Re: Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study
In their recent prospective propensity score matched study Grosse-Sundrup et al. found that the use of intermediate-acting non-depolarizing neuromuscular blocking agents during anaesthesia was associated with an increased risk of postoperative desaturation and reintubation. They demonstrated that qualitative neuromuscular monitoring, e.g. by tactile or visual evaluation of the response to train-of-four (TOF) stimulation, did not reduce this risk and neostigmine reversal even further increased it. In addition, reintubation requiring unplanned admission to an intensive care unit was associated with a 90-fold higher risk of dying in hospital.1 In particular this finding is in sharp contrast to that of a large well-designed case-control study published by Arbous et al. where a decreased risk of mortality was associated with reversal of neuromuscular block (odds ratio 0.10) at the end of anaesthesia.2
Grosse-Sundrup et al. suggest that the strategies used in their trial to prevent residual postoperative blockade should be revisited. We fully agree with the authors and ask them to provide additional information to elucidate the extent to which their strategies are in disagreement with current evidence-based recommendations for the management of neuromuscular block and, hence, were at least partially “responsible” for their “unexpected” results.3-5 At the study site only 50% of patients receiving muscle relaxants were reported to have been monitored for neuromuscular transmission, and neostigmine was given in 63.8% of patients. From the latter only 37.2% were also monitored.1 What about the portion of “routine reversal without monitoring” and neostigmine doses in general at the study site? This information would be of particular interest, as it is well known that neostigmine given to fully recovered patients may decrease activity of the upper airway muscles and the diaphragm, and may contribute to respiratory complications.67 A ceiling effect of neostigmine is probably reached at neostigmine doses of 40 to 70 mcg/kg.4 A recent survey suggests that dosing of neostigmine significantly differs between anaesthesiologists in the US and Europe (doses equal to or higher than 50 mcg/kg are administered in 68.7% of patients in the US compared to 21.0% of patients in Europe).8 In addition, when relying on qualitative neuromuscular monitoring, reversal of even a moderate (rocuronium-induced) block is associated with a clinically significant potentially unsafe period of recovery.9
Additional questions refer to the method of propensity score matching. Patients receiving at least one dose of an intermediate-acting non-depolarizing muscle relaxant for tracheal intubation (n=18,579) were matched with patients who did not receive any.1 The authors do not mention whether the latter patient group, which included emergency cases and cardiac surgical patients, was intubated using succinylcholine or no muscle relaxant at all.
After a single dose of an intermediate-duration muscle relaxant (atracurium, rocuronium and vecuronium) and no reversal, residual paralysis is common, even more than 2 h after the administration of the muscle relaxant.10In the study by Grosse-Sundrup et al. the risk of reintubation was higher when non-depolarizing neuromuscular blocking agents were administered for surgeries of short duration (<120 minutes).1 Two thirds of patients received cisatracurium, which may be considered an intermediate-acting muscle relaxant only if twice the ED95 is given. However, if the recommended intubation dose of cisatracurium (i.e. 3- and 4-times its ED95) was routinely used, cisatracurium is a long-acting agent (i.e. clinical duration > 50 min) with a potential influence on the observed respiratory complications.
Finally, we are interested to know whether the results of the study and concerns raised by the authors have led to a change in the guidelines for the management of neuromuscular block at their institution in terms of quality improvement.1 A study performed in France between 1995 and 2004 clearly demonstrated that residual neuromuscular block decreased in parallel with an increasing use of quantitative neuromuscular monitoring and reversal.11 We agree with the authors that the role of sugammadex, a selective relaxant binding agent, and its potential to decrease respiratory morbidity following the use of (aminosteroid) muscle relaxants require further studies. However, there seems to be sufficient evidence (gathered over the last 15 years) to recommend the use of quantitative neuromuscular monitoring for making the decision whether to reverse or not and for selecting the right dose of neostigmine and sugammadex, respectively.
1.Grosse-Sundrup M, Henneman JP, Sandberg WS, Bateman BT, Uribe JV, Nguyen NT, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ 2012;345:e6329.
2. Arbous MS, Meursing AE, van Kleef JW, de Lange JJ, Spoormans HH, Touw P, et al. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005;102:257-68.
3. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg 2010;111:129-40.
4. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010;112:1013-22.
5. Viby-Mogensen J, Claudius C. Evidence-based management of neuromuscular block. Anesth Analg 2010;111:1-2.
6. Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C, Chamberlin NL. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing. Br J Anaesth 2008;101:344-9.
7. Herbstreit F, Zigrahn D, Ochterbeck C, Peters J, Eikermann M. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology 2010;113:1280-8.
8. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg 2010;111:110-9.
9. Illman HL, Laurila P, Antila H, Meretoja OA, Alahuhta S, Olkkola KT. The duration of residual neuromuscular block after administration of neostigmine or sugammadex at two visible twitches during train-of-four monitoring. Anesth Analg 2011;112:63-8.
10. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042-8.
11. Baillard C, Clec'h C, Catineau J, Salhi F, Gehan G, Cupa M, et al. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth2005;95:622-6.
