The Role of General Anesthetics in Post-Operative Cognitive Dysfunction (POCD)

Post-operative cognitive dysfunction (POCD) is an expansive definition for the wide spectrum of cognitive deficits seen in patients after anesthesia and surgery. Most common deficits of POCD include cognitive impairments, such as memory and information processing, which can also be present in the aftermath of anesthetics. Current data suggests that POCD is most directly caused by neuroinflammation and microglial activation, which triggers an immuno-hormonal cascade increasing the permeability of the blood-brain barrier, ultimately promoting the influx of macrophages into the brain parenchyma. The pro-inflammatory cytokines synthesized by these macrophages cause neuronal damage, apoptosis, and impaired neurotransmission to the hippocampus, medial prefrontal cortex, amygdala, and the cingulate cortex, brain regions critical in memory, reward, emotion, and judgement [1-3].  

Eckenhoff et. al.’s research in 2004 demonstrated clinically relevant concentrations of inhaled anesthetics such as halothane and isoflurane could induce the oligomerization of amyloid β (peptides that compose the amyloid plaques in Alzheimer’s patients) and amyloid-β-induced cytotoxicity [4]. However, intravenous anesthetics such as ethanol and propofol did not have this effect. While desflurane (another inhalational agent) alone does not induce caspase-3 activation or affect amyloid precursor protein cells, a combination of desflurane and hypoxia does both [5]. Additionally, abnormal tau tangles are one of the hallmarks of AD. In 2007, a murine study found anesthetics including chloral hydrate, pentobarbital and isoflurane produced rapid and massive tau protein hyperphosphorylation and inhibition of Ser/Thr phosphatase (PP) activity. These researchers confirmed PP2A (a subtype of PPs) is the main phosphatase driving tau dephosphorylation; their inhibition is a direct result of hypothermia induced by anesthesia [6,7]. Another preclinical study found the inhaled anesthetic sevoflurane generated behavioral deficits in spatial learning and memory in aged rats; the rats also experienced hippocampal alterations, most notably a downregulation of the cAMP/CREB signaling pathway, a pathway extensively implicated as a “hot spot” of long-term potentiation, memory, and neuroprotection [8].  

Following the use of intravenous agents, specific neurological and behavioral changes have been reported. A prolonged infusion of propofol significantly impaired spatial learning in mice, as measured by the Morris water maze behavioral assessment. The CA1 region of the hippocampus showed significant autophagy inhibition, leading to the observed cognitive deficits [9]. Autophagy is the fundamental catabolic process involving degradation of dysfunctional cellular molecules to supply energy and compounds for further biosynthesis. Defective autophagy is associated with increased aging as well as diseases like cancer or neurodegenerative and muscular disorders [10]. Inhaled anesthetics also affect this process, as sevoflurane may cause impaired memory performance and increase hippocampal neuronal apoptosis through its suppression of autophagic processes, potentially increasing the risk of POCD [11]. However, rapamycin, an immunosuppressive drug, reduced the cognitive effects of sevoflurane by inducing autophagy [9,11].

POCD in human patients is often thought to be induced by increased activity of GABAA receptors, which most general anesthetics act on. The subtypes of GABAA receptors may be responsible for the different effects of general anesthesia, such as amnesia, sedation, and hypnosis [13]. Preclinical investigations have pinpointed the alpha-5 subunit of GABAA receptors to be especially responsible, given their significant upregulation after administration of GABAergic anesthetics [12]. Sevoflurane may damage synaptic plasticity by decreasing postsynaptic density protein in mPFC, highlighting another potential mechanism ultimately generating POCD [14].

Although research has proposed plausible mechanisms by which general anesthetics may lead to POCD, interesting perspectives for future consideration involve in-depth study of predisposing and precipitating factors of POCD.

References 

  1. Wang, B., Li, S., Cao, X., Dou, X., Li, J., Wang, L., Wang, M., & Bi, Y. (2017). Blood-brain barrier disruption leads to postoperative cognitive dysfunction. Current Neurovascular Research, 14(4), 359–367. https://doi.org/10.2174/1567202614666171009105825 
  1. Vacas, S., Degos, V., Feng, X., & Maze, M. (2013). The neuroinflammatory response of postoperative cognitive decline. British Medical Bulletin, 106, 161–178. https://doi.org/10.1093/bmb/ldt006  
  1. Cascella, M., & Bimonte, S. (2017). The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research, 12(11), 1780–1785. https://doi.org/10.4103/1673-5374.219032  
  1. Eckenhoff, R. G., Johansson, J. S., Wei, H., Carnini, A., Kang, B., Wei, W., Pidikiti, R., Keller, J. M., & Eckenhoff, M. F. (2004). Inhaled anesthetic enhancement of amyloid-β oligomerization and cytotoxicity. Anesthesiology, 101(3), 703–709. https://doi.org/10.1097/00000542-200409000-00019  
  1. Zhang, B., Dong, Y., Zhang, G., Moir, R. D., Xia, W., Yue, Y., Tian, M., Culley, D. J., Crosby, G., Tanzi, R. E., & Xie, Z. (2008). The inhalation anesthetic desflurane induces caspase activation and increases amyloid β-protein levels under hypoxic conditions *. Journal of Biological Chemistry, 283(18), 11866–11875. https://doi.org/10.1074/jbc.M800199200  
  1. Planel, E., Richter, K. E. G., Nolan, C. E., Finley, J. E., Liu, L., Wen, Y., Krishnamurthy, P., Herman, M., Wang, L., Schachter, J. B., Nelson, R. B., Lau, L.-F., & Duff, K. E. (2007). Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. Journal of Neuroscience, 27(12), 3090–3097. https://doi.org/10.1523/JNEUROSCI.4854-06.2007  
  1. Nicolson, S. C., Montenegro, L. M., Cohen, M. S., O’Neill, D., Calfin, D., Jones, L. A., & Jobes, D. R. (2010). A comparison of the efficacy and safety of chloral hydrate versus inhaled anesthesia for sedating infants and toddlers for transthoracic echocardiograms. Journal of the American Society of Echocardiography: Official Publication of the American Society of Echocardiography, 23(1), 38–42. https://doi.org/10.1016/j.echo.2009.11.019  
  1. Xiong, W.-X., Zhou, G.-X., Wang, B., Xue, Z.-G., Wang, L., Sun, H.-C., & Ge, S.-J. (2013). Impaired spatial learning and memory after sevoflurane–nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLOS ONE, 8(11), e79408. https://doi.org/10.1371/journal.pone.0079408  
  1. Yang, N., Li, L., Li, Z., Ni, C., Cao, Y., Liu, T., Tian, M., Chui, D., & Guo, X. (2017). Protective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy. Neuroscience Letters, 649, 85–92. https://doi.org/10.1016/j.neulet.2017.04.019  
  1. Papáčková, Z., & Cahová, M. (2014). Important role of autophagy in regulation of metabolic processes in health, disease and aging. Physiological Research, 63(4), 409–420. https://doi.org/10.33549/physiolres.932684  
  1. Zhang, X., Zhou, Y., Xu, M., & Chen, G. (2016). Autophagy is involved in the sevoflurane anesthesia-induced cognitive dysfunction of aged rats. PLOS ONE, 11(4), e0153505. https://doi.org/10.1371/journal.pone.0153505  
  1. Zurek, A. A., Yu, J., Wang, D.-S., Haffey, S. C., Bridgwater, E. M., Penna, A., Lecker, I., Lei, G., Chang, T., Salter, E. W. R., & Orser, B. A. (2014). Sustained increase in α5GABAA receptor function impairs memory after anesthesia. The Journal of Clinical Investigation, 124(12), 5437–5441. https://doi.org/10.1172/JCI76669  
  1. Bonin, R. P., & Orser, B. A. (2008). GABAA receptor subtypes underlying general anesthesia. Pharmacology Biochemistry and Behavior, 90(1), 105–112. https://doi.org/10.1016/j.pbb.2007.12.011 
  1. Ling, Y., Ma, W., Yu, L., Zhang, Y., & Liang, Q. (2015). Decreased PSD95 expression in medial prefrontal cortex (mPFC) was associated with cognitive impairment induced by sevoflurane anesthesia. Journal of Zhejiang University-SCIENCE B, 16(9), 763–771. https://doi.org/10.1631/jzus.B1500006  

