Perioperative Neuroscience: Translational Research

Perioperative Neurosciences: Translational Research examines current clinical research focused on complications and the improvement of patient outcomes in neuroanesthesia and neurocritical care. The book addresses important translational topics including neuroanesthetics, pharmacogenomics, neuroprotection and neurotoxicity. In addition, it covers special considerations for topics such as stroke, traumatic brain injury and pain, as well as for specific patient populations like geriatric and pediatric.

• Addresses translational developments in pharmacogemonics, brain protection and neurotoxicity
• Discusses ethical concerns relevant to clinical research in perioperative neuroscience
• Collates insights from international experts in translating research to practice

• Language: English
• Publisher: Academic Press
• Release date: Feb 25, 2022
• ISBN: 9780323910040

Book preview

1

Introduction

Indu Kapoor, Charu Mahajan and Hemanshu Prabhakar,    Department of Neuroanesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Abstract

Translational research is the process of applying basic biology and clinical trials knowledge to techniques and interventions that address critical needs. This kind of research is designed to improve health care outcomes. In neurosciences, apart from neurosurgery and neurology, neuroanesthesia has also emerged as a super specialty discipline. There are several areas of interest where basic research needs to be translated to clinical benefits, which include pain modulation, neurotransmission, neurotoxicity, neuroprotection, cognitive awareness, spinal cord and cerebral blood flow, and neurotrauma. The neurotoxic and neuroprotective effects of anesthetic agents are the most commonly studied research areas in neuroanesthesia that have been further translated to the clinical setting. There are many more areas of interest for translational research in neurosciences like cognitive dysfunction, cerebral function monitoring, traumatic brain injury, pharmacogenomics etc., where translational research has immense scope, which may further help find answers to queries related to these fields.

Keywords

Translational research; neuanesthesia; neurosurgery; neurology; neurotrauma

Translational research is the process of applying basic biology and clinical trials knowledge to techniques and interventions that address critical needs. This kind of research is basically designed to improve health care outcomes. It consists of a team of experts who focus on translating useful information from laboratories to health care providers, institutes, and hospitals. Translational research can be of three types: T1—developing treatments and interventions; T2—testing the efficacy and effectiveness of these treatments and interventions; and T3—dissemination and implementation research for system-wide change. The term translational research was first used in the late 1990s.¹ In the last decades of the 20th century, discovery and spending in the basic medical sciences increased significantly, but the improvement in health care outcomes remained very slow. One of the major reasons was found to be the lag between basic discovery and the appearance of new drugs and treatments. This lag time ranged from 10–20 years and the cost for developing a successful drug was found to be very high.² Another important reason for this gap between discovery and clinical application was the decrease in the number of clinician-scientists. In response to that, there has been a drive for more clinician-scientists which should help close this time gap.³

