the metablog

Cartoons reduce anxiety during anesthesia induction in children

Tue, 21 Oct 2014 00:00:00 +0000

Two studies caught my eye in Anesthesia & Analgesia. Teams from both Canada and South Korea independently investigated the anxiolytic value of using cartoons during paediatric induction.

The concept is not new, though this evidence is. The teams looked at different admission and induction types and in two distinctly different cultures, but showed very similar and significant benefits of using cartoons during pediatric induction.

Both papers highlighted the cost of perioperative anxiety in children. Anyone with even a passing pediatric anesthetic practice will agree with the reported 50% incidence of perioperative anxiety. Intense anxiety is associated with negative behavioural adaptations, some of which persist for months or longer. Severe childhood anxiety at anesthetic induction is almost as distressing for parents and anesthetist alike as it is for the poor child.

"Kain et al.¹ showed that 67% of children had behavior changes the day after surgery , and this persisted for 6 months in 20% and for 1 year in 7% of the children." - Lee ²

Both authors highlighted that oral midazolam premedication, still a common tool for managing perioperative anxiety, leads to its own logistic and childhood behavioral problems. Some of the related research has been collected here on metajournal.

Lee's team investigated the use cartoons chosen by the child displayed on a tablet or laptop computer during the induction. 130 ASA 1 or 2 South Korean children aged 3 to 7 years old were admitted and cannulated the night before, then underwent intravenous induction (thiopentone or ketamine). Surgeries included tonsillectomies, herniorrhaphy and ophthalmic surgery. Three groups were compared: control; favorite toy; and cartoon distraction.

While the group permitted to bring their favorite toy had significantly lower pre-operative anxiety than the other groups in the pre-anesthetic room, the cartoon distraction group demonstrated the lowest anxiety level in theatre. Not only was the average anxiety level for the group lower (45% lower than the control, 26% lower than favorite toy group), but also the number of children showing no increased anxiety was the greatest (43% versus 23% and 7% for favorite toy & control groups respectively). All results were statistically significant.

Lee's study was a prospective, randomized trial, although not blinded. The cartoon was started in the pre-anesthetic bay and parents accompanied all children for their induction. Four children were excluded from the favorite toy group after forgetting to bring the toy, and these were unfortunately not included in the analysis. Although non-ideal statistically, it is likely that including them in the analysis would only have further improved the demonstrated benefit of cartoon distraction.

Cartoon Distraction Alleviates Anxiety in Children During Induction (Lee 2012)

Quality of Study
★ ★ ★ ☆ ☆
Moderately sized, single-centre, randomized controlled trial. Did not analyze with intention-to-treat. Potential observer bias.

Clinical significance
★ ★ ★ ★ ☆
Study demonstrates a significant improvement (up to 45%) in a problem experienced by at least half of all pediatric surgical patients.

General applicability
★ ★ ☆ ☆ ☆
Maybe limited outside countries where night-before admission and cannulation is the norm; or where parents are not routinely allowed into the OR.

In Real Life
★ ★ ★ ★ ☆
Given ubiquity of both portable video devices and children's love of cartoons, would be easy to institute with very little cost. Can be applied by individual anaesthetist.

Overall Practice Changing Strength
★ ★ ★ ★ ☆
In the right setting with only a little preparation, cartoon distraction at induction is easy to institute with little risk and likely a significant benefit

Mifflin and team designed an elegant study, comparing 42 children distracted with cartoons in theatre to 47 controls exposed only to the humor and jokes of their anesthesiologist.³ Children aged between 2 and 10 presenting for ambulatory surgery were selected for the study and underwent inhalation induction with nitrous oxide and sevoflurane. No analyzed children were premedicated.

In her preamble, Mifflin also highlighted Kain's findings, associating peri-operative anxiety with "...more pain during recovery, longer hospital stays, and more negative behavior changes."³ As well as mentioning the questionable benefits of other anxiety-alleviating techniques, such as parental presence at induction.

In an innovative twist Mifflin's team used the pre-existing laparoscopic video towers to stream cartoons selected by the children from YouTube. Consistent with Lee's findings, they noted a significant reduction in induction-related anxiety:

"Children in the video distraction group were significantly less anxious at induction and showed a significantly smaller change in anxiety from holding to induction than did children in the control group."

Average anxiety measured by the 'modified Yale Preoperative Anxiety Scale' was 61% lower in the video distraction group than in the control. The median of mYPAS differences between each group was 31.2 (95% CI, 27.1?33.3), or almost half the average mYPAS score of the control group. Again, all results were statistically significant.

Mifflin also experienced participant loss and then failed to analyze by intention-to-treat. Unfortunately the two subjects lost were from the video distraction group, one through withdrawal of consent and the other inadvertently premeditated. There was no blinding, although Mifflin attempted to identify observer bias using two coder observers for 20% of the cases. No bias was evident, though this technique is far from perfect and true observer blinding would be preferred.

