bluuebunny/crossref_metadata_2025 huggingface dataset:
Case 10
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 45-year-old man with a total AVB after a Bentall procedure had been implanted with a dual-chamber PM. During follow-up, he experienced dizzy spells during moderate exercise.
Case 11
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient had undergone aortic valve replacement and was equipped with temporary epicardial pacing.
Case 13
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient had recently received a dual-chamber PM after mitral valve replacement.
Case 14
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient awaiting AVN ablation for rapidly conducted AF had a PM implanted.
Case 15
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 12-lead ECG recorded during a threshold test in a patient.
Case 19
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 12-lead ECG was recorded in a patient with HBP during a capture threshold test at implantation.
Case 23
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with complete AVB had been recently implanted with a dual-chamber PM with an atrial lead and a His lead. He presented with bouts of lightheadedness.
Case 25
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with slowly conducted AF and LBBB was implanted with LBBAP.
Case 27
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with intermittent third-degree AVB had a leadless Micra AV PM implanted. The device was programmed to VDD mode. Non-tracking of the P-waves was observed on the day following implantation.
Case 28
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with mitral valve prolapse and polymorphic VT with syncope was implanted with a dual-chamber ICD.
Case 32
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 34-year-old man is brought to the emergency room via ambulance reporting multiple conscious shocks from his device. He had a VVI ICD implanted 3 years previously for dilated cardiomyopathy with severe LV systolic dysfunction and haemodynamically unstable VT.
Case 35
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 35-year-old patient with dilated cardiomyopathy implanted with a CRT-D presented for follow-up. He complained of occasional palpitations.
Case 36
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with arrhythmogenic RV dysplasia and a VVI ICD implanted 5 years ago consulted the outpatient clinic after syncope.
Case 37
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

Remote monitoring was performed in a patient with a DDD ICD which had been implanted 9 years ago. Electrical parameters were normal, except for battery voltage which was reaching elective replacement indicator.
Case 39
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 53-year-old man attended the emergency department reporting shocks from his ICD followed shortly by syncope. Two weeks prior, he had been implanted with a single-chamber ICD for primary prevention of sudden death in the setting of hypertrophic cardiomyopathy. Past medical history included permanent AF.
Case 41
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 75-year-old male attends the device clinic having experienced dizziness for a few hours. He had a CRT-D implanted 2 weeks earlier for dilated cardiomyopathy with second-degree AVB.
Case 42
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 68-year-old man attends the pacing clinic following an unprovoked syncopal episode. He had a VVI ICD implanted 4 years previously for ischaemic cardiomyopathy (NYHA class II) with severe LV systolic dysfunction and normal QRS duration.
Case 43
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with dilated cardiomyopathy was implanted with a dual-chamber ICD for primary prevention of sudden death. The patient was asymptomatic. An arrythmia episode was retrieved from the device memory.
Case 44
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

An 18-year-old youth, implanted with a subcutaneous ICD for idiopathic VF, consulted after having received a shock preceded by palpitations. A stored event was retrieved from the device memory.
Case 46
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 30-year-old man with a hypertrophic cardiomyopathy and a history of non-sustained VT had been implanted with an S-ICD for primary prevention of sudden death. He consulted after having received a shock. A stored event was retrieved from the device memory.
Case 47
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 35-year-old woman implanted 2 years ago with an S-ICD for syncopal sustained polymorphic VT presented with a shock while practising yoga.
Case 48
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with a S-ICD received a shock while driving his car. He had no complaints preceding the shock.
Case 50
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with idiopathic VF and resuscitated sudden death was referred after having been implanted with an S-ICD. At implantation, the S-ICD failed to defibrillate induced VF at 65 J and 80 J, which required external defibrillation.
Case 51
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient implanted with a CRT-D was managed by remote monitoring.
Case 53
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with dilated cardiomyopathy, LV ejection fraction of 25%, and NYHA class II heart failure under optimal medical therapy was implanted with a CRT-D. She presented with worsening dyspnoea 8 weeks after implantation.
Case 56
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 67-year-old patient with a CRT-D was seen at follow-up. The patient complained of breathlessness upon exertion. Lead testing was normal. The patient underwent a treadmill test.
Case 57
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient complained of persistent heart failure symptoms 6 months after CRT implantation. Device follow-up showed excellent capture thresholds with 99% VP and no sustained arrhythmias. The paced AVI had been programmed at the default value of 130 ms.
Case 58
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with a CRT pacemaker presented to the out-patient clinic for routine device follow-up.
Case 59
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A patient with a CRT-P device was seen at device follow-up. He did not have any complaints.
Case 60
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 59-year-old man with a non-compaction cardiomyopathy and symptomatic heart failure had been implanted with a CRT-D. He presented for regular follow-up and did not report any complaints.
Case 62
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 67-year-old man with ischaemic cardiopathy, NYHA class II heart failure, and a wide QRS complex received a CRT-D for primary prevention of sudden cardiac death.
Case 65
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 45-year-old woman with non-ischaemic dilated cardiomyopathy, classified as NYHA class III, and reduced LVEF had been implanted with a cardiac resynchronization defibrillator. During follow-up, an event classified as CRT pacing interruption was transmitted by remote monitoring.
Case 68
Authors: Burri Haran , Johansen Jens Brock , Linker Nicholas J. , Theuns Dominic
Published: March 2022