Famotidine for COVID-19

Famotidine is a histamine-2 receptor antagonist [1]. While it has traditionally been used to quell gastric acid production, recent clinical data suggests that famotidine may reduce COVID-19-associated morbidity and mortality [1, 2]. It is widely available in low-cost forms, either as generic or branded medications, and its pharmacology is well-documented [Malone]. Accordingly, if famotidine is resolutely found to be an effective COVID-19 treatment, it could be incredibly useful in controlling the ongoing pandemic.

Early studies were optimistic about the efficacy of famotidine. Freedberg et al. conducted a retrospective cohort study (n = 1,620) [1]. The subjects of the study were COVID-19 patients who had been administered either 10, 20, or 40 mg doses of the drug while they were infected [1]. Overall, people who received famotidine experienced a significantly reduced risk of intubation and death compared to people who did not receive the medication, indicating that famotidine is highly effective [1]. Subsequent studies have demonstrated similar results [2, 3].

Other studies have indicated that famotidine not only reduces COVID-19-related morbidity and mortality but also decreases the prevalence of certain symptoms. Janowitz and colleagues evaluated the effect of famotidine within a small cohort on five common symptoms: fatigue, anosmia, headaches, cough, and shortness of breath [4]. Among the ten COVID-19 patients analyzed, severity scores for all five symptoms significantly improved compared to baseline levels [4]. These patients had self-administered high-doses of famotidine orally, with the most common regime consisting of 80 mg ingested three times daily for a median duration of 11 days [4]. On a related note, Hogan et al. studied the relationship between famotidine and Acute Respiratory Distress Syndrome [5]. The 110 patients, all of whom had been placed on famotidine regimes, were intubated at significantly reduced rates, compared with COVID-19 patients who did not take famotidine [5]. 

Despite these promising results, not all studies have indicated that famotidine is particularly effective at countering COVID-19 or its adverse events [2]. Indeed, since Freedberg and colleagues’ early experiment, more recent studies have reported variable results [2]. For instance, an anonymous, web-based survey taken by 307 otolaryngology patients already on famotidine regimens found no association between the medication and incidence of COVID-19 [6]. 

One explanation for this discrepancy could be the differing dosage administered across studies. Many studies, especially those conducted retrospectively, have not published the amount of famotidine taken by their subjects, while other studies set dose levels at the standard used to treat gastroesophageal reflux disease (GERD) [2]. An early case series indicated that to effectively treat COVID-19, patients must receive famotidine at higher-than-standard doses [2]. While more evidence is needed to corroborate this theory, it could help explain the difference in results reported across scientific studies. 

Another question related to famotidine warranting further investigation is its mechanism of action against COVID-19. Malone and colleagues advanced a compelling theory: famotidine may block the histamine H2 receptor, which is implicated in the development of clinical COVID-19 [2]. The medication may also activate other G Protein-Coupled Receptors (GPCRs) [2]. Strong evidence supports these theories, but they warrant further investigation to be confirmed.

References 

[1] D. E. Freedberg et al., “Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study,” Gastroenterology, vol. 159, no. 3, p. 1129-1131.E3, September 2020. [Online]. Available: https://doi.org/10.1053/j.gastro.2020.05.053

[2] R. W. Malone et al., “COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms,” Frontiers in Pharmacology, Updated March 23, 2021. [Online]. Available: https://doi.org/10.3389/fphar.2021.633680

[3] J. F. Mather, R. L. Seip, and R. G. McKay, “Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19,” American Journal of Gastroenterology, vol. 115, no. 10, p. 1-7, August 2020. [Online]. Available: https://doi.org/10.14309/ajg.0000000000000832

[4] T. Janowitz et al., “Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series,” Gut, vol. 69, no. 9, p. 1592-1597, June 2020. [Online]. Available: https://doi.org/10.1136/gutjnl-2020-321852

[5] R. B. Hogan II et al., “Dual-histamine receptor blockade with cetirizine – famotidine reduces pulmonary symptoms in COVID-19 patients,” Pulmonary Pharmacology & Therapeutics, vol. 63, p. 1-7, August 2020. [Online]. Available: https://doi.org/10.1016/j.pupt.2020.101942

[6] B. Balouch et al., “Role of Famotidine and Other Acid Reflux Medications for SARS-CoV-2: A Pilot Study,” Journal of Voice, January 2021. [Online]. Available: https://doi.org/10.1016/j.jvoice.2021.01.007

Pregnancy and Anesthesia Considerations

Literature demonstrates that anywhere from 0.2 – 2.2% of pregnant women undergo non-obstetric surgeries and anesthesia per year [1, 2]. The decision to proceed with surgery and anesthesia during pregnancy requires special attention to several maternal adaptations that occur during pregnancy, including changes in maternal blood volume and cardiac output, alterations in acid-base and respiratory status, increased hypercoagulability, reduced lower esophageal sphincter tone, increased gastric volume and acidity, and increased sensitivity to opioids and inhalation agents [2]. In addition to physiological changes, actual timing of surgery in relation to trimester matters significantly for reducing poor fetal outcomes [1-3].

