INTRODUCTION

As an anesthesia professional, you likely know that malignant hyperthermia (MH) strikes out of the blue and can rapidly lead to muscle rigidity, hyperthermia, elevated end tidal CO₂, respiratory and metabolic acidosis, and if not treated promptly and specifically, it can result in death. You also may know that, despite MH being inherited in an autosomal dominant manner, there is a higher incidence in males than females and that the syndrome occurs at a higher rate in children than adults.¹

Here we present a recent case of MH, give a historical perspective on the success anesthesia professionals have had in furthering our understanding of MH, and propose a future direction in which we may also play a critical role in caring for patients long after their acute episode—to ensure proper workup and understanding of post-episode sequelae.

MH CASE

An otherwise healthy 11-year-old girl presents to the hospital to have an incidentally discovered ovarian teratoma removed laparoscopically. She had no prior surgeries or encounters with anesthesia. Soon after induction of anesthesia with sevoflurane, paralysis with rocuronium, and intubation, she developed persistent tachycardia (heart rate 120 bpm from a baseline in the 80s), her temperature rose to 39.4°C, and her end-tidal CO₂ (ETCO₂) climbed to 110 mmHg. Muscle rigidity was also observed in the patient’s arms despite having received non-depolarizing neuromuscular blockade. As soon as these MH signs presented, help was called to assist in managing the crisis. The sevoflurane was discontinued, and Ryanodex® (dantrolene sodium, Eagle Pharmaceuticals, Inc., Woodcliff Lake, NJ, USA) was quickly administered. Within a few minutes, her heart rate, temperature, ETCO₂, and musculoskeletal tone all improved. Other stabilization measures included starting a total intravenous anesthesia (TIVA), obtaining additional IV access and an arterial line, active cooling with administration of cold IV fluids, and aggressive hydration. Once stabilized, the surgery was quickly completed, and the patient transferred to the ICU. Dantrolene treatment was continued. Notably her first creatine kinase (CK) was abnormally high at 34,000 IU. The patient was extubated the following day. Over the next few days, she continued to improve, and her rhabdomyolysis resolved.

Over multiple visits in the days following the event, the anesthesia professionals learned that the patient had previously had episodes of heat intolerance and that her grandmother had an incidental finding of chronically elevated CK, but had not undergone a muscle biopsy. A comprehensive genetic panel testing 129 genes associated with rhabdomyolysis and metabolic myopathy was ordered along with consultation with a geneticist and neurologist. The genetic testing revealed an alteration in the ryanodine receptor (RYR1), confirming the diagnosis of MH. Interestingly, while she was found to have a RYR1 variant which is officially characterized as a variant of unknown significance (VUS) by the National Human Genome Institute and American College of Medical Genetics, it is considered a pathogenic variant by the European MH group, and has previously been associated with elevated CK levels, rhabdomyolysis, and weakness.² She was ultimately discharged on postoperative day 5 with close follow-up with the medical genetics, neurology, and neuromuscular clinics.

MH: A SUCCESS STORY

This story of a patient developing MH and being successfully diagnosed and treated reflects the accumulated knowledge from scientific contributions of scientists over many years and from all over the world. Since the first description of MH in Melbourne, Australia, in 1960 by Denborough and Lovell, much progress has been made in terms of defining the pathophysiology, discovering an effective therapeutic treatment, and disseminating information about MH to the anesthesia community.³ As a result, MH mortality has declined from 70% to as low as about 10% in countries prepared for the syndrome with ready access to dantrolene and other supplies (Table 1),⁴ a coordinated approach to diagnosis and management including ICU observation, and post-episode coordination with family members of the person who experienced MH.

Table 1: MH Cart Medication and Supplies.

FUTURE DIRECTIONS

As in much of science, solving one problem often leads to more questions. In addressing these questions, it has become apparent that we should not think of MH as an episodic, idiosyncratic disorder, but as a pharmacogenetic disorder and an inherited myopathy with consequences that may be far removed from the anesthetic experience.

First, what do we know about the implications of RYR1 mutations outside of MH? Further study is needed to understand how RYR1 associated conditions (such as statin-induced myopathy, exertional rhabdomyolysis, heat stroke, and chronically elevated CK syndromes) relate to MH susceptibility (MHS).⁵ There is also a need to understand the role and efficacy of dantrolene for the treatment of these other syndromes.

Second, after an MH episode, how should we confirm a diagnosis of MHS? Advances in genetic testing to assess MHS have led genetics to essentially replace the tried-and-true muscle biopsy caffeine halothane contracture test in much of the world. The European MH society formally changed their recommendation to use genetics as the first line test in MHS diagnosis in 2015 and most MH experts around the world have followed this lead.⁶ In the US, there are only two centers (located in Minnesota and North Carolina) and the testing can cost up to $20,000 USD, which is generally not paid for by insurance companies. On the other hand, the cost of genetic testing has declined over 99% since the first sequencing of the human genome and is usually reimbursed by insurance companies. Specific costs vary by the type of test selected. A panel test for the three genes associated with MHS (RYR1, CACNA1S, and STAC3) costs less than $500 USD,7 versus a more comprehensive metabolic and myopathy panel which costs around $1,500 USD.⁸

Third, what is the role of the anesthesia professional in the care of MHS patients after their episode, and how should they interact with other providers such as geneticists and neurologists? Whose responsibility is it to advise family members on the significance of a pathogenic DNA variant predisposing to MH? Specialists who treat patients who have experienced an MH episode can help them to understand whether they are expected to make a full recovery, but they may be less able to address longer lasting questions such as if such patients are predisposed to rhabdomyolysis or muscle weakness, and for how long. A method of flagging an MHS diagnosis, including specific genetic variant, in the electronic medical record should be ensured. Artificial intelligence or third-party services that can process data across genetic testing platforms and improve communication of this critical diagnosis to practitioners can make care safer for MHS patients. Though the incidence of acute MH in MHS patients exposed to triggering agents is unknown and difficult to estimate, all MHS patients should be treated with a “clean” nontriggering anesthesia technique.^9-11 This includes avoidance of succinylcholine and volatile anesthetics, preparation of the anesthesia machine by flushing the circuit and ventilator with high flows over the manufacturer recommended amount of time or insertion of activated charcoal filters in the breathing circuit, use of fresh CO₂ absorbent, and taping off vaporizers to prevent accidental use. Intraoperative monitors should include EKG, pulse oximetry, blood pressure, core body temperature, and capnography for general anesthesia.¹²

Finally, MH has been reported from countries all over the world and there is no known ethnic propensity to MHS. A broader public health concern is how do resource-limited countries balance the cost of a life-saving drug dantrolene for an infrequent disorder, versus the need for expenditures on more frequently occurring disorders? A report from China in the February 2024 issue of Anesthesiology reported mortality from MH over 50% in areas without dantrolene.¹³ While it has been questioned in the US as to whether ambulatory facilities who do not routinely use volatile agents and reserve succinylcholine for emergency airway management need to stock dantrolene, there is evidence to show that stocking dantrolene is both cost-effective and optimal for safe patient care where triggering agents may possibly be used.^14-17

THE FOUR C’S OF MH MANAGEMENT

In our opinion it is time to broaden our perspective on the MH syndrome to regard the problem as not unique to anesthesiology and surgery. We need to expand patient care goals beyond the confines of managing the acute MH episode, to include appropriate follow-up and assessment of other potentially associated skeletal-muscle-related conditions. A multidisciplinary approach to the diagnosis, treatment, and genetic counseling for patients and families is of utmost importance. Therefore, we propose the 4C’s of MH Management:

1. Control the acute syndrome
2. Consult genetic and neurologic colleagues
3. Confirm with genetic testing
4. Communicate the results and plans for care with the patient, family, and other health care providers.

NEXT STEPS

It is within our scope of practice as anesthesia professionals to take these actions to improve the care of MHS patients going forward. The enlightened management of MH fits with the goals of the APSF and other patient safety organizations. Next steps include: 1) revision of MHS diagnostic testing recommendations by the Malignant Hyperthermia Association of the United States (MHAUS) to include genetic testing after all suspected MH cases, 2) creation of a system to connect anesthesia professionals who manage MH to clinical geneticists, genetic testing platforms, and neurologists familiar with MH, 3) assurance of communication of an MHS diagnosis in electronic medical records, and 4) dissemination of MH education globally, including advocating for stocking dantrolene in all centers where triggering agents may be used.

REFERENCES

1. Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93. PMID: 26238698
2. Witting N, Laforêt P, Voermans NC, et al. Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome. Acta Neurol Scand. 2018;137:452–461. PMID: 29635721
3. Denborough MA. Malignant hyperthermia. 1962. Anesthesiology. 2008;108:156–157.
4. Malignant Hyperthermia Association of the United States (MHAUS) Professional Advisory Council. “What should be on an MH cart?” MHAUS.org. https://www.mhaus.org/healthcare-professionals/be-prepared/what-should-be-on-an-mh-cart/. Accessed July 20, 2024.
5. Fiszer D, Shaw MA, Fisher NA, et al. Next-generation sequencing of RYR1 and CACNA1S in malignant hyperthermia and exertional heat illness. Anesthesiology. 2015;122:1033–1046. PMID: 25658027
6. Hopkins PM, Rüffert H, Snoeck MM, et al. on behalf of European Malignant Hyperthermia Group. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531–539. PMID: 26188342
7. “Invitae Malignant Hyperthermia Susceptibility Panel.” Invitae. https://www.invitae.com/us/providers/test-catalog/test-03285. Accessed July 20, 2024.
8. “Metabolic Myopathy and Rhabdomyolysis Panel.” Blueprint Genetics. https://blueprintgenetics.com/tests/panels/neurology/metabolic-myopathy-and-rhabdomyolysis-panel/. Accessed July 20, 2024.
9. Ibarra Moreno CA, Hu S, Kraeva N, et al. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology. 2019;131:983–991. PMID: 31206373
10. Shaw MA, Hopkins PM; Mission impossible or mission futile?: estimating penetrance for malignant hyperthermia. Anesthesiology. 2019;131:957–959. PMID: 31335544
11. Yu KD, Betts MN, Urban GM, et al. Evaluation of malignant hyperthermia features in patients with pathogenic or likely pathogenic RYR1 variants disclosed through a population genomic screening program. Anesthesiology. 2024; 140:52–61. PMID: 37787745
12. Rüffert H, Bastian B, Bendixen D, et al. European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120–130. PMID: 33131754
13. Yu H, Tan L, Deng X. Improving dantrolene mobilization in regions with limited availability. Anesthesiology. 20241;140:1201–1202. PMID: 38329334
14. Joshi GP, Desai MS, Gayer S, Vila H Jr. Society for Ambulatory Anesthesia (SAMBA). Succinylcholine for emergency airway rescue in class B ambulatory facilities: the Society for Ambulatory Anesthesia position statement. Anesth Analg. 2017;124:1447–1449. PMID: 27984222
15. Litman RS, Smith VI, Larach MG, et al. Consensus statement of the Malignant Hyperthermia Association of the United States on unresolved clinical questions concerning the management of patients with malignant hyperthermia. Anesth Analg. 2019;128:652–659. PMID: 30768455
16. Larach MG, Klumpner TT, Brandom BW, et al.; Multicenter Perioperative Outcomes Group. Succinylcholine use and dantrolene availability for malignant hyperthermia treatment: database analyses and systematic review. Anesthesiology. 2019;130:41–54. PMID: 30550426
17. Aderibigbe T, Lang BH, Rosenberg H, et al. Cost-effectiveness analysis of stocking dantrolene in ambulatory surgery centers for the treatment of malignant hyperthermia. Anesthesiology. 2014;120:1333–1338. PMID: 24714119

Anesthesia professionals have consistently been leaders in patient safety and have long recognized the importance of hand hygiene in the anesthesia workspace.¹ Hand contamination is associated with pathogen transmission across multiple anesthesia workspace reservoirs, and genome analysis of bacteria cultured from provider hands and infection causing pathogens have confirmed that providers transmit pathogens that result in patient infections.^2,3,4 Staphylococcus aureus (S. aureus) transmission among anesthesia workspace reservoirs is associated with an increased risk of surgical site infection (SSI).⁵ In fact, SSI risk increases over fivefold when the pathogens are sensitive to the prophylactic antibiotic employed and ninefold when the pathogens are resistant to the prophylactic antibiotic employed.⁶ In order to reduce this risk, a multifaceted approach is indicated to prevent SSIs.⁷ When improved hand hygiene is incorporated as part of a multifaceted program, substantial reductions in S. aureus transmission and SSIs can be achieved.^8,9 These findings should provide the impetus for widespread improvements in hand hygiene compliance for all intraoperative personnel, with anesthesia professionals taking the lead.

