four ratios (TOFRs) were obtained upon arrival to the PACU (t = 0), after 5 min (t = + 5) and after +10 min (t = + 10). MAIN RESULTS: There was there was no significant difference in the mean TOFRs obtained with the TG and TS at t = 0 (0.97 ± 0.18 vs 0.94 ± 0.13, P = 0.06, respectively) and t = + 5 (0.96 ± 0.20 vs 0.95 ± 0.12, P = 0.29, respectively). At (t = + 10), there was a statistically significant difference in mean TOFRs obtained with the TG and TS, (0.99 ± 0.14 vs 0.94 ± 0.12, P < 0.001, respectively). The bias between devices at t = 0 was estimated to be 0.03 (95% CI, -0.29 to 0.35, P = 0.26); at t = + 5 min, it was estimated to be 0.02 (95% CI, -0.36 to 0.40, P = 0.54); and at t = +10 min, it was estimated to be 0.05 (95% CI, -0.25 to 0.36, P = 0.77). CONCLUSIONS: TS and TG provide interchangeable quantitative measurements once the TOF ratio has returned to a value of 0.90 or greater in the PACU.

Awake Volunteer Pain Scores During Neuromuscular Monitoring.

BACKGROUND: There is a need for easy to use, reliable neuromuscular monitors (NMMs). This multicenter, prospective, unblinded study compared the discomfort associated with neurostimulation in unmedicated healthy volunteers when using the new electromyography (EMG)-based TetraGraph and acceleromyography (AMG)-based TOF-Watch NMMs. The secondary aim was to compare the repeatability of the train-of-four (TOF) ratios (TOFRs) obtained with the 2 devices. METHODS: The TOF measurements of 135 volunteers from 3 university hospitals were analyzed (age: 38.3 ± 12 years [mean ± standard deviation [SD]]; male/female ratio = 63:72). The left or right ulnar nerve was stimulated at the wrist in TOF mode with 20, 30, 40, and 50 mA stimulating current intensities with both devices in random order. The TOF-Watch used standard electrocardiography (ECG) electrodes (Red Dot; 3M Health Care) for nerve stimulation. The stimulating surface area of 1 ECG electrode is 113 mm. The piezoelectric probe was attached to the thumb, and a hand adapter was used to ensure consistency of AMG measurements. The TetraGraph uses proprietary surface strip electrodes for nerve stimulation and muscle action potential recording, whose stimulating surface area is roughly twice as big as that of standard ECG electrodes (228.5 mm). The volunteers were asked to rate the discomfort associated with neurostimulation on a 0-10 verbal numerical rating scale (VNRS) score anchored with 0 (no pain) and 10 (worst pain ever experienced). A linear mixed-effects model was used to evaluate the difference in VNRS scores between devices. P <.05 was accepted as the level of significance. RESULTS: In the linear mixed-effects model, there were no differences in VNRS scores between devices at any of the stimulating current intensities, P = .38. The median (range) VNRS scores obtained with TOF-Watch and TetraGraph devices were 2 (0-7) vs 2 (0-8) at 20 mA, 3 (1-9) vs 3 (1-9) at 30 mA, 5 (1-10) vs 5 (1-10) at 40 mA, and 5 (1-10) vs 6 (1-10) at 50 mA stimulating current intensities. The mean of the 1469 TOFRs obtained with TetraGraph was 100.43% ± 7.74% (standard error = 0.2%). Due to technical difficulties, the repeatability of the TOFRs could not be determined. CONCLUSIONS: Despite the different size and design of the stimulating electrodes, the 2 NMMs caused the same level of discomfort in unmedicated healthy volunteers.

International survey of neuromuscular monitoring in two European countries: a questionnaire study among Hungarian and Romanian anaesthesiologists.

