the metablog

Sugammadex and rocuronium anaphylaxis

Thu, 23 Oct 2014 00:00:00 +0000

I have been intrigued since the first case reports appeared describing the use of sugammadex in rocuronium anaphylaxis. It sounds beautiful and elegant. A drug that magically mops up the offending molecule, removing it from circulation; quickly reversing the cardiovascular collapse as rapidly as it reverses muscle relaxation.

The little we know

There have been case reports from 5 countries showing dramatic improvement of rocuronium-confirmed anaphylaxis after administration of sugammadex.
One case study showed a dose-dependent effect of sugammadex on modifying anaphylaxis.
There are not yet any published cases of rocuronium anaphylaxis where sugammadex was administered without clinical improvement (though beware).
Sugammadex although incompletely encapsulating rocuronium, does prevent the rocuronium epitope from binding IgE.
Cutaneous and in vitro models of hypersensitivity have shown no or limited ability of sugammadex to modify type 1 hypersensitivty after triggering.
Our understanding of the pathophysiology of anaphylaxis is over-simplified and incomplete.

Unfortunately the truth is not quite as clear. Case reports showing impressive recovery of rocuronium anaphylaxis minutes after giving sugammadex are tempered by in vitro and in vivoimmunological studies suggesting an inability of sugammadex to modify a type 1 hypersensitivity reaction. The reality is likely somewhere in between, highlighting our limited understanding of anaphylaxis and our tendency to rush to over-simplified models of disease processes.

The story so far...

Jones and Turkstra first raised the possibility of using sugammadex to treat rocuronium anaphylaxis in 2010.¹ One year later Nolan McDonnell and team published the first case report of a remarkable use of sugammadex to manage rocuronium anaphylaxis.² McDonnell described a 33 year old having an elective diagnostic laparoscopy suffering anaphylaxis to rocuronium. After 19 min of conventional resuscitation, involving CPR, 3500 mL of intravenous fluids and 4 mg of epinephrine/adrenaline - 500 mg of sugammadex was given with remarkable effect:

"A dose of 500 mg (6.5 mg kg21) was given while chest compressions were in progress. The last dose of epinephrine had been given 4 min previously. Approximately 45 s after administration and while chest compressions were in progress, the patient suddenly opened her eyes and reached for her tracheal tube.

"Her next recorded arterial pressure and SpO2 (which had been unrecordable on administration of the sugammadex) were 111/56 mm Hg and 97%, respectively, with a heart rate of 126 beats/min. This was recorded 2 min after she had exhibited spontaneous movement."

It is difficult not to be impressed. McDonnel was apropriately cautious when discussing possible mechanisms for the effect:

"...it may be that the binding of the rocuronium molecule by sugammadex prevented further vasoactive mediator release and allowed the previously administered epinephrine to have increased efficacy. ... it may be that the associated increase in muscle tone assisted with the restoration of venous return and cardiac output. It is also possible that the effect was purely by coincidence and that the reversal in her clinical condition was secondary to the epinephrine and fluid resuscitation that had been instituted. Other as yet unidentified processes may also have played a role."

Since that first Australian case report there has been a steady trickle of others.³ Funnell, Griffiths and Hodzovic published a report from the UK of a 47 year old woman undergoing a laparoscopic cholecystectomy with confirmed rocuronium anaphylaxis. Sugammadex 400 mg was given after 1 hour of conventional therapy with remarkable results:⁴

"Within 2.5 min, the patient awoke and resumed spontaneous respiration, airway pressures improved, and it was possible to half the epinephrine infusion to 0.09 mg/kg."

Motamed, Baguenard and Bourgain from the Institut Gustave Roussy in France described management of rocuronium anaphylaxis in a 61 year old woman with 4 mg/kg sugammadex 14 min after intubation.⁵ Also from France, Barthel and team successfully managed anaphylaxis in a 44 year old woman with sugammadex 16 mg/kg, and suggested a dose-related effect.⁶ There are other case reports, now from a total of five countries, with likely many more unpublished.⁷ Notably there are not yet any case reports of confirmed rocuronium anaphylaxis where sugammadex was not beneficial.⁸

In healthy contrast Wordsworth reports a 50 year old lady experiencing rocuronium anaphylaxis with spontenaous recovery after 18 minutes of conventional resuscitation in the absence of sugammadex. This should give us pause.⁹ Admittedly this case was much less severe anaphylaxis than the sugammadex case reports, but could the reported 'sugammadex rescues' be the result of spontaneous recovery? The natural cessation of mast cell degranulation and the effectiveness of conventional resuscitation, helped along by improvements in venous return with recovery of skeletal muscle tone - and with a little wishful thinking and confirmation bias thrown in?

Requirements for sugammadex to modify anaphylaxis

Take a step back and consider what would sugammadex need to biochemically achieve in order to modify anaphylaxis? Are there other prerequisites?

Conveniently, smarter minds than I have considered this very question. Jones and Turkstra neatly layout five requirements that need to be satisfied:¹

Rocuronium must be the cause of anaphylaxis. "This would appear to be self-evident, but the causative agent is incorrectly identified at the time of the reaction in approximately one-third of cases."
"Concentration of rocuronium at the effect site (tissue-bound mast cells and circulating basophils) [must] fall rapidly as a result of encapsulation by sugammadex."
"The affinity of sugammadex for rocuronium exceeds the affinity of the complementary cell-bound IgE antibodies."¹⁰
"Encapsulation [must] hide the epitope responsible for rocuronium-induced anaphylaxis."¹¹
"Endogenous and exogenous steroids [need] to be preserved in concentrations that would favour homeostasis."¹²

Unfortunately these neat requirements assume that anaphylaxis is entirely an IgE mediated process. This is not true. We are only just beginning to understand the depths of our ignorance when it comes to anaphylaxis; identifying alternate pathways for mast cell activation (IgG, macrophages, platelet activating factor) and the importance of other mediators in the process, like nitric oxide.¹³

Immunological studies: in vitro and in vivo

Three prospective studies have examined aspects of the immune-modifiying potential of sugammadex.

