Intermediate-acting Muscle Relaxant Research Articles

Anesthetic concerns in recipients of hematopoietic stem cell transplant.

Dear Editor, Since the advent of bone marrow transplant in 1957, our understanding of the biology behind Hematopoietic Stem Cell Transplant (HSCT) has improved[1] and almost 50,000 HSCT take place globally in a year.[2] Although anesthetic concerns of patients undergoing solid organ transplantation have been addressed, there is a dearth of literature relating to HSCT, especially after the recent advancements like targeted therapy.[3,4] HSCT entails the regeneration of different blood cell lineages from donor stem cells and embarks on the interplay between recipient T lymphocytes, natural killer (NK) cells and donor antigen presenting cells (APC) and lymphocytes. Allogenic transplant brings forth graft vs. tumor effect (GVT) which helps to prevent recurrences but is shadowed by the graft vs. host disease (GVHD), necessitating chronic immunosuppression. Post HSCT patients are at increased risk of opportunistic infections, especially before engraftment and subtle signs of infections may be missed in the preoperative period as well as there may be delayed wound healing after surgery. While exaggerated increase in host immunity may enhance GVHD, overt diminution by immunosuppressant may lead to secondary infections and reactivation of cytomegalovirus. Therefore, it is prudent to delay elective surgeries before engraftment and while the patient is on immune-modulators.[5] Moreover, anesthesiologist should be aware of long-term adverse effects of chemotherapeutic drugs including potential difficult airway due to gum hypertrophy (cyclosporine) and lymph node enlargement as part of post-transplant lymphoproliferative disorder (PTLD). Acute GVHD may involve different organ systems, leading to potentially dreaded complications like acute lung injury, veno-occlusive disease of liver, thrombotic micro angiopathy (TMA) which should be evaluated during the pre-anesthetic check-up.[5] Surgical stress leads to a temporary state of immunosuppression via various mechanisms like raised catecholamines, angiogenic factors, matrix metalloproteinases (MMPs) and attenuated NK cell activity and cell mediated immunity (CMI). Volatile agents, especially isoflurane may promote tumor growth and spread by reducing NK cell activity, T cell depletion, increased angiogenesis by up-regulation of hypoxia inducible factor (HIF-1 alpha), whereas N2O causes bone marrow suppression. However, sevoflurane was found to stabilize the anti-cancer gene P38. Similar to inhaled agents, ketamine and thiopentone induces T cell apoptosis and NK cell underactivity. Propofol appears to be beneficial by reducing angiogenesis and maintaining T cell activity. Despite report showing impairment of macrophage-monocyte function, midazolam appears to be safer. Action of muscle relaxants may get prolonged due to immunomodulators like cyclosporine, as seen in renal transplant recipients.[6] Although anecdotal reports showed that IV opioids reduced NK cell, T cell and TLR (Toll like Receptor) activity on macrophage, it might enhance tumor lysis by stabilizing P53 and P38 and induce tumor death via NF-kB (nuclear factor kappa beta) and Fas-FasL pathway. Thus, immunomodulating effects of opioids are dose and concentration dependent and judicial perioperative analgesia by opioids seems logical.[7] Whenever feasible, use of regional anesthesia must be emphasized as local anesthetics increase local NK cell activity. Propofol along with paravertebral block have been found to be associated with reducing tumor burden in ER-negative breast cancer. Specific concerns of immune-modulators are provided in Table 1 and perioperative concerns are summarized in Table 2.Table 1: Side effects of commonly used agents and their concernsTable 2: Perioperative concerns in a nutshellInduction by propofol/etomidate, followed by maintenance with total intravenous anesthesia (TIVA) with propofol, intermediate acting muscle relaxants with minimal organ dependent metabolism (e.g., atrcurium, cisatracurium) and use of regional anesthesia may be considered as preferred techniques of choice. With the growing number of HSCTs, the authors feel the need for renewed interest and good quality research in this area. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

