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The ongoing COVID-19 pandemic is caused by the emergence of the SARS-CoV-2 coronavirus. Without any adequate vaccine or therapeutics available at the moment, many researchers have turned their attention to prevention methods by studying the SARS-CoV-2 structure and its mechanism of cell entry. If the virus could be blocked from entering human cells, SARS-CoV-2 would be unable to replicate and invade the host immune system. Proteases essential for viral entry have been identified, and research reveals that protease inhibitors might be the key to stopping this infectious virus.

SARS-CoV-2 is closely related to SARS-CoV, a strain of coronavirus responsible for the SARS outbreak in 2003. Reports reveal that the two coronaviruses share 76 percent similarity in amino-acid sequence¹. Therefore, the mechanism in which SARS-CoV-2 enters host cells shares many similarities with that of SARS-CoV. From previous research, it has been determined that SARS-CoV relies on the protein angiotensin-converting enzyme 2 (ACE2) to enter host cells. The S1 unit of the spike protein of SARS-CoV-2 binds to ACE2, which is the host’s transmembrane endopeptidase. Infectivity of SARS-CoV-2 is then made possible by the serine protease TMPRSS2. TMPRSS2 is critical in facilitating the spread of the virus because the virus uses it for S protein priming on its surface. Cysteine protease cathepsin B and L (CatB/L) is another protease that performs the same function as TMPRSS2. S protein priming results in the fusion of viral and host membranes, subsequently completing viral cell entry². Heavy viral dependence on protease activity suggests that if protease inhibitors were utilized, SARS-CoV-2 infectivity could be eliminated.

Camostat mesilate is a commercial serine protease inhibitor that inhibits TMPRSS2 activity. Clinical trial results showed that camostat mesilate was successful in partially blocking SARS-CoV-2 entry into Caco-2 and Vero-TMPRSS2 cells. E-64d is an inhibitor of Catb/L, and when used conjunctively with camostat mesilate, full inhibition of viral entry was attained. The additive efficacy of the two inhibitors indicates that SARS-CoV-2 entry is driven by both TMPRSS2 and E-64d priming. However, S priming by TMPRSS2 is essential for viral cell entry, while CatB/L priming is not required for viral spread. Therefore, inhibitor drugs targeted at TMPRSS2 activity have become a more attractive option. Similar to past study results on SARS-CoV, camostat mesilate significantly reduced SARS-CoV-2 cell entry into the human lung cell Calu-3.³

Although camostat mesilate appears to be promising, another study has shown that the protease furin also plays an indispensable role in the cleavage of the SARS-CoV-2 spike protein.⁴ Unlike TMPRSS2, furin cleavage is not conserved across the coronavirus family, posing challenges for researchers looking to past research for guidance. Barile et al. tested camostat mesilate and used it to inhibit furin activity. Unfortunately, they discovered that camostat mesilate is a poor inhibitor of furin. The team suggested that future research should focus on developing a cocktail of inhibitors that can efficiently block both furin and TMPRSS2 activity.⁵

Host protease cleavage is critical to SARS-CoV-2 infection; therefore, focusing on the discovery of efficient protease inhibitors could effectively slow down transmission. More research needs to be conducted to determine protease inhibitors that can successfully inhibit the majority of proteases utilized by SARS-CoV-2. Trials on protease inhibitors are still in the early stages, but results show promise.

References

1. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., Zhao X., Huang B., Shi W., Lu R. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.

• Kawase M., Shirato K., van der Hoek L., Taguchi F., Matsuyama S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J. Virol. 2012; 86:6537–6545.

• Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181(2), 271–280.e8. https://doi.org/10.1016/j.cell.2020.02.052

• Lukassen S., Chua R.L., Trefzer T., Kahn N.C., Schneider M.A., Muley T. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 2020;39

• Barile E., Baggio C., Gambini L., Shiryaev S.A., Strongin A.Y., Pellecchia M. (2020). Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming. Molecules. 25(10), 2424.

In the toolkit of strategies to stop the spread of COVID-19, many countries are reaching for smartphone apps¹. From Iceland to Israel, more than 30 contact-tracing systems are being developed by governments and health authorities. They promise to automate the laborious process of tracking down the contacts of infected individuals, helping to slow the spread of coronavirus through the population and save lives². Such apps can complement a country’s overall COVID-19 control strategies — including testing, contact tracing, isolation and social distancing — but they cannot serve as a replacement for them, or the thousands of contact-tracing teams they require. Like any health-care intervention, coronavirus apps need to conform to the highest standards of safety and efficacy. And yet, despite the pandemic’s global nature, countries are developing apps independently, and there are no global standards — which is rightly raising concerns².

COVID-19 apps have, to some extent, been inspired by the experiences of South Korea and Singapore — where electronic surveillance methods have helped to control infections. South Korea, in particular, is regarded as a model because it avoided severe lockdowns¹. The foundation for South Korea’s COVID-19 response is a comprehensive testing strategy, backed by a nationwide network of highly-trained contact-tracers. The strategy includes the use of phone alerts. When a person tests positive for COVID-19, a text alert is sent to everyone living nearby. This alert typically includes a link to a detailed log of the infected person’s movements — in some cases to the nearest minute. These movements are reconstructed from public data, such as closed-circuit television cameras.

