Dr. Gustin's Blog

Fentanyl Deaths Seen in Emergency Departments

One of the consequences of an open Southern Border is the entrance into the U.S. of unprecedented amounts of illicit drugs.  Many of these drugs have been spiked with lethal doses of fentanyl.  Unbeknowst to the drug user, they will consume fentanyl without even knowing it.  This is the source of most accidental deaths secondary to fentanyl.  Fentanyl is the most potent of all narcotics.  On a dose:dose basis fentanyl is 50 times stronger than heroin, and 100 times stronger than morphine.  What this means is that extremely small doses of fentanyl can cause respiratory depression and death.  


The United States (US) overdose crisis has escalated in an exponential fashion for over four decades, yet with a shifting profile of drugs implicated in each successive ‘wave’ of the crisis. The first wave of the overdose crisis is typically argued to have begun in the late 1990s or early 2000s with the rise of deaths involving prescription opioids, the second wave beginning in 2010 driven by a shift to heroin, and the third wave beginning in 2013 driven by illicit fentanyl analogues. Recently, scholars have argued that the ‘fourth wave’ of the US overdose crisis has begun, in recognition of rapidly rising polysubstance overdose deaths involving illicitly manufactured fentanyls, with stimulants playing a key role. Recent studies have highlighted an increasing rate of polysubstance overdose deaths involving fentanyls and stimulants, disproportionately affecting racial/ethnic minority communities. A wide range of polysubstance formulations have been noted in drug checking and overdose mortality data, with myriad substances implicated across numerous drug classes. However, more evidence is needed about exact geographic, temporal, race/ethnicity and demographic trends, as well as which emerging polysubstance formulations are most commonly involved in fatalities.


The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% (n = 235) in 2010 to 32.3% (34 429) in 2021, with the sharpest rise starting in 2015. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015–2021. Intersectional group analysis reveals particularly high rates for older Black and African American individuals living in the West.


The rise of illicitly manufactured fentanyls has ushered in an overdose crisis in the United States of unprecedented magnitude. This has created conditions that have promoted a number of other shifts in the illicit drug supply, leading to rising polysubstance overdose deaths—the so-called ‘fourth wave’ of the crisis, especially involving stimulants and fentanyl co-use starting in 2015. Mixtures of fentanyl analogues and drugs of various drug classes, such as stimulants, benzodiazepines, tranquilizers and other opioids have been noted in distinct geographies.

In 2010, fentanyl was most commonly found alongside prescription medication (opioids and benzodiazepines) and alcohol (i.e. largely products produced in legal markets). Over the past decade this has shifted first to heroin-fentanyl combinations in specific states, and then universally to illicit stimulants. The fraction of all overdose deaths involving both fentanyl and stimulants grew rapidly between 2010 and 2021 and is on track to represent the single largest component of the overdose crisis in the near future. However, this has occurred in a distinct fashion based on geography and time. The northeastern states saw a period of heroin-fentanyl co-involvement, which was also found in some parts of the Midwest and South, but was completely absent from the western states (which transitioned rapidly from black tar heroin to fentanyl with methamphetamine co-involvement). By 2021, cocaine predominated in the Northeast and methamphetamine had become the most common drug found alongside fentanyls in the rest of the country.

There are now two basic archetypes of states in the United States with respect to overdose death rates: (a) states where fentanyl and cocaine co-use predominates; and (b) states where fentanyl and methamphetamine co-use predominates, with surprising little overlap between these two groups. This may reflect the combination of very low-cost, high-purity methamphetamine outcompeting cocaine and other stimulants at the national level, in addition to an enduring, well-entrenched illicit cocaine market in the Northeast and other pockets of the country.

The rise of deaths involving cocaine and methamphetamine must be understood in the context of a shifting illicit opioid drug market increasingly dominated by illicit fentanyls. Recent ethnographic and qualitative research suggests that fentanyls have created conditions that make polysubstance use more sought-after and commonplace. For instance, many individuals report that mixing a small amount of methamphetamine into injected doses of fentanyl subjectively prolongs the onset of withdrawal symptoms, increases euphoria, decreases overdose risk and improves energy levels. These perceived advantages may be particularly important given the short duration of fentanyls, requiring individuals to inject far more frequently than heroin, and the heightened overdose risk from each injection. 

Similar findings have been reported in qualitative studies of the veterinary tranquilizer, xylazine, and other drugs commonly added to fentanyls, suggesting possible structural similarities across various emerging polysubstance patterns. Given the increased risk of negative health outcomes such as overdose not fully responsive to naloxone often requiring additional life-saving measures such as airway management.

A critical consideration is the growing prevalence of counterfeit pills, which resemble psychoactive pharmaceuticals such as oxycodone or alprazolam, but contain illicit fentanyls, often mixed with other illicit substances such as stimulants, benzodiazepines, xylazine and other opioids. In recent years, counterfeit pills have grown to represent over a quarter of all illicit fentanyl seizures. Counterfeit pills have the potential to transform overdose risk as they may expand the markets for illicit synthetic drugs to subpopulations, such as adolescents, who may be less likely to consume powder fentanyl products . In the ongoing surveillance of the US overdose crisis, tracking deaths involving counterfeit pills versus other formulations represents an important dimension that is currently difficult within the existing data landscape.


By 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more sought-after and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges.

The information above was gleaned from a soon to be published study by Drs. Friedman and Shover. Addiction. 1-9, 2023

E-Cigarette and E-Liquid Intoxications Presenting to the Emergency Department

Toxicologic Emergencies present to physicians staffing the Emergency Department of a hospital with regularity.  Over the past decade e-liquid and e-cigarette poisonings have become increasingly common in the ED, particularly amongst children less than 5 years old.  A recent MMWR report from the CDC documents the incidence of this problem.  The article is listed below and was printed by the CDC on June 23, 2023 (72:694)

E-cigarette–associated cases reported to U.S. poison centers have fluctuated during the past decade, increasing during 2010–2014, and then decreasing during 2015–2017 (1). During 2017–2018, the number of e-cigarette exposure cases increased by 25% (from 2,320 to 2,901), and in 2018 nearly two thirds (63.3%) of cases occurred among children aged <5 years (1). To understand the number and characteristics of e-cigarette exposure cases in the United States, the Food and Drug Administration (FDA) analyzed National Poison Data System (NPDS) data* from the most recently available 12-month period (April 1, 2022–March 31, 2023). NPDS is maintained by U.S. poison centers. FDA’s analyses report a further increase in the number of e-cigarette exposure cases, particularly among children aged <5 years.