Clarke, Sadleir and Platt from Sir Charles Gairdner Hospital, Perth, Australia conducted an elegant prospective study of known rocuronium-sensitive individuals using a cutaneous model of anaphylaxis.¹⁴ Using different order, timing and concentrations of rocuronium and sugammadex they investigated its ability to modify the cutaneous immune response to rocuronium. They showed two important results:

Sugammadex pre-mixed with rocuronium was successful in preventing a type 1 hypersensitivity reaction, demonstrating that while sugammadex does not completely encapsulate the rocuonium molecule it does prevent the epitope from binding IgE.
Sugammadex was however unable to modify the hypersensitivity reaction after it had been triggered by rocuronium - when using a cutaneous model measuring wheal and flare.

They concluded:

"...there is no evidence that sugammadex should be used for the treatment of rocuronium-induced anaphylaxis, and clinical management should follow established protocols ... our main concern is that the use of sugammadex in anaphylaxis may distract the clinician from instituting well-established management protocols for anaphylaxis."

Leysen and team conducted an in vitro experiment using basophils isolated form known rocuronium-sensitive subjects.¹⁵ Their findings were consistent with Clarke's, showing that while sugammadex pre-mixed with rocuronium prevented basophil activation, sugammadex could not prevent ongoing activation after basophils had been triggered by rocuronium, even at very high sugammadex concentrations.

Finally, Tomak et al. investigated the ability of sugammadex to reduce mast cell degranulation in the rat liver.¹⁶ They showed that sugammadex administered five minutes after rocuronium did reduce the tryptase concentration in rat liver. The applicability of this to human physiology and its use as an anaphylaxis model are questionable (obviously these were not rocuronium-sensitive rats!), although it may hint at an alternate mechanism for sugammadex's benefit: directly modifying the rocuronium-mast cell interaction through non-IgE means.¹⁷

So, what are we to believe?

On one hand we have case reports showing dramatic improvement - we do our patients a disservice to dismiss these as coincidence. On the other hand, testing of conventional models of anaphylaxis produce no such dramatic effect.

Sugammadex is again demonstrated to be a unique drug; it is the first time we have had the ability to rapidly remove a drug allergen from the circulation. Our view of anaphylaxis as an irreversible biochemical cascade entirely dependent on IgE is likely inadequate and incomplete. The observed clinically benefits from sugammadex in the setting of rocuronium anaphylaxis may well be due to modifying processes at the fringes of our current understanding of anaphylaxis.

The case for using sugammadex in the resuscitation of rocuronium anaphylaxis

Quality of Evidence
★ ★ ☆ ☆ ☆
Evidence in favor is limited to single case reports, and evidence in opposition to prospective, non-clinical immunological studies involving imperfect models of anaphylaxis.

Quantity of Evidence
★ ★ ☆ ☆ ☆
A small number of case studies and a very small number of prospective non-clinical immunological studies.

In Real Life
★ ★ ★ ☆ ☆
Where sugammadex is available, it's use in suspected rocuronium anaphylaxis resistant to conventional resuscitation is practical and easily instituted. The most likely adverse effect is unwanted reversal of muscle relaxation, which may not always be desirable in a critically ill patient. Administering sugammadex should never delay conventional anaphylaxis resuscitation.

Overall Practice Changing Strength
★ ★ ☆ ☆ ☆
There is insufficient evidence to alter the resuscitation priorities in conventional management of anaphylaxis, however once these have been instituted, if sugammadex is available and its use will not delay other therapies (eg. epinephrine) it could be considered.

Jones PM, Turkstra TP. Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown. Anaesthesia. 2010 Jan;65(1):89-90; author reply 90. ↩
McDonnell NJ, Pavy TJ, Green LK, Platt PR. Sugammadex in the management of rocuronium-induced anaphylaxis. Br J Anaesth. 2011 Feb;106(2):199-201. ↩
Interestingly all in women, reflecting their disproportionately higher incidence of perioperative anaphylaxis. ↩
Funnell AE, Griffiths J, Hodzovic I. A further case of rocuronium-induced anaphylaxis treated with sugammadex. Br J Anaesth. 2011 Aug;107(2):275-6. ↩
Motamed C, Baguenard P, Bourgain JL. Possible mitigation of rocuronium-induced anaphylaxis after administration of sugammadex J Anaesthesiol Clin Pharmacol. 2012 Jan;28(1):127-8. ↩
They initially gave 12 mg/kg with only a temporary improvement in BP. A further 4 mg/kg produced sustained cardiovascular stability. Barthel F, Stojeba N, Lyons G, Biermann C, Diemunsch P. Sugammadex in rocuronium anaphylaxis: dose matters. Br J Anaesth. 2012 Oct;109(4):646-7. ↩
Anesthetists from my own institution successfully used sugammadex in a rocuronium-anaphylaxis scenario where conventional therapy had failed. ↩
While this may represent a reporting or publication bias, given the body of case reports now showing sugammadex benefit a report describing the opposite would be significant and readily publishable. Nonetheless we caution "...the absence of evidence is not evidence of absence." ↩
Wordsworth HI, Raja Y, Harrison S. Sugammadex and rocuronium-induced anaphylaxis. Br J Anaesth. 2011 Jun;106(6):911-2. ↩
Non-NMBD sensitized IgE often shows very high allergen affinity, although there are many reasons to not assume the same for NMBD-sensitized IgE as discussed by Brain Baldo: respond2articles 'Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown. ↩
This has been confirmed! See Leysen (2011) and Clarke (2012) below. ↩
There is no evidence that sugammadex binds endogenous steroids to a clinically meaningful degree. ↩
Baldo B. Sugammadex and rocuronium-induced anaphylaxis Anaesthesia. 2012 Oct;67(10):1174-5 ↩
Clarke RC, Sadleir PH, Platt PR. The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model. Anaesthesia. 2012 Mar;67(3):266-73. ↩
Leysen J, Bridts CH, De Clerck LS, Ebo DG. Rocuronium-induced anaphylaxis is probably not mitigated by sugammadex: evidence from an in vitro experiment. Anaesthesia. 2011 Jun;66(6):526-7. ↩
Tomak Y, et al Effects of sugammadex and rocuronium mast cell number and degranulation in rat liver. Anaesthesia. 2012 Oct;67(10):1101-4. ↩
Unfortunately the authors mistakenly claimed that Clarke et al. showed sugammadex attenuated hypersensitivity reactions, when in fact they did not. ↩

Sugammadex, suxamethonium and the rapid sequence induction

Thu, 09 Oct 2014 00:00:00 +0000

Does sugammadex mean the end of suxamethonium for rapid sequence induction?