It must be noted that the South Korean strategy is based on a degree of surveillance that people in many other countries would find hard to accept¹. The South Korean government is also permitted to access confidential records, such as credit-card transactions. The data are then stored centrally by government agencies. At the same time, people’s movements are anonymized and published online. As of July 16, some 6 months after the outbreak spread to South Korea, only a handful of new cases are being reported daily and only 291 deaths have been recorded in total³.

India is one of the few democracies that has made downloading its contact tracing app mandatory. Employees must use the app in order to get into offices or to travel. If they do not, they could face criminal prosecution. The Aarogya Setu app, meaning “healthcare bridge” in Hindi, has racked up more than 100 million downloads since launching on April 2 — a substantial number but only a small fraction of India’s population of 1.3 billion⁴. Using a phone’s Bluetooth and location data, Aarogya Setu lets users know if they have been near a person with Covid-19 by scanning a database of known cases of infection. While names and numbers of individuals won’t be made public, the app does collect this information, as well as gender, travel history, and if someone is a smoker. As Aarogya Setu stores location data and requires constant access to the phone’s Bluetooth, experts say that the app is invasive from a security and privacy viewpoint. Additionally, Aarogya Setu is not open source, which means that it cannot be audited for security flaws by independent coders and researchers⁵.

Apps with more limited scope have had some success. Police in Kerala, the first Indian state to report a coronavirus case, used the Covid Safety App to help enforce the quarantine of about 20,000 people in Kasargod, one of the worst-affected districts. Users voluntarily downloaded the app so police could track their location. The app had an SOS button that people could press if they needed essential goods or were in an emergency. As of April 15, Kerala had reported only four coronavirus deaths⁴.

While there have been successful attempts at mobile tracing technology in some countries, these efforts so far have fallen flat in the U.S. For example, the state of New Jersey is neither pursuing nor promoting exposure notification or digital alerting technology, according to Phil Murphy, the governor of the state⁶. New Jersey isn’t alone. Most states are giving the cold shoulder to smartphone apps. A survey of state health officials from Business Insider conducted the week of June 12th showed that only three states — Alabama, North Dakota and South Carolina — said they were going to use the software provided by Apple and Google. The number hasn’t grown since the same three states reported interest in May, and none have launched an app with the Google-Apple software⁶.

One serious concern with contact tracing apps is accuracy. Apps that link to official validated tests are obviously more likely to give accurate results. An alert based on self-diagnosis that turns out to be wrong — a false positive — could, of course, be corrected. But if incorrect information has been sent to a large group of contacts, it will have caused unnecessary alarm, and could have wrongly sent people into isolation for weeks.

An equally important concern is privacy. Researchers have shown that it is possible to re-identify individuals even when anonymized and aggregated data sets are incomplete. And then there’s the communications technology itself. Most apps share information using Bluetooth, a radio-frequency technology that allows devices to exchange information at close range. This is convenient, since most smartphones have it. But it has a history of security breaches that have been well-reported and studied. Smartphone users are usually advised to turn off Bluetooth when it is not needed, and especially when in close proximity to other phone users. But to work, COVID-19 apps need users to keep Bluetooth running — particularly when they are in public places¹.

Researchers and policymakers have worked hard over many decades to ensure that medicines, vaccines and health-care products conform to agreed standards of safety and efficacy. These often need to be global standards. COVID-19 smartphone apps are a health-care intervention, too, and will potentially affect hundreds of millions of lives. But they are being rolled out without pilot studies or risk assessments being published. Speed is, of course, of the essence — but so is due diligence and due process. This includes public dialogue; more involvement from researchers, including those who study ethics, law and public engagement; and a cast-iron commitment from governments that the information being harvested is secure and will only ever be used for the reasons it is being requested¹. 

References

1. Show evidence that apps for COVID-19 contact-tracing are secure and effective. (2020). Nature, 580(7805), 563–563. https://doi.org/10.1038/d41586-020-01264-1
2. Burgess, M. (2020, May 1). Coronavirus contact tracing apps were meant to save us. They won’t. WIRED. https://www.wired.co.uk/article/contact-tracing-apps-coronavirus.
3. COVID-19 CORONAVIRUS PANDEMIC. (n.d.). Retrieved March 22, 2020, from https://www.worldometers.info/coronavirus/
4. Findlay, S. (2020, May 18). Coronavirus contact-tracing apps struggle to make an impact. Financial Times. https://www.ft.com/content/21e438a6-32f2-43b9-b843-61b819a427aa.
5. Clarance, A. (2020, May 15). Aarogya Setu: Why India’s Covid-19 contact tracing app is controversial. BBC News. https://www.bbc.com/news/world-asia-india-52659520.
6. Ingram, D. (2020, June 12). Coronavirus contact tracing apps were tech’s chance to step up. They haven’t.NBCNews.com. https://www.nbcnews.com/tech/tech-news/coronavirus-contact-tracing-apps-were-tech-s-chance-step-they-n1230211.

