ISSN NUMBER: 1938-7172
Issue 13.7

Michael A. Fiedler, PhD, CRNA

Contributing Editors:
Mary A Golinski, PhD, CRNA
Dennis Spence, PhD, CRNA

Assistant Editor
Heather Whitten, MEd.

A Publication of Lifelong Learning, LLC © Copyright 2019

New health information becomes available constantly. While we strive to provide accurate information, factual and typographical errors may occur. The authors, editors, publisher, and Lifelong Learning, LLC is/are not responsible for any errors or omissions in the information presented. We endeavor to provide accurate information helpful in your clinical practice. Remember, though, that there is a lot of information out there and we are only presenting some of it here. Also, the comments of contributors represent their personal views, colored by their knowledge, understanding, experience, and judgment which may differ from yours. Their comments are written without knowing details of the clinical situation in which you may apply the information. In the end, your clinical decisions should be based upon your best judgment for each specific patient situation. We do not accept responsibility for clinical decisions or outcomes.

Table of Contents

Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial

Br J Anaesth 2018;121:749-757

DOI: 10.1016/j.bja.2018.05.056

Min KC, Bondinskey R, Schulz V, Woo T, Assaid C, Yu W, Reynders T, Declerq R, McCrea J, Dennie J, Adkinson F, Sheperd G, Gutstein DE



Purpose   The purpose of this study was to describe the potential risk of hypersensitivity and anaphylaxis with sugammadex in healthy, non-anesthetized volunteers. Secondarily, to examine blood samples for the presence of anti-sugammadex IgG and IgE antibodies, and Tryptase.


Background   Sugammadex is a cyclodextrin derivative used to reverse rocuronium and vecuronium neuromuscular block at doses of 2 to 4 mg/Kg, and with 16 mg/Kg to immediately reverse an intubating dose of rocuronium. It has a low incidence of hypersensitivity and anaphylaxis in post-marketing surveys. However, further research is needed to characterize the hypersensitivity and anaphylaxis risk after exposure in healthy, non-anesthetized volunteers.


Methodology   This was a prospective, randomized, double-blind, placebo-controlled trial conducted at four centers in the USA and 2 centers in Belgium. Healthy adults aged 18-55 years with a BMI >18 and <33 Kg/m2 were randomized to either three repeated administrations of sugammadex 4 mg/Kg, 16 mg/Kg, or placebo. A 5-week washout period was required between sugammadex administration to allow for potential sensitization.


Hypersensitivity was defined as objectively reproducible signs and symptoms of an allergic reaction after exposure to the drug. Sampson criteria were used to define anaphylaxis which included acute onset of hives, urticaria, flushing; swollen lips, or swollen tongue or airway, with at least one of the following: respiratory compromise (bronchospasm, dyspnea, stridor, reduced peak expiratory flow, or hypoxemia), and reduced blood pressure. All patients with suspected hypersensitivity reactions and a subset of control subjects had anti-sugammadex sugammadex-specific IgG/IgE antibodies levels drawn. Tryptase levels were drawn before administration of the study drug / placebo, at 3 hours post-dose, and in all subjects with potential hypersensitivity reactions. Tryptase is released from mast cells when they are activated as part of a normal immune response as well as in allergic (hypersensitivity) responses. Tryptase levels peak at 15 to 120 minutes and have a half-life of 1.5 to 2.5 hours.


Result   There were N = 375 subjects randomized to one of three groups:

  • sugammadex 4 mg/Kg (n = 151)
  • sugammadex 16 mg/Kg (n = 148)
  • placebo (n = 76)

No significant differences were seen in baseline demographics; mean age was 38 years and 53% were female. There were 25 subjects who experienced a hypersensitivity reaction after receiving at least 1 dose of sugammadex:

  • 4 mg/Kg n = 10/151 (6.6%)
  • 16 mg/Kg n = 14/148 (9.5%)
  • placebo n = 1/76 (1.3%)

All but one symptomatic subject experienced one or more symptoms within an hour of receiving sugammadex / placebo. A single subject experienced a delayed reaction 22 hours post-dose.


