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The influence of unrestricted use of sugammadex on clinical anaesthetic practice in a tertiary teaching hospital.

Despite the availability of intermediate acting neuromuscular blocking (NMB) agents such as rocuronium and vecuronium, residual paralysis with subsequent physiological sequelae remains a significant postoperative problem (1,2). As the development of a safe ultra-short acting NMB agents and cleaner more effective anticholinesterase NMB antagonists remains elusive, neostigmine is the only affordable reversal agent for routine use in Australia (3).

In this era of 'designer drugs' Anton Bom made the serendipitous discovery that despite excellent solubility in cyclodextrins, the potency and bioavailability of rocuronium was significantly reduced (4).

Studies using nuclear magnetic resonance and X-ray crystallography identified a steroid binding cavity within the cyclodextrin molecule, which was then modified to create the [gamma]-cyclodextrin, sugammadex; the first selective relaxant binding agent capable of forming tight complexes with steroidal neuromuscular blocking agents such as rocuronium and vecuronium to rapidly reverse any depth of neuromuscular blockade (5).

In their article entitled "Clinical implications of sugammadex", Caldwell and Miller (6) pose the question "where will sugammadex fit into or alter clinical practice?" In particular, will anaesthetists 'switch' to rocuronium and vecuronium; is suxamethonium still necessary; and will it improve outcomes for patients? Sugammadex also avoids the need for acetyl cholinesterase inhibitors (e.g. neostigmine) and antimuscarinic drugs such as atropine or glycopyrrolate, with their associated potential side-effects, and therefore may improve patient recovery.

Given this promise of efficacy and providing no serious safety concerns arise, sugammadex has the potential to change the use and reversal of muscle relaxants in anaesthesia. However, currently in Australia and many other countries, the high cost of sugammadex restricts its use to emergency situations such as failed intubation or use in special patient groups with comorbidities such as obesity.

This study reports our experience during an industry sponsored trial to determine what changes would be observed if the cost of sugammadex was reduced such that it was no longer a restriction to its use.

METHODS

The opportunity for this study arose in the context of an industry (Merck, Sharp, Dohme) initiated trial to assess whether supplying sugammadex at a lower price would increase its use and make it economically feasible for the supplier. This study was a department retrospective casenote audit investigating how this new unrestricted availability of sugammadex impacted on muscle relaxant use and reversal, operating theatre and post-anaesthesia care unit (PACU) time, length of stay and selected patient outcomes such a postoperative nausea and vomiting (PONV) and oxygen desaturation during the PACU stay. It was approved by the Human Research Ethics Committee application number 2011083 (Adelaide Health Service). Prior to this intervention, departmental guidelines restricted the use of sugammadex because of its cost. Approved indications were limited to 'can't intubate, can't oxygenate' scenarios, morbid obesity, unexpected early end to surgery and severe respiratory disease. During the trial period, all restrictions were lifted and all our anaesthetists were made aware that there were no cost implications with use of sugammadex during this time.

The financial restraint on sugammadex was removed (intervention) on 14 December 2010 and the audit was performed six weeks before and after this date, with a one-week adjustment period after the changeover.

The Queen Elizabeth Hospital Department of Anaesthesia consists of 31 full-time equivalent consultants, five visiting specialists and 15 registrars working in 12 theatres, where 600 to 700 operations, elective and emergency, are performed each month. Sugammadex (100 mg.[ml.sup.-1], 2 ml) was placed in the top drawer of all anaesthetic drug trolleys next to neostigmine, while sugammadex (500 mg.[ml.sup.-1]) was available on a central emergency airway trolley.

Patients for the study were initially selected using our Operating Room Information System software during the two audit periods. The patient list was then examined and only those patients who were likely to require endotracheal intubation were included in the study. Patient casenotes were accessed from medical records and the anaesthetic chart was analysed. Patient demographics, operation type anaesthetic duration (induction to transfer PACU), NMB technique, reversal and PACU information were collected on a pro forma data sheet. Desaturation was defined as a documented [S.sub.a][O.sub.2] <93%, inadequate reversal if a repeat dose of NMB antagonism was required, and PONV if antiemetics were administered in the PACU.

The patients who did not require endotracheal intubation (e.g. laryngeal mask airway use or regional anaesthesia) or were transferred to the intensive care unit still intubated were excluded from the study.