The American Association for Accreditation of Ambulatory Surgery Facilities, Inc. (AAAASF) was established in 1980 to standardize and improve the quality of medical and surgical care in outpatient facilities and assure the public that patient safety is the top priority in an accredited facility (1). The AAAASF was originally known as the American Association for Accreditation of Ambulatory Plastic Facilities (AAAASPF), as it only regulated the quality of outpatient plastic surgical facilities. In 1992, the AAAASPF morphed into its current form, recognizing the need for similar standards for all American Board of Medical Specialties (ABMS) surgeons who operated in single surgical or multispecialty ASCs and were board-certified, practicing within the scope of their specialty (2). The AAAASF now accredits thousands of international and domestic facilities, making it one of the largest not-for-profit accrediting organizations in the United States. Physicians, clinicians, legislators, state and national health agencies, and patients acknowledge that the AAAASF sets the “gold standard” for quality patient care (1).

AAAASF programs include outpatient surgical, procedural, oral maxillofacial, international surgical, rehabilitation, and dental. AAAASF is also approved by the Centers for Medicare and Medicaid Services (CMS) to accredit ambulatory surgery centers, rehabilitation and outpatient physical therapy agencies, as well as rural health clinics (3). The AAAASF Accreditation Program requires 100% compliance with its standards to be an accredited facility, and each accreditation cycle is three years. The facility is expected to continue to meet the criteria during the entire time. A self-evaluation form is sent to the facility which completes it and self-reports compliance during the interim years between inspections, along with reporting the required peer review activities (4). An accredited facility will be fully equipped to perform procedures in the medical specialty or specialties listed on its accreditation application. After a survey, a facility will be given 30 days to correct any deficiencies cited. Once completed, all new facilities are sent to an accreditation committee for approval. After approval has been granted, accreditation will be activated, and the facility will be promptly notified. The entire process typically takes about 90 days (5). Accreditation represents a high level of attention to the details that make an ambulatory medical facility safer. The AAAASF has developed stringent, nationally recognized standards that are continuously reviewed and revised as new developments occur. Patient safety is never compromised when standards are amended (3).

The AAAASF International (AAAASF-I) program surveys and accredits clinics that exceed superior standards. Globally, there is a growing need and demand for uniform standards and practices to ensure quality health care and patient safety. The AAAASF-I is an accreditation program certifying to the medical and dental community and the general public that a facility meets internationally recognized standards (3). In 2015, the AAAASF-I received a 4-year approval from the International Society for Quality in Health Care (ISQUA), known as the “accreditor of accreditors.” ISQUA approval of AAAASF standards provides further evidence to ministries of health, patients, and health providers that the facilities using the AAAASF standards meet international requirements (3).

Improving safety is a never-ending task and a priority for ethical physicians. The AAAASF has played a significant role in the area in ambulatory surgery, especially plastic surgery. The future holds safer, better results which will be achieved through continued modifications of standards, research, evidence-based medicine, better data about outcomes, and by identifying the root causes of untoward results (2).

References

1. Who We Are. (n.d.). Retrieved from https://www.aaaasf.org/who-we-are/
2. Robert Singer, Geoffrey R Keyes, Foad Nahai, American Association for Accreditation of Ambulatory Surgical Facilities (AAAASF) History: Its Role in Plastic Surgery Safety, Aesthetic Surgery Journal Open Forum, Volume 1, Issue 2, June 2019, ojz008, https://doi.org/10.1093/asjof/ojz008
3. What Can AAAASF Do For You? (n.d.). Retrieved from https://www.aaaasf.org/docs/default-source/news-events/for-the-media/information-packet.pdf
4. 3 Different Organizations Can Accredit OBA Sites. (n.d.). Retrieved from https://www.apsf.org/article/3-different-organizations-can-accredit-oba-sites/#:~:text=The origin of AAAASF dates, specialties office-based surgery units
5. Accreditation Fact Sheet. (n.d.). Retrieved from https://www.aaaasf.org/docs/default-source/news-events/for-the-media/fact-sheet-accreditation.pdf?sfvrsn=2

