Intellewave and Heart Rate Variability: Applications in Anesthesia

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Heart rate variability (HRV) is a parameter not often heard about in clinical practice, yet it has been studied for over a decade as a marker for autonomic nervous system function. Heart rate varies with respiration, a physiologic process controlled by autonomic reflexes and central autonomic input. A decrease in this physiologic variation in heart rate has been associated with impairment in the cardiovascular system’s ability to adapt to various stressors. Abnormalities in HRV have been observed in various populations and pathologies in which the autonomic nervous system has been compromised, and in many cases (such as after acute coronary syndrome or in critically ill neurosurgery patients) can predict mortality and adverse outcomes.

Measurement of HRV is commonly done via time domain analysis and frequency domain analysis of R-R intervals on EKG. Parameters calculated from these spectral analyses infer the functionality of the sympathetic and parasympathetic nervous systems.

Intellewave is an automated cardiac monitoring device that utilizes frequency domain analysis to provide real-time quantitativeassessment of HRV. It uses novel artificial intelligence techniques to differentiate between high frequency (HF) and low frequency (LF) components of this spectral analysis. The HF band reflects parasympathetic activity and the LF band represents mixed input from both sympathetic and parasympathetic modulation. Interpretation of the spectral parameters has yet to be well-defined, but is the subject of ongoing study in various populations.heart rate

Intellewave’s Nerve Express algorithm was compared to the gold standard CHRONOS algorithms for power spectral analysis of R-R intervals, the latter of which was shown to predict mortality in coronary disease and to quantify physical fitness in athletes. Its advantage over CHRONOS, which relied on Holter monitoring and required skilled technicians, was designed to be a stand-alone automated system that could be used in an office setting.

The applications for HRV in general and Intellewave in particular within the perioperative theater have yet to be closely examined. From pre-operative risk stratification of patients at risk for intraoperative complications due to autonomic dysfunction, to postoperative monitoring and predicting outcomes in an intensive care setting, the possibilities are broad. There exist however confounding factors to the utilization of HRV in practice, for in the very breadth of its potential applications lies its weakness: the autonomic system affects so many variables and is affected by so many pathologies, medications, and stressors that it would be difficult to tease out what exactly is causing a change in HRV and what it could be predicting. Nevertheless, it remains an intriguing forefront of research.

The IntuiTap Medical Device

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Anesthesiologists commonly perform spinal blocks for a multitude of procedures, including lower body surgeries involving the genitourinary tract, orthopedic surgeries like knee replacements, lower abdominal surgeries, and cesarean sections. Spinal anesthesia involves the single injection of medication into the intrathecal space — into the fluid surrounding the spinal cord — to cause complete numbness and analgesia from the waist down.  The onset of anesthesia is only a few minutes, and the effects can last up to a couple of hours before wearing off without further intervention.  Spinal anesthesia is often supplemented with light or moderate sedation for patient comfort, though a spinal block alone is sufficient anesthesia for an operation.  Spinal blocks offer reliable and rapid onset anesthesia and are a safe and effective alternative to general anesthesia.

The technique for administering spinal anesthetics involves palpating for landmarks and identifying an appropriate space along the vertebral column, usually the L3-L4 or L4-L5 intervertebral spaces at the midline.  Once identified, the skin is numbed with local anesthetic, and then the spinal needle is inserted via an introducer needle.  When cerebrospinal fluid is aspirated to confirm correct positioning, the medication is injected, the needle is removed, and the procedure is complete.

According to startup company IntuiTap Medical, this current technique is “highly unpredictable and requires significant guesswork.”  This can be even more pronounced when the bony landmarks are difficult to palpate, such as in obese patients or patients with scoliosis or history of spinal surgeries.  As a result, multiple attempts may be necessary to correctly identify the intrathecal space, resulting in a distressing experience for the patient and physician, as well as increased risk of post-dural puncture headaches.  These complications can increase risk of readmission and threaten patient satisfaction.  
IntuiTap has created a handheld device that integrates imaging of the spine with needle guidance and analytics to increase first-pass success.  The device enhances palpation by showing a real-time image of the underlying vertebrae on a handheld LCD screen and projecting, using a proprietary algorithm, exactly where the needle will end up if inserted at that location.  A digital pressure sensor confirms positioning of the needle and measures opening pressure, obviating the need for a separate and cumbersome manometer.