Twenty-one of 25 subjects experienced mild hypersensitivity reactions. There were 11 subjects who had a reaction on one or more administrations of sugammadex. Only 3 of the 25 subjects experienced a moderate hypersensitivity reaction. Only 1 experienced a severe reaction necessitating treatment with antihistamines and corticosteroids after receiving the first dose of 16 mg/Kg sugammadex. All subjects rapidly responded to treatment. One of the three subjects experienced anaphylaxis immediately after the dose with presentation of mild sneezing, nasal congestion, conjunctival edema, and a decrease in peak expiratory flow 30% below baseline. This patient did not experience hypotension. None of the subjects in the 4 mg/Kg group experienced anaphylaxis. The incidence of hypersensitivity reactions is reported in Figure 1.


Of the n = 25 subjects who experienced a hypersensitivity reaction, n = 2 (8%) were positive for anti-sugammadex IgG antibody. One subject had a positive test prior to receiving the first dose of sugammadex but was negative for antibody on the second and third dose. The second subject only had a positive antibody test before the second and third dose of sugammadex and had a hypersensitivity reaction after the second dose. None of the patients with a hypersensitivity reaction were positive for anti-sugammadex IgE. Results suggest a low likelihood of development of IgG or IgE antibodies to sugammadex with repeated administration and that these antibodies are not associated with a confirmed hypersensitivity reaction. There were no cases of elevated Tryptase levels with confirmed hypersensitivity reactions.


Figure 1. Incidence of Hypersensitivity


Conclusion   Hypersensitivity reactions and anaphylaxis can occur after administration of sugammadex. Hypersensitivity appears not to be mediated through IgG or IgE mast cell stimulation in non-anesthetized volunteers. Hypersensitivity does not necessarily occur each time the patient is dosed with sugammadex.




The rate of hypersensitivity reactions (allergic reactions) in this study is much higher than what has been reported in Phase 2 and 3 clinical trials. In those trials, the rate of allergic reactions after 3,230 exposures was 0.3% with doses ranging from 2 to 4 mg/Kg. In this study the incidence of allergic reactions was 4% after the first administration of sugammadex 4 mg/Kg in non-anesthetized patients. All these cases were considered mild reactions.

The lower rate seen in Phase 2 and 3 clinical trials is probably because signs and symptoms were not recognized or were blunted in anesthetized patients. Many patients receive dexamethasone for nausea and vomiting prophylaxis which may help prevent allergic reactions. Interestingly, only one subject in this study experienced symptoms that likely would have been classified as a hypersensitivity reaction had they occurred during general anesthesia. This 1 subject of 299 who received sugammadex equals 0.33% — almost identical to the incidence of hypersensitivity reported in previous studies with anesthetized patients.

The take home message from this study is that anesthesia providers need to be aware of the allergic reaction potential of sugammadex and be prepared to treat this adverse event with antihistamines, corticosteroids, and epinephrine if needed.

Dennis Spence, PhD, CRNA

The views expressed in this article are those of the author and do not reflect official policy or position of the Department of the Navy, the Department of Defense, the Uniformed Services University of the Health Sciences, or the United States Government.

© Copyright 2019 Anesthesia Abstracts · Volume 13 Number 7, June 20, 2019

A comparison of the analgesic efficacy of local infiltration analgesia vs. intrathecal morphine after total knee replacement: A randomised controlled trial

Eur J Anaesthesiol 2019;36:264–271

DOI: 10.1097/EJA.0000000000000943

McCarthy D, McNamara J, Galbraith J, Loughnane F, Shorten G, Iohom G



Purpose   The purpose of this study was to compare the efficacy of local infiltration analgesia (Local group) to intrathecal morphine (Spinal morphine group) for postoperative analgesia after total knee arthroplasty.


