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The rates of knee surgeries continue to rise globally [1]. Appropriate pain management is paramount to ensure the best possible patient outcomes, especially since orthopedic surgeries are associated with relatively high levels of discomfort. Peripheral nerve block is a critical tool for pain management during and after knee surgery.

For a peripheral nerve block focused on the knee, an anesthesiologist administers an anesthetic near the nerves of the knee. The block lasts about 24 hours following surgery. Most patients experience the most pain following a knee replacement in the first 24 hours postoperatively. A peripheral nerve block, in addition to oral or intravenous pain medications, thus maximizes a patient’s relief during this early recovery phase. Even with a nerve block, however, a patient will usually still experience some pain and discomfort [2].

The anesthesiologist pinpoints the location of the nerve and injects the anesthetic medication near the nerve. The process takes 10 minutes and is not painful. The patient will experience a certain degree of pain relief within the first 15 to 20 minutes, with the full effect taking place within 30 minutes. The nerve block may be performed at the beginning of the knee surgery, as part of the anesthetic regimen for the OR, or after surgery, to focus on postoperative pain relief.

A peripheral nerve block is recommended for people undergoing knee replacement surgery for pain management purposes. Patients who get peripheral nerve blocks experience pain relief, and are able to rely less on opioid medications, participate more in rehabilitation therapy, and be more active after surgery, thereby lowering their risk of surgical complications like blood clots.

A recent study from 2022 sought to further investigate the use of nerve blocks for perioperative total knee arthroplasty analgesia [4]. Overall, the data demonstrated that the safety profile varies depending on which block is used, but the data suggests that an optimally chosen and administered peripheral nerve block may provide an extremely safe and effective solution for perioperative analgesia.

A patient will experience numbness in their leg after waking up from knee surgery alongside pain relief until peripheral nerve block eventually wears off. The nerve block does not affect your strength, but if a patient experiences thigh weakness, it is important to tell a clinician. It is also critical to follow explicit instructions from the clinical team with regard to walking and standing again.

Peripheral nerve blocks are considered a safe option for almost all patient, and complications from peripheral nerve blocks remain extremely rare. These include but are not limited to a risk of infection or bleeding at the injection site, seizures, abnormal heart rhythms, and prolonged thigh numbness [2].

Imaging technologies have recently become even more advanced, increasing the feasibility of using a nerve block for pain management in knee surgery. Newer equipment and improved ultrasound imaging, as well as the decreased cost of equipment, are rendering nerve blocks more and more accessible. This is increasingly allowing clinicians to address pain more effectively. Moreover, it significantly reduces the side effects of traditional pain medications, including nausea and sedation, speeding up patient recovery [3].

References

1. Nham, F. H., Patel, I., Zalikha, A. K. & El-Othmani, M. M. Epidemiology of primary and

revision total knee arthroplasty: analysis of demographics, comorbidities and outcomes from the national inpatient sample. Arthroplasty (2023). doi:10.1186/s42836-023-00175-6

2. Peripheral Nerve Block for Knee Replacement Surgery | University of Utah Health. Available at: https://healthcare.utah.edu/orthopaedics/specialties/joint-replacement/knee-replacement/peripheral-nerve-block. (Accessed: 7th January 2024)

3. Innovative Nerve Blocks Ease Pain & Impact From Knee Replacements. Available at: https://www.orlandoortho.com/innovative-nerve-blocks-ease-pain-impact-from-knee-replacements/. (Accessed: 7th January 2024)

4. Hasegawa, M. et al. Review on Nerve Blocks Utilized for Perioperative Total Knee Arthroplasty Analgesia. Orthop. Rev. (Pavia). 14, 2022 (2022). doi: 10.52965/001c.37405

Long Covid, also known as post-Covid condition, long-haul Covid, or post-acute Covid-19, is the continuation or development of new symptoms 3 months or more after the initial SARS-CoV-2 infection (the virus that causes Covid-19), with these symptoms lasting for at least 2 months, according to the World Health Organization.1 Common symptoms include fatigue, shortness of breath, and a state of cognitive confusion and lack of concentration known as “brain fog.” 18 million Americans have said they had long Covid at some point, while 8.8 million said they had the condition in 2022.2 The exact etiology of long Covid is still unclear, though an autoimmune response, lingering SARS-CoV-2, and organ damage have all been implicated. The lasting effects seen in long Covid raise questions about patients’ immune state and interactions with continued vaccination or booster shots.

Thanks to a recent study from scientists at the Montreal Clinical Research Institute, is that long Covid patients who received Covid-19 vaccination, or booster shots, had reduced symptoms and improved overall well-being.3 In this study, 83 participants previously infected with SARS-CoV-2 and diagnosed with long Covid were given two doses of the Covid-19 vaccine approximately three weeks apart (the Pfizer, Moderna, and AstraZeneca vaccines were all used). About half of the participants had been vaccinated against Covid-19 prior to the study.

To assess the effects of booster shots on long Covid, the researchers measured the participants’ saliva SARS-CoV-2 concentration and blood plasma levels of cytokines (proteins involved in the immune response), SARS-CoV-2 proteins, and antigens to the viral proteins. Participants also completed the World Health Organization-5 Well-Being Index, an assessment tool that measures mental health, and reported on their symptoms (including fatigue, trouble with concentration, and trouble with memory) throughout the study. Compared to clinical data from unvaccinated participants, the vaccinated group showed a significant reduction in long Covid symptoms, as well as lower plasma concentrations of SARS-CoV-2 proteins and antigens and inflammatory cytokines. Additionally, 77.8% of participants reported improved mental wellbeing scores.

