Article

Monitoring of intense neuromuscular blockade in a pig model

Authors:
  • University of Copenhagen and Odense University Hospital
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Abstract

Intense neuromuscular blockade (NMB) measured by post tetanic count (PTC) was monitored, reversed and verified in this pig model. In a cross-over assessor blinded design six pigs were randomized to either no NMB followed by intense NMB, or intense NMB followed by no NMB. Neuromuscular measurements were performed with acceleromyography [train-of-four (TOF) Watch SX]. In all pigs, the response to TOF nerve stimulation was stable and intense NMB (PTC 0-1) was established with rocuronium 3 mg/kg. For reversal, the pigs received sugammadex 20-35 mg/kg and returned to TOF-ratio above 0.90 within 2.15 min after injection. We established a pig model for monitoring intense NMB with surface stimulation electrodes and acceleromyography. We verified total relaxation of the diaphragm and the abdominal muscles at the PTC 0-1 by suction test and with surface electromyography. This pig model is suitable for studies with experimental abdominal surgery with monitoring of intense NMB, and where relaxation of the diaphragm and the abdominal muscles are required.

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... Dedicated monitoring equipment objectively assesses the degree of neuromuscular blockade and aid in correct administration. Different neuromuscular monitoring setups are available, and most often, it involves fixating a limb and avoiding any manipulation of the animal's leg [8,9]. Although monitoring is possible, NMBAs are rarely objectively monitored and often administered to clinically apparent effect in pigs [1]. ...
... Neuromuscular monitoring was performed according to international guidelines for good clinical research practice in pharmacodynamic studies of NMBAs [19] except for calibration of twitch height, which is not necessary with the Stimpod NMS450X. Fixation and electrode placement were modified from Madsen et al. [8] and refined during pilot studies to ensure a stable TOF ratio baseline. The skin was cleansed, shaved, and rubbed with 85% ethanol. ...
... To disclose whether ketamine supplementation introduces significant variation in the neuromuscular recovery time, such interactions should be further investigated in the relevant species. Moreover, we investigated the neuromuscular recovery of the thoracic limb measured by acceleromyography according to Madsen et al. [8]. However, when investigating neuromuscular recovery in future studies, it is also advisable to take into account that different NMUs have different sensitivity to NMBAs and are accordingly more or less relevant for RNMB. ...
Article
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Background Neuromuscular blocking agents are frequently administered to pigs used for research. In humans, administration of the drugs is not without risk and may result in accidental awareness under general anaesthesia and postoperative residual neuromuscular blockade that can lead to serious respiratory complications. Despite the extensive administration, the pharmacodynamics of neuromuscular blocking agents are not thoroughly studied in pigs. Therefore, this study investigates the neuromuscular response of two infusion rates of rocuronium, a commonly used non-depolarizing neuromuscular blocking agent. A group of 14 female Danish Landrace-Yorkshire-Duroc pigs used for supervised surgical training, weighing 40.3 ± 2.1 kg (mean ± SD), were included in the study. They received a loading dose of 0.85 mg/kg rocuronium intravenously followed by infusion of either 2.5 mg/kg/hour (L, low dose) or 5 mg/kg/hour (H, high dose) rocuronium for 30 min. Neuromuscular monitoring was performed with acceleromyography using train-of-four (TOF) stimulation. Onset time, time to reappearance of T1, T4, TOF ratio 90% and 100% were recorded. Results All pigs in group H experienced loss of T1 throughout rocuronium infusion, whereas six out of seven pigs in group L had reappearance of T1 during rocuronium infusion, with additional reappearance of T4 in three of these pigs. The time to recovery of TOF ratio 90% was 14.0 ± 5.4 (L) and 21.7 ± 6.1 (H) minutes and recovery to TOF ratio 100% was 18.7 ± 6.5 (L) and 27.9 ± 9.2 min (H) (mean ± SD). Substantial inter-animal variation in neuromuscular recovery time was observed. Conclusion The large inter-animal variation in pharmacodynamic profiles emphasizes that individual neuromuscular monitoring and titration to effect should be used routinely in research protocols that include rocuronium. In addition to other important measures, these actions are key in order to avoid overdosing and limit the risk of residual neuromuscular blockade.
... After the pigs were positioned, the right forelimb was extended horizontally and strapped on a box, to avoid excessive movement of the limb, as described by Madsen et al. (2014). The hoof was allowed to move freely. ...
... AMG is, nowadays, one of the most used methods in neuromuscular blockade monitoring, although mechanomyography is still considered the gold standard(Fuchs-Buder, Schreiber, & Meinstelman, 2009). In the present study, AMG was used to establish the time profile of cisatracurium in the pig due to its ease of use for research purposes obtaining objective and repeatable measurements(Madsen et al., 2014). The recovery point was fixed in a TOFR ≥ 90% to avoid postanaesthetic complications and allow for a full recovery of the laryngeal muscles as recommended in human medicine(Fuchs-Buder et al., 2007).The ulnar nerve was used for electrical stimulation as described byMadsen et al. (2014). ...
... In the present study, AMG was used to establish the time profile of cisatracurium in the pig due to its ease of use for research purposes obtaining objective and repeatable measurements(Madsen et al., 2014). The recovery point was fixed in a TOFR ≥ 90% to avoid postanaesthetic complications and allow for a full recovery of the laryngeal muscles as recommended in human medicine(Fuchs-Buder et al., 2007).The ulnar nerve was used for electrical stimulation as described byMadsen et al. (2014). This monitoring site allowed for repeatable measurements without the possibility of inadvertent movements of the limb as it was fixed in a box. ...
Article
Neuromuscular blocking agents should be included as part of a balanced anaesthetic protocol to improve anaesthetic management, although doses are not always established for each species. Cis‐atracurium is a benzylisoquinolinium neuromuscular blocking agent with an intermediate duration of action devoid of significant adverse effects previously used in pigs with a wide dosage range. Cis‐atracurium was administered at 1 mg/kg bolus to sixteen pigs to establish its time profile and effects. The pigs were premedicated intramuscularly with 4 mg/kg azaperone, 8 mg/kg ketamine and 0.2 mg/kg morphine IM and maintained with isoflurane in oxygen. After cis‐atracurium administration, neuromuscular monitoring via acceleromyography was started until the recovery of the 90% of the train of four ratio. Complete decrease in the train of four ratio was accomplished in eleven pigs. Onset of action was 70 s, with a recovery of the fourth twitch at 26 min and a recovery of a train of four ratio greater than 90% in 60 min. In conclusion, 1 mg/kg intravenous cis‐atracurium in the pig allowed for a rapid onset of action and a complete recovery after 60 min although high variability in the time profile is seen.
... The TOF is the most commonly used electrical stimulation pattern and has already been described in experimental pigs (Madsen et al. 2014). Mechanomyography is the gold standard in assessing NMB. ...
... The decision to use AMG was based on previous findings that tactile assessment, compared with AMG assessment, may provide inaccurate measurements (Greer et al. 1998). The use of elastic preload (a rubber band that partially immobilizes the limb) has been proved to reduce variability in AMG measurements in humans and pigs (Fuchs-Buder et al. 2007;Madsen et al. 2014). Unfortunately, elastic preload had not been used in the present study and this needs to be acknowledged as a limitation. ...
... Owing to limited access to the patient, the decision to use the superficial peroneal nerve for electrical stimulation was taken, although Madsen et al. (2014) described and validated a different stimulation site in pigs. Superficial peroneal nerve stimulation is frequently used on different domestic species due to its easy access and was already described in pigs (Veres-Ny eki et al. 2012). ...
Article
Objective: To determine the dose of cis-atracurium needed to produce a moderate neuromuscular blockade (NMB) in pigs. Study design: Prospective experimental study. Animals: Seven pigs [five females and two males; median (range) body weight: 47 (36-64) kg]. Methods: Pigs were premedicated with intramuscular midazolam (0.3 mg kg(-1)) and ketamine (7 mg kg(-1)). Anaesthesia was induced with intravenous (IV) propofol 3 (1-4) mg kg(-1) and maintained with isoflurane in oxygen. Based on a preliminary study, the subjects were administered 0.3 mg kg(-1) cis-atracurium followed by 0.48 mg kg(-1) hour(-1) constant rate infusion (CRI) IV. A moderate NMB was defined as a train-of-four (TOF) count of ≤2 by acceleromyography. When the TOF count was >2, 0.1 mg kg(-1) cis-atracurium was administered and the CRI was increased. The cis-atracurium CRI was decreased when the TOF count was under 2 for more than 15 minutes. The total dose of cis-atracurium required to maintain a moderate NMB was calculated as the total amount of cis-atracurium used (both CRI and supplementary boluses) divided by the administration time. Results: The cis-atracurium CRI lasted for 87 (76-151) minutes. To induce and maintain a moderate neuromuscular blockade, the initial dose of cis-atracurium was 0.3 (0.3- 0.5) mg kg(-1) and the CRI was 0.71 (0.37-0.98) mg kg(-1) hour(-1). Conclusions and clinical relevance: The doses described in our study may help researchers obtain a moderate NMB using cis-atracurium in pigs.
... The use of non-depolarizing neuromuscular blocking agents (NMBAs) is common during experimental laparoscopic procedures in swine [1][2][3][4][5]. Acceleromyography to measure the train of four ratio (TOFR) has recently been described to monitor neuromuscular blockade (NMB) in pigs [5]. ...
... The use of non-depolarizing neuromuscular blocking agents (NMBAs) is common during experimental laparoscopic procedures in swine [1][2][3][4][5]. Acceleromyography to measure the train of four ratio (TOFR) has recently been described to monitor neuromuscular blockade (NMB) in pigs [5]. During pneumoperitoneum the insufflation of carbon dioxide (CO 2 ) into the abdominal cavity leads to gas absorption and hence hypercapnic acidemia that may not be controlled with mechanical ventilation [1,4,6]. ...
Article
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Neuromuscular blocking agents (NMBAs) are commonly used in experimental laparoscopy in swine undergoing carbon dioxide pneumoperitoneum. Hypercapnia may be present and may prolong NMBAs’ pharmacologic activity. The aim of this study is to evaluate the effect of permissive hypercapnia on the neuromuscular blockade of atracurium in swine. Six Large White swine weighing 30.5 ± 1.6 kg were sedated with intramuscular ketamine and medetomidine, after which anaesthesia was induced with propofol and maintained with sevoflurane. Atracurium 0.4 mg/kg was administered intravenously and the neuromuscular block monitored by acceleromyography during normocapnic and hypercapnic conditions (PaCO2 range 35–45 mmHg and 60–70 mmHg, respectively). Onset time and time to reach a train of four ratio (TOFR) of 0.7 and 0.9 were recorded. Cardiorespiratory parameters, electrolytes and acid-base status were measured under both conditions. Onset time was similar between the two conditions. Time to reach a TOFR of 0.7 and 0.9 (duration of the neuromuscular block) was longer in hypercapnic compared to normocapnic animals being 1325 ± 300 vs 855 ±111 (p = 0.002) and 1823 ± 434 vs 1218 ± 210 seconds (p = 0.005), respectively. Three hypercapnic swine had a TOF count of 2 and 1 instead of a count of 4 with fade. Permissive hypercapnia was associated with a decrease in pH from 7.444 ± 0.039 to 7.257 ± 0.025 (p < 0.001). No differences were observed for heart rate, end-tidal concentration of sevoflurane, body temperature and arterial haemoglobin saturation. Nonetheless, hypercapnic swine had a statistically significant increase in mean arterial pressure (p = 0.020) and plasma potassium concentration (p = 0.003). The values of PaCO2 achieved during hypercapnia were well tolerated in swine undergoing CO2 pneumoperitoneum for laparoscopy. Permissive hypercapnia increased the duration of the atracurium effect and caused an increase in the intensity of the neuromuscular block in few swine.
... A peripheral nerve stimulator (Ministim, Avanos Medical, Alpharetta, GA) was placed on a distal hindlimb, and neuromuscular measurements were performed via acceleromyography using train-of-four. 23 Adequate depth of anesthesia was assessed by monitoring blood pressure and HR, and bispectral index monitoring was available as a supplement. A Rad-57 pulse oximeter (Massmio, Irvine, CA) was used to measure the noninvasive pulse variability index. ...
Article
Full-text available
The Yorkshire-cross swine model is a valuable translational model commonly used to study cardiovascular physiologyand response to insult. Although the effects of vasoactive medications have been well described in healthy swine, the effects of these medications during hemorrhagic shock are less studied. In this study, we sought to expand the utility of the swine model by characterizing the hemodynamic changes that occurred after the administration of commonly available vasoactive medications during euvolemic and hypovolemic states. To this end, we anesthetized and established femoral arterial,central venous, and pulmonary arterial access in 15 juvenile Yorkshire-cross pigs. The pigs then received a series of rapidlymetabolized but highly vasoactive medications in a standard dosing sequence. After completion of this sequence, each pigunderwent a 30-mL/kg hemorrhage over 10 min, and the standard dosing sequence was repeated. We then used standard statisticaltechniques to compare the effects of these vasoactive medications on a variety of hemodynamic parameters betweenthe euvolemic and hemorrhagic states. All subjects completed the study protocol. The responses in the hemorrhagic state wereoften attenuated or even opposite of those in the euvolemic state. For example, phenylephrine decreased the mean arterialblood pressure during the euvolemic state but increased it in the hemorrhagic state. These results clarify previously poorlydefined responses to commonly used vasoactive agents during the hemorrhagic state in swine. Our findings also demonstratethe need to consider the complex and dynamic physiologic state of hemorrhage when anticipating the effects of vasoactivedrugs and planning study protocols.
... Our results suggest that deep NMB can eliminate reactions caused by surgical stimulation and traction. These findings are consistent with previous work showing that deep NMB (PTC ≤ 1) can inhibit the diaphragm response to tracheal carina stimulation, significantly reducing the incidence of coughing and other adverse events [22,23]. ...
Article
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Background Laparoscopic surgery typically requires deep neuromuscular blockade (NMB), but whether deep or moderate NMB is superior for thoracoscopic surgery remains controversial. Methods Patients scheduled for thoracoscopic lobectomy under intravenous anesthesia were randomly assigned to receive moderate [train of four (TOF) 1–2] or deep NMB [TOF 0, post-tetanic count (PTC) 1–5]. Depth of anesthesia was controlled at a Narcotrend rating of 30 ± 5 in both groups. The primary outcome was the need to use an additional muscle relaxant (cisatracurium) during surgery. Secondary outcomes included surgeon satisfaction, recovery time of each stage after drug withdrawal [time from withdrawal until TOF recovery to 20% (antagonists administration), 25, 75, 90, 100%], blood gas data, VAS pain grade after extubation, the time it takes for patients to begin walking after surgery, postoperative complications and hospitalization time. Results were analyzed on an intention-to-treat basis. Results Thirty patients were enrolled per arm, and all but one patient in each arm was included in the final analysis. Among patients undergoing moderate NMB, surgeons applied additional cisatracurium in 8 patients because of body movement and 5 because of coughing (13/29, 44.8%). Additional cisatracurium was not applied to any of the patients undergoing deep NMB (p < 0.001). Surgeons reported significantly higher satisfaction for patients undergoing deep NMB (p < 0.001, Wilcoxon rank sum test). The mean difference between the two groups in the time from withdrawal until TOF recovery of 25% or 90% was 10 min (p < 0.001). The two groups were similar in other recovery data, blood gas analysis, VAS pain grade, days for beginning to walk and mean hospitalization time. Conclusions Deep NMB can reduce the use of additional muscle relaxant and increase surgeon satisfaction during thoracoscopic lobectomy. Trial registration Chinese Clinical Trial Registry, ChiCTR-IOR-15007117, 22 September 2015.
Article
Purpose: Intense neuromuscular block may improve surgical conditions in ileus laparotomies; however, it is difficult to evaluate. The aim of this study was to investigate if neuromuscular block improved surgical conditions in pigs with artificial ileus laparotomy. Methods: Six pigs were endotracheally intubated, mechanically ventilated, anesthetized with propofol and fentanyl, and randomized into two groups in a cross-over assessor-blinded design. Neuromuscular block was established with rocuronium. Artificial laparotomy for ileus was performed. We investigated the influence of intense neuromuscular block on surgical conditions with a subjective rating scale, force needed to close the fascia, incidences of abdominal contractions while suctioning the lungs, width of the wound diastase and operating time as outcome parameters. Results: In all six pigs no abdominal contractions occurred while suctioning the lungs at intense neuromuscular block. Without neuromuscular block we detected abdominal contractions seen as hiccups and bucking. In all six pigs during intense neuromuscular block we found no visible electromyographic (EMG) activity in the abdominal muscles while suctioning the lungs. Without neuromuscular block suctioning the lungs elicited brief periods of abdominal EMG activity. No difference was found in the force needed to close the fascia when comparing no neuromuscular block with intense neuromuscular block. Furthermore, no significant differences were found in the width of the diastase, operating time and subjective ratings using a four-point rating scale when comparing no neuromuscular block with intense neuromuscular block. However, these outcomes were related to the order of the suturing round. Conclusion: Intense neuromuscular block prevented abdominal muscle contractions but did not influence the force needed to close the fascia.
Article
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TOF-Watch(®) monitors are designed to display train-of-four (TOF) count when neuromuscular block is intense, and to display TOF ratio when it is less intense. In dogs recovering from non-depolarizing neuromuscular block, when all four twitches are easily visible and apparently of similar magnitude, TOF-Watch(®) monitors often display TOF counts and not TOF ratios, as would be expected. We have never encountered this problem when the monitor was calibrated before neuromuscular blocking agent administration. Fourteen healthy female dogs undergoing ovariohysterectomy were investigated. Recovery from neuromuscular block was assessed with a calibrated TOF-Watch SX(®) monitor. When the TOF ratio returned to 90%, the TOF-Watch SX(®) was replaced with an uncalibrated TOF-Watch(®) monitor. The output obtained from the uncalibrated TOF-Watch(®) was compared with that of the calibrated device. The median TOF ratio measured by the calibrated TOF-Watch SX(®) unit at recovery was 91 (86-100)% (n=14). The uncalibrated TOF-Watch(®) monitor displayed TOF counts in six dogs [2 (0, 4)] and TOF ratios in the remaining eight dogs [91 (79, 98)%], that is, the uncalibrated device failed to display appropriately >40% of the time. TOF-Watch(®) monitors must be calibrated before neuromuscular blocking agents are administered to dogs. When these devices are not so calibrated, they default to a reference value for twitch magnitude that was defined in healthy adult people. Even though neuromuscular transmission was restored in these dogs, we surmise that they did not achieve the default reference value, causing the monitor to display TOF counts rather than TOF ratios.
Article
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A recovery profile from neuromuscular block similar to that of abdominal (AB) muscles, but different to that of the adductor pollicis (AP) muscle, has been demonstrated at the corrugator supercilii (CSC) muscle. We hypothesized that neuromuscular transmission (NMT) monitoring of CSC might provide useful information on AB relaxation compared with AP. We compared the visual estimation of NMT at CSC and AP with electromyographic measurements of AB during recovery from a vecuronium block. Ten adult patients were studied during balanced anaesthesia. After induction of anaesthesia and tracheal intubation without neuromuscular blocking agents, supramaximal stimulations were applied to three nerves: left 10th intercostal, ulnar, and facial. Electromyographic activity (EMG) of AB was measured (ABemg). After a bolus dose of vecuronium 0.1 mg kg-1, an independent observer blinded to the EMG measurements counted visually detectable train-of-four (TOF) responses at CSC and AP. Values of ABemg associated with 1 to 4 TOF responses at CSC and AP were compared. Values are means (sd). Reappearance of the first and second TOF responses at CSC occurred significantly (P<0.05) earlier and at lower ABemg recovery than that of AP [35 (8) and 41 (9) min vs 51 (10) and 56 (12) min; and 17 (8) and 26 (9)% vs 56 (10) and 75 (11)%, respectively]. We demonstrated that the TOF response count at the CSC, compared with the AP, allowed a better quantification of the degree of AB muscle relaxation during recovery from vecuronium block.
Article
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Because the intensity of neuromuscular block at the diaphragm (DIA) is indirectly assessed, the electromyographic measurements of the DIA (DIA(EMG)) from surface electrodes were related to information provided by visual estimation of neuromuscular transmission at the adductor pollicis (AP) and the corrugator supercilii (CSC) during recovery from vecuronium block. Twelve adult patients were studied during balanced anaesthesia. After induction of anaesthesia and tracheal intubation without neuromuscular blocking agent, supramaximal stimulations were applied to phrenic, ulnar and facial nerves. During recovery from vecuronium 0.1 mg kg(-1) an independent observer blinded to DIA(EMG) counted visually detectable train-of-four (TOF) at CSC (TOF(CSC)) and post-tetanic AP (PTC(AP)) responses. Times to recovery of PTC(AP) = 1, <or=5, <10 and >10, and TOF(CSC) = 1-4 responses were related to DIA(EMG). Values are means (sd). Reappearance of the first response to PTC(AP) occurred significantly (P < 0.05) earlier and for a lower recovery of DIA(EMG) than that of TOF(CSC) [24 (8) min vs 33 (9) min, and 10 (10)% vs 25 (8)%, respectively]. With PTC(AP) <or= 5 response, DIA(EMG) recovery was 21 (11)%. Recovery of TOF(CSC) = 1 and 2 coincided with DIA(EMG) recovery of 25 (8)% and 47 (9)%, respectively. PTC(AP) may better reflect early recovery of vecuronium-induced DIA paralysis than TOF(CSC). The findings suggested that PTC(AP) <or= 5 warranted deep neuromuscular block of the DIA.
Article
To quantify the dose of pancuronium required to obtain moderate neuromuscular blockade as monitored by acceleromyography (NMB(mod) : train-of-four count of ≤2) as a part of a balanced anaesthetic protocol in pigs used in cardiovascular research. Prospective cross-sectional study. Five pigs (median body weight: 60 (range 60-63) kg). Anaesthesia was induced with xylazine, ketamine, atropine and midazolam and maintained with isoflurane in O(2) :air and fentanyl. Pigs received 0.1 mg kg(-1) pancuronium initial bolus to reach NMB(mod) followed by 0.1 mg kg(-1) hour(-1) constant rate infusion (CRI). During anaesthesia a twitch count of 3 or measureable T4/T1 ratio indicated unsatisfactory NMB. In this case additional 0.4 mg boluses of pancuronium were administered IV to effect in addition to the CRI. Descriptive statistical analysis was performed to express the median and range of the bolus and CRI dose of pancuronium in pigs. Cardiovascular parameters were analyzed at selected time points with Friedman Repeated Measures Analysis on Ranks. Spearman Rank test was used to evaluate correlation between parameters. Acceleromyographic monitoring of NMB is feasible in anaesthetized pigs. The median initial dose and rate of pancuronium required to achieve NMB(mod) were 0.10 (range 0.10-0.13) mg kg(-1) and 0.11 (range 0.10-0.21) mg kg(-1) hour(-1) , respectively. The administration rate showed considerable individual variation. These pancuronium doses can be used as a guideline to achieve NMB(mod) in pigs as part of a balanced anaesthetic protocol. Instrumental NMB monitoring is essential because of individual kinetic variations and compliance to monitoring guidelines.
Article
The patient's individual anemia tolerance is pivotal when blood transfusions become necessary, but are not feasible for some reason. To date, the effects of neuromuscular blockade (NMB) on anemia tolerance have not been investigated. 14 anesthetized and mechanically ventilated pigs were randomly assigned to the Roc group (3.78 mg/kg rocuronium bromide followed by continuous infusion of 1 mg/kg/min, n = 7) or to the Sal group (administration of the corresponding volume of normal saline, n = 7). Subsequently, acute normovolemic anemia was induced by simultaneous exchange of whole blood for a 6% hydroxyethyl starch solution (130/0.4) until a sudden decrease of total body O(2) consumption (VO(2)) indicated a critical limitation of O(2) transport capacity. The Hb concentration quantified at this time point (Hb(crit)) was the primary endpoint of the protocol. Secondary endpoints were parameters of hemodynamics, O(2) transport and tissue oxygenation. Hb(crit) was significantly lower in the Roc group (2.4 ± 0.5 vs. 3.2 ± 0.7 g/dl) reflecting increased anemia tolerance. NMB with rocuronium bromide reduced skeletal muscular VO(2) and total body O(2) extraction rate. As the cardiac index increased simultaneously, total body VO(2) only decreased marginally in the Roc group (change of VO(2) relative to baseline -1.7 ± 0.8 vs. 3.2 ± 1.9% in the Sal group, p < 0.05). Deep NMB with rocuronium bromide increases the tolerance of acute normovolemic anemia. The underlying mechanism most likely involves a reduction of skeletal muscular VO(2). During acellular treatment of an acute blood loss, NMB might play an adjuvant role in situations where profound stages of normovolemic anemia have to be tolerated (e.g. bridging an unexpected blood loss until blood products become available for transfusion).
Article
The aim of the second part of this review is to examine optimal neuromuscular management strategies that can be used by clinicians to reduce the risk of residual paralysis in the early postoperative period. Current evidence has demonstrated that frequently used clinical tests of neuromuscular function (such as head lift or hand grip) cannot reliably exclude the presence of residual paralysis. When qualitative (visual or tactile) neuromuscular monitoring is used (train-of-four [TOF], double-burst, or tetanic stimulation patterns), clinicians often are unable to detect fade when TOF ratios are between 0.6 and 1.0. Furthermore, the effect of qualitative monitoring on postoperative residual paralysis remains controversial. In contrast, there is strong evidence that acceleromyography (quantitative) monitoring improves detection of small degrees (TOF ratios >0.6) of residual blockade. The use of intermediate-acting neuromuscular blocking drugs (NMBDs) can reduce, but do not eliminate, the risk of residual paralysis when compared with long-acting NMBDs. In addition, complete recovery of neuromuscular function is more likely when anticholinesterases are administered early (>15-20 minutes before tracheal extubation) and at a shallower depth of block (TOF count of 4). Finally, the recent development of rapid-onset, short-acting NMBDs and selective neuromuscular reversal drugs that can effectively antagonize deep levels of blockade may provide clinicians with novel pharmacologic approaches for the prevention of postoperative residual weakness and its associated complications.
Article
To evaluate the post-tetanic count (PTC) for predicting the return of reversible neuromuscular blockade at the n. facialis-m. nasolabialis (nF-mNL) and n. ulnaris-mm. carpi flexorii (nU-mCF) nerve-muscle units (NMUs) during profound vecuronium neuromuscular blockade in halothane-anaesthetized dogs. Randomized, prospective, experimental study. Twenty-five dogs (seven male 18 female) undergoing surgery; mean age: 4.8 years; mean body weight 22 kg. Thirty minutes after acepromazine (0.05 mg kg(-1)) and morphine (0.5 mg kg(-1)) pre-medication, anaesthesia was induced with intravenous (IV) thiopental and maintained with halothane, N(2)O and O(2). The lungs were mechanically ventilated and end-tidal halothane concentration (Fe'(HAL)) maintained at 1.04%. Neuromuscular transmission was monitored using the train-of-four count (TOFC) at one nF-mNL and both nU-mCF units. Vecuronium (50 microg kg(-1) IV) was injected after 15 minutes constant Fe'(HAL). When the first twitch (T1) at both nU-mCF units had disappeared (t = 0) one (randomly allocated) ulnar nerve was stimulated every 5 minutes using PTC; TOF stimulation continued at the other sites. The PTC was plotted against the interval between recording time and T1's reappearance at the other NMUs. At t = 0, the mean PTC in the contralateral nU-mCF unit was 18 (range 0-20). Mean PTC was a minimum at t = 5, rising to the maximum (20) at 25 minutes. Six dogs were vecuronium-resistant as monitored by PTC. Excluding data from these revealed a strong negative relationship between ulnar PTC and the time taken for T1's return at the facial (r = -0.7018; p < 0.00001) and contralateral ulnar (r = -0.8409; p < 0.00001) NMUs. Post-tetanic count monitoring beginning >5 minutes after the TOFC at nU-mCF = 0 provided a reliable estimate of T1's return at ulnar and facial NMUs.
Article
The correlation between degree of peripheral neuromuscular blockade and response to carinal stimulation was evaluated in two groups of 25 patients: one group was anaesthetized with thiopental, N2O and halothane, and the other group received thiopental, N2O and fentanyl. The degree of peripheral blockade was evaluated using train-of-four (TOF) and posttetanic twitch (PTC) stimulation of the ulnar nerve. The degree of diaphragmatic paralysis was evaluated indirectly by stimulating the carina and observing the corresponding muscular response, which was graded as severe, mild or absent. During halothane anaesthesia a PTC of 0 always indicated that no response to carinal stimulation could be elicited. On the appearance of the first response to posttetanic twitch stimulation (PTC = 1), 2% of the patients showed a mild response to carinal stimulation. At the first response to TOF stimulation, 48% of the patients reacted with a mild response. During thiopental, N2O, fentanyl anaesthesia one of 25 patients showed a mild response to carinal stimulation at a PTC of 0. When PTC was 1, 20% of the patients reacted mildly to the stimulation. At the first response to TOF stimulation, 92% showed a response to carinal stimulation; 24% of these responses were severe, necessitating intervention. It is concluded that the TOF response elicited peripherally is a late sign of neuromuscular recovery of the diaphragm, and that the method of counting posttetanic twitches is superior to the TOF response in evaluating early recovery of this muscle. Further, to ensure total diaphragmatic paralysis, the neuromuscular blockade of the peripheral muscles should be so intense that no response to posttetanic twitch stimulation (PTC = 0) can be elicited.
Article
The methods commonly used for monitoring neuromuscular transmission do not allow evaluation of an intense neuromuscular blockade. Thus the doses of non-depolarizing relaxant used for endotracheal intubation cause disappearance of the response to single, tetanic, and train-of-four (TOF) nerve stimulation for a variable period of time. During this time, the magnitude of neuromuscular blockade cannot be evaluated by the traditional stimulation forms. Heisterkamp et al. found that the enhancement of posttetanic twitch tension (posttetanic facilitation) in partially curarized patients remained constant regardless of the dose of non-depolarizing muscle relaxant or magnitude of neuromuscular blockade, the response to posttetanic twitch stimulation after the injection of a non-depolarizing muscle relaxant must appear earlier than the response to pretetanic twitch or TOF nerve stimulation. The present study was designed to evaluate the neuromuscular blockade during the period of no response to single or TOF stimulation by quantifying the degree of posttetanic facilitation.
Article
Rapid assessment of hepatic function early after reperfusion of the liver graft is of great importance, because it may allow for prompt detection of incipient hepatic graft failure. The current study was undertaken to determine whether the continuous recording of neuromuscular transmission could be used as an on-line assessment of hepatic function during liver transplantation when a muscle relaxant with high hepatic uptake is used. We quantified and compared the effect of liver exclusion and graft reperfusion on the level of vecuronium-induced neuromuscular blockade in nine pigs studied twice within 3 days. During the 1st day (control session), an intravenous infusion of vecuronium was administered to maintain a constant 90-95% twitch depression during 180 min. The twitch response was then allowed to recover spontaneously to 75% of its prerelaxant value. Neuromuscular transmission was continuously measured on the right anterior leg using an acceleration transducer. During the same time period, the metabolic rate of 14C-labeled aminopyrine (a well-established quantitative test of the liver microsomal function) was determined by measuring the excretion of 14CO2 in expired air after administration of an intravenous bolus of 14C-labeled aminopyrine. Two days later, the pigs underwent a hepatic autotransplantation, during which vecuronium was administered to maintain a constant 90-95% twitch depression. After reperfusion of the liver graft, the vecuronium infusion rate was maintained at its anhepatic level, and the recovery index of the neuromuscular blockade (the time from 25% to 75% recovery of twitch height) was calculated. The aminopyrine breath test was performed during the last 30 min of the anhepatic phase, and during 3 h after reperfusion of the liver graft. During control studies, the mean infusion rate of vecuronium was 1.30 +/- 0.33 mg.kg-1.h-1 and the recovery index was 3.4 +/- 0.5 min. During liver dissection, the infusion rate of vecuronium was similar to the control value (1.18 +/- 0.16 mg.kg-1.h-1), then considerably decreased to 0.05 +/- 0.03 mg.kg-1.h-1 during the anhepatic phase. After reperfusion of the liver graft, the recovery index was markedly prolonged to 35.5 +/- 15.8 min, indicating a prolongation of the recovery of neuromuscular blockade by a factor of 10.4. Excretion of 14CO2 was equal to zero during the anhepatic phase and then increased to 0.19 +/- 0.11% during the 1st h after reperfusion of the liver graft, an excretion rate corresponding to 11.2% of control conditions. The relationship between individual changes in the recovery index of the neuromuscular blockade and 14CO2 excretion in expired air after reperfusion of the liver graft showed a strong significant correlation (r2 = 0.71). These results indicate that, compared with the control studies, there is a similar decrease in the recovery rate of vecuronium-induced neuromuscular blockade and in the metabolic rate of 14C-labeled aminopyrine during the progressive recovery of hepatic function immediately after unclamping of the liver vessels. Metabolism of 14C-labeled aminopyrine increased progressively during the reperfusion phase. Therefore, recording of neuromuscular transmission during liver transplantation could serve as a continuous and easy to perform assessment of liver graft function provided that a muscle relaxant with a high hepatic uptake is used for neuromuscular blockade.
Article
The need for the routine use of muscle relaxants to provide an adequate surgical field for intraabdominal surgery has not been established. This study tested the hypothesis that vecuronium decreases the frequency of unacceptable operating conditions for patients undergoing radical retropubic prostatectomy who are anesthetized with isoflurane and fentanyl. After obtaining informed consent, patients in this blinded, placebo-controlled study were randomized to receive either an infusion of vecuronium or saline (placebo) beginning 5 min after fascial incision during the maintenance of anesthesia with at least 1 minimum alveolar concentration end-tidal isoflurane and fentanyl infusion. The surgical field was graded from 1 (excellent) to 4 (unacceptable) by the surgeons at 15-min intervals. If a grade 4 rating occurred (defined as a treatment failure), the patient received rescue vecuronium. A total of 120 patients are included in this report (59 in the vecuronium group and 61 in the placebo group). The frequency of treatment failure in the placebo group was 17 of 61 (27.9%) versus 1 of 59 (1.7%) in the control group who received vecuronium (P < 0.001). Thirty-eight patients (62.3%) in the placebo group and 52 patients (88.1%) in the vecuronium group had surgical field ratings of < or = 2 (good to excellent) at each time assessed throughout the procedure. The study hypothesis was confirmed. However, an isoflurane-fentanyl anesthetic alone produced a good to excellent surgical field in approximately two thirds of patients undergoing radical retropubic prostatectomy without the use of muscle relaxants. Thus, the routine use of muscle relaxants in adequately anesthetized patients undergoing this procedure may not be indicated.
Article
Several studies have found a correlation between the onset time of muscle relaxants, cardiac index, and muscle blood flow. Ephedrine increases these hemodynamic variables and shortens onset time of rocuronium in humans. Our aim in this animal study was to determine the effect of ephedrine on the onset time of rocuronium, cardiac index, and muscle blood flow after administration of thiopental. At predefined measuring points, mean arterial blood pressure and cardiac index were measured invasively and onset time was determined mechanomyographically. Twenty-four pigs were randomly assigned to three groups. Group I received etomidate and subsequently rocuronium (2 x 95% effective dose). Instead of etomidate, Group II received thiopental. In Group III, ephedrine 100 mug/kg was given before thiopental; additionally, muscle blood flow was measured (fluorescent microspheres). Although there were differences in hemodynamics between Groups I and II, this was not reflected in different onset times of rocuronium. In Group III, ephedrine compensated the thiopental-induced decrease of mean arterial blood pressure, cardiac index, and muscle blood flow, but no significant shortening of onset time (Group I: 74 +/- 21 s; Group II: 71 +/- 24; Group III: 69 +/- 22 s) was found. Our results demonstrated that ephedrine-related increases in cardiac index and blood flow did not shorten onset time of rocuronium in healthy pigs.
Article
A clinical trial to determine whether continuous infusion administration technique was suitable for maintaining neuromuscular blockade with rocuronium bromide in dogs. Twenty-two dogs, 10 males and 12 females, median age 2 years 4 months, median weight 32 kg undergoing elective surgical procedures under general anaesthesia: ASA classification I or II. After induction of anaesthesia, neuromuscular function was evaluated using train-of-four (TOF) stimulation of the dorsal buccal branch of the facial nerve. A bolus dose of 0.5 mg kg(-1) rocuronium was administered intravenously and an infusion of 0.2 mg kg(-1) hour(-1) was started immediately. Neuromuscular blockade was assessed visually by counting the number of twitches observed during TOF stimulation repeated at 10-second intervals. The bolus dose of rocuronium abolished the response to TOF stimulation in 21 of the 22 dogs. The median onset time of neuromuscular blockade (complete loss of all four twitches) was 82 seconds (range 38-184 seconds). Median infusion duration was 76 minutes (range 20.3-146 minutes). This protocol of rocuronium administration was considered to be effective in dogs. Constant infusion of rocuronium is easily applicable to clinical practice and further work is required on infusion titration.
Article
The set of guidelines for good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents, which was developed following an international consensus conference in Copenhagen, has been revised and updated following the second consensus conference in Stockholm in 2005. It is hoped that these guidelines will continue to help researchers in the field and assist the pharmaceutical industry and equipment manufacturers in enhancing the standards of the studies they sponsor.
Article
This systematic review describes the evidence on the use of acceleromyography for perioperative neuromuscular monitoring in clinical practice and research. The review documents that although acceleromyography is widely used in research, it cannot be used interchangeably with mechanomyography and electromyography for construction of dose-response curves or for recording different pharmacodynamic variables after injection of a neuromuscular blocking agent. Some studies indicate that it may be beneficial to use a preload to increase the precision of acceleromyography, and to "normalize" the train-of-four ratio to decrease the bias in relation to mechanomyography and electromyography. However, currently the evidence is insufficient to support the routine clinical use of preload and "normalization." In contrast, there is good evidence that acceleromyography improves detection of postoperative residual paralysis. A train-of-four ratio of 1.0 predicts with a high predictive value recovery of pulmonary and upper airway function from neuromuscular blockade.
Herlev Ringvej 75, 2730 Herlev, Denmark e-mail: Matias.vested.madsen@regionh.dk A
  • M V Madsen
  • M R M Gä
  • J Donatsky
  • Rosenberg
M. V. Madsen (&) Á M. R. Gä Department of Anesthesiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark e-mail: Matias.vested.madsen@regionh.dk A. M. Donatsky Á J. Rosenberg Department of Surgery, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark B. R. Jensen Department of Nutrition, Exercise and Sports, University of Copenhagen, Nørre Allé 51, 2200 Copenhagen N, Denmark K. P. Hammelev Laboratory Animal Veterinarian, Department of Experimental Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark References