Sugammadex (ORG 25969) is a unique neuromuscular blockade reversal drug. It was the first selective relaxant binding agent, which is a relatively novel class of drugs that reverse neuromuscular blockade (NMB) induced by a specific NMB agent. Sugammadex reverses the aminosteroid non-depolarizing muscle relaxants rocuronium and vecuronium, commonly used during general anesthesia. Currently manufactured by Merck & Co., Inc. under the brand name Bridion, it must be administered according to specific protocols to exert its unique effects. 

Sugammadex, named after “Su”, for sugar, and “gammadex”, for the gamma-cyclodextrin molecule inherent to its structure,¹ has a unique three-dimensional structure resembling a hollow doughnut.² On administration, it does not produce any metabolites and is mostly excreted through urine in the same form it was ingested within 24 hours.  

 The minimal reversal dose of sugammadex is 2 mg/kg (intravenous). It is to be administered as a single intravenous bolus, delivered over less than 10 seconds. As such, the drug is currently only available for intravenous administration, in vials of 200 or 500 mg, to be stored un-refrigerated.  

Sugammadex may interfere with the chemotherapeutic drug Toremifene, a selective estrogen receptor modulator; Toremifene may delay the reversal by displacing the formation of the rocuronium-sugammadex complex. Sugammadex may also theoretically bind with contraceptive steroids but has a much lower affinity for steroids compared to aminosteroid NMBs. Additional interactions have also been noted, including with fusidic acid and magnesium.³ However, further investigations are required to probe other possible drug interactions. Sugammadex is contraindicated in individuals who are hypersensitive to it or to any of its excipients.  

 Sugammadex inactivates rocuronium by encapsulating the free molecule to form a stable molecular complex.⁴ As a result, robust recovery from neuromuscular blockade has been seen across a broad variety of clinical contexts.⁵ 

By reliably and effectively reversing moderate or deep neuromuscular blockade, sugammadex has become a core drug in anesthesia practice. Older methods of reversing rocuronium and other aminosteroid muscle relaxants, such as using neostigmine, are accompanied by several shortcomings.³

A phase 3, multicenter, randomized, blinded clinical study recently demonstrated that patients treated with sugammadex achieved faster recovery of neuromuscular function following rocuronium or vecuronium administration than with neostigmine.⁶ In addition, sugammadex also avoids side-effects associated with neostigmine, including but not limited to nausea, vomiting, and undesired autonomic adverse effects.⁷ 

 Despite its benefits, the routine, global use of sugammadex remains limited by economic constraints.⁸ This said however, it was approved by the Food and Drug Administration (FDA) in 2015, marking a turning point in its clinical use and greatly facilitating its clinical adoption.⁹ 

 Sugammadex has established itself as a key drug in anesthesia,¹⁰ undoubtedly representing a clinical milestone in the safety and quality of anesthetic care. In the meantime, additional research into its implementation and regulatory advances are required for its consistent, regular, global clinical implementation.  

References  

1. Kovac, A. L. Sugammadex: the first selective binding reversal agent for neuromuscular block. Journal of clinical anesthesia (2009). doi:10.1016/j.jclinane.2009.05.002
2. Naguib, M. Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth. Analg. (2007). doi:10.1213/01.ane.0000244594.63318.fc
3. Singh, D. et al. Sugammadex: A revolutionary drug in neuromuscular pharmacology. Anesth. Essays Res. (2013). doi:10.4103/0259-1162.123211
4. Bom, A. et al. A novel concept of reversing neuromuscular block: Chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew. Chemie – Int. Ed. (2002). doi:10.1002/1521-3773(20020118)41:2<265::AID-ANIE265>3.0.CO;2-Q
5. Herring, W. J. et al. Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies. J. Clin. Anesth. (2017). doi:10.1016/j.jclinane.2017.06.006
6. Merck’s BRIDION® (sugammadex) Receives FDA Approval for the Reversal of Neuromuscular Blockade Induced by Rocuronium and Vecuronium in Adults Undergoing Surgery – Merck.com. Available at: https://www.merck.com/news/mercks-bridion-sugammadex-receives-fda-approval-for-the-reversal-of-neuromuscular-blockade-induced-by-rocuronium-and-vecuronium-in-adults-undergoing-surgery/. (Accessed: 17th August 2022)
7. Naguib, M. & Magboul, M. M. Adverse effects of neuromuscular blockers and their antagonists. Middle East journal of anesthesiology (1998). doi: 10.2165/00002018-199818020-00002.
8. Ledowski, T. et al. Introduction of sugammadex as standard reversal agent: Impact on the incidence of residual neuromuscular blockade and postoperative patient outcome. Indian J. Anaesth. (2013). doi:10.4103/0019-5049.108562
9. FDA Approves Bridion (sugammadex) to Reverse Effects of Neuromuscular Blocking Drugs. Available at: https://www.drugs.com/newdrugs/fda-approves-bridion-sugammadex-reverse-neuromuscular-blocking-4316.html. (Accessed: 17th August 2022)
10. Tayal, G., Kundra, S. & Grewal, A. Sugammadex – New neuromuscular block reversal. J. Anaesthesiol. Clin. Pharmacol. (2008). doi: 10.4103/0259-1162.123211

Initially recognized as a respiratory system disease, COVID-19 has been found to interact with and affect the cardiovascular system, resulting in a slew of cardiac ailments ranging from myocardial damage to cardiac and endothelial dysfunction (1). Cardiac damage has been noted even without clinical features of respiratory disease. Further, some cardiac symptoms have been known to persist in certain patients, greatly complicating their recovery. Recently however, a treatment has emerged in ivabradine for persistent cardiac COVID-19 symptoms.  

At the start of the COVID-19 pandemic, a surprising volume of hospitalized patients were found to have elevated levels of cardiac troponin, a marker of myocardial injury. Soon thereafter, echocardiograms confirmed cardiac functional abnormalities in many patients (2). A recent meta-analysis of studies on long COVID-19 found that up to 11% of COVID-19 patients report experiencing palpitations or an increased heart rate (3). These may include, but are not limited to, myocardial infarction, coronary artery disease, arrhythmias, and conduction system disease. While the underlying causes remain unclear, one study based on an online survey of over 2,000 adults with long COVID interestingly found that up to two thirds of patients have symptoms suggestive of an impaired autonomic nervous system, which controls “automatic” functions of the body, including blood pressure, digestion, body temperature – and heart rate. 

COVID-19-related cardiac symptoms are similar to the broader condition known as postural orthostatic tachycardia syndrome (POTS). Even prior to the COVID-19 pandemic, POTS was known to affect more than 24 million Americans, especially in patients recovering from influenza or another viral infection. POTS can impact employment and education, similar to severe cardiac ailments, and it is important to treat quickly and effectively.  

While beta blockers and calcium channel blockers may be administered, these can lower blood pressure and may make patients feel worse. Ivabradine (Procoralan), meanwhile, is a drug that selectively reduces heart rate via ion channel current inhibition in the heart’s sinoatrial node without inducing a negative effect on inotropy. Confirming results found prior to the COVID-19 pandemic, a 2021 randomized controlled clinical trial involving 22 people demonstrated that ivabradine was effective at lowering the heart rate in POTS patients, which suggests that it may be applicable to COVID-19 patients as well (4). While its precise mechanism of action remains unknown, ivabradine is now commonly prescribed, along with exercises, to hundreds of POTS patients, including many with long COVID-19 (5).  

Besides selective heart rate reduction, ivabradine has been found to result in a number of addition beneficial effects. These include anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative effects, in addition to attenuating endothelial dysfunction and neurohumoral activation (6). 

Ivabradine has emerged as a promising drug in the treatment of persistent cardiac COVID-19 symptoms, with minimal negative side effects. Additional research will be required to elucidate its precise mechanism of action and improve its administration protocol.  

References  

1. Basu-Ray I, Soos MP. Cardiac Manifestations Of Coronavirus (COVID-19). StatPearls. 2020.
2. Abbasi J. Researchers Investigate What COVID-19 Does to the Heart. JAMA – J Am Med Assoc. 2021;
3. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021; doi: 10.1101/2021.01.27.21250617. 
4. Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC. Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome. J Am Coll Cardiol. 2021; doi: 10.1016/j.jacc.2020.12.029.
5. Heart-Failure Drug Used to Treat Long Covid Symptoms – Bloomberg [Internet]. [cited 2022 Jul 25]. Available from: https://www.bloomberg.com/news/articles/2022-05-25/heart-failure-drug-used-to-treat-long-covid-symptoms
6. Baka T, Repova K, Luptak I, Simko F. Ivabradine in the management of COVID-19-related cardiovascular complications: A perspective. Curr Pharm Des. 2022; doi: 10.2174/1381612828666220328114236. 