A 62-year-old woman was admitted to the intensive care unit with acute pulmonary oedema requiring intubation. She had a past medical history of myocardial infarction with LVEF of 25%, NYHA class III heart failure, and LBBB for which an Abbott CRT-D had been implanted. The doctors on the intensive care unit were concerned as they saw intermittent loss of pacing spikes on telemetry.
Understanding early medical abortion
Authors: Parsons Jordan A. , Romanis Elizabeth Chloe
Published: March 2022

In this chapter, we consider the wider context of abortion care from a medical perspective. To do so, we explain various commonly practiced abortion methods. This is to situate early medical abortion within the range of available options—particularly in relation to surgical methods—and to aid in an understanding of how early medical abortion might map onto a telemedical care pathway. In discussing early medical abortion, we also detail the distinction between medical abortion and early medical abortion. We also examine the evidence regarding the safety, effectiveness, and acceptability of early medical abortion. Aside from clinical indications, we highlight why a person may prefer one method of abortion over another, particularly in terms of convenience and side effects. We demonstrate that whilst (early) medical abortion is preferable to many, there are important reasons why surgical methods might be chosen by some, and we must not disregard the value of these preferences.
Socio-legal barriers to early medical abortion
Authors: Parsons Jordan A. , Romanis Elizabeth Chloe
Published: March 2022

In this chapter, we illustrate how abortion law and regulation in the UK and US has constructed legal barriers to abortion access and prevented abortion providers from evolving service provision in line with best practice. Abortion ‘exceptionalism’ has resulted in significant limitations on access. Beyond the law, there are also many intersecting nonlegal barriers that prevent individuals obtaining abortions as broader social circumstances significantly limit access to treatment even where abortion is legal or lawfully available. In this chapter, we consider how these factors (geographical, social, and socioeconomic) intersect with the law to limit the capacity of individuals—particularly vulnerable minorities—in both the UK and US, to access abortion care.
Early medical abortion and the telemedical imperative
Authors: Parsons Jordan A. , Romanis Elizabeth Chloe
Published: March 2022

In this chapter, we advance our core case for telemedical provision of early medical abortion. Applying the ‘telemedical imperative’ framework, we argue that there is a moral duty for telemedical care to be introduced wherever possible. This is predicated on the safety and effectiveness of abortion care provided in this way, and the acceptability of telemedical abortion care pathways to patients—all of which are demonstrated. Further, we outline the lack of valid service-specific concerns by demonstrating how those that have been raised are empirically unfounded. Specifically, we examine potential issues surrounding clinic closures, safeguarding, and the dating of pregnancies. Finally, we consider the benefits of introducing telemedicine into early medical abortion provision. Beyond progress with health equality through the increased accessibility of abortion care, we argue that the addition of telemedicine can enhance patient autonomy and improve the efficiency of wider service provision.
Legal and policy restrictions on telemedical early medical abortion in the United States during COVID-19
Authors: Parsons Jordan A. , Romanis Elizabeth Chloe
Published: March 2022

In this chapter, we outline the failures of the federal and state governments in the US to enable remote abortion care during the COVID-19 pandemic. First, federal requirements that people must attend an abortion clinic for early medical abortion to be dispensed to them have constituted an absolute barrier to the establishment of telemedical provision nationwide, which the Supreme Court inadequately failed to recognise and enjoin. Second, there remain state barriers to telemedical early medical abortion that would have presented an obstacle even if federal requirements were lifted that must be addressed. Finally, we highlight how some state executives monopolised on the COVID-19 crisis to erect yet more barriers to abortion care. Whilst abortion access improved in Great Britain due to the pandemic because of telemedical provision, it is, unfortunately, a very different story in the US, in which people (especially vulnerable minorities) were effectively denied their constitutional right to privacy.
Conclusion
Authors: Parsons Jordan A. , Romanis Elizabeth Chloe
Published: March 2022