Statistical analysis

Categorical data (patient and surgery characteristics, outcomes) were compared before and after unrestricted use of sugammadex using chi-square or Fisher exact tests. Continuous data (age and weight) were compared between the two time periods using two sample t-tests for normally distributed variables. To control for potential confounders in the comparison of theatre duration and hospital stay between time periods, multivariate negative binomial regression models were fitted with adjustment for age, gender, weight, American Society of Anesthesiologists physical status and type of surgery. Theatre duration was also adjusted for in the analysis of hospital stay. All confounders were given equal weight, pre-specified for statistical adjustment and were considered to be biologically plausible predictors of theatre duration and hospital stay.

Statistical significance was assessed at the two-sided P <0.05 level. No adjustments were made for multiple comparisons. All analyses were carried out using SAS 9.2 (SAS Institute Inc., Cary, NC, USA).

RESULTS

During the restricted sugammadex period 186 consecutive patients were identified, but 13 case notes were unavailable, and a further 29 were excluded because NMB was not used or the patient was not extubated on the day of surgery. During the unrestricted sugammadex period, 188 patients were identified, 14 case notes were unavailable and 30 were excluded.

Table 1 shows that demographic data were comparable with a significant number of elderly and American Society of Anesthesiologists physical status II to III patients, and similar types of operations.

Table 2 shows that sugammadex use increased from 7.1% to 65.3% (P <0.0001) while 'neostigmine use' decreased from 59.6% to 12.5% (P <0.0001). There was no significant change in the number of patients 'not reversed'. The median sugammadex dose was 200 mg with only two cases of reduced dose in elderly patients, and only three cases where neuromuscular monitoring was documented prior to dosing. There were no documented adverse events attributed to sugammadex during the unrestricted period.

While the number of rapid sequence inductions was higher 11.1 vs 4.4% (P=0.03) in the unrestricted sugammadex period, the use of suxamethionium was unchanged (P=0.58), with a modified rapid sequence induction using rocuronium used in the remainder. From a high 'baseline' of 90.8%, rocuronium use decreased to 79.2% (P=0.006), while vecuronium use increased from 2.1 to 8.3% (P=0.02). Cisatracurium use from a low baseline was unchanged (P=0.58).

Table 3 presents rocuronium use before and during unrestricted availability of sugammadex. While the mean rocuronium dose did not change (55.9 to 60.4 mg, P=0.13) and the number of doses also did not increase (1.90 vs 1.96), the time interval between last dose of rocuronium and the administration of reversal decreased from 91.7 to 62.0 minutes (P=0.0002).

Table 4 outlines selected patient outcomes and shows that when use of sugammadex was unrestricted, we observed fewer cases of inadequate reversal but the numbers were not significant. The mean anaesthetic theatre time was reduced from 143.5 to 120.0 minutes (P=0.01), but the intervention had no effect on time spent in the PACU, the incidence of PONV or the incidence of oxygen desaturation in the PACU. When adjusted for confounding variables, the difference in mean anaesthetic theatre time before and after unrestricted use of sugammadex remained statistically significant (ratio of means 1.17, 95% confidence interval 1.03 to 1.34, P=0.02), although it is unclear whether our retrospective observational study had sufficient power to exclude the effect of all potential confounders, and the design of the study was such that we can make no inferences about causality.

On univariate analysis, hospital duration was reduced from 4.2[+ or -]3.5 to 3.4[+ or -]3.0 days (P=0.04). After adjustment for potential confounders however, the difference in hospital stay before and after the intervention was not statistically significant (ratio of means 1.04, 95% confidence interval 0.89 to 1.20, P=0.59).

DISCUSSION

This opportunistic retrospective casenote audit provides an interesting 'window' to the future on how unrestricted access to sugammadex might affect anaesthetic practice. Given that sugammadex, although a new drug, is a water-soluble sugar molecule with no intrinsic biological activity and well tolerated in humans so far, it is not surprising that when restrictions due to cost are removed, this study found that its use increased significantly from 7 to 65% for reversal of NMB. While such high usage may represent the 'novelty' effect of a new drug or possibly a Hawthorne effect, given the impressive efficacy and safety profile of sugammadex, it is a likely prediction of its future use if the cost implications are removed. Nevertheless, it is not clear what the costs of sugammadex are likely to be in the absence of specific arrangements with individual departments and which may be linked to minimum usage criteria. The drop in neostigmine use as expected was a mirror image, falling from 60 to 13%.