With respect to timing, it is commonly accepted that surgery during the first trimester should be avoided unless emergent [1-3]. Most researchers and practitioners advocate for surgery and anesthesia during the third trimester due to the completion of organogenesis by this period [1-3]. However, a 16-year retrospective, matched case-control, cohort study by Devroe et al., which examined the use of anesthesia for non-obstetric operations, demonstrated increased incidence overall of preterm births in the surgical group and increased risk of preterm birth secondary to surgery in the third trimester. Within the surgical group, the study did not find significant associations between the overall incidence of preterm births and the trimester during which surgery was performed.

Timing aside, another factor to consider is the use of general vs. regional anesthesia. The common consensus is to use local anesthesia whenever possible, in order to avoid systemic transfer of the anesthetic to the fetus. Kuczkowski 2004 explains that virtually every drug and inhalation anesthetic is considered teratogenic to some fetuses under certain conditions, and thus, there is no “best” anesthetic agent to use. He also highlights that the commonly deployed nitrous oxide (NO) has been shown to oxidize vitamin B12, and interfere with tetrahydrofolate regeneration and DNA synthesis. Some studies have experimented with using B12 and folic acid prophylaxis when using NO in pregnant women, however the benefit of doing so is not clinically apparent.

A contrasting opinion on NO use can be found in Ramirez et al.’s paper, which argued that nitrous oxide is a weak teratogen whose reproductive effects only occur after prolonged exposure and high concentrations, conditions unlikely to be met in pregnant women undergoing surgery. However, Devroe et al.’s study demonstrated a statistically significant increase in low birth rates in women exposed to general anesthesia, which often included the use of NO. The differences in opinions in these studies highlight the ongoing discourse surrounding the use and safety of anesthesia in pregnancy, however, medical professionals should always choose anesthetics with the highest track record of safety in pregnant women and optimize their use during surgery.

Finally, as aforementioned in the first paragraph, the physiological changes that happen during pregnancy are many and can complicate routine surgery. For these reasons, it is important to closely monitor parameters such as blood pressure, heart rate, oxygenation and respiratory status intraoperatively to avoid maternal and/or fetal complications [3]. Aortocaval compression is of particular concern during surgery, as pregnant women positioned on their backs can suffer bouts of decreased blood pressure and cardiac output secondary to inferior vena cava compression. The decrease in blood pressure can lead to decreased placental perfusion, hypoxia, and fetal acidosis and poor fetal outcomes. Fetal heart rates (FHR) have been shown to decrease in hypoxic environments and can thus serve as a useful gauge of hypoxia intraoperatively [3]. Lastly, because the stress of surgery can cause premature contractions, deployment of a tocodynamometer can be a valuable asset during surgery. All in all, though complicated and multifactorial, surgery during pregnancy is sometimes necessary and requires thorough planning and safety optimization.

References 

  1. Devroe, S., Bleeser, T., Van de Velde, M., Verbrugge, L., De Buck, F., Deprest, J., … & Rex, S. (2019). Anesthesia for nonobstetric surgery during pregnancy in a tertiary referral center: a 16-year retrospective, matched case-control, cohort study. International journal of obstetric anesthesia, 39, 74-81.DOI:10.1097/01.aoa.0000661412.51134.86 
  1. Ramirez, V., Valencia, G., & Catalina, M. (2020). Anesthesia for nonobstetric surgery in pregnancy. Clinical obstetrics and gynecology, 63(2), 351-363. DOI:10.1097/GRF.0000000000000532
  1. Kuczkowski, K. M. (2004). Nonobstetric surgery during pregnancy: what are the risks of anesthesia?. Obstetrical & gynecological survey, 59(1), 52-56. DOI:10.1097/01.OGX.0000103191.73078.5F

Retained Surgical Items: Surgical Tools Left Inside Patients

Every year in the United States, at least 1,500 to 2,000 retained surgical items (RSIs) are discovered in the bodies of postsurgical patients (1). Retained surgical items, also known as retained surgical foreign bodies (RFBs), include instruments, needles, sponges, and other materials used in a prior surgery. RSIs threaten the safety and survival of patients, with around 70% sustaining minor complications and 15% suffering severe harm (2). Surgical instruments, like forceps, can puncture organs and cause immediate damage; more frequently, however, cotton surgical materials, or “sponges,” are left behind, resulting in a gossypiboma that can cause obstruction, infection, sepsis, and death (3). Most commonly occurring in the abdominal, thoracic and pelvic cavities (4), RSIs present a serious threat to patient safety and typically require reoperation to be removed (2-4). However, with the right operating room culture and perioperative procedures, the occurrence of RSIs can be significantly minimized.

The risk factors associated with RSIs fall into two categories: the characteristics of the operation and perioperative procedure errors. First, although little research has been conducted on surgical errors such as RSIs, the current literature suggests positive associations between RSI occurrences and emergency operations, prolonged procedures, and multiple operative teams (1, 2). However, perioperative procedure errors more commonly resulted in RSIs, including incorrect instrument and sponge counts and poor communication (1, 3). In roughly 80% of RSI cases involving sponges — the most common RSI — the sponge count performed at the end of the surgery was erroneously called correct (4, 5). Incomplete body cavity examinations and incorrect instrument counts often stem from communication and cooperation problems between the surgeons and nurses, i.e. failing to work together to rectify an incorrect count or the dismissal of requests to look for missing items (1, 4). Moreover, some studies suggest that the communication errors that result in RSIs originate from the operating room “culture,” or the social ecosystem involving relationships between members of a surgical team (1, 3, 4).