We began this book with some ambitious goals. Our overarching purpose has been to demonstrate the importance of TEMA, and to consider how TEMA has been and can be implemented effectively. In doing so, we have covered a lot of ground. Let us revisit some of the key points....
Overview: Ketogenic Diets and Pediatric Epilepsy
Authors: Kossoff Eric
Published: March 2022

When the classic ketogenic diet was created in 1921, now 100 years ago, it was one of the few treatments in existence for epilepsy. As a result, its use was widespread, and publications were plentiful. The advent of modern antiseizure drugs and lack of collaboration and mentorship by ketogenic diet experts in the field in the 1940s led to relative disuse of the ketogenic diet for many decades, however, until the Charlie Foundation reinvigorated interest and research in 1994. Today, there are five major diets available, there are myriad methods for starting and managing patients on this therapy, and growing numbers of adolescents and adults are being treated. This section, “Ketogenic Diet for Epilepsy in the Clinic” discusses all the advances in practical implementation of dietary therapy. In addition, chapters focus on the “indications” for dietary therapy that are both proven and investigational currently. Last, methods to prevent side effects are outlined. The section has been fully updated for the second edition.
Ketogenic Diet Therapies in Adults
Authors: Johnson Emily L. , Cervenka Mackenzie C.
Published: March 2022

Ketogenic diet therapy for epilepsy has been used in adults for over 100 years. Adults with medically refractory epilepsy as well as children on diet therapies transitioning to adult care need specialty providers to support diet use. About 20% to 60% of adults report at least a 50% improvement in seizure frequency on diet therapy, and many patients report improvement in cognition and other areas as well. Diet therapy is also used in status epilepticus, with resolution of refractory status epilepticus reported in over 70% of patients. Long-term cardiovascular effects and the effects of diet therapy in pregnancy are areas of ongoing study.
How Do You Implement the Diet?
Authors: Bergqvist A. G. Christina
Published: March 2022

How the ketogenic diet (KD) is implemented varies between centers. Some randomized published data now exist, to support implementation practices, differences are center specific and preference based. In an attempt to unify practices, a consensus statement was written in 2008 and was updated in 2018. The KD can be safely used in patients of all ages, can be modified for specific dietary needs, and can be administered as food, formula, or intravenous alimentation. Effectiveness, compliance, and minimization of side effects are achieved using a team-based, family-centered support structure. The KD is commonly initiated in an inpatient setting with a gradual increase in the fat content. A few centers still initiate the KD with a brief fast. Outpatient initiation with slower advancement to a full diet can be challenging but can be safely executed. Time to determine response and duration of treatment vary. Side effects are now better understood and best managed proactively by monitoring, but they cannot always be prevented and must be weighed against the benefits of continuing the therapy.
Ketogenic Diet for Other Epilepsies
Authors: Hsieh David T. , Thiele Elizabeth A.
Published: March 2022

The ketogenic diet is the treatment of choice for epilepsy in certain disorders of brain metabolism, particularly glucose transporter type 1 deficiency and pyruvate dehydrogenase deficiency. The International Ketogenic Diet Study Group has listed several other conditions for which the ketogenic diet has been reported as being consistently more beneficial than average and for which the diet could be offered earlier. Whether efficacy in these conditions is due in part to the broad-spectrum efficacy of the ketogenic diet or due to mechanisms specific to these conditions is still under investigation. This chapter covers the use of dietary therapies for the treatment of epilepsy in certain genetic disorders, including Angelman syndrome and tuberous sclerosis complex, as listed by the International Ketogenic Diet Study Group, and in addition the chapter considers the use of epilepsy dietary therapies in patients with Rett syndrome and Sturge-Weber syndrome.
The Ketogenic Diets in Genetic Generalized Epilepsy Syndromes
Authors: Kessler Sudha Kilaru
Published: March 2022

This chapter reviews the evidence for the effectiveness of the ketogenic diet and related therapies in idiopathic (genetic) generalized epilepsy. The discussion focuses chiefly on the two most common syndromes—childhood absence epilepsy and juvenile myoclonic epilepsy. Perhaps because the proportion of patients with genetic generalized epilepsy that have pharmacoresistant seizures is lower than for other epilepsy types, they constitute a small percentage of patients treated with the ketogenic diet and related therapies. However, for patients with genetic generalized epilepsy who are pharmacoresistant, limited evidence shows that the ketogenic diet can be an effective therapy.
Overview
Authors: Rho Jong M.
Published: March 2022