NPDS is a repository of cases reported to U.S. poison centers that are recorded by specially trained and certified health care professionals (2). Information on exposure cases (reports or reported incidents by persons who contact poison centers regarding an exposure to a substance) in NPDS is recorded based on generic codes (a required general identification code for a substance or group of products) and product codes (product-specific codes, often by brand; these are not required upon case intake). Cases involving e-cigarettes were identified using generic codes; brands were identified using product codes. E-cigarette exposure cases were defined as an exposure to e-cigarettes or e-liquids and were examined by age group, exposure route, level of care provided, medical outcome, and product brand. This study was determined as exempt by the FDA Institutional Review Board for Human Subject Protection.§

During April 1, 2022–March 31, 2023, a total of 7,043 e-cigarette exposure cases were reported (Table), representing a 32% increase, from 476 in April 2022 to 630 in March 2023. Among all exposures, 6,074 (87.8%) occurred among children aged <5 years. Inhalation or nasal (4,298; 61.0%) and ingestion or oral (2,818; 40.0%) exposure routes were most common. Overall, 43 (0.6%) e-cigarette exposure cases resulted in hospital admission, and 582 (8.3%) required treatment at a health care facility. A major effectwas experienced in 12 (0.2%) exposure cases and a moderate effect in 133 (1.9%) cases. One reported case resulted in death (a suspected death by suicide of a person ≥18 years). Approximately one half of reported cases resulted in either a minor effect (27.2%) or no reported effect (19.8%); 50.9% of cases were not followed.** Among 342 (4.9%) cases with brand information, the most commonly reported brand was Elf Bar (60.8%), a disposable e-cigarette available in a variety of flavors; monthly cases involving Elf Bar increased from two in April 2022 to 36 in March 2023. More than 90% of Elf Bar exposures were among children aged <5 years.

NPDS relies on voluntary reporting of poisoning exposure cases; thus, the number of cases is likely underreported (3). In addition, because product codes are not required, only a small proportion of e-cigarette exposure cases included information on the brand associated with the exposure.

The number of reported U.S. e-cigarette exposure cases during this 12-month period is approximately double the number reported in 2018 (1). Most of the cases were among children aged <5 years. Among the 5% of cases for which brand was available, Elf Bar, for which sales in the United States have recently increased (4), was reported more often than all the other reported brands combined, with nearly all Elf Bar cases occurring among children aged <5 years.

Continued surveillance is critical to guiding efforts to prevent poisoning exposure associated with e-cigarettes, particularly among young children. Health care providers; the public health community; e-cigarette manufacturers, distributors, sellers, and marketers; and the public should be aware that e-cigarettes have the potential to cause poisoning exposure and are a continuing public health concern (5). Adult e-cigarette users should store their e-cigarettes and e-liquids safely to prevent access by young children.

Clinical Case Study- Altered Mental Status

Clinical Toxicology Case Study:

Altered mental status could be due to any number of medical or toxicologic conditions.  The following is a case of depressed consciousness in a young man returning to the U.S. from a Third World country.  His traveling companions were all well.  The case is indicative of an increasingly common phenomenon especially at our southern border.  Here is the case:

A 22-year-old man with no significant medical history is transferred from the airport to the emergency department (ED) in a semiconscious state after returning from a 3-week vacation in a malarial zone. According to one of his traveling companions, the patient was at his baseline mental status when boarding the plane for the return trip home. He ate lunch and then took a nap.

After landing, the patient's companion was unable to wake the patient. The companion then called for help, and the patient was rushed to the ED. His other traveling companions, who were also on the same flight, are all asymptomatic.

Physical Examination and Work-up:

 The physical examination reveals a physically fit man who is obtunded and minimally arousable. Vital signs reveal an oral temperature of 98.7°F (37°C), pulse of 85 beats/min, blood pressure of 110/70 mm Hg, respiratory rate of 7 breaths/min, and an oxygen saturation of 98% while breathing room air. Diffuse flushing of the skin is noted, without lesions or bruising.

The patient's heart sounds are normal, without any murmurs, rubs, or gallops, and the lungs are clear to auscultation bilaterally. Examination of the head and neck is unremarkable, other than pinpoint pupils. The abdominal examination reveals normal bowel sounds without distention, tenderness to palpation, or organomegaly. Rectal examination shows normal rectal tone, heme-negative stool, and no masses.

The laboratory analysis includes a complete blood cell count (CBC) with differential, a complete metabolic panel, a coagulation profile, a fingerstick blood glucose measurement, and a urine analysis. The CBC reveals a normal white blood cell count without a left shift. The remainder of the laboratory analysis is within normal limits, including a creatinine level of 1.2 mg/dL, glucose of 90 mg/dL, prothrombin time of 12.1 seconds, and a partial thromboplastin time of 28.5 seconds.

The urinalysis is negative for bacteria and has a specific gravity of 1.010. It is noted in the patient's past medical record that he had a negative HIV test approximately 4 months ago.

 A routine chest radiograph shows suspicious objects overlying his left diaphragm, which prompts abdominal radiography.


The plain abdominal radiograph (Figure 1) demonstrated heroin-filled condoms in the stomach, small intestine, colon, and rectum. Presumably, the patient swallowed the condoms and one of them ruptured during the flight, thereby causing the patient's drowsiness.

“Body packing” refers to individuals who swallow or pack body orifices with drugs to transport them across borders. Often, this involves the use of rubber or condoms to prevent the packets from rupturing. “Body stuffing” is a term used to describe when an individual swallows drugs in an attempt to avoid prosecution by the police.

The first reported case of body packing was in 1973, when a body packer had developed a small-bowel obstruction nearly 2 weeks after swallowing a condom filled with hashish. The patient underwent surgical removal.[1] Cocaine, heroin, amphetamines, 3,4-methylenedioxymethamphetamine ("ecstasy"), marijuana, and hashish are the drugs that are usually smuggled in this manner.[2]

Body packers usually carry about 2.2 lb (1 kg) of drugs, divided into 50-100 packets of 0.29-0.35 oz (8-10 g) each; however, persons carrying more than 200 packets have been reported.[2] The packets are usually well-designed and constructed, possibly with the help of machines, so as to make them resistant to rupture.[3] The drug is first packed into a balloon or condom, followed by additional layers of latex and, finally, sealed with wax.[2] If a packet ruptures, however, it releases a high dose of drug into the gastrointestinal tract that can lead to drastic consequences. The acute drug intoxication that can result is associated with high mortality rates.[3]

Body packing should be suspected in anyone exhibiting signs of drug-induced toxic effects after a recent arrival on an international flight, or when there is no history of recreational drug use.[2] When a suspected body packer presents to a physician, a detailed history should be obtained, followed by a thorough physical examination. Information should be gathered on the type of drug, the number of packets, the nature of the wrapping, and the presence of any gastrointestinal symptoms.

Assessment of vital signs, mental status, pupil size, bowel sounds, and skin findings can provide useful clues to the nature of the drug. Gentle rectal and vaginal examination should be carried out to disclose the possible presence of packets.[2]

Cocaine intoxication manifests with marked anxiety, tachycardia, mydriasis, neuropsychologic symptoms, hyperthermia, seizures, emesis, respiratory depression, dysrhythmia, and myocardial depression.[3] Heroin overdose can result in sedation, miosis, and diminished bowel sounds, followed by respiratory depression.[2] Body packers may also present with symptoms of intestinal obstruction or other complications, such as gastrointestinal hemorrhage or perforation.[2,3]

 Imaging studies should begin with plain radiographs of the abdomen and pelvis; these have a sensitivity of 85%-90%.[2] The packets are visualized as multiple round or oval, well-defined, radioopaque objects along the distribution of the intestine. Three different forms of radioopacity have been described, depending on the contents of the packet and purity of the drug: Hashish appears denser than stool; cocaine appears similar to stool; and heroin has a gaseous transparence.[4] Owing to their method of construction, some types of cocaine packets may exhibit a small radiolucent band around them.[3]

Barium and CT studies of the abdomen can be ordered for suspicious cases. Contrast-enhanced CT of the abdomen and pelvis is more sensitive than plain radiography and reveals the presence of foreign bodies surrounded by a small amount of gas. Barium studies identify the packets as filling defects within the contrast medium.[2] Urinary toxicology tests are often performed because body packers do not usually provide precise information about the contents of the packets. Positive urine toxicology results were obtained in up to 78% of patients in one study.[5] However, many toxicologists now have significant questions about the clinical use of these studies due to the rate of false-positives.