BACKGROUND: Accumulating evidence indicates that objective neuromuscular monitoring and pharmacological reversal of neuromuscular block reduces the occurrence of residual muscle paralysis in the acute postoperative phase. However, objective neuromuscular monitoring is not a routine habit in anaesthesia. In order to change this situation, we wished to find out, as a first step to improvement, the current use of neuromuscular monitors and the custom of anaesthetists for reversal of neuromuscular block before tracheal extubation. METHODS: A ten-point questionnaire was available via the Surveymonkey website and the link was sent to 2202 Hungarian and Romanian anaesthetists by email. RESULTS: Three hundred and two (13.7%) of the 2202 registered anaesthetists responded. Less than 10% of them regularly use neuromuscular monitors. They underestimated the occurrence of residual block; only 2.2% gave a correct answer. Neuromuscular monitors are available in 74% of hospitals but are scarcely used. One third of anaesthetists rarely or never use reversal; approximately 20% regularly reverse before extubation. The responders typically believe that clinical signs of residual block are reliable. Instead of monitoring, they use the "timing methods" for tracheal extubation such as time elapsed from last dose, the duration of action of relaxant, the number of top-up doses, the cumulative dose, the return of adequate respiratory tidal volume and the ability to sustain a 5 s head lift. CONCLUSIONS: We concluded that neuromuscular monitoring in these two European countries is suboptimal as is the reversal strategy. Given the fact that monitors are available in the hospitals, the mentality should be changed towards evidence based practice.

Reversal of Deep Pipecuronium-Induced Neuromuscular Block With Moderate Versus Standard Dose of Sugammadex: A Randomized, Double-Blind, Noninferiority Trial.

BACKGROUND: Certain surgical interventions may require a deep neuromuscular block (NMB). Reversal of such a block before tracheal extubation is challenging. Because anticholinesterases are ineffective in deep block, sugammadex 4 mg/kg has been recommended for the reversal of rocuronium- or vecuronium-induced deep NMB. However, this recommendation requires opening 2 vials of 200 mg sugammadex, which results in an increase in drug costs. Therefore, we sought a less expensive solution for the induction and reversal of deep NMB. Although the optimal dose of sugammadex for antagonism of deep block from pipecuronium has not been established, data pertaining to moderate block are available. Accordingly, we hypothesized that sugammadex 2 mg/kg would be a proper dose to reverse deep pipecuronium block, enabling us to avoid cost increases. In the present study, we compared sugammadex 2 mg/kg with the standard dose of 4 mg/kg for reversal of deep block from pipecuronium. METHODS: This single-center, randomized, double-blind, 2 parallel-arms, noninferiority study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX). Noninferiority margin was specified beforehand as an increase in reversal time of no >10% (corresponding to 1 minute for the primary outcome). When the block spontaneously recovered to posttetanic count 1, the patients randomly received sugammadex 2 or 4 mg/kg, and the time from the injection to the train-of-four (TOF) ratio of 1.0 was measured. Primary outcome was the time to achieve the normalized TOF ratio of 0.9 in a particular patient. Residual or recurrent postoperative NMB was additional end point. RESULTS: Each patient recovered to the normalized TOF ratio of 0.9. In the 2 mg/kg group, reversal time was 1.73 ± 1.03 minutes (95% confidence interval [CI], 1.33-2.13; n = 25), and in the 4 mg/kg group, reversal time was 1.42 ± 0.63 minutes (mean ± standard deviation) (95% CI, 1.17-1.67; n = 25). The mean difference in reversal times between the 2 groups was 0.31 minutes (95% CI, -0.18 to 0.8), and the upper limit of CI was below the noninferiority margin of 1 minute. Postoperative block did not occur. CONCLUSIONS: The effect of sugammadex 2 mg/kg was noninferior to that of 4 mg/kg in reversing posttetanic count-1 degree pipecuronium block. Sugammadex reversal of deep pipecuronium block appears to be effective.

Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model: Correlation with physicochemical features and clinical information.

The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions (HSRs) known as complement (C) activation-related pseudoallergy (CARPA). In order to explore the roles of iron core composition and particle surface coating in SPION-induced CARPA, we measured C activation by 6 different SPIONs in a human serum that is known to react to nanoparticles (NPs) with strong C activation. Remarkably, only the carboxymethyldextran-coated (ferucarbotran, Resosvist®) and dextran-coated (ferumoxtran-10, Sinerem®) SPIONs caused significant C activation, while the citric acid, phosphatidylcholine, starch and chitosan-coated SPIONs had no such effect. Focusing on Resovist and Sinerem, we found Sinerem to be a stronger activator of C than Resovist, although the individual variation in 15 different human sera was substantial. Further analysis of C activation by Sinerem indicated biphasic dose dependence and significant production of C split product Bb but not C4d, attesting to alternative pathway C activation only at low doses. Consistent with the strong C activation by Sinerem and previous reports of HSRs in man, injection of Sinerem in a pig led to dose-dependent CARPA, while Resovist was reaction-free. Using nanoparticle tracking analysis, it was further determined that Sinerem, more than Resovist, displayed multimodal size distribution and significant fraction of aggregates - factors which are known to promote C activation and CARPA. Taken together, our findings offer physicochemical insight into how key compositional factors and nanoparticle size distribution affect SPION-induced CARPA, a knowledge that could lead to the development of SPIONs with improved safety profiles.