English

BACKGROUND Cisatracurium and atracurium are intermediate acting muscle relaxants which do not depend on renal or hepatic metabolism for elimination since they undergo Hofmann elimination. Despite the advantages of cisatracurium such as minimal effects on the cardiovascular system, no accumulative effects, no metabolite toxicity, and metabolic product has no neuromuscular blocking effects, due to slow onset and unsatisfactory intubating conditions, the use of cisatracurium is limited compared with those seen with equipotent doses of other neuromuscular blocking agents. This study was undertaken to find onset time and intubating conditions with 3 × ED95 doses of atracurium versus cisatracurium. METHODS ASA grade 1 or 2 patients, (N = 220) were randomly allocated into 2 groups to receive equipotent doses of either atracurium or cisatracurium. Intubating conditions were assessed using Cooper et al scale and neuromuscular monitoring done using TOF Watch SX. Haemodynamic responses and any adverse effects were noted. RESULTS The onset time was 167.36 ± 75.41 seconds (2.78 ± 1.25 minutes) in atracurium group whereas in cisatracurium group, onset time was 249.26 ± 75.90 seconds (4.15 ± 1.26) and the difference was statistically significant with p value of < 0.001. The difference in intubating conditions between the groups was statistically insignificant. However, atracurium produced a higher incidence of clinically acceptable conditions (excellent in 94.4 %) than cisatracurium (excellent in 87.3 %). The incidence of adverse effects such as erythema, flushing and bronchospasm was greater in Atracurium group though hypotension was observed in both groups. CONCLUSIONS Onset time and intubating conditions are significantly better with equipotent doses of atracurium compared to cisatracurium. But atracurium is associated with higher incidence of adverse effects such as erythema, flushing and bronchospasm, though the potential of cisatracurium to cause anaphylactoid reactions cannot be ignored. KEYWORDS Cisatracurium, Atracurium, Muscle Relaxants, Neuromuscular Blocking Agents, Erythema, Flushing, Bronchospasm, Hypotension, Anaphylactoid Reactions

The Occurrence of Postoperative Residual Curarization among Post-Coronary Artery Bypass Graft Patients in a Surgical Intensive Care Unit of a Tertiary Hospital

BACKGROUND: Intermediate-acting muscle relaxants have gained favor in fast-track cardiac anesthesia since these are associated with early extubation. However, postoperative residual curarization (PORC) still occur in the post anesthesia care unit. This study aims to determine the occurrence of PORC among post-coronary artery bypass graft (CABG) patients in the surgical intensive care units (SICU) of the Philippine Heart Center. METHODS: A cross-sectional study was undertaken among 60 patients for elective CABG surgery. Within an hour from SICU arrival, Train of Four (TOF) ratio was obtained and a value of <0.7 signified the presence of PORC. RESULTS: 57 out of 60 (95%) were found to have PORC. Patients without PORC were significantly warmer (36.4oC vs 34.8oC, p-value=0.019) upon SICU arrival compared to those with PORC. The duration of ventilatory support was significantly longer in those with PORC (510 min vs 305 mins, p-value=0.021). The rocuronium induction dose and duration of infusion did not differ between those with and without PORC while the use of reversal drug was seen to significantly prevent its occurrence (p-value=0.003). CONCLUSION: This study showed a high incidence of PORC among post-CABG patients in the SICU with the current practice of Rocuronium infusion during surgery. The use of muscle relaxant reversal drug was seen to significantly prevent the development of PORC while higher body temperature upon SICU arrival was observed in patients that did not develop PORC. This study was also able to show that the development of PORC prolonged post-operative mechanical ventilatory support hindering the goals of fast-track cardiac surgery.

Do clinical signs of recovery from neuromuscular blockade compare reliably with objective parameters of train-of-four and double burst stimulation: An observational single-center study

Background: Recovery from neuromuscular blockade is commonly assessed by clinical signs. There exists wide disparity in what is recommended to monitor neuromuscular blockade and routine clinical practice by anesthesiologists. The objective signs of train-of-four (TOF) ratio of >0.9 and double burst stimulation (DBS) ratio of 1.0 indicate adequate neuromuscular function. This study was planned at a tertiary care hospital to evaluate the ongoing practice of assessing neuromuscular recovery employing clinical signs and comparing with simultaneous TOF and DBS values. Design: A cross-sectional analytical study. Methodology: A total of 100 consecutive patients undergoing surgical procedures lasting more than 1-h duration under general anesthesia with intermediate acting muscle relaxant were enrolled and data of 60 patients analyzed. After extubation, an independent observer recorded simultaneous TOF and DBS ratio using acceleromyography as the clinical signs of neuromuscular recovery (eye opening, tongue protrusion, head lift, sustained bite, hand grip strength, and ability to cough) were attained. Statistical Analysis: Statistical analysis was done utilizing SPSS version 20 (SPSS Inc., Chicago IL, USA) software. Continuous variables are expressed as mean (standard deviation) and Pearson's correlation coefficient was applied to study the correlation between the clinical parameters and quantitative measures of neuromuscular recovery. Results: There was a significant association between ability to retain tongue depressor (sustained bite), absent double vision and ability to cough effectively and TOF and DBS ratios (P 0.9 or DBS ratio of 1.0. Conclusion: Clinical signs of recovery fail to reliably predict postoperative residual paralysis compared to objective neuromuscular monitoring.