Perhaps one of the most unique characteristics of the COVID-19 pandemic has been the large variability in infection-related morbidity and mortality. Disparities have been noted on several levels: between different ethnic groups and even within relatively homogenous demographics. Questions remain as to why some healthy, young adults have asymptomatic or mild infections while others require admission to the intensive care unit. For some researchers, these trends point towards the possibility of genetic and evolutionary determinants of COVID-19 susceptibility.1 

For patients with known genetic abnormalities, deletory effects on immune response to infection might be expected. For example, inborn errors of immunity, which include primary immunodeficiencies, increase susceptibility to a number of different infections, COVID-19 included, as well as autoimmune, inflammatory, and allergic diseases.2 A study performed by the COVID Human Genetic Consortium demonstrated that a myriad of monogenic predispositions which had been previously associated with influenza susceptibility also increased susceptibility to COVID-19. By performing both exomic and genomic sequencing on a large cohort of critically ill COVID-19 patients, the Consortium revealed thirteen such genes, including core immune genes TLR3, IRF7 and IRF9.2 

However, most individuals with genetic susceptibility to COVID-19 infection likely have a more complex etiology, orchestrated by multiple genes. The growing prevalence of genetic testing, both commercially and in healthcare settings, has made large-scale GWAS studies in the COVID-19 era possible. For example, the largest meta-analysis of genetic susceptibility to COVID-19 infection included approximately 125,500 cases and over 2.5 million controls.3 As a result of this mass study, the COVID-19 Host Genetics Initiative identified almost two dozen loci significantly associated with disease susceptibility or severity. One locus which was particularly prominent in their findings was on chromosome three, location 3p21.31 – a gene thought to encode an ACE-2 interacting sodium transporter.3 Given that SARS-CoV-2 targets the ACE-2 receptor on the cell membrane, the relationship between the 3p21.31 locus and increased disease susceptibility is consistent with known mechanisms of COVID-19 infection.  

As previously mentioned, significant discrepancies in the severity of SARS-CoV-2 infection have been noted across different ethnicities. Individuals of European ancestry tend to have reduced morbidity and mortality related to infection. While there is speculation that this disparity could be attributed to pervasive socioeconomic differences across racial groups, adjusting for these variables failed to fully ameliorate the difference for Black and South Asian populations, suggesting additional factors at play.4 Continued investigation revealed one unexpected predictor for susceptibility to COVID-19 infection: Neanderthal ancestry.5,6,7 A study conducted by the COVID-19 Host Genetics Initiative reported that a roughly 75kb haplotype, which is likely traceable to Neanderthal descent and is absent in African Homosapiens, is associated with a nearly 25 percent reduction in hospitalization risk due to COVID-19.6 The haplotype encodes antiviral enzymes which contribute to improved immunity. However, the beneficial effect of this haplotype may be negated by the inheritance of other, less advantageous genes: on chromosome 3, 3p21.31, a 50kb Neanderthal haplotype has been linked to increased severity of COVID-19 infection.7 This specific Neanderthal haplotype is at least three times more prevalent in South Asian populations and is associated with as much as a 60 percent increase in hospitalization.7 

Overall, much is still to be learned concerning evolutionary and genetic susceptibility to SARS-CoV-2 infection, particularly when it comes to the influence of Neanderthal ancestry on disease severity. However, continued investigation will continue to improve our understanding of the mechanisms underlying severe COVID-19 infection and may even help us to better identify at-risk populations or create more targeted curative treatments. 

References 

1 Kerner, G., & Quintana-Murci, L. (2022). The genetic and evolutionary determinants of COVID-19 susceptibility. European journal of human genetics : EJHG, 1–7. Advance online publication. https://doi.org/10.1038/s41431-022-01141-7 

2 Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I., Hodeib, S., Korol, C., Rosain, J., Bilguvar, K., Ye, J., Bolze, A., Bigio, B., Yang, R., Arias, A. A., Zhou, Q., Zhang, Y., Onodi, F., … Casanova, J. L. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science (New York, N.Y.), 370(6515), eabd4570. https://doi.org/10.1126/science.abd4570 

3 COVID-19 Host Genetics Initiative (2021). Mapping the human genetic architecture of COVID-19. Nature, 600(7889), 472–477. https://doi.org/10.1038/s41586-021-03767-x 