The anesthesia workspace is a complex environment that includes the patient, the surgical bed/table, the anesthesia machine, the intravenous (IV) pole(s) with attached infusion devices, a cart with clean supplies, and medications stored within the cart or a separate medication station. Anesthesia professionals interact with the patient and multiple components of the anesthesia workspace during routine anesthesia practice.^10,11 Given the complexity of this environment, hand decontamination is necessary to interrupt transmission events and reduce infection propagation. The World Health Organization (WHO) defines events, after which hand hygiene should be performed as the, “Five Moments of Hand Hygiene.”¹² These moments that call for hand hygiene arethe following: before touching a patient, before a clean or sterile procedure, after touching a patient, after a task with a body-fluid exposure risk, and after touching the patient’s surroundings (Figure 1).¹² Compliance with WHO and similar recommendations would require the anesthesia professional to perform hand hygiene as often as 54 times per hour¹³ up to 150 times per hour.^11,13 However, studies reveal that anesthesia professionals perform hand hygiene less than once per hour.¹⁴ Clearly, there is substantial opportunity for some improvement. It might seem that fighting against the transmission of pathogens is impossible, given how ubiquitous bacteria are in our environment. However, research suggests that reducing the levels of S. aureus on provider hands to less than 100 colony-forming units (CFU) is an achievable goal that can help to protect our patients.^9,15

Figure 1: Your 5 Moments for Hand Hygiene. Geneva, Switzerland. World Health Organization. 2009. License: CC BY-NC-SA 3.0 IGO.

The APSF Patient Safety Priorities Advocacy Group: Infectious Disease recommends that anesthesia professionals perform hand hygiene at least approximately eight times per hour during anesthesia care.¹⁶ Washing one’s hands or using hand sanitizer at a frequency of eight times per hour optimally reduced environmental and stopcock contamination and subsequent infection development.¹⁴ However, the proper methodology to prompt hand hygiene compliance at this frequency is not clear.¹⁶ Important future research include products (e.g., alcohol-based or soap and water), dispenser locations, cleansing technique, and potential risks.

While hands can be effectively decontaminated using alcohol-based solutions, visibly contaminated hands or potential contact with spore-forming organisms should be decontaminated with soap and water.^14,17 Since scrub sinks must be outside the operating room, alcohol is the primary hand hygiene option for anesthesia professionals, and because it is associated with less skin irritation than soap and water, it may reduce the risk of irritated skin and higher bacterial counts on the irritated skin.^18,19

Dispenser locations should be determined by task density, which is the number of tasks that need to be done in a period of time. Health care infection prevention organizations recommend dispenser placement in locations that are easily accessible within the patient care arena.²⁰ Using dispensers placed outside the anesthesia work area (e.g., on the wall or near the entrance to the operating room) may disrupt patient care. The importance of task density is well-delineated. In one study, anesthesia professional use of a personalized, body-worn alcohol dispenser increased hand hygiene compliance 37-fold, and, in turn, reduced the incidence of environmental and stopcock contamination and health care associated infections.¹⁴ Other investigators evaluated dispenser placement on the intravenous pole to the left of the provider as part of a multifaceted program.^8,9 Dispenser placement in this location reduced the incidence of bacterial transmission and subsequent SSI development.^8,9

Because provider hand contamination is associated with environmental contamination, improving the frequency and quality of environmental cleaning may also help to augment hand hygiene improvement efforts. In one study, separating the anesthesia workspace into “clean” and “dirty” areas was associated with a reduction in the proportion of sites reaching ≥ 100 CFUs.^14,21 It is intuitive that alcohol dispensers should be placed in areas designated as clean. For example, the dispenser may be secured to the anesthesia machine or supply cart with a mounting rack, or on the intravenous pole. If secured to the intravenous pole, then caution should be taken to protect the patient, surgical field, and underlying electrical plugs from splashes and drips (Table 1).

Table 1: Potential Considerations for Hand Sanitizer Locations in the Anesthesia Workspace.

While anesthesia professionals must have ready access to a hand sanitizer, there are potential hazards to consider. All alcohol-based sanitizers contain 60–80% ethyl or isopropyl alcohol and water. This is because a sufficient water component is necessary to hydrolyze microorganism membranes and slow evaporation of the product.^22,23 Because alcohol products are flammable, fire codes regulate the total volume of sanitizers allowed within a procedure room and the minimum separation distance between alcohol dispensers. Dispensers must be separated by a minimum distance of four feet, and their combined volume in one room must not exceed 1.2 liters.²⁴ The Centers for Disease Control and Prevention also espouses these fire safety recommendations.²⁵ The volume for personalized, body-worn alcohol dispensers and one-handed alcohol pumps on an IV pole is less than 3 ounces.^8,9,14 While there have not been reports of fires related to hand sanitizers, it is risk worth considering.

In summary, improved hand hygiene by anesthesia professionals is an essential element of a multifaceted approach to reducing bacterial transmission and infection development. Eight hand hygiene events per hour during routine anesthesia care should be encouraged. Alcohol-based sanitizers in the anesthesia workspace should be placed in clean and easily accessible locations that are clearly visualized by the clinician.