In addition to reducing the symptoms of long Covid in patients with the condition, vaccination before a diagnosis of long Covid can mean fewer symptoms once a patient develops the condition. A July 2023 study published in the Journal of Investigative Medicine 4 involved 477 participants with long Covid, about half of whom had received at least one dose of the Covid-19 vaccine prior to becoming infected. People in the vaccinated group were half as likely to experience abdominal pain as those in the unvaccinated group and less likely to report other symptoms, such as dizziness, chest pain, loss of smell, and weakness.

Based on the findings mentioned above, it’s not surprising that the best defense against long Covid of any severity is preemptive vaccination. A National Institutes of Health study of more than 47000 individuals found that vaccination led to lower rates of long Covid, even after accounting for the fact that vaccination helps prevent SARS-CoV-2 infection in the first place.5 As the SARS-CoV-2 virus continues to evolve, and our understanding of long Covid continues to improve, the role of vaccination and booster shots in mitigating and preventing the harmful effects of this often-debilitating condition will hopefully become clearer.

References

1. Post COVID-19 condition (Long COVID). World Health Organization. https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition

2. Adjaye-Gbewonyo, D., Vahratian, A., Cria G., P. & Bertolli, J. Long COVID in Adults: United States, 2022. https://stacks.cdc.gov/view/cdc/132417 (2023), DOI:10.15620/cdc:132417.

3. Nayyerabadi, M. et al. Vaccination after developing long COVID: Impact on clinical presentation, viral persistence, and immune responses. Int. J. Infect. Dis. 136, 136–145 (2023), DOI: 10.1016/j.ijid.2023.09.006

4. Vanichkachorn, G. et al. Potential reduction of post-acute sequelae of SARS-CoV-2 symptoms via vaccination. J. Investig. Med. 71, 889–895 (2023), DOI: 10.1177/10815589231191812

5. Brannock, M. D. et al. Long COVID risk and pre-COVID vaccination in an EHR-based cohort study from the RECOVER program. Nat. Commun. 14, 2914 (2023), DOI: 10.1101/2022.10.06.22280795

Phosphodiesterase inhibitors are a class of drugs that inhibit phosphodiesterase enzymes. These agents can be tailored against specific families of phosphodiesterase, which number 11 in total,¹ or can non-specifically block phosphodiesterase throughout the body. Phosphodiesterase inhibitors can be used to manage a number of medical conditions, including chronic obstructive pulmonary disease, erectile dysfunction, pulmonary arterial hypertension, and acute decompensated heart failure.² They induce smooth muscle relaxation and the widening of blood vessels (vasodilation) by preventing their target phosphodiesterase enzymes from degrading and inactivating the cellular signaling molecules, such as cyclic guanosine monophosphate (cGMP) that induce these effects.² Phosphodiesterase inhibitors also display interactions with some anesthetics, making them important to consider for anesthesia and surgery.

Phosphodiesterase inhibitors are important when it comes to surgery and anesthesia. Though these inhibitors do not induce anesthesia on their own, they can modify some of the effects of anesthesia if administered alongside anesthetic agents, as shown by several scientific studies. In a 2005 paper published in Anesthesia & Analgesia, Engelhardt et al. demonstrated that administering the phosphodiesterase inhibitor sildenafil alongside the anesthetic propofol can increase the speed of recovery from anesthesia without affecting the requirements for propofol sedation.³ The authors do not offer an explanation for this effect, but note that further testing of other phosphodiesterase inhibitors with propofol, and using several classes of phosphodiesterase inhibitor together, could further enhance this effect.

Interestingly, co-administering certain phosphodiesterase inhibitors with certain inhalation anesthetics seems to potentiate, or increase the effects, of the anesthesia. Phosphodiesterase 4 inhibitors and the anesthetic agent sevoflurane are both known to dilate bronchi, but in a 2014 study, researchers found that the two had an additive bronchodilator effect.⁴ They found that guinea pigs administered sevoflurane and the phosphodiesterase inhibitor roflumilast had lower total lung resistance and muscle tensions compared to guinea pigs that received only one or neither of the two drugs. Because patients with hyperreactive airway diseases, like chronic obstructive pulmonary disease and asthma, experience narrowing of the bronchi, a strategy of combining sevoflurane and roflumilast could lead to better outcomes. In a similar study, researchers found that several phosphodiesterase 4 inhibitors potentiated the effects of the anesthesia isoflurane in mice.⁵

Though patients taking phosphodiesterase inhibitors can typically receive most types of anesthesia, there are certain considerations that these patients should be aware of. Phosphodiesterase 5 inhibitors are contraindicated with nitrates, as these chemicals also increase cGMP levels, which can lead to increase vasodilation and potentially hypotension (low blood pressure).⁶ The anesthetic agent nitrous oxide and dietary sources of nitrate are not contraindicated with phosphodiesterase inhibitors, as neither contribute to plasma levels of nitrous oxide, but inhaled nitrates known as “poppers” can cause severe hypotension when taken with certain phosphodiesterase inhibitors.⁶ However, if the risks associated with phosphodiesterase inhibitors are managed, the drugs can be beneficial in a wide variety of surgical contexts. Studies report that phosphodiesterase 5 inhibitors reduce the risk of mortality and metastasis when administered to patients following surgery for colorectal cancer,⁷ and can be administered perioperatively to manage hypertension in patients undergoing liver transplantation.⁸ Future research into the properties of phosphodiesterase inhibitors will enable these drugs to benefit even more patients.  