Treatment is tailored to the nature of the presentation and the severity of the toxidrome. Asymptomatic body packers may be managed conservatively in an intensive care unit (ICU) while waiting for spontaneous evacuation.[2] Medical treatment is mandated in the event of drug-induced toxic effects and in cases presenting with intestinal obstruction or perforation.

For intoxication cases, initial management includes careful attention to the airway, breathing, and circulation (ABCs) and adequate resuscitation measures. Further management is based on the nature of the drug and toxidrome. Opioid poisoningis treated with naloxone. High doses may be necessary because large doses of drug may be released upon gastrointestinal rupture of the packets. Acute lung injury caused by opioid poisoning is treated with supplemental oxygen or intubation as needed.[2]

For cocaine poisoning, treatment should be initiated with high doses of benzodiazepines followed by intensive care management.[5] Ventricular arrhythmia should be managed with lidocaine and hypertonic sodium bicarbonate, and cocaine-induced hypertension should be treated with intravenous sodium nitroprusside or phentolamine.[2] In cases of leaking cocaine packets, immediate surgical removal is indicated because no specific antidote is available for cocaine overdose.[2]

Management of amphetamine poisoning is similar to that of cocaine poisoning, including prompt surgical removal of leaking packets.[2]  Marijuana and hashish intoxication is managed with supportive treatment.[2]

In the case of bowel obstruction, activated charcoal can be given for cocaine packers at a dose of 1 g per kg of body weight (up to 50 g) every 4 hours for several doses. Oil-based laxatives should be avoided; however, whole-bowel irrigation with polyethylene glycol electrolyte lavage solution can be attempted to aid gentle passage of the packets.[2]Ipecac syrup, enemas, and cathartics carry a possibility of packet rupture and must not be used.[3] Endoscopic retrieval of packets also entails risk for rupture; therefore, this method is not usually recommended unless carried out in an ICU or operating room.[2,3] Imaging is to be repeated until three packet-negative stools are obtained or according to the count given by the packer to confirm that no packet is left behind.

Prompt surgical management is indicated for packers who present with complications of intestinal obstruction or perforation.[2] Enterotomy incisions are made as required, and the intestinal contents are milked toward the incisions or the anus.[2] Postoperative imaging (CT or barium study) should be done to ensure the complete removal of packets.[2]

In this case, the patient was administered naloxone and was prepared for surgery. Evidence of packet rupture was found, and the packets were successfully removed. The patient survived the surgery and recovered well.

Cases of body packing have been increasing recently because strict border security procedures have made conventional drug smuggling difficult.[6] Physicians and radiologists should therefore be aware of this potentially fatal form of drug smuggling, its various presentations, and the relevant imaging findings in order to make a prompt diagnosis and begin the appropriate management.


  1. Deitel M, Syed AK. Intestinal obstruction by an unusual foreign body. Can Med Assoc J. 1973;109:211-212. Source 
  2. Traub SJ, Hoffman RS, Nelson LS. Body packing--the internal concealment of illicit drugs. N Engl J Med. 2003;349:2519-2526. Source 
  3. Pidoto RR, Agliata AM, Bertoline R, Mainini A, Rossi G, Giani G. A new method of packaging cocaine for international traffic and implications for the management of cocaine body-packers. J Emerg Med. 2002;23:149-153. Source 
  4. Hergan K, Kofler K, Oser W. Drug smuggling by body packing: what radiologists should know about it. Eur Radiol. 2004;14:736-742. Source 
  5. Dueñas-Laita A, Nogué S, Burillo-Putze G. Body packing. N Engl J Med. 2004;350:1260-1261. Source 
  6. Cappelletti S, Picacentino D, Ciallella C. Systemic Review of Drug Packaging Methods in Body Packing and Pushing: A Need for New Classification. Am J Forensic Med Pathol. 2019 Mar; 40(1):27-42. Source

Source:  Medscape Case Challenge, April 9, 2023

Paxlovid, Antivirals, and Risk of COVID REBOUND

A new study just published in Lancet shows that Paxlovid does not increase the incidence of rebound COVID infections.  Rebound is defined as an increase in viral load after a short period of recovery from a primary COVID infection.  The rebound rates in those who took Paxlovid were not statistically different than rebound rates in those who did not take the drug. The large study involving 4,592 people also found that rebound risk was increased in the 18-65 age group (vs older patients), those with chronic medical conditions, and in those receiving steroid treatment for an unrelated condition.  Also, the severity of the rebound infection was no greater in those who took Paxlovid than those who didn't take the medication. The hospitalization and death rates were essentially equivalent.  The conclusion of this study is antivirals such as Paxlovid should be prescribed to people who are at high risk of developing severe COVID.

Click here to read the full study

Chronic and Acute Poisoning From Substances in Air, Food, and Water

Environmental toxins that find their way into our air, food, and water over the past few decades have dramatically increased.  Many of these substances have adverse health effects in both humans and animals that may account for the increase of cancer, including an increase in colon cancer in younger age groups.  Patients often present to the Emergency Room with vague complaints that leave Emergency Physicians without a clear diagnosis.  Vague symptoms and general malaise may be secondary to acute or chronic exposure to environmental and occupational toxins.  The following article that appeared in a recent issue of Medscape for Physicians summarizes the toxicology and dangers of several of the more common environmental adulterants. 

If the pandemic served as a window into our health, what it revealed was a US population that is not only sick but also seemingly only getting sicker. Life expectancy is falling precipitously. Three fourths of Americans are overweight or obese, half have diabetes or prediabetes, and a majority are metabolically unhealthy. Furthermore, the rates of allergic, inflammatory, and autoimmune diseases are rising at rates of 3%-9% per year in the West, far faster than the speed of genetic change in this population.

Of course, diet and lifestyle are major factors behind such trends, but a grossly underappreciated driver in what ails us is the role of environmental toxins and endocrine-disrupting chemicals. In years past, these factors have largely evaded the traditional Western medical establishment; however, mounting evidence now supports their significance in fertility, metabolic health, and cancer.


Although several industrial chemicals and toxins have been identified as carcinogens and have subsequently been regulated, many more remain persistent in the environment and continue to be freely used. It is therefore incumbent upon both the general public and clinicians to be knowledgeable about these exposures. Here, we review some of the most common exposures and the substantial health risks associated with them, along with some general guidance around best practices for how to minimize exposure.


"Microplastics" is a term used to describe small fragments or particles of plastic breakdown or microbeads from household or personal care products, measuring less than 5 mm in length.


Plastic waste is accumulating at alarming and devastating proportions — by 2050, it is estimated that by weight, there will be more plastic than fish in the oceans. That translates into hundreds of thousands of tons of microplastics and trillions of these particles in the seas. A recent study demonstrated that microplastics were present in the bloodstream in the majority of 22 otherwise healthy participants.

Since the 1950s, plastic exposure has been shown to promote tumorigenesis in animal studies, and in vitro studies have demonstrated the toxicity of microplastics at the cellular level. However, it is not well known whether the plastic itself is toxic or if it simply serves as a carrier for other environmental toxins to bioaccumulate.