A pulmonary embolism (PE) occurs when a blood clot that forms in a blood vessel in one area of the body (an embolus) breaks off and travels to a lung artery where it suddenly blocks blood flow. This can block the blood supply to a particular organ. This blockage of a blood vessel by an embolus is called an embolism. The most common symptoms for PE include sudden shortness of breath (most common), chest pain, dizziness, irregular heartbeat, palpitations, coughing and/or coughing up blood, and low blood pressure (1). PE is often difficult to diagnose because its symptoms are often found in many other conditions and diseases. However, along with a complete medical history and physical exam, tests used to look for a PE include chest X-ray, computed tomography (CT or CAT scan), and magnetic resonance imaging (MRI) (1). Interestingly, there appears to be a higher observed higher incidence of PE in COVID-19 patients. In March 2020, a study published in the European Heart Journal suggests a causal relationship between COVID-19 pneumonia and acute PE (APE) (2). Furthermore, according to a study submitted to the Lancet by Chen et. al, elevated level of D-dimer (a potential sign of PE) was reported in some patients with COVID-19 pneumonia on admission, especially in critically ill COVID-19 patients. However, it was still unknown whether this abnormality was associated with PE, as PE cannot be solely diagnosed by elevated D-dimer levels, because D-dimer can also be elevated in a series of other conditions such as cancer, peripheral vascular disease, pregnancy, and inflammatory diseases (3). Thus, the authors of the study aimed to confirm these findings through computed tomography pulmonary angiography (CTPA) in COVID-19 patients.  

In this study, Chen et. al retrospectively identified 25 COVID-19 patients in total, who had CTPA examinations during the COVID-19 course, by searching in the electronic medical records database in the Central Hospital of Wuhan between January 2020 and February 2020. The Central Hospital of Wuhan hospitalized a total of 1008 patients with COVID-19 pneumonia between January 2020 and February 2020 (3). Diagnosis of COVID-19 pneumonia was based on Guidelines for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Infection published by the National Health Commission of China (Trial Version 5). All patients enrolled in the study were COVID-19 positive according to this clinical diagnostic criterion. They had undergone CTPA scans due to suspected PE and other clinical concerns and underwent D-dimer tests. Twenty patients received one or more follow-ups of the D-dimer test, and 3 patients underwent a follow-up CTPA examination to assess remission of PE after anticoagulant therapy. The interval between the CTPA examination and D-dimer test was less than 2 days. This study was approved by the Ethics of Committees of The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology. The need for patient informed consent was waived because of its retrospective nature (3). 

A total of 25 patients (15 males and 10 females) were retrieved from the medical records. The median age was 65 years old (interquartile range (IQR): 56-70, range: 36-78 years). 15 of these patients were diagnosed positive for COVID-19 infection using RT-PCR, but the other 10 

patients who tested negative using the RT-PCR test were diagnosed COVID-19 positive according to clinical diagnostic criteria. According to diagnostic criteria of COVID-19 classification, 11 cases (44%) were moderate and 14 cases (56%) were severe. Several chronic medical diseases, including hypertension (ten [40%]), diabetes (five [20%]), and cardiovascular disease (four [16%]) were recorded in some patients. By Feb 29, 2020, nine patients remained in hospital under close observation with improvement in symptoms, 10 patients were discharged, and 6 patients (2 with APE and 4 without APE on CTPA) had died. Abnormalities in laboratory tests were shown at the time when CTPA were performed. 10 patients were APE positive according to CPTA images, and had D-dimer levels with a median value of 1107μg/ml [IQR, 712-2166]; 15 patients were APE negative, and had D-dimer levels with a median value of 244μg/ml [IQR, 168-834]. There was a significant difference in D-dimer levels between the two groups with P < 0.05 (3). No significant difference was found between APE positive and APE negative groups for any other recorded laboratory data. In addition, twenty patients were treated with anticoagulant therapy (low molecular weight heparin, 0.6mg/kg per 12hours) regardless of any APE findings from CTPA and underwent a follow-up D-dimer test afterwards. The D-dimer levels decreased in all patients. For the 3 patients who underwent a follow-up CTPA examination after anticoagulant therapy, all APE lesions were smaller compared with the first CTPA examination, and the corresponding D-dimer levels also decreased (3). Among 10 patients with APE, six patients had bilateral pulmonary artery branches with thrombosis, and four patients had unilateral pulmonary artery branches with thrombosis. The thrombus-prone sites were the right lower lobe (70%), left upper lobe (60%), bilateral upper lobe (40%) and right middle lobe (20%).  

Essentially, Chen et. al confirmed that there is indeed a relationship between elevated D-dimer levels (found in COVID-19 patients) and APE (3). However, it is still unclear why there is a higher incidence of APE in COVID-19 patients. Autopsy results of SARS patients showed that vascular thromboses were common in lung specimens, suggesting there may be an increased underlying thrombophilia in the lungs of people infected by coronaviruses. On the other hand, another autopsy study of 8 SARS patients showed that PE was found in the pulmonary arteries in 4 patients, in which 3 patients had deep vein thrombosis (DVT), which suggests that pulmonary artery thrombus derives from the deep vein of lower limb. Due to the COVID-19 quarantine requirement, the reduced physical movements of patients likely result in higher risk of DVT in patients’ lower limbs, leading to an increased incidence of PE (3).  

