There is a significant need for cost-effective, suitable equipment for anesthesia providers in low-resource areas.² Low-resource settings are mostly found in countries defined by the World Bank as low-income countries.¹ However, it is important to highlight that low-resource settings and low-income countries are not always synonymous, as there exist resource inequalities within countries.¹ As Michael Dobson points out in his book Anesthesia at the District Hospital, “good anesthesia depends much more on the skills, training, and standards of the anesthetist than on the availability of expensive and complicated equipment.² Special consideration must be given to the suitability of anesthesia equipment in economically challenged settings so anesthesiologists can administer safe and effective care to patients.² 

In areas with sufficient resources, anesthesia machines are high-tech workstations which necessitate a stable electricity supply and compressed gases (like oxygen).² They contain sophisticated controls and can deliver a wide range of anesthetics to patients.² The issue is that this equipment requires highly trained and skilled biomedical technologists for service and maintenance.² In low-resource settings, where electricity is variable and compressed gasses are rare, these machines are nonfunctional.² Therefore, anesthesiologists working in low-resource areas must depend on a different type of anesthesia equipment.² The exact requirements for providing safe anesthesia in resource-poor settings have never been properly defined.³ Guidelines published in 1993 by the World Federation of Societies of Anesthesiologists have been the best recommendations to follow.³ The basic requirements for administering anesthesia in low-resource settings include the equipment for delivering the anesthetic, a monitoring apparatus, a cannula, rubber gloves, and medications (both anesthetic and emergency drugs).³ 

Although there has been significant reduction in anesthesia-related perioperative mortality in the last 50 years, patients undergoing surgery in low-resource areas still have two to three times increased mortality risk compared with high-resource areas.⁴ In the presence of limited financial and logistical resources, anesthesiologists often administer the same anesthetic agents irrespective of type of surgical procedure, which contributes to the increase in anesthetic-related morbidity and mortality seen in resource-deficient areas.⁴ Researchers in the Ivory Coast have pushed for expanding the use of spinal anesthesia in low-resource settings, as opposed to general anesthesia.⁵ In addition to its cost-effectiveness, spinal anesthesia acts locally, helping to prevent airway-related complications.^4,5 In low-resource areas, more focus on spinal anesthesia may prevent anesthesia-related morbidity and mortality.⁵ 

Furthermore, according to the Lancet Commission on Global Surgery, more than 90% of people in resource-poor areas do not have access to emergency or essential surgery.⁶ Interestingly, the primary limitation is not trained surgeons or operating rooms.⁶ Instead, it is inadequate anesthesia services, known as the “anesthesia gap”, that often results in absent or delayed surgical care.⁶ Researchers at Harvard University have advocated for the emergency use of ketamine in low-resource settings, as a short-term solution to the anesthesia gap.⁶ Ketamine is safer than most anesthetics because ventilation is typically well maintained and life-threatening hemodynamic disturbances are rare.⁶ Also, it can be administered in an emergency situation by non-anesthetist experienced providers.⁶ In a prospective series of more than 1,200 surgical cases in Kenya, there were no deaths or serious complications related to ketamine anesthesia.⁷ Ketamine is not designed to compete with formal anesthesia services, but can be used in emergency situations in low-resource settings where there are no reasonable alternatives.^6,7 

Widespread, safe anesthesia is achievable, but it requires a commitment by health systems to provide anesthesiologists with the basic requirements for anesthesia.³ In working to close the anesthesia gap, it is important to recognize the unique challenges presented by low-resource settings.³ 