Competing interests:
A clinical study with sugammadex sponsored by Merck was carried out at the institution of HS during the last two years. The authors had no financial relationships with any organisation or company that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
25 November 2012
Harald J. Sparr
Anaesthesiologist
Thomas Heidegger
Department of Anaesthesia and Intensive Care Medicine, General Hospital Dornbirn
Rapid Response:
Re: Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study
In their recent prospective propensity score matched study Grosse-Sundrup et al. found that the use of intermediate-acting non-depolarizing neuromuscular blocking agents during anaesthesia was associated with an increased risk of postoperative desaturation and reintubation. They demonstrated that qualitative neuromuscular monitoring, e.g. by tactile or visual evaluation of the response to train-of-four (TOF) stimulation, did not reduce this risk and neostigmine reversal even further increased it. In addition, reintubation requiring unplanned admission to an intensive care unit was associated with a 90-fold higher risk of dying in hospital.1 In particular this finding is in sharp contrast to that of a large well-designed case-control study published by Arbous et al. where a decreased risk of mortality was associated with reversal of neuromuscular block (odds ratio 0.10) at the end of anaesthesia.2
Grosse-Sundrup et al. suggest that the strategies used in their trial to prevent residual postoperative blockade should be revisited. We fully agree with the authors and ask them to provide additional information to elucidate the extent to which their strategies are in disagreement with current evidence-based recommendations for the management of neuromuscular block and, hence, were at least partially “responsible” for their “unexpected” results.3-5 At the study site only 50% of patients receiving muscle relaxants were reported to have been monitored for neuromuscular transmission, and neostigmine was given in 63.8% of patients. From the latter only 37.2% were also monitored.1 What about the portion of “routine reversal without monitoring” and neostigmine doses in general at the study site? This information would be of particular interest, as it is well known that neostigmine given to fully recovered patients may decrease activity of the upper airway muscles and the diaphragm, and may contribute to respiratory complications.67 A ceiling effect of neostigmine is probably reached at neostigmine doses of 40 to 70 mcg/kg.4 A recent survey suggests that dosing of neostigmine significantly differs between anaesthesiologists in the US and Europe (doses equal to or higher than 50 mcg/kg are administered in 68.7% of patients in the US compared to 21.0% of patients in Europe).8 In addition, when relying on qualitative neuromuscular monitoring, reversal of even a moderate (rocuronium-induced) block is associated with a clinically significant potentially unsafe period of recovery.9
Additional questions refer to the method of propensity score matching. Patients receiving at least one dose of an intermediate-acting non-depolarizing muscle relaxant for tracheal intubation (n=18,579) were matched with patients who did not receive any.1 The authors do not mention whether the latter patient group, which included emergency cases and cardiac surgical patients, was intubated using succinylcholine or no muscle relaxant at all.
After a single dose of an intermediate-duration muscle relaxant (atracurium, rocuronium and vecuronium) and no reversal, residual paralysis is common, even more than 2 h after the administration of the muscle relaxant.10 In the study by Grosse-Sundrup et al. the risk of reintubation was higher when non-depolarizing neuromuscular blocking agents were administered for surgeries of short duration (<120 minutes).1 Two thirds of patients received cisatracurium, which may be considered an intermediate-acting muscle relaxant only if twice the ED95 is given. However, if the recommended intubation dose of cisatracurium (i.e. 3- and 4-times its ED95) was routinely used, cisatracurium is a long-acting agent (i.e. clinical duration > 50 min) with a potential influence on the observed respiratory complications.
Finally, we are interested to know whether the results of the study and concerns raised by the authors have led to a change in the guidelines for the management of neuromuscular block at their institution in terms of quality improvement.1 A study performed in France between 1995 and 2004 clearly demonstrated that residual neuromuscular block decreased in parallel with an increasing use of quantitative neuromuscular monitoring and reversal.11 We agree with the authors that the role of sugammadex, a selective relaxant binding agent, and its potential to decrease respiratory morbidity following the use of (aminosteroid) muscle relaxants require further studies. However, there seems to be sufficient evidence (gathered over the last 15 years) to recommend the use of quantitative neuromuscular monitoring for making the decision whether to reverse or not and for selecting the right dose of neostigmine and sugammadex, respectively.
1. Grosse-Sundrup M, Henneman JP, Sandberg WS, Bateman BT, Uribe JV, Nguyen NT, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ 2012;345:e6329.
2. Arbous MS, Meursing AE, van Kleef JW, de Lange JJ, Spoormans HH, Touw P, et al. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005;102:257-68.
3. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg 2010;111:129-40.
4. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010;112:1013-22.
5. Viby-Mogensen J, Claudius C. Evidence-based management of neuromuscular block. Anesth Analg 2010;111:1-2.
6. Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C, Chamberlin NL. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing. Br J Anaesth 2008;101:344-9.
7. Herbstreit F, Zigrahn D, Ochterbeck C, Peters J, Eikermann M. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology 2010;113:1280-8.
8. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg 2010;111:110-9.
9. Illman HL, Laurila P, Antila H, Meretoja OA, Alahuhta S, Olkkola KT. The duration of residual neuromuscular block after administration of neostigmine or sugammadex at two visible twitches during train-of-four monitoring. Anesth Analg 2011;112:63-8.
10. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042-8.
11. Baillard C, Clec'h C, Catineau J, Salhi F, Gehan G, Cupa M, et al. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth 2005;95:622-6.
Competing interests: A clinical study with sugammadex sponsored by Merck was carried out at the institution of HS during the last two years. The authors had no financial relationships with any organisation or company that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.