Division Chief Awarded Duke-Singapore Collaborative Grant

Ashraf S. Habib, MBBCh, MSc, MHSc, FRCADuke University and the Duke-National University of Singapore (NUS) Medical School have awarded Duke Anesthesiology’s Ashraf Habib, MBBCh, MSc, chief of the Women’s Anesthesia Division, and his collaborator at KK Hospital in Singapore, Ban Leong Sng, MD, a $200,000 grant for their Duke/Duke-NUS pilot project, titled “Evaluation and risk assessment for persistent postsurgical pain after breast surgery: a collaborative prospective cohort study.”

The overall aim of this study is to identify clinically-relevant and genetic risk factors for persistent postsurgical pain that can be reliably distinguished statistically. Specifically, the focuses include 1) risk factors representing biopsychosocial processes that influence chronic pain, such as pain and psychological vulnerability, and 2) genetic factors relating to mechanistic pathways to persistent pain generation.

According to the project’s abstract, breast cancer is a leading cancer diagnosis among women worldwide, with more than one million new cases each year. Chronic pain following breast cancer surgery has been recognized as a major humanitarian and socioeconomic burden, affecting more than 50 percent of patients after lumpectomy and mastectomy leading to chronic physical disability and psychological distress. This chronic pain may involve the site of lumpectomy/mastectomy, axilla and even proximal medial arm. The cause of persistent postsurgical pain in breast cancer patients may be attributed to various reasons, such as surgical trauma, tumor recurrence, or factors related to radiotherapy or chemotherapy.

Despite a number of studies investigating risk factors, almost all of the information has originated from single center studies and often focuses on only a few elements. Additionally, surgical approaches and analgesic regimens have changed in recent years, therefore limiting the interpretation of previous studies. Yet, tools to identify those at high risk and preventive interventions are still lacking.

Dr. Habib and his team of investigators propose to study the risk factors related to persistent postsurgical pain in breast cancer patients, and to develop a prediction model that could serve as a screening tool for patients at high risk of developing persistent pain after breast cancer surgery. Pre-existing pain and severe postoperative pain have been predictors of persistent pain after surgery, but a complete understanding on the development of persistent pain is still lacking. A major challenge facing progress in this field has been the wide variation in patient experience of pain after similar types of surgery and the inability to identify individuals who are more likely to experience severe pain after surgery. A better understanding of the risk factors of postsurgical pain will help identify the subset of patients who are likely to develop severe acute pain and persistent pain. This could help in targeting those high-risk patients with focused perioperative interventions that could reduce their risk of developing severe acute pain and persistent pain.

Chris KeithDivision Chief Awarded Duke-Singapore Collaborative Grant
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Dr. Privratsky Receives Mentored Research Award

Jamie Privratsky, MD, PhDThe International Anesthesia Research Society (IARS) has awarded Duke Anesthesiology’s Jamie Privratsky, MD, PhD, a two-year, $175,000 2017 Mentored Research Award for his project, titled “The role of macrophage IL-1 signaling in acute kidney injury and recovery.”

According to the project statement, acute kidney injury (AKI) dramatically increases morbidity and mortality and can lead to downstream chronic kidney disease (CKD). The mechanisms that direct renal recovery after AKI and prevent the AKI to CKD transition are poorly understood.

Based on preliminary data, Dr. Privratsky’s central hypothesis is that IL-1R1 activation sustains detrimental macrophage polarization to drive acute renal injury and promote the AKI to CKD transition, culminating in kidney fibrosis. The specific aims of he and his team of investigators include: Aim 1) determine the effects of IL-1R1 signaling on renal macrophage polarization during AKI. Mice with macrophage-specific deletion of IL-1R1 (IL-1R1 MKO) and controls will be subjected to ischemia/reperfusion (I/R)-induced AKI. They will measure the severity of kidney damage, assess the polarization of infiltrating macrophages via fluorescent cell sorting and RT-PCR, and characterize injury in renal tubular cells following co-culture with isolated WT and IL-1R1 MKO macrophages from injured kidneys. Aim 2) determine the effect of IL-1R1 receptor signaling on the development of renal fibrosis following AKI. Investigators will subject IL-1R1 MKO mice and littermate controls (WT) to I/R-induced AKI and 28 days later examine the extent of kidney fibrosis. At multiple time points, intra-renal macrophages will be phenotyped by fluorescent cell sorting and analyzed for pro-inflammatory and pro-fibrotic gene expression by RNAseq. The capacity of a commercially available IL-1R1 antagonist to alter macrophage polarization and prevent renal fibrosis following AKI will be tested.