References

1. Levy, I., Horvath, A., Azevedo, M., de Alexandre, R. B. & Stratakis, C. A. Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment. Curr. Opin. Pharmacol. 11, 689–697 (2011), DOI: 10.1016/j.coph.2011.10.003

2.         Padda, I. S. & Tripp, J. Phosphodiesterase Inhibitors. in StatPearls (StatPearls Publishing, 2023).

3. Engelhardt, T., MacDonald, J., Galley, H. F. & Webster, N. R. Selective Phosphodiesterase 5 Inhibition Does Not Reduce Propofol Sedation Requirements but Affects Speed of Recovery and Plasma Cyclic Guanosine 3′,5′-Monophosphate Concentrations in Healthy Volunteers. Anesth. Analg. 101, 1050 (2005), DOI: 10.1213/01.ane.0000168264.41341.7d

4. Zhou, J., Iwasaki, S. & Yamakage, M. Phosphodiesterase 4 Inhibitor Roflumilast Improves the Bronchodilative Effect of Sevoflurane in Sensitized Airways. Anesthesiology 120, 1152–1159 (2014), https://doi.org/10.1097/ALN.0000000000000160

5. Aragon, I. V. et al. Inhibition of cAMP-phosphodiesterase 4 (PDE4) potentiates the anesthetic effects of Isoflurane in mice. Biochem. Pharmacol. 186, 114477 (2021), DOI: 10.1016/j.bcp.2021.114477

6. Schwartz, B. G. & Kloner, R. A. Drug Interactions With Phosphodiesterase-5 Inhibitors Used for the Treatment of Erectile Dysfunction or Pulmonary Hypertension. Circulation 122, 88–95 (2010), DOI: 10.1161/CIRCULATIONAHA.110.944603

7. Huang, W., Sundquist, J., Sundquist, K. & Ji, J. Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer. Nat. Commun. 11, 3191 (2020), DOI: 10.1038/s41467-020-17028-4

8. Onoe, T. et al. Perioperative management with phosphodiesterase type 5 inhibitor and prostaglandin E1 for moderate portopulmonary hypertension following adult-to-adult living-donor liver transplantation: a case report. Surg. Case Rep. 4, 15 (2018), DOI: 10.1186/s40792-018-0423-6

Over the past few years, ownership of medical practices has increasingly shifted from physicians to corporations. Changes in ownership models raise questions about compliance with state laws that regulate the corporate practice of medicine, as large healthcare systems may span states with different regulations, and the impact of these changes on the quality of healthcare for patients.

Corporate practice of medicine doctrines restrict corporations from employing physicians or providing medical services, aiming to protect the patient-physician relationship and promote physicians’ independent medical judgment (2). More than 30 states have some form of corporate practice of medicine laws in place that vary in stringency (4). These laws have been enacted over the years through a combination of state legislation, court cases, actions by state medical licensing boards, and attorney general opinions (2). However, even states like California and Texas–which have some of the regulations–allow numerous exceptions to the doctrine (4). Exceptions and loopholes have contributed to increasing corporate ownership in medicine in the United States.

For example, every state with corporate practice of medicine laws allows for the creation of professional corporations to provide medical services (2). Many of these states restrict shareholders and directors of these professional corporations to licensed physicians working in the same area of medicine as the physicians employed by the corporation (2). However, some states allow other shareholders or directors to be included at a minority percentage; for example, in Colorado, physician assistants can also be shareholders of a professional medical corporation (2). Some states also permit the creation of multi-service corporations that combine various medical specialties (2). For instance, Rhode Island allows physicians, nurses, optometrists, psychologists, physical therapists, and other medical practitioners to create joint professional corporations (2). Most states also allow certain entities, notably hospitals, to employ physicians (2). Some states only allow nonprofit hospitals to employ physicians, while others provide an official exemption from the corporate practice of medicine doctrine to all hospitals (2).

In recent years, there has been an increase in the consolidation of medical practices and in private equity investment in healthcare services. Multi-billion dollar corporations–especially insurance companies–have been buying up primary care offices nationwide to create multi-state chains of primary care centers (1). Furthermore, private equity firms have been acquiring nursing homes and fertility treatment centers across the country (4). According to a study of hospice agencies from 2021, private equity ownership of hospice care facilities increased by over 200% between 2011 and 2019 (4). Another study from 2020 found that between 2017 and 2019, twice as many fertility care centers were acquired by private equity firms compared to the previous seven years combined (4). Nursing homes and fertility treatment centers often charge patients and payers higher out-of-pocket costs than other medical centers, creating an incentive for increased profits for corporations (4).

Higher rates of corporate ownership in medicine may have negative consequences for patients and payers, with healthcare in the United States already facing a cost crisis. A study published in the BMJ in July found that private equity investment correlated with a 32% increase in healthcare costs (3). The authors systematically reviewed 55 research studies on private equity in healthcare, focusing on four dimensions: healthcare quality, price to payers and patients, cost to healthcare operators, and health outcomes (3). Of the four dimensions, private equity investment in healthcare was most closely associated with higher patient healthcare costs (3). Insurance companies argue that corporate ownership of medicine helps consolidate medical services, facilitating the transition from pay-per-service to value-based care (4). However, the benefit of corporate ownership of medicine for patients is yet to be determined.

