A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

A geologic display currently on exhibit at the National Institutes of Health Clinical Center in Bethesda, Md., includes several samples of minerals that can be utilized in dermatology.

The “Minerals in Medicine” exhibit, put on by the Clinical Center in partnership with the Smithsonian National Museum of Natural History, includes “more than 40 minerals that are crucial to human health and biomedicine,” according to an NIH statement.

NIH Clinical Center, Smithsonian National Museum of Natural History

NIH Clinical Center, Smithsonian National Museum of Natural History

[email protected]

A geologic display currently on exhibit at the National Institutes of Health Clinical Center in Bethesda, Md., includes several samples of minerals that can be utilized in dermatology.

The “Minerals in Medicine” exhibit, put on by the Clinical Center in partnership with the Smithsonian National Museum of Natural History, includes “more than 40 minerals that are crucial to human health and biomedicine,” according to an NIH statement.

NIH Clinical Center, Smithsonian National Museum of Natural History

NIH Clinical Center, Smithsonian National Museum of Natural History

[email protected]

A geologic display currently on exhibit at the National Institutes of Health Clinical Center in Bethesda, Md., includes several samples of minerals that can be utilized in dermatology.

The “Minerals in Medicine” exhibit, put on by the Clinical Center in partnership with the Smithsonian National Museum of Natural History, includes “more than 40 minerals that are crucial to human health and biomedicine,” according to an NIH statement.

NIH Clinical Center, Smithsonian National Museum of Natural History

NIH Clinical Center, Smithsonian National Museum of Natural History

[email protected]

And remember: you must never, under any circumstances, despair. To hope and to act, these are our duties in misfortune.

—Boris Pasternak, Doctor Zhivago

This editorial is being written on Veterans Day. Likely you will read it when the stores and streets are lined with holiday decorations. Thanksgiving will have come and gone. All these celebrations have the common themes of giving and gratitude, and among the many requests clamoring for your attention at this season are care package collections for active-duty service members and donations for disadvantaged veterans. These efforts are well intentioned on the part of givers and appreciated on the part of those who receive them. Yet these themes remind me of the hackneyed saying we likely have all heard, and many of us have said: Thank you for your service.

Many of you may recall the controversy that emerged surrounding this seemingly innocuous cliché. It has had an Internet resurgence on this day set out to honor those who wore or are in uniform.¹ For those who don’t remember the phenomenon, I will briefly summarize. A journalist was interviewing a combat veteran from Afghanistan on a different subject but knowing he had been in the military and the reporter thinking he was being kind and respectful, like so many of us, thanked him for his service. The astute journalist could tell from the expression on the veteran’s face that the comment had touched a wound he never expected to open. But he cared enough to try and understand how the veteran heard these words from out of the depths of his memories of war.

The emotions that emerged from the interview and the online blogs and comments that followed reflect the toll that war takes: anger, anguish, alienation, which these “have a nice day” words seem to evoke, even though they are never meant to create distance, dismissal, or dishonor. This interaction was a painful one for the veteran, and even for the journalist, and created what psychologists call cognitive dissonance, “a condition of conflict or anxiety resulting from inconsistency between belief and action.”²

The reason those 5 words strike a raw nerve in some—but by no means all—who were or are in the armed forces is that those to whom they are spoken know in a deep and personal way, that we who say them usually do not know what we are talking about. I can see this reaction when I watch several of my VA colleagues who actually are combat veterans say the words but from a different theory of mind, a theory of mind they share. Theory of mind is another psychological concept that is at the core of interpersonal and communication skills, the ability to see and feel the world as another person sees it. When someone who has never fought or even served says “thank you for your service,” some veterans feel that their individual experience of combat or even of being in the military is being expressed inauthentically, even perhaps insincerely.

“To these vets, thanking soldiers for their service symbolizes the ease of sending a volunteer army to wage war at great distance—physically, spiritually, economically,” journalist Matt Richtel writes. “It raises questions of the meaning of patriotism, shared purpose and, pointedly, what you’re supposed to say to those who put their lives on the line and are uncomfortable about being thanked for it.”²

My father, a World War II combat veteran and career army physician, told me when I was young that there were 3 experiences that could never be understood unless you lived them: pregnancy, medical school, and combat. I’m not sure why or how he chose these although I am sure they were not original, but having gone through the second, I believe it was because these events are of such personal intensity, such immediate contact with the human condition in all its suffering and resilience that they cannot be faithfully replicated in any in vitro simulation but only in vivo.