A prospective randomized comparative study of the efficacy of atracurium and cisatracurium during general anaesthesia

Introduction: The neuromuscular blocking drugs (NMBDs) has revolutionized the management of balanced General Anaesthesia (GA). Atracurium and Cisatracurium are intermediate-acting muscle relaxants without any much side effects and recovery due to non-organ dependent elimination. Aim: To compare the efficacy of Atracurium and Cisatracurium in general anaesthesia with endotracheal intubation.Methods: In this prospective randomized comparative study 156 patients who fulfilled the eligibility criteria were systematically randomized into two groups of 78 each, Group. A (Atracurium) and Group B (cisatracurium). Patients' duration of surgery, vital parameters, intubation score were recorded. Results: Cisatracurium Besylate subjects had a mean onset time of 165.95 seconds, mean duration of action of 57.41 minutes and mean recovery time of 121.62 minutes. Similarly group Atracurium Besylate subjects had a mean onset time of 196.95 seconds, mean duration of action of 34.58 minutes and mean recovery time of 150.65 minutes. Cisatracurium Besylate subjects had a mean jaw relaxation score of 2.90, mean vocal cord score of 2.77, mean intubation response score of 2.85 and mean intubating score of 8.51. Similarly, group Atracurium Besylate subjects had a mean jaw relaxation score of 2.55, mean vocal cord score of 2.42, mean intubation response score of 2.43 and mean intubation score of 7.38. There were no adverse drug reactions observed in both groupsConclusion: Cisatracurium with lesser side effects and a better hemodynamic profile is safe and more efficacious as compared to atracurium.

Incidence of Residual Neuromuscular Blockade in a Post-Anaesthetic Care Unit

We conducted a prospective observational study to assess the incidence of residual neuromuscular blockade (RNMB) in a post-anaesthetic care unit (PACU) of a tertiary hospital. The subjects were 102 patients undergoing general anaesthesia with neuromuscular blockade (NMB). The procedural anaesthetists were unaware of their patients' inclusion in the study, and the choice of muscle relaxant and use of reversal agents were at the anaesthetists' discretion. On arrival to the PACU, the train-of-four ratio was assessed using electromyography, repeated every five minutes until the train-of-four ratio exceeded 0.9. RNMB was defined as a train-of-four ratio < 0.9. The requirement for airway support, incidence of desaturation while in the PACU and time to eligibility for PACU discharge were recorded. The mean interval between the last dose of relaxant and arrival in the PACU for patients with RNMB was 81 minutes. An intermediate-acting muscle relaxant had been used for most patients. Despite this, RNMB was observed in 31% (95% confidence interval 25 to 47%) of patients. Our findings suggest that RNMB in the PACU is common. As RNMB may predispose to postoperative complications, anaesthetists should utilise quantitative monitoring to assess neuromuscular blockade and optimise reversal use. Anaesthetists should be aware that intervals between the last dose of relaxant of well over one hour do not exclude the possibility of RNMB, even when using intermediate-acting neuromuscular blockade agents.

The Risk of Anaphylactic Reactions to Rocuronium in the United States Is Comparable to That of Vecuronium: An Analysis of Food and Drug Administration Reporting of Adverse Events