According to Dr. Privratsky, an assistant professor of anesthesiology in Duke Anesthesiology’s Critical Care Medicine Division, these studies should underpin the development of novel immunomodulatory therapies for AKI, which are expected to have a significant positive impact on perioperative and critically ill patients.

Chris KeithDr. Privratsky Receives Mentored Research Award
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Extreme Everest 2017: Reflections From a Scientific Expedition

Extreme Everest 2017: Reflections From a Scientific ExpeditionOn March 30, we (members of Duke Anesthesiology) left Durham to participate in Extreme Everest 2017, a scientific expedition to the Everest base camp and Kala Patthar in the Himalayas. This had been organized by a British team, including Professors Monty Mythen and Mike Grocott, who had summited Mount Everest and performed numerous groundbreaking studies in 2007 and 2013. In the current expedition, we headed for Nepal for the second time, this time joined by a Duke Undersea and Hyperbaric Medicine (UHM) fellow, Dr. Chris Martin, and former Duke UHM fellow, Dr. Nicole Harlan, along with Dr. Joe Wiater and Fran Cullen, a financial advisor in Durham. The aim was to trek from Lukla to Everest base camp over 11 days, while measuring pulse oximetry continuously in a cohort of 14 individuals.

Why do this? What can be achieved from an observational study during the field expedition? The answer is that no one knows the lower limits of acceptability on blood oxygenation. While tens of thousands of individuals have trekked to Everest base camp without a problem, their oxygen saturation values have largely been unknown. Several studies have incorporated spot measurement of SpO2 but no published studies thus far have measured it continuously. In 2013, we obtained some data using wrist oximeters; the plan this year was to extend those studies.

Our team flew to Kathmandu, arriving on March 31. Among the 46 members of the group, several were doing research projects. These included an investigation of the microbiome and echocardiography at three different altitudes. Another investigation was looking for antigens that might explain the ubiquitous ‘Khumbu cough’ as due to inhalation of aerosolized yak dung particles. For our study, we signed up a number of the trekkers and obtained overnight baseline measurements. On April 3, we made our way to Kathmandu airport for the 40-minute flight in a Twin Otter aircraft to Lukla, altitude 9,317 feet. The Tenzing-Hillary airport at Lukla is reported to be the most dangerous airport in the world because its unique runway is positioned between two cliffs which leaves no room for error on landing. However, we landed safely and after gathering in a coffee shop for a brief refreshment, we headed up the mountain toward Monjo. Hiking in North Carolina can be challenging, but it is nothing like this. Unacclimatized as we initially were, dyspnea was a constant accompaniment. After several hours of hard trekking, we reached Monjo in the dark, and the next day to Namche (altitude 11,283ft), where we spent three days. Glancing periodically at our pulse oximeters revealed measurements that were consistently in the 70s. Apart from the shortness of breath, we felt fine and were able to carry on up the trail. Namche is a small town and would be the last ‘comfort stop’ on the way to base camp: there were coffee shops, lattes and just about anything you might need to buy for the remainder of the trip. The guest house where we stayed was owned by a man who was completely deaf due to meningitis as a child. However, he was a brilliant lip reader and an even more brilliant photographer. He plans to use proceeds from the sale of his photographs to fund a museum.