The answer: No, not by a long shot. Let me explain...

Suxamethonium (succinylcholine) is a depolarising muscle relaxant and often the first choice for muscle paralysis when a rapid sequence induction (RSI)¹ is needed. In addition to working quickly suxamethonium has a very rapid offset. For both anaesthetist and patient these are very desirable characteristics, although they come at a price. The price is suxamethonium's long list of side effects, ranging from minor to life threatening.² Were it not for it's life-saving fast-kinetics, suxamethonium's use in modern anaesthesia would no longer be justifiable.

This article is part two in a three part series beginning with 'If sugammadex is the answer, what is the question?'.

Enter rocuronium

When rocuronium was first introduced in the 1990s it was met with excitement.³ Rocuronium's claim to fame was a very fast onset of action. Because it was less potent than other non-depolarising muscle relaxants of its generation (atracurium & vecuronium) a larger dose was required to achieve the same level of muscle paralysis. This dose created a large concentration gradient between plasma and the neuromuscular junction resulting in a faster onset of action. By giving a very large dose of rocuronium the anaesthetist could produce acceptable intubating conditions within 60 seconds, creation the first reliable modified rapid sequence induction.

Unfortunately the result of using such a large dose of rocuronium is a prolonged blockade. Even at lower doses (0.6 mg/kg 2x ED95) rocuronium produces a block that lasts at least five times longer than suxamethonium. At the 1.2 mg/kg (4x ED95) modified-RSI-dose of rocuronium the block duration stretches out even longer, reaching the duration of pancuronium. In the event of being unable to intubate, or worse unable to ventilate, prolonged blockade is disastrous. At this point rocuronium only provided half a solution for the replacement of suxamethonium.

Sugammadex

Sugammadex is a modified Ɣ-cyclodextrin and the first 'selective relaxant binding agent' (SRBA). Sugammadex has a high binding affinity for the aminosteroid rocuronium, reversing its neuromuscular blockade almost instantly. By using a large modified-RSI dose of Rocuronium (1.2 mg/kg) and then a deep-paralysis-reversal dose of sugammadex (16 mg/kg ~$1,200), reversal of muscle relaxation has been demonstrated to be faster even than the offset of suxamethonium.

But does this really mean the end of sux?

Enter sugammadex

Sugammadex reignited the anaesthesia community's interest in replacing suxamethonium. For the first time we could not only use rocuronium for a modified rapid sequence induction, but then use sugammadex to reverse the paralysis even faster than suxamethonium could itself wear-off. Several studies showed that sugammadex 16 mg/kg could reverse even deep rocuronium relaxation.⁴ Sørensen also showed no difference in the quality of laryngoscopy views, although the study was not powered to detect such a difference. Sørensen et al. simulated rapid sequence inductions, showing rocuronium-sugammadex yielded a median time from intubation to spontaneous ventilation of 216 s compared with 406 s for suxamethonium alone.⁵ Sugammadex is an ideal drug to reverse even large doses of rocuronium in a 'Cannot Intubate Cannot Ventilate' (CICV) scenario.

This seems to make rocuronium-sugammadex a natural successor to suxamethonium. However in our rush to replace suxamethonium we are neglecting the goal of the rapid sequence induction.

Rapid sequence induction, like it says on the tin

Just as it says on the tin, the aim of the rapid sequence induction is to rapidly induce anaesthesia allowing fast intubation and airway protection. Rapid offset, while desirable is not the primary goal. Suxamethonium has a warm place in many anaesthetist's heart because it quickly produces excellent intubating conditions. Fast onset and excellent conditions lead to quickly protecting the airway from blood or gastric contents.

Rocuronium reliably produces acceptable intubating conditions within 60 seconds⁶ - but likely only excellent conditions at a higher dose (1-1.2 mg/kg). Most of the time the difference will not matter. But 'most of the time' is not an acceptable foundation for an anaesthetic technique.

"There was a statistically significant RR favouring succinylcholine when comparing the primary outcome of excellent intubating con- ditions with a RR of 0.86, (95% CI 0.80 to 0.92). The number needed to harm (NNH) for this outcome was 8." Perry JJ, et al.

Perry and team's Cochrane meta-analysis of 37 studies comparing suxamethonium to rocuronium included data from 1,300 patients.⁷ Sub-group analysis showed significantly better intubating conditions at 60 seconds for suxamethonium compared with rocuronium doses of 0.6-0.7 mg/kg. The authors showed no significant differences at higher rocuronium doses but due to the small number of studies could not make a recommendation.

"...did not find conclusive evidence that increasing doses of rocuronium led to better intubating conditions. Succinylcholine created significantly more excellent intubation conditions than rocuronium at doses of 0.6-0.7 mg/kg . There was no statistical difference for the 0.9-1.0 mg/kg or 1.2 mg/kg groups. It is difficult to draw conclusions regarding the higher doses of rocuronium as there are relatively few studies which have examined the higher dose (1.2mg/kg) of rocuronium (n = 86)."

And here lies the problem.

The purpose of rapid sequence induction is rapid intubation. If rocuronium cannot be shown to provide as good intubating conditions as suxamethonium even at a higher dose, then rocuronium should not universally replace suxamethonium.

In that context it is ironic that the arrival of a drug suitable for reversing rocuronium when intubation fails is driving this debate.

Rocuronium-sugammadex: Theory versus reality

The final problem is the practicality of using sugammadex in a CICV situation. Sørensen's comparison of rocuronium-sugammadex to suxamethonium is impressive but the artificial nature of the trial undermines its applicability to real world anaesthesia:

Reversal of deep rocuronium paralysis in a 70kg patient requires 1.1 grams of sugammadex. In a 100kg patient we need 1.6 g; that's eight ampoules of sugammadex! Ignoring the cost (upwards of $1,600) drawing up eight ampoules of anything takes time. We need immediate access to eight ampoules (is it in your anaesthetic trolley, difficult airway cart or locked in a drug cupboard?) and someone to draw-up and administer that drug. In a critical airway situation none of that happens quickly.
Sørensen's study started the clock at intubation then immediately gave sugammadex. In a true CICV crisis the critical factor will be time to decision to reverse.

When we use suxamethonium the clock starts at the end of the syringe. When we use sugammadex the clock cannot start until we decide, prepare and give our wonder drug.