Published reports from France and Norway suggest a frequent incidence of anaphylaxis to rocuronium and have raised concerns about its safety. We hypothesized that the Food and Drug Administration Adverse Event Reporting System could be used to confirm whether there has been an unusual incidence of anaphylactic events for rocuronium in the United States (U.S.) and whether the reporting patterns differ within and outside of the U.S.. We queried the Food and Drug Administration Adverse Event Reporting System for 1999 through the first quarter of 2002 for all adverse events for the drugs rocuronium and vecuronium and then searched on the terms considered to represent possible anaphylaxis using proprietary software. We compared the frequency of these terms in data both for rocuronium and vecuronium. We then assessed the occurrence of reports of anaphylaxis-related terms in reports from the U.S. compared with reports originating outside of the U.S.. For rocuronium, the database contained 311 reports, 166 domestic and 145 from foreign sources. Fifty percent of the foreign reports contained an anaphylaxis term versus 20% of the domestic reports (P < 0.001). For vecuronium, the comparable figures were 17% and 19% (not significant) and the total number of reports was 243. The incidence of the reports containing anaphylaxis terms did not differ between vecuronium and rocuronium in the U.S. but were significantly different for foreign reports (P < 0.001). These data confirm that U.S. anesthesia providers have not observed a significant difference in anaphylactic reactions between the two commonly used intermediate-acting muscle relaxants and suggest that frequency of reports of anaphylaxis may be significantly influenced by the area from which the reports originate.

The Incidence of Low Saturation by Pulse Oximetry in the Postanesthesia Care Unit

Background: Patients are most likely to develop severe arterial desaturation during the early postoperative period. Respiratory complications in postanesthesia care unit (PACU) increase the risk of major adverse cardiac outcomes, unanticipated ICU admission or delay in PACU discharges. The increased use of inhalation agents with low blood, gas partition coefficient, intermediate-acting muscle relaxants and continuous pulse oximeter monitoring over the past 10 years may have altered the incidence of immediate postoperative hypoxemia. This study was undertaken to determine the overall incidence of immediate postoperative hypoxemia in PACU. Methods: Hypoxemia was defined as a pulse oxygen saturation () of less than 90% lasting for at least 20 sec. The occurrence of hypoxemia was documented and notified to the anesthesiologist by PACU nurses. The anesthesiologist recorded contributory factors and the management modalities used in patients with hypoxemia. Results: The incidence of hypoxia was 3.5 per 1,000 patients after general anesthesia. Most hypoxemic events (88%) occurred during the first 5 minutes after arrival in PACU. Upper airway obstruction was the major contributory factor for hypoxemia (75.5%) and most of these patients recovered simply after a jaw thrust or the insertion of an oral or nasal airway. Conclusions: Postoperative hypoxemia does not occur often in PACU, but when it does, it is associated with major morbidity and increased medical costs. Therefore, oxygen supply is recommended in patients with risk factors of hypoxemia during transfer from operating rooms to PACU. Close monitoring of hypoxemia in PACU is needed in all patients after general anesthesia.

Does Perioperative Monitoring of the Train-of-Four Response Influence the Frequency of Postoperative Residual Curarization in Propofol Anesthesia?

Background : Sometimes hypoxemia occurs in the postoperative recovery room because of post- operative residual curarization (PORC). Some reports show that postoperative residual curarization is common. FORC occurs after the use of the long-acting muscle relaxants. It has been recommended to use intermediate-acting muscle relaxants and a TOF monitor to decrease PORC. The purpose of this study was to examine whether the use of the TOF monitor during propofol anesthesia affects the incidence of postoperative residual curarization. Methods : 38 ASA I or II patients were divided randomly into two groups of 19 each. They received propofol-fentanyl-nitrous oxide for anesthesia. Pancuronium (80 ― 100 μg/kg) was used to facilitate tracheal intubation and additional doses were used to maintain surgical relaxation. The requirement for incremental doses of pancuronium and adequacy of recovery following reversal were assessed, either with (control group: n = 19) or without (experimental group: n = 19) TOF monitoring. Fifteen minutes after the arrival at the recovery room, neuromuscular function was assessed clinically and by using TOF. Results : There were no statistical differences in body weight, age, or duration of operation between the two groups. There was no statistical difference in the total dose of pancuronium and total dose of pancuronium relative to body weight and duration of operation. There were statistical differences in TOF ratio in the recovery room (0.73 vs. 0.86). The incidence of PORC was 47% in the control group and 5% in the experimental group. Conclusions : Though the monitoring of TOF did not effect the dose of muscle relaxant, it may have reduced the incidence of PORC. However, the PORC had no clinical significance because the mean TOF ratio in the two groups was over 0.7 and there were no clinical signs of residual muscle weakness. (Korean J Anesthesiol 2000; 38: 783-788)

Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488).

Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL x kg(-1) x min(-1) x with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL x kg(-1) x min(-1) with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min(-1)) is markedly larger than that for Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 microg/mL) than for Org 9488 (1.83 microg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.

