Calls for Sparing Use of Oxygen for Dyspnea in the Emergency Department

 Oxygen therapy is used too often in patients with respiratory difficulties, says one expert, and should only be given when oxygen saturation levels (SpO2) drop below 93%, as per the current guidelines. Florian Negrello, MD, an emergency medicine specialist at University Hospital of Martinique in Fort-de-France, reiterated this message at the 2023 conference held by France's emergency medicine society (Urgences 2023). The recommendation is intended to prevent hyperoxia; increasing evidence indicates the harmful effects of such a state on the body. 

"This is a real problem. Oxygen therapy is given all too readily despite studies now showing that excess oxygen is harmful, especially in patients with head trauma, ischemic stroke, or cardiac arrest," stated the session's moderator, Patrick Plaisance, MD, PhD, a doctor at Lariboisière Hospital in Paris. 

No Proven Hypoxia

Described as difficulty breathing or shortness of breath, dyspnea is common in the emergency department, occurring in 5%-9% of patients. Close to 20% of intensive care unit admissions involve patients with dyspnea. "Since this is a very subjective symptom, it's possible it's being underdiagnosed," said Negrello.

Lower respiratory tract infection, acute heart failure, chronic obstructive pulmonary disease, and exacerbation of asthma are the four main diagnoses linked to dyspnea, but this symptom is also seen in several medical conditions (gastrointestinal, metabolic, neurologic, etc.), he noted. 

Often seen as a harmless treatment option, oxygen therapy is commonly administered to patients with breathing difficulties even when no hypoxemia is documented. This is particularly the case for patients brought into hospital via ambulance who are treated with oxygen without even having had their blood oxygen levels, SpO2, and partial pressure of oxygen checked. 

In the United States, one of the few studies published on the topic showed that one third of patients transported via ambulance are put on oxygen, with SpO2 being measured in just 5% of these cases. Finally, just 17% of patients receiving oxygen were experiencing hypoxia, defined as SpO2 < 94%. 

Oxidative Stress 

Recently, several research studies have revealed the potential dangers of unjustified use of oxygen, which can lead to hyperoxia and increased mortality in hospitalized patients. 

A meta-analysis reported a linear relationship between severe hyperoxia, in-hospital mortality, and length of stay in intensive care. Another study revealed a greater mortality rate in patients with acute respiratory distress syndrome (ARDS) experiencing an episode of hyperoxia, regardless of the severity of ARDS. 

Oxygen toxicity in intensive care is said to be linked to oxidative stress caused by increased growth of reactive oxygen species but also to the systemic inflammation caused by hyperoxia, explained Negrello. Excess oxygen may also cause lung lesions with necrosis, the severity of which is proportional to the fraction of inspired oxygen and the length of exposure. 

According to the most up-to-date international recommendations published in 2018 on the use of oxygen therapy in treating acute conditions, oxygen should not be used when SpO2 ≥ 93%. When treatment has been started, it must be stopped when SpO2 reaches 96%. SpO2 cannot be maintained above 96%, according to experts. 

These threshold values can be found in the COVID-19 treatment guidelines produced by the French-Language Society of Respiratory Medicine, with oxygen therapy being recommended when SpO2 < 92%, added Negrello. The aim is to maintain normal oxygen levels, with SpO2 between 92% and 96%. 

Use Sparingly 

For patients with COPD, the target levels are lower, due to the risk of hypercapnia (higher than normal carbon dioxide levels in the blood). Oxygen saturation levels should then be kept between 88% and 92%, "by using the minimum amount of oxygen necessary," per the guidelines. 

"Oxygen should be used sparingly," concluded Negrello. "To treat our patients without harming them, we must be able to use it at the right time, meaning when a patient really has low blood oxygen, by focusing on normal saturation levels as the end goal."

SpO2 measurement is the first step to be taken to determine oxygen requirements, followed by, if necessary, blood gas analysis once the patient has been admitted, he explained. 

Questioned at the end of his session on how long oxygen therapy can be given for, Negrello reiterated that the risk for death is correlated with the length of time spent in a state of hyperoxia but that it is difficult to establish a maximum timeframe to be adhered to strictly.