References

1. Abelson, Reed. “Corporate Giants Buy Up Primary Care Practices at Rapid Pace.” The New York Times, May 12 2023, https://www.nytimes.com/2023/05/08/health/primary-care-doctors-consolidation.html
2. “Issue brief: Corporate practice of medicine.” American Medical Association, 2015, corporate-practice-of-medicine-issue-brief_1.pdf
3. Niewjik, Grace. “New findings show private equity investments in healthcare may not lower costs or improve quality of care.” Uchicago Medicine, July 25 2023, https://www.uchicagomedicine.org/forefront/research-and-discoveries-articles/private-equity-investments-in-healthcare-may-not-lower-costs#skipToContent
4. Weiss, Haley. “What Happens When Private Equity Buys Your Doctor’s Office?” TIME, July 31 2023, https://time.com/6299770/private-equity-health-care-impact/
5. Wilmott, Matt et al. “Corporate Practice of Medicine Doctrine: Increased Enforcement on the Horizon?” The National Law Review, Jan 17 2023, https://www.natlawreview.com/article/corporate-practice-medicine-doctrine-increased-enforcement-horizon

Mental disorders are highly debilitating conditions of the central nervous system and are among the leading causes of disability-adjusted life years worldwide. It is generally accepted that these disorders result from abnormal neural activity in certain brain regions, which has the potential to affect neural networks and neuronal plasticity in the entire brain.¹ General anesthetics are largely heterogenous chemical substances which are employed during surgery to induce loss of consciousness and amnesia.² While they are extremely useful in the perioperative setting, their ability to modulate neuronal networks makes it so even a single exposure to these drugs may have long-lasting effects on central nervous system physiology.³ As a result, the effects of anesthesia on depression are of great interest to researchers. 

Major depressive disorder (MDD) is a heritable psychiatric condition that is associated with significant cellular and molecular changes in neural networks. Since MDD rarely presents with a clear-cut phenotype, and many of its primary symptoms are hard to measure in animal models (e.g. insomnia or hypersomnia), understanding the underlying neurobiology of MDD has been difficult.⁴ Currently, available pharmaceutical treatments are also limited by their long onset of action and relatively low rate of efficacy.⁵ As a direct result, the global burden of MDD continues to increase.  

Before pharmacological treatments became the norm for psychiatric disorders, electroconvulsive therapy (ECT) was the most widely practiced treatment for MDD. In practice, this therapy was accompanied by the administration of general anesthesia, to minimize discomfort and other severe consequences. When early observations showed patients with depression who were treated with ECT (and thiopentone anesthesia) and patients treated with only thiopentone had no significant difference in depressive states at follow-up, more clinical trials were conducted to isolate and test this intriguing finding. In 1978, researchers in the United Kingdom conducted a controlled evaluation of ECT, with 16 patients with depressive psychosis receiving unilateral pulse shocks under methohexitone anesthesia and 16 patients receiving the same ECT pre-treatment with a simulated shock therapy.⁶ Results showed comparable scores on the Hamilton Rating Scale of Depression, assessed under double-blind conditions. A later study conducted in 1995 confirmed these results with isoflurane anesthesia.⁷ 18 years later, the antidepressant effects of isoflurane anesthesia was again confirmed in a study of 20 patients with medication-refractory depression (or treatment-resistant MDD).^2,8 The potential for anesthesia to be able to directly reduce depression symptoms has led to significant further research on how exactly that may happen. 

An emerging pathophysiological concept is that patients with MDD have alterations in synaptogenesis and neural plasticity, which can lead to serious dysfunction of cortical neuronal circuitries, especially those involved in mood modulation.² A meta-analysis of neuroimaging methods (including positron emission tomography and functional magnetic resonance imaging) on adults with MDD identified hypoactive regions in the cingulate cortex and hyperactive regions in frontal areas of the brain.⁹ On a molecular level, both clinical and pre-clinical data show that ketamine (which is an anesthetic well known for its anti-depressive effects) injection increases glutamate release in the cingulate cortex. Subsequent work revealed a positive correlation between these metabolic changes and an improvement in the Montgomery-Asberg Depression Rating Scale.^2,10 Ketamine has also been shown to activate the mechanistic target of rapamycin complex 1 (mTORC1), a signaling molecule which regulates activity-dependent protein synthesis in synaptic plasticity. Reductions in mTORC1 signaling are associated with a decreased number and functionality of dendritic spine synapses. 

Impaired neural plasticity is one of the most important aspects in the pathogenesis of all psychiatric illnesses, including MDD. Because drugs used in general anesthesia are known to be powerful modulators of synaptic activity in neuronal networks, studying their effect can pave the way towards a better understanding of the human brain and its illnesses, including depression.  

References 

1. Krishnan, Vaishnav, and Eric J. Nestler. “The Molecular Neurobiology of Depression.” Nature, vol. 455, no. 7215, Oct. 2008, pp. 894–902. www.nature.com, https://doi.org/10.1038/nature07455  

2. Vutskits, Laszlo. “General Anesthetics to Treat Major Depressive Disorder: Clinical Relevance and Underlying Mechanisms.” Anesthesia & Analgesia, vol. 126, no. 1, Jan. 2018, p. 208. journals.lww.com, https://doi.org/10.1213/ANE.0000000000002594  

3. Vutskits, Laszlo, and Zhongcong Xie. “Lasting Impact of General Anaesthesia on the Brain: Mechanisms and Relevance.” Nature Reviews Neuroscience, vol. 17, no. 11, Nov. 2016, pp. 705–17. www.nature.com, https://doi.org/10.1038/nrn.2016.128  

4. Krishnan, Vaishnav, and Eric J. Nestler. “Linking Molecules to Mood: New Insight into the Biology of Depression.” American Journal of Psychiatry, vol. 167, no. 11, Nov. 2010, pp. 1305–20. ajp.psychiatryonline.org (Atypon), https://doi.org/10.1176/appi.ajp.2009.10030434  