REFERENCES

1. Warner MA, Warner ME. The evolution of the anesthesia patient safety movement in America: lessons learned and considerations to promote further improvement in patient safety. Anesthesiology. 2021;135:963–974. PMID: 34666350
2. Dexter F, Loftus RW. Estimation of the contribution to intraoperative pathogen transmission from bacterial contamination of patient nose, patient groin and axilla, anesthesia practitioners’ hands, anesthesia machine, and intravenous lumen. J Clin Anesth. 2024;92:111303. Epub 2023 Oct 22. PMID: 37875062.
3. Loftus RW, Brindeiro CT, Loftus CP, et al. Characterizing the molecular epidemiology of anaesthesia work area transmission of Staphylococcus aureus sequence type 5. J Hosp Infect. 2024;143:186–194. Epub 2023 Jul 13. PMID: 37451409.
4. Loftus RW, Brown JR, Koff MD, et al. Multiple reservoirs contribute to intraoperative bacterial transmission. Anesth Analg. 2012;114:1236–1248. Epub 2012 Mar 30. PMID: 22467892.
5. Hopf, Harriet W. MD. Bacterial reservoirs in the operating room. Anesthesia & Analgesia. 2015;120:p 700–702. PMID: 25790198
6. Loftus RW, Dexter F, Brown JR. Transmission of Staphylococcus aureus in the anaesthesia work area has greater risk of association with development of surgical site infection when resistant to the prophylactic antibiotic administered for surgery. J Hosp Infect. 2023;134:121–128. doi: 10.1016/j.jhin.2023.01.007. Epub 2023 Jan 21. PMID: 36693592.
7. Dexter F, Brown JR, Wall RT, Loftus RW. The efficacy of multifaceted versus single anesthesia work area infection control measures and the importance of surgical site infection follow-up duration. J Clin Anesth. 2023;85:111043. Epub 2022 Dec 23. PMID: 36566648.
8. Loftus RW, Dexter F, Goodheart MJ, et al. The effect of improving basic preventive measures in the perioperative arena on Staphylococcus aureus transmission and surgical site infections: a randomized clinical trial. JAMA Netw Open. 2020;3: e201934. PMID: 32219407
9. Wall RT, Datta S, Dexter F, et al. Effectiveness and feasibility of an evidence-based intraoperative infection control program targeting improved basic measures: a post-implementation prospective case-cohort study. J Clin Anesth. 2022; 77:110632. Epub 2021 Dec 17. PMID: 34929497.
10. Sharma A, Fernandez PG, Rowlands JP, et al. Perioperative infection transmission: the role of the anesthesia provider in infection control and healthcare-associated infections. Curr Anesthesiol Rep. 2020;10:233–241. Epub 2020 Jul 17. PMID: 32837343
11. Rowlands J, Yeager MP, Beach M, et al. Video observation to map hand contact and bacterial transmission in operating rooms. Am J Infect Control. 2014;42:698–701. PMID: 24969122
12. WHO guidelines on hand hygiene in health care: first global patient safety challenge clean care is safer care. Geneva: World Health Organization; 2009. 21, The WHO Multimodal Hand Hygiene Improvement Strategy. Available from: https://www.who.int/publications/i/item/9789241597906. Accessed July 5, 2024
13. Biddle C, Shah J. Quantification of anesthesia providers’ hand hygiene in a busy metropolitan operating room: what would Semmelweis think? Am J Infect Control. 2012;40:756–759. Epub 2012 Feb 9. PMID: 22325482.
14. Koff MD, Loftus RW, Burchman CC, et al. Reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a novel device. Anesthesiology. 2009;110:978–985. PMID: 19352154.
15. Dexter F, Walker KM, Brindeiro CT, et al. A threshold of 100 or more colony-forming units on the anesthesia machine predicts bacterial pathogen detection: a retrospective laboratory-based analysis. Can J Anaesth. 2024;71:600–610. English. Epub 2024 Feb 27. PMID: 38413516.
16. Charnin JE, Hollidge M, Bartz R, et al. A best practice for anesthesia work area infection control measures: what are you waiting for? APSF Newsletter. 2022;37:103-106. https://www.apsf.org/article/a-best-practice-for-anesthesia-
    work-area-infection-control-measures-what-are-you-waiting-for/ Accessed August 9, 2024.
17. WHO guidelines on hand hygiene in health care: first global patient safety challenge clean care is safer care. Appendix 2. Guide to appropriate hand hygiene in connection with Clostridium difficile spread. https://www.ncbi.nlm.nih.gov/books/NBK144042/. Accessed May 29, 2024.
18. Pedersen LK, Held E, Johansen JD, Agner T. Short-term effects of alcohol-based disinfectant and detergent on skin irritation. Contact Dermatitis. 2005;52:82–87. PMID: 15725285
19. Larson EL, Hughes CA, Pyrek JD, et al. Changes in bacterial flora associated with skin damage on hands of health care personnel. Am J Infect Control. 1998;26:513–521. PMID: 9795681
20. Glowicz JB, Landon E, Sickbert-Bennett EE, et al SHEA/IDSA/APIC practice recommendation: strategies to prevent healthcare-associated infections through hand hygiene: 2022 update. Infect Control Hosp Epidemiol. 2023;44:355–376. PMID: 36751708
21. Clark C, Taenzer A, Charette K, Whitty M. Decreasing contamination of the anesthesia environment. Am J Infect Control. 2014 Nov;42(11):1223-5. Epub 2014 Oct 30. PMID: 25444268.
22. Ali Y, Dolan MJ, Fendler EJ, Larson EL. Alcohols. In: Block SS, ed. Disinfection, sterilization, and preservation. Philadelphia: Lippincott Williams & Wilkins, 2001:229–254.
23. Rutala WA, Weber DJ, and the Healthcare Infection Control Practices Advisory Committee. Guideline for disinfection and sterilization in healthcare facilities, 2008. https://stacks.cdc.gov/view/cdc/47378 Accessed August 9, 2024.
24. National Fire Protection Association (NFPA). NFPA 101 Life Safety Code. 2018 edition. Quincy, MA: National Fire Protection Association; 2018. https://www.nfpa.org/codes-and-standards/all-codes-and-standards/list-of-codes-
    and-standards/detail?code=101 Accessed August 9, 2024.
25. Centers for Disease Control and Prevention (CDC). Clinical safety: hand hygiene for healthcare workers – fire safety and Alcohol-Based Hand Sanitizer (ABHS). https://www.cdc.gov/clean-hands/hcp/clinical-safety/?CDC_AAref_Val=https://www.cdc.gov/handhygiene/firesafety/index.htm Accessed July 5, 2024.