References 

1. Pulmonary Embolism. (n.d.). Retrieved April 27, 2020, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/pulmonary-embolism 

2. Gian Battista Danzi, Marco Loffi, Gianluca Galeazzi, Elisa Gherbesi, Acute pulmonary embolism and COVID-19 pneumonia: a random association?, European Heart Journal, , ehaa254, https://doi.org/10.1093/eurheartj/ehaa254 

3. Chen J., Wang X., Zhang S. Findings of acute pulmonary embolism in COVID-19 patients. The Lancet Infectious Diseases. 3/1/2020 

Oftentimes, an anesthesia provider’s role involves helping patients with long-term pain management.¹ In fact, some anesthesia professionals specialize in managing chronic pain or do research to develop effective treatments for chronic pain.² Patients with long-lasting pain may take various types of drugs, including opioids.³ Chronic opioid use is accompanied by several side effects, such as tolerance and dependence, and recent research has focused on opioids’ effects on sleep.⁴ Before prescribing opioids for long-term use, anesthesia providers should be familiar with the effects of chronic opioid use, the definition of sleep apnea and the relationship between opioid therapy and sleep difficulties. 

Adverse effects of long-term opioid therapy include constipation, tolerance, endocrinopathies, sleep disorders, cognitive effects, respiratory depression, overdose and addiction.⁵ Data show a higher risk of overdose and death with increased daily opioid doses, particularly above the equivalent of 100 milligrams of oral morphine per day.⁵ While extended-release or long-acting formulations may be beneficial for patients using opioids for long periods of time, they may be associated with a higher risk for abuse due to their large dosages.⁵ Long-term opioid use can lead to hypogonadism, immunosuppression and increased risk of myocardial infarction.⁶ In addition, patients who use opioids frequently may develop tolerance and hyperalgesia (pain sensitivity), and may be at risk for complications during acute anesthesia.³ Though many patients may not develop opioid use disorder (OUD), the physical dependence from long-term opioid use can complicate attempts to wean off or discontinue opioid use.⁷ Evidently, chronic opioid use has many acute and long-lasting effects on a patient’s body. 

Opioids cause breathing to slow and become irregular,⁸ and this effect continues throughout chronic use.⁹ Apnea, which is temporary cessation of breathing, can be a risk for patients who use opioids over long periods of time.⁹ Sleep apnea is a potentially serious sleep disorder in which breathing repeatedly stops and starts.¹⁰ It is marked by loud snoring and exhaustion even after a full night’s sleep.¹⁰ The three main types of sleep apnea are obstructive sleep apnea (OSA), the most common form that occurs when throat muscles relax; central sleep apnea (CSA), which occurs when the brain does not send proper signals to the muscles that control breathing; and complex sleep apnea syndrome, also known as treatment-emergent central sleep apnea, which occurs when someone has both OSA and CSA.¹⁰ The general population has a high prevalence of OSA, which often goes undiagnosed.⁹ 

The combination of opioid use and potential for sleep apnea can create dangerous sleep issues for opioid-maintained patients.⁸ According to Pattinson, there had been few studies on the effects of opioids on breathing during sleep in humans when he wrote his review in 2008.⁸ Since then, however, many researchers have investigated the effects of opioids on respiration and sleep quality. Van Ryswyk and Antic’s review found a clear link between opioid use and sleep-disordered breathing (SDB), which affects the majority of chronic opioid users in a dose-dependent fashion.¹¹ Chowdhuri and Javaheri suggest that opioid-related SDB is related to binding to the pre-Bötzinger complex, hypoglossal nerve nucleus and chemoreceptor sites.¹² Ventilatory instability is especially prominent in opioid users during non-rapid eye movement (non-REM) sleep.¹² Chronic opioid users are also predisposed to CSA and, to a lesser extent, OSA.¹¹ Indeed, a review by Correa et al. showed that overall prevalence of CSA in patients taking chronic opioids was 24 percent.¹³ Opioid-related SDB is associated with poor sleep quality¹⁴ and risks of respiratory depression and even death.¹⁵ For patients who already have OSA, chronic opioid use may confer greater mortality risk.¹⁶ Treatments for opioid-related SDB, CSA and OSA include cognitive behavioral therapy, medication, positive airway pressure (PAP), oral devices and adaptive servo-ventilation (ASV).^11,14 However, more research is needed to evaluate long-term outcomes of PAP and ASV.^11,12 Also, there are limited data available on perioperative management of patients with opioid-related sleep apnea.¹³ 

Anesthesia providers who care for patients with chronic pain must be familiar with long-term opioid use and its consequences. Opioids can cause issues ranging from constipation to tolerance and psychological addiction. Chronic opioid use is also related to breathing issues during sleep, such as SDB, CSA and OSA, all of which can increase risk for respiratory depression and mortality. Further research is needed to establish the long-term effects of mechanical ventilation as a solution for opioid-related sleep issues. 

1.American Society of Anesthesiologists. Role of Physician Anesthesiologist. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/anesthesia-101/role-of-physician-anesthesiologist/. 

2.American Society of Anesthesiologists. Types of Pain: Chronic Pain. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/pain-management/types-of-pain/chronic/. 

3.Miclescu A. Chronic pain patient and anaesthesia. Romanian Journal of Anaesthesia and Intensive Care. 2019;26(1):59–66. 