The company was co-founded by its CEO Jessica Traver and CTO Nicole Moskowitz, both of whom were featured in Forbes annual list of 30 under 30 for healthcare.  Over the past year, IntuiTap has started seed funding rounds and has been awarded space at Johnson & Johnson Innovation’s JLABS and taken part in TMCx and MedTech Innovator accelerator programs.

ASC Market Growth to Increase Demand for Outpatient Anesthesia Services

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According to a recent medGadget article reporting on findings from Hexa Research, the market for ASCs is projected to increase at a compound rate of 6 percent annually between 2016 and 2024. High government expenditure, increased government initiatives focused on team-based primary care, and technological advancements are only a few key factors involved in driving market growth for ASCs. Additionally, primary care offices reported revenues upwards of $400 billion dollars in 2014, the same year North America led the market and Europe’s demand powered market growth in the area. Higher healthcare costs and more chronic conditions are expected to fuel Asia Pacific’s growth to 7 percent CAGR in 2016-2024. It is estimated that up to 50 percent of surgeries in the United States occur in an ASC facility, according to UC Davis Health. Further, a Becker’s ASC Review from earlier this year states that surgeons have moved away from hospital settings to perform higher acuity cases in ASCs, such as spinal fusions and joint replacements, due to financial incentives and patient preferences, as the outpatient setting is ideal for otherwise healthy individuals who have minimal risk of pain, nausea, and bleeding after surgery. Utilizing ambulatory surgical and anesthesia services for minimally invasive procedures are beneficial to many patients as well, as they provide a lower cost alternative and shorter procedure length. Additionally, some surgical procedures performed in ASCs are ideal for older individuals that wish to avoid costly and time-consuming hospital stays that may pose more risk for infection or other illness during recovery time.

ASC

Utilizing ASCs for outpatient surgical procedures has its benefits; according to a 2014 HealthAffairs study by Munnich and Parente, surgical procedure lengths at ASCs are an average of 25 percent shorter than those performed in hospitals, indicating one reason for ambulatory surgery centers’ ability to reduce costs and attend to the dramatic increase in demand for outpatient surgery that has been observed since 1981. Due to the rising demand for outpatient surgical procedures, anesthesia management groups often contract with ASCs, thus the market for outpatient anesthesia services has been steadily increasing in recent years as well. The Anesthesia Quality Institute’s National Anesthesia Clinical Outcomes Registry reports the number of anesthesia cases outside of hospital operating rooms increased from 2010 to 2014 from 28 percent of anesthesia cases, or 5.9 million in 2010, to 36 percent of cases, or 12.4 million by 2014. The use of outpatient anesthesia services will likely continue increasing given the projected global ASC market growth and high demand for outpatient surgical procedures in the United States. A 2012 Oschner Journal study by Sarin and colleagues found that specialized ambulatory anesthesia teams contribute to decreased recovery times, and may be a valuable asset to anesthesia management companies and healthcare institutions by increasing perioperative efficiency, as well as both surgeon and patient satisfaction. As outpatient surgery and anesthesia services become a more attractive option due to patient preferences, lower-costs and expedited, high-quality services that reduce the likelihood of patient readmission and allow for early ambulation, the demand for outpatient anesthesia management services can also be expected to increase through 2024, parallel to the overall projected market trend for ASCs.

How Do Anesthetics Work?

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It’s a common query our patients spring on us the morning of surgery. “How exactly do the anesthetics you administer put me out?” For intravenous agents we can often get by with a lay explanation of targeted receptors, but for volatile anesthetics the truthful answer has been, “No one really knows.”

Around 1900, Hans Horst Meyer and Charles Ernest Overton independently presented what is now known as the Meyer-Overton correlation: that the minimal alveolar concentration (MAC) of volatile anesthetics is inversely proportional to its lipid solubility. That is, the potency of a volatile anesthetic is proportional to its oil:gas coefficient. This correlation led to the theory that the mechanism of action of anesthetic agents resulted from their interaction with the neuronal lipid bilayer, rather than from a specific lock-and-key model of ligand-receptor binding. This was popular given the varied structural conformations of different anesthetics, making it less likely that they all targeted a common receptor.