INTRODUCTION

The International Organization for Standardization (ISO) was established in 1947 as a nongovernmental organization (NGO) in the United Nations with the aim of revitalizing the global economy post-World War II. ISO has primarily focused on standardizing industrial products and manufacturing processes to facilitate international trade. Participation and voting rights are on a country-by-country basis, but implementation is worldwide and the way each country aggregates opinions varies.

The ISO standards are formulated primarily by manufacturers, but diverse input from health care professionals is essential in sectors like medical devices. Manufacturers often lead the development of standards due to their expertise in manufacturing processes and regulatory compliance. However, without sufficient input from clinical experts, there is a risk of standards not fully addressing the clinical needs and safety concerns of medical professionals.

Unlike general industrial equipment, many clinical medical devices place greater emphasis on how they are used rather than their technical specifications. It is important to recognize that the ultimate responsibility for the use of medical devices rests with the clinician, who must take full responsibility for the lives of their patients.

Despite efforts to integrate the opinions of medical experts through Technical Committees, clinician involvement remains limited in some areas, with manufacturers often driving discussions.

ISO 80369

Growing international awareness of medical safety spurred the ISO to address medical accidents caused by misconnections and misadministration by developing unique connector design standards for enteral, respiratory, urinary, blood pressure, neuraxial, and intravenous patient care systems.^1,2 ISO started releasing the ISO 80369 series of standards in 2016.² Participating countries have been encouraged to adopt these international standards without delay (Table 1, Figure 1).

Table 1: ISO 80369:

Figure 1: Old standard (Luer) connector and New standard (ISO 80369-6) connector.

PMDA Medical Safety Information, No.55 August 2018, Connections of new and old standard products http://www.pmda.go.jp/english/safety/info-services/safety-information/0001.html

Japan implemented a nationwide introduction of ISO 80369-6 (neuraxial applications) under governmental leadership upon receiving information (source unknown) that the introduction of ISO 80369-6 had begun globally, including parts of the United States. The transition is now almost complete, and while no major accidents involving loss of life have been reported during the transition process, numerous serious issues were experienced. As far as we know, no other country has yet fully switched over to this new standard, so Japan’s experience can contribute to patient safety worldwide by raising awareness of the associated problems that can occur.

NEED FOR NEW STANDARD FOR NEURAXIAL APPLICATIONS (ISO 80369-6)

For many years in clinical practice, the Luer connection (ISO-594) was standard for injections and connecting small-diameter tubing. Health care providers benefited from the convenience provided by its universal connectivity. However, preventing accidental injections due to misconnecting Luer connections depends solely on the vigilance and responsibility of the medical personnel involved.

Human error, an unavoidable cause of patient injury, has therefore led to misconnecting many types of medical devices.¹ Discussions on the ISO 80369 series began around 2005 with the goal of developing purpose-specific connections utilizing physical noninterfacing mechanisms specific to each application to ensure that misconnections are simply not possible.

Discussions on a purpose-specific compatibility standard for preventing misconnections (ISO 80369 series) were undertaken by ISO in Technical Committee 210 (TC 210, quality management), liaising with TC 121 via Joint Working Group 4. TC 210 covers a broader range of topics and is not necessarily an anesthesia-focused TC, especially compared to TC 121 where many prominent anesthesia professionals participate. A joint working group was formed under TC 210 to convey the voices of TC 121 on this matter, but, unfortunately it was ineffective.

Anesthesia professionals have actively participated since the early stages, making significant contributions to the field of anesthesia and intensive care. TC 121 has SC-3 (Subcommittee) that deals with products directly handled by anesthesia professionals, such as ventilators, oxygen concentrators, and related patient monitors.

THE DECISION-MAKING PROCESS FOR THE IMPLEMENTATION OF ISO 80369-6 IN JAPAN

In Japan, the implementation system essentially remains the same as it was when ISO was first established. The main supervisory body for medical devices that affect human lives is the Ministry of Health, Labour, and Welfare (MHLW), which also holds licensing authority. However, the Ministry of Economy, Trade and Industry (METI), which oversees general industries, liaises with ISO. In practice, information flows from METI to MHLW. As a result, there is a lack of supervision and a lack of proactive participation by clinicians on a domestic and international level.

When the implementation of ISO 80369 was first discussed at the Safety Division of MHLW in 2015 with some health care representatives, the switchover to ISO 80369-6 was already assumed. Concerns were raised at the time by anesthesia professionals regarding potential confusion from the switchover, but in practice, there were no meetings that included clinical physicians or the Japanese Society of Anesthesiologists (JSA). The procedures and deadlines for the introduction were determined between MHLW and an industrial organization, MTJAPAN. The Ministry explained that Japan, as a member of the World Trade Organization, has a fundamental obligation to comply or harmonize with ISO standards.³ Although exceptions do exist, Japan is required to adopt the ISO standard as the national standard without delay after a new standard is issued, and changes that would create international trade barriers are not permitted.

While it is essential to carefully consider the risk-benefit balance in clinical settings before implementing ISO standards, there are no organizations or opportunities to deliberate on these considerations in Japan.

The MHLW issued a notification in December 29, 2017, stating that the sale of old products affected by ISO 80369-6 must cease by the end of February 2020. The deadline for product supply was set at the convenience of the company, so anesthesia professionals had no choice but to comply.

At the strong request of anesthesia professionals onsite, an interchangeable adapter was not introduced for safety reasons. Awareness activities were conducted by the industry association for manufacturers and suppliers (MTJAPAN), targeting relevant academic societies. The Pharmaceuticals and Medical Devices Agency (PMDA) provided specific details on the implementation procedures. Despite these measures, awareness of the need for and possibility of switching was not well known to anesthesia professionals.