Translational research and neurosciences

Translational research in the medical field has become an attractive word. Many research institutes and universities are increasingly developing their translational research credentials. In neurosciences, apart from neurosurgery and neurology, neuroanesthesia has also emerged as a superspeciality discipline for now nearly five decades.⁴ There are several areas of interest where basic research needs to be translated to clinical benefits, which include pain modulation, neurotransmission, neuro-toxicity, neuro-protection, cognitive awareness, spinal cord and cerebral blood flow, and neurotrauma.⁵ In the past, neuroanesthesiologists have conducted basic research in this field, but translating it to clinical settings has not been successful. However, it has been observed that some amount of research work in neuroanesthesia has been translated to actual clinical scenarios.⁶–¹⁴ The scope of translational research in neuroanesthesia is immense. The neuro-toxic and neuro-protective effects of anesthetic agents are the most commonly studied research areas that have been further translated to the clinical setting. Several studies have confirmed the immediate neurotoxic effect of anesthetic agents in immature rodents; however, these research papers did not study the long-term cognitive consequences in these animals.⁶,⁷ The rodent studies using isoflurane⁶ and sevoflurane⁷ have confirmed the early neurotoxicity at a cellular level but differed significantly with respect to long-term cognitive outcomes. However, behavioral deficits persisting into adulthood have been found in the clinical research using sevoflurane but not isoflurane. Among intravenous anesthetic agents like thiopental, propofol, ketamine, which act on either N-methyl-D-aspartate (NMDA) or gamma aminobutyric acid (GABA) receptors, studies suggest that when administered either alone or in combination to mice, they can also cause behavioral alterations in adulthood.⁸,⁹ Overall, this evidence suggests that different anesthetic agents with different molecular mechanisms of action can potentially increase cerebral apoptosis in rodents and can lead to long-lasting neuro-behavioral consequences. In an order to cause neurotoxicity, dosage and duration of administration of anesthetic agents should coincide with the brain growth spurt as well as the period of intense neurogenesis and synaptogenesis.¹⁰ These anesthetic agents produce excitotoxicity by acting on either GABA¹¹ or NMDA receptors. After the withdrawal of the NMDA blockers (ketamine), increased calcium influx could lead to both apoptotic and necrotic cell death.¹² It has been observed that the blockade of NMDA glutamate receptors for even for few hours can trigger widespread apoptotic neuro-degeneration in the developing rat brain.¹³ The early research examining the cerebral protective effect of drugs started with anesthetic agents. The first reports to suggest the cerebroprotective effect of anesthetic agents included sodium thiopental. During carotid endarterectomy, it has been observed that sodium thiopental might improve the neurological outcome.¹⁴ Michenfelder et al. examined the patterns of cerebral metabolism in a dog that continuously received thiopental.¹⁵ They found that the electroencephalogram (EEG) became isoelectric following the administration of thiopental, but that further dosages of thiopental thereafter did not result in further suppression of cerebral metabolism. He established the basic concept behind thiopental-induced suppression of cerebral metabolism. Thiopental also causes therapeutic inhibition of global protein synthesis, protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells.¹⁶ It has been observed that pharmacological agents that either act directly on GABAA receptors or modulate GABAA receptor activity (such as propofol, midazolam) are capable of reducing the severity of brain injury following ischemia in gerbils. It has been reported that at clinically relevant concentrations, propofol inhibits glutamate release by blocking current through sodium channels or by activating GABAA receptors. Studies have assessed that by intracerebroventricular administration of propofol, 3 or 10 mg/kg, although exhibits neuroprotection in transient global forebrain ischemia, the extracellular glutamate level during ischemia is not a major determinant of the neuroprotective activity of propofol.¹⁷ Furthermore, the glutamate receptor antagonists have been shown to protect rodents and cats from cerebral injury in both focal ¹⁸,¹⁹ and transient global ischemia ²⁰ models.

There are many more areas of interest for translational research in neurosciences like cognitive dysfunction, cerebral function monitoring, traumatic brain injury, pharmacogenomics etc., where translational research has immense scope, which may further help find answers to queries related to these fields. Postoperative cognitive dysfunction is another unexplored research area where a good quality translational research can be planned, which may further help find an answer to queries related to cognitive functions and may help understand the conditions like aging, dementia, and Alzheimer’s disease.²¹,²² In the neurointensive care as well as in operation theaters, the need and the importance to preserve neuronal viability demands research into good technologies that have better sensitivity and specificity. In acute brain injury like traumatic brain injury, in comparison to primary insult, secondary insults play a significant role in increasing the morbidity and mortality of the patients. As of now, there is no definitive therapy that restores the neuronal integrity after traumatic brain injury and that calls for translational research with an aim to prevent secondary injury. With regard to translational research in cerebral function monitoring, its need of the hour since the existing monitors are cumbersome, expensive, invasive with limited sensitivity and specificity. The importance to preserve neuronal viability during surgery and also in the neuro-intensive care units demands research into newer, innovative non-invasive, inexpensive technologies that have better sensitivity and specificity. If we talk about pharmacogenomics, the study of the effect of drugs based on the individual genetic profile of the patient, in recent years there has been evidence that anesthetic drugs, their action, and their side effects are dependent on genetic polymorphism. It has been observed that genetic factors do contribute to a majority of severe adverse drug reactions.²³ Days are not far when anesthetics will be chosen on the basis of the genetic profile of the patient in order to avoid any unwanted side effects.²⁴ About mechanical ventilation in patients with neurological diseases like Guillain–Barre syndrome and myasthenia gravis, research done during 1950s European polio epidemics may be considered a pioneering effort at translational science that paved the way for mechanical ventilation to save lives of patients with reversible neuromuscular diseases.²⁵,²⁶ The successful ventilation strategies in these patients in present times in neurological practice are only because of the translational work of those early years.