Sugammadex's 200 second lead will be quickly eaten up and exceeded in a true airway crisis. It is the rare anaesthetist or anesthesiologist who can make the decision to bail out of a failing intubation in the first 2 minutes. The psychological pressure of an emergency induction makes our fixation on intubation more likely rather than less.

Suxamethonium reversal is (generally) automatic. Rocuronium reversal requires a decision by the anaesthetist at a time when decisions are often not well made.

Relaxant reversal is no panacea in an airway crisis. Kyle, Gaylard and Riley described a CICV scenario where reversal with sugammadex did not relieve the airway loss and a surgical airway was still required.⁸ The perception of sugammadex as an RSI safety net may encourage anaesthetists to make decisions that they normally would not.

Sugammadex: some answers, still many questions

The choice to use rocuronium-sugammadex for rapid sequence induction in your practice will depend upon on three criteria:

Ease of intubation for this patient. Will compromised intubating conditions with rocuronium matter? How critical is it to protect the airway quickly for this patient?
Accessibility of sugammadex. Is it in the room? Is there enough for this patient? Is there someone other than my anaesthesia assistant and I who can quickly prepare and administer it?
Risk of suxamethonium versus rocuronium for your population. Is the risk of anaphylaxis (or other serious side effects) for suxamethonium significantly greater than for rocuronium for this population (e.g. in the US) or not (e.g. in Europe and likely Australia).

Sugammadex for RSI Criteria

Your decision to use rocuronium-sugammadex must be contextualised: to your resources, your population, your patient and your patient's needs. Over simplified black-and-white rules have very little place in anaesthesia.

Sugammadex is a unique drug with an amazing ability to reverse rocuronium paralysis. It extends the situations where rocuronium is a good relaxant choice, particularly for modified rapid sequence inductions. While sugammadex increases the safety of rocuronium use for rapid sequence induction, the evidence does not yet support a wholesale shift from sux to roc-sugammadex.

It is important for us not to loose sight of the purpose of the RSI: rapid intubation and airway protection. The drug that best facilitates this in each individual patient is the drug to use. Suxamethonium still has much to offer our patients.

The case to replace suxamethonium with rocuronium-sugammadex

Quality of Evidence
★ ★ ★ ★ ☆
Sugammadex has been shown to quickly, effectively and consistently reverse even deep rocuronium relaxation. In the RSI situation rocuronium reversal is faster than even the offset of suxamethonium.

Quantity of Evidence
★ ★ ★ ☆ ☆
There are only a small number of studies investigating sugammadex use in the RSI. Most studies use simulated RSI.

In Real Life
★ ★ ☆ ☆ ☆
The practical use of sugammadex for reversal of Roc-RSI is questionable outside the controlled environment of an RSI simulation.

Overall Practice Changing Strength
★ ★ ★ ☆ ☆
Roc-sugammadex offers an alternative to suxamethonium in specific situations where it is contraindicated, but the weight of evidence does not currently support total replacement of suxamethonium.

Finally, in part three next week I will explore the evidence for and against using sugammadex to manage rocuronium anaphylaxis.

The rapid sequence induction, as the name suggests, involves very fast induction of general anaesthesia with rapid intubation of the trachea in order to protect the airway quickly, often in emergency situations. ↩
Most significantly, anaphylaxis, hyperkalaemia and malignant hyperthermia, and also including suxamethonium apnoea and various cardiac arrythmias. Not to mention the 'minor' side effect of feeling run over by a truck after recovering from a suxamethonium paralysis. Suxamethonium adverse effects - wikipedia ↩
Hunter JM. Rocuronium: the newest aminosteroid neuromuscular blocking drug. Br J Anaesth. 1996 Apr;76(4):481-3. ↩
Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007362. ↩
Sørensen MK, et al. Rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine: a randomized trial. Br J Anaesth. 2012 Apr;108(4):682-9. Epub 2012 Feb 6. ↩
Larsen PB, et al. Intubation conditions after rocuronium or succinylcholine for rapid sequence induction with alfentanil and propofol in the emergency patient. Eur J Anaesthesiol. 2005 Oct;22(10):748-53. ↩
Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002788. ↩
Kyle BC, Gaylard D, Riley RH. A persistent 'can't intubate, can't oxygenate' crisis despite rocuronium reversal with sugammadex. Anaesth Intensive Care. 2012 Mar;40(2):344-6. ↩

If sugammadex is the answer what is the question?

Thu, 02 Oct 2014 13:49:00 +0000

Sugammadex (Bridion®) is a remarkable drug. It also has a cool name. The anaesthesia community has moved very quickly to embrace the potential of this first and only 'selective relaxant binding agent' (SRBA), despite it's considerable cost.

"Sugammadex is likely the most exciting drug in clinical neuromuscular pharmacology since the introduction of atracurium and vecuronium in the middle 1980s." - Miller RD ¹

Novel pharmacology and a cool name are however insufficient reasons alone to alter our practice. There is a certain lack of clarity in the community and literature as to where sugammadex fits into anaesthesia practice and to what extent it should alter how we currently manage muscle relaxation and reversal. There has also been very limited discussion of the unintended consequences of a shift to rocuronium-sugammadex based techniques over other neuromuscular drugs.

There is no doubt that sugammadex offers a new and improved way of reversing aminosteroid muscle relaxation, in particular that from rocuronium. The speed at which it reverses even profound neuromuscular blockade is incredible and potentially life saving. Sugammadex‘s onset is 10 times faster than neostigmine and three times faster than edrophonium.²

Sugammadex

Sugammadex is a modified Ɣ-cyclodextrin and the first 'selective relaxant binding agent' (SRBA). The addition of eight carboxyl-thio-ether groups at the C6 positions extends the size of the lipophilic cavity, enabling encapsulation of the NMBD rocuronium bromide. The high binding affinity for the aminosteroid rocuronium effectively prevents biological interaction of rocuronium.

As rocuronium in plasma binds within sugammadex, rocuronium molecules in the neuromuscular junction move down their concentration gradient into the circulation where they too are selectively bound to sugammadex in a 1:1 ratio. Rocuronium is strongly bound to sugammadex by electrostatic forces between the positively charged rocuronium quaternary ammonium ion and the negatively charged sugammadex side-chains. The rate of molecular binding to dissociation is approximately 25 million to 1 for rocuronium and 10 million to 1 for vecuronium.

A Cochrane review by Abrishami et al.³ of 18 RCTs totalling 1,300 patients supported the superiority of sugammadex over neostigmine at all studied levels of blockade (see below in the sidebar). Importantly there were no more adverse events compared with neostigmine (< 1%) - though it is worth highlighting that these are still relatively small numbers and we cannot ascertain the true level of safety until a significant period of market surveillance passes.⁴ Reminding us that very little in life or medicine is risk-free, there have been at least three cases of hypersensitivity to sugammadex reported from Japan.⁵

Neville Gibbs and Peter Kam very nicely outlined the three current indications for use of sugammadex⁶ even at it's current high cost:

Pre-planned early reversal of rocuronium when suxamethonium is contraindicated. The most obvious example is electroconvulsive therapy in patients with a pseudocholinesterase deficiency or neuromuscular denervation conditions.

Pre-planned reversal of rocuronium by sugammadex rather than neostigmine in situations where even very mild residual neuromuscular block carries significant risk to the patient. Examples fall into two groups: patients with neuromuscular disorders such as myotonic dystrophy or myasthenia gravis; and patients with severe pulmonary disease with limited reserve. The editors extended this to also include "...patients in whom reversal with anticholinesterases may be only partially effective (e.g. patients with poor renal function, hypothermia, acidosis)...".

Unplanned early reversal of rocuronium in patients with an unexpectedly difficult intubation where rapid reversal may allow awakening of the patient. Given the professional fear we have of the 'Can't Intubate Can't Ventilate' scenario it is unsurprising that it is this indication, likely the most rare of the three, that has captured anaesthesia community's greatest interest.

Since sugammadex's appearance in clinical practice, case reports covering examples of use from all three groups have been widely published. I would add a fourth indication:

Rescue from residual curarisation in those patients whom despite 'reversal' with neostigmine still have identifiable neuromuscular blockade.⁷ Incomplete reversal and residual curarisation is likely a lot more common in the PACU than we appreciate, although the clinical consequences (ie. possible increased pulmonary complications) are still poorly defined.⁸

Cochrane 2009 / Abrishami A, et al.

2 mg/kg reversal at TOF 2 appearance.
4 mg/kg reversal at PTC 1-2.
16 mg/kg reversal 3-5 min post-induction.

Should sugammadex then replace neostigmine for all aminosteroid reversal?

Clearly sugammadex offers faster and more complete NMBD reversal than either neostigmine or edrophonium. In fact sugammadex given at an appropriate dose at almost any level of neuromuscular blockade has a faster onset of action than neostigmine even at much more advanced levels of neuromuscular recovery (Geldner et al.⁹)

Additionally, use of sugammadex leads to less increase of heart-rate than when using neostigmine-glycopyrrolate or edrophonium-atropine and almost total avoidance of the dry-mouth associated with the later (5% vs 85-95%).²

There is however a degree of breathless excitement among anaesthetists proposing undemonstrated benefits of sugammadex that may lead to ill-considered changes in our practice.

"If large doses of rocuronium can be given, the surgeons may be presented with better surgical conditions with a more intense neuromuscular block, and reversal can still be accomplished..." - Miller RD¹

(The degree of muscle relaxation provided by our current titrated-use of modern NMBDs provides excellent surgical conditions - to suggest that a greater, more profound degree of relaxation will give an unspecified benefit to surgeon and patient stretches the likely benefits of sugammadex too far.)

"Will sugammadex‘s increased effectiveness, in comparison to neostigmine, lessen the need for or use of monitoring neuromuscular function?" - Miller RD¹

Surprisingly, while approved for use in Europe, UK and Australia, sugammadex's application for approval was rejected by the FDA in 2008. At the time sugammadex was owned by Schering-Plough (now owned by Merck) having bought the original intellectual property owner Organon BioSciences for $14 billion in 2007 - thought to be driven by the opportunity to control sugammadex. The primary reason for the FDA rejection is concern over hypersensitivity reactions.

Dr Ronald Miller presented on the company's behalf at the FDA meeting, "It was extremely surprising and disappointing, and bordering on unbelievable ... It‘s really a very regrettable situation ... Time may prove the FDA to be correct, but I don't think so."

No doubt the FDA's experience with Rapacuronium, a past drug from Organon, gives them good reason for conservatism. Check the status of FDA sugammadex approval here: drugs.com/history/sugammadex.

It is one thing to identify the clear advantages of sugammadex over anti-cholinesterase inhibitors - but it is quite another to rush to change our practice before a clear outcome benefit has been shown. A study from White et al.¹⁰ highlighted the wide variability in time to return to a TOF ratio of 0.9 among patients after reversal with sugammadex. While 80% of patients reached TOFR 0.9 ≤ 5 min the wide variability included one patient for whom reversal took 22 minutes. Clearly it is not yet time to throw out our neuromuscular monitors.

There are three major reasons why sugammadex should not yet be our first reversal choice in most surgical cases:

1. Sugammadex: Cost

The current open-market price for sugammadex is an order of magnitude greater than for anti-cholinesterase inhibitor / anti-cholinergic combinations. Until the cost of sugammadex falls it is difficult to justify its use as a standard reversal agent.

Several reports have attempted to identify the effects of giving anaesthetists unrestricted access to sugammadex as a reversal agent. These have been conducted in the setting of hospitals fortunate enough to negotiate (confidential) reduced pricing for the drug. Ledowski et al.[^ledowski] demonstrated an increase of about AUS$85 per case (using the list price of sugammadex) for muscle relaxation and reversal costs. While this appears a small amount, as a colleague pointed-out, multiply by tens-of-thousands of cases and this quickly becomes a significant new drain on a hospital budget.

An economic study of the cost effectiveness of sugammadex¹¹ suggested that it may be cost effective if there are significant time savings in the operating theatre but not if the savings are instead in the PACU. However even then it is unlikely that time savings achieved through faster reversal will translate directly into theatre savings given that there are many factors determining case turn-over.