MHLW SURVEY ON THE SWITCHOVER TO ISO 80369-6 IN JAPAN

The transition was carried out and the switchover was completed in approximately two years. In June 2024, MHLW released a report on the transition to ISO 80369-6, which began in 2021.⁴ The report includes the results of a postal survey of limited scope, of anesthesia professionals and MTJAPAN. The survey was mainly targeted at facilities accredited by the Japan Society of Anesthesiologists (JSA), with 1447 facilities contacted, and 329 valid responses.

The MHLW survey was not intended to ascertain patient-related contingencies, but rather to investigate product-related issues; thus, there was a possibility for under-reporting untoward events handled by anesthesia professionals.

MHLW SURVEY RESULTS AND ISSUES

The main survey results are summarized in Table 2. We were shocked by the number of initial troubles experienced.

Table 2: Issues Encountered With the Change to ISO 80369-6.

Inadequate advisories before the switchover put clinicians at a disadvantage, as they were not prepared for the changes. Numerous cases of breakage and leakage during patient care were reported. No patients were harmed due to quick thinking on the part of anesthesia professionals.

Drug misadministration was a constant worry as connector sets with connectors and pre-filled syringes were not fully available.⁵ Errors due to incorrect connection to medication were avoided only due to professional diligence.⁶

Incomplete switchovers, due to the nonavailability of all syringes and connectors, created confusion at the bedside, as old and new connectors were placed side by side. Other unnecessary confusion resulted from poor translation, overlap in connector colors, inadequate product availability, and wasted resources. Above all, there were no processes available to clinicians, before or after the switchover, to convey or report problems.

Several issues were raised, as follows:

1. Insufficient clinical involvement

Both the ISO 80369-6 standard formulation process and the Japanese domestic implementation process by the government and manufacturers suffered from lack of practical clinical information.

Once ISO 80369 standards were set, there was little discussion of whether to implement or accommodate the domestic clinical situation by governmental agencies in Japan.

2. Imbalanced perspectives (clinicians, manufacturers, and regulatory agencies)

Manufacturers assumed it was acceptable, indeed unavoidable, to produce fittings that, while compliant with the standard, were hard to use, especially by uninformed users. Clinicians, had they been aware of this, would have refused to use products as patient safety was at risk.

The transition to smaller diameters without clinical trials led to confusion in usage related to changes in liquid flow and increased push-in and rotational forces. Problems included difficulty of use and snap breakage of connectors. This forced clinicians to deal with issues like extra-strong fittings and liquid leaks from cracked connectors while working in the field.

3. Lack of clinical feasibility trials

It was absolutely necessary to do clinical feasibility studies across products (between products of various companies) before domestic implementation to avoid patient harm and physician’s liability. However, clinical feasibility trials before full-scale introduction were actively denied based on a false and biased perception among regulatory agencies and manufacturers saying this would violate competition laws. Most of the problems Japan experienced during implementation could have been avoided with proper information and preparation. It is regrettable that clinicians were effectively eliminated from this discussion, with their only option being to accept the administrative decision.

4. Lack of transparency

Regulatory agencies were under the mistaken belief that clinical feasibility trials were unnecessary as the newly introduced products already complied to the new authoritative ISO standard. Manufacturers did not see the need to inform clinicians of “small” changes in how the new products fit together. Clinicians were not aware of this situation in Japan and had no place to address these concerns.

The consensus-building process in ISO is not available to those outside the group, but compliance with the standards produced is mandatory and strongly promoted by local administrative agencies in Japan. At present, users (clinicians), who are required to follow the standards, are only able to learn about them after purchasing ISO’s official publications.

This process needs to be improved as it not only impedes the timely dissemination of information, but also is too technical for ordinary health care workers to understand. Unaware that the new standards resulted in products that differed significantly from before, clinicians experienced such dire clinical consequences as liquid leaks and cracked connections due to extra-strong fittings. They had to deal with such problems while patients were undergoing procedures.

ROLE OF CLINICIANS IN DOMESTIC IMPLEMENTATION OF ISO STANDARDS

Domestically, challenges arise in ensuring standards meet local health care requirements, usability, and patient safety. These include consideration of product availability, changes in functionality from preexisting standards, education level, and scope of professional responsibility.

Feasibility studies by clinicians before introduction are crucial to protect patients and validate the efficacy of the standards in specific national contexts, but were denied under the pretext of competition law. Effective integration of ISO standards requires balancing manufacturer efficiency with comprehensive clinician involvement and responsive domestic adoption processes. From a clinician’s perspective, the lack of clinical usability tests before the implementation was truly regrettable.

A similar issue is happening with ISO 80369-3 (enteral applications). Pediatricians experienced practical problems, such as the inability to administer blended diets or to aspirate stomach contents because of the much smaller diameter of the new standard. The switchover, which started in 2019 and was to be completed by 2021, was delayed. MHLW already had introduced its own noninterchangeable connection in 2000 (MHLW No. 888) that was well-received, but was forced to switch to ISO 80369-3. Japan was forced into allowing both the old and new standards in May 2022.⁷ Confusion persists to this day.

Incredibly, such a basic error went unnoticed during the creation of the ISO standard. Japan introduced its own noninterchangeable enteral connection standard in 2000, and it is regrettable that the already-proven Japanese standard was not adopted by ISO.

SUMMARY

ISO issued a series of ISO 80369 standards to physically restrict connections between syringes, needles, and other small-diameter components to their intended purposes only. Japanese administrative authorities started a nationwide initiative to introduce ISO 80369-6 (neuraxial applications) in 2018 as part of the implementation of the new standards. To our knowledge, this is the first country level switchover in the world.

This decision was made without adequate consultation with clinicians or professional anesthesia organizations. New products were approved in Japan if they conformed to the new ISO standards, but were introduced into clinical practice without any preliminary feasibility trials. Anesthesia professionals in the field lacked sufficient information and encountered numerous unexpected problems, such as breakage and leaks.

No disastrous accidents involving human lives were reported during the switchover, but we experienced serious incidents that cannot be ignored.