Reversal of Vecuronium-induced Neuromuscular Blockade with Low-dose Sugammadex at Train-of-four Count of Four: A Randomized Controlled Trial.

BACKGROUND: Rocuronium-induced neuromuscular block that spontaneously recovered to a train-of-four count of four can be reversed with sugammadex 0.5 or 1.0 mg/kg. We investigated whether these doses of sugammadex can also reverse vecuronium at a similar level of block. METHODS: Sixty-five patients were randomly assigned, and 64 were analyzed in this controlled, superiority study. Participants received general anesthesia with propofol, sevoflurane, fentanyl, and vecuronium. Measurement of neuromuscular function was performed with acceleromyography (TOF-Watch-SX, Organon Teknika B.V., The Netherlands ). Once the block recovered spontaneously to four twitches in response to train-of-four stimulation, patients were randomly assigned to receive sugammadex 0.5, 1.0, or 2.0 mg/kg; neostigmine 0.05 mg/kg; or placebo. Time from study drug injection to normalized train-of-four ratio 0.9 and the incidence of incomplete reversal within 30 min were the primary outcome variables. Secondary outcome was the incidence of reparalysis (normalized train-of-four ratio less than 0.9). RESULTS: Sugammadex, in doses of 1.0 and 2.0 mg/kg, reversed a threshold train-of-four count of four to normalized train-of-four ratio of 0.9 or higher in all patients in 4.4 ± 2.3 min (mean ± SD) and 2.6 ± 1.6 min, respectively. Sugammadex 0.5 mg/kg reversed the block in 6.8 ± 4.1 min in 70% of patients (P < 0.0001 vs. 1.0 and 2.0 mg/kg), whereas neostigmine produced reversal in 11.3 ± 9.7 min in 77% of patients (P > 0.05 vs. sugammadex 0.5 mg/kg). The overall frequency of reparalysis was 18.7%, but this incidence varied from group to group. CONCLUSIONS: Sugammadex 1.0 mg/kg, unlike 0.5 mg/kg, properly reversed a threshold train-of-four count of four vecuronium-induced block but did not prevent reparalysis.

Impact of reversal strategies on the incidence of postoperative residual paralysis after rocuronium relaxation without neuromuscular monitoring: A partially randomised placebo controlled trial.

BACKGROUND: Electronic neuromuscular monitoring is not widely used to determine either the reversal requirements for neuromuscular block before extubation of the trachea, or to determine if there is any subsequent postoperative residual neuromuscular block (PORNB). OBJECTIVES: To investigate the incidence of PORNB using acceleromyography after spontaneous recovery of rocuronium-induced block and to compare this with the administration of sugammadex, neostigmine or a placebo. DESIGN: Partially randomised, partially randomised, placebo-controlled, double-blind, four-group parallel-arm study. SETTING: Single-centre study performed between October 2013 and December 2015 in a university hospital. PATIENTS: Of the 134 eligible patients, 128 gave their consent and 125 of these completed the study. INTERVENTIONS: Patients received general anaesthesia with propofol, sevoflurane, fentanyl and rocuronium. Neuromuscular transmission was measured by acceleromyography (TOF-Watch-SX; Organon Teknika B.V., Boxtel, the Netherlands) but the anaesthetist was blind to the results. If the anaesthetist deemed pharmacological reversal to be necessary before extubation of the trachea then patients were assigned randomly to receive either sugammadex (2.0 mg kg), neostigmine (0.05 mg kg) or a placebo. In the postanaesthesia care unit, an independent anaesthetist, unaware of the treatment given, assessed the neuromuscular function using acceleromyography. MAIN OUTCOME MEASURES: The incidence of a normalised train-of-four ratio less than 0.9 on arrival in the recovery room. RESULTS: In total, 125 patients were recruited. Neuromuscular block was allowed to recover spontaneously in 50 patients, whereas the remainder received either sugammadex (27), neostigmine (26) or placebo (22). The number of cases with PORNB were one (3.7%), four (15%), 13 (26%) and 10 (45%) after sugammadex, neostigmine, spontaneous recovery and placebo, respectively. Sugammadex and neostigmine were more effective than placebo [odds ratio (OR): 0.05, 95% confidence interval (CI): 0.005 to 0.403, P = 0.005; OR: 0.22, 95% CI: 0.056 to 0.85, P = 0.028, respectively]. Sugammadex performed better than spontaneous recovery (OR: 0.11, 95% CI: 0.014 to 0.89, P = 0.039) unlike neostigmine (OR: 0.52, 95% CI: 0.15 to 1.79, P = 0.297). Yet, antagonism (pooled data) was more effective than spontaneous recovery (OR: 0.3, 95% CI: 0.1 to 0.9, P = 0.03). CONCLUSION: Although pharmacological reversal based on clinical signs was superior to spontaneous recovery it did not prevent PORNB, irrespective of the reversal agent. TRIAL REGISTRATION: The study is registered under EUDRACT number 2013-001965-17.