In conclusion, we can say that translational research has improved the efficiency of health care providers in past. In the future, there will be much more progress in this field which will help medical research to excel beyond its scope and achieve a new height.

References

1. Butler D. Translational research: crossing the valley of death. Nature. 2008;453:840–842.

2. Collins FS. Reengineering translational science: the time is right. Sci Transl Med. 2011;3 90cm17.

3. Davidson A. Translational research: what does it mean?. Anesthesiology. 2011;115:909–911.

4. Michenfelder JD, Gronert GA, Rehder K. Neuroanesthesia. Anesthesiology. 1969;30:65–100.

5. Khan FA. Translational research and anesthesia. J Anaesthesiol Clin Pharmacol. 2014;30:151–152.

6. Loepke AW, Istaphanous GK, McAuliffe III JJ, et al. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009;108:90–104.

7. Satomoto M, Satoh Y, Terui K, et al. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009;110:628–637.

8. Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioural deficits. Anesthesiology. 2007;107:427–436.

9. Viberg H, Ponten E, Eriksson P, Gordh T, Fredriksson A. Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly. Toxicology. 2008;249:153–159.

10. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–882.

11. Ben-Ari Y. Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci. 2002;3:728–739.

12. Slikker Jr W, Zou X, Hotchkiss CE, et al. Ketamine induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98:145–158.

13. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283:70–74.

14. Wells BA, Keats AS, Cooley DA. Increased tolerance to cerebral ischemia produced by general anesthesia during temporary carotid occlusion. Surgery. 1963;54:216–223.

15. Michenfelder JD, ed. Anesthesia and the Brain. New York: Churchill Livingstone; 1988.

16. Schwer CI, Lehane C, Guelzow T, et al. Thiopental inhibits global protein synthesis by repression of eukaryotic elongation factor 2 and protects from hypoxic neuronal cell death. PLoS One. 2013;8:e77258.

17. Yano T, Nakayama R, Ushijima K. Intracerebroventricularpropofol is neuroprotective against transient global ischemia in rats: extracellular glutamate level is not a major determinant. Brain Res. 2000;883:69–76.

18. Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J. Focal cerebral ischaemia in the cat: treatment with the glutamate antagonist MK-801 after induction of ischaemia. J Cereb Blood Flow Metab. 1988;8:757–762.

19. Sarraf YS, Sheng H, Miura Y, et al. Relative neuroprotective effects of dizocilpine and isoflurane during focal cerebral ischemia in the rat. Anesth Analg. 1998;87:72–78.

20. Gill R, Foster AC, Woodruff GN. MK-801 is neuroprotective in gerbils when administered during the post-ischaemic period. Neuroscience. 1988;25:847–855.

21. Fodale V, Ritchie K, Rasmussen L, Mandal PK. Anesthetics and Alzheimer’s disease: Background and research. Preface J Alzheimers Dis. 2010;22(1-3):57.

22. Fodale V, Santamaria LB, Schiffilliti D, Mondal PK. Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s disease. Anaesthesia. 2010;65:388–395.

23. Chidambaran V, Ngamprasertwong P, Vinks AA, Sadhasivam S. Pharmacogenetics and anesthetic drugs. Curr Clin Pharmacol. 2012;7:78–101.