Clinicians and medical societies, such as JSA and APSF, should become more involved to raise awareness in ISO, industry, and domestic regulatory agencies of the essential importance of clinical input. One of the reasons the government and industries have an overly strong voice in Japan is related to the extreme fragmentation of medical specialties making it harder for everyone to work together.

In a clinical setting, it is very important to consider how a product is used coupled with the quality of the product itself. The most important thing is to protect patients’ lives. Anesthesia professionals must not condone situations that threaten patient safety. We should be more involved in the decision-making process of perioperative devices approved by the ISO.

REFERENCES

1. Examples of Medical Device Misconnections. https://www.fda.gov/medical-devices/medical-device-connectors/examples-medical-device-misconnections. Accessed July 30, 2024.
2. ISO 80369-6:2016 Small bore connectors for liquids and gases in healthcare applications, Part 6: Connectors for neuraxial applications, published (Edition 1, 2016). https://www.iso.org/standard/50734.html. Accessed July 30, 2024.
3. Article 2.4 of the TBT Agreement: Agreement on technical barriers to trade, technical regulations and dtandards, Article 2: Preparation, adoption and application of technical regulations by central government bodies, 1995. https://www.wto.org/english/docs_e/legal_e/17-tbt_e.htm. Accessed July 30, 2024
4. Miyajima A. Pharmaceuticals and medical devices regulatory science policy research project: research on post-market safety measures for the safer and more effective use of new types of medical devices, etc. FY 2023 Summary and Joint Research Report (21KC2007). 2023 (In Japanese)
5. Lefebvre PA, Meyer P, Lindsey A, et al. Unraveling a recurrent wrong drug-wrong route error— tranexamic acid in place of bupivacaine: a multistakeholder approach to addressing this important patient safety issue. APSF Newsletter. 2024;39:37,39–41. https://www.apsf.org/article/unraveling-a-recurrent-wrong-drug-wrong-route-error-tranexamic-acid-in-place-of-bupivacaine/. Accessed July 30, 2024.
6. Institute for Safe Medication Practices (ISMP). Implement strategies to prevent persistent medication errors and hazards. ISMP Medication Safety Alert! Acute Care. 2023;28 (6):1–4. https://psnet.ahrq.gov/issue/implement-strategies-prevent-persistent-medication-errors-and-hazards Accessed July 30 2024.
7. The distribution of new standard products (ISO80369-3) has been phased in starting from December 2019. https://www.pmda.go.jp/files/000246586.pdf. Accessed July 30 2024.

INTRODUCTION

The APSF Newsletter in 2009 discussed the risk of late thrombosis after drug-eluting stent placement as an ongoing patient safety concern.¹ It found that in-stent thrombosis, though rare, accounted for a 60% myocardial infarction (MI) rate and a mortality of 45% when it occurred. Early animal studies found that complete endothelialization with bare metal stents (BMS) occurred in 28 days, whereas first-generation drug-eluting stents (DES) uniformly showed incomplete healing at 180 days.² In 2008, the American College of Chest Physicians (ACCP) recommended delaying elective surgery for 12 months after the placement of a drug-eluting stent,³ placing burdens on patients needing urgent surgery. As such, the APSF Newsletter acknowledged in 2009 the lack of universally accepted protocols for managing patients presenting for noncardiac surgery following recent stent placement. It emphasized the necessity for collaborative decision-making involving the patient, internist, surgeon, anesthesia professional, and cardiologist, stating that this multidisciplinary discussion should consider the type and timing of stent placed, the nature and urgency of the proposed surgery, the management of perioperative antiplatelet therapy, and the choice of facility at which to perform the surgery. If surgery must be performed in patients with recent stent placement, it should ideally take place at a facility with a 24-hour interventional cardiologist available, as emergent percutaneous coronary intervention (PCI) remains the best treatment option for in-stent thrombosis.¹

Technology has since evolved dramatically and the recommended duration of dual antiplatelet therapy (DAPT) has changed substantially. First generation stents consisted of a standard bare metallic stent, and a coated polymer mixed with an antirestenotic drug such as sirolimus or paclitaxel. Newer-generation drug-eluting stents such as biodegradable polymer stents or bioresorbable scaffolds are available, which have been shown to lead to lower rates of stent thrombosis. These newer-generation stents may permit a shorter course of DAPT without compromising patient safety.

Perhaps the most important consideration when deciding on the optimal duration of DAPT is balancing the risk of in-stent thrombosis with the risk of bleeding complications. Studies have shown that prolonged DAPT therapy is associated with an increased risk of bleeding, particularly in elderly patients or those with co-morbidities.^4,5 Bleeding complications significantly increase the risk of morbidity and mortality, and high bleeding risk (HBR) is present in approximately 40% of patients presenting for PCI.⁵ Tools that evaluate bleeding risk with DAPT include the PRECISE-DAPT Score⁶ and the Academic Research Consortium for High-Risk Bleeding (ARC-HBR) Criteria.⁴

SUPPORTING EVIDENCE FOR SHORTER DAPT DURATION

High Bleeding Risk (HBR) is defined according to the presence of at least 1 HBR criteria (Table 1).⁷

Two early studies examined high-risk patients who underwent PCI and completed a short duration of DAPT with either ticagrelor monotherapy or ticagrelor plus aspirin. Ticagrelor is a reversible and direct-acting oral P2Y12 receptor antagonist that provides faster, greater, and more consistent platelet inhibition than clopidogrel. The first study found that ticagrelor in combination with aspirin for 1 month, followed by ticagrelor alone, improved outcomes after PCI compared to standard antiplatelet regimens.⁸ The second study examined high-risk patients who underwent PCI and completed 3 months of DAPT, determining that ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, MI, or stroke.⁹

Several other pivotal trials have recently been published that highlight the safety and efficacy of the earlier discontinuation of dual antiplatelet therapy (Table 2). These newer stents are ideal for patients who are at higher risk of bleeding. These studies have uniformly found lower rates of ischemia, allowing shorter duration of DAPT, which lessens patients’ bleeding risk. These newer stents also compare favorably to bare metal stents in terms of all-cause mortality, myocardial infarction, stroke, and ischemia-driven target lesion revascularisation.^10-14

Table 2: Summary of Recent Studies Examining Abbreviated DAPT Regimens.