Like other surgical errors, RSI cases are completely preventable. Hospitals around the country that have implemented perioperative and systematic strategies to prevent the retention of any surgical object have significantly decreased RSI cases (6). Using only radiopaque materials — such as gauze pads with x-ray markers — intracorporeally and performing x-rays to identify any missing materials before closing the incision are a vital preventative method that can take place perioperatively (1, 4, 7). Creating a standardized and robust counting system for each type of surgical material, often by using designated dry-erase boards or discrete plastic holders, constitutes one of the most successful preventative techniques (1, 4). Additionally, as some researchers argue that the communication errors that result in RSIs are systematic, changing the “culture” of the operating room is often necessitated (1). Encouraging communication and collaboration between all members of the surgical team remains one of the most important methods needed to reduce the incidence of retained surgical items.

References

1: Gibbs, V. 2011. Retained surgical items and minimally invasive surgery. World Journal of Surgery, vol. 35. DOI: 10.1007/s00268-011-1060-4.

2: Steelman, V., Shaw, C., Shine, L. and Hardy-Fairbanks, A. 2018. Retained surgical sponges: a descriptive study of 319 occurrences and contributing factors from 2012 to 2017. Patient Safety in Surgery, vol. 12. DOI: 10.1186/s13037-018-0166-0.

3: Feldman, D. 2011. Prevention of retained surgical items. Mount Sinai Journal of Medicine, vol. 78. DOI: 10.1002/msj.20299.

4: Gibbs, V., Coakley, F. and Reines, H. Preventable errors in the operating room: retained foreign bodies after surgery — part I. 2007. Current Problems in Surgery, vol 44. DOI: 10.1067/j.cpsurg.2007.03.002.

5: Kaiser, C., Friedman, S., Spurling, K., Slowick, T. and Kaiser, H. 1996. The retained surgical sponge. Annals of Surgery, vol. 224. DOI: 10.1097/00000658-199607000-00012.

6: Weprin, S., Crocerossa, F., Meyer, D., Maddra, K., Valancy, D., Osardu, R., Kang, H., Moore, R., Carbonara, U., Kim, F. and Autorino, R. 2021. Risk factors and preventive strategies for unintentionally retained surgical sharps: a systematic review. Patient Safety in Surgery, vol. 15. DOI: 10.1186/s13037-021-00297-3.

7: Hariharan, D. and Lobo, D. 2013. Retained surgical sponges, needles and instruments. Annals of the Royal College of Surgeons of England, vol. 95. DOI: 10.1308/003588413X13511609957218.

Paxlovid: A Potential Antiviral Covid Pill

Pfizer, the company that collaborated to create the first mRNA coronavirus vaccine to receive emergency use authorization, is now seeking emergency use authorization from the FDA for its Covid-19 antiviral pill. On November 5, Pfizer announced in a press release that its new oral antiviral treatment, Paxlovid, significantly reduced the risk of hospitalization and death from COVID-19 (Pfizer, 2021). Interim analysis of the data from Pfizer’s Phase 2-3 clinical trials found that “among participants who received treatments within three days of Covid-19 symptoms starting, the risk of COVID-related hospital admission or death from any cause was 89% lower in the Paxlovid group than the placebo group” (Mahase, 2021).

The Paxlovid trial included 1,219 participants with a coronavirus infection at higher risk of developing severe COVID-19 (Citroner, 2021). In the study, participants were randomized 1:1, with half receiving a placebo pill and the other half receiving Paxlovid (Mahase, 2021). Of the participants who were treated within three days of symptom onset, 0.8% of patients who received Paxlovid were hospitalized up to day 28 after randomization, and no deaths occurred. In the comparison group of participants who were given a placebo, 7% of patients were admitted to the hospital, with seven deaths (Pfizer, 2021). Similar reductions were seen in participants treated within five days of symptom onset. Overall, throughday 28, “no deaths were reported among patients who received Paxlovid, while 10 people (1.6%) in the placebo group died” (Mahase, 2021). “[This news] is a real game-changer in the global efforts to halt the devastation of this pandemic,” said Albert Bourla, chairman and CEO of Pfizer, in a statement (Pfizer, 2021). “These data suggest that our oral antiviral candidate, if approved or authorized by regulatory authorities, has the potential to save patients’ lives, reduce the severity of COVID-19 infections, and eliminate up to nine out of ten hospitalizations,” he continued.

So how does Paxlovid work? Antiviral drugs like Paxlovid inhibit a virus’ ability to infect or replicate inside our cells. The coronavirus “wreaks havoc on the body” by inserting itself into cells, and then hijacking cell machinery to make copies of itself. Those copies then burst out of the cells and “invade other cells, spreading through the body” (Hickok, 2021). Paxlovid consists of two components: “an experimental molecule called PF-07321332 and an existing drug called ritonavir. Both are protease inhibitors, which means they block an enzyme (called a protease) that cuts apart long strands of nonfunctional viral proteins into smaller, functional proteins” (Hickok, 2021). In essence, Paxlovid aims to stop the coronavirus from replicating. “These drugs can be administered at any stage of the infection based on their mode of action,” said Fenyong Liu, a virologist at the University of California, Berkeley. However, “because more severe complications and damage due to infection are always associated with later stages,” they will be more effective if they’re given in the early stages of the infection (Hickok, 2021). In the Paxlovid clinical trial, Pfizer started the treatment within five days of symptom onset.

Antiviral COVID drugs “arrived with minimal fanfare but represent the biggest advance yet in treating patients already infected with COVID-19,” says Monica Gandhi, professor of medicine and associate division chief of HIV, Infectious Diseases, and Global Medicine at UCSF / San Francisco General Hospital (Gandhi, 2021). Ahead of its approval, the UK purchased 250,00 courses of thePaxlovid; according to news reports, the Biden administration is “set to buy 10 million courses” of the pills (Pager et al., 2021). Millions of Americans remain unvaccinated, while millions more around the globe still don’t have access to the vaccine; as such, the need and public demand for effective medication to reduce the severity of symptoms for both unvaccinated and vaccinated patients alike remain evident.

