Article Notes
- Ultra-low dose intrathecal (≤50 mcg) or epidural (≤1 mg) morphine in low-risk women does not require extra respiratory monitoring.
- Low dose intrathecal (50-150 mcg) or epidural (1-3 mg) morphine in low-risk women should have respiratory rate and sedation monitored every 2h for the first 12h.
- Women with significant comorbities, sedation risk factors or if receiving higher morphine doses should be monitored as per ASA/ASRA guidelines.
- Low-dose intrathecal (50-150 mcg) or epidural (1-3 mg) morphine provides the best balance between analgesia and minimising side effects.
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Buprenorphine is also a kappa and delta receptor antagonist, a weak partial NOP/Nociceptin receptor agonist, and has potent local anaesthetic effects. It behaves as a full agonist for analgesia in the opioid-naive, but a partial agonist for respiratory depression. ↩
- Very few ASA 4 (5%) patients were enrolled.
- Only volatile-maintenance anaesthesia was studied not propofol/TIVA.
- We can draw no conclusion regarding the consequences of extreme-depth (ie. BIS << 35).
- The actual depth difference between the BIS-35 and BIS-50 groups was not as much as perhaps ideal: mean BIS 39 vs 47 respectively...
This thorough review of the global epidemiology of perioperative hypersensitivity (POH), reflects our increasing awareness that anaphylaxis varies geographically.
Incidence
Reported incidence ranges from 1 in 18,600 to 1 in 353, although NAP6 (UK) and French studies independently estimate life-threatening anaphylaxis at 1 in 10,000.
Mortality
Anaphylaxis mortality was generally ~4% (UK, France, USA, Japan), although Western Australian data estimated a lower range of 0-1.4%.
Causal agents
Implicated agents commonly include neuromuscular blocking drugs (1st or 2nd commonest in most studies), although the higher incidence seen with specific NMBDs (eg. Sux and Roc) appears to occur in some regions but not others. Pholcodine has been implicated as causative in these regional differences.
Sugammadex has increasingly been implicated as a cause of POH, though notably also with regional variation. A dose-related effect has also been reported.
Antibiotics are an increasingly common cause of POH, in particular β-lactams. Nevertheless, ‘pan-β-lactam allergy’ is probably rare, and some examples like cefazolin, have limited cross-reactivity.
“Cefazolin does not share an R1 and R2 group with any other β-lactam...”
Latex POH is declining, while chlorhexidine is increasing (9% in NAP6, with significant regional variability), albeit often as a ‘hidden’ precipitant.
Surgical dyes (patent blue V, isosulfan blue, methylene blue) are also increasingly common causes of POH (4th most common in NAP6 (~1 in 7,000), 3rd in France).
Less common POH causes include povodine-iodine and colloids.
Hypnotics, local anaesthetic, aprotinin, protamine and NSAIDs are very uncommon-to-rare causes of POH. Opioids are sometimes implicated via the MRGPRX2 receptor, although true opioid IgE-mediated hypersensitivity is very rare.
Bottom-line
The wide geographic variations in anaphylaxis incidence and causation reveal a complex interplay of genetics and environment, along with our evolving understanding of the complexity of anaphylaxis.
Go deeper...
Read Florvaag & Johansson’s seminal article The Pholcodine Story for an intriguing story of geographic POH differences.
Daniel Jolley
“Cyclodextrin is frequently used in foods and cosmetics because it can change the physical properties of various compounds by their encapsulation within the cyclic structure. The average person is thought to ingest about 4 g of gamma-cyclodextrin per day from food. ... even people who have never received sugammadex may be sensitised by food and cosmetics.” (Mertes 2019)
Daniel Jolley
This consensus statement from the Society for Obstetric Anesthesia and Perinatology (SOAP) provides post-operative monitoring guidelines for women receiving neuraxial morphine for cesarean section analgesia.
The context
Neuraxial morphine is a widely used and effective technique for managing post-cesarean pain in the first 24 hours. However because of morphine’s low-lipid solubility, the risk of delayed repsiratory depression has required frequent respiratory monitoring in this first 24 hour period.
The SOAP task force aimed to balance opioid safety needs while avoiding excessive respiratory monitoring in new mothers. Existing ASA/ASRA guidelines were considered by many obstetric anesthesiologists to be too rigorous when applied to the healthy post-natal population, both because of their lower risk of respiratory depression and even greater need to minimize sleep interruptions.
“The SOAP Task Force members strongly agree that neuraxial morphine should be the preferred method for postcesarean delivery analgesia in healthy women.”
The recommendations
Explore more...
The paper’s full-text goes into more detail covering the evidence for the safety and efficacy of neuraxial morphine, the incidence of respiratory depression, respiratory monitoring techniques and duration, optimal dosing and analgesic regimes.
Daniel Jolley
The title of this paper is pretty vague and possibly even misleading: “unexpectedly unfavorable outcomes”...? Generally ‘outcome’ is used in service to something broader and longer-term, such as procedural success, long-term comfort, time to discharge, or functional recovery.
A more appropriate and descriptive title would have been: “Remifentanil for abdominal surgery is associated with worse analgesia and more PONV in the PACU.” 👍
Daniel Jolley
Although we know that OIH and AOT are issues for remifentanil and may explain the PACU analgesia differences observed in this study, it’s also possible that worse PACU pain scores occur because anesthetists/anesthesiologists have not adequately transitioned from short-acting to longer-acting analgesics at the end of the case.
That is, the findings may represent inadequate pre-emergence analgesia because of the complexity of managing pharmacokinetic transitions, rather than a direct pharmacodynamic effect of remifentanil...
My money is still on this being acute hyperalgesia and tolerance, but keep an open mind...
Daniel Jolley
What’s the relevance?