After a century of clinical use, the ketogenic diet is firmly established as a highly effective treatment for medically intractable epilepsy in both children and adults. Intriguingly, there is growing experimental evidence that the ketogenic diet and its metabolites also render neuroprotective and potentially disease-modifying effects. Hence, dietary and metabolic therapies have been attempted in a variety of neurologic disorders other than epilepsy, including malignant brain cancer, neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease, other cognitive disorders, autism spectrum disorder, neurotrauma, pain, and multiple sclerosis. More recently, a parallel approach has been taken to treat mental health disorders such as depression, anxiety, bipolar disorder, and even schizophrenia. This section, “Ketogenic Diet—Emerging Clinical Applications and Future Potential,” explores the current preclinical and clinical evidence for metabolism-based treatments designed to counter the myriad disease processes seen in many neurologic (and potentially psychiatric) conditions. Specific attention has been given to the effects of the ketogenic diet in malignant brain cancer, autism spectrum disorder, Alzheimer’s disease, traumatic brain and spinal cord injury, pain, and schizophrenia. Furthermore, the anti-inflammatory effects of the ketogenic diet and dietary effects on the gut microbiome are summarized.
Metabolism-Based Treatments for Managing Cancer
Authors: Seyfried Thomas N. , Mukherjee Purna , Chinopoulos Christos
Published: March 2022

Mounting evidence indicates that cancer is primarily a mitochondrial metabolic disease rather than a genetic disease. Abnormalities in cancer cell mitochondria impair oxidative phosphorylation, thus causing a gradual shift in cellular energy production from respiration to fermentation. Glucose and glutamine are the two major fermentable fuels for cancer cells. Glucose drives tumor growth through glycolysis in the cytoplasm, while glutamine drives tumor growth through glutaminolysis in the mitochondria. Restriction of fermentable fuels is therefore an effective therapeutic strategy for cancer management. Ketogenic metabolic therapy (KMT) lowers blood glucose while elevating blood ketone bodies, a “super fuel” for normal cells, but a nonfermentable fuel for cancer cells. The efficacy of KMT for cancer management can be enhanced when used together with glutamine-targeting drugs and procedures that further inhibit fermentation. Hence, KMT represents an alternative, nontoxic strategy for managing and preventing a broad range of cancers and could also be important in reducing healthcare costs in the emerging era of global budgeting.
Ketogenic Diet as Adjunctive Therapy for Malignant Brain Cancer
Authors: Scheck Adrienne C. , Syed Nelofer
Published: March 2022

Malignant brain tumors are devastating despite aggressive treatments, including surgical resection, chemotherapy, and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately 18 months, and increased survival requires the design of new therapeutic modalities, especially those that enhance currently available treatments. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacologic means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). Preclinical work has shown that the KD does indeed reduce tumor growth in vivo, and it reduces angiogenesis, inflammation, peritumoral edema, migration, and invasion. Furthermore, the KD can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of radiation. The pluripotent effects exhibited by ketogenic therapy may be due, in part, to epigenetic changes. The main ketone, β-hydroxybutyrate, is a class 1 histone deacetylase inhibitor, and we have shown that the expression of a number of microRNAs is altered in tumors of mice fed a KD compared to standard diet. Thus, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas.
Ketogenic Diet and Ketones for Improving Neurologic Outcomes after Acute Neurotrauma
Authors: Seira Oscar , Kolehmainen Kathleen L. , Plunet Ward T. , Yarar-Fisher Ceren , Tetzlaff Wolfram
Published: March 2022

Traumatic injuries to the brain and spinal cord have a global estimated incidence of several million people every year. Despite strong research efforts to find possible neuroprotective or neurorestorative therapies, treatment for people with neurotrauma is limited. For spinal cord injury (SCI), the standard of care is surgical stabilization followed by rehabilitation programs. Hence, there is an urgent need for treatments aiming to protect the nervous system from the secondary damage that occurs after the primary injury event. Preclinical data in rodents show that ketogenic diets (KDs) or ketone supplementation initiated after injury improves the outcomes from SCI or traumatic brain injury. This chapter describes the potential mechanisms by which KDs or ketone bodies provide protection after neurotrauma and reviews their current translation from the preclinical to the early clinical settings, where pilot trials in humans have shown promise.
Overview: Ketogenic Diet in the Laboratory
Authors: Boison Detlev
Published: March 2022

Clinical and public interests in the ketogenic diet and metabolic treatments continue to spur research into mechanisms underlying their anticonvulsant, neuroprotective, and antiepileptogenic efficacy. Opportunities beyond seizure control are being explored and discovered in basic, translational, and clinical research paradigms. The range of specific mechanisms includes transcription factors, enzymes, energy molecules, ion channels, and more. Clinical opportunities discussed in this section include neurodegenerative disease, seizure disorders, and psychiatric disorders, as well as pan-disease benefits, such as reduced inflammation and even increased longevity. Many of these benefits are likely due to a combination of acute and long-lasting effects of metabolic therapy.
Ketogenic Diet and PPARγ‎
Authors: Simeone Timothy A.
Published: March 2022

The ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial functions that are thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. Here, we focus on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ). PPARγ regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews current knowledge concerning PPARγ in the brain, the evidence that PPARγ has neuroprotective and antiseizure properties, and the evidence suggesting that PPARγ may be involved in the antiseizure mechanisms of the KD.
Ketogenic Diet and Epigenetic Mechanisms of Epileptogenesis
Authors: Murugan Madhuvika , Tescarollo Fabio C. , Boison Detlev
Published: March 2022

Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, such as traumatic brain injury, cerebrovascular insult, or infections. After an insult, the brain enters a period during which progressive neurobiologic alterations convert a non-epileptic brain into a brain capable of generating spontaneous and recurrent seizures, which are defined as epilepsy. The series of events is known as epileptogenesis. Epigenetic (DNA methylation) changes may affect several genes thought to represent risk factors for epilepsy; epigenetic changes are potentially reversible and may constitute a novel target for therapeutic intervention. DNA hypermethylation related to adenosine deficiency results in a vicious cycle associated with the onset of epileptogenesis and leading to chronic pharmacoresistant epilepsy. DNA hypermethylation is restored by the ketogenic diet (KD) via adenosine augmentation, a shift in the S-adenosylhomocysteine and S-adenosylmethionine homeostasis, and aiding DNA methylation by DNA methyltransferases. The KD-induced increase in ketone bodies inhibits histone deacetylases and prevents histone deacetylation. A clearer understanding of how KD therapy affects adenosine metabolism and its epigenetic sequelae may guide the development of therapies designed to directly restore adenosine homeostasis.
Effects of the Ketogenic Diet on the Blood–Brain Barrier
Authors: Janigro Damir
Published: March 2022

The ketogenic diet (KD) is considered a valuable nonpharmacologic approach for treating multiple neurologic disorders, for attenuating the neurologic sequelae of brain injury, and for reducing seizure burden. The mechanisms by which the KD works are largely unknown. Glucose is virtually the sole energy source for the brain. However, during times of starvation, the liver produces ketone bodies (KBs), which can supply up to 70% of the brain’s energy needs. Acetoacetate and β-hydroxybutyrate (βHB) are the most abundant KBs, whereas acetone, present in small quantities, is not commonly utilized as an energy source. Ketones are also advantageous in neuroinflammatory conditions because they decrease the production of free radicals. Studies suggest a significant increase in cerebral ketone uptake after brain injury. KBs are always present in the blood, and their levels increase after high-fat dietary intake, prolonged exercise, or extended fasting. Thus, one can predict an effect on the brain capillary endothelium from high levels of ketones in the blood. Prolonged exposure of blood–brain barrier (BBB) endothelial cells to KBs induces expression of monocarboxylate transporters and enhances the cerebral uptake rate of KBs. In addition, cell migration and expression of gap junction proteins are upregulated by KBs. Altogether, reports suggest that the beneficial effects of the KD may depend on increased brain uptake of KBs to match metabolic demand as well as repair of the disrupted BBB. As the effects of KBs on the BBB and transport mechanisms across the BBB are better understood, it will be possible to develop alternative strategies to optimize therapeutic benefits for brain disorders where the BBB is compromised.
Nicotinamide Adenine Dinucleotide as a Central Mediator of Ketogenic Therapy
Authors: Elamin Marwa , Ruskin David N. , Masino Susan A. , Sacchetti Paola
Published: March 2022

The ability of a ketogenic diet to treat seizures and to render a neuronal network more resistant to strong electrical activity has been observed for a century in clinics and for decades in research laboratories. Along with ongoing efforts to understand how this therapy works to stop seizures, metabolic health is increasingly appreciated as a critical buffer to resisting and recovering from acute and chronic disease. Accordingly, links between metabolism and health, and the broader emerging impact of the ketogenic diet in improving diverse metabolic, immunologic, and neurologic conditions, have served to intensify the search for its key and/or common mechanisms. Here, diverse evidence for increased levels of NAD+, and thus an altered NAD+/NADH ratio, during ketogenic therapy is reviewed. Increased NAD+ is a potential unifying mechanism, and the chapter highlights some of the evidence linking an altered NAD+/NADH ratio with reduced seizures and with a range of short and long-term changes associated with the beneficial effects of a ketogenic diet. An increase in the NAD+/NADH ratio is consistent with multiple lines of evidence and hypotheses, and therefore increased NAD+ may be a common mechanism underlying beneficial effects of ketogenic diet therapy.
Overview
Authors: D’Agostino Dominic P.
Published: March 2022