Given that excess oxygen is harmful to patients in intensive care, "it would be better, when in doubt, to focus on physiological levels" and simply stop treatment when target saturation levels are reached. 

https://www.medscape.com/viewarticle/expert-calls-sparing-use-oxygen-dyspnea-emergency-department-2023a1000jk9

Aspirin for Secondary CVD Prevention Underused Worldwide

 Aspirin has long been recommended for secondary prevention of cardiovascular disease (CVD), but a new global study highlights considerable underuse for that purpose, especially in lower-income countries.

Nationally representative survey data from 51 countries showed that fewer than half of eligible people overall, including less than one-quarter in low-income and lower-middle-income countries, were taking aspirin for secondary CVD prevention.

"Our findings were not surprising but rather disappointing," first author Sang Gune Yoo, MD, fellow in cardiovascular disease, Washington University School of Medicine in St Louis, Missouri, told theheart.org | Medscape Cardiology.

"We had hoped that the rates of aspirin use for secondary prevention would have increased after decades of effort to promote cardiovascular health worldwide," Yoo said.

In high-income countries, such as the United States, rates of aspirin use for secondary CVD prevention were higher — at around 65% — but that's also "really low and not particularly good or anything to be proud of," Deepak Bhatt, MD, MPH, director of Mount Sinai Heart, in New York City, who wasn't involved in the study, told theheart.org | Medscape Cardiology.

The study was published online August 22 in JAMA. It provides the most extensive and up-to-date estimates of the worldwide use of aspirin for secondary prevention of CVD.

The researchers did a cross-sectional analysis using pooled, individual participant data from nationally representative health surveys conducted from 2013 to 2020 in 51 low-, middle-, and high-income countries.

The overall pooled sample included 124,505 nonpregnant adults (mean age, 52 years; 51% women). A total of 10,589 (8.1%) had a self-reported history of CVD and about 40% of these individuals were taking aspirin.

However, rates differed markedly by country, with use rates lowest in low-income and lower-middle-income countries and highest in upper-middle-income and high-income countries.

Rates of Aspirin Use for Secondary CVD Prevention by Country Income Level 

Income Level	Aspirin Use (%)	95% Confidence Interval
Low-income	16.6	12.4 to 21.9
Lower-middle-income	24.5	20.8 to 28.6
Upper-middle-income	51.1	48.2 to 54.0
High-income	65.0	59.1 to 70.4

Primary vs Secondary Prevention

The study did not explore the factors or reasons behind suboptimal aspirin use for secondary CVD prevention. 

For example, it did not investigate whether data demonstrating that aspirin is not helpful in primary prevention is having a negative effect on use rates for secondary prevention. However, "rates of aspirin use for secondary prevention were low previously and remain suboptimal," Yoo told theheart.org | Medscape Cardiology.

Bhatt said that the "suboptimal" use of aspirin for secondary prevention is "a bit perplexing because this is a medicine that's familiar, the data in secondary prevention are broadly known to physicians and it's a cheap medicine so we can't, in this case, blame high cost."

Bhatt said it's possible that coverage in the lay media of "negative" aspirin trials that may not distinguish between a primary and secondary prevention trial may contribute to confusion about aspirin. "In some cases, the doctor may think the patient is taking aspirin, but self discontinues it based on something they read or saw on the internet," he noted.

Yoo and colleagues say that to meet the goal of reducing premature mortality from noncommunicable diseases, including CVD, "national health policies and health systems must develop, implement and evaluate strategies to promote evidence-based use of aspirin."

"Strategies to boost appropriate aspirin use must be contextualized to the country and its health system," Yoo added.

JAMA. Published online August 22, 2023. Abstract

The study had no commercial funding. Yoo has disclosed no relevant financial relationships. Bhatt has previously disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

https://www.medscape.com/viewarticle/995728

University in Nashville Doubles Debt to Build New Medical School

 Nashville’s Belmont University is more than doubling its debt to build classrooms for a not-yet-accredited new medical school, aiming to help alleviate a nationwide doctor shortage.

The Health and Educational Facilities Board of The Metropolitan Government of Nashville and Davidson County is selling $187.5 million of municipal bonds on behalf of Belmont. Proceeds will be used to construct laboratories and classrooms for a school “focused on training diverse physician leaders who embrace and value a whole-person approach to healing,” according to the bond-offering documents. A portion of funds will also be used to finance the construction of a 719-bed residence hall.