References 

Citroner, G. (2021, November 8). Pfizer antiviral drug may be 90% effective against severe Covid-19: what we need to know. Healthline. https://www.healthline.com/health-news/pfizer-antiviral-drug-may-be-90-effective-against-severe-covid-19-what-to-know.

Gandhi, M. (2021, November 29). The new COVID drugs are a bigger deal than people realize. The Atlantic. https://www.theatlantic.com/ideas/archive/2021/11/covid-drugs-molnupiravir-paxlovid-treatment-antiviral/620819/.

Hickok, K. (2021, November 12). How Covid antiviral pills work and what that could mean for the pandemic. NBC News. https://www.nbcnews.com/health/health-news/covid-antiviral-drugs-merck-pfizer-pills-work-rcna5317.

Mahase E. (2021, November 8). Covid-19: Pfizer’s Paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ doi:10.1136/bmj.n2713

Pager et al. (2021, November 16). Biden administration to buy Pfizer antiviral pills for 10 million people, hoping to transform pandemic. The Washington Post. https://www.washingtonpost.com/health/2021/11/16/administration-purchases-pfizer-anti-covid-pill/.

Pfizer, Inc. (2021, November 5). Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study. Business Wire. https://www.businesswire.com/news/home/20211105005260/en/

Mobile Stroke Units

A mobile stroke unit (MSU) is a specialized ambulance that contains a CT scanner, mobile laboratory, and telemedicine connection for treating stroke patients before arrival at a hospital [1]. The proposed benefit of mobile stroke units is to reduce the time between an emergency call and administration of therapy. After German researchers first deployed an MSU in 2010, hospitals in Germany and the United States have deployed their own MSUs [1][2]. Throughout that time, researchers have evaluated the medical benefits and practical considerations of MSUs.

Guidelines for stroke treatment follow the “time is brain” paradigm: the faster a patient is treated, the better their outcomes will be. MSUs have received funding and attention because they are thought to decrease time to treatment. Stroke patients can receive a CT scan and have it analyzed by a neurologist on their way to the hospital. If deemed necessary and appropriate, onboard paramedics can administer intravenous tissue-type plasminogen activator (tPA), a drug that can dissolve blood clots [1]. These steps can happen before the patient arrives at the hospital, potentially improving the patient’s outcomes.

Randomized control trials have investigated the potential benefits of MSUs. One study measured the average time from the emergency call to the specialist’s therapy decision: 76 minutes for a regular hospital, 35 minutes for a hospital with an MSU [1]. Separately, two studies assessed whether the neurologist should be remotely connected or physically onboard the MSU. In both studies, a remote neurologist agreed with an onboard neurologist in over 88% of cases, suggesting that a remote connection is sufficient for good outcomes [3][4]. Overall, MSUs appear to offer the same quality of treatment as standard hospital care (excluding surgical interventions), but much faster.

However, MSUs are complex to assemble and maintain. The researchers behind the first MSU in the United States documented the technical and business challenges to deploy an MSU [5]. For example, a mobile CT scanner requires specialized radiation shielding to protect all passengers in the vehicle. To facilitate its telemedicine capability, an MSU must have on-board communications technology, and the parent hospital must have a base station capable of communicating with the MSU. Onboard paramedics and remote staff need additional training to make full use of the MSU’s capabilities. On the business side, funding and purchasing are key considerations. The hospital running the pilot program had to coordinate licensing and insurance policies for both staff and equipment. Although this paper does not contribute novel findings about MSU as a medical technology, it does present a template for medical stakeholders who want to deploy their own MSU.

Despite the promise of MSUs, two challenges remain in their future. First, MSU research has challenged the “time is brain” paradigm, questioning whether time to treatment is correlated with patient outcomes [1]. Along these lines, not enough MSU research has concretely studied medical outcomes for patients. Second, MSUs are experiencing fundraising challenges. If tPA or other stroke-related drugs are administered inside a hospital building, the provider is eligible for reimbursement through the federal government or private insurance companies. However, if the medicine is administered inside an MSU, the provider is ineligible because no coverage rules exist for MSUs [6]. Today, MSUs rely on funding from private donations and government grants, which is an effective but unsustainable funding source for the long term.

References

[1] S. Walter, et al. Diagnosis and Treatment of Patients with Stroke in a Mobile Stroke Unit versus in Hospital: A Randomised Controlled Trial. The Lancet Neurology 2012; 11: 5. DOI:10.1016/S1474-4422(12)70057-1.

[2] S. Walter, et al. Bringing the Hospital to the Patient: First Treatment of Stroke Patients at the Emergency Site. PLOS One 2010. DOI:10.1371/journal.pone.0013758.

[3] T.-C. Wu, et al. Telemedicine Can Replace the Neurologist on a Mobile Stroke Unit. Stroke 2017; 48. DOI:10.1161/STROKEAHA.116.015363.

[4] R. Bowry, et al. Benefits of Stroke Treatment Using a Mobile Stroke Unit Compared With Standard Management. Stroke 2015; 46. DOI:10.1161/STROKEAHA.115.011093.

[5] S. A. Parker, et al. Establishing the First Mobile Stroke Unit in the United States. Stroke 2015; 46. DOI:10.1161/STROKEAHA.114.007993.

[6] Life-Saving Role of Mobile Stroke Units at Risk Due to Reimbursement Limitations. American Heart Association 2021. URL: https://newsroom.heart.org/news/life-saving-role-of-mobile-stroke-units-at-risk-due-to-reimbursement-limitations.

Interventions For High Blood Pressure

High blood pressure, or hypertension, is a global crisis; 1.39 billion people are estimated to have hypertension around the world, with low- and middle-income countries bearing the brunt of it due to the global disparities around hypertension awareness, control and treatment3. As a major risk factor for cardiovascular disease, particularly later in life, prevention and interventions for high blood pressure are a public health concern3.

High blood pressure causes the arteries in the body to stiffen and become less elastic, and this effect is exacerbated by age, leading to cardiovascular complications2. However, studies have shown time and time again that high blood pressure is a clinically modifiable condition and that one of the best interventions is regular aerobic exercise2. Two important measures of arterial elasticity are carotid artery compliance and carotid-femoral pulse wave velocity, and aerobic exercise has been shown to improve both measures in middle-aged and older people, likely due to decreased oxidative stress on the arterial wall2. This shows that exercise is not only therapeutic in improving arterial stiffness in older people, but also a way to prevent complications of hypertension in younger people as they get older2. Furthermore, while resistance and strength training alone don’t seem to have any protective effects on arterial stiffness, studies show that resistance training before aerobic exercise can augment the positive effects of aerobic exercise2.