According to Tasha Stoiber, a senior scientist at the Environmental Working Group (EWG), "Microplastics have been widely detected in fish and seafood, as well as other products like bottled water, beer, honey, and tap water." EWG states there are no formal advisories on fish consumption to avoid exposure to microplastics at the moment.

Pressure also is mounting for a ban on microbeads in personal care products.


Until such bans are put in place, it is advised to avoid single-use plastics, favor reusable tote bags for grocery shopping rather than plastic bags, and opt for loose leaf tea or paper tea bags rather than mesh-based alternatives.



Phthalates are chemicals used to make plastics soft and durable, as well as to bind fragrances. They are commonly found in household items such as vinyl (eg, flooring, shower curtains) and fragrances, air fresheners, and perfumes.


Phthalates are known hormone-disrupting chemicals, exposure to which has been associated with abnormal sexual and brain development in children, as well as lower levels of testosterone in men. Exposures are thought to occur via inhalation, ingestion, and skin contact; however, fasting studies demonstrate that a majority of exposure is probably food related.


To avoid phthalate exposures, recommendations include avoiding polyvinyl chloride plastics (particularly food containers, plastic wrap, and children's toys), which is identifiable by the recycle code number 3, as well as air fresheners and fragranced products.


The EWG's Skin Deep database provides an important resource on phthalate-free personal care products.


Despite pressure from consumer advocacy groups, the US Food and Drug Administration has not yet banned phthalates in food packaging.


Bisphenol A (BPA) 

BPA is a chemical additive used to make clear and hard polycarbonate plastics, as well as epoxy and thermal papers. BPA is one of the highest-volume chemicals, with roughly 6 billion pounds produced each year. BPA is traditionally found in many clear plastic bottles and sippy cups, as well as in the lining of canned foods.


Structurally, BPA acts as an estrogen mimetic and has been associated with cardiovascular diseaseobesity, and male sexual dysfunction. Since 2012, BPA has been banned in sippy cups and baby bottles, but there is some debate as to whether its replacements (bisphenol S and bisphenol F) are any safer; they appear to have similar hormonal effects as BPA.


As with phthalates, the majority of ingestion is thought to be food related. BPA has been found in more than 90% of a representative study population in the United States.


Guidance advises avoiding polycarbonate plastics (identifiable with the recycling code number 7), as well as avoiding handling thermal papers such as tickets and receipts, if possible. Food and beverages should be stored in glass or stainless steel. If plastic must be used, opt for polycarbonate- and polyvinyl chloride–free plastics, and food and beverage should never be reheated in plastic containers or wrapping. Canned foods should ideally be avoided, particularly canned tunas and condensed soups. If canned products are bought, they should ideally be BPA free.


Dioxins and Polychlorinated Biphenyls (PCBs) 

Dioxins are mainly the byproducts of industrial practices; they are released after incineration, trash burning, and fires. PCBs, which are somewhat structurally related to dioxins, were previously found in products such as flame retardants and coolants. Dioxins and PCBs are often grouped in the same category under the umbrella term "persistent organic pollutants" because they break down slowly and remain in the environment even after emissions have been curbed.


Tetrachlorodibenzodioxin, perhaps the best-known dioxin, is a known carcinogen. Dioxins also have been associated with a host of health implications in development, immunity, and reproductive and endocrine systems. Higher levels of PCB exposure have also been associated with an increased risk for mortality from cardiovascular disease.


Notably, dioxin emissions have been reduced by 90% since the 1980s, and the US Environmental Protection Agency (EPA) has banned the use of PCBs in industrial manufacturing since 1979. However, environmental dioxins and PCBs still enter the food chain and accumulate in fat.


The best ways to avoid exposures are through limiting meat, fish, and dairy consumption and trimming the skin and fat from meats. The level of dioxins and PCBs found in meat, eggs, fish, and dairy are approximately 5-10 times higher than they are in plant-based foods. Research has shown that farmed salmon is likely to be the most PCB-contaminated protein source in the US diet; however, newer forms of land-based and sustainable aquaculture probably avoid this exposure.



The growth of modern monoculture agriculture in the United States over the past century has coincided with a dramatic surge in the use of industrial pesticides. In fact, over 90% of the US population have pesticides in their urine and blood, regardless of where they live. Exposures are thought to be food related.


Approximately 1 billion pounds of pesticides are used annually in the United States, including nearly 300 million pounds of glyphosate, which has been identified as a probable carcinogen by European agencies. The EPA has not yet reached this conclusion, although the matter is currently being litigated.


A large European prospective cohort trial demonstrated a lower risk for cancer in those with a greater frequency of self-reported organic food consumption. In addition to cancer risk, relatively elevated blood levels of a pesticide known as beta-hexachlorocyclohexane (B-HCH) are associated with higher all-cause mortality. Also, exposure to DDE — a metabolite of DDT, a chlorinated pesticide heavily used in the 1940s-1960s that still persists in the environment today — has been shown to increase the risk for Alzheimer's-type dementia as well as overall cognitive decline.


Because these chlorinated pesticides are often fat soluble, they seem to accumulate in animal products. Therefore, people consuming a vegetarian diet have been found to have lower levels of B-HCH. This has led to the recommendation that consumers of produce should favor organic over conventional, if possible. Here too, the EWG provides an important resource to consumers in the form of shopper guides regarding pesticides in produce.


Per- and Polyfluoroalkyl Substances (PFAS) 

PFAS are a group of fluorinated compounds discovered in the 1930s. Their chemical composition includes a durable carbon-fluoride bond, giving them a persistence within the environment that has led to their being referred to as "forever chemicals."


PFAS have been detected in the blood of 98% of Americans, and in the rainwater of locations as far afield as Tibet and Antarctica. Even low levels of exposure have been associated with an increased risk for cancer, liver disease, low birthweight, and hormonal disruption.


The properties of PFAS also make them both durable at very high heat and water repellent. Notoriously, the chemical was used by 3M to make Scotchgard for carpets and fabrics and by Dupont to make Teflon for nonstick coating of pots and pans. Although perfluorooctanoic acid (PFOA) was removed from nonstick cookware in 2013, PFAS — a family of thousands of synthetic compounds — remain common in fast-food packaging, water- and stain-repellent clothing, firefighting foam, and personal care products. PFAS are released into the environment during the breakdown of these consumer and industrial products, as well as from dumping from waste facilities.


Alarmingly, the EWG notes that up to 200 million Americans may be exposed to PFAS in their drinking water. In March 2021, the EPA announced that they will be regulating PFAS in drinking water; however, the regulations have not been finalized. Currently, it is up to individual states to test for its presence in the water. The EWG has compiled a map of all known PFAS contamination sites.


To avoid or prevent exposures from PFAS, recommendations include filtering tap water with either reverse osmosis or activated carbon filters, as well as avoiding fast food and carry-out food, if possible, and consumer products labeled as "water resistant," "stain-resistant," and "nonstick."


In a testament to how harmful these chemicals are, the EPA recently revised their lifetime health advisories for PFAS, such as PFOA, to 0.004 parts per trillion, which is more than 10,000 times smaller than the previous limit of 70 parts per trillion. The EPA also has proposed formally designating certain PFAS chemicals as "hazardous substances."