In this study, a median dose of sugammadex of 200 mg and limited documented neuromuscular monitoring suggest a 'recipe-based' approach to NMB reversal. While some commentators suggest sugammadex's increased effectiveness may lessen the need for neuromuscular monitoring, others suggest good clinical practice should be to monitor routinely in order to use the minimum effective dose in case re-intubation is necessary (6).

Similar predictions for the demise of suxamethonium (7) with the advent of sugammadex may be premature, because we found that there was no difference in suxamethonium use. However, there were more modified rapid sequence inductions using rocuronium (1.2 mg.[kg.sup.-1]) with unrestricted sugammadex. Recent successful use of rocuronium for obstetric rapid sequence induction (8) and a study comparing suxamethonium with profound rocuronium blockage (1.2 mg.[kg.sup.-1]) (9) suggest that perhaps with time we will see less suxamethonium used.

This study confirmed that rocuronium was a very popular nondepolarising muscle relaxant in our hospital (91% usage before the intervention) and it is therefore not surprising that usage did not increase with unrestricted availability of sugammadex. It was, however, unexpected to find lower usage after the intervention, although a compensatory increase in vecuronium use may explain the decrease. Cisatracurium use did not decrease as predicted by some commentators, but prior to routine use of sugammadex it was low at 9%. There was no increase in the mean dose of rocuronium and no change in the number of doses, but we observed that the time between the last dose and reversal was shortened by about 30 minutes. While we can only speculate about the reason for this finding, one explanation is a greater willingness to maintain more profound NMB closer to the end of the surgical procedure in some cases given the ease of reversibility with sugammadex.

The unrestricted use of sugammadex may provide other benefits to patients. In particular, while numbers were small and not significant, there were no cases of documented inadequate reversal in the post sugammadex period, but four cases in the restricted period. On the other hand, the diagnosis of inadequate reversal in this audit was clinical with no routine neuromuscular function monitoring in either group. Anaesthetic theatre time was shorter by 23 minutes on average in the unrestricted sugammadex group. This could be due to a more rapid reversal of NMB at the end of the operation and quicker transfer to PACU, but any inferences about causality must be very guarded given the observational design of the study, the incomplete data, and the exploratory design of the analysis. Nevertheless, the finding is encouraging and would be an important area for further investigation.

Univariate analysis on the effect of sugammadex on hospital stay showed a reduction of almost one day. However, when adjusted for confounding factors the difference was not statistically significant.

The effect of neostigmine on PONV is controversial, but the most recent view is that at doses of 50 /[micro]g.[kg.sup.-1] it increases nausea, but not vomiting10. However, in this study PONV rates were similar in both neostigmine (~30 /[micro]g.[kg.sup.-1]) and sugammadex groups. Similarly there was no difference in time in the PACU, or the incidence of oxygen desaturation in PACU.

As a small non-randomised retrospective audit, the study has several limitations. Given the reliance on accurate casenote documentation and the ability to retrieve this information, the quality of the data could not be verified and a large number of casenotes were not available for both groups. The study was not formally powered to detect a pre-defined clinically important difference between time periods, thus important differences may have been missed. The study involved a single anaesthetic unit where rocuronium usage was high, and the findings may not apply to other units. The differences observed in anaesthetic theatre time may also be due to other unmeasured confounders such as the diverse range of procedures and differing seniority of the surgeons. A further limitation was the testing of multiple outcomes, which increases the probability of making a type-I statistical error. The probability of type II errors was completely unknown. Despite these limitations, the analysis shows that there are some interesting signals emerging on how sugam-madex may impact on anaesthetic practice.

In summary, we observed that when the restriction of sugammadex use due to high costs was removed, overall amino steroid NMB use did not change, but sugammadex use increased considerably. Rocuronium dosing occurred closer to the completion of surgery and there was a reduction in theatre anaesthetic time, although we can make no inferences in relation to causality. There was no change in PACU times, the incidence of oxygen desaturation in PACU, or overall length of stay, although we may not have had sufficient power to fully assess these outcomes. Given the limitations of this retrospective audit, a larger prospective randomised controlled trial is warranted.