2. Sugammadex: Unproven outcome benefit

The pharmacological advantages of sugammadex are undeniable. But outside the few edge cases discussed ('Can't Intubate Can't Ventilate' being the most prominent) no outcome benefit has been shown for most surgical cases. Over the past two decades the definition of residual neuromuscular blockade has progressively risen from a TOF ratio (T4/T1) of 0.7 to a TOF ratio of 0.9. Residual blockade even with intermediate agents rocuronium and atracurium is more common than most anaesthetists would like to admit.¹² Though pharyngeal tone dysfunction has been demonstrated to occur at a TOFR < 0.9, possibly increasing the risk of aspiration, the clinical significance for most patients remains uncertain.¹³ ¹⁴

Audit data suggesting modest shortening of hospital stay when sugammadex is used is intriguing, though far from definitive or consistent between studies.¹⁵ It is conceivable that a reduction in post-operative pulmonary complications due to a decrease in residual blockade incidence could have this benefit.

3. Sugammadex: Unintended consequences of a shift to rocuronium

Hospitals that provided unrestricted access to sugammadex saw a dramatic increase in the consumption of rocuronium if they were not already a predominate rocuronium consumer. The consequences of this shift to rocuronium have not been properly discussed.

In parts of Europe, notably France and Norway, rocuronium is a disproportionate cause of anaphylaxis. However in the US the incidence of anaphylaxis to rocuronium is quite low. The reason for this incongruity are best discussed elsewhere (see: Pholcodine: significance for anesthesia?) but may lead to an increase in perioperative anaphylaxis in regions where rocuronium sensitivity is more common. The situation in Australia is less clear; some unpublished reports claim that the incidence of rocuronium anaphylaxis is similar to that of suxamethonium, while older published-reports suggest that it instead merely tracks market share.

Sugammadex offers a unique and supremely effective reversal of aminosteroid muscle relaxation. It is a revolutionary and potentially life saving drug, but likely only for very specific anaesthetic scenarios. Only time will tell if its usefulness lives up to the hype for the majority of relaxant cases.

Next week, in part two I will discuss the merits of replacing suxamethonium with rocuronium/sugammadex for rapid sequence induction; and in part three explore evidence for and against using sugammadex to manage rocuronium anaphylaxis.

Miller RD. Sugammadex: an opportunity to change the practice of anesthesiology? Anesth Analg. 2007 Mar;104(3):477-8. ↩
Sacan O, White PF, Tufanogullari B, Klein K. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg. 2007 Mar;104(3):569-74. ↩
Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007362. ↩
Additionally, avoid giving under the 2 mg/kg minimum recommended dose. Eleveld and team showed that there is a limited clinical range of inadequate sugammadex dosing which can lead to recurarisation. Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Anesth Analg. 2007 Mar;104(3):582-4. ↩
Godai K, et al. Three cases of suspected sugammadex-induced hypersensitivity reactions. Br J Anaesth. 2012 Aug;109(2):216-8. Epub 2012 May 22. ↩
Gibbs NM, Kam PC. Sugammadex: restricted vs unrestricted or selective vs non-selective? Anaesth Intensive Care. 2012 Mar;40(2):213-5. ↩
A case report of this situation was recently published by de Menezes - though one could extend this argument to then include all reversal so as to avoid residual paralysis in the first place: de Menezes CC, Peceguini LA, Silva ED, Simões CM. Use of sugammadex after neostigmine incomplete reversal of rocuronium-induced neuromuscular blockade. Rev Bras Anestesiol. 2012 Jul;62(4):543-7. ↩
Fink H, Hollmann MW. Myths and facts in neuromuscular pharmacology. New developments in reversing neuromuscular blockade. Minerva Anestesiol. 2012 Apr;78(4):473-82. ↩
Geldner G, et al. A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery. Anaesthesia. 2012 Sep;67(9):991-998. ↩
White and colleagues were primarily investigating whether the degree of residual block at the time of sugammadex administration translated to a longer time to achieve reversal, when using sugammadex 4 mg/kg at least 15 min after the last dose of rocuronium: "...times to achieve a TOF of 0.9 varied from 0.8 to 22.3 and 0.7 to 8.5 min in the 0 twitch and > or = 1 twitch groups, respectively." White PF, et al. The effect of residual neuromuscular blockade on the speed of reversal with sugammadex. Anesth Analg. 2009 Mar;108(3):846-51. ↩
Paton F, et al. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation. Br J Anaesth. 2010 Nov;105(5):558-67. ↩
Possibly as high as 27% for surgery up to 90 min duration. Schreiber JU, Mucha E, Fuchs-Buder T. Residual paralysis following a single dose of atracurium: results from a quality assurance trial. Eur J Anaesthesiol. 2010 Nov;27(11):993-4. ↩
Eriksson LI, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology. 1997 Nov;87(5):1035-43. ↩
An audit by Ledowski et al. showed over 50% reduction in post-operative desaturations with sugammadex, though it was unclear whether the comparison was to neostigmine or to a combined 'neostigmine or no-reversal group'. T. Ledowski, et al. Introduction of sugammadex: influence on the incidence of residual paralysis at a tertiary teaching hospital. Anaesth Intensive Care. 2012 Sep;39(5):963. ↩
Watts RW, London JA, van Wijk RM, Lui YL. The influence of unrestricted use of sugammadex on clinical anaesthetic practice in a tertiary teaching hospital. Anaesth Intensive Care. 2012 Mar;40(2):333-9. ↩

Neuromuscular myths: We need to do better

Thu, 11 Sep 2014 00:00:00 +0000

The rise of sugammadex has lead me down a path looking into wider aspects of my own neuromuscular blocking drug (NMBD) use. The evidence for NMBD use, monitoring and reversal is interesting, both for how consistently the same messages have been repeated over the past three decades – and for how little we have improved our practice in spite of mounting evidence demanding that we should.¹

I need to do better and you probably also need to do better with how we manage NMBDs.

What is PORC?

Post-operative residual curarisation (PORC) or residual paralysis, refers to persisting neuromuscular blockade in a patient after extubation. It is considered present when the Train-of-four (TOF) ratio is less than 0.9, usually measured in recovery or the post anesthesia care unit (PACU).

The historical comparison of studies investigating PORC is difficult because for many years a TOF ratio of 0.7 was considered the cutoff value for PORC. Volunteers given d-tubocurarine had normal vital capacity and inspiratory force when the TOFR recovered above 0.7. Then in the mid-1990s a TOF ratio of 0.8 was used in studies investigating PORC.

Now in the 21st century a TOFR 0.9 is considered the cut-off for defining PORC. A TOFR 0.9 has been chosen because consequences of residual paralysis, such as pharyngeal dysfunction and impairment of respiratory function have been shown below this TOF ratio.