Pharmacokinetics and Pharmacokinetic-Dynamic Relationship Between Rapacuronium (Org 9487) and Its 3-Desacetyl Metabolite (Org 9488)

Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL [center dot] kg-1 [center dot] min-1 with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL [center dot] kg-1 [center dot] min-1 with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min-1) is markedly larger than that for Org 9488 (0.105 min-1). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 [micro sign]g/mL) than for Org 9488 (1.83 [micro sign]g/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. Implications: We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. (Anesth Analg 1999;88:640-7)

Pharmaceutical Practice Guidelines

Pharmaceutical Practice Guidelines

Does The Choice of Muscle Relaxants Really Affect Postoperative Recovery Time?

In Response: In our article [1], we reported the mean and standard error of the mean for length of surgery and recovery time. Although the re-ported mean length of surgery using long-acting muscle relaxants was longer than that using short- and intermediate-acting muscle relaxants, there was actually considerable overlap between the two groups, with the short- and intermediate-acting muscle relaxants ranging from 45 to 780 min, and the long-acting muscle relaxants ranging from 73 to 820 min. For the sake of simplicity, we chose not to include details of all the regression models we explored. We presented linear models comparing the recovery time associated with the two muscle relaxant groups, controlling for different confounders. By plotting the length of surgery and recovery time on a logarithmic scale, we could have misled readers about our choice of regression model. However, there was a strong linear relationship between the length of recovery time and the length of surgery (r = 0.31 with P < 0.001). The issues of problems with extrapolation mentioned by Bronheim et al. are not relevant to our data and analyses because we did not extrapolate. Jane C. Ballantyne, FRCA YuChiao Chang, PhD Department of Anesthesia and Critical Care; Massachusetts General Hospital; Boston, MA 02114

Does The Choice of Muscle Relaxants Really Affect Postoperative Recovery Time?

In Response: In our article [1], we reported the mean and standard error of the mean for length of surgery and recovery time. Although the re-ported mean length of surgery using long-acting muscle relaxants was longer than that using short- and intermediate-acting muscle relaxants, there was actually considerable overlap between the two groups, with the short- and intermediate-acting muscle relaxants ranging from 45 to 780 min, and the long-acting muscle relaxants ranging from 73 to 820 min. For the sake of simplicity, we chose not to include details of all the regression models we explored. We presented linear models comparing the recovery time associated with the two muscle relaxant groups, controlling for different confounders. By plotting the length of surgery and recovery time on a logarithmic scale, we could have misled readers about our choice of regression model. However, there was a strong linear relationship between the length of recovery time and the length of surgery (r = 0.31 with P < 0.001). The issues of problems with extrapolation mentioned by Bronheim et al. are not relevant to our data and analyses because we did not extrapolate. Jane C. Ballantyne, FRCA YuChiao Chang, PhD Department of Anesthesia and Critical Care; Massachusetts General Hospital; Boston, MA 02114

Does The Choice of Muscle Relaxants Really Affect Postoperative Recovery Time?

To the Editor: Data published in Ballantyne and Chang's article demonstrate that the length of procedures differed greatly between the short- and intermediate-acting muscle relaxants (169 +/- 6.8 min) and the longacting muscle relaxants (256 +/- 16 min) with little, if any, overlap [1]. Regression analysis performed under these circumstances requires extrapolation well beyond the range of observation for each group-a well known pitfall in regression analysis, which should be performed only with extreme caution [2]. In addition, no information about the regression model assumed, or the corresponding parameter estimates, is given. Only the adjusted mean recovery times are given. This is especially important because the relationship as presented between length of surgery and recovery time is exponential, not linear. Furthermore, these huge differences in surgical times probably represent surgical procedures of a significantly higher complexity that result in differences in the entire associated anesthetic plan, not just the choice of muscle relaxants. Are these two groups really comparable? This article may overestimate the effect of pancuronium usage on readiness to discharge. David Bronheim, MD Mark Abel, MD Carol Bodian, PhD Department of Anesthesiology; Mount Sinai Medical Center; New York, NY 10029