The ketone bodies β-hydroxybutyrate and acetoacetate are produced from fatty acids in the liver and serve as alternative energy sources for the brain, heart, skeletal muscle, and other peripheral tissues during prolonged fasting, calorie restriction, strenuous exercise, or adherence to a low-carbohydrate diet. Emerging evidence has revealed nutritional ketosis as a powerful metabolic therapy for general health and a growing number of medical conditions in addition to epilepsy. Data indicate that many of the benefits of the ketogenic diet are mechanistically attributable to elevated ketone bodies, leading researchers to investigate the use of ketone body-boosting supplements to circumvent the need for restrictive diets. This section includes chapters that discuss the expanding medical and performance applications of nutritional ketosis and the emerging science of ketones and related metabolites.
Ketone Supplementation for Health and Disease
Authors: Poff Angela M. , Kesl Shannon L. , Koutnik Andrew P. , Moss Sara E. , Rogers Christopher Q. , D’Agostino Dominic P.
Published: March 2022

The physiologic state of ketosis is characterized by decreased blood glucose, suppression of insulin, and an increase in the blood ketones β-hydroxybutyrate (βHB) and acetoacetate (AcAc), which serve as alternative sources of ATP in the brain. Ketones are elevated by fasting, caloric restriction, exercise, or the ketogenic diet (KD), and until recently these were the only known methods of inducing and sustaining ketosis in a nonpathologic setting. Many studies have revealed therapeutic effects of the KD, and data suggest that the benefits are mediated largely by ketone body metabolism and signaling. However, the KD often causes reduced patient compliance, which can make the KD a suboptimal long-term treatment. This has led researchers to develop exogenous ketone supplements—compounds that release or are metabolized into βHB and/or AcAc. The supplements rapidly elevate blood ketones in a dose-dependent manner, making them a practical method for inducing therapeutic ketosis. Ketone supplementation could potentially be used as stand-alone therapy in certain conditions, or possibly as a way to further augment the efficacy of the KD in the conditions in which it is being used or investigated, and it could increase compliance by allowing patients to maintain a less restrictive diet. Ketone supplements may also serve as an effective preventative medicine due to their potential to protect and enhance mitochondrial function. Preliminary evidence suggests there are several conditions for which ketone supplementation may be beneficial, including epilepsy, Alzheimer’s disease, glucose transporter type 1 deficiency syndrome, cancer, atrophy-related diseases, and metabolic syndrome.
Neuroprotective and Behavioral Benefits of Exogenous Ketone Supplementation-Evoked Ketosis
Authors: Kovacs Zsolt , D’Agostino Dominic P. , Ari Csilla
Published: March 2022

Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts and ketone esters, may have a therapeutic influence on several central nervous system disorders through neuroprotective and behavioral effects. Therefore, ketone supplementation is a potential therapeutic tool for epilepsy, neurodegenerative, and psychiatric disorders. Ketosis evoked by exogenous ketone supplements can exert its beneficial effects, for example, through modulation of mitochondrial function, hydroxycarboxylic acid receptor 2, histone deacetylases, and the NOD-like receptor pyrin domain 3 inflammasome. In this chapter, the ketone-induced metabolic and downstream signaling effects associated with mitigating treatment-resistant neurodegenerative and behavioral disorders are summarized and the rationale for the development and testing of specific ketone-based adjunctive treatments is outlined.
Identifying the Molecular Mechanism of the MCT (Ketogenic) Diet
Authors: Walker Matthew C. , Williams Robin S. B.
Published: March 2022

The medium-chain triglyceride (MCT) ketogenic diet is a highly effective and commonly used approach for treating drug-resistant epilepsy. Due to the restrictive nature of the diet and compliance issues, it is mainly used in children. The diet is associated with elevated levels of ketone bodies and two MCT-derived fatty acids, decanoic and octanoic acid. The therapeutic role for decanoic acid and a range of novel related chemicals has been shown in seizure control in multiple acute in vitro and in vivo models. Furthermore, a principal mechanism of decanoic acid has been shown to be through direct inhibition of AMPA receptors, a key excitatory neurotransmitter receptor widely recognized as a therapeutic target for seizure control. These data suggest that a therapeutic mechanism of action of the MCT ketogenic diet may be through a direct fatty acid-dependent mechanism, independent of ketosis. This discovery will enable the development of an improved and, potentially, better-tolerated diet and the generation of a corresponding pharmaceutical approach. Thus, the MCT ketogenic diet should be more correctly termed the MCT diet, because the ketosis may not be necessary for seizure control.
Low-Carbohydrate, Ketogenic Diets for the Treatment of Type 2 Diabetes and Obesity
Authors: Westman Eric C. , Tondt Justin , Yancy William S.
Published: March 2022