ACKNOWLEDGEMENTS

This study was funded and supported through Department of Anaesthesia, Queen Elizabeth Hospital resources.

CONFLICT OF INTEREST

Dr Roelof van Wijk received remuneration as member of the MSD Bridion Advisory Board.

REFERENCES

(1.) Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 2010; 111:120-128.

(2.) Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuro nium. Acta Anaesthesiol Scand 1997; 41:1095-1103.

(3.) Booij LHDJ. Cyclodextrins and the emergence of sugammadex. Anaesthesia 2009; 64 Suppl 1:31-37.

(4.) Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. Anesthesiology 2003; 99:632-637; discussion 6A.

(5.) Naguib M, Brull SJ. Sugammadex : a novel selective relaxant binding agent. Expert Review Clinical Pharmacology 2009; 2:37-53.

(6.) Caldwell JE, Miller RD. Clinical implications of sugammadex. Anaesthesia 2009; 64 (Suppl 1):66-72.

(7.) Lee C. Goodbye suxamethonium! Anaesthesia 2009; 64 (Suppl 1):73-81.

(8.) Williamson RM, Mallaiah S, Barclay P. Rocuronium and sugammadex for rapid sequence induction of obstetric general anaesthesia. Acta Anaesthesiol Scand 2011; 55:694-699.

(9.) Lee C, Jahr JS, Candiotti K, Warriner B, Zornow MH. Reversal of profound rocuronium NMB with sugammadex is faster than recovery from succinylcholine. Anesthesiology 2007; 107: A988.

(10.) Cheng C-R, Sessler DI, Apfel CC. Does neostigmine administration produce a clinically important increase in postoper-ative nausea and vomiting? Anesth Analg 2005; 101: 1349-1355.

R. W. WATTS *, J. A. LONDON ([dagger]), R. M. A. W. van WIJK ([double dagger]), Y.-L. LUI ([section]) Department of Anaesthesia, Queen Elizabeth Hospital, Adelaide, South Australia, Australia

* BSc (Hons), BM, BS, MD, FRACGP, Adjunct Associate Professor.

([dagger]) BSc (Hons), BMedSci, BM, BS, Anaesthetic Registrar.

([double dagger]) MD, PhD, FANZCA, FFPMANZCZ, Director of Anaesthesia.

([section]) MAppStat, Statistician, Data Management and Analysis Centre, Discipline of Public Health, University of Adelaide.

Address for correspondence: Dr R. W. Watts, Senior Consultant Anaesthetist (GP), Department of Anaesthesia, Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011. Email: richard.watts@health.sa.gov.au

Accepted for publication on December 28, 2011.
Table 1
Demographic data of patients undergoing an operation requiring
intubation with neuromuscular block for two six-week periods during
restricted and unrestricted availability of sugammadex for
neuromuscular block reversal

Variable Restricted, n (%)

Age ** 141
 <31 20 (14.2)
 31-50 42 (29.8)
 51-70 57 (40.4)
 [greater than or equal to] 71 22 (15.6)
Weight * (mean [+ or -] SD) 128 (79.0 [+ or -] 19.2)
 Gender ** 141
 Female 74 (52.5)
 Male 67 (47.5)
ASA physical status *** 139
 I 35 (25.2)
 II 72 (51.8)
 III 30 (21.6)
 IV 2 (1.4)
Surgery type ** 141
 ENT/thyroid 31 (22)
 Cardiac (AF ablation) 9 (6.4)
 Laparoscopic 39 (27.7)
 Laparotomy open 47 (33.3)
 Orthopaedic 15 (10.6)

Variable Unrestricted, n (%) P value

Age ** 144 0.50
 <31 29 (20.1)
 31-50 45 (31.3)
 51-70 52 (36.1)
 [greater than or equal to] 71 18 (12.5)
Weight * (mean [+ or -] SD) 127 (81.2 [+ or -] 19.8) 0.37
 Gender ** 143 0.10
 Female 89 (62.2)
 Male 54 (37.8)
ASA physical status *** 143 0.91
 I 37 (25.9)
 II 69 (48.3)
 III 34 (23.8)
 IV 3 (2.1)
Surgery type ** 144 0.07
 ENT/thyroid 35 (24.3)
 Cardiac (AF ablation) 10 (6.9)
 Laparoscopic 55 (38.2)
 Laparotomy open 39 (27.1)
 Orthopaedic 5 (3.5)

Values are mean (SD) or proportion (%). P values relate to * a two
sample t-test, ** chi-square test, and *** Fisher's exact test.
ASA=American Society of Anesthesiologists, ENT=ear nose and throat
AF=atrial fibrillation. Missing data relate to incomplete anaesthetic
chart documentation.