24. Mikstacki A, Skrzypczak ZM, Tamowicz B, Zakerska BO, Szalata M, Slomski R. The impact of genetic factors on response to anaesthetics. Adv Med Sci. 2013;58:9–14.

25. Sund KH, Lunding M. Two early Danish respirators designed for prolonged artificial ventilation. Acta Anaesthesiol Scand Suppl. 1978;67:96–105.

26. Haglund G. Respiratory treatment in polio epidemics 1953-1961. Acta Anaesthesiol Scand Suppl. 1962;12:25–29.

2

Basic principles of translational research

Yusuke Naito and Masahiko Kawaguchi,    Department of Anesthesiology, Nara Medical University, Kashihara, Japan

Abstract

This chapter outlined the basic principles of translational research that include a vast array of research methods and researchers, in which basic research is initiated based on clinical needs that are subsequently offered to society as resolutions to a problem. For the effective promotion of translational research, it is important to understand the gaps that exist between each study.

Keywords

History; ethics; carrier; education; current concept

Introduction to translational research

The COVID-19 outbreak that was reported at the end of 2019 rapidly caused a pandemic, resulting in many hospitalizations and halting economic activity. Although governments and health organizations have proposed effective measures as of 2020, including limiting social activities (e.g., maintaining a social distance and locking down cities), prevention methods (e.g., face masks and face shields), and therapeutic agents (e.g., remdesivir and dexamethasone), the pandemic has yet to be resolved. Under these circumstances, the development of an effective vaccine has become of primordial importance, but this development can take many years, up to a decade, before it can be released to the market. However, due to high social demands and large research investments, some countries approved compassionate distribution by the end of 2020 and several countries expected to introduce the vaccine by 2021. Research that begins on the basis of such high social demands, and that will contribute to actual clinical practice and society, is called translational research (TR). Morris et al. noted that it takes an average of 17 years for a basic research project to transition through clinical research and be fully translated into day-to-day clinical practice, and that many of these projects are buried along the way without ever being adopted into daily practice.¹ Therefore, the ultimate mission of TR is to clarify and remove obstacles, and shorten this lengthy study/application period. The purpose of this chapter is to outline the existing TR and overview its history, current concepts, ethical issues, and education to determine the gaps within the studies and effectively promote the significance of such research.

What is translational research?

According to the current definition, TR is a series of studies starting with questions arising from clinical practice, followed by basic research, and ending with research that provides benefits to society. This broad definition encompasses a wide array of processes and research, including basic research, animal testing, propagating research results, research focused on human application, comparisons with existing treatments, clinical guideline development, collaborations with manufacturers, epidemiological studies, promoting patients’ behavioral changes, reflecting research results in policy, and stimulating research in peripheral areas. In this section, we describe TR using Gruentig’s research in coronary catheterization, one of the most famous examples of TR.

Currently, the standards of care for coronary artery stenosis are either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), the latter of which emerged first. In 1946, Veinberg reported on the endocardial implantation of the internal thoracic artery in 88 patients² and in 1967, Favaloro et al. successfully performed a direct anastomosis of the coronary arteries using the interposition method with the great saphenous vein graft, a method that is still used today.³ However, at that time, only the on pump CABG was performed, as knowledge on postoperative multidisciplinary management was lacking, and this frequently ended with complications and deaths, due to excessive surgical stress. Gruentzig, a former radiologist in Germany, tried to apply the concept of catheterization for atherosclerosis obliterans, proposed by Zeitler et al., to the treatment of coronary artery stenosis. After completing his clinical work, Gruentzig worked with his assistant and family in his kitchen to develop a high-pressure, low-volume balloon that could be used to open coronary arteries. Subsequent animal studies showed that coronary artery patency was possible and this originated the current percutaneous old balloon angioplasty, representing the first step of TR, from bedside to bench. He presented the results at the 50th American Heart Association Scientific Session and actively gave live demonstrations, teaching the technique to physicians all over the world, which quickly spread the method (results