R. C. Clarke

Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011

BACKGROUND Neuromuscular blocking drugs (NMBDs) are the most common cause of intraoperative anaphylaxis in Western Australia. Differences in the rates of anaphylaxis between individual agents have been surmised in the past, but not proven, and are an important consideration if agents are otherwise equivalent. METHODS We estimated a rate of anaphylaxis to NMBDs by analysing cases of NMBD anaphylaxis referred to the only specialized diagnostic centre in Western Australia over a 10 yr period. Exposure was approximated by analysing a 5 yr period of NMBD ampoule sales data. Agents were also ranked according to the prevalence of cross-reactivity in patients with previous NMBD anaphylaxis. RESULTS Rocuronium was responsible for 56% of cases of NMBD anaphylaxis, succinylcholine 21%, and vecuronium 11%. There was no difference in the severity of reactions for different NMBDs. Rocuronium had a higher rate of IgE-mediated anaphylaxis compared with vecuronium (8.0 vs 2.8 per 100,000 exposures; P=0.0013). The prevalence of cross-reactivity after NMBD anaphylaxis suggested that succinylcholine also has a high risk of triggering anaphylaxis. Cisatracurium had the lowest prevalence of cross-reactivity in patients with known anaphylaxis to rocuronium or vecuronium. CONCLUSIONS Rocuronium has a higher rate of IgE-mediated anaphylaxis compared with vecuronium, a result that is statistically significant and clinically important. Cisatracurium had the lowest rate of cross-reactivity in patients who had previously suffered anaphylaxis to rocuronium or vecuronium.

The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model*

The availability of sugammadex as a selective encapsulating agent for rocuronium has led to speculation that it may be useful in mitigating rocuronium‐induced anaphylaxis. Off‐label use of sugammadex for this indication has already been documented in case reports although there are theoretical objections to the likelihood of an allergen‐binding agents being able to attenuate the immunological cascade of anaphylaxis. Using a cutaneous model of anaphylaxis in rocuronium‐sensitised patients, we were unable to demonstrate that sugammadex was effective in attenuating the type‐1 hypersensitivity reaction after it has been triggered by rocuronium, but we were able to demonstrate that these patients are anergic to sugammadex‐bound rocuronium. These findings demonstrate that a cyclodextrin can bind an allergen and exclude it from interacting with the immune system, and may potentially lead to novel applications in other allergic diseases. However, there is no evidence that sugammadex should be used for the treatment of rocuronium‐induced anaphylaxis, and clinical management should follow established protocols.

Survival from perioperative anaphylaxis in Western Australia 2000–2009

BACKGROUND The mortality from perioperative anaphylaxis has recently been quoted in a range between 3 and 9%. However, it was our impression in Western Australia that we had had no deaths from perioperative anaphylaxis for over a decade. As we have comprehensive processes in place to investigate both perioperative anaphylaxis and anaesthesia-related deaths, we undertook this study to determine our actual perioperative anaphylaxis mortality rate. METHODS We obtained the number of deaths related to perioperative anaphylaxis for the decade 2000-2009 from the database of the West Australian Anaesthetic Mortality Committee; in Western Australia it is a legal requirement to report all deaths that occur within 48 h of an anaesthetic, and all deaths due to a complication of an anaesthetic. We obtained the number of cases of perioperative anaphylaxis for the same period from the database of the West Australian Anaesthetic Drug Reaction Clinic. RESULTS From 2000 to 2009, there were 45 anaesthesia-related deaths in Western Australia, but none of these involved anaphylaxis. Over this period, there were 264 cases classified by the West Australian Anaesthetic Drug Reaction Clinic as anaphylaxis. The 95% confidence interval for the observed 0/264 mortality rate is 0-1.4%. There were about three million anaesthetics administered in Western Australia over the decade, giving a perioperative anaphylaxis rate of ~1:11,000. CONCLUSIONS Our incidence of perioperative anaphylaxis was within expectations, but our mortality rate was lower than recently quoted figures. It is likely that the current true perioperative anaphylaxis mortality rate is within the range 0-1.4%.

Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis

Neuromuscular blocking agents (NMBAs) are the most commonly implicated drugs in IgE‐mediated anaphylaxis during anaesthesia that can lead to perioperative morbidity and mortality. The rate of NMBA anaphylaxis shows marked geographical variation in patients who have had no known prior exposure to NMBAs, suggesting that there may be external or environmental factors that contribute to the underlying aetiology and pathophysiology of reactions. Substituted ammonium ions are shared among NMBAs and are therefore thought to be the main allergenic determinant of this class of drugs. Substituted ammonium ions are found in a wide variety of chemical structures, including prescription medications, over‐the‐counter medications and common household chemicals, such as the quaternary ammonium disinfectants. Epidemiological studies have shown parallels in the consumption of pholcodine, a nonprescription antitussive drug which contains a tertiary ammonium ion, and the incidence of NMBA anaphylaxis. This link has prompted the withdrawal of pholcodine in some countries, with an ensuing fall in the observed rate of NMBA anaphylaxis. While such observations are compelling in their suggestion of a relationship between pholcodine exposure and NMBA hypersensitivity, important questions remain regarding the mechanisms by which pholcodine is able to sensitize against NMBAs and whether there are other, as yet unidentified, agents that can elicit similar hypersensitivity reactions. This review aims to explore the evidence linking pholcodine exposure to NMBA hypersensitivity and discuss the implications for our understanding of the pathophysiology of these reactions.

Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study.

We report 13 cases of presumed rocuronium‐induced anaphylaxis in which sugammadex was administered with the intention of reversing the immunological reaction. Of these 13 cases, eight (62%) were later confirmed to be type‐1 hypersensitivity reactions to rocuronium, three (23%) were triggered by an antibiotic and two (15%) were non‐immunologically mediated. Response to treatment was scored by the treating anaesthetist, and compared with haemodynamic and inotrope measurements from the resuscitation and anaesthetic records. Haemodynamic improvement was seen in only six (46%) cases, three of which were associated with a non‐rocuronium trigger. Of the three cases in which the treating anaesthetist thought that sugammadex had been beneficial, one was not caused by rocuronium, one had no improvement in blood pressure and one required 8.5 times as much adrenaline in boluses after, compared with the period before, sugammadex administration. These data suggest that sugammadex does not modify the clinical course of a suspected hypersensitivity reaction.

The First Case Report of Anaphylaxis Caused by the Inclusion Complex of Rocuronium and Sugammadex

A 50-year-old man developed a severe anaphylactic reaction shortly after the administration of sugammadex at the end of an uneventful laparoscopic appendectomy. Subsequent skin testing was negative to all agents to which the patient was exposed including sugammadex. Because of the temporal relationship to the administration of sugammadex, further skin testing was performed with premixed sugammadex and rocuronium that produced a markedly positive response. This is the first case report of anergy to the individual components but sensitivity to the inclusion complex of rocuronium and sugammadex. Written informed consent was obtained from the patient for skin testing, photography, laser perfusion imaging, and publication of this case report.

Sugammadex, rocuronium and mast cell numbers in the rat liver

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Cefalotin as antimicrobial prophylaxis in patients with known intraoperative anaphylaxis to cefazolin

BACKGROUND The most common trigger for intraoperative anaphylaxis in Western Australia for the period 2014-5 was an antibiotic used for surgical prophylaxis, cefazolin. In these patients who subsequently present for surgery, alternative cephalosporins are forbidden by current guidelines because of concerns regarding an increased risk of anaphylaxis. However, consideration of the structure-activity relationships relevant to anaphylaxis suggests that cefalotin is a safe alternative because of structural dissimilarities, although there are no pubished clinical data relevant to the perioperative setting. METHODS Patients diagnosed with intraoperative anaphylaxis to cefazolin at the Western Australian Anaesthetic Allergy Clinic were tested with intradermal cefalotin and, if negative, subsequently challenged i.v. If tolerated, cefalotin was recommended for subsequent surgery, and subjects were followed up to determine the safety of subsequent intraoperative doses. RESULTS Twenty-one subjects diagnosed with immediate hypersensitivity to cephazolin, including 19 subjects with confirmed anaphylaxis, participated. None tested positive to intradermal cefalotin, and all received a graded i.v. challenge to cefalotin without developing signs or symptoms of anaphylaxis. Three subjects subsequently received intraoperative cefalotin 12-139 days later without adverse events. CONCLUSIONS A negative intradermal cefalotin skin test has a good negative predictive value in patients who have previously suffered anaphylaxis to cefazolin, allowing the rational and desirable use of this alternative cephalosporin for future surgery and the avoidance of less desirable antimicrobial agents.

Sugammadex in anaphylaxis – a case-control study? A reply

nium triggered or not [1], acknowledging the lack of existing evidence and practical difficulties of obtaining it. I would like the authors to clarify the question they were seeking to answer in their paper. They state that they wanted to compare cases treated with sugammadex and subsequently confirmed to be triggered by rocuronium, with those that were not. However, they draw the conclusion that sugammadex cannot be relied upon as an effective treatment in anaphylaxis and does not modify the immunological cascade of a suspected hypersensitivity reaction. Do the authors consider that their study was adequately designed to either confirm or refute this? Secondly, I question the rigor of the peer review process for the paper. It is clearly stated in the title that this is a case-control study, although the method used is far from that of a case-control study. Indeed, there has been no search and selection of cases to use as controls. Those presumed to be controls are a subset of those identified while searching for cases. This is unfortunate, as a well designed, case-control study would have been a very appropriate methodology (providing one of the higher levels of evidence achievable) to gather evidence on the use of sugammadex in suspected anaphylaxis due to rocuronium, given the low frequency of cases. Have the authors considered identifying a group of suitable controls and using that as a comparison for the cases already identified? Nevertheless, this case series provides interesting reading in the run up to the imminent NAP6 study on peri-operative anaphylaxis.