5. Jick, Hershel, et al. “Antidepressants and the Risk of Suicidal Behaviors.” JAMA, vol. 292, no. 3, July 2004, pp. 338–43. Silverchair, https://doi.org/10.1001/jama.292.3.338  

6. Lambourn, J., and D. Gill. “A Controlled Comparison of Simulated and Real ECT.” British Journal of Psychiatry, vol. 133, no. 6, Dec. 1978, pp. 514–19. DOI.org (Crossref), https://doi.org/10.1192/bjp.133.6.514  

7. Langer, G., et al. “Isoflurane Narcotherapy in Depressive Patients Refractory to Conventional Antidepressant Drug Treatment.” Neuropsychobiology, vol. 31, no. 4, 1995, pp. 182–94. DOI.org (Crossref), https://doi.org/10.1159/000119190  

8. Weeks, Howard R., et al. “Antidepressant and Neurocognitive Effects of Isoflurane Anesthesia versus Electroconvulsive Therapy in Refractory Depression.” PLoS ONE, edited by Lin Lu, vol. 8, no. 7, July 2013, p. e69809. DOI.org (Crossref), https://doi.org/10.1371/journal.pone.0069809  

9. Diener, Carsten, et al. “A Meta-Analysis of Neurofunctional Imaging Studies of Emotion and Cognition in Major Depression.” NeuroImage, vol. 61, no. 3, July 2012, pp. 677–85. ScienceDirect, https://doi.org/10.1016/j.neuroimage.2012.04.005  

10. Nugent, Allison C., et al. “Neural Correlates of Rapid Antidepressant Response to Ketamine in Bipolar Disorder.” Bipolar Disorders, vol. 16, no. 2, Mar. 2014, pp. 119–28. DOI.org (Crossref), https://doi.org/10.1111/bdi.12118  

Major depressive disorder is a serious psychiatric illness that results in functional impairment in many people. Many different treatments have been used through the years in an attempt to treat major depressive disorder. While monoaminergic antidepressants have effectively been used for many, these antidepressants are limited in that they have delayed onset of action and some patients are treatment resistant.  

There has thus been a need to develop antidepressants with a novel target. To this end researchers have directed their attention to the glutamatergic system, especially ketamine, to treat depression, which has had some promising results but also conflicting data in the literature.  

Ketamine, which can also be used in other psychiatric diagnoses (including suicidality, obsessive compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder ¹), despite being initially developed as an anesthetic, has been found to have antidepressant effects at sub-anesthetic doses. Its mechanism of action is via N-Methyl-D-aspartic acid (NMDA) receptor blockade as well as NMDA receptor- independent pathways ². However, the scientific data on the efficacy of ketamine for depression is conflicting. 

A recent review identified the clinical evidence regarding single-dose intravenous administration of (R,S)-ketamine as well as intranasal administration of the S-enantiomer, esketamine, only to treat depression ¹. Initial studies demonstrated that a single subanesthetic-dose intravenous ketamine infusion rapidly, within a day, improved depressive symptoms in individuals with major depressive disorder and bipolar depression, and that antidepressant effects lasted three to seven days. 

Several open-label and saline-control studies of treatment-resistant depression have demonstrated a greater antidepressant response with multiple doses compared to a single dose of ketamine. Studies have been subsequently carried out to specifically elucidate the best ketamine administration regimen to treat depression. Data from a study comparing the efficacy and safety of single versus six repeated ketamine using midazolam as active placebo found that repeated infusions were relatively well-tolerated, and that repeated ketamine showed greater effects on depression to midazolam following five infusions, but fell short of significance when compared to add-on single ketamine to midazolam at the end of two weeks ³. In other words, multiple infusions of ketamine were not significantly different than midazolam plus one infusion of ketamine, casting some doubt on the need for repeated infusions. 

Despite limited data, the side effects resulting from antidepressant doses of ketamine—including dissociative symptoms, hypertension, and confusion/agitation—appear tolerable and limited to approximately the time of treatment ¹. Additional research has confirmed that repeated ketamine infusions significantly decrease depression symptoms without impacting cognitive performance ⁴. However, relatively little remains known about ketamine’s longer-term effects, including increased risks of abuse and/or dependence ¹. The long-term safety of ketamine use needs to be taken into consideration as ketamine has abuse potential and is associated with psychological side effects such as dissociative or psychotomimetic effects. 

Additional research remains to be performed in order to properly elucidate the evidence in support of or against the use of ketamine in depression, as well as what the most effective and safe protocol is. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure. Understanding why some studies have found promising results in treating depression with ketamine while others have found disappointing results is also critical, as conflicting data holds back the successful development of therapeutics. Studying ketamine use in greater depth also has the potential to transform our understanding of the mechanisms underlying mood disorders. 

References 

1. Yavi, M., Lee, H., Henter, I. D., Park, L. T. & Carlos A. Zarate, J. Ketamine treatment for depression: a review. Discov. Ment. Heal. 2, 9 (2022). doi: 10.1007/s44192-022-00012-3.  

2. Shin, C. & Kim, Y. K. Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives. Psychiatry Investig. 17, 181 (2020). doi: 10.30773/pi.2019.0236 

3. Shiroma, P. R. et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl. Psychiatry 2020 101 10, 1–9 (2020). doi: 10.1038/s41398-020-00897-0 

4. Dai, D. et al. Neurocognitive effects of repeated ketamine infusion treatments in patients with treatment resistant depression: a retrospective chart review. BMC Psychiatry 22, 1–8 (2022). doi: 10.1186/s12888-022-03789-3. 