SOCIETAL GUIDELINES

Based on the available and updated evidence, The American College of Cardiology (ACC) and the American Heart Association (AHA) give a Class 2a (moderate) recommendation for a shorter duration of DAPT. Select patients undergoing PCI may safely transition to P2Y12 inhibitor monotherapy and discontinue aspirin after 1–3 months of DAPT, where the benefits outweigh the risks.¹⁵

In contrast, the European Society of Cardiology offers the following guidance on DAPT duration.¹⁶ Following PCI for non-ST-segment elevation acute coronary syndrome (NSTE-ACS), DAPT with a potent P2Y12 receptor inhibitor and aspirin is generally recommended for 12 months, regardless of stent type, unless contraindicated. However, in specific clinical contexts, such as high bleeding risk (e.g., based on the PRECISE-DAPT scoring of > 25 or meeting ARC-HBR criteria), clinicians may consider shortening DAPT duration (<12 months) or modifying the regimen based on ischemic and bleeding risks, adverse events, comorbidities, concomitant medications, and drug availability. Notably, in NSTE-ACS patients with stent implantation at high bleeding risk, discontinuation of P2Y12 receptor inhibitor therapy after 3–6 months should be considered. In cases of very high bleeding risk, such as a recent (past 30 days) bleeding episode or imminent nondeferrable surgery, a regimen of 1 month of aspirin and clopidogrel may be appropriate.

In 2022, the American College of Chest Physicians (ACCP) updated its recommendations regarding the timing of DAPT after DES placement.¹⁷ The ACCP provides a conditional recommendation for patients scheduled for elective surgery who have had stent placement within the last 3 to 12 months and are on DAPT. It recommends the discontinuation of the P2Y12 inhibitor prior to surgery, based on indirect evidence and expert opinion suggesting the safety of stopping P2Y12 inhibitors in patients with stents implanted more than 3 months prior (Table 3).

Table 3: Societal Recommendations for Shortening DAPT Prior to Surgery.

CONCLUSION

Paradigms within the field of cardiology regarding the duration of DAPT have changed dramatically since the 2009 APSF Newsletter. Newer generation stent technology has led to less stent thrombosis, and cardiology experts have in turn reduced their recommended duration of DAPT on these new drug-eluting stents to 1–3 month courses of anticoagulation in patients with stable coronary artery disease. Due to the enhanced performance of these newer stents, BMS have been rendered relatively obsolete and have fallen out of favor, and therefore, not frequently placed. Decisions of duration of DAPT in the setting of urgent surgery should be made by cardiologists, in close cooperation with surgical and anesthesia teams, and may include a very short course of DAPT. Anesthesia professionals must be mindful of these shorter durations of DAPT and be cognizant of the fact that durations of anticoagulation of as little as one month may be recommended for their recently stented patients, based on the evidence of enhanced safety profile of these newer-generation stents.

REFERENCES

1. Greenberg SB, Matten EC, Murphy GM, Vender JS. Perioperative coronary stent thrombosis: a continuing safety concern. APSF Newsletter. 2009;24:17. https://www.apsf.org/article/perioperative-coronary-stent-thrombosis-
   a-continuing-safety-concern/ Accessed August 8, 2024.
2. Tsimikas S. Drug-eluting stents and late adverse clinical outcomes: lessons learned, lessons awaited. J Am Coll Cardiol. 2006;47:2112–2115. PMID: 16697332
3. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:299S–339S. PMID: 18574269
4. Ueki Y, Bär S, Losdat S, et al. Validation of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in patients undergoing percutaneous coronary intervention and comparison with contemporary bleeding risk scores. EuroIntervention. 2020;16:371–379. PMID: 32065586
5. Capodanno D, Morice MC, Angiolillo DJ, et al. Trial design principles for patients at high bleeding risk undergoing PCI. JACC Scientific Expert Panel. J Am Coll Cardiol. 2020;76:1468–1483. PMID: 32943165
6. PreciseDAPT Web calculator. PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy. http://www.precisedaptscore.com/predapt/ Accessed August 9, 2024.
7. Pivato CA, Reimers B, Testa L, et al. One-month dual antiplatelet therapy after bioresorbable polymer everolimus-eluting stents in high bleeding risk patients. J Am Heart Assoc. 2022;11:e023454. PMID: 35114814
8. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;15;392:940–949. PMID: 30166073
9. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 2019;381:2032–2042. PMID: 31556978
10. Natsuaki M, Morimoto T, Yamamoto E, et al. One-year outcome of a prospective trial stopping dual antiplatelet therapy at 3 months after everolimus-eluting cobalt-chromium stent implantation: ShortT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent (STOPDAPT) trial. Cardiovasc Interv Ther. 2016;31:196–209. PMID: 26518420
11. Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet. 2018;39:41–50. PMID: 29102362
12. Kirtane AJ, Stoler R, Feldman R, et al. Primary Results of the EVOLVE Short DAPT study evaluation of 3-month dual antiplatelet therapy in high bleeding risk patients treated with a bioabsorbable polymer-coated everolimus-eluting stent. Circ Cardiovasc Interv. 2021;14:e010144. PMID: 33641374
13. Mehran R, Cao D, Angiolillo DJ, et al. 3- or 1-month DAPT in patients at high bleeding risk undergoing everolimus-eluting stent implantation. JACC Cardiovasc Interv. 2021;14:1870–1883. PMID: 34503737
14. Watanabe H, Morimoto T, Natsuaki M, et al. Comparison of clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome The STOPDAPT-2 ACS Randomized Clinical Trial). JAMA Cardiol. 2022;7:407–417. PMID: 35234821
15. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2022;145:e18–e114. PMID: 34882435
16. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42:1289–1367. PMID: 32860058
17. Douketis JD, Spyropoulos AC, Murad H, et al. Perioperative management of antithrombotic therapy: An American College of Chest Physicians clinical practice guideline. CHEST. 2022;162:e207–e243. PMID: 35964704