The problem that many clinicians run into with an exercise prescription, however, is that many people are non-compliant1. This can be due to limitations on time, access, transportation and facility access, which results in less than 40% of adults following the recommended guidelines of 150 minutes a week of moderate exercise1. Therefore, combatting high blood pressure and mediating its effects on long-term health requires interventions that everyone can try1. A new form of physical training, known as Inspiratory Muscle Strength Training, has been shown to have promising effects on hypertensive patients1. It requires patients to repeatedly inhale against resistance, thus building strength in inspiratory accessory muscles, and the most recent training program is only 30 breaths and can be performed with a handheld device that acts as a trainer1. A 6-week long, double-blind, randomized control trial evaluated the efficacy of this particular IMST paradigm on the cardiovascular health of middle-aged and older patients with increased systolic blood pressure1. Results showed that, overall, IMST reduced systolic blood pressure and diastolic pressure, and this reduction was roughly 75% sustained after completion of the program1. This sustainability sets IMST apart from improvements after aerobic exercise and hypertensive therapies, in which blood pressure typically returns to pre-intervention levels once they are stopped1. IMST also improved nitric oxide-mediated vasodilation, vascular endothelial function, and levels of CRP, which is a sensitive biomarker for inflammation1. And most importantly, this study showed very high levels of adherence in this study population, potentially bridging the gap in efficacy that is seen with aerobic exercise recommendations1.

IMST is still a relatively new intervention, but these early studies have shown that it is a promising therapeutic and preventative measure that also has a good compliance profile. More research is needed to strengthen these associations, however, IMST may become a clinically important recommendation to reduce the prevalence of hypertension and its cardiovascular complications.

References  

  1. Craighead DH, Heinbockel TC, Freeberg KA, Rossman MJ, Jackman RA, Jankowski LR, Hamilton MN, Ziemba BP, Reisz JA, D’Alessandro A, Brewster LM, DeSouza CA, You Z, Chonchol M, Bailey EF, Seals DR. Time-Efficient Inspiratory Muscle Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO Bioavailability, and Oxidative Stress in Midlife/Older Adults with Above-Normal Blood Pressure. Journal of the American Heart Association, 2021; 10(13): 501-506. https://doi.org/10.1177/0267659117696140
  1. Craighead DH, Freeberg KA, Seals DR. The protective role of regular aerobic exercise on vascular function with aging. Exercise Physiology, 2019; 10: 55-53. https://doi.org/10.1016/j.cophys.2019.04.005
  1. Wyss F, Coca A, Lopez-Jaramillo P, Ponte-Negretti C. Position statement of the InterAmerican Society of Cardiology on the current guidelines for prevention, diagnosis and treatment of arterial hypertension. International Journal of Cardiology Hypertension, 2020; 6. https://doi.org/10.106/j.ijchy.2020.100041

Indications for Nasotracheal Intubation

Nasotracheal intubation (NTI) is a common form of airway management [1]. During NTI, an endotracheal tube enters the patient’s trachea, following the pathway of the narrow nasal cavity [1]. Physicians need to be well aware of the indications and contradictions of NTI to ensure a favorable outcome for the patient [1]. According to those indications, special precautions or an alternate form of airway management may be necessary [1].

Multiple types of surgeries call for the use of nasotracheal intubation [1]. Often, NTI is used on patients undergoing oral and maxillofacial surgery, given the improved surgical field and mobility that it offers physicians during such operations [1]. More specifically, NTI can be appropriate for intranasal, oropharyngeal, mandible, dental, orthognathic, and rigid laryngoscope and orthognathic surgery [1, 2]. It can also be the airway management procedure of choice for patients receiving tonsillectomies, as well as for those undergoing “complex intra-oral procedures” that require mandibular reconstruction [2, 3].

Beyond certain types of surgery, other situations also benefit from the use of NTI. For one, patients who, due to trismus, have a limited mouth opening, should avoid orotracheal intubation and, therefore, turn to nasotracheal intubation [1]. Additionally, patients who suffer from either cervical spine degeneration or instability may benefit from NTI [1].

Anesthesia providers must also consider a variety of contraindications before deciding on nasotracheal intubation as their strategy of choice. Patients with basilar skull fractures, either with or without corresponding cerebrospinal fluid leakage, could experience severe trauma in their frontal lobes during NTI [1]. Coagulopathy can also place patients at risk of complication via severe epistaxis [1]. Other contraindications for NTI include midface instability, prosthetic heart valves, frequent epistaxis, epiglottitis, and nasal bone fracture [2]. If a patient has foreign bodies in their nasal passage, such as sizeable polyps, or has undergone recent nasal surgery, they may also not be a suitable candidate for NTI [2]. More recently, Zhu et al. found evidence to suggest that having a retropharyngeal internal carotid artery can narrow the pharyngeal cavity and even increase the risk of a tear during intubation [3]. Consequently, it may be beneficial for anesthesia providers to consider RICA before intubation to determine whether the nasotracheal technique is appropriate.

Technical and tube-related contraindications should also be considered. In terms of tube factors, physicians should carefully prevent the selection of too big of a tube, heightened cuff pressure, and the co-existing presence of a nasogastric tube [4]. As for technology, poor larynx visualization, several intubation attempts, and forceful intubation may also compromise the success of nasotracheal intubation [4].

To successfully identify indications and contraindications before deciding on NTI as the correct course of action, physicians should first engage in a meticulous pre-anesthesia evaluation within 48 hours of surgery [4]. During that time, it may become clear which side of the nose should be the one through which the endotracheal tube is passed [4]. However, if the physician remains undecided following the evaluation, a physical exam or an anterior rhinoscopy can be helpful [4]. To reduce the risk of complications, physicians can use a softened or smaller tube, as well as adrenaline to constrict the patient’s blood vessels, depending on the patient’s unique risk factors [5].

In the end, developing a patient-specific strategy that takes into account all relevant indications and contraindications, and applies techniques to meet those needs, is essential to successful nasotracheal intubation.