Residual neuromuscular blockade: management and impact on postoperative pulmonary outcome.

PURPOSE OF REVIEW: To revise the current literature on concepts for neuromuscular block management. Moreover, consequences of incomplete neuromuscular recovery on patients' postoperative pulmonary outcome are evaluated as well. RECENT FINDINGS: The incidence of residual paralysis may be as high as 70% and even small degrees of residual paralysis may have clinical consequences. Neostigmine should not be given before return of the fourth response of the train-of-four-stimulation and no more than 40-50 µg/kg should be given. Sugammadex acts more rapidly and more predictably than neostigmine. Finally, there is convincing evidence in the literature that incomplete neuromuscular recovery may lead to a poor postoperative pulmonary outcome. SUMMARY: New evidence has emerged about the pathophysiological implications of incomplete neuromuscular recovery. Not only are the pulmonary muscles functionally impaired, but respiratory control is also affected. Residual paralysis endangers the coordination of the pharyngeal muscles and the integrity of the upper airway. However, neuromuscular monitoring and whenever needed pharmacological reversal prevent residual paralysis.

Reversal of Pipecuronium-Induced Moderate Neuromuscular Block with Sugammadex in the Presence of a Sevoflurane Anesthetic: A Randomized Trial.

BACKGROUND: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding γ-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal. METHODS: This single-center, randomized, double-blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed. RESULTS: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed. CONCLUSIONS: Sugammadex adequately and rapidly reverses pipecuronium-induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB.

Assessment of severity and time course of critical illness neuropathy in septic patients: a prospective observational study.

OBJECTIVE: In this prospective observational study we investigated electrophysiological alterations in the early phase of critical illness and correlated electrophysiological findings with the clinical picture and outcome. METHODS: We enrolled 21 critically ill surgical patients having ≥ 12 Acute Physiology and Chronic Health Evaluation (APACHE) II scores on admission. Routine non-invasive bilateral electroneurography (ENG) examination of median and ulnar nerves was done on five consecutive days starting in two days after admission. Then weekly follow-up was performed. Motor and sensory nerve conduction indices were calculated and correlated with APACHE II and Simplified Acute Physiology Score II severity scores. RESULTS: On the first examination 18/21 patients had > 20% reduction in the motor and sensory nerve conduction indices. Severity score systems showed significant negative correlation with the daily change of CMAP and SNAP amplitudes and calculated nerve conduction indices (Spearman's correlation, p < 0.001). Mortality was higher in the patients with worse admission ENG and/or stagnant electrophysiological status or declining tendency in the first week. CONCLUSIONS: Electrophysiological alterations appeared soon after the development of critical illness. Early phase alterations showed a strong correlation with patients' general condition and more severe electrophysiological alterations predisposed to higher mortality. In several cases early alterations proved to be reversible.

Non-invasive pulse wave analysis for monitoring the cardiovascular effects of CO2 pneumoperitoneum during laparoscopic cholecystectomy--a prospective case-series study.