The new medical school will be affiliated with HCA Healthcare Inc., the largest US hospital chain. HCA didn’t respond to a request for comment.

The Thomas F. Frist, Jr. College of Medicine is named after a co-founder of HCA and brother of former Senate majority leader Bill Frist. It’s scheduled to open next year. The hospital chain has helped make health care the largest industry in the Music City.

“The addition of a medical school certainly is a reflection of the need out there in US health care for doctors and other medical professionals,” said Gabe Diederich, a portfolio manager at Robert W. Baird & Co. That is especially true in fast-growing areas like Nashville, he said.

The new bonds — which are scheduled to price Wednesday — will bump Belmont’s outstanding debt to about $314 million, from $128.7 million as of last May, according to S&P Global Ratings. S&P assigned an A rating to the debt, pointing to recent application and enrollment increases and “extraordinary operating performance.”

https://finance.yahoo.com/news/university-nashville-doubles-debt-build-150558970.html

FDA Panel 'Backs' ReCor's Renal Denervation System for Hypertension

The Paradise ultrasound renal denervation system got backing from the FDA's Circulatory System Devices Panel as a possible treatment for hypertension, as manufacturer ReCor continues to hope for regulatory approval.

On Tuesday, FDA advisors voted 10-2 that the benefits of the Paradise catheter-based system outweigh its risks when used to reduce blood pressure (BP) in patients with uncontrolled hypertension who do not respond to or tolerate antihypertensive medications, the proposed indication in the premarket application for the device.

"It's not a panacea but it's certainly an option, and I think it should be approved," said John Somberg, MD, of Rush Medical College in Chicago.

High BP is a risk factor for heart disease and stroke and affects nearly half of adult Americansopens in a new tab or window. Fewer than one in four adults with hypertension have it under control with lifestyle interventions and available medications, according to the CDC. The last new drug class for hypertension, the direct renin inhibitors, was approved in 2007opens in a new tab or window, suggesting innovation is needed.

Some panel members expressed their reluctance to vote yes on the Paradise, however, owing to the modest and short-term BP reductions observed after ultrasound renal denervation. The committee ultimately voted unanimously 12-0 that the Paradise system is safe, and 8-3 (with one abstention) that it is effective for the proposed indication.

"The risk seems very low, but the benefit seems very low so there's my ambivalence. It's hard for me to judge risk-benefit when both seem very low," said statistician Janet Wittes, PhD, of Washington, D.C. She later abstained from the effectiveness question but voted yes that the system's benefit outweighs its risk.

Pooling people with mild-to-moderate and stage II hypertension who discontinued their BP medications, the RADIANCE-HTN SOLO

opens in a new tab or window and RADIANCE IIopens in a new tab or window trials had together shown an average 6.3 mm Hg lower daytime ambulatory systolic BP (ASBP) at 2 months after the Paradise procedure compared with sham. For peers with resistant hypertension despite staying on at least three antihypertensives in RADIANCE-HTN TRIOopens in a new tab or window, Paradise's BP reduction amounted to just 4.5 mm Hg -- which may not back ReCor's proposed indication for people not responding to BP medications, the panel said.

These results just hover around the 5-mm Hg threshold for a BP reduction to be of clinical significance in terms of preventing actual cardiovascular events, as agreed upon by FDA and industry during discussions in 2018opens in a new tab or window.

"I think the totality of the evidence does favor a positive benefit-risk profile ... I think the average treatment benefit might be modest, but it's highly variable. But that's also true for medication," argued Robert Yeh, MD, MSc, MBA, of Beth Israel Deaconess Medical Center in Boston.

Abdulla Damluji, MD, PhD, MPH, of Inova Health in Fairfax, Virginia, said he agreed, adding that there is a "big space" in finding super-responders to Paradise therapy.

Nevertheless, FDA advisors generally said it is difficult to evaluate the durability of renal denervation given the available data.

Longer-term BP data suggest that the Paradise recipients' mean daytime ASBP reduction over sham was no longer significant at 6 months due to further BP lowering in both treatment arms later on in the three trials. Complicating the durability issue are the uptitration of medications in both groups at 6 and 12 months, and unblinding and permission of crossovers was allowed at these time points.

