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Three Part Question

In [adult patients with clinical signs of anaphylaxis likely due to rocuronium]
Does [the administration of sugammadex]
Result in [improved haemodynamic parameters]

Clinical Scenario

A forty-year-old patient is brought to the Emergency Department (ED) by paramedics with suspected drug intoxication. They have a Glasgow-Coma-Scale score of 3 and the decision is made to perform a Rapid-Sequence-Induction (RSI) to enable control of the airway, neuroprotective anaesthesia and facilitate transfer to the radiology department. Immediately following administration of Alfentanil, Propofol and Rocuronium, they develop profound cardiovascular instability thought likely to be Rocuronium-induced anaphylaxis. Following initial treatment (with adrenaline, steroids and antihistamines), the Anaesthetic Consultant in attendance suggests giving Sugammadex to encapsulate the Rocuronium. You wonder if Sugammadex can really improve cardiovascular instability in established anaphylaxis?

Search Strategy

PubMed whole catalogue (search date 11/10/2020)
OVID Medline 1946 – October Week 5 2020
CENTRAL via Cochrane Register of Studies Online (CRSO)
PubMed whole catalogue (search date 11/10/2020):
(rocuronium OR (“rocuronium” [MeSH])) AND (sugammadex OR (“Sugammadex” [MeSH])) AND (anaphylaxis OR urticaria OR hypersensitivity OR (“hypersensitivity, immediate” [MeSH]) OR mast cells OR (“mast cells” [MeSH]) OR hypotension OR (“hypotension” [MeSH]) OR shock OR (“shock” [MeSH]) OR angioedema OR (“angioedema” [MeSH]) OR cardiac arrest OR (“heart arrest” [MeSH]))

OVID Medline 1946 – October Week 5 2020:
((((((((anaphy* OR (exp Drug Hypersensitivity/ OR exp Hypersensitivity/)) OR exp Hypersensitivity, Immediate/) OR exp Mast Cells/) OR exp Hypotension/) OR exp Shock/) OR exp Angioedema/) OR exp heart arrest/) AND exp Rocuronium/) AND exp Sugammadex/

CENTRAL via Cochrane Register of Studies Online (CRSO):
#1 rocuronium, #2 MeSH descriptor: [Rocuronium] explode all trees, #3 sugammadex, #4 MeSH descriptor: [Sugammadex] explode all trees, #5 anaphylaxis, #6 hypersensitivity, #7 MeSH descriptor: [Hypersensitivity] explode all trees, #8 MeSH descriptor: [Heart Arrest] explode all trees, #9 MeSH descriptor: [Hypotension] explode all trees, #10 MeSH descriptor: [Mast Cells] explode all trees, #11 MeSH descriptor: [Shock] explode all trees
Search: (#1 OR #2) AND (#3 OR #4) AND (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11).
All searches limited to Humans and English

Search Outcome

PubMed – 67 results.
OVID Medline – 44 results.
Cochrane– 19 results
Studies were excluded manually that were duplicates or didn’t directly answer the clinical question.
The remaining 7 publications were reviewed:

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Barbosa & Da Cunha 2012 Brazil	A 62-year-old female. Interventions: - 1.5mg ADR - 2L crystalloid. - SUG 9.7mg/Kg concomitantly with additional 300mcg ADR	4 (Case Report)	Clinical Signs	CVS parameters improved within 2 minutes following SUG. Cutaneous signs resolved	No clear exclusion of other causes of CVS instability. Unclear ADR dose and route. Unclear timing of SUG dose. SUG given with ADR bolus.
			Further CVS support after SUG	None
			Immuno-chemical evidence	Not reported
Binczak et al 2019 France	A 74-year-old female. Interventions: - Salbutamol (10 puffs) - ADR 20mcg - SUG 800mg (15mg/kg) - ADR 110mcg	4 (Case Report)	Clinical Signs	Heart rate improved immediately, blood pressure improved 15-20 minute post-SUG	Long delay with further interventions prior to CVS stability. Management of anaphylaxis not in line with UK practice.
			Further CVS support after SUG	Yes – ADR 10 + 100mcg given
			Immuno-chemical evidence	Raise histamine, normal tryptase, ROC IgE positive.
Hakozaki et al 2016 Japan	A 19-year-old male. Interventions: - Phenylepherine 1mg - ADR 300mcg - Hydrocortisone 100mg - Chlorpheniramine 10mg - SUG 2.7mg/Kg given 24 mins post-ROC - Further ADR 300mcg bolus - ADR infusion	4 (Case Report)	Clinical Signs	CVS improved prior to SUG, then deteriorated following SUG.	Comparably small dose of SUG given. No timing provided for tryptase or histamine results.
			Further CVS support after SUG	Yes – ADR bolus + infusion
			Immuno-chemical evidence	tryptase & histamine, Skin-prick reaction to ROC.
Harper et al 2018 UK	19 cases identified within a National Audit Project of suspected perioperative anaphylaxis given SUG within 6h of presentation. 7 cases later confirmed to be ROC-induced. Median dose SUG 300mg (range 150-1200mg).	4 (Case Series)	Clinical Signs	Not reported	Very minimal detail given within a much larger publication. Unclear timings of any drugs given, ADR or other drug requirements or outcomes. Outcomes for non-ROC induced anaphylaxis not reported in detail.
			Further CVS support after SUG	Not required in 4 out of 7 cases
Hashimoto et al 2019 Japan	2 adults. Interventions: Case 1: - Methyl-prednisolone 375mg - SUG 4mg/Kg Case 2: - Ephedrine 4mg - Rapid crystalloid infusion - Methyl-prednisolone 125mg - SUG 4mg/Kg	4 (Case Series)	Clinical Signs	1: HR improved, no BP drop pre- or post-SUG. 2: CVS instability and cutaneous signs improved.	Unclear timing of CVS parameter improvement. Other drugs given not typical of UK anaphylaxis protocols.
			Further CVS support after SUG	None
			Immuno-chemical evidence	1. Urograffin confirmed as trigger 2. patient refused testing
Platt et al 2015 Australia	13 cases from “drug reaction clinic” referrals – 61% of these later confirmed as ROC-induced anaphylaxis. Interventions: - SUG 2.7-19.3mg/Kg	4 (Case Series)	Clinical Signs	Systolic BP higher in 46% following SUG (38% in confirmed ROC-induced)	Heterogenous case reports. Unclear if retrospective or prospective. Biased cohort based on clinician suspected ROC-induced anaphylaxis. ‘Impression of effectiveness’ is subjective and variable even within isolated case reports. High variability of SUG dose. Minimal reporting of other interventions.
			Further CVS support after SUG	Further ADR given in 61% (87% of confirmed ROC-induced)
			Immuno-chemical evidence	ROC-induced confirmed in 8/13
			Impression of effectiveness	Definite 23% Possible 38% No 38%
Plaud, B 2014 France	Literature review of 8 case reports. Interventions: - Crystalloids - Colloids - Hydrocortisone - Metaraminol - Chlorpheniramine - Epherdrine - ADR in 7/8 cases (200mcg – 4mg) - SUG 4-18mg/Kg	4 (Literature Review)	Clinical Signs	Correction of hypotension in <2 minutes in 50% of cases	Heterogeneous case reports. Includes patient also reported in Platt et al (2015). Limited meta-analysis of the case reports. Literature search methodology not reported. One included paper is only available in French. Variable drugs given, timing and dosage.
			Further CVS support after SUG	Of those receiving ADR infusion, 75% were weaned post-SUG.
Spoerl et al 2016 Switzerland	2 adults (within 3 reported) with hypotension. Interventions: Case 1: - Hydrocortisone - Clemastane - ADR - IV fluids - SUG 200mg Case 2. - IV fluids - ADR 1.5mg total - SUG 400mg	4 (Case Series)	Clinical Signs	Case 1. rapid CVS stability after SUG. Case 2. CVS stabilised rapidly after SUG.	Poor detail in individual case reports. Unclear timing of interventions. In case 2, ROC given twice despite haemodynamic compromise. Compromised validity of immuno-chemical testing.
			Further CVS support after SUG	Not reported
			Immuno-chemical evidence	Raised tryptase & positive skin test in one of the two cases reported

Comment(s)