A Tsunami of Viral Infections Is Due this Fall and Winter

Emergency Physicians have been consulting with primary care, public health, and infectious disease consultants regarding an anticipated spike of viral infections in the coming fall and winter months.  Central to this discussion is treatment and the safety of prophylactic vaccines, how to educate patients, how to identify these viral agents, and what treatement to administer.  The following is the latest communication from the CDC concerning these matters including treatment recommendations.  It is included here for general information.  Email me if you have any questions.    Dr. Gustin/Emergency Physician

The Centers for Disease Control and Prevention (CDC) is issuing this Health Alert Network (HAN) Health Advisory about early, elevated respiratory disease incidence caused by multiple viruses occurring especially among children and placing strain on healthcare systems. Co-circulation of respiratory syncytial virus (RSV), influenza viruses, SARS-CoV-2, and others could place stress on healthcare systems this fall and winter. This early increase in disease incidence highlights the importance of optimizing respiratory virus prevention and treatment measures, including prompt vaccination and antiviral treatment, as outlined below.

Many respiratory viruses with similar clinical presentations circulate year-round in the United States and at higher levels in fall and winter. In the past 2 years, respiratory disease activity has been dominated by SARS-CoV-2, and seasonal circulation of other respiratory viruses has been atypical or lower than pre-COVID-19 pandemic years. Currently, the U.S. is experiencing a surge and co-circulation of respiratory viruses other than SARS-CoV-2. CDC is tracking levels of respiratory syncytial virus (RSV), influenza, and rhinovirus/enterovirus (RV/EV) that are higher than usual for this time of year, especially among children, though RV/EV levels may have plateaued in recent weeks. SARS-CoV-2 also continues to circulate in all U.S. states.

CDC surveillance has shown an increase in RSV detections and RSV-associated emergency department visits and hospitalizations in all but two U.S. Department of Health and Human Services (HHS) regions (regions 4 and 6), with some regions already near the seasonal peak levels typically observed in December or January. This year, rates of RSV-associated hospitalizations began to increase during late spring and continued to increase through the summer and into early fall. Preliminary data from October 2022 show that weekly rates of RSV-associated hospitalizations among children younger than 18 years old are higher than rates observed during similar weeks in recent years. While RSV activity appears to be plateauing in some places, the timing, intensity, and severity of the current RSV season are uncertain.

CDC has been tracking early and increasing influenza activity in recent weeks. The highest levels of influenza activity have been found in the southeast and south-central parts of the country. The most common viruses identified to date have been influenza A(H3N2) viruses, with most infections occurring in children and young adults. Cumulative influenza-associated hospitalization rates for children (age 0–4 years and 5–17 years) and all ages combined are notably higher compared to the same time periods during previous seasons since 2010–2011. Although the timing, intensity, and severity of the 2022–2023 influenza season are uncertain, CDC anticipates continued high-level circulation of influenza viruses this fall and winter.

CDC data are available to monitor COVID-19 community levels, which are based on hospitalization and case data and can be used to track SARS-CoV-2 activity. SARS-CoV-2 activity is expected to increase in the winter as has been observed in previous years. Rates of COVID-19-associated hospitalizations among all age groups including children have decreased since August, but rates in infants younger than 6 months remain higher than in other pediatric age groups and higher than in all adult age groups except those 65 years and older. CDC expects continued high-level circulation of SARS-CoV-2 this fall and winter.

Recommendations for Healthcare Providers
CDC recommends that healthcare providers offer prompt vaccination against influenza and COVID-19 to all eligible people aged 6 months and older who are not up to date. Vaccination can prevent hospitalization and death associated with influenza and SARS-CoV-2 viruses.

Influenza vaccines have been updated for the current season (1). Of influenza A(H3N2) viruses that have been analyzed in the United States since May 2022, most A(H3N2) viruses are genetically and antigenically closely related to the updated A(H3N2) vaccine component. These data suggest influenza vaccination this season should offer protection against the predominant A(H3N2) viruses to date.

Currently approved SARS-CoV-2 bivalent mRNA booster doses for use in patients 5 years of age and older offer protection against both the ancestral SARS-CoV-2 virus and the currently predominant Omicron BA.4 and BA.5 subvariants that cause COVID-19. Emerging evidence suggests that COVID-19 vaccination provides some protection against multisystem inflammatory syndrome in children (MIS-C) and against post-COVID-19 conditions, and that vaccination among persons with post–COVID-19 conditions might help reduce their symptoms (2).

To prevent RSV-associated hospitalizations, eligible high-risk children should receive palivizumab treatment in accordance with AAP guidelines. In brief, children eligible for palivizumab include infants prematurely born at less than 29 weeks gestation, children younger than 2 years of age with chronic lung disease or hemodynamically significant congenital heart disease, and children with suppressed immune systems or neuromuscular disorders.

While vaccination is the primary means for preventing influenza and COVID-19, antiviral medications are important adjuncts used to treat illness in persons with severe illness and those at increased risk for complications. Both influenza and COVID-19 antiviral medications are most effective in reducing complications when treatment is started as early as possible after symptom onset.

Specific Considerations for Healthcare Providers

1. Recommend and offer vaccinations against influenza and COVID-19 for all eligible persons aged 6 months or older

Anyone who has not received an influenza vaccine this season or who is not up to date with COVID-19 vaccination should be vaccinated now. Influenza and COVID-19 vaccines can be administered at the same visit. Vaccination is the best way to reduce the chance of illness and complications, including those resulting in hospitalization and death, from influenza and COVID-19. For the 2022-2023 influenza season, CDC recommends influenza vaccination with a licensed age-appropriate influenza vaccine for all people months and older (3). For COVID-19, CDC recommends that everyone 6 months and older complete a primary series of COVID-19 vaccines (4). In addition, CDC recommends that people 5 years and older receive one updated (bivalent) booster, if it has been at least 2 months since their last COVID-19 vaccine dose, whether that was a primary series or original (monovalent) booster (4). This recommendation includes people who have received more than one original (monovalent) booster. To date, uptake of both the current seasonal influenza vaccine and COVID-19 booster vaccines remains suboptimal (5, 6, 7).

For COVID-19, preexposure prophylaxis with EVUSHELDTM, a monoclonal antibody, may help prevent COVID-19 in persons 12 years and older who are moderately to severely immunocompromised who might not mount an adequate immune response after COVID-19 vaccination, as well as persons for whom COVID-19 vaccination is not recommended because of their personal risk for severe adverse reactions. These guidelines may be updated based on circulation of variants with reduced susceptibility to monoclonal antibodies.

2. Use diagnostic testing to guide treatment and clinical management

With multiple co-circulating respiratory viruses, particularly influenza and SARS-CoV-2, for which there are antiviral options recommended for specific groups, diagnostic testing can guide treatment and management to improve patients’ clinical course and outcomes. Diagnostic testing should be considered for patients with suspected respiratory virus infections, particularly among hospitalized patients, those with factors placing persons at high risk for severe outcomes from flu and COVID-19, and those with severe or progressive illness. Molecular assays are recommended when testing for RSV, influenza, SARS-CoV-2, and other respiratory viruses in hospitalized patients with suspected respiratory virus infections, and multiplex respiratory testing should be considered since multiple respiratory viruses may cause severe illness. Information to assist clinicians about when to consider respiratory virus testing is available at Information for Clinicians on Influenza Virus TestingRespiratory Syncytial Virus for Healthcare Professionals, and COVID-19 Testing: What You Need to Know. Information on RV/EV, EV-D68 testing was described in detail in a HAN Health Advisory released on September 9, 2022.