This article was inspired by Fink & Hollman's "Myths and facts in neuromuscular pharmacology".² An up-to-date collection of articles related to post-op residual curarisation can be found here: Neuromuscular myths: the lies we tell ourselves.

Myth 1: Post-operative residual curarisation (PORC) is uncommon

Several surveys of anesthetists show that we falsely consider the incidence of PORC in the post-anesthesia care unit to be very low. Videira surveyed anesthetists in Brazil who estimated the incidence of PORC at 5%,³ while surveyed anesthetists and anesthesiologists in Europe and the US estimated the PORC incidence to be <1%.⁴

The truth is quite different. Schreiber found a 27% incidence of a TOF ratio <0.9 after surgery between 60 and 90 minutes long.⁵

A before-and-after audit by Bailard highlighted a drop in PORC from 62% to 3% of patients over a ten year period when a department improved quantitative neuromuscular monitoring of patients from 2% to 60% and the use of anti-cholinesterase reversal agents from 6% to 40% of patients.⁶ The dramatic fall in PORC incidence should not over-shadow the persistence of the problem (3.5%) even in the presence of quantitative monitoring and routine reversal.

Videira also showed that anesthetists considered the prevalence of residual block much higher in their colleague ‘s practices than their own. This illusory superiority (also called the above average effect) is a cognitive bias that leads us to overestimate the positive while underestimating our negative characteristics relative to others.⁷ It is likely a core reason why non-evidence-based NMBD management persists in our specialty.

Myth 2: PORC is not clinically significant

Anesthetists argue that even if common, PORC is not clinically significant. The evidence suggests otherwise.

Back in 1997 Berg identified a correlation between pancuronium, PORC and post-operative pulmonary complications during six days of post-op follow-up.⁸ Pancuronium-receiving patients with PORC (defined as TOFR < 0.7 in this study) suffered a three-times greater incidence of atelectasis, infiltrates and pneumonia than those without PORC – although there was no such increased incidence in those receiving atracurium or vecuronium.

Before we congratulate ourselves having moved away from pancuronium, more recent studies have focused on the intermediate NMBDs atracurium, vecuronium and rocuronium. Murphy showed that patients monitored by quantitative acceleromyography before extubation experienced less PORC, less desaturation below 90% (0% versus 21%) and less airway obstruction (0% versus 11%) during transport to the PACU.⁹^,¹⁰

"The incidence, severity, and duration of hypoxemic events during the first 30 min of PACU admission were less in the acceleromyography group (all p < 0.0001)."

Lars Eriksson's research group in Stockholm has shown that at a TOFR <0.9 there is pharyngeal dysfunction and increased aspiration risk, in addition to a depression of hypoxic and hypercarbic ventilatory responses.¹¹

"...partial paralysis cause pharyngeal dysfunction and increased risk for aspiration at mechanical adductor pollicis TOF ratios < 0.90. Pharyngeal function is not normalized until an adductor pollicis TOF ratio of > 0.90 is reached."¹²

"Partial neuromuscular paralysis caused by atracurium is associated with a four- to fivefold increase in the incidence of misdirected swallowing. The majority of misdirected swallows resulted in penetration of bolus to the larynx."¹³

Kumar et al. showed that forced vital capacity and peak expiratory flow were both 20% lower, relatively, in patients with PORC compared to those with TOFR > 0.9 (13% and 9% in absolute terms).¹⁴

"As respiratory muscle weakness results in ineffective cough and inability to clear secretions from airways, FVC recovery is considered important for preventing pulmonary complications."

There is evidence that PORC is not free of consequences, although most patients likely escape significant complication. 'Getting away with it' is however not reason enough to ignore the problem. Surgical patients worldwide are now older, less fit, more obese, suffering a longer list of comorbidities and undergoing more complex surgery than ever before – each factor making PORC less physiologically tolerable.

Myth 3: Neuromuscular blocking drugs are predictable

Although the intermediate NMBDs such as vecuronium, atracurium, rocuronium and cisatrucurium provide greater reliability and improved kinetics over their predecessors, the recovery from neuromuscular blockade is still notoriously unpredictable.

Debaene et al. investigated residual paralysis in the PACU after a single intubating dose of intermediate NMBD in the absence of reversal.¹⁵ They identified PORC (TOFR <0.9) in 45% of patients, with time since NMBD ranging from 30 to 400 minutes. In the subgroup of patients 2 hours after a single NMBD dose there was still a 37% incidence of PORC. Additionally there was very wide inter-patient variability, with PORC persisting more than 6 hours in three patients, and several patients with TOFR of only 0.2 after 2 hours. Other studies confirm the wide, unpredictable inter-patient variability of NMBD duration.¹⁶

It is naive to believe it is safe to not reverse NMBDs after an arbitrary period, especially in the absence of objective neuromuscular monitoring.

"...even after the administration of a single intubating dose of intermediate-acting muscle relaxant, quantitative assessment of TOF ratio is mandatory at the end of the surgical procedure to assess the presence or the absence of residual paralysis. At best, this measurement needs to be performed in the operating room rather than in the PACU to reverse the block before extubating."

In Videira's survey almost 70% of anesthetists did not believe antagonism was necessary if more than 60 minutes had passed after giving a NMBD. Videira rightly points out that this has little relevance when deciding whether pharmacological reversal is needed:

"Textbooks state that the duration of action of atracurium and rocuronium varies from 30 to 45 minutes. However – this concept expresses a return to a mechanomyographic response equivalent to 25% of the control value (T1/T0 ~ 25%) in single twitch stimuli that corresponds to an acceleromyographic T4/T1 (TOF) ratio of 0.1."

Myth 4: Objective quantitative neuromuscular monitoring is unnecessary

Anesthetists who appreciate the importance of reversing neuromuscular blockade often still have misplaced confidence in their ability to clinically assess neuromuscular function. Videira identified that in addition to the interval since last NMBD, anesthetists commonly used the adequacy of spontaneous minute ventilation as a decision heuristic for deciding on the need for reversal.

"The adequacy of the breathing pattern was also cited heavily – This visual cue may be erroneously interpreted as a sufficient sign for tracheal extubation, instead of a necessary one. This heuristic assesses function of the diaphragm, not of the upper airway muscles."