The lipid bilayer theory dominated until the 1970s, when Franks and Lieb showed that the Meyer-Overton correlation could be preserved in the absence of lipids: they found that clinical doses of anesthetic inhibited water soluble, lipid-free proteins such as firefly luciferase with potencies that were again inversely correlated to their MAC. A number of potential targets, both ligand-gated (such as GABA) and voltage-gated ion channels have been identified, however receptor binding affinities are low and it remained a point of dispute whether the principle mechanism of anesthesia could be attributed to direct binding to these targets.

In their study published this year, Herold et al used a well described gramicidin-based fluorescence assay (GBFA) to test whether lipid bilayer properties were affected by volatile anesthetics. The model is based on the channel-forming antibiotic gramicidin, which dimerizes across the lipid bilayer to allow ions to pass across it. To do so, its two monomers must expend a certain energy cost to deform th
e bilayer, as the length of the channel is shorter than the span of the bilayer. Deformations in lipid bilayer properties disturb the ability of gramicidin to dimerize, leading to changes in its ion conduction capacity (as can be measured by a fluroescence assay). The study found no changes in gramicidin channel conduction when exposed to clinically relevant doses of various anesthetics. Toxic doses did cause sufficient alteration of bilayer properties to affect gramicidin conduction.

The jury is still out on the exact mechanism of volatile anesthetics, but recent data are siding against the lipid bilayer as the culprit.

References:

Hemmings HC Jr, et al. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci (2005)  26(10):503–510.

Herold KF, Sanford RL, Lee W, Andersen OS, Hemmings HC Jr. Clinical concentrations of chemically diverse general anesthetics minimally affect lipid bilayer properties  Proc Natl Acad Sci U S A. 2017 114 (12) 3109-3114

Ketamine in Chronic Pain Management

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Over the last few decades, chronic pain has become one of the most common reasons people seek medical attention including anesthesia services.  Treatment for chronic pain includes both pharmacologic and non-pharmacologic therapies and tends to be based on a trial and error approach applied to each individual patient.  Unfortunately, regardless of which treatment is selected, only 30-40% of patients demonstrate adequate-to-good pain relief.  For many patients, using a combination of drugs that target more than one pain pathway can reduce dose requirements of each drug and result in better analgesia with fewer adverse effects.Ketamine in low doses can be used to treat chronic pain syndromes, especially those with a neuropathic component.  Based on several randomized controlled trials, chronic pain syndromes that may benefit from ketamine usage include the following: migraines, breakthrough non-cancer pain, central neuropathic pain, chemotherapy-induced neuropathy, complex regional pain syndrome, fibromyalgia, painful limb ischemia, peripheral nerve injury, phantom limb pain, post-herpetic neuralgia, spinal cord injury, temporomandibular pain, trigeminal neuropathic pain, and whiplash.

KetamineKetamine was first developed in the 1960s as a safer alternative to phenycyclidine and subsequently was found to produce profound analgesia and amnesia.  Ketamine acts as an NMDA receptor antagonist with some effects on opioid, muscarinic, and monoaminergic receptors.  An important mechanism of chronic neuropathic pain development includes activation and upregulation of the NMDA receptor from prolonged nociceptive stimulation; thus, ketamine can produce strong analgesia in neuropathic pain states.  There is evidence that NMDA antagonists such as ketamine can stop the onslaught of nociceptive input to the brain and provide an alternative to existing treatments of chronic pain syndromes.  Despite its known potential benefits, there is no consensus on the administration protocol.  Duration of infusion may determine the duration of analgesia, and long term infusions of ketamine may be required for lasting analgesia following treatment.  Ketamine could even be used to reduce chronic pain development in the first place, such as that which may occur following surgery.

Multimodal approaches to treating chronic pain are often the most effective.  Ketamine is often administered in conjunction with opioid analgesics and can reduce opioid requirements, reduce associated nausea and vomiting, and improve the efficacy of opioid treatment.  Ketamine is an analgesic itself and can be additive or synergistic when interacting with opioids.  It also has potent antidepressent qualities, which may greatly benefit many chronic pain patients who cope with depressive symptoms.  Despite the many potential benefits of ketamine for use in chronic pain management, more evidence is needed to determine its efficacy, and therefore ketamine should be considered only if first- and second-line agents such as opioids and antidepressants are not effective.