3. Treat patients with suspected or confirmed influenza who meet clinical criteria with influenza antivirals

CDC recommends influenza antiviral treatment as early as possible for any patient with confirmed or suspected influenza who is: a) hospitalized; b) an outpatient at higher risk for influenza complications; or c) an outpatient with severe, complicated, or progressive illness. Treatment with influenza antivirals has been shown to be safe and have clinical and public health benefit for both children and adults. Evidence from observational studies, randomized controlled trials, and meta-analyses of randomized controlled trials shows influenza antivirals reduce illness and severe outcomes of influenza (8, 9, 10, 11, 12). Clinical benefit is greatest when antiviral treatment is administered as early as possible after illness onset (ideally within 48 hours), although antiviral treatment initiated later than 48 hours after illness onset can still be beneficial for some patients (e.g., outpatients at increased risk for complications and hospitalized patients). Clinicians should not wait for laboratory confirmation to decide when to start influenza antiviral treatment in patients with suspected influenza.

Oral oseltamivir (generic formulation or Tamiflu®) is the recommended antiviral for outpatients with severe, complicated, or progressive illness and for hospitalized influenza patients. Oral baloxavir marboxil (Xofluza®) is approved by the U.S. Food and Drug Administration (FDA) for treating acute uncomplicated influenza in people 5 years and older who are otherwise healthy or in people 12 years and older who are at high risk of developing influenza-related complications. Oseltamivir is available as both an oral suspension and as capsules, whereas baloxavir is available only as tablets in the United States this fall and winter. Inhaled zanamivir and intravenous peramivir are less commonly used influenza antiviral medications. There is additional information on influenza antiviral medications for clinicians on the CDC website.

4. Treat outpatients and hospitalized patients with confirmed SARS-CoV-2 infection who are at increased risk for severe illness and meet age- and weight-eligibility requirements 

COVID-19 antiviral agents reduce risk for hospitalization and death when administered soon after diagnosis. The antiviral medications nirmatrelvir and ritonavir (Paxlovid) or remdesivir (Veklury) are the preferred treatment options for COVID-19 in patients with mild to moderate illness who are at increased risk for severe illness, including older adults, unvaccinated persons, and those with certain medical conditions (14). The antiviral medication molnupiravir (Lagevrio) and monoclonal antibody bebtelovimab are alternative treatment options when Paxlovid and Veklury are contraindicated or not available. Additional information is available about treatment options for hospitalized adults and children and outpatient adults and childrenGuidelines may be updated based on information about susceptibility of circulating SARS-CoV-2 variants.

5. Resources for patient education

In addition to practicing everyday prevention methods, like avoiding close contact with people who are sick, staying home when sick, covering coughs and sneezes, and hand washing, there are additional considerations for patients to help control the spread of and treat influenza, RSV, and COVID-19.

For patients and the general public who would like to know more about RSV, and clinicians who would like to learn about the impact of RSV infections among older adults, see Older Adults are at High Risk for Severe RSV Infection. Materials describing RSV prevention information in English and Spanish are also available.

Only about half of the U.S. population receives an annual influenza vaccine for various reasons, including misinformation about vaccination. Patient education materials are available at the Seasonal Flu Partner Resources Center. In addition, results from unpublished CDC qualitative research shows that many people are not aware that there are drugs to treat influenza illness. A fact sheet for patients is available.

Symptoms of COVID-19, options when experiencing symptoms (including getting tested for COVID-19 and isolation guidance), when to seek emergency medical attention, and differences between influenza and COVID-19 are described here: Symptoms of COVID-19 | CDC. CDC also provides easy-to-read COVID-19 materials.

For More Information 






  1. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2022-2023 northern hemisphere influenza season. Accessed October 27, 2022.  https://www.who.int/publications/m/item/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2022-2023-northern-hemisphere-influenza-season
  2. Zambrano LD, Newhams MM, Olson SM, et al. BNT162b2 mRNA Vaccination Against COVID-19 is Associated With a Decreased Likelihood of Multisystem Inflammatory Syndrome in Children Aged 5–18 Years—United States, July 2021 – April 2022, Clinical Infectious Diseases 2022; ciac637. https://doi.org/10.1093/cid/ciac637
  3. Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2022-23 Influenza Season. MMWR Recomm Rep 2022;71(1);1–28. http://dx.doi.org/10.15585/mmwr.rr7101a1
  4. Centers for Disease Control and Prevention.  Use of COVID-19 Vaccines in the United States. Accessed November 3, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
  5. Centers for Disease Control and Prevention.  Weekly Flu Vaccination Dashboard. Accessed November 3, 2022. https://www.cdc.gov/flu/fluvaxview/dashboard/vaccination-dashboard.html
  6. Black CL, O’Halloran A, Hung M, et al. Vital Signs: Influenza Hospitalizations and Vaccination Coverage by Race and Ethnicity-United States, 2009-10 Through 2021-22 Influenza Seasons. MMWR Morb Mortal Wkly Rep 2022;71:1366-1373. https://dx.doi.org/10.15585/mmwr.mm7143e1
  7. Saelee R, Zell E, Murthy BP, et al. Disparities in COVID-19 Vaccination Coverage Between Urban and Rural Counties — United States, December 14, 2020–January 31, 2022. MMWR Morb Mortal Wkly Rep 2022;71:335–340. https://doi.org/10.15585/mmwr.mm7109a2
  8. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis 2019;68(6):895-902. https://doi.org/10.1093/cid/ciy874
  9. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018;379(10):913-923. https://doi.org/10.1056/NEJMoa1716197
  10. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2(5):395-404. https://doi.org/10.1016/S2213-2600(14)70041-4
  11. Venkatesan S, Myles PR, Bolton KJ, et al. Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection. J Infect Dis 2020;221(3):356-366. https://doi.org/10.1093/infdis/jiz152
  12. Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomized, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214.  https://doi.org/10.1016/S1473-3099(20)30004-9
  13. CDC: Influenza Antiviral Medications: Summary for Clinicians. Accessed October 28, 2022. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm
  14. CDC. Interim clinical considerations for COVID-19 treatment in outpatients. Atlanta, GA: US Department of Health and Human Services, CDC; 2022. Accessed November 4, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/outpatient-treatment-overview.html

The Inflation Reduction Act Will Doom New Drug Development

Recently an article appeared in the Wall Street Journal by Joe Grogan a USC visiting professor regarding the Inflation Reduction Act and the effects it will have on the development of new medical and surgical treatments.  Those effects are numerous and profound, and also come with a health and safety impact.  Thus, toxicologists and other medical safety experts have been paying close attention to developments.  I include the WSJ article below for your information.

It may take years before we can fully appreciate the impact of the Inflation Reduction Act on the pharmaceutical industry, but we’re already getting signs of the damage. While Democrats boast that they’ve given Medicare the power to “negotiate” drug prices, the effect has been to saddle manufacturers with a complex and ill-conceived price-setting scheme. In response, many have canceled drug-development programs, resulting in an unfortunate but predictable loss for patients nationwide.