After our mandatory acclimatization, we headed up the trail toward Debouche (altitude 12,369 ft) and then Pheriche (14,010 ft), where we spent three nights, again to acclimatize. Pheriche is the site of the Himalayan Rescue Association, a bare bones facility but regularly and effectively staffed by doctors from around the world. Although most of us felt okay, medical problems started to occur. The first was one of our co-trekkers who abruptly lost consciousness while sitting outside a teahouse waiting for lunch. A couple of days later someone on another trek was visibly ataxic as he walked along the trail. The diagnosis: high altitude cerebral edema – HACE. Dr. Chris Imray, one of the British medical leaders, administered dexamethasone, walked with him to a helipad and escorted him back to Kathmandu by helicopter. Later, two of our group members would suffer HACE themselves. Fortunately, in all instances, dexamethasone and descent did the trick.

Gorak Shep (altitude 17,126 ft), the original base camp for the Hillary-Tenzing expedition in 1953, was our last stop. The day after our arrival there, most of the group trekked on to the current base camp at about the same altitude. The two of us, along with four other trekkers, including Chris Imray and Jeet Sherpa, hiked up Kala Patthar (altitude 18,519 ft). The prize on this mountain is a spectacular view of four peaks: Everest, Pumori, Lhotse and Nuptse. Although we didn’t quite make the summit due to incoming inclement weather, we did get the view and a backdrop for the Duke Anesthesiology banner. The climb nevertheless was tough, and my pulse oximeter was reading its lowest value of the trek: in the low 60s.

The next morning was the planned start of the descent. Before heading down, several of the trekkers set out at 5 a.m. to climb Kala Patthar. We and the British medical leaders had waited until their return before setting out. Unfortunately, as it turned out, one of our trekkers returned with a case of HACE. It would have been impossible to evacuate by helicopter as it was snowing, so she was given dexamethasone and allowed to sleep. The cure was miraculous: a few hours later she and her doctor, Dan Martin, zoomed past us on their way to the next stop at Loboche.

The downhill trek seemed uneventful until we were a few hours past Dingboche. As we walked through a small village, we were debating whether to stop for coffee when we spotted a few of our fellow trekkers. In the end, we decided to sit down with them to enjoy a few minutes of rest, but a few minutes later we heard someone yelling for help. Both of us, along with Aine Burns, a London nephrologist, and her daughter Brid, a medical student, rushed up the trail as fast as we were capable, where we found a man lying on the ground. The sherpa who had been accompanying him reported that he had not felt well earlier in the morning and had been advised to hike slowly. Abruptly, he had fallen down, unconscious. Fortunately, Nima (our Sherpa) had the medical kit with which we were able to check the man’s glucose to exclude hypoglycemia and then administer IV dexamethasone for presumed HACE. The stars had lined up for this man as a Nepali Army platoon was hiking through the village and was able to request a helicopter and carry the man up the hill for evacuation.

That night was spent at Tengboche, then we headed to Namche and then Lukla followed by the short hop back to Kathmandu.

What about our study? The data is being analyzed, but we had clearly observed that normal hikers trekked at altitude for long periods of time at SpO2 values, which if seen in any of our hospital patients would elicit panic. However, it was great to get back to normoxia where we could climb stairs and walk up hills with relative ease. We hope that the eventual publication, which might be entitled, “Oxygen saturation: How low can you go?” will elicit conversations as to alternative strategies for treating hypoxia in patients.

By Drs. Richard Moon and Eugene Moretti

Chris KeithExtreme Everest 2017: Reflections From a Scientific Expedition
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Dr. Berger Receives Prestigious K76 Award

Miles Berger, MD, PhDThe National Institutes of Health has awarded Duke Anesthesiology’s Miles Berger, MD, PhD, and his team of investigators a Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76); a five-year, $1,195,505 grant for their project, titled “Neuro-inflammation in Postoperative Cognitive Dysfunction: CSF and fMRI Studies.”