Economic Analysis of Anesthetic Drug Use

Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, North Carolina 27710.In Reply:-Dr. Riley makes some important points. At Stanford University, if nursing and other OR labor time really has been extended and if turnover really has been prolonged those extra 3 min (this may not be true, see response to Drs. Bailey and Egan), then some savings may be negated at Stanford. The purpose of any study with well-defined methods is to allow those who would implement the methods of that study to decide how they apply to that particular institution. Stanford is relatively unique in that they have managed to pay their nurses to the minute. I would be willing to bet, however, that nurses do not keep such an accurate accounting of their time so as to enable them to discern a 3-min interval. If they do, Stanford is to be congratulated on such precise time-keeping and salary cost control.Dr. Riley is mistaken in his analysis of the one case of prolonged mechanical ventilation resulting from pancuronium administration. The incidence, overall, was not any different before versus after the implementation of practice guidelines. There previously were cases of prolonged ventilation resulting from use of intermediate-acting muscle relaxants. Regardless of whether one used primarily intermediate-acting muscle relaxants or long-acting muscle relaxants, our results statistically demonstrated that no difference existed and that no great difference could theoretically exist (see 95% confidence limits) in the incidence of pulmonary complications, including postoperative ventilation. Because of the strong feelings on this issue, we repeated that survey without telling our staff to make sure that we had not changed the issue that we were studying by studying it (accounting for the Hawthorne effect). Again, the incidence of postoperative mechanical ventilation was no different than when we used intermediate muscle relaxants. In all, we studied 2,500 patients for evidence of an effect of switching from one muscle relaxant to another and could not find any effect. Dr. Riley suggests a risk resulting from residual muscle relaxation. I would refer him to my response to the letters of Drs. Egan and Bailey. As for paying me an extra $18 for vecuronium, that would be fine, but it would not change the incidence of postoperative mechanical ventilation and it would not statistically lower the risk of a course of postoperative mechanical ventilation.Finally, Dr. Riley makes an important point that one should include all the other costs. We did not account for the effect on time outside the hospital (e.g., the time not paid for, patient suffering, and rare complications, and so on, as mentioned by Dr. Riley). It would have been better if we did. There is some cost to society in spending an extra 3 min caring for a patient, and, according to recent guidelines on performing cost-effectiveness evaluations, [1–3] we should have also approached the costs of recovery room care and of operating room care from society's viewpoint. The guidelines suggest considering the semi-fixed and fixed OR costs and including them when evaluating costs from society's viewpoint. However, this article was undertaken from the viewpoint of the hospital and was completed long before those guidelines were published. In retrospect, it would have been wise to include the concerns raised by my learned colleagues so that the costs from the hospital and society's viewpoints could have been calculated exactly. No matter how the calculations were done, those costs would in no way approach the cost savings attributed to the program we instituted.We believe that we examined all of the pertinent outcomes that were possible to study, and again we welcome the efforts of anyone who wishes to supplement our findings. Fine medical economics research is performed at Stanford's anesthesia department, and we look forward to future contributions as we all seek the best care for our patients. Our own practice guidelines are fluid and in transition. Anytime another investigator proves that the use of a drug is good or bad, we will take that into account, and we will change what we do. But for now, we will be driven by data, not by opinion or fear.David A. Lubarsky, M.D.Department of Anesthesiology; Duke University Medical Center; Box 3094; Durham, North Carolina 27710(Accepted for publication July 29, 1997.)

Vecuronium for Emergency Intubations?

To the Editor: It has come to my attention that some prehospital rescue protocols now in place and being developed nationally include the use of vecuronium in the field as a first-line neuromuscular blocker. The use of a long- or intermediate-acting muscle relaxant under unpredictable tracheal intubating conditions is at best contraindicated and at worst lethal. As trained experts and clinicians, we anesthesiologists and anesthetists have a responsibility to our institutions and communities to provide advice and guidance to other health care professionals in airway management. In some instances, we have the opportunity to set standards for airway management protocols and algorithms, and we should emphasize the hazards of the use of such drugs and discourage their use. After all, we are usually the ones called for help when all other efforts at intubation have failed. Then the circumstances rarely are optimal for our success and don't allow back up with fiberoptics, jet ventilators, or other alternatives routinely available to us in the operating room. This letter is an effort to inform and alert our colleagues about this situation so that we can try to influence the quality of prehospital emergency care. This issue has an effect on us as professionals and potentially as patients as well. Yvonne E. Wagner, MD Thomas K. Clarke, MD Department of Anesthesiology Geisinger Clinic Danville, PA 17822