"What I grapple with is, Are we approving a product that could be used in lieu of medication and is that reasonable to have an invasive procedure in lieu of noninvasive [medication]?" said panel member Keith Allen, MD, of St. Luke's Hospital of Kansas City, Missouri, who ultimately voted no on the risk-benefit question.

"I personally don't think that the denervation will be durable. I can't think of a single area where denervation's been used ... where re-innervation doesn't occur," he said. "I think the benefit, if any, is acute, not durable, and is marginal."

The other no vote on risk-benefit came from Mark Lockhart, MD, MPH, of University of Alabama at Birmingham, who cited the durability issue and reiterated the committee's recommendation to change Paradise's proposed indication to reflect that it does not perform as well in resistant hypertension.

Regardless of effectiveness, FDA advisors said they did not have significant safety concerns of Paradise renal denervation other than a low risk related to vascular access. "I don't think the issue here is safety," Allen said.

The pooled primary safety endpoint of major adverse events through 30 days and new renal artery stenosis through 6 months was a low 1.1% across the Paradise trials. However, the system was also associated with mild-to-moderate diameter stenosis at 12 months on angiograms and MRI scans.

The Paradise system includes a catheter with an ultrasound transducer that is delivered percutaneously through the femoral artery to the renal artery under fluoroscopic guidance. An accompanying distal balloon contains cooling water to prevent arterial wall injury during thermal ablation.

ReCor has proposed a long-term postmarket registry that would pool RADIANCE II participants with up to 500 new people in a continued access study. The study proposes to track office and home BP measurements alone after Paradise denervation without 24-hour ambulatory monitoring.

The FDA is not required to follow the advice of its advisory committees, but it often does.

The panel will reconvene on Wednesday for deliberations on another endovascular renal denervation system, the Symplicity Spyral from Medtronicopens in a new tab or window.

https://www.medpagetoday.com/cardiology/hypertension/105999

Organovo Advances Timelines for Ulcerative Colitis, Updates on NASH Phase 2

 Organovo Holdings, Inc. (Nasdaq: ONVO) (Organovo), a clinical stage biotechnology company that is focused on developing novel human therapies with demonstrated function in high fidelity three-dimensional (3D) tissues that recapitulate key aspects of human disease, today announced more details about its clinical program for FXR314, an FXR agonist that has completed initial clinical trials. FXR314 is a drug with safety and tolerability after daily oral dosing in Phase 1 and Phase 2 trials. Further, FXR314 has FDA clinical trial authorization for a Phase 2 trial in ulcerative colitis.

Organovo’s FXR program announcement updates its previous guidance on clinical trial starts for the company, with the Company accelerating its timeline to first clinical trials by approximately two years. The Company previously announced in March 2023 that it would give guidance on Phase 2 timelines for FXR314 after an internal determination of the best path forward. The Company continues to expect to file INDs starting in 2025 for fully internally developed molecules and expects to issue additional guidance on pipeline programs in the coming months.

In addition, Organovo is anticipating the release of final Phase 2 data on the performance of FXR314 in NASH. Performance of the drug to date in treatment of NASH has been encouraging. Interim results in Phase 2 showed that FXR314 lowered liver fat content, with mean relative reductions of 26.9±27.8 percent in the 3 mg cohort and 9.3±55.8 percent in the 6 mg cohort, compared with 7.5±21.0 percent in the placebo cohort. Median liver fat reduction was 28.6 percent in the 3 mg cohort, 26.9 percent in the 6 mg cohort compared to 1.5% in the placebo arm. A post-hoc comparative assessment of relative liver fat reduction in the interim cohort found the decrease with the 3 mg dose to be statistically significant compared to placebo (p=0.006). FXR314 achieved greater than 30 percent liver fat reduction in 47 percent of patients (8/17) in the 3 mg cohort and 35 percent (6/17) in the 6 mg cohort, compared with 12 percent (2/17) in the placebo arm. To date, the drug has been generally well-tolerated, with no treatment-related serious adverse events. All treatment-related adverse events have been mild-moderate with no apparent dose relationship. Full Phase 2 data is expected to be released in 1H 2024.

https://finance.yahoo.com/news/organovo-advances-clinical-timelines-fxr314-120500379.html

Employment: 'Preliminary annual benchmark revision shows downward adjustment of 306,000 jobs'

 The BLS released the preliminary annual benchmark revision showing 306,000 fewer payroll jobs as of March 2023. The final revision will be published when the January 2024 employment report is released in February 2024. The number is then "wedged back" to the previous revision (March 2022).  Usually, the preliminary estimate is pretty close to the final benchmark estimate.