Background   Effective analgesia and early ambulation lead to earlier discharge after total knee replacement. Local anesthetic infiltration is a technique of periarticular local anesthetic admixture injection into the knee joint and surgical wound combined with placement of an intra-articular catheter for additional injections. Previous studies have found this technique provides good postoperative analgesia with a low rate of adverse effects. This study compared the effect of local infiltration to spinal morphine on postoperative pain scores after surgery. Secondary outcomes included opioid consumption and the incidence of opioid-related side effects.


Methodology   This was a prospective, randomized, single-blind study which enrolled ASA I-III patients undergoing unilateral total knee replacement with 15-17.5 mg isobaric bupivacaine spinal anesthesia. Patients were randomized to receive either local infiltration by the surgeon or 300 µg preservative-free spinal morphine. Local infiltration consisted of an injection of 0.5% levobupivacaine (2 mg/Kg) and epinephrine 0.5 mg diluted with 100 mL 0.9% normal saline. The surgeon infiltrated the deep structures (posterior capsule, ligaments) prior to prosthesis insertion followed by infiltration of the structures around the inserted prosthesis and finally infiltration of the fascia and subcutaneous layers. An intra-articular 18-gauge epidural catheter was placed at the lateral side of the knee joint prior to capsule closure. On the morning of the first postoperative day patients were given an intra-articular bolus of 15 mL of levobupivacaine 0.5% through the intraarticular catheter.


During surgery, patients were sedated with midazolam and a propofol infusion. No intraoperative opioids were administered. Surgeries were performed by the same two surgeons. Postoperatively, patients received patient-controlled analgesia which delivered morphine 1 mg every 5 minutes. They also received acetaminophen 1 g every 6 hours and diclofenac sodium 75 mg every 12 h. Patients were prescribed oral or intramuscular cyclizine 50 mg every 8 hours and oral or intravenous ondansetron 4 mg every 8 hours as needed for postoperative nausea and vomiting.


The primary outcome of this study was postoperative pain scores 24 hours after surgery. Secondary outcomes include pain scores at 2, 6, 12, and 48 hours; opioid consumption, and incidence of opioid-related side effects. A subset of 5 patients in the Local group had serial blood sampling for bupivacaine levels 2 and 6 hours postoperatively, pre-intraarticular bolus, and then at 4 and 10 hours after intraarticular bolus. Statistical analysis and sample size calculations were appropriate.


Result   There were 42 subjects who completed the study (Local group n = 22 and Spinal morphine group n = 21). No significant differences were found in patient or perioperative characteristics. Pain scores, both at rest and with passive flexion, were significantly lower in the Local group than the Spinal morphine group at 24 hours (P < 0.05). At 48 hours, pain scores at rest were similar between groups but, with movement, pain scores were significantly lower in the Local group (P = 0.037; Figure 1). No significant differences were seen in pain scores at rest or with movement at 2, 6, or 12 hours postoperatively.


No significant differences were found in opioid consumption at 24 hours (median difference 4 mg) or 48 hours (median difference 2 mg). Nausea rates were significantly lower in the Local group compared to the Spinal morphine group (16% vs. 30%, P = 0.047). Pruritus rates were also significantly lower in the Local group (3 vs. 32%, P = 0.01). No differences were found in urinary retention rates. No patient experienced respiratory depression. Bupivacaine levels at 4 hours post bolus on the morning of postop day 1 were below toxic levels in 4 of 5 subjects. One patient exceeded toxic levels of bupivacaine; but no patient experienced signs or symptoms of local anesthetic toxicity.


Figure 1. Pain Scores between Groups

Notes: LIA = local anesthetic infiltration. ITN = intrathecal (spinal). Asterisk (*) = statistical significance.


Conclusion   Local infiltration with levobupivacaine provided analgesia equal or superior to 300 µg spinal morphine (depending on time point) after total knee replacement with lower rates of opioid-related side effects (nausea and pruritus), and similar IVPCA opioid consumption.