Which brings me to the title of the column. How can we say thank you to our friends and family members, our coworkers, and our patients who went to war and returned, who enlisted ready to go into combat even if the fates did not send them? Reading the comments of these men and women in response to the superficial phrase with which we habitually acknowledge their sacrifice leaves me wondering what to say to express our obligation to those who struggled through foreign tribulations while we remained safe at home. Their reflections offer some surprising suggestions that seem prophetic as we as a country process the results of the recent election with grief, triumph, or indifference.

We can say thank you through voting, donations, or advocacy as long as we act to promote the most fundamental good for humanity. We say thank you when we act to help a veteran to live a decent and rewarding life, to have a safe place to live, to grow through education, to share life with companions, and to find a job or another way to contribute to society. Actions to improve the living conditions of veterans now and a better future for those who leave the ranks are seeds of gratitude that come to fruition long after the empty phrases are forgotten.

We say thank you when we think and question long and hard until it hurts, until we too experience cognitive dissonance, until our theory of mind is stretched beyond its comfortable boundaries about the purpose of war in general and the justification for any particular conflict in which our government contemplates sending the young and brave to fight and die. Acting and thinking honor sacrifice as words never can.

And remember: you must never, under any circumstances, despair. To hope and to act, these are our duties in misfortune.

—Boris Pasternak, Doctor Zhivago

This editorial is being written on Veterans Day. Likely you will read it when the stores and streets are lined with holiday decorations. Thanksgiving will have come and gone. All these celebrations have the common themes of giving and gratitude, and among the many requests clamoring for your attention at this season are care package collections for active-duty service members and donations for disadvantaged veterans. These efforts are well intentioned on the part of givers and appreciated on the part of those who receive them. Yet these themes remind me of the hackneyed saying we likely have all heard, and many of us have said: Thank you for your service.

Many of you may recall the controversy that emerged surrounding this seemingly innocuous cliché. It has had an Internet resurgence on this day set out to honor those who wore or are in uniform.¹ For those who don’t remember the phenomenon, I will briefly summarize. A journalist was interviewing a combat veteran from Afghanistan on a different subject but knowing he had been in the military and the reporter thinking he was being kind and respectful, like so many of us, thanked him for his service. The astute journalist could tell from the expression on the veteran’s face that the comment had touched a wound he never expected to open. But he cared enough to try and understand how the veteran heard these words from out of the depths of his memories of war.

The emotions that emerged from the interview and the online blogs and comments that followed reflect the toll that war takes: anger, anguish, alienation, which these “have a nice day” words seem to evoke, even though they are never meant to create distance, dismissal, or dishonor. This interaction was a painful one for the veteran, and even for the journalist, and created what psychologists call cognitive dissonance, “a condition of conflict or anxiety resulting from inconsistency between belief and action.”²

The reason those 5 words strike a raw nerve in some—but by no means all—who were or are in the armed forces is that those to whom they are spoken know in a deep and personal way, that we who say them usually do not know what we are talking about. I can see this reaction when I watch several of my VA colleagues who actually are combat veterans say the words but from a different theory of mind, a theory of mind they share. Theory of mind is another psychological concept that is at the core of interpersonal and communication skills, the ability to see and feel the world as another person sees it. When someone who has never fought or even served says “thank you for your service,” some veterans feel that their individual experience of combat or even of being in the military is being expressed inauthentically, even perhaps insincerely.

“To these vets, thanking soldiers for their service symbolizes the ease of sending a volunteer army to wage war at great distance—physically, spiritually, economically,” journalist Matt Richtel writes. “It raises questions of the meaning of patriotism, shared purpose and, pointedly, what you’re supposed to say to those who put their lives on the line and are uncomfortable about being thanked for it.”²

My father, a World War II combat veteran and career army physician, told me when I was young that there were 3 experiences that could never be understood unless you lived them: pregnancy, medical school, and combat. I’m not sure why or how he chose these although I am sure they were not original, but having gone through the second, I believe it was because these events are of such personal intensity, such immediate contact with the human condition in all its suffering and resilience that they cannot be faithfully replicated in any in vitro simulation but only in vivo.