References

[1] D. H. Park et al., “Nasotracheal intubation for airway management during anesthesia,” Anesthesia and Pain Medicine, vol. 16, no. 3, p. 232-247, July 2021. [Online]. Available: https://doi.org/10.17085/apm.21040.

[2] T. B. Folino, G. McKean, and L. J. Parks et al., “Nasotracheal Intubation,” Treasure Island (FL): StatPearls Publishing, Updated January 19, 2021. [Online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK499967/.

[3] W-P. Zhu et al., “Retropharyngeal internal carotid artery: a potential risk factor during nasotracheal intubation,” Surgical and Radiologic Anatomy, p. 1-8, June 2021. [Online]. Available: https://doi.org/10.1007/s00276-021-02784-9.

[4] D. Prasanna and S. Bhat, “Nasotracheal Intubation: An Overview,” Journal of Maxillofacial Oral Surgery, vol. 13, no. 4, p. 366-372, October-December 2014. [Online]. Available: https://doi.org/10.1007/s12663-013-0516-5.

[5] D. G. Canpolat and S. O. Yasli, “Does a Nasal Airway Facilitate Nasotracheal Intubation or Not? A Prospective, Randomized, and Controlled Study,” Journal of Oral and Maxillofacial Surgery, vol. 79, no. 1, p. 89.e.1-89.e.9, January 2021. [Online]. Available: https://doi.org/10.1016/j.joms.2020.08.029.

Health Incentives: Lessons for COVID-19 Vaccine Campaigns

While most countries still lack adequate access to COVID-19 vaccines, in the U.S., vaccine supply has begun to outstrip demand. As of July 2021, nearly 70 percent of adults have received at least one shot.1 But vaccination rates vary significantly across the country, and in some regions, opposition to vaccines is entrenched, with estimates of “hesitancy” and “strong hesitancy” hovering at one-third of a state’s population.2 To promote public health efforts — and to draw customers back through their doors — businesses have begun to offer incentives for vaccinated customers: Krispy Kreme made headlines in March 2021 when it announced free donuts for anyone who could prove they had been inoculated, and the New York Yankees and Mets are offering free tickets to fans who get vaccinated at ballparks before games. Local governments are approving six-digit budgets for vaccine perks and giveaways, and many states are instituting incentives-based programs as well: Maryland is paying fully vaccinated state employees $100, and in West Virginia, 16- to 35-year-olds who get vaccinated can receive $100 savings bonds.3

In spite of the popular appeal of vaccine incentives, some scholars have questioned their ethics. In a JAMA Network paper published in July 2021, Govind Persad and Dr. Ezekiel Emanuel respond to worries about coercion and exploitation by arguing that vaccination’s benefits — among them preventing harm from COVID-19 and protecting disadvantaged populations facing barriers to vaccination — do not threaten to deprive anyone of anything to which they were entitled. They do validate the legitimacy of two particular concerns: the potential to waste public funds and the potential to make vaccination look riskier than it is by offering compensation. They write that the former could be addressed by carefully calibrating benefits to what is needed to encourage vaccination and that the latter could be addressed by targeting vaccine incentives to only the most receptive groups.4

However, designing incentive programs that strike this balance is notoriously difficult. Positive incentives have proven to be effective in other health campaigns. For example, participants in a fitness-based employee wellness program who received a mere $20 monthly incentive maintained higher levels of exercise than non-participants over a 3-year period, after adjusting for pre-intervention differences in activity levels. However, those who had previously exercised the least were also the least likely to join the program.5 The results of studies like this one and others6,7 indicate that rewards-based incentives can be powerful tools for swaying certain segments of the population to change their behaviors, but that those most entrenched in their practices or beliefs may not be reached so easily.

An Axios-Harris poll from May 2021 found that nearly one-third of unvaccinated Americans say they’ll either “get the vaccine whenever they get around to it” or “will wait awhile and see before getting the vaccine” — suggesting that with well-strategized incentivization, the U.S. can continue to narrow the gap toward heard immunity.3 However, the question stands as to how to persuade the most staunchly opposed groups.

The backlash prompted by Israel’s brief consideration of a vaccination mandate is indicative of why tactical public health education programs are necessary.8 Though Israel acquired a sufficient supply of vaccines early on, many groups’ distrust of the vaccine compelled the state to implement a “Green Pass,” in which proof of vaccination or recovery from COVID-19 serves as a passport to communal events and spaces.9 The program’s punitive edge — barring unvaccinated individuals from the social, commercial, and cultural opportunities they may crave — comes with its own controversies. For example, Mexico’s tax on sugar-sweetened beverages has been criticized as an unfair instance of a government overstepping its place. On the other hand, Mexico’s sugar tax reduced purchases by nearly 10% in 2015.10 The tax is projected to prevent 239,900 cases of obesity and 61,340 cases of diabetes, which a Health Affairs article estimates saves $3.98 per dollar spent on the tax’s implementation.11 As for Israel’s Green Pass, over 80 percent of the adult population has now been fully vaccinated.9 Incentives can be powerful, but they must be implemented alongside robust public-health education campaigns.

References 

  1. The New York Times. See how vaccinations are going in your county and state. The New York times. https://www.nytimes.com/interactive/2020/us/covid-19-vaccine-doses.html. Published July 16, 2021. 
  1. Vaccine hesitancy for COVID-19: State, county, and local estimates. U.S. Department of Health and Human Services. Published June 17, 2021. https://aspe.hhs.gov/pdf-report/vaccine-hesitancy 
  1. Ducharme J. From free beer to $100 payments, states are incentivizing COVID-19 vaccination. Will it work? Time. Published online May 5, 2021. https://time.com/6046238/covid-19-vaccine-incentives/ 
  1. Persad G, Emanuel EJ. Ethical considerations of offering benefits to COVID-19 vaccine recipients. JAMA. Published online 2021. doi:10.1001/jama.2021.11045
  1. Crespin DJ, Abraham JM, Rothman AJ. The effect of participation in an incentive-based wellness program on self-reported exercise. Prev Med. 2016;82:92-98. 
  1. Strohacker K, Galarraga O, Williams DM. The impact of incentives on exercise behavior: a systematic review of randomized controlled trials. Ann Behav Med. 2014;48(1):92-99. 
  1. Burns RJ, Donovan AS, Ackermann RT, Finch EA, Rothman AJ, Jeffery RW. A theoretically grounded systematic review of material incentives for weight loss: implications for interventions. Ann Behav Med. 2012;44(3):375-388. 
  1. Wilf-Miron R, Myers V, Saban M. Incentivizing vaccination uptake: The “Green Pass” proposal in Israel. JAMA. 2021;325(15):1503-1504. 
  1. Kershner I. With most adults vaccinated and case numbers low, Israel removes many restrictions. The New York Times. Published June 1, 2021. https://www.nytimes.com/2021/06/01/world/middleeast/israel-covid-restrictions.html.
  1. Colchero MA, Rivera-Dommarco J, Popkin BM, Ng SW. In Mexico, evidence of sustained consumer response two years after implementing A sugar-sweetened beverage tax. Health Aff (Millwood). 2017;36(3):564-571. 
  1. Basto-Abreu A, Barrientos-Gutiérrez T, Vidaña-Pérez D, et al. Cost-effectiveness of the sugar-sweetened beverage excise tax in Mexico. Health Aff (Millwood). 2019;38(11):1824-1831. 