One poorly crafted provision is driving companies away from research into treating rare diseases. In its Oct. 27 earnings statement, Alnylam announced it is suspending development of a treatment for Stargardt disease, a rare eye disorder, because of the company’s need “to evaluate impact of the Inflation Reduction Act.” Alnylam’s decision turns on a provision in the Democrats’ bill that exempts from price-setting negotiations drugs that treat only one rare disease. The company’s drug is currently marketed as treating only amyloidosis, and thus is exempt from Medicare’s price setting. If Alnylam proceeded with research into treating Stargardt, it would lose its exemption.

That disincentive might be most pronounced in cancer treatments. On Tuesday, Eli Lillyannounced it is canceling work on a drug that had been undergoing studies for certain blood cancers. “In light of the Inflation Reduction Act,” the company wrote to Endpoints News, “this program no longer met our threshold for continued investment.”

When pharmaceutical companies develop cancer drugs, they usually first develop them for a single indication. Only after the first approval do they research additional indications. Merck’s Keytruda, which successfully treated President Jimmy Carter, was first approved for advanced melanoma in 2014. Today the company lists 19 approved indications on its website. Genentech’s Herceptin, a critical breast-cancer treatment, gained approval in the adjuvant cancer setting eight years after its original approval in the metastatic setting. Today it also has an indication for treating gastric cancer.

Nearly 60% of oncology medications approved a decade ago received additional approvals in later years. The new law eliminates the incentive to conduct additional research, because its price-setting mechanisms kick in after nine years for small-molecule drugs and 13 years for biologics, regardless of how much research companies conduct after the drug’s initial approval.

In devising their bill this way, Democrats have effectively undone decades of bipartisan policy that promoted research and development by balancing profit incentives with cost concerns. The Orphan Drug Act of 1983, which Alnylam counted on in developing its now-abandoned program, provided a combination of tax credits, grants and market exclusivity to create incentive for investment in rare-disease drugs. Fifty-two Republicans and 118 Democrats co-sponsored the law, which Democratic Rep. Henry Waxman called “an example of government at its finest, demonstrating how Congress applies itself to solve overlooked, but deeply important, problems that affect millions of Americans.”

The next year, Mr. Waxman and Republican Sen. Orrin Hatch led another bipartisan coalition to pass the Hatch-Waxman Act. Their bill granted innovators a temporary market monopoly of five years with potential extensions. In return, innovators would submit to generic competition at the end of their monopoly period. The monopoly-to-commodity-pricing pipeline has been a boon for the generic-drug industry and innovators, as well as patients and their families. 

The Hatch-Waxman Act also provided six months of market exclusivity for generic manufacturers that undertook the expense and risk of developing first-on-the-market generic drugs. This allowed generics to recoup costs over those first six months as they gained market share against the innovator. As other generics entered the market, prices would plummet for patients and insurers, such as Medicare. According to the Association for Accessible Medicines, more than 90% of prescriptions in Medicare’s Part D program in 2019 were for generic drugs, which saves more than $96 billion annually for Medicare and billions more for seniors. With the impending price caps, these incentives are lost. 

Yet that’s still not all the bipartisan legislation that the Inflation Reduction Act destroys. The Food and Drug Administration Modernization Act (1997) provided six months of market exclusivity to manufacturers that conduct pediatric studies for their drugs. That too was a cross-party success, shepherded by a bipartisan cast of eight senators. Pediatric clinical trials carry a host of challenges: Parents are often reluctant to include their children in them and research ethics boards impose more-stringent protections for kids. These challenges lead companies to test therapies for adult indications first. If these are successful, then they may initiate pediatric trials. The new law undercuts these incentives by mandating drastic Medicare price reductions, reducing resources available for pediatric trials and disrupting entire R&D programs.

The Democrats may have achieved a short-term talking point for the midterm elections, but in the long term this partisan healthcare bill will prevent patients from receiving innovative, lifesaving treatments. A new Congress would serve Americans well by replacing the Inflation Reduction Act with an approach that recognizes the need for economic incentives to bring new treatments to patients.

Aspirin--No longer Recommended for Primary Cardiac Disease Prevention

Aspirin is to date the most used drug worldwide and, in 2018, with some dispute about its real birth date, celebrated its 121st birthday; 2018 will most probably be remembered as the year when aspirin came of age, whereby multiple studies re-examined, and at least partially questioned, its risk/benefit ratio in various clinical settings.[1–4] While aspirin remains the cornerstone treatment for secondary prevention in patients with established cardiovascular disorders, three large, independent, and high quality randomized controlled trials have shed new light on aspirin in primary prevention.[2–4] These recent results now have to be incorporated within the context of previously existing evidence, which altogether questions the somewhat liberal use of aspirin that has so far been recommended by some,[5] but not by other, guidelines committees.[6]

In this issue of the European Heart Journal, Mahmoud and colleagues furnish the findings on a meta-analysis and trial sequential analysis of randomized trials evaluating the efficacy and safety of aspirin among patients without prior known history of atherosclerotic cardiovascular disease.[7] A total of 11 studies with 157 248 participants met the pre-defined inclusion criteria, amongst which were (i) a randomized study design; (ii) comparing aspirin vs. placebo/no aspirin control; (iii) in adult patients without prior history of atherosclerosis; and (iv) including 500 patients or more. It should be emphasized that unlike some previous meta-analyses,[8] which also were claimed to focus on primary prevention, studies including patients with known atherosclerosis and peripheral vascular disease without having yet experienced an ischaemic event or revascularization (the so-called 1.5 prevention setting) had been excluded for the analysis. Yet, a sensitivity analysis, which also included patients with an established atherosclerotic disorder, mainly in the peripheral system, is provided and yields almost identical implications for practice.

This updated meta-analysis focused on mortality as the principal endpoint. This did not differ between the aspirin and control groups [4.6% vs. 4.7%; relative risk (risk ratio (RR)) = 0.98, 95% confidence interval (CI) 0.93–1.02, P = 0.30], without heterogeneity across studies and no signal of any treatment effect at interaction testing across pre-defined subgroups including the 10-year risk, diabetes, mid-enrolment year, aspirin dose, risk of bias, and follow-up duration.

The incidence of major bleeding was higher with aspirin, yielding a 47% higher RR and a number needed to harm (NNH) in the range of 250.

Similarly, the risk of intracranial bleeding, which was a pre-defined component of the major bleeding definition in all except one study,[9] was increased with a 33% relative and 0.1% absolute (NNH =1000) difference.

Cardiovascular mortality or stroke did not differ in patients with or without aspirin, which seriously contributes to the unfavourable risk/benefit profile of aspirin in the primary prevention setting.

However, the incidence of myocardial infarction (MI) was lower with aspirin [2.0% vs. 2.3%, 95% CI 1.7–2.8%; RR = 0.82, 95% CI 0.71–0.94, P = 0.006, number needed to treat (NNT) = 333]. One may wonder whether trading a single MI for bleeding would be an acceptable option. The comparative prognostic implications of bleeding vs. a non-fatal MI for mortality have been investigated at least in the secondary prevention setting and, unsurprisingly, the outcomes depend on the severity of bleeding, with intracranial episodes greatly exceeding the prognostic role of an MI in terms of mortality.[10] Yet, the key upstream question remains of whether the effect of aspirin on MI prevention is real and reproducible in contemporary practice. When looking at the current pooled analysis, the effect size of aspirin on MI was characterized by a high degree of heterogeneity between the studies included (I 2 = 67%) and a secondary analysis excluding older trials with mid-enrolment year prior to 2000 showed the lack of aspirin benefit even on MIs in more recent trials (RR = 0.90, 95% CI 0.79–1.02, P = 0.10). This observation may have multiple and not necessarily mutually exclusive explanations. Mahmoud and colleagues place emphasis on the fact that old studies pre-dated the universal definitions of MI and used relatively insensitive cardiac markers for the diagnosis of an MI.