BACKGROUND: Peritoneal insufflation results in hemodynamic changes during laparoscopic cholecystectomy. The aim of the present work is to test whether non-invasive applanation tonometry is suitable for reflecting these hemodynamic alterations. METHODS: 41 patients undergoing laparoscopic cholecystectomies were monitored using the SphygmoCor pulse wave analysing system. Peripheral blood pressures (PBP), central aortic blood pressures (CBP), augmentation index (ALX@HR75) and subendocardial viability ratio (SVR) were measured at rest (Phase 1), after anesthetic induction (Phase 2), after peritoneal inflation (Phase 3) and after peritoneal deflation (Phase 4). RESULTS: Induction of anesthesia resulted in a statistically significant reduction in both the peripheral blood pressure and central aortic pressures, accompanied by a decrease in augmentation pressure and augmentation index. Peripheral blood pressures did not change along with the peritoneal cavity insufflation, except for a moderate increase in systolic blood pressure. In contrast to this, an increase could be observed in central aortic pressure (106.77 ± 18.78 vs. 118.05 ± 19.85 mmHg, P < 0.01) which was accompanied by increased augementation pressure (18.97 ± 10.80 vs. 31.55 ± 12.01; P < 0.001) and augmentation index (7.31 ± 5.59 vs. 12.61 ± 7.56, P < 0.001), indicating a rise in peripheral arterial stiffness. CONCLUSIONS: The Sphigmocor pulse wave analysis system can be reliably used for detecting and monitoring cardiovascular changes occurring during laparoscopic cholecystectomy.

Features of complement activation-related pseudoallergy to liposomes with different surface charge and PEGylation: comparison of the porcine and rat responses.

Pigs are known to provide a sensitive model for studying complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction to liposomal and many other nanomedicines that limits their clinical use. The utility of rats as a CARPA model has, however, not been analyzed to date in detail. The present study compared the two models by inducing CARPA with i.v. bolus injections of two reactogenic liposomes that differed from each other in surface properties: one was AmBisome, a strong anionic, free-surface small unilamellar liposome (SUV), while the other was neutral, polyethylene glycol (PEG)-grafted SUV wherein the 2 kDa-PEG was anchored to the membrane via cholesterol (Chol-PEG). Both in pigs and rats AmBisome caused significant consumption of C3, indicating C activation, along with paralleling massive changes in blood pressure, white blood cell, platelet counts and in plasma thromboxane B2 levels, indicating CARPA. These processes were similar in the two species in terms of kinetics, but significantly differed in the doses that caused major hemodynamic changes (~0.01 and ~22 mg phospholipid (PL)/kg in pigs and rats, respectively). Pigs responded to AmBisome with pulmonary hypertension and systemic hypotension, and the reaction was not tachyphylactic. The major response of rats was systemic hypotension, leukopenia followed by leukocytosis, and thrombocytopenia. Chol-PEG liposomes caused severe reaction in pigs at 0.1 mg/kg, while the reaction they caused in rats was mild even at 300 mg PL/kg. Importantly, the reaction to Chol-PEG in pigs was partly tachyphylactic. These observations highlight fundamental differences in the immune mechanisms of porcine and rat CARPA, and also show a major impact of liposome surface characteristics, determining the presence or absence of tachyphylaxis. The data suggest that rats are 2-3 orders of magnitude less sensitive to liposomal CARPA than pigs; however, the causes of these differences, the PEG-dependent tachyphylaxis and the massive reactivity of Chol-PEG liposomes remain unclear.

Hemocompatibility assessment of two siRNA nanocarrier formulations.

PURPOSE: Since the discovery of RNAi and its therapeutic potential, carrier systems have been developed to deliver small RNAs (particularly siRNA) for modulation of gene expression at the post-transcriptional level. An important factor determining the fate and usability of these systems in vivo is interaction with blood components, blood cells, and the immune system. In this study, a lipid-based and a polymer-based carrier system containing siRNA have been investigated in vitro in terms of their hemocompatibility. METHODS: The nanocomplexes studied were Angiplex, a targeted lipid-based system, and pHPMA-MPPM polyplex, a formulation based on a cationic polymer. siVEGFR-2 was encapsulated in both carriers and activation of platelets, coagulation, and complement cascade as well as induction of platelet aggregation were evaluated in vitro. RESULTS: Both systems had been shown before to cause significant silencing in vitro. Our findings indicated that pHPMA-MPPM polyplex triggered high platelet activation and aggregation although it did not stimulate coagulation substantially. Angiplex, on the other hand, provoked insignificant activation and aggregation of platelets and activated coagulation minimally. Complement system activation by Angiplex was in general low but stronger than pHPMA-MPPM polyplex. CONCLUSIONS: Taken together, these in vitro assays may help the selection of suitable carriers for systemic delivery of siRNA in early preclinical investigations and reduce the use of laboratory animals significantly.