4 Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., Curtis, H. J., Mehrkar, A., Evans, D., Inglesby, P., Cockburn, J., McDonald, H. I., MacKenna, B., Tomlinson, L., Douglas, I. J., Rentsch, C. T., Mathur, R., Wong, A., Grieve, R., Harrison, D., … Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430–436. https://doi.org/10.1038/s41586-020-2521-4 

5 Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. https://doi.org/10.1038/s41586-020-2818-3 

6 Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., Oosthuyzen, W., … Baillie, J. K. (2021). Genetic mechanisms of critical illness in COVID-19. Nature, 591(7848), 92–98. https://doi.org/10.1038/s41586-020-03065-y 

7 Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. https://doi.org/10.1038/s41586-020-2818-3 

Patient monitoring during anesthesia is critical to ensuring their well-being. This includes monitoring a patient’s ventilation, circulation, body temperature, and oxygenation in both their inspired gas and in their blood. Blood oxygen monitoring during surgery is particularly important for maintaining adequate tissue and organ perfusion. This prevents the development of hypoxemia, hyperoxemia, and other such complications that can lead to negative outcomes 1,2. This is particularly problematic among patients who already have or are predisposed to respiratory problems, including but not limited to obstructive sleep apnea. To this end, blood oxygen monitoring methods such as pulse oximetry have been developed and successfully implemented during anesthesia. 

In order to gauge a patient’s oxygenation level, healthcare providers can assess (1) the saturation level of oxygen in hemoglobin via pulse oximetry, (2) the hematocrit, an indicator of hemoglobin concentration, and (3) the partial pressure of oxygen in arterial blood.  

Pulse oximetry noninvasively and continuously assesses the saturation of oxygen bound to hemoglobin. In particular, it measures the percentage of oxyhemoglobin and reduced hemoglobin present in arterial blood. Its downsides include the fact that it may be affected by many factors, including motion artifacts, ambient light, reduced peripheral blood flow (which can be caused by hypotension or vasoconstriction), electrical noise from surgical instruments, increased carboxyhemoglobin or methemoglobin concentrations in the blood, or darkly pigmented skin. 

Meanwhile, a patient’s hematocrit can be measured by a blood sample analysis usually prior to surgery, or, in some cases, from blood samples collected during surgery. In cardiac surgery in particular, it is critical to ensure that a patient’s hematocrit remains within a specified range 3. 

Finally, arterial blood gas measures probe the partial pressure of oxygen in arterial blood samples; this partial pressure of oxygen in arterial blood is directly linked to oxygen saturation levels in blood hemoglobin according to a linear relationship in most clinical contexts. 

Today, the standard protocol laid forth by the American Society of Anesthesiologists is to use a quantitative method of assessing oxygenation such as pulse oximetry 4. Adequate illumination and exposure of the patient are necessary to assess color, and an audible pulse tone and low threshold alarm should be used.  

A somewhat recent study sought to assess broadly conducted research on the effectiveness of pulse oximetry to identify hypoxemia and related events among a large general surgery population 5. The research team found no evidence that use of pulse oximetry affected the outcome of anesthesia. Specifically, routine continuous pulse oximetry monitoring neither reduced the rate of transfer to the intensive care unit nor decreased mortality. As such, the researchers concluded that the value of perioperative monitoring via pulse oximetry remains questionable as regards improved outcomes, effectiveness and efficiency.  

Intraoperative oxygen monitoring is critical to patient well-being, but further studies are required to improve our understanding of the clinical impact of intraoperative hypoxemia and the strategies that are most efficient in minimizing its occurrence.  

References 

1. Ehrenfeld, J. M. et al. The incidence of hypoxemia during surgery: Evidence from two institutions. Can. J. Anesth. (2010). doi:10.1007/s12630-010-9366-5
2. Karalapillai, D. et al. Frequency of hyperoxaemia during and after major surgery. Anaesth. Intensive Care (2020). doi:10.1177/0310057X20905320
3. Kolotiniuk, N. V., Manecke, G. R., Pinsky, M. R. & Banks, D. Measures of Blood Hemoglobin and Hematocrit During Cardiac Surgery: Comparison of Three Point-of-Care Devices. J. Cardiothorac. Vasc. Anesth. (2018). doi:10.1053/j.jvca.2017.11.022
4. American Society of Anestesiologist. Standards for Basic Anesthetic Monitoring. J. Chem. Inf. Model. (2020).
5. Pedersen, T. et al. Pulse oximetry for perioperative monitoring. Cochrane Database of Systematic Reviews (2014). doi:10.1002/14651858.CD002013.pub3