According to the project description, each year, more than 16 million older Americans undergo anesthesia and surgery, and up to 40 percent of these patients develop postoperative cognitive dysfunction (POCD), a syndrome of postoperative thinking and memory deficits. Although distinct from delirium, POCD (like delirium) is associated with decreased quality of life, long term cognitive decline, early retirement, increased mortality, and a possible increased risk for developing dementia, such as Alzheimer’s disease. Strategies are needed to prevent POCD, but first, we need to understand what causes it. A dominant theory holds that brain inflammation causes POCD, but little work has directly tested this theory in humans. Dr. Berger and his team’s preliminary data strongly suggests that there is significant postoperative neuro-inflammation in older adults who develop POCD.

In this K76 award, the team of investigators will prospectively obtain pre and postoperative cognitive testing, fMRI imaging and CSF samples in 200 surgical patients over the age of 65. This will allow them to evaluate the role of specific neuro-inflammatory processes in POCD, its underlying brain connectivity changes, and postoperative changes in cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers, such as the microtubule-associated protein tau. This project will advance understanding of neuro-inflammatory processes in POCD and clarify the potential link(s) between these processes and postoperative changes in AD pathology, in line with the National Institute of Aging’s mission to understand aging and fight cognitive decline due to AD.

The K76 is a mentored career development award; Dr. Berger’s mentoring team includes Drs. Joseph Mathew (chairman of Duke Anesthesiology) and Harvey Cohen (director of the Duke Center for the Study of Aging and Human Development ), as well as Drs. Roberto Cabeza (from the Duke Center for Cognitive Neuroscience), Kent Weinhold (vice chair for research of Duke Surgery), and Heather Whitson (deputy director of the Duke Center for the Study of Aging and Human Development). Co-investigators and collaborators include Drs. Niccolò Terrando (Duke Anesthesiology), Jeffrey Browndyke (Duke Psychiatry & Behavioral Sciences) and David Murdoch (Duke Medicine).

During this K76 grant period, Dr. Berger, an assistant professor of anesthesiology, will also complete an individually-tailored MS degree in translational research that will include training in immunology methods, fMRI imaging, cognitive neuroscience, geroscience, and physician leadership. This career development plan will provide him with transdisciplinary skills to pursue his longer term goal of improving postoperative cognitive function for the more than 16 million older Americans who have anesthesia and surgery each year.

Chris KeithDr. Berger Receives Prestigious K76 Award
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Dr. Zhang Wins Poster Award at Inaugural Pain Meeting

Dr. Zhang with is award winning poster.

Duke Anesthesiology’s Xin Zhang, MD, PhD, received an award for “Outstanding Poster” at the first Translational Pain Research Symposium, held on June 21 – 23 at Duke Kunshan University in China. His poster is titled, “Activation of peripheral β2 and β3ARs leads to increased nociceptor activity.”

Zhang and Nackley China June 2017

Drs. Zhang and Nackley

As noted in the abstract, Dr. Zhang’s research shows that i) COMT inhibition leads to pain sensitivity, in line with increased ERK phosphorylation in DRG neurons and strengthened nociceptor activity in response to noxious stimuli, ii) COMT-dependent increases in pain sensitivity and nociceptor activity are driven by peripheral β2- and β3ARs, and iii) treatments targeted towards peripheral β2- and β3ARs and downstream effectors may prove useful in the management of functional pain syndromes. The team of investigators includes Duke Anesthesiology’s Andrea Nackley, PhD, Seungtae Kim, MD, PhD, and Sandra O’Buckley.

Dr. Zhang is a postdoctoral fellow with The Nackley Lab, part of Duke Anesthesiology’s Center for Translational Pain Medicine which is dedicated to unraveling the causes of painful conditions to better improve patient care. The Translational Pain Research Symposium was held on the new state-of-the-art campus of Duke Kunshan University. The goals of the conference were to present recent advances in basic science research of pain mechanisms, introduce cutting-edge techniques in pain research, and bridge the gap between basic research and clinical applications.

Chris KeithDr. Zhang Wins Poster Award at Inaugural Pain Meeting
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