References 

1. Baker, T. (2015). Critical Care in Low Resource Settings. Karolinska Institutet. https://doi.org/10.1007/978-1-4939-0811-0_16 
2. Roth, R., Frost, E., Gevirtz, C., & Atcheson, C. (2015). The Role of Anesthesiology in Global Health. Springer International Publishing. ISBN: 978-3-319-09422-9 
3. McCormick, B., & Eltringham, R. (2007). Anaesthesia equipment for resource-poor environments. Anaesthesia, 62(2), 54-60. https://doi.org/10.1111/j.1365-2044.2007.05299.x 
4. Bharati, S., Chowdhury, T., Gupta, N., Schaller, B., Cappellani, R., & Maguire, D. (2014). Anaesthesia in underdeveloped world: Present scenario and future challenges. Niger Med J, 55(1), 1-8. https://doi.org/10.4103/0300-1652.128146 
5. Mgbakor, A., & Adou, B. (2011). Plea for greater use of spinal anaesthesia in developing countries. Tropical Doctor, 42(1), 49-51. https://doi.org/10.1258/td.2011.100305 
6. Suarez, S., Burke, T., Yusufali, T., Makin, J., & Sessler, D. (2018). The role of ketamine in addressing the anesthesia gap in low-resource settings. Journal of Clinical Anesthesia, 49, 42-43. https://doi.org/10.1016/j.jclinane.2018.06.009 
7. Burke, T., Suarez, S., Senay, A., Masaki, C., Rogo, K., & Sessler, D. et al. (2017). Safety and Feasibility of a Ketamine Package to Support Emergency and Essential Surgery in Kenya when No Anesthetist is Available: An Analysis of 1216 Consecutive Operative Procedures. World J Surg, 41(12), 2990-2997. https://doi.org/10.1007/s00268-017-4312-0 

A mechanical ventilator is a device that supports breathing by moving air into or out of a patient’s lungs. Mechanical ventilation is one of several treatments for respiratory failure, but long-term ventilator use can cause lung damage [1]. When a patient is deemed ready, they are weaned from ventilation, ideally recovering their normal, spontaneous breathing faculties [2]. However, multiple factors in the weaning process can lead to higher risk of failure, including the patient’s underlying conditions, the specialist’s handling of the recovery process, and the specific type (also called “mode”) of ventilator used [2]. Advances in ventilator technology play a crucial role in improving the safety of mechanical ventilation, such as by facilitating weaning. In particular, neurally adjusted ventilatory assist may improve patient outcomes.  

Many modes of ventilation follow a “partial assist” model: the patient initiates a breath, and the ventilator detects this attempt and provides assistance, resulting in a full breath. The most common example is the “pressure support ventilation” mode (PSV), where the ventilator detects pressure changes to determine breathing attempts [3]. In contrast, the mode called “neurally adjusted ventilatory assist” (NAVA) measures the electrical activity of the diaphragm, using an array of electrodes inserted into the esophagus across from the diaphragm [4]. Diaphragm movement is more accurate than changes in air pressure for detecting a patient’s attempted breaths.  

The accuracy of detected breaths is correlated with better patient outcomes. In the literature, “asynchrony” refers to a mismatch between patient respiratory efforts and ventilator assists. For instance, when the patient inhales, their ventilator should respond promptly with an inhalation assist. Otherwise, when the patient exhales, their ventilator might still be inhaling, leading to “wasted energy expenditure” [5]. Consequences include stress or injury on the patient’s diaphragm, errors in the assessment of patient readiness, and worse overall outcomes [5]. If NAVA is more accurate than other modes, it has the potential to improve patient recovery, weaning, and outcomes.  

NAVA was invented in 1999, but it began appearing in clinical trials around the late 2000s. Researchers sought to compare it against a proven baseline: PSV. A study from 2010 evaluated eleven patients with acute respiratory distress syndrome, finding that NAVA reduces asynchrony, stabilizes the volume of breaths, and improves patient-ventilator interactions [6]. An unaffiliated study from 2011 agreed that NAVA reduced asynchrony among patients with acute respiratory failure [7]. However, neither study assessed patient outcomes directly, a task left to later research.  

In 2016, researchers in France studied 128 adults across 11 ICUs, comparing their outcomes and experiences with NAVA. Like previous studies, they concluded that NAVA reduces asynchrony. After leaving the ventilator, patients using NAVA reported less shortness of breath, and they were less likely to return to ventilation, compared to patients using PSV. However, NAVA did not reduce the duration of ventilation [8]. This finding conflicts with research from 2020 on Chinese patients considered “difficult to wean” from ventilation. For this subset of struggling patients, NAVA reduced the duration of ventilation and increased the proportion of patients with successful weaning [9]. These findings suggest that, overall, NAVA is effective in weaning patients and supporting their outcomes.  

The future of NAVA appears promising, but current research has yet to explore several possibilities. First, a cost-benefit analysis could determine if providers should adopt NAVA on a wider scale. Second, clinical trials with other respiratory conditions, including severe cases of COVID-19, might improve the clinical credibility of NAVA. Finally, a redesign of NAVA could measure the brain’s respiratory center instead of the diaphragm, potentially increasing measurement accuracy and improving outcomes further.  

References 

[1] Respiratory Failure. (N.d.) Retrieved September 25, 2020 from https://www.nhlbi.nih.gov/health-topics/respiratory-failure.  

[2] Boles J.-M., et al. Weaning from Mechanical Ventilation. European Respiratory Journal 2007; 29: 5. DOI: 10.1183/09031936.00010206.  

[3] Dosch M.P. and Tharp D. The Anesthesia Gas Machine. March 2016. College of Health Professions, University of Detroit Mercy. Retrieved September 25, 2020 from https://healthprofessions.udmercy.edu/academics/na/agm/08.htm.  

[4] Sinderby C., et al. Neural Control of Mechanical Ventilation in Respiratory Failure. Nature Medicine 2000; 5: 12. DOI: 10.1038/71012.  

[5] Thille A.W., et al. Patient-Ventilator Asynchrony during Assisted Mechanical Ventilation. Intensive Care Medicine 2006; 32. DOI: 10.1007/s00134-006-0301-8.  

[6] Terzi N., et al. Neurally Adjusted Ventilatory Assist in Patients Recovering Spontaneous Breathing after Acute Respiratory Distress Syndrome: Physiological Evaluation. Critical Care Medicine 2010; 38: 9. DOI: 10.1097/CCM.0b013e3181eb3c51.  

[7] Piquilloud L., et al. Neurally Adjusted Ventilatory Assist Improves Patient-Ventilator Interaction. Intensive Care Medicine 2011; 37. DOI: 10.1007/s00134-010–2052–9.  

[8] Demoule A., et al. Neurally Adjusted Ventilatory Assist as an Alternative to Pressure Support Ventilation in Adults: A French Multicentre Randomized Trial. Intensive Care Medicine 2016; 42. DOI: 10.1007/s00134-016–4447–8.  

[9] Liu L., et al. Neurally Adjusted Ventilatory Assist versus Pressure Support Ventilation in Difficult Weaning: A Randomized Trial. Anesthesiology 2020; 132. DOI: 10.1097/ALN.0000000000003207.  

Over the past three decades, concerns about protecting patients’ rights have led to the passage of legislation meant to ensure the safety and privacy of patients. In particular, laws such as HITECH, GINA, HIPAA and EMTALA are meant to protect the privacy of patient data, provide patients with the autonomy to control the distribution of their data, and safeguard against discrimination based on that information.  

The Emergency Medical Treatment and Active Labor Act (EMTALA) was enacted in 1986 and required hospitals to care for and treat patients, regardless of their ability to pay. The law was created in response to patient dumping, a practice common in the mid-20th century where poor or uninsured patients were transferred from hospital to hospital because of their inability to pay [1]. A landmark 1984 study by Himmelstein et al. found that 97% of patients transferred to public hospitals had no insurance or were government-insured [2]. With the passage of EMTALA, hospitals were required to treat emergency conditions, as defined by the bill, and stabilize patients before releasing them. Failure to do so can result in a penalty of up to $50,000 for both hospitals and physicians. Importantly, malpractice insurance does not usually cover the fine, meaning that physicians who violate EMTALA must pay the fee out of their own pocket [3]. 

The Health Insurance Portability and Accounting Act (HIPAA) was passed in 1996. Building off of the foundational belief that patients have a right to keep personal health information private, HIPAA developed a privacy framework for a digital age. With informational tools such as privacy notices and requirements for detailed authorization requests, HIPAA was meant to inform patients about how their data would be shared [4]. Importantly, the act set a federal minimum for the protection of patient data, which individual states could then develop accordingly. 

As genetic testing and sequencing developed in the 1990s and early 2000s, it became apparent that legislation to protect patients would need to cover genetic information, as well. In 2008, lawmakers passed the Genetic Information Nondiscrimination Act (GINA), which prohibited health insurers and employers from requiring genetic tests, requesting genetic information from patients, or discriminating based on that information. While some of these restrictions were set in place by HIPAA, they were strengthened and standardized under GINA. A paper by Hudson et al. noted that GINA would likely reduce the “fear factor” associated with genetic information, making it more likely that patients would participate in studies that collect genetic information [5]. 

The Health Information Technology for Economic and Clinical Health Act (HITECH), which was signed into law in 2009, was primarily meant to accelerate the adoption of electronic health records (EHR). The law was fairly successful — a study by Adler-Milstein and Jha found that adoption of EHR among eligible hospitals rose from 3.2% before the passage of HITECH to 14.2% after the law was passed [6]. The HITECH Act also allowed patients to access their EHR which, coupled with increased adoption of EHR at medical facilities, made it easier for individuals to share their health data across organizations. 

One of the most recent legislative additions to the patient protection framework is the Patient Protection and Affordable Care Act, which became law in 2010. The law extended Medicaid enrollment to around 15 million people with the ultimate goal of ensuring all Americans were covered by health insurance. While healthcare coverage is the best-known part of the law, ACA also included legislation aimed at improving care to underserved populations and making information about the cost of healthcare more transparent [7]. While parts of the policy, like the individual mandate, have since been rolled back, many of the patient protection measures remain in place. 

References 

[1] Mayere Lee, Tiana. “An EMTALA Primer: The Impact of Changes in the Emergency Medicine Landscape on EMTALA Compliance and Enforcement.” Annals of Health Law, vol. 13, no. 1, 2004, pp. 145–178., https://lawecommons.luc.edu/cgi/viewcontent.cgi?article=1231&context=annals. 

[2] Himmelstein, D U, et al. “Patient Transfers: Medical Practice as Social Triage.” American Journal of Public Health, vol. 74, no. 5, 1984, pp. 494–497. doi:10.2105/ajph.74.5.494. 

[3] Zibulewsky, Joseph. “The Emergency Medical Treatment and Active Labor Act (Emtala): What It Is and What It Means for Physicians.” Baylor University Medical Center Proceedings, vol. 14, no. 4, 2001, pp. 339–346. doi:10.1080/08998280.2001.11927785. 

[4] Annas, George J. “HIPAA Regulations — A New Era of Medical-Record Privacy?” The New England Journal of Medicine, vol. 348, no. 15, 10 Apr. 2003, pp. 1486–1490. doi:10.1056/NEJMlim035027. 

[5] Hudson, Kathy L., et al. “Keeping Pace with the Times — The Genetic Information Nondiscrimination Act of 2008.” New England Journal of Medicine, vol. 358, no. 25, 2008, pp. 2661–2663. doi:10.1056/nejmp0803964. 

[6] Adler-Milstein, Julia, and Ashish K. Jha. “HITECH Act Drove Large Gains In Hospital Electronic Health Record Adoption.” Health Affairs, vol. 36, no. 8, 2017, pp. 1416–1422. doi:10.1377/hlthaff.2016.1651. 

[7] Rosenbaum, Sara. “The Patient Protection and Affordable Care Act: Implications for Public Health Policy and Practice.” Public Health Reports, vol. 126, no. 1, 2011, pp. 130–135. doi:10.1177/003335491112600118. 

Anesthesia for cesarean section commonly involves a single-shot spinal injection of local anesthetic with opioid included to cover postoperative pain as part of a multimodal analgesic pathway. Intrathecal preservative-free morphine is considered the gold-standard for post–cesarean analgesia by obstetric anesthesiologists given its low-risk profile; however, hydromorphone has gained attention as an alternate agent due to drug shortages. 

Hydromorphone was chosen partly due to its hydrophilicity, which causes it to persist within the cerebrospinal fluid (CSF) for several hours, providing bimodal analgesia at the segmental and supraspinal levels. Lipophilic opiates such as fentanyl and sufentanil diffuse more quickly, exhibiting a rapid segmental effect with more systemic uptake, making them less ideal in this setting. Dosing studies have shown that the effective intrathecal dose (ED90) for morphine and hydromorphone are 150mcg and 75mcg respectively for post-cesarean analgesia [8]. 

While several retrospective studies have compared the two drugs when administered in the central nervous system, there is only one prospective study published on this subject to date. Observational studies were performed by multiple groups including Beatty et al., who found no significant difference in patient pain between intrathecal morphine 100mcg and hydromorphone 40mcg. However, it is important to note these doses are not necessarily equipotent and standard guidelines for equianalgesic dosing of the two drugs in the intrathecal space are not yet available. The morphine dose was chosen based on prior studies showing absence of analgesic benefit for intrathecal doses above 75mcg, while the hydromorphone dose was merely the most common dose among participating providers [3].

Based on dosing studies by Rathmell et al. and later Sviggum et al., a 2:1 conversion ratio is commonly selected, however this ratio needs further validation [7][8]. In June 2020, Sharpe et al. published a randomized clinical trial comparing intrathecal opioids (150mcg morphine vs. 75mcg hydromorphone), and reported similar pain scores through 36 hours postpartum and no difference in breakthrough analgesics given. Regarding side effects, there was no difference in incidence of nausea/vomiting or moderate or severe sequelae. The median difference in time to first opioid dose was not statistically significant but may be relevant clinically given the 5h span for hydromorphone compared to 12h for morphine. There was also a notable difference in postpartum opioid consumption that did not reach statistical significance, possibly indicating a need for more power in this study [6]. 

It is important to note that, while the pharmacokinetic profile of hydromorphone (hydrophilicity, less rostral spread) would theoretically imply less incidence of nausea or respiratory depression, studies have not supported this hypothesis. Given how infrequent episodes of respiratory depression are in the postpartum setting, there is simply not enough data at this point to properly evaluate the comparative safety of intrathecal hydromorphone. In 2019, the Society of Obstetric Anesthesia and Perinatology published a consensus stating that intrathecal morphine is preferred if readily available given the paucity of data on intrathecal hydromorphone’s safety profile [2]. Furthermore, studies are limited by the lack of a standard method for comparing intrathecal opioid doses. Until a standard conversion ratio for intrathecal opiates becomes available, comparative studies will remain limited by lack of verification that equianalgesic doses of intrathecal opioid are being administered. Statistical differences may be found in future analyses if additional research changes the current 2:1 conversion ratio. 

References 

1. Abboud TK, Dror A, Mosaad P, et al. Mini-dose intrathecal morphine for the relief of post-cesarean section pain: Safety, efficacy, and ventilatory responses to carbon dioxide. Anesth Analg. 1988;67(2):137-143. 
2. Bauchat JR, Weiniger CF, Sultan P, et al. Society for obstetric anesthesia and perinatology consensus statement: Monitoring recommendations for prevention and detection of respiratory depression associated with administration of neuraxial morphine for cesarean delivery analgesia. Anesth Analg. 2019;129(2):458-474. doi:10.1213/ANE.0000000000004195.
3. Beatty NC, Arendt KW, Niesen AD, Wittwer ED, Jacob AK. Analgesia after cesarean delivery: A retrospective comparison of intrathecal hydromorphone and morphine. J Clin Anesth. 2013;25(5):379-383. doi:10.1016/j.jclinane.2013.01.014.
4. Marroquin B, Feng C, Balofsky A, et al. Neuraxial opioids for post-cesarean delivery analgesia: Can hydromorphone replace morphine? A retrospective study. Int J Obstet Anesth. 2017;30:16-22. doi:10.1016/j.ijoa.2016.12.008.
5. Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg. 2005;101(5 Suppl):30. doi:10.1213/01.ane.0000177101.99398.22.
6. Sharpe EE, Molitor RJ, Arendt KW, et al. Intrathecal morphine versus intrathecal hydromorphone for analgesia after cesarean delivery: A randomized clinical trial. Anesthesiology. 2020;132(6):1382-1391. doi:10.1097/ALN.0000000000003283.
7. Sultan P, Halpern SH, Pushpanathan E, Patel S, Carvalho B. The effect of intrathecal morphine dose on outcomes after elective cesarean delivery: A meta-analysis. Anesth Analg. 2016;123(1):154-164. doi:10.1213/ANE.0000000000001255.
8. Sviggum HP, Arendt KW, Jacob AK, et al. Intrathecal hydromorphone and morphine for postcesarean delivery analgesia: Determination of the ED90 using a sequential allocation biased-coin method. Anesth Analg. 2016;123(3):690-697. doi:10.1213/ANE.0000000000001229.

Dexmedetomidine (DEX) is an α2 adrenoceptor agonist that is commonly administered before general anesthesia as a short-term sedative [1–3]. In this setting, dexmedetomidine has several well-studied benefits, most notably a reduction in the need for opioids during surgical procedures while producing sedation and analgesia throughout the entire perioperative period, as well as an elimination of otherwise common post-surgical respiratory depression [1–2]. Patients under the effect of dexmedetomidine retain psychomotor functions without sacrificing comfort, allowing for cooperation and physiological arousal [2]. First approved for ICU use in December 1999 and used at Baylor University Medical Center in August 2000, dexmedetomidine is commonly sold under the trade name Precedex today [2–3]. 

As an α2 adrenoceptor agonist, dexmedetomidine targets presynaptic receptors in the peripheral and central nervous systems, as well as in platelets, the pancreas, eyes, kidneys, and liver [2]. Via a negative feedback mechanism, this imidazole compound regulates norepinephrine and adenosine triphosphate levels [2]. α2 receptor agonists activate guanine-nucleotide regulatory binding proteins that activate cellular responses through two primary methods: the modulation of ion channel activity or the firing of a second messenger system [2]. The former of these methods produces the hyperpolarization of the cell membrane, facilitating the expulsion of potassium and, consequently, suppressing neuronal activity [2]. 

Dexmedetomidine differs from other means of sedation because of the combined effects of presynaptic and postsynaptic α2 adrenoceptor activation [2]. Presynaptic activation preserves norepinephrine levels, effectively stifling pain signals, while postsynaptic activation centralized in the central nervous system contributes to reduced sympathetic activity [2]. These two forms of activation enable dexmedetomidine to become a singular source of sedation, anxiolysis, and analgesia [2]. Consequently, some of the challenges associated with the administration of several disparate medications are eliminated [2]. However, despite this knowledge, dexmedetomidine’s analgesic mechanisms are not yet fully understood [4]. 

In anesthetic contexts, dexmedetomidine can be administered intravenously or intrathecally, although intravenous administration is more common [1]. Numerous studies have revealed that dexmedetomidine can result in as much as a 50% decrease in opioid consumption through the surgical process [4–5]. When managing refractory cancer pain, combined treatments consisting of dexmedetomidine and opioids have even been considered optimal in terms of analgesic effects in comparison to opioid-only treatments [6]. Additional noted effects, including diminished delirium in non-cardiac surgeries in elderly patients [7], improved recovery after laparoscopic colectomy [8], and reduced depression rates following cancer treatment [1], demonstrate the widespread benefits of this agonist. 

However, it is important to note the side effects previously observed following dexmedetomidine administration, including hypotension, hypertension, nausea, bradycardia, and dry mouth [2]. These side effects were observed immediately during or following loading; consequently, they can be diminished by controlling the loading dose [2]. Additionally, patients might be afflicted by withdrawal, similar to that associated with clonidine, following treatment [2]. 

Scientists continue to investigate the power of dexmedetomidine use, particularly concerning its effects on children. A notable recent study [9] demonstrated how dexmedetomidine can reduce inflammatory factors and ameliorate cardiopulmonary bypass-resultant neurodevelopmental damage when treating adolescent congenital heart disease. Another study [10] compared how minimal dosages of dexmedetomidine and midazolam prevented emergency delirium in children following exposure to sevoflurane anesthesia. Although both medications had equal efficacy when administered at the end of surgical procedures, dexmedetomidine had significantly higher postoperative efficacy. 

Evidently, the extent of dexmedetomidine’s potential is still being discovered by the scientific community and, thus, the medication remains a powerful tool in the anesthetic sphere. 