Which brings me to the title of the column. How can we say thank you to our friends and family members, our coworkers, and our patients who went to war and returned, who enlisted ready to go into combat even if the fates did not send them? Reading the comments of these men and women in response to the superficial phrase with which we habitually acknowledge their sacrifice leaves me wondering what to say to express our obligation to those who struggled through foreign tribulations while we remained safe at home. Their reflections offer some surprising suggestions that seem prophetic as we as a country process the results of the recent election with grief, triumph, or indifference.

We can say thank you through voting, donations, or advocacy as long as we act to promote the most fundamental good for humanity. We say thank you when we act to help a veteran to live a decent and rewarding life, to have a safe place to live, to grow through education, to share life with companions, and to find a job or another way to contribute to society. Actions to improve the living conditions of veterans now and a better future for those who leave the ranks are seeds of gratitude that come to fruition long after the empty phrases are forgotten.

We say thank you when we think and question long and hard until it hurts, until we too experience cognitive dissonance, until our theory of mind is stretched beyond its comfortable boundaries about the purpose of war in general and the justification for any particular conflict in which our government contemplates sending the young and brave to fight and die. Acting and thinking honor sacrifice as words never can.

And remember: you must never, under any circumstances, despair. To hope and to act, these are our duties in misfortune.

—Boris Pasternak, Doctor Zhivago

This editorial is being written on Veterans Day. Likely you will read it when the stores and streets are lined with holiday decorations. Thanksgiving will have come and gone. All these celebrations have the common themes of giving and gratitude, and among the many requests clamoring for your attention at this season are care package collections for active-duty service members and donations for disadvantaged veterans. These efforts are well intentioned on the part of givers and appreciated on the part of those who receive them. Yet these themes remind me of the hackneyed saying we likely have all heard, and many of us have said: Thank you for your service.

Many of you may recall the controversy that emerged surrounding this seemingly innocuous cliché. It has had an Internet resurgence on this day set out to honor those who wore or are in uniform.¹ For those who don’t remember the phenomenon, I will briefly summarize. A journalist was interviewing a combat veteran from Afghanistan on a different subject but knowing he had been in the military and the reporter thinking he was being kind and respectful, like so many of us, thanked him for his service. The astute journalist could tell from the expression on the veteran’s face that the comment had touched a wound he never expected to open. But he cared enough to try and understand how the veteran heard these words from out of the depths of his memories of war.

The emotions that emerged from the interview and the online blogs and comments that followed reflect the toll that war takes: anger, anguish, alienation, which these “have a nice day” words seem to evoke, even though they are never meant to create distance, dismissal, or dishonor. This interaction was a painful one for the veteran, and even for the journalist, and created what psychologists call cognitive dissonance, “a condition of conflict or anxiety resulting from inconsistency between belief and action.”²

The reason those 5 words strike a raw nerve in some—but by no means all—who were or are in the armed forces is that those to whom they are spoken know in a deep and personal way, that we who say them usually do not know what we are talking about. I can see this reaction when I watch several of my VA colleagues who actually are combat veterans say the words but from a different theory of mind, a theory of mind they share. Theory of mind is another psychological concept that is at the core of interpersonal and communication skills, the ability to see and feel the world as another person sees it. When someone who has never fought or even served says “thank you for your service,” some veterans feel that their individual experience of combat or even of being in the military is being expressed inauthentically, even perhaps insincerely.

“To these vets, thanking soldiers for their service symbolizes the ease of sending a volunteer army to wage war at great distance—physically, spiritually, economically,” journalist Matt Richtel writes. “It raises questions of the meaning of patriotism, shared purpose and, pointedly, what you’re supposed to say to those who put their lives on the line and are uncomfortable about being thanked for it.”²

My father, a World War II combat veteran and career army physician, told me when I was young that there were 3 experiences that could never be understood unless you lived them: pregnancy, medical school, and combat. I’m not sure why or how he chose these although I am sure they were not original, but having gone through the second, I believe it was because these events are of such personal intensity, such immediate contact with the human condition in all its suffering and resilience that they cannot be faithfully replicated in any in vitro simulation but only in vivo.