Sugammadex is a modified gamma cyclodextrin indicated in the reversal of neuromuscular blockade due to the aminosteroids Rocuronium and Vecuronium (European Medicines Agency 2015). In the UK, Sugammadex is currently given in ‘approximately a quarter of cases when the anaesthetist suspected Rocuronium as a trigger for anaphylaxis’ (Harper, 2018:123). Whilst it is an off-licence indication, it is understandable why Sugammadex could be seen as a beneficial agent in this context. McDonnell et al (2011) initially suggested encapsulation of the Rocuronium molecule would prevent IgE cross-linkage and thereby “remove” the trigger to the anaphylaxis. Additional hypotheses on the mechanism of action later emerged; Sugammadex may increase muscular tone promoting venous return (Motamed et al 2012) or have inherent vasoactive properties that are as-yet unquantified (Platt et al 2015). Concerningly, there has also been evidence that Sugammadex (or the Sugammadex-Rocuronium complex) can itself be a trigger for anaphylaxis (Harper 2018). Sugammadex will also simultaneously reverse the neuromuscular blockade conferred by the Rocuronium; this will have potentially negative implications on airway and ventilation management in the anaphylactic patient (Clarke et al 2012). It is this dichotomy that prompts the need for evidence in this clinical context. The above case reports/series comprise the main body of the available evidence. There are several common issues with these retrospective observational case reports: • Small (or n=1) cases not chosen from a representative population. • Biased convenience sampling based on clinician’s judgement at the time of the event. • Lack of control groups, therefore, causality cannot be established. • Lack of an ability to generalise to a population. • They are subject to publication bias; more of the above case reports indicating a benefit from Sugammadex may be a reflection of this. Within the case reports there are further issues. There is significant heterogeneity in: • Variability of timing of Sugammadex administration and dosage. • Numerous and variable concomitant medication. • Variable doses for all medications across all reports. • Variable immunochemical evidence of immediate hypersensitivity reactions to Rocuronium, including cases where alternative triggers were positively evidenced. • Non-standardised indications for CPR affecting drug delivery. Fundamentally, one of the biggest issues with the current evidence is that the observed results (in all cases to date), could be explained by the other medication given alongside Sugammadex. Due to the rarity of the condition, it seems unlikely that obtaining high level evidence will be feasible in the immediate future. Case-control studies remain an avenue for further study but would require significant investment and organisation. Alternative study designs such as cutaneous reactions (Clarke et al 2012) may provide insight but are of limited value in assessing the cardiovascular effects of Sugammadex in established anaphylaxis.

Editor Comment

CVS = cardiovascular, CPR – cardiopulmonary resuscitation, ROSC = return of spontaneous circulation, SUG = Sugammadex, ADR = Adrenaline, ROC = Rocuronium

Clinical Bottom Line

The current evidence does not support the routine use of Sugammadex in suspected Rocuronium-induced anaphylaxis. There is some low-level evidence that might support its off-licence use in refractory anaphylaxis in extremis, by senior clinicians on a case-by-case basis only.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Barbosa, F. T., & da Cunha, R. M. Case of anaphylaxis induced by rocuronium treated with sugammadex. Revista brasileira de anestesiologia 2012: 62(4), 538–542
2. Binczak, M., Fischler, M., & Le Guen, M. Efficacy of Sugammadex in Preventing Skin Test Reaction in a Patient With Confirmed Rocuronium Anaphylaxis: A Case Report. A&A practice 2019: 13(1), 17–19.
3. Hakozaki, T., & Murakawa, M. Rocuronium-induced anaphylaxis not improved by low dose sugammadex: a case report. Anaesthesia and intensive care 2016: 44(4), 522
4. Harper, N., Cook, T. M., Garcez, T., Lucas, D. N., Thomas, M., Kemp, H., Kong, K. L., Marinho, S., et al. NAP 6 Chapter 11: Immediate management and departmental organisation in Royal College of Anaesthetists (2018) Anaesthesia, Surgery and Life-Threatening Allergic Reactions Royal College of Anaesthetists 2018: 112-136
5. Hashimoto, M., Sato Boku, A., Tachi, N., Okumura, Y., Kadoi, K., Harada, J., & Okuda, M. Two Cases of Rocuronium-Induced Anaphylaxis/Anaphylactic Shock Successfully Treated With Sugammadex. Anesthesia progress 2019: 66(3), 151–155.
6. Platt, P. R., Clarke, R. C., Johnson, G. H., & Sadleir, P. H. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study. Anaesthesia 2015: 70(11), 1264–1267
7. Plaud, B. A new option for the treatment of anaphylaxis linked to steroidal neuromuscular blockers: How much value should we grant to case reports? Canadian journal of anaesthesia = Journal canadien d'anesthesie 2014: 61(6), 511–518
8. Spoerl, D., D'Incau, S., Roux-Lombard, P., Harr, T., & Czarnetzki, C. Non-IgE-Dependent Hypersensitivity to Rocuronium Reversed by Sugammadex: Report of Three Cases and Hypothesis on the Underlying Mechanism. International archives of allergy and immunology 2016: 169(4), 256–262