I recall when I first started doing anesthesia, we were using intrathecal morphine for postoperative analgesia after total knee replacement. We shifted to single-shot femoral nerve blocks, and then to femoral nerve block catheters combined with multimodal analgesia with around the clock acetaminophen, celecoxib, and oxycontin immediate and sustained release. We abandoned femoral nerve block catheters because we had too many patients falling (one is too many). Then at my facility we moved to adductor canal blocks and later to a local infiltration analgesia technique without placement of an intra-articular catheter. We have found pain scores are a little higher, but the patients are getting discharged almost a day earlier.


So, when I read this study, I was interested to see that some centers in Ireland are still using intrathecal morphine for postoperative analgesia. It is not surprising that the investigators found better pain relief with local infiltration analgesia when compared to intrathecal morphine at 24 and 48 hours postoperatively. Especially, since they gave a second injection on postoperative day 1. The study confirms that intrathecal morphine 300 µg is associated with about a 30% rate of nausea and pruritus when no prophylactic agents are given.


The most novel findings of the study were the fact that one patient had a toxic level of bupivacaine 4 hours after the injection despite a lack of symptoms. It is unknown if this was just an outlier given only five patients had samples drawn. Nonetheless, it should remind us to always be prepared for local anesthetic toxicity and to make sure our surgical colleagues and nurses are aware of the signs and symptoms of this complication.


Dennis Spence, PhD, CRNA

The views expressed in this article are those of the author and do not reflect official policy or position of the Department of the Navy, the Department of Defense, the Uniformed Services University of the Health Sciences, or the United States Government.

© Copyright 2019 Anesthesia Abstracts · Volume 13 Number 7, June 20, 2019

Sugammadex is associated with better respiratory recovery than neostigmine following reversal of anaesthesia-associated neuromuscular blockade in the morbidly obese patients following elective laparoscopic surgery

Laparoscopic, Endoscopic and Robotic Surgery 2018;1:33-36

DOI: 10.1016/j.lers.2018.03.002

Johnson M, Khan OA, McGlone ER, Roman AA, Qureshi JS, Kayal A



Purpose   The purpose of this study was to compare the reversal of neuromuscular blockade with sugammadex vs. neostigmine in morbidly obese patients.


Background   Sugammadex molecules form a complex with steroidal neuromuscular blocking drugs inactivating the muscle relaxant and reversing its effect. Clinically, this applies to rocuronium and vecuronium. Sugammadex has been demonstrated to be safe and effective and it reverses neuromuscular block faster than the anticholinesterase neostigmine. Data on the use of sugammadex in morbidly obese patients is limited. The morbidly obese are at risk for adverse respiratory events after general anesthesia.


Peak Expiratory Flow Rate (PEFR) is a proxy for overall respiratory muscle strength. Low PEFRs have been associated with impaired swallowing, coughing, and pharyngeal protective reflexes. Low PEFRs have also been linked to hypoventilation and hypercarbia. A low PEFR can be caused by residual neuromuscular block, even residual block that is difficult to detect without quantitative neuromuscular block monitoring. Residual block results in a weak or absent cough reflex and a greater risk of atelectasis. Studies have linked residual block with adverse respiratory events.


Methodology   This was a prospective study of 40 patients with a Body Mass Index (BMI) > 35 Kg/m2 undergoing laparoscopic cholecystectomy or bariatric procedures. The doses of drugs used for general anesthesia and the study neuromuscular block reversal drugs were calculated based upon Corrected Body Weight (CBW) [see notes at end]. There is some evidence that corrected body weight is the best fit for calculating drug doses in the morbidly obese.


All subjects received fentanyl 0.1 mg/Kg CBW, propofol 2 mg/Kg CBW, and rocuronium between 0.6 mg/Kg and 1.1 mg/Kg CBW. Up to 2 additional doses of rocuronium 0.1 to 0.2 mg/Kg CBW were given during anesthesia. General anesthesia was maintained with sevoflurane, oxygen, and air. Prior to emergence all subjects received 1 gm acetaminophen and 100 µg fentanyl. Neuromuscular block was monitored with a quantitative accelerometer neuromuscular block monitor (TOF-Watch). Neuromuscular blockade monitoring was at the orbicularis oculi every 15 seconds.