Obesity and type 2 diabetes mellitus (T2DM) have reached epidemic proportions in the modern world. Because the excessive fat mass of obesity leads to insulin resistance, and insulin resistance contributes to T2DM, obesity is an underlying contributing cause of T2DM. So, treating obesity and T2DM simultaneously would be of particular interest in the treatment of T2DM. Low-carbohydrate diets, also known as carbohydrate-restricted diets, have been used since the late 1800s to treat obesity and type 2 diabetes, but only recently have they been included in clinical research to assess their mechanisms and long-term safety. Clinical studies have shown that carbohydrate restriction leads to appetite reduction, weight loss, and improvements in glycemic and insulin control. Over a 2-year period, carbohydrate restriction can lead to remission and cure of T2DM. The recent clinical research supporting the use of a carbohydrate-restricted diet in individuals with obesity and T2DM is reviewed.
Intermittent Exogenous Ketosis for Athletic Performance, Recovery, and Adaptation
Authors: Stubbs Brianna J. , Hespel Peter
Published: March 2022

Sports nutrition science seeks to determine optimal dietary protocols for athletes pushing the limits of human physiology in power, endurance, and skill. Traditionally, dietary interventions aimed to stimulate performance have focused on strategic intake of carbohydrates, protein, and fat. However, recent development of oral ketone supplements has increased the popularity of intermitted exogenous ketosis (IEK) as a potential nutritional strategy to stimulate training adaptation and performance in athletes. Several physiologic mechanisms are implicated in acute modulation of exercise performance by IEK. These include use of ketone bodies as an alternative substrate for oxidative ATP production in contracting muscles and ketone-mediated inhibition of glycolytic flux. The latter could lead to glycogen sparing, which may increase endurance; on the other hand, glycolytic inhibition in conjunction with ketoacidosis could be ergolytic in short maximal exercise bouts. Furthermore, preliminary evidence suggests that acute and chronic post-exercise ketosis may stimulate recovery from training. Acute IEK could stimulate muscle protein synthesis and glycogen repletion, and chronic ketone ester intake blunted overreaching symptoms during short-term endurance training overload. This protection could be attributed to improved autonomic neural balance, appetite and stress hormone regulation, and possibly attenuation of exercise-induced inflammation and oxidative stress. Such effects could conceivably either down- or upregulate training adaptation. However, research to date describing both acute and chronic exogenous ketosis in exercise and training is limited and inconclusive. Further studies are required to elucidate the specific contexts and mechanisms whereby IEK could maximally benefit athletes.
Advancing the Awareness and Application of Ketogenic Therapies Globally
Authors: Zupec-Kania Beth , Abrahams Jim , Williams Emma , Masino Susan A. , Rho Jong M.
Published: March 2022

The Charlie Foundation was formed in 1994 out of the desire to spare others the unnecessary seizures, drugs, and surgery that Charlie Abrahams endured before being cured of his epilepsy by the ketogenic diet. The Abrahams family shared their story in 1994 on Dateline NBC, and in a 1997 movie called First Do No Harm. Despite these dramatic testimonials, the diet remained underutilized until two simultaneous events occurred. In 2008, the Charlie Foundation commissioned medical professionals with ketogenic experience to collaborate on agreed-upon methods of prescribing the diet. Publication of their resulting guidelines appeared in Epilepsia, an international medical journal. In the same year, a Class I study was published in Lancet Neurology that confirmed proof of the diets’ effectiveness for epilepsy. Use of ketogenic diet therapy grew worldwide. With this increase came a broader understanding of its benefits for other disorders. Less restrictive versions of the diet were developed to meet the needs of older children and adults. Since its inception, The Charlie Foundation began educating all people with epilepsy to eliminate sugar, to reduce refined carbohydrates, and to choose mostly a whole-foods diet. In addition, the foundation has expanded efforts to reach other conditions that can benefit from ketogenic therapies, including other neurologic disorders, endocrine disorders, and certain cancers.
The ECMO Circuit and Troubleshooting
Authors: Hermann Marcus , Keller Harald
Published: March 2022

Managing and troubleshooting extracorporeal membrane oxygenation (ECMO) requires a comprehensive understanding of modern circuit components and their respective implications. Complications are rarely technical, but instead arise from the interactions between the artificial organs and the cardiovascular system. A case involving veno-arterial (V-A) and veno-venous (V-V) ECMO is presented, outlining the most commonly found complications in clinical practice. Emphasizing the methods of troubleshooting, the underlying principles of gas exchange, extracorporeal blood flow, and anticoagulation are discussed. Assisting ECMO specialists in the decision-making process of identifying complications by means of algorithmic flow charts greatly improves the quality of troubleshooting in acute situations and further promotes beneficial outcomes during ECMO therapy.
Acute Renal Failure and Renal Replacement Therapy in ECMO Patients
Authors: Coull Julia , Burrell Aidan
Published: March 2022