Ophthalmic Surgery Advancements and Changes in Anesthesia Strategies

Ophthalmic surgery is one of the most common surgical fields requiring anesthesia in developed countries; in the United States alone, over 3 million cataract lenses are extracted annually 1. In the future, ophthalmic surgeries will only continue to increase in frequency given the high incidence of age-related ophthalmic ailments in an overall aging population 2,3.

Either topical, regional or general anesthesia can be used for eye surgery, depending on patient background and clinical context. Topical anesthesia usually involves the administration of a topical anesthetic such as xylocaine, paracaine, tetracaine, or bupivacaine 4; however, it remains limited by its tendency to trigger allergies, endothelial and epithelial toxicity, or keratopathy. Local anesthesia is usually preferable for ophthalmic surgery since it is economical, safe, easy, has a rapid onset, and yields a dilated pupil with low intraocular pressure, in addition to incurring minimal post-operative restlessness, lung complications, and bleeding. Regional anesthesia can be used for nearly all eye surgeries, such as keratoplasty, cataract extraction, glaucoma, iridectomy, strabismus, and retinal detachment surgeries. For regional anesthesia as such, the conjunctiva, globe and orbicularis are paralyzed by a combination of surface and facial anesthesia, alongside, traditionally, a retrobulbar block. Rarely used, general anesthesia is preferred for ocular surgeries in anxious individuals, psychiatric patients, and youth – as well as for major surgeries such as exenteration or perforating ocular injuries. In such contexts, general anesthesia is advantageous in that it results in total akinesia, controlled intraocular pressure, and a safe operating environment.

In the past decade, as a result of drastic technological improvements, the practice of ophthalmic anesthesia has been transformed. In general, vast improvements have been made to minimally invasive surgery, primarily for glaucoma and cataracts 5–7, by refining smaller incisions for surgery. These improvements have laid the foundation for multiple changes to surgical and anesthesia approaches for opthalmic surgery.

First, resorting to general anesthesia is increasingly infrequent. Second, phacoemulsification techniques have gained prominence in light of their ability to facilitate the conduction of cataract surgery under topical anesthesia and to avoid the venous air embolisms that can be caused by suture-free vitrectomy ports; their advent has resulted in topical anesthesia representing a viable alternative for most cataract surgeries. Third, the sub-Tenon’s blockhas gained popularity given its ability to produce satisfactory anesthesia for most intraocular procedures and its circumvention of the inherent risks of needle-based blocks, including globe perforation and optic nerve injury. It is primarily used for cataract surgery but remains effective in a variety of other eye surgeries, including strabismus correction, vitreoretinal surgery, and trabeculectomy 8. Finally, the retrobulbar block has been largely replaced by the peribulbar approach 9, whereby needles are kept at a greater distance from vital adnexa and globe. Since peribulbar anesthesia has a prolonged latency of action, it is preferable to perform the block at least ten minutes prior to the start of surgery; these are increasingly performed in the holding room to increase efficiency.

In parallel, certain surgical techniques have also emerged as useful additions to these surgical approaches. For example, ultrasound-guided eye blocks have proven useful during ophthalmic surgeries. The potential benefits of ultrasound guidance include the real-time visualization of needle trajectory, thereby minimizing the chance of globe perforation 9, and the tracking of anesthetic spread, thereby improving the quality and safety of blocks. In the same vein, hyaluronidase, despite its allergenicity, has emerged as a useful adjuvant during surgery for its promotion of local anesthetic diffusion and hastening of block onset time. Teaching curricula will have to be updated to ensure the complete training of anesthesiologists as the field evolves 9. Of critical importance in light of an aging population, anesthesia strategies in ophthalmic surgery ostensibly continue to rapidly progress and dynamically adapt to ongoing technological advancements.

References

1.        Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009.

2.        Colby SL, Ortman JM. Projections of the Size and Composition of the U.S. Population: 2014 to 2060. Program. 2014.

3.        Swenor BK, Ehrlich JR. Ageing and vision loss: looking to the future. Lancet Glob Heal. 2021. doi:10.1016/S2214-109X(21)00031-0

4. Local Anaesthesia for Eye Surgery. https://web.archive.org/web/20121025132106/http://www.nda.ox.ac.uk/wfsa/html/u12/u1205_01.htm.

5.        Yang S-A, Mitchell W, Hall N, et al. Trends and Usage Patterns of Minimally Invasive Glaucoma Surgery in the United States. Ophthalmol Glaucoma. 2021. doi:10.1016/j.ogla.2021.03.012

6.        Singh K, Misbah A, Saluja P, Singh A. Review of manual small-incision cataract surgery. Indian J Ophthalmol. 2017. doi:10.4103/ijo.IJO_863_17

7.        De Gregorio A, Pedrotti E, Russo L, Morselli S. Minimally invasive combined glaucoma and cataract surgery: clinical results of the smallest ab interno gel stent. Int Ophthalmol. 2018. doi:10.1007/s10792-017-0571-x

8.        Guise P. Sub-Tenon’s anesthesia: An update. Local Reg Anesth. 2012. doi:10.2147/LRA.S16314

9.        Palte HD. Ophthalmic regional blocks: Management, challenges, and solutions. Local Reg Anesth. 2015. doi:10.2147/LRA.S64806