Remifentanil’s ultrashort-acting kinetics have driven its growth as a reliable technique for maintaining intraoperative analgesia. It is now one of the most widely used synthetic opioids in anesthesia.
However these unique pharmacological characteristics are associated with both Opioid Induced Hyperalgesia and Acute Opioid Tolerance, and possibly increase the risk of chronic pain after surgery.
Details:
Niedermayer and team performed a large, multicenter, propensity-matched observational study of remifentanil use during intra-abdominal surgery, and its association with postoperative pain in the PACU. Importantly the patients receiving epidural analgesia in addition to TIVA GA were also included. Volatile GA was excluded.
Among 16,420 patients meeting inclusion criteria, 3,652 GA/TIVA patients received remifentanil and were matched to 3,318 controls, and 829 GA/epi received remifentanil, being matched to 631 controls. Mean remifentanil infusions rates were 0.11 and 0.13 mcg/kg/min for non-EA and EA groups respectively.
They showed:
Among GA-only patients, remifentanil was associated with higher PACU pain scores (both on arrival and discharge), greater analgesic requirements and more PONV – however there was no decrease of either time-to-extubation or PACU discharge.
Interestingly, the epidural analgesia cohort also showed higher PACU pain scores when receiving remifentanil.
The rapid nociceptive changes due to remifentil are well known, however real clincial consequences remain unclear. This large observational study highlights the detrimental analgesic effects of remifentanil in the most immediate post-op period, reminding anesthetists and anesthesiologists that gold-standard intraoperative analgesia may come at a cost.
Dig deeper
Explore collected articles answering: Is remifentanil associated with Opioid Induced Hyperalgesia and Acute Opioid Tolerance?
Daniel Jolley
Why is this important?
Buprenorphine (Subutex, Tamgesic, Suboxone, Norspan) is a partial opioid agonist with high mu-receptor affinity, though limited by a ceiling effect. Because of its favourable safety profile it is used for opioid dependence, chronic and, increasingly, acute pain.1
Patients historically often have regular buprenorphine (BUP) ceased post-operatively when needing opioid analgesia. It was assumed that because of it’s high mu-receptor affinity, BUP blocks the efficacy of additional opioid analgesics. In reality, ceasing buprenorphine creates more complexity and may precipitate acute withdrawal.
Be smart
Haber, DeFries & Martin point out that despite the high receptor affinity of BUP, there are still additional receptors remaining for full-agonist opioids to bind and activate. This is supported by the literature (Kornfeld 2010 & Harrison 2018). Even in the post-operative period buprenorphine can be easily continued, although with patients sometimes needing higher doses of acute opioid analgesics (Goel 2019 & Hansen 2016).
“Temporarily discontinuing buprenorphine introduces unnecessary complexity to a hospitalization, places the patient at risk of exacerbation of pain, opioid withdrawal...“
Bottom-line
If buprenorphine is regularly being taken then it should not be ceased for hospital admission. Additional short-acting opioids can be added if needed. Doses required may be higher, but this is primarily due to opioid tolerance rather than receptor competition with BUP. Alternatively, a maintenance BUP dose can be split into 3-4 divided doses and/or increased to cover acute analgesic needs.
Daniel Jolley
What’s all the fuss?
Significant observational evidence suggested an association between mortality and deep anaesthesia, in particular a 2017 meta-analysis. However it has been suspected that anaesthetic depth may merely be a surrogate marker for intraoperative hypotension, a well-established risk factor for post-operative mortality and morbidity.
With this large RCT, the Balanced Anaesthesia Study Group has shown that deep general anaesthesia is not associated with an increase 1-year mortality.
What did they do?
The researchers conducted an ambitious, large (6,644 patients), multi-center, randomised controlled trial. Patients aged ≥60 years undergoing major surgery (expected ≥2h surgery and ≥2d hospital stay) were randomised to receive volatile general anaesthesia targeting BIS 50 or BIS 35.
To minimise intra-operative blood pressure as a confounder, anaesthetists were required to specify a target MAP before BIS-group allocation.
They found...
Not only was there no mortality difference between the BIS 50 and BIS 35 groups, there were also no major or moderate morbidity differences, or difference in recovery or length of stay. BIS targets were adequately achieved, though not perfect, and MAP was clinically similar for both groups.
Context is everything
This is about as high-quality as a large, modern study looking at longer-term outcomes can get. It is widely applicable to most populations and common general anaesthetic scenarios, except for a few important caveats:
Final thought
...there was (only) one case of awareness in the light-depth BIS 50 group, despite 39% of patients receiving volatile < 0.7 MAC.
Daniel Jolley
Pholcodine, rocuronium and suxamethonium, showing common tertiary/quaternary ammonium epitopes.Australia and New Zealand both experience an unusually high incidence of perioperative anaphylaxis, particularly to neuromuscular blocking drugs. The opioid-based anti-tussive pholcodine has been implicated in increasing population hypersensitivity to muscle relaxants.
Although historically difficult to identify accurate denominator numbers for incidence calculations, more recent data shows that the anaphylaxis risk for rocuronium is particularly high in Australia & New Zealand and may in fact be roughly comparable to the local risk of suxamethonium anaphylaxis, at 1 in 2,000-3,000 exposures.
Rocuronium also has a higher risk of anaphylaxis than it’s aminosteroid-sibling vecuronium, and up to a ten-times greater risk than the benzylisoquinolinium atracurium (~1 in 22,500, depending on population). Cisatracurium demonstrates the lowest incidence of anaphylaxis (~1 in 50,000).
Additionally, as sugammadex appears as a new anaphylaxis cause the potential for a rocuronium-sugammadex combination having an even higher risk of anaphylaxis than suxamethonium needs to be considered.
Daniel Jolley