4.Rosen IM, Aurora RN, Kirsch DB, et al. Chronic Opioid Therapy and Sleep: An American Academy of Sleep Medicine Position Statement. Journal of Clinical Sleep Medicine. 2019;15(11):1671–1673. 

5.Harned M, Sloan P. Safety concerns with long-term opioid use. Expert Opinion on Drug Safety. 2016;15(7):955–962. 

6.Chou R, Deyo R, Devine B, et al. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evid Rep Technol Assess (Full Rep). 2014(218):1-219. 

7.Rosenquist R. Use of opioids in the management of chronic non-cancer pain. In: Crowley M, ed. UpToDate. Alphen aan den Rijn, South Holland, Netherlands: Wolters Kluwer; October 1, 2019. 

8.Pattinson KTS. Opioids and the control of respiration. BJA: British Journal of Anaesthesia. 2008;100(6):747–758. 

9.Shafazand S. Sleep-disordered breathing in patients chronically using opioids. In: Eichler AF, ed. UpToDate. Alphen aan den Rijn, South Holland, Netherlands: Wolters Kluwer; January 22, 2020. 

10.Mayo Clinic. Sleep apnea. Diseases & Conditions July 25, 2018; https://www.mayoclinic.org/diseases-conditions/sleep-apnea/symptoms-causes/syc-20377631. 

11.Van Ryswyk E, Antic NA. Opioids and Sleep-Disordered Breathing. Chest. 2016;150(4):934–944. 

12.Chowdhuri S, Javaheri S. Sleep Disordered Breathing Caused by Chronic Opioid Use: Diverse Manifestations and Their Management. Sleep Medicine Clinics. 2017;12(4):573–586. 

13.Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic Opioid Use and Central Sleep Apnea: A Review of the Prevalence, Mechanisms, and Perioperative Considerations. Anesthesia & Analgesia. 2015;120(6):1273–1285. 

14.Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018;87:234–244. 

15.Cao M, Javaheri S. Effects of Chronic Opioid Use on Sleep and Wake. Sleep Medicine Clinics. 2018;13(2):271–281. 

16.Chowdhuri S, Wiitala W, Ratz D, Davis J. Sleep Apnea and Prescription Opioid Use in U.S. Veterans: Results from a National Database. B63. My Way: OSA Outpatient Models of Care: American Thoracic Society; 2016:A4182. 

Anesthesia providers are responsible for delivering anesthesia and analgesia in many contexts, ranging from perioperative to critical care.¹ Some anesthesiology professionals focus their practices on treating chronic pain, such as migraine headaches, back pain or pain related to conditions like cancer or fibromyalgia.¹ Approaches to chronic pain management can include ablative techniques to destroy nerves, acupuncture, nerve blocks, botulinum toxin (Botox) injections to relax muscles, electrical nerve stimulation, epidural or intrathecal drug therapies, local anesthetics, minimally invasive surgeries, pharmacologic management, physical therapy, psychologic treatment or trigger point injections.² One approach to chronic pain is iontophoretic drug delivery, which is a noninvasive strategy to manage soft tissue pain.³ In order to provide the best chronic pain care to their patients, clinicians should understand the mechanisms of iontophoresis and its applications in anesthesiology. 

Iontophoresis is defined as the facilitation of ions across a membrane.⁴ It is a form of transdermal drug delivery that uses electrical current to push ionized drugs through the skin’s outer layer, known as the stratum corneum.³ The stratum corneum serves as the body’s first barrier from the external environment and its functions include mechanical reinforcement, protection of cells from ultraviolet (UV) damage, regulation of immune system-regulated inflammation and hydration maintenance.⁵ Though these functions help protect the body, they also prevent the types of molecules that can penetrate the skin.⁶ Iontophoresis uses an electric current to drive hydrophilic and charged molecules through the skin barrier.⁶ This current can be achieved using either a positive or negative electrode, depending on the charge of the molecule that is meant to cross into the body.⁷ Iontophoresis is advantageous in that it can be used to deliver medications locally without injection.⁸ This is particularly useful for patients with fear of needles or pediatric patients.⁸ Additionally, iontophoresis may be useful for a variety of medications, including antibiotics.^8,9 Research on iontophoresis is conflicting, as some reports argue that iontophoresis does not deliver enough medication to deep enough tissue to be effective.⁸ However, use of iontophoresis in dermatology, ophthalmology, dentistry and physical medicine have brought this drug delivery method to the forefront of scientific exploration.¹⁰ 