Other clinical tests of PORC are also inadequate, whether lifting limbs or opening eyes. The 5-second Head Lift Test and the Tongue Depressor Test, often used to detect PORC in the PACU are of limited use for detecting TOFR < 0.9, having sensitivities of only 11% and 13% and specificities of 87% and 90% respectively.¹⁵ The Head Lift Test cannot identify POCR with a TOFR > 0.5. Debaene ‘s study population demonstrated Positive and Negative Predictive Values of the Head Lift and Tongue Depressor Tests of only 53-58%!

Subjective, qualitative neuromuscular monitors fare no better: Tactile TOF Fade and Double Burst Stimulation (DBS) have similar sensitivities (11% and 13% respectively), although high specificities (99% each). This provides a good Positive Predictive Value (93% & 97%) but a very poor Negative Predictive Value (57% & 58%) (depending on the incidence of PORC).¹⁵

Unfortunately a survey of anesthetists and anaesthesiologists in both Europe and the US in 2010 showed disappointingly low rates of quantitative neuromuscular monitoring: half of the anesthetists in Europe and only 20% in the US regularly monitored quantitative TOFR. 20% of Europeans and almost 10% of Americans never use neuromuscular monitors.

Neither clinical tests, clinical experience nor a visual or tactile train of four assessment will detect PORC with reliable accuracy. The weight of evidence asserts that objective quantitative neuromuscular monitoring be mandatory whenever a patient is paralysed.

Myth 5: Sugammadex will make PORC a problem of the past

The most recent interest in PORC has been stimulated by the appearance of sugammadex. The unique nature of sugammadex as a true reversal agent for aminosteroid NMBDs, such as rocuronium, offers hope that PORC may be avoidable altogether. This hope needs be tempered by one point:

We already possess the knowledge, pharmacology (neostigmine) and technology (objective quantitative neuromuscular monitors) to dramatically reduce the incidence of PORC, yet have not. PORC occurs not because of our lack of ability but because of our practice and behaviour – our lack of will. The ability to reverse one class of NMBDs with sugammadex will not magically change our willingness to do so.

The greater reliability, faster speed of onset and lesser inter-patient variability of sugammadex compared with the anticholinesterases may very likely reduce PORC incidence. Case reports of sugammadex ‘s use in neuromuscular disorders normally at high risk of residual paralysis are certainly very positive.¹⁷ However the existence of sugammadex is unlikely to dramatically change anaesthetist behaviour, and it is still too early to know the true impact of sugammadex on residual paralysis.

We need to look at our practice

Perhaps you are already a regular user of quantitative neuromuscular monitors – if so, great! But if like many you are not; or if you believe that good spontaneous minute volumes two hours after a single dose of atracurium mean that you don‘t need to reverse – then it may be beneficial to have a closer look at your neuromuscular practice.

I know I will.

The case for routine quantitative neuromuscular monitoring

Quality of Evidence
★ ★ ★ ★ ☆
High quality evidence somewhat hampered by the evolution of the definition of PORC and the progress of neuromuscular pharmaceuticals over the past 30 years. Most recent outcome evidence relies on surrogate markers of patient harm.

Quantity of Evidence
★ ★ ★ ★ ★
Large amounts of evidence covering three generations of NMBDs and spanning three decades of anesthetic practice.

In Real Life
★ ★ ★ ★ ☆
Objective neuromuscular monitoring is non-invasive, simple, effective and essentially risk free. Requires access to quantitative neuromuscular monitor.

Overall Practice Changing Strength
★ ★ ★ ★ ☆
The weight of evidence strongly supports routine monitoring of neuromuscular function, with little risk yet likely significant benefit – especially for older patients or those with comorbidities.

Case in point: Donati F. Neuromuscular monitoring: what evidence do we need to be convinced? Anesth Analg. 2010 Jul;111(1):6-8. (pubmed) ↩
Fink H, Hollmann MW. Myths and facts in neuromuscular pharmacology. New developments in reversing neuromuscular blockade. Minerva Anestesiol. 2012 Apr;78(4):473-82. ↩
Videira RL, Vieira JE. What rules of thumb do clinicians use to decide whether to antagonize nondepolarizingneuromuscular blocking drugs? Anesth Analg. 2011 Nov;113(5):1192-6. ↩
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 ↩
Schreiber JU, Mucha E, Fuchs-Buder T. Residual paralysis following a single dose of atracurium: results from a quality assurance trial. Eur J Anaesthesiol. 2010 Nov;27(11):993-4. ↩
Baillard C, Clec'h C, Catineau J, Salhi F, Gehan G, Cupa M, Samama CM. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth. 2005 Nov;95(5):622-6. ↩
The above average effect has been identified in many areas, from academic performance to driving ability. Related to this is the Dunning-Kruger effect whereby those with the lowest skill in an area have the least insight into how their skill level compares with others. ↩
Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ. 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 pancuronium. Acta Anaesthesiol Scand. 1997 Oct;41(9):1095-1103. ↩
Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, Nisman M. Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. Anesthesiology. 2008 Sep;109(3):389-98. ↩
Murphy ‘s methodology has been quite rightfully criticised for using subjective 'visual TOFR' as the control. Nonetheless the results stand as a demonstration of a correlation between an increased incidence of PACU pulmonary complication and PORC. ↩
Eriksson LI. Reduced hypoxic chemosensitivity in partially paralysed man. Acta Anaesthesiol Scand. 1996 May;40(5):520-3. ↩
Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, Kuylenstierna R. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology. 1997 Nov;87(5):1035-43. ↩
Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology. 2000 Apr;92(4):977-84. ↩
Kumar GV, Nair AP, Murthy HS, Jalaja KR, Ramachandra K, Parameswara G. Residual Neuromuscular Blockade Affects Postoperative Pulmonary Function. Anesthesiology. 2012 Oct 19; ↩
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 May;98(5):1042-8. ↩
Maybauer DM, Geldner G, Blobner M, Pühringer F, Hofmockel R, Rex C, Wulf HF, Eberhart L, Arndt C, Eikermann M. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia. 2007 Jan;62(1):12-7 ↩
Stewart PA, Phillips S, De Boer HD. Sugammadex reversal of rocuronium-induced neuromuscular blockade in two types of neuromuscular disorders: Myotonic dystrophy and spinal muscular atrophy Rev Esp Anestesiol Reanim. 2012 Sep 1. ↩