Modern medicine is pushing away from opioid-based pain management through different innovative approaches. That being said, opioids are still sometimes necessary due to their potent effects. Both remifentanil and fentanyl, two synthetic drugs, represent strong opioid-based analgesic solutions. Remifentanil and fentanyl are related formulations but have significant differences.

Remifentanil is chemically related to fentanyl and has similar pharmacodynamic properties, with a rapid onset of action. However, it is slightly more potent than fentanyl. Remifentanil is also unique in that its metabolism is independent of organ function ¹.  

Researchers have long investigated the clinical differences between remifentanil and fentanyl. One study seeking to compare the use of remifentanil and fentanyl during elective supratentorial craniotomy for space-occupying lesions identified that their induction hemodynamics were similar. Intracranial pressure and cerebral perfusion pressure were also similar, as was the median time to tracheal extubation, and the incidence of nausea and vomiting. However, isoflurane use was found to be greater in the patients who received fentanyl, as was systolic blood pressure. Furthermore, while no patient receiving remifentanil required naloxone, which can quickly reverse a too-high dose of opioids, seven patients receiving fentanyl needed it. In the end, the researchers concluded that remifentanil may be a reasonable alternative to fentanyl in the context of elective supratentorial craniotomy. 

Another study sought to assess the effects of three different opioid approaches for cardiac surgery on postoperative pain, time to extubation, time to intensive care unit discharge, time to hospital discharge, and cost. Data analyses demonstrated that the more expensive but shorter-acting opioids, including remifentanil, produced equally rapid extubation, similar stays, and similar costs to fentanyl—indicating that any of these opioids may be recommended for fast-track cardiac surgery ². 

Finally, a randomized, double-blind study sought to probe the analgesic efficacy and side effects of continuous constant-dose infusions of remifentanil following total abdominal hysterectomy, comparing it to fentanyl ³. Data failed to reveal any significant differences in visual analogue scale scores of pain, time to first postoperative analgesics, or additional analgesics between the two groups. In particular, the incidences and severities of postoperative nausea and vomiting and opioid related side effects were no different across the groups. The researchers concluded that the continuous infusion technique of remifentanil was not superior compared to fentanyl.  

Research has also shown, however, that there are clinical differences among various opioids, including remifentanil and fentanyl in particular. One study found clear, statistically significant differences among remifentanil and fentanyl in terms of the bispectral index and effect-site concentration in the different study groups ⁴. 

More recently though, a double-blind, randomized, multicenter study was conducted to compare the efficacy and safety of remifentanil and fentanyl for intensive care unit sedation and analgesia ⁵. Analgesia-based sedation with remifentanil titrated to response was demonstrated to provide effective sedation and rapid extubation without the need for propofol in most individuals. Fentanyl was similar, likely because the dosing algorithm required frequent monitoring and adjustment, thereby preventing over-sedation. However, the rapid offset of analgesia with remifentanil resulted in a greater incidence of pain, highlighting the need for proactive pain management when transitioning to longer acting analgesics. 

References 

1. Simmons, B. & Kuo, A. Analgesics, Tranquilizers, and Sedatives. Card. Intensive Care 421–431.e5 (2019). doi:10.1016/B978-0-323-52993-8.00040-0 

2. Engoren, M., Luther, G. & Fenn-Buderer, N. A comparison of fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia. Anesth. Analg. (2001). doi:10.1097/00000539-200110000-00011 

3. Choi, S. H. et al. Comparison of Remifentanil and Fentanyl for Postoperative Pain Control after Abdominal Hysterectomy. Yonsei Med. J. 49, 204 (2008). doi: 10.3349/ymj.2008.49.2.204 

4. Lysakowski, C., Dumont, L., Pellégrini, M., Clerque, F. & Tassonyi, E. Effects of fentanyl, alfentanil, remifentanil and sufentanil on loss of consciousness and bispectral index during propofol induction of anaesthesia. Br. J. Anaesth. (2001). doi:10.1093/bja/86.4.523 

5. Muellejans, B. et al. Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713]. Crit. Care 8, R1 (2004). doi: 10.1186/cc2398 

Since the start of the Covid-19 pandemic, the origin of the SARS-CoV-2 virus has remained the subject of intense scientific and political debate. A recent report presented to the World Health Organization in March 2023 provides the most substantial evidence to date that the coronavirus was first transmitted to human populations from a wild-animal source. This new data points toward a more definitive understanding of the origins of Covid-19. 

A French evolutionary biologist discovered a collection of genetic sequences from samples collected at the Huanan Seafood Wholesale Market—the location where Covid-19 was first reported—on a coronaviruses database (3). Chinese researchers had quietly uploaded the genetic sequences, which were collected from swabs of surfaces in the market in late 2019 (3). New analyses from this data suggest a particular origin for Covid-19 — that live mammals for sale illegally at the market could have been shedding the coronavirus when the pandemic began (3). In particular, the genetic material of raccoon dogs—a foxlike member of the canine family native to East Asia—was found in the same places as pieces of SARS-CoV-2’s genome (1). 

A portion of the genetic material in the report was RNA molecules, which degrade quickly. Thus, the presence of RNA material from live mammals may indicate that these animals were present at the market just before the swabs of the surfaces were collected (3). 