Table 2
Use of neuromuscular blocking drugs during restricted and
unrestricted availability of sugammadex (intervention)

Variable Restricted, Unrestricted, P value
 n (%) n (%)

Sugammadex use 141 144 <0.0001
 No 131 (92.9) 50 (34.7)
 Yes 10 (7.1) 94 (65.3)
Neostigmine use 141 144 <0.0001
 No 57 (40.4) 126 (87.5)
 Yes 84 (59.6) 18 (12.5)
No reversal 139 144 0.12
 No 100 (71.9) 115 (79.9)
 Yes 39 (28.1) 29 (20.1)
RSI 138 144 0.03
 No 132 (95.7) 128 (88.9)
 Yes 6 (4.4) 16 (11.1)
Suxamethonium use 141 144 0.58
 No 136 (96.4) 137 (95.1)
 Yes 5 (3.6) 7 (4.9)
Rocuronium use 141 144 0.006
 No 13 (9.2) 30 (20.8)
 Yes 128 (90.8) 114 (79.2)
Cisatracurium use 141 144 0.58
 No 129 (91.5) 129 (89.6)
 Yes 12 (8.5) 15 (10.4)
Vecuronium use 141 144 0.02
 No 138 (97.9) 132 (91.7)
 Yes 3 (2.1) 12 (8.3)

Values are proportion (%) and P values relate to a chi-square test.
RSI=rapid sequence induction. Missing data are due to incomplete
collection.

Table 3
Rocuronium use during restricted and unrestricted availability of
sugammadex

 Restricted
Variable
 n Mean SD

Rocuronium dose, mg 128 55.9 24.1
Rocuronium, no. of doses 127 1.90 1.48
Rocuronium, last dose to reversal, min 122 91.7 68.1

 Unrestricted
Variable
 n Mean SD P value

Rocuronium dose, mg 114 60.4 22.3 0.13
Rocuronium, no. of doses 114 1.96 1.27 0.71
Rocuronium, last dose to reversal, min 112 62.0 52.4 0.0002

Values are mean and standard deviation and P values relate to a two
sample t-test.

Table 4A
Patient outcomes during restricted and unrestricted availability
of sugammadex

Variable Restricted, Unrestricted, P value
 n (%) n (%)

PONV * 138 141 0.93
 No 114 (82.6) 117 (83.0)
 Yes 24 (17.4) 24 (17.0)
Inadequate reversal ** 138 141 0.06
 No 134 (97.1) 141 (100.0)
 Yes 4 (2.9) 0
PACU oxygen desaturation * 138 141 0.95
 No 111 (80.4) 113 (80.1)
 Yes 27 (19.6) 28 (19.9)

Values are proportion (%) and P values * relate to PONV and PACU
desaturation using a chi-square test while P values ** relate to a
Fisher's exact test. PONV=postoperative nausea and vomiting,
PACU=post-anaesthetic care unit.

Table 4B
Patient outcomes during restricted and unrestricted availability
of sugammadex

Variable Sugammadex use N Mean SD P value

Theatre time, min 0.01
 Restricted 140 143.5 85.8
 Unrestricted 143 120.0 71.2
Time in PACU, min 0.23
 Restricted 134 79.6 31.5
 Unrestricted 141 75.2 28.4
Hospital stay, days 0.035
 Restricted 139 4.2 3.5
 Unrestricted 143 3.4 3.0

Values are mean and standard deviation and P values relate to a two
sample t-test. PACU=post-anaesthetic care unit.
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Article Details
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Author:Watts, R.W.; London, J.A.; van Wijk, R.M.A.W.; Lui, Y.-L.
Publication:Anaesthesia and Intensive Care
Geographic Code:8AUST
Date:Mar 1, 2012
Words:3544
Previous Article:Rural anaesthetic audit 2006 to 2010.
Next Article:Unrestricted access to sugammadex: impact on neuromuscular blocking agent choice, reversal practice and associated healthcare costs.
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