References 

[1] Huang, G., Liu, G., Zhou, Z. et al., “Successful Treatment of Refractory Cancer Pain and Depression with Continuous Intrathecal Administration of Dexmedetomidine and Morphine: A Case Report,” Pain and Therapy, vol. 9, no. 1, July 2020. [Online]. Available: https://doi.org/10.1007/s40122-020-00183-3. [Accessed Aug 9, 2020]. 

[2] Gertler, R., Brown, H. C., Mitchell, H., Silvius, E., “Dexmedetomidine: A Novel Sedative-Analgesic Agent,” Baylor University Medical Center Proceedings, vol. 14, no. 1, p. 13-21, 2001. [Online]. Available: https://doi.org/10.1080/08998280.2001.11927725. [Accessed Aug 9, 2020]. 

[3] Sassi, M. et al, “Safety in the Use of Dexmedetomidine (Precedex) for Deep Brain Stimulation Surgery: Our Experience in 23 Randomized Patients,” Neuromodulation: Technology at the Neural Interface, vol. 16, no. 5, p. 401-407, Jan 2013. [Online]. Available: https://doi.org/10.1111/j.1525-1403.2012.00483.x. [Accessed Aug 9, 2020]. 

[4] Sadhasivam, S., Boat, A., Mahmoud, M.., “Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children,” Journal of Clinical Anesthesia, vol. 21, no. 7, p. 493-501, Dec. 2009. [Online]. Available: https://doi.org/10.1016/j.jclinane.2008.12.017. [Accessed Aug 9, 2020]. 

[5] Wallace, S., Mecklenburg, B., Hanling, S., “Profound Reduction in Sedation and Analgesic Requirements Using Extended Dexmedetomidine Infusions in a Patient With an Open Abdomen,” Military Medicine, vol. 174, no. 11, p. 1228-1230, Nov. 2009. [Online]. Available: http://doi.org/10.7205/MILMED-D-00-6009. [Accessed Aug 9, 2020]. 

[6] Roberts, S, Wozencraft, C., Coyne, P., Smith, T.., “Dexmedetomidine as an Adjuvant Analgesic for Intractable Cancer Pain,” Journal of Palliative Medicine, vol. 14, no. 3, p. 371-373, Mar. 2011. [Online]. Available: http://doi.org/10.1089/jpm.2010.0235. [Accessed Aug 9, 2020]. 

[7] Pan, Hao, Chengxiao Liu, Xiaochun Ma, Yanbing Xu, Mengyuan Zhang, and Yan Wang, “Perioperative Dexmedetomidine Reduces Delirium in Elderly Patients after Non-Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials,” Canadian Journal of Anesthesia/Journal Canadien d’anesthésie, vol. 66, no.12, p. 1489, Dec. 2019. [Online]. Available: http://doi.org/10.1007/s12630-019-01440-6. [Accessed Aug 9, 2020]. 

[8] Pan, W., Liu, G., Li, T., Sun, Q., Jiang, M., Liu, G., et al., “Dexmedetomidine combined with ropivacaine in ultrasound-guided tranversus abdominis plane block improves postoperative analgesia and recovery following laparoscopic colectomy,” Experimental and therapeutic medicine, vol. 19, no. 4, p. 2535-2542, Apr. 2020. [Online]. Available: http://dx.doi.org/10.3892/etm.2020.8508. [Accessed Aug 9, 2020]. 

[9] Yongsheng Qiu et al., “Effects of Dexmedetomidine on the Expression of Inflammatory Factors in Children with Congenital Heart Disease Undergoing Intraoperative Cardiopulmonary Bypass: A Randomized Controlled Trial,” Pediatric Investigation, vol. 4, no. 1, p. 23-28, Mar. 2003. [Online]. Available: http://doi.org/10.1002/ped4.12176. [Accessed Aug 9, 2020]. 

[10] Cho, E., Cha, Y., Shim, J. et al., “Comparison of single minimum dose administration of dexmedetomidine and midazolam for prevention of emergence delirium in children: a randomized controlled trial,” Journal of Anesthesia, vol. 34, p. 59-65, 2020. [Online]. Available: Springer Link, http://link.springer.com. [Accessed Aug 9, 2020].