Unlike the Lee study, almost all children were unaccompanied by parents (only 2 in the study group and 3 in the control had parental accompaniment), reflecting the local institutional practice. Also of marked difference, all children received inhalation induction for day ambulatory surgery, compared with night-before admission and intravenous induction in Lee's studied group. Both teams used the modified Yale Preoperative Anxiety Scale for measuring perioperative anxiety.

Video to Reduce Anxiety in Children During Inhaled Induction (Mifflin 2012)

Quality of Study
★ ★ ★ ☆ ☆
Moderately sized, single-centre, randomized controlled trial. Did not analyze with intention-to-treat. Potential observer bias.

Clinical significance
★ ★ ★ ★ ☆
Study demonstrates a large improvement (up to 61%) in a problem experienced by at least half of all pediatric surgical patients.

General applicability
★ ★ ★ ☆ ☆
Maybe limited outside of ambulatory surgery; outside of inhalation induction; or where parents are routinely allowed into the OR.

In Real Life
★ ★ ★ ★ ★
Given ubiquity of both portable video devices and children's love of cartoons, would be easy to institute with very little cost. Researchers themselves conducted study without requiring any extra equipment.

Overall Practice Changing Strength
★ ★ ★ ★ ☆
In the right setting with only limited preparation, cartoon distraction at induction is easy to institute with little risk and a large benefit.

It is the differences between these two studies conducted on opposite sides of the planet that make the results all the more interesting. Taken individually it would seem questionable to apply their findings to other surgical settings: ambulatory surgery versus admission; intravenous versus inhalation induction; pre-cannulation versus cannulation; parental presence versus none.

Despite these marked cultural and practical differences the degree of the improvement in peri-induction anxiety was very consistent: from 40 to 60% reduction in the children's mYPAS score with a very simple, practical and cheap intervention. While it would be hasty to generalize this to all pediatric cases, there was clearly a benefit for these two disparate practice flavors.

I must conclude with a sober note though: while the studies both show dramatical reductions in anxiety we cannot assume that this also translates into an improvement in post-operative behavioral changes in children. Let us hope it does, but these studies alone are not yet enough to conclude that.

Nonetheless it is time to consider how video distraction may improve your pediatric anesthesia practice.

Kain ZN, Mayes LC, O'Connor TZ, Cicchetti DV. Preoperative anxiety in children: predictors and outcomes. Arch Pediatr Adolesc Med 1996;150:1238?45 ↩
Lee J, et al. Cartoon Distraction Alleviates Anxiety in Children During Induction of Anesthesia. Anesth Analg. 2012 Sep 25. ↩
Mifflin KA, Hackmann T, Chorney JM. Streamed Video Clips to Reduce Anxiety in Children During Inhaled Induction of Anesthesia. Anesth Analg. 2012 Oct 9. ↩

Combatting decision fatigue in anaesthesia and critical care

Tue, 14 Oct 2014 00:00:00 +0000

Dynamic decision making' describes the practice of anaesthesia more than any other single characteristic - and anaesthesia is characterised by dynamic decision making more than any other medical speciality. The typical surgical case requires the anaesthetist or anesthesiologist to make hundreds of decisions, modified to suit the evolving environment of the case. Each decision itself modifies the patient context, creating a multiverse of decision and outcome possibilities.

"No plan survives contact with the [surgeon and patient] – Helmuth von Moltke

These decisions add up. Big and small, decision after decision over the day leads to a measurable fall in the quality of our decisions by the final case. Psychologists describe this as 'ego depletion', colloquially called 'decision fatigue'.¹

Though not yet widely appreciated in medicine (though it is gaining traction on the medical front-line²), decision fatigue has been identified in many decision-focused professions. Decision fatigue has been identified in judges ruling on cases, with parole decisions made later in the day being of 'lesser quality' and having lower rates of parole than those at the start of the day (10% vs 70% for the first case of the day heard).³

"We find that the percentage of favorable rulings drops gradually from ~65% to nearly zero within each decision session and returns abruptly to ~65% after a break."

Most people have experienced decision fatigue when shopping: rows of impulse-and-sugar presented invitingly next to the supermarket checkout queue. Fatigued by a constant stream of decision making while shopping, we are more susceptible to the impulse buying of a treat. Dan Spears, a Princeton economist, studied this consumer decision fatigue in the poor.⁴ He used a model of selling soap in an Indian village, demonstrating that for the poor each financial transaction (ie. buying soap, even if at a cheap price) required a significant weighing of cost and benefit. This cognitive overhead accumulates, worsening the quality and rationality of subsequent decisions.