Iontophoresis can play various roles in analgesia, including—but not limited to—management of pain related to migraines, surgeries or cancer.¹¹ Iontophoresis has been used for chronic pain treatment for at least 40 years.¹²According to Karpiński, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, ibuprofen, aspirin and indomethacin can be used in iontophoresis to relieve joint pain related to rheumatoid arthritis or other injuries.¹³ When applied iontophoretically, NSAIDs do not cause the usual gastrointestinal irritation that comes with their oral administration.¹³ Japour et al. found that acetic acid iontophoresis helped patients with chronic heel pain,¹⁴ and Osborne and Allison showed that acetic acid iontophoresis was more effective than dexamethasone in relieving pain associated with plantar fasciitis.¹⁵ Meanwhile, Yarrobino et al. found that lidocaine iontophoresis reduced pain in patients with chronic epicondylitis (tennis elbow).¹⁶ Nonetheless, the clinical efficacy of iontophoresis in chronic pain remains inconclusive; some researchers even suggest that pain relief may be due to the direct electric current, rather than the transdermal medications.¹⁷ 

Iontophoretic drug delivery can be employed to deliver a variety of medications across the skin barrier. Iontophoresis works by using an electric current to push charged molecules, such as medications, through the skin. In chronic pain management, iontophoresis can deliver substances ranging from NSAIDs to acetic acid to reduce symptoms. More longitudinal, prospective studies are needed to assess the benefits of iontophoretic drug delivery for pain control. Additionally, researchers should investigate the efficacy of self-powered iontophoretic systems that use biomechanical motions as an energy source. 

1.American Society of Anesthesiologists. Role of Physician Anesthesiologist. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/anesthesia-101/role-of-physician-anesthesiologist/. 

2.Rosenquist RW, Benzon HT, Connis RT, et al. Practice Guidelines for Chronic Pain Management: An Updated Report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2010;112(4):810–833. 

3.Marovino T, Graves C. Iontophoresis in Pain Management. Practical Pain Management. February 21, 2011;8(2). 

4.Daly SM. Biophotonics for blood analysis. In: Meglinski I, ed. Biophotonics for Medical Applications: Woodhead Publishing; 2015:243–299. 

5.Murphrey MB, Miao JH, Zito PM. Histology, Stratum Corneum. StatPearls. Web: StatPearls Publishing LLC; October 30, 2019. 

6.Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Advanced Drug Delivery Reviews. 2004;56(5):619–658. 

7.Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E. General and ocular pharmacology. In: Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E, eds. The Eye (Fourth Edition): W.B. Saunders; 2016:338–369.e331. 

8.Merrick MA. Therapeutic Modalities As an Adjunct to Rehabilitation. In: Andrews JR, Harrelson GL, Wilk KE, eds. Physical Rehabilitation of the Injured Athlete (Fourth Edition). Philadelphia: W.B. Saunders; 2012:104–142. 

9.Mohammed MI, Makky AMA, Teaima MHM, Abdellatif MM, Hamzawy MA, Khalil MAF. Transdermal delivery of vancomycin hydrochloride using combination of nano-ethosomes and iontophoresis: In vitro and in vivo study. Drug Delivery. 2016;23(5):1558–1564. 

10.Nayak AK, Dey S, Pal K, Banerjee I. Iontophoretic drug delivery systems. In: Pal K, Kraatz H-B, Khasnobish A, Bag S, Banerjee I, Kuruganti U, eds. Bioelectronics and Medical Devices: Woodhead Publishing; 2019:393–420. 

11.Pontrelli G, Lauricella M, Ferreira JA, Pena G. Iontophoretic transdermal drug delivery: A multi-layered approach. Mathematical Medicine and Biology: A Journal of the IMA. 2016;34(4):559–576. 

12.Csillik B, Knyihar-Csillik E, Szucs A. Treatment of chronic pain syndromes with iontophoresis of vinca alkaloids to the skin of patients. Pain. 1983;16(2):212. 

13.Karpiński TM. Selected Medicines Used in Iontophoresis. Pharmaceutics. 2018;10(4):204. 

14.Japour C, Vohra R, Vohra P, Garfunkel L, Chin N. Management of heel pain syndrome with acetic acid iontophoresis. Journal of the American Podiatric Medical Association. 1999;89(5):251–257. 

15.Osborne HR, Allison GT. Treatment of plantar fasciitis by LowDye taping and iontophoresis: Short term results of a double blinded, randomised, placebo controlled clinical trial of dexamethasone and acetic acid. British Journal of Sports Medicine (BJSM). 2006;40(6):545–549. 

16.Yarrobino TE, Kalbfleisch JH, Ferslew KE, Panus PC. Lidocaine iontophoresis mediates analgesia in lateral epicondylalgia treatment. Physiotherapy Research International. 2006;11(3):152–160. 

17.Press JM, Bergfeld DA. Physical Modalities. In: Frontera WR, Herring SA, Micheli LJ, Silver JK, Young TP, eds. Clinical Sports Medicine. Edinburgh: W.B. Saunders; 2007:207–226. 

 

The healthcare field has recently seen changes in drug delivery systems as a result of a movement to improve the efficacy of existing systems while lowering side effects [1].Drug delivery systems are useful in delivering the required amount of drugs efficiently to specific target sites. This allows them to increase bioavailability and absorption of molecules, sustain levels for long-term treatment, and decrease the total amount of drugs and doses required for patients, as well as the damage to normal tissues [1].