The report from the biologist and international colleagues came to light only three weeks after the U.S. Energy Department concluded “with low confidence” that the coronavirus pandemic was likely started by a laboratory leak (2). The virus may have been transmitted from the Wuhan Institute of Virology, which is known for its high expertise in studying coronaviruses (2). Laboratory leaks have happened before; in 2014, personnel at the CDC’s Roybal Campus were exposed to viable anthrax. However, the new data showing raccoon dog DNA suggests that the Covid-19 pandemic may have had purely natural origins, with the raccoon dog serving as an intermediary host for the virus (2). 

More information is necessary for researchers to draw definite conclusions, and scientists speculate that there could be more data available, considering how long it took for the genetic sequences to come to light (3). The WHO has publicly indicated that additional data should be presented by the Chinese researchers who collected them (3). Deducing the origins of Covid-19 has important implications, considering that the virus has killed nearly 7 million people worldwide and inflicted many others with chronic illness (3). Understanding the origins of Covid-19 will empower public health officials and government authorities to take steps to prevent similar outbreaks and continue developing more effective treatments and vaccines. 

References 

1. Kang, David and Maria Cheng. “New COVID origins study links pandemics beginning to animals, not a lab.” PBS, 17 Mar 2023, www.pbs.org/newshour/science/new-covid-origins-study-links-pandemics-beginning-to-animals-not-a-lab 

2. Stolberg, Sheryl Gay et al. “The Origins of the Covid Pandemic: What We Know and Don’t Know.” The New York Times, 17 Mar 2023, www.nytimes.com/article/covid-origin-lab-leak-china.html 

3. Wu, Katherine J. “A Major Clue to COVID’s Origins Is Just Out of Reach.” The Atlantic, 21 Mar 2023, www.theatlantic.com/science/archive/2023/03/covid-pandemic-origins-missing-evidence-debate/673460/ 

4. Wu, Katherine J. “The Strongest Evidence Yet That an Animal Started the Pandemic.” The Atlantic, 16 Mar 2023, www.theatlantic.com/science/archive/2023/03/covid-origins-research-raccoon-dogs-wuhan-market-lab-leak/673390/ 

Effective analgesia, in particular epidural anesthesia, is a much discussed and essential part of optimizing patient care. Epidural anesthesia is both safe and inexpensive with the purpose of providing intra- and postoperative pain control¹. Epidurals often involve a multidrug regimen with adjuvants added to a long-acting local anesthetic such as ropivacaine. Using adjuvants is advantageous as the anesthetic and analgesic doses can be reduced while often achieving analgesia and anesthesia quicker. This article will examine adjuvants to ropivacaine and provide a comparison of the different options. 

Opioids have commonly been used as adjuvants, but their adverse effects of respiratory depression, and nausea and vomiting, especially in older patients, have limited their usage². Steroids, such as dexamethasone, as well as anti-inflammatory drugs, like parecoxib and lornoxicam, have been used as adjuvants with varying success². Epinephrine is another adjuvant, which has long been used alongside various anesthetic agents. However, continuous infusions of epinephrine have been associated with neurotoxicity, limiting the ability to use it for epidural infusions³. Midazolam, which acts on benzodiazepine receptors, and fentanyl, an NMDA receptor antagonist, have both also been explored as anesthetic adjuvants. However, both midazolam and fentanyl are not recommended for peripheral blocks, and there is concern surrounding neurotoxicity in both agents^{4, 5}. By far the most common adjuvants for anesthesia are the alpha agonists clonidine and dexmedetomidine. A comparison of ropivacaine adjuvants has shown clonidine and dexmedetomidine to have both sedating and analgesic effects, but with less harmful adverse effects than other options⁶.  

When comparing alpha-2 adrenergic agonists, studies have shown that both clonidine and dexmedetomidine result in more rapid onset of anesthesia with longer duration when added to an anesthetic⁷. One study found that using dexmedetomidine resulted in faster onset and longer duration of pain control than clonidine¹. Dexmedetomidine also demonstrated acceptable hemodynamic stability and sedation. The side effects of both include bradycardia, hypotension, nausea and itching. Importantly, respiratory depression has not been noted in patients given clonidine or dexmedetomidine adjuvants, giving them an edge over other agents such as opioids³. These adjuvants have been shown to be useful not only in epidurals but nerve blocks as well, including peripheral, axillary, and sciatic nerve blocks.  

Current research in the realm of anesthetic adjuvants is directed at finding a drug that both prolongs anesthesia duration but with safer adverse effect profiles. Novel approaches include the usage of charged molecules such as tonicaine and n-butyl tetracaine, neuromuscular blocking agents, and even adenosine. However, there has been concern regarding neuromuscular blocking agents and the association with anesthetic toxicity as well as prolonged motor blockade. Meanwhile, adenosine did not have neurotoxicity concerns but was found to have no additional benefit for peripheral nerve blocks². Further studies are warranted to search for and provide a comparison of potential other adjuvants to ropivacaine and other anesthetics, with the goal of improved safety profiles and enhanced analgesic effects, that may be used in diverse settings including the operating room, the ICU, and labor and delivery wards.    

References  

1 Soni P. Comparative study for better adjuvant with ropivacaine in epidural anesthesia. Anesth Essays Res 2016; 10 (2): 218-222. 

2 Swain A, Nag DS, Sahu S et al. Adjuvants to local anesthetics: Current understanding and future trends. World J Clin Cases 2017; 5 (8): 307-323. 

3 Neal JM. Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: Neurotoxicity and neural blood flow. Reg Anesth Pain Med 2003; 28 (2): 124-134. 