Which brings me to the title of the column. How can we say thank you to our friends and family members, our coworkers, and our patients who went to war and returned, who enlisted ready to go into combat even if the fates did not send them? Reading the comments of these men and women in response to the superficial phrase with which we habitually acknowledge their sacrifice leaves me wondering what to say to express our obligation to those who struggled through foreign tribulations while we remained safe at home. Their reflections offer some surprising suggestions that seem prophetic as we as a country process the results of the recent election with grief, triumph, or indifference.

We can say thank you through voting, donations, or advocacy as long as we act to promote the most fundamental good for humanity. We say thank you when we act to help a veteran to live a decent and rewarding life, to have a safe place to live, to grow through education, to share life with companions, and to find a job or another way to contribute to society. Actions to improve the living conditions of veterans now and a better future for those who leave the ranks are seeds of gratitude that come to fruition long after the empty phrases are forgotten.

We say thank you when we think and question long and hard until it hurts, until we too experience cognitive dissonance, until our theory of mind is stretched beyond its comfortable boundaries about the purpose of war in general and the justification for any particular conflict in which our government contemplates sending the young and brave to fight and die. Acting and thinking honor sacrifice as words never can.

Click here to access the December 2016 Digital Edition

Table of Contents

• How Can We Say Thank You?
• How Well Does the Braden Nutrition Subscale Agree With the VA Nutrition Classification Scheme Related to Pressure Ulcer Risk?
• Proton Pump Inhibitor-Associated Hypomagnesemia
• Simulation Training, Coaching, and Cue Cards Improve Delirium Care
• Memory Skills Classes for Older Veterans With a History of Posttraumatic Stress Disorder
• Neurosurgical Subspecialty Bedside Nursing Guide Improves Confidence
• A Primary Care Approach to Managing Chronic Noncancer Pain
• "Where’s the Music?" Using Music Therapy for Pain Management

Click here to access the December 2016 Digital Edition

Table of Contents

• How Can We Say Thank You?
• How Well Does the Braden Nutrition Subscale Agree With the VA Nutrition Classification Scheme Related to Pressure Ulcer Risk?
• Proton Pump Inhibitor-Associated Hypomagnesemia
• Simulation Training, Coaching, and Cue Cards Improve Delirium Care
• Memory Skills Classes for Older Veterans With a History of Posttraumatic Stress Disorder
• Neurosurgical Subspecialty Bedside Nursing Guide Improves Confidence
• A Primary Care Approach to Managing Chronic Noncancer Pain
• "Where’s the Music?" Using Music Therapy for Pain Management

Click here to access the December 2016 Digital Edition

Table of Contents

• How Can We Say Thank You?
• How Well Does the Braden Nutrition Subscale Agree With the VA Nutrition Classification Scheme Related to Pressure Ulcer Risk?
• Proton Pump Inhibitor-Associated Hypomagnesemia
• Simulation Training, Coaching, and Cue Cards Improve Delirium Care
• Memory Skills Classes for Older Veterans With a History of Posttraumatic Stress Disorder
• Neurosurgical Subspecialty Bedside Nursing Guide Improves Confidence
• A Primary Care Approach to Managing Chronic Noncancer Pain
• "Where’s the Music?" Using Music Therapy for Pain Management

Not all cancers are the same, and quality of life (QOL) for cancer survivors is not the same across the board. Researchers from Fudan University in Shanghai, China, say the effects of exercise for cancer survivors are different, too.

The researchers surveyed 3,392 cancer survivors (colorectal, lung, ovarian, cervical, liver, and endometrial). They asked the patients about the type of physical activity (PA) they engaged in (eg, vigorous walking, table tennis, tai chi) for at least 30 minutes once a week in the previous month. They also asked about frequency (1 – 4 times a week and 5 or more times a week). They used a 27-item self-reporting instrument to measure QOL, with questions on functional status, symptoms, and emotional and social well-being.

Related: Exercise Lowers Risk of Some Cancers

Liver cancer survivors had the poorest QOL in several areas, including the highest level of appetite loss, worst emotional well-being, and worst financial difficulties. Lung cancer survivors reported worse physical functioning than did gynecologic or colorectal cancer survivors, as well as higher scores for dyspnea. Colorectal cancer survivors had the second highest scores on appetite loss and the most serious diarrhea.

However, survivors of all cancer types who engaged in PA reported statistically significant higher scores in physical functioning than did their counterparts. Survivors of lung, gynecologic, and colorectal cancer reported significantly better cognitive functioning. The association was not observed among liver cancer survivors.