The annual revision is benchmarked to state tax records. From the BLS:

n accordance with usual practice, the Bureau of Labor Statistics (BLS) is announcing the preliminary estimate of the upcoming annual benchmark revision to the establishment survey employment series. The final benchmark revision will be issued in February 2024 with the publication of the January 2024 Employment Situation news release.

Each year, the Current Employment Statistics (CES) survey employment estimates are benchmarked to comprehensive counts of employment for the month of March. These counts are derived from state unemployment insurance (UI) tax records that nearly all employers are required to file. For National CES employment series, the annual benchmark revisions over the last 10 years have averaged plus or minus one-tenth of one percent of total nonfarm employment. The preliminary estimate of the benchmark revision indicates a downward adjustment to March 2023 total nonfarm employment of −306,000 (−0.2 percent).
emphasis added

Construction was revised up by 30,000 jobs, and manufacturing revised down by 43,000 jobs.

This preliminary estimate showed 358,000 fewer private sector jobs, and 52,000 more government jobs (as of March 2023) than originally estimated.

https://www.calculatedriskblog.com/2023/08/employment-preliminary-annual-benchmark.html

Maui residents who disobeyed barricade survived fires: AP

 Those who disobeyed the barricaded road closures during the Maui fires survived the disaster, while many of those who heeded orders to turn around perished in their cars and homes with no way out, The Associated Press reported.

At least 114 people were killed in the fires earlier this month, and the FBI is estimating that up to 1,100 more are unaccounted for. Officials are facing increased scrutiny for the emergency response, including why the emergency sirens were not set off and whether closing the roads prevented people from getting to safety.

In the early hours of the Maui fires, there were more than 30 power poles downed alongside the Honoapiilani Highway at the south end of Lahaina — a historic town that was decimated in the fires earlier this month. Officials closed Lahaina Bypass Road due to the fires, blocking the only way out of Lahaina to the southern part of the island.  

Maui Police Chief John Pelletier said during a news conference that officers never stopped people from leaving the area, but the AP report suggests that residents were discouraged from disobeying the barricade. 

One family swerved around the barricade set up to escape the flames, while another resident took a dirt road uphill to climb above the fire, according to the AP. However, many others who stayed in the cars on that road were stuck in a gridlock, with fires surrounding them on most sides with the ocean on the remaining side.

Nate Baird and Courtney Stapleton recounted their experience to the outlet, saying they loaded the car up with their two sons, Baird’s mother and one dog to escape the flames. When they turned south to escape Lahaina, they were met with cones and were told to turn around to Lahaina, which was already burning.

Instead of turning around, they swerved past the cones and escaped to a neighboring town.

“Nobody realized how little time we really had,” Baird said. “Like even us being from the heart of the fire, we did not comprehend. Like we literally had minutes and one wrong turn. We would all be dead right now.”

Baird told the reporter that if they had 10 more minutes, they could have saved children who were left home alone in their neighborhood during the fires.

“The kids just don’t have a filter. So their son ran up and was just telling our son, you know, ‘This kid is dead. This kid is dead.’ And it’s like, all my son’s friends that they come to our house every day,” he said. “And their parents were at work, and they were home alone. And nobody had a warning. Nobody, nobody, nobody knew.”

Kim Cuevas-Reyes said that she survived with her two sons by ignoring orders to turn right onto Front Street, which has now been devastated by the fires. Instead, she turned left and drove in the wrong lane to escape the town.

“The gridlock would have left us there when the firestorm came,” Cuevas-Reyes, 38, told the AP. “I would have had to tell my children to jump into the ocean as well and be boiled alive by the flames or we would have just died from smoke inhalation and roasted in the car.”

https://thehill.com/homenews/state-watch/4166222-maui-residents-who-disobeyed-barricade-survived-fires-ap-reports/