4 Lee IO, Kim WK, Kong MH et al. No enhancement of sensory and motor blockade by ketamine added to ropivacaine interscalene brachial plexus blockade. Acta Anaesthesiol Scand 2002; 46 (7): 821-826. 

5 Kirksey MA, Haskins SC, Cheng J et al. Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review. PLoS One 2015; 10 (9): e0137312. 

6 Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology 2000; 93 (5): 1345-1349. 

7 El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM et al. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. Br J Anaesth 2009; 103 (2): 268-274. 

Anesthesia incident reporting systems aim to identify and aggregate adverse events in anesthesia care [1, 2]. They typically consist of a brief description of the patient, the context in which the practitioner saw the patient, and the adverse event that occurred [2]. Medical professionals input this information into a database which may then be accessible by a single anesthesiology department, a healthcare facility, regional institutions, or even an entire national or international healthcare system [2]. The aspiration is that, by making incidents publicly accessible to other practitioners, an anesthesia incident reporting system can help prevent future, similar errors. 

Reporting systems are not unique to medicine: they have long been in use in other industries, such as the nuclear power and airline industries [1]. Nevertheless, they have deep roots in anesthesia, with the practice of spreading learning lessons from incidents by word-of-mouth or via letter long being common among anesthesiologists [1]. In 1954, Flanagan was the first to describe the “critical incident technique;” a few years later came a report on critical incidents owing to hospital medication errors, followed by the formal introduction of reporting to the United States in 1978 [1]. The digital age has since prompted a transformation in reporting systems, as files have changed from written to digital format and information has become easier to disseminate widely [2].  

Designing an effective anesthesia incident reporting system is no easy feat. Dutton recommends that systems incorporate twenty-five elements, including being “easy to find,” containing “no mandatory elements,” providing an “option for anonymous data entry,” and assuring confidentiality [2]. However, researchers have debated the value of anonymity. Anonymity eases practitioner concerns of reputational damage and, thus, discourages subsequent underreporting [1, 3]. However, it also eliminates the possibility of personal feedback, meaning that individual anesthesiologists may not receive instruction on how to avoid similar incidents unless their conduct reflects a larger, identified trend [3]. Arnal-Velasco and Barach suggest that the solution to this issue is the development of trust by practitioners, which could include introducing protective legislation to lower or rule out the risk of retaliation [4]. Notwithstanding this potential solution, this example indicates how any system would have to reconcile trade-offs, thereby rendering the design rather complex. 

Still, the various benefits of reporting systems may make them worth the struggle. Because of the power of the narrative-based structure, an anesthesia incident reporting system can help develop teaching cases for educational simulations and presentations [2].  

Meta-analyses of incident reports can also help identify incident trends among practitioners and thus be used to recommend changes in practice to reduce risks [2, 5]. For example, Schulz and colleagues referred to the German anesthesia incident reporting system to track the frequency with which situation awareness errors occurred [6]. Their subsequent finding that such errors occurred in 81.5% of analyzed cases, particularly on the levels of perception and comprehension, provided helpful instruction for regional improvement in anesthesia care [6]. This example demonstrates the power of reporting systems in identifying actionable areas for improvement [6]. It is important to note, however, that data alone is not intrinsically helpful; the willingness of stakeholders to turn data into action is key to unlocking the benefits of reporting databases [7]. 

Anesthesia incident reporting systems can be valuable tools for tracking outcomes and instructing anesthesia practitioners. To ensure that systems are maximally effective, they, like the practice of the professionals they document, should continuously be assessed and revised. 

References 

[1] P. J. Guffey, M. Culwick, and A. F. Merry, “Incident Reporting at the Local and National Level,” International Anesthesiology Clinics, vol. 52, no. 1, pp. 69-83, Winter 2014. [Online]. Available: https://doi.org/10.1097/AIA.0000000000000008.  

[2] R. P. Dutton, “Improving Safety Through Incident Reporting,” Current Anesthesiology Reports, vol. 4, pp. 84-89, January 2014. [Online]. Available: https://doi.org/10.1007/s40140-014-0048-7. 

[3] J. C. de Graaff et al., “Anesthesia-related critical incidents in the perioperative period in children; a proposal for an anesthesia-related reporting system for critical incidents in children,” Pediatric Anesthesia, vol. 25, no. 6, pp. 621-629, February 2015. [Online]. Available: https://doi.org/10.1111/pan.12623. 

[4] D. Arnal-Velasco and P. Barach, “Anaesthesia and perioperative incident reporting systems: Opportunities and challenges,” Best Practice & Research Clinical Anaesthesiology, vol. 35, no. 1, pp. 93-103, May 2021. [Online]. Available: https://doi.org/10.1016/j.bpa.2020.04.013.  

[5] R. Botney, “Improving Patient Safety in Anesthesia: A Success Story?,” International Journal of Radiation Oncology – Biology – Physics, vol. 71, no. 1, supp. 1, pp. S181-2186, May 2008. [Online]. Available: https://doi.org/10.1016/j.ijrobp.2007.05.095.  

[6] C. M. Schulz et al., “Situation awareness errors in anesthesia and critical care in 200 cases of a critical incident reporting system,” BMS Anesthesiology, vol. 16, no. 4, pp. 1-10, January 2016. [Online]. Available: https://doi.org/10.1186/s12871-016-0172-7.  

[7] R. P. Dutton, “Making a Difference: The Anesthesia Quality Institute,” Anesthesia & Analgesia, vol. 120, no. 3, pp. 507-09, March 2015. [Online]. Available: https://doi.org/10.1213/ANE.0000000000000615.