Extracorporeal membrane oxygenation (ECMO)-associated acute kidney injury (EAKI) is a common syndrome encountered in over half of ECMO patients and is associated with increased mortality. The pathophysiology of EAKI is complex, with significant overlap between the patient’s underlying medical comorbidities, intercurrent illness, and the ECMO itself. The pathophysiology can be subdivided into factors that affect renal perfusion pressure, renal microcirculation, and secondary renal parenchymal cell death. Several modes and configurations can be used to provide renal replacement therapy in ECMO patients, with continuous renal replacement therapy being the most frequently used mode. Data regarding the recovery of renal function in this cohort of patients is limited.
Implications and Experiences With Long-Run ECMO
Authors: Jaouni Hani , Maybauer Marc O. , Raza Tasleem
Published: March 2022

Extracorporeal membrane oxygenation (ECMO) is gaining worldwide acceptance as rescue therapy in patients with severe cardiopulmonary failure. This form of extracorporeal life support (ECLS) provides cardiocirculatory (veno-arterial [V-A] ECMO) and respiratory (veno-venous [V-V] ECMO) support during times of cardiopulmonary insufficiency. ECMO support is most commonly employed as a bridge to recovery of native cardiac or lung function. However, it can also be a bridge to destination therapy, such as a ventricular assist device (VAD) implantation, cardiac and/or lung transplantation, or bridge to decision. ECMO runs for more than 2–3 weeks are considered prolonged runs. Long ECMO runs are becoming more common after the realization that some patients may recover their lung function weeks or even months after the initial insult. Prolonged ECMO runs have unique challenges beyond the usual ECMO care issues and complications. These include high risk of nosocomial infections, multiple circuit changes, bleeding and coagulopathy, progressive right ventricular failure, muscle wasting and deconditioning, ECMO-to-“nowhere” scenarios, and multiple psychosocial and ethical issues. This chapter summarizes the challenges of a long-run ECMO case of more than 300 days.
The Unholy Blood–Biomaterial Interaction in Extracorporeal Circulation
Authors: Hartley Emma L. , Millar Jonathan , Fraser John F.
Published: March 2022

Extracorporeal membrane oxygenation (ECMO) results in widespread activation of the innate immune system in response to blood contact with the nonendothelialized surface. This reaction is similar to the systemic inflammatory response syndrome (SIRS) and can result in widespread inflammation and tissue damage and may affect the function and longevity of the circuit. The pathophysiology of the inflammatory and coagulative processes involving the complex interplay of the contact system and complement and leukocyte activation are reviewed here. An understanding of these events allows for a tailored approach to current and future treatment modalities, including circuit modifications, novel pharmaceuticals, and blood purification devices.
Pharmacological Considerations for Analgesia and Sedation of ECMO Patients
Authors: Chew Joshua , Cheng Vesa , Shekar Kiran
Published: March 2022

As the ability to provide extracorporeal membrane oxygenation (ECMO) becomes increasingly available, it will be applied to a variety of clinical contexts in patients with cardiorespiratory failure or for those who may benefit from periprocedural support. Analgesia and sedation are integral to the safe management of these patients in the intensive care unit. As the candidates for ECMO support are heterogeneous, so also must be the strategies for analgesia and sedation. The strategy is first shaped by the clinical context and then the clinical course. Patient comfort, safety, the optimization of physiology, and early rehabilitation are all relevant considerations. Apart from this, the influence of ECMO will alter the pharmacokinetics and pharmacodynamics of selected sedatives and analgesics. This chapter covers the role, considerations, potential options, and implications for analgesia and sedation. The case discussions highlight distinct presentations and incorporate a critical review of the literature. This serves as a concise problem-based learning tool to better understand analgesia and sedation in ECMO.
Vasopressor and Inotropic Support in ECMO Patients With Refractory Shock
Authors: Harper Michael D. , Maybauer Marc O.
Published: March 2022

The pharmacologic management of circulatory and cardiogenic shock states while on extracorporeal membrane oxygenation (ECMO) support, either veno-arterial (V-A) or veno-venous (V-V), represents a higher level of complexity as compared to patients not on ECMO. Multimodal monitoring of hemodynamics, the use of serial echocardiograms, and consideration of medication effects on both the patient and the extracorporeal circuit are required. A case discussion followed by a critical review of the current literature is detailed in the chapter. Multiple-choice board-style questions assess key learning points from the chapter as it pertains to pharmacological management of circulatory and cardiogenic shock in patients on ECMO.