Physically active survivors also generally reported lower symptom levels—although only insomnia was significantly lower (among liver cancer survivors). Physically active survivors did not show statistically significant improvements in constipation or diarrhea.

Related: Improving the Quality of Life and Care for Cancer Survivors

Physically active survivors of lung, gynecologic, and colorectal cancer received significantly higher scores on well-being scales. The relationship between PA and QOL was not statistically significant among liver cancer survivors.

The researchers did not observe associations between increased frequency of PA and physical functioning or physical well-being among gynecologic or liver cancer survivors. In fact, gynecologic cancer survivors with more frequent PA reported poorer QOL in role functioning, social functioning, and global health status, as well as lower scores on many symptom scales. The researchers found similar results among colorectal and liver cancer survivors; they say this may be because higher PA frequency is related to poorer QOL conditions for some measures.

Related: The Impact of Obesity on the Recovery of Patients With Cancer

Finally, the researchers were not able to define a statistically significant association between PA frequency and QOL. Based on their findings, they “cautiously advocate” for not “strongly” suggesting a higher frequency of PA to gynecologic, colorectal, or liver cancer survivors.

Source:
Tang F, Wang J, Tang Z, Kang M, Deng Q, Yu J. PLoS ONE. 2016;11(11):e0164971.

Not all cancers are the same, and quality of life (QOL) for cancer survivors is not the same across the board. Researchers from Fudan University in Shanghai, China, say the effects of exercise for cancer survivors are different, too.

The researchers surveyed 3,392 cancer survivors (colorectal, lung, ovarian, cervical, liver, and endometrial). They asked the patients about the type of physical activity (PA) they engaged in (eg, vigorous walking, table tennis, tai chi) for at least 30 minutes once a week in the previous month. They also asked about frequency (1 – 4 times a week and 5 or more times a week). They used a 27-item self-reporting instrument to measure QOL, with questions on functional status, symptoms, and emotional and social well-being.

Related: Exercise Lowers Risk of Some Cancers

Liver cancer survivors had the poorest QOL in several areas, including the highest level of appetite loss, worst emotional well-being, and worst financial difficulties. Lung cancer survivors reported worse physical functioning than did gynecologic or colorectal cancer survivors, as well as higher scores for dyspnea. Colorectal cancer survivors had the second highest scores on appetite loss and the most serious diarrhea.

However, survivors of all cancer types who engaged in PA reported statistically significant higher scores in physical functioning than did their counterparts. Survivors of lung, gynecologic, and colorectal cancer reported significantly better cognitive functioning. The association was not observed among liver cancer survivors.

Physically active survivors also generally reported lower symptom levels—although only insomnia was significantly lower (among liver cancer survivors). Physically active survivors did not show statistically significant improvements in constipation or diarrhea.

Related: Improving the Quality of Life and Care for Cancer Survivors

Physically active survivors of lung, gynecologic, and colorectal cancer received significantly higher scores on well-being scales. The relationship between PA and QOL was not statistically significant among liver cancer survivors.

The researchers did not observe associations between increased frequency of PA and physical functioning or physical well-being among gynecologic or liver cancer survivors. In fact, gynecologic cancer survivors with more frequent PA reported poorer QOL in role functioning, social functioning, and global health status, as well as lower scores on many symptom scales. The researchers found similar results among colorectal and liver cancer survivors; they say this may be because higher PA frequency is related to poorer QOL conditions for some measures.

Related: The Impact of Obesity on the Recovery of Patients With Cancer

Finally, the researchers were not able to define a statistically significant association between PA frequency and QOL. Based on their findings, they “cautiously advocate” for not “strongly” suggesting a higher frequency of PA to gynecologic, colorectal, or liver cancer survivors.

Source:
Tang F, Wang J, Tang Z, Kang M, Deng Q, Yu J. PLoS ONE. 2016;11(11):e0164971.

Not all cancers are the same, and quality of life (QOL) for cancer survivors is not the same across the board. Researchers from Fudan University in Shanghai, China, say the effects of exercise for cancer survivors are different, too.

The researchers surveyed 3,392 cancer survivors (colorectal, lung, ovarian, cervical, liver, and endometrial). They asked the patients about the type of physical activity (PA) they engaged in (eg, vigorous walking, table tennis, tai chi) for at least 30 minutes once a week in the previous month. They also asked about frequency (1