Augenblick and Nicholson showed that as voters considering candidates or propositions further down a lengthy ballot list there was an increased "...tendency of voters to abstain or rely on decision shortcuts, such as voting for the status quo or the first listed candidate." ⁵

It appears that we possess only a finite decision making capacity. Baumeister and colleagues first observed this in 1998, labelling it 'ego depletion', when subjects exerting self-control by abstaining from chocolate then quit earlier on subsequent puzzles.⁶

The nature of decision fatigue is not yet completely understood. Two characteristics appear to play a role:

The sheer number of decisions;
The complexity of these decisions.

Together these wreak a toll on our decision making performance, though the exact reason is unclear.

"No matter how rational and high-minded you try to be, you can‘t make decision after decision without paying a biological price. It‘s different from ordinary physical fatigue – you‘re not consciously aware of being tired – but you‘re low on mental energy."¹

Consequences of decision fatigue fall into two groups: 1. making reckless, lower-quality decisions by relying on shortcuts or over-simplified rule-based heuristics; or 2. 'decision paralysis', abstaining from making any decision at all. Fischer showed that the consumption of limited 'self-control resources' required during decision making then lead to greater risk taking by the subjects.⁷

Decision fatigue can have a critical effect on anaesthetist performance, particularly in crisis situations when faced with a hundred small decisions over a few dynamic, rapidly-evolving minutes. The correct decisions may quickly resolve the crisis while flawed choices escalate or worsen the situation. The more complex and mentally demanding each decision is the greater the withdrawal from an anaesthetist's finite mental resources.

Three ways to combat decision fatigue

1. Avoid unnecessary complexity

Complex anaesthesia techniques not only create more points of failure, but also place a greater decision burden on the anaesthetist. This is not to say that you should only practice simple anaesthetic techniques, but rather avoid unnecessary complexity when it adds little benefit for your patient.

Do not walk a path of increasing complexity in your chosen technique without good reason;
Appreciate that there are small costs to complex techniques that may need to be paid: will your patient pay that price?

2. Use and practice personal checklists and crisis algorithms

The rise of the medical checklist has been a useful addition to our practice, though in many instances the checklist ideology is driven by a bureaucratic need for auditability instead of quality improvement.

Checklists and crisis algorithms (eg. difficult airway and advanced life support algorithms) that have been optimised for your own practice simplify the decision making process during critical moments. The key is to have both an ownership of the algorithm (be invested in actually applying it) and to have repeatedly practiced or simulated the process before.

By having previously considered the scenario you both reduce the mental cost of making each decision (by reducing available options from infinite to manageable) as well as increasing the chance that the correct decision will be made.

3. Call for help

In a crisis calling for help should be one of our first actions. Calling for help breaks decision paralysis and by providing an outsider's perspective on the problem improves decision quality. The caveat is that we can get too much of a good thing; too many helpers dilute responsibility and distract from critical priorities. The key is calling for the right help.

Like many performance traps in anaesthesia, half the battle is won when we gain insight into how a challenge is expressed in our own practice. Decision fatigue is a particularly insidious threat as we are often unaware of its presence or effect. The anaesthetic crisis is a particularly ripe time for decision fatigue to undermine our performance.

"...know yourself and you will win all battles" – Sun Tzu

Tierney J. "Do You Suffer From Decision Fatigue?". New York Times Magazine. August 21 2011. ↩
Oto B. When thinking is hard: managing decision fatigue. EMS World. 2012 May;41(5):46-50. ↩
Danzigera S, Levav J, Avnaim-Pessoa L, "Extraneous factors in judicial decisions", Proceedings of the National Academy of Sciences. Feb 25 2011. ↩
Spears D. Bounded Rationality as Deliberation Costs: Theory and Evidence from a Pricing Field Experiment in India. October 13 2009. ↩
Augenblick N, Nicholson S. Ballot position, choice fatigue, and voter behaviour. July 2011 ↩
Baumeister RF, Bratslavsky E, Muraven M, Tice DM. Ego depletion: is the active self a limited resource? J Pers Soc Psychol, 74(5):1252?1265, 1998. ↩
Fischer P, Kastenmüller A, Asal K. Ego depletion increases risk-taking. J Soc Psychol. 2012 Sep-Oct;152(5):623-38. ↩

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. ↩

Articles and metajournal Notes

Fri, 03 Oct 2014 10:11:00 +0000

A great way to capture and share knowledge gleaned from the evidence is with...

Article Notes

You may have noticed that suggested articles arriving in your emailed metajournal or appearing in online article lists have a pearl or summary above the abstract. My aim is to make keeping up to date and understanding the current literature even more time efficient.

You can add your own notes to any article or abstract you read — both to help you capture the most actionable 'take-away' message, and also to share your wisdom with others. Simple scroll down below the article abstract to find a list of notes and a text-box for you to add your own.

Notes can be either pearls, summaries or comments, depending on the type of information you want to share.

Two examples of articles with notes to get you started:

The 2008 POISE study: Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery.
Fink & Hollman's 2012 'Myths and facts in neuromuscular pharmacology'.

Jump in and share your wisdom!

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. ↩