If one plots the use of statins and the relative risk reductions for MI across the 11 included studies, an obvious association emerges between no or minimal use of statins and greater absolute effect of aspirin on MI prevention.

Among the contemporary studies evaluating aspirin in primary prevention, only the Japanese Primary Prevention Project observed a significant MI benefit with aspirin.[9]Interestingly, in this study, >70% of the patients had known dyslipidemia, but only 51% of them received statins during the course of the study.[9]

In the HOT trial, allocation to aspirin was also associated with a significant 35% MI risk reduction.[11] Yet, only 7% of the patients were treated with lipid-lowering drugs, and the mean total cholesterol was 235 mg/dL, suggesting a non-negligible proportion of patients with hypercholesterolaemia who may have derived benefit from lipid-lowering agents.[11] In primary prevention trials, the use of statins is known to be associated with a 25% decrease in the risk of major vascular events for every 1 mmol/L decrease in the LDL cholesterol level (rate ratio with statin vs. placebo, 0.75; 95% CI 0.69–0.82).[12] This statistically significant benefit was associated with an excellent safety profile and was not associated with the bleeding risks observed consistently throughout all aspirin trials.

Moreover, an intriguing observation regarding cholesterol levels and MI benefit of aspirin in the primary prevention setting comes from the Physicians' Health Study, which ante-dated the availability of statins.[13] In this trial, a significant interaction was noted between baseline cholesterol level and relative risk reduction for MI, with greater benefit observed in patients with the highest baseline cholesterol levels. Hence, taken together, current evidence raises concerns that aspirin can significantly contribute to MI prevention in patients when properly treated with lipid-lowering agents as per todays' practice and guidelines.

The recent results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), where high-dose icosapent ethyl led in the primary prevention setting to a consistent reduction of the primary composite ischaemic endpoint, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, without a significant increase in bleeding risk—albeit with a higher incidence of atrial fibrillation or flutter whose implications and mechanisms need to be better understood—further highlights the key role of lipid-lowering agents even in patients in whom the median LDL cholesterol level was 75.0 mg/dL at baseline.[14]

Whether routine antiplatelet agents, other than aspirin, will still have a possible role in high-risk patients in the truly primary prevention setting remains unclear, but it appears rather unlikely given the well-known trade-off between risks and benefits observed consistently across all antithrombotic agents investigated so far.

The issue of the management of patients fulfilling the 1.5 prevention setting, i.e. in whom an atherosclerotic disorder has been established prior to the occurrence of an ischaemic event or to the development of related symptoms, still remains unresolved. A pragmatic approach in this setting might be a selected use of aspirin only for patients on the low bleeding risk spectrum in the hope that this strategy might maximize the benefits over the risks.[15]

The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS, NCT01991795) is designed to evaluate the efficacy and safety of ticagrelor in >20 000 patients aged 50 years or more with type 2 diabetes with known coronary artery disease but without a history of an MI or stroke. Patients are being randomized to ticagrelor 60 mg twice daily or placebo in a double-blinded fashion. The primary endpoint is the composite of cardiovascular death, MI, or stroke at 48 months. Results of the THEMIS trial are expected in early 2019 and will greatly contribute to our current understanding about the future role of antiplatelet agents as a primary means to avoid the consequences of plaque rupture in patients who may have ongoing yet asymptomatic plaque rupture episodes. Meanwhile, we should get ready to say a farewell to aspirin even in asymptomatic patients in whom an atherosclerosis disorder is not established, irrespective of the anticipated risk of future ischaemic events or concomitant cardiovascular risk factors.


  1. Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S, GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018;392:940–949.
  2. Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, Howard G, Pearson TA, Rothwell PM, Ruilope LM, Tendera M, Tognoni G; ARRIVE Executive Committee. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018;392:1036–1046.
  3. Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379:1529–1539.
  4. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, Reid CM, Lockery JE, Kirpach B, Storey E, Shah RC, Williamson JD, Margolis KL, Ernst ME, Abhayaratna WP, Stocks N, Fitzgerald SM, Orchard SG, Trevaks RE, Beilin LJ, Johnston CI, Ryan J, Radziszewska B, Jelinek M, Malik M, Eaton CB, Brauer D, Cloud G, Wood EM, Mahady SE, Satterfield S, Grimm R, Murray AM, ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509–1518.
  5. Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016;164:836–845.
  6. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S, ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–2381.
  7. Mahmoud AN, Gad MM, Elgendy AY, Elgendy IY, Bavry AA. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J 2019;40:607–617.
  8. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–1860.
  9. Ikeda Y, Shimada K, Teramoto T, Uchiyama S, Yamazaki T, Oikawa S, Sugawara M, Ando K, Murata M, Yokoyama K, Ishizuka N. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA 2014;312:2510–2520.
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Kratom Products from Southeast Asia are Contaminated with Heavy Metals

Final results of tests performed by the US Food and Drug Administration (FDA) on 30 kratom products confirm the presence of heavy metals, including lead and nickel, at concentrations not considered safe for human consumption, the FDA said Wednesday.

The FDA first warned of "disturbingly" high levels of heavy metals, including lead and nickel, last November, as reported by Medscape Medical News.  The FDA has posted a list of the kratom products and concentrations of heavy metals found in them on its website. Based on reported patterns of kratom use, heavy kratom users may be exposed to levels of lead and nickel many times greater than the safe daily exposure, the FDA warns in a statement.

Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and increased risk of certain cancers, the agency adds.

"Over the last year, the FDA has issued numerous warnings about the serious risks associated with the use of kratom, including novel risks due to the variability in how kratom products are formulated, sold and used both recreationally and by those who are seeking to self-medicate for pain or to treat opioid withdrawal symptoms," FDA Commissioner Scott Gottlieb, MD, said in the statement.

Gottlieb said the FDA has been "attempting to work" with the companies whose kratom products contain high levels of heavy metals.  The agency has released the final laboratory results to the public to "help make sure consumers are fully informed of these risks." "The data from these results support our public warning about the risk of heavy metals in kratom products. The findings of identifying heavy metals in kratom only strengthen our public health warnings around this substance and concern for the health and safety of Americans using it," he added.

No Approved Use Kratom is derived from the leaves of the kratom tree (Mitragyna speciosa), which is native to Thailand, Indonesia, and Papua New Guinea. The botanical's popularity has been increasing in the United States, with manufacturers — and those who take it — claiming it can help treat pain, anxiety, depression, and more recently, opioid withdrawal. Last year, an analysis of kratom by FDA scientists found that its compounds act like prescription-strength opioids. In addition to heavy metal contamination, kratom products have also been found to be contaminated with Salmonella, resulting in numerous illnesses and product recalls. Kratom has been linked to numerous deaths in the United States. There are currently no FDA-approved uses for kratom, and the agency has advised against using kratom or its psychoactive compounds mitragynine and 7-hydroxymitragynine in any form and from any manufacturer.

Health providers are encouraged to report any adverse reactions related to kratom products to MedWatch, the FDA's safety information and adverse event reporting program.

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