Intranasal delivery allows direct delivery to the cerebrospinal fluid conveniently and painlessly, with hardly any loss in bioavailability [2]. This is because most anesthetics can easily pass through the mucous membrane, and nasal delivery allows a way for them to completely bypass the blood-brain barrier [2, 3].

Pulmonary drug delivery systems include metered dose inhalers, nebulizers, and dry powder inhalers, which all offer the advantages of larger surface area and proximity to blood flow [4]. There has been a strong effort to develop a way to deliver opioids by inhalation, which has the benefit of increasing patient compliance, since the doses would be lower and less burdensome [1].

Buccal mucosal delivery systems, which consist of drug absorption through the membrane in the inner lining of the cheeks and the bottom of the mouth, are beneficial because they allow drugs to avoid being metabolized through the “first pass effect,” therefore decreasing the amount of the drugs that are needed [5]. While it generally has a slower onset because the buccal mucous is less permeable, it has been proven effective in delivering fentanyl and buprenorphine hydrochloride [6].

Intra-articular drug delivery systems, referring to delivery in the tissue between joints, are thought to prolong the residence time of drugs because of the presence of microspheres that are designed to improve uptake in these areas [7].

Transdermal delivery systems, patches worn on the skin, have been shown to bypass the first pass effect, keep drug levels relatively constant, and decreases gastrointestinal side-effects [1, 8].  After application of a patch, the skin underneath absorbs the drugs and it concentrates in the upper skin levels, gradually diffusing through the skin’s membranes and entering the body [9]. A disadvantage of this system is that only lipophilic, low molecular weight drugs can pass through the skin, but by incorporating enhancers and active energy-dependent methods into the system, dermal anesthesia with hydrophobic substances like lignocaine has been achieved [10].

New molecules with semi-permeable membranes have been developed as carriers that can better target specific tissues and increase absorption rate [1]. Liposomes are nanovesicles that are surrounded by a membrane and are nontoxic, biodegradable, and nonimmunogenic – thus they are promising carriers for drug delivery [11].  However, because of a lot of quality assurance and costs, they have made little strides in clinical practice [12].

Computerized drug delivery systems have been developed inter-disciplinarily, in an attempt to utilize technology to optimize patient care. The advent of these systems, which can be either open-loop or closed-loop, has created a shift towards total intravenous anesthesia [1].  Open-loop systems are known as target-controlled infusion pumps, in which drug concentrations are calculated using a computer and pharmacokinetic models, and the TCI pumps gradually decrease or increase the rate of infusion to meet the desired drug concentration set by an anesthesiologist [1, 13].  Closed-loop systems monitor a patient’s variables such as muscle relaxation, hypnosis, and analgesia in real-time, while a computer-controlled feedback mechanism delivers drugs based on these parameters [14].  This type of computerized system is being developed as a way to provide anesthesia in distant locations, known as tele-anesthesia [15].

References

1. Sona Dave, Deepa Shriyan, and Pinakin Gujjar: New drug delivery systems in anesthesia. J Anaesthesiol Clin Pharmacol. 2017 Apr-Jun; 33(2): 157–163.

2. Talegaonkar S, Mishra PR. Intranasal delivery: An approach to bypass the blood brain barrier. Indian J Pharmacol. 2004;36:140–7

3. Sakane T, Akizuki M, Yoshida M, Yamashita S, Nadai T, Hashida M, et al. Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity. J Pharm Pharmacol. 1991;43:449–51

4. Shaikh S, Nazim S, Khan T, Shaikh A, Zameeruddin M, Quazi A. Recent advances in pulmonary drug delivery system: A review. Int J Appl Pharm. 2010;2:27–31.

5. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. J Pharm Pharm Sci. 1998;1:15–30

6. Gilhotra RM, Ikram M, Srivastava S, Gilhotra N. A clinical perspective on mucoadhesive buccal drug delivery systems. J Biomed Res. 2014;28:81–97

7. Zhang Z, Huang G. Intra-articular lornoxicam loaded PLGA microspheres: Enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis. Drug Deliv. 2012;19:255–63

8. Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb AL. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1:109–31

9. Viscusi ER, Reynolds L, Tait S, Melson T, Atkinson LE. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: A double-blind, placebo-controlled trial. Anesth Analg. 2006;102:188–94

10. Polat BE, Blankschtein D, Langer R. Low-frequency sonophoresis: Application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin Drug Deliv. 2010;7:1415–32

11. Bergese SD, Ramamoorthy S, Patou G, Bramlett K, Gorfine SR, Candiotti KA. Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. J Pain Res. 2012;5:107–16

12. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286

13. Schnider TW, Minto CF, Struys MM, Absalom AR. The safety of target-controlled infusions. Anesth Analg. 2016;122:79–85

14. Glen JB. The development of ‘Diprifusor’: A TCI system for propofol. Anaesthesia. 1998;53(Suppl 1):13–21

15. Hemmerling TM. Automated anesthesia. Curr Opin Anaesthesiol. 2009;22:757–63