At the end of each case, when two twitches were present on a train-of-four the study drug was administered; either sugammadex 2 mg/Kg CBW or neostigmine 0.05 mg/Kg CBW plus glycopyrrolate 0.01 mg/Kg CBW. From then on neuromuscular block was monitored with a train-of-four every 15 seconds until the train-of-four ratio was 0.9 or greater. Peak Expiratory Flow Rate (PEFR), used here as a proxy for overall respiratory function, was previously measured prior to induction of anesthesia. This baseline PEFR was compared with measurements at 5, 10, and 20 minutes after administration of the study reversal drugs. 


Result   Half the subjects received sugammadex and half neostigmine and glycopyrrolate, 20 in each group. Although groups were consecutive patients anesthetized by two anesthesia providers and the study drug they received was not randomized, there was no difference in demographics or duration of surgery between groups. Specifically the average BMI of each group was nearly identical. Baseline PEFRs were not different between groups.


After administration of sugammadex or neostigmine, recovery of the PEFR was significantly better in the sugammadex group at all time points. Five minutes after the study drugs, the sugammadex group had recovered 60% of baseline PEFR vs. 45% in the neostigmine group. At 20 minutes the sugammadex group had recovered 77% of baseline PEFR vs. 59% in the neostigmine group. Likewise, the time from administration of the study drugs to recover of the train-of-four ratio to 0.9 was 3.4 minutes in the sugammadex group vs. 7.5 minutes in the neostigmine group; over twice as fast with sugammadex. Each of these results were highly statistically significant (P values between 0.005 and 0.0002).


Conclusion The recommended dose of sugammadex resulted in faster recover of both the Peak Expiratory Flow Rate and the train-of-four ratio in morbidly obese patients compared to neostigmine.




Hopefully, by now we all understand that our old ideas about reversal of neuromuscular block left patients at risk. Many adverse events in the PACU are the result of residual neuromuscular block, but have not been attributed to this cause and, thus, the complications have been hard to address. The new standard of a train-of-four ratio ≥ 0.9 greatly improves patient safety and can be determined only with a quantitative neuromuscular block monitor such as the one used in this study.


Also, by now, I hope everyone is getting the idea that sugammadex is far superior to anticholinesterases for reversal of neuromuscular block. Previous studies have shown that over 40% of all patients and almost 70% of elderly patients arrive in the PACU with residual neuromuscular block when reversed with neostigmine. Due to its cost I don’t know of any department that is using sugammadex exclusively and, of course, it is only good for rocuronium and vecuronium. That said, in emergencies or at risk patients, sugammadex is indispensable.


And that brings us to this study. Morbidly obese patients are at risk for numerous adverse respiratory events caused by residual neuromuscular block. Thinking only about respiratory mechanics, the morbidly obese start out at a disadvantage, a condition which gets worse when they lie supine and undergo general anesthesia. Many times patients are positioned supine from before induction through to emergence. As a result of these factors alone they develop atelectasis before arriving in the PACU. So they are respiratory compromised even without their respiratory status being further impeded by residual neuromuscular block.


As we make decisions about what reversal drug to use in at risk patients, including the morbidly obese, it would be good to keep in mind that complications and additional care are even more expensive than sugammadex. Delayed respiratory recovery in the morbidly obese is directly related to delayed PACU discharge and/or ICU admission. At about $100 for the most commonly used dose, sugammadex is about $70 more expensive than neostigmine and robinul. I’m pretty sure that extra PACU time costs more than that.


Michael A. Fiedler, PhD, CRNA

The original article summarized here is available free full text at the following url:


Corrected Body Weight = Ideal Body Weight + 0.4 x (Total Body Weight - Ideal Body Weight)


We’ve published a number of other abstracts and comments about sugammadex. Please use the advanced search feature and search for “sugammadex” to find them.






© Copyright 2019 Anesthesia Abstracts · Volume 13 Number 7, June 20, 2019