Alcuronium

Alcuronium may be considered a muscle relaxant of historical rather than clinical significance.However, recent information from the manufacturer revealed its persisting clinical use in 26 countries worldwide. Thus, a pharmacodynamic-pharmacokinetic update appears mandatory. An intravenous (IV) single-bolus injection of alcuronium (0.25 mg/kg = ED95) was administered to 10 patients undergoing maxillofacial surgery during nitrous-oxide opioid anesthesia. Alcuronium neuromuscular block (evoked twitch tension), plasma concentration, and renal elimination (high-performance liquid chromatography [HPLC] assay) were measured during the 12-h after its administration. The time of onset, the time from end of injection to recovery to 25% of control twitch tension (DUR25%), and the recovery index were 2.2 +/- 1.2, 54 +/- 14, and 37 +/- 11 min, respectively (mean +/- SD). Two hours after the injection of alcuronium, partial recovery from the neuromuscular block had occurred from 100% to 26% +/- 24% depression of twitch tension, although less than 25% of the injected dose was recovered from the urine. The 12-h plasma concentration and urinary recovery were 0.1 +/- 0.08 mg/L (one-sixth of the 50% inhibitory concentration) and 61% +/- 20%, respectively. Recovery from neuromuscular block was dominated by intercompartmental distribution rather than by renal elimination. Since alcuronium does not undergo biodegradation, our data may serve as a reference for the complex pharmacokinetics of readily metabolized modern muscle relaxants. The long plasma half-life with slow excretion merits attention with respect to the erroneous original perception that alcuronium was an intermediate-acting muscle relaxant. (Anesth Analg 1995;80:373-7)

Alcuronium: a pharmacodynamic and pharmacokinetic update.

Alcuronium may be considered a muscle relaxant of historical rather than clinical significance. However, recent information from the manufacturer revealed its persisting clinical use in 26 countries worldwide. Thus, a pharmacodynamic-pharmacokinetic update appears mandatory. An intravenous (IV) single-bolus injection of alcuronium (0.25 mg/kg = ED95) was administered to 10 patients undergoing maxillofacial surgery during nitrous-oxide opioid anesthesia. Alcuronium neuromuscular block (evoked twitch tension), plasma concentration, and renal elimination (high-performance liquid chromatography [HPLC] assay) were measured during the 12-h after its administration. The time of onset, the time from end of injection to recovery to 25% of control twitch tension (DUR25%), and the recovery index were 2.2 +/- 1.2, 54 +/- 14, and 37 +/- 11 min, respectively (mean +/- SD). Two hours after the injection of alcuronium, partial recovery from the neuromuscular block had occurred from 100% to 26% +/- 24% depression of twitch tension, although less than 25% of the injected dose was recovered from the urine. The 12-h plasma concentration and urinary recovery were 0.1 +/- 0.08 mg/L (one-sixth of the 50% inhibitory concentration) and 61% +/- 20%, respectively. Recovery from neuromuscular block was dominated by intercompartmental distribution rather than by renal elimination. Since alcuronium does not undergo biodegradation, our data may serv as a reference for the complex pharmacokinetics of readily metabolized modern muscle relaxants. The long plasma half-life with slow excretion merits attention with respect to the erroneous original perception that alcuronium was an intermediate-acting muscle relaxant.

Postoperative neuromuscular block following atracurium or alcuronium in children

Postoperative neuromuscular block (NMB) was evaluated in 60 children who received randomly either atracurium or alcuronium to induce and maintain an 85-95 per cent NMB during balanced anaesthesia. The EMG-monitor was turned away from the anaesthetist 10-15 min before the end of surgery. The average NMB was comparable between the groups at the time of reversal with neostigmine 50 micrograms.kg-1 (84 +/- 9 per cent, mean +/- SD) as were the NMB and the train-of-four ratio when the tracheas were extubated on a clinical basis (32 +/- 20 per cent and 50 +/- 18 per cent, respectively). Patients who had been paralyzed with atracurium arrived at the recovery room earlier and on arrival had greater train-of-four ratios than the patients paralyzed with alcuronium (P less than 0.01). Time to a train-of-four ratio of greater than 90 per cent was significantly shorter in the atracurium group (10 +/- 5 min vs 26 +/- 15 min, P less than 0.001). Thus, an intermediate-acting muscle relaxant offers a safer recovery profile of the NMB than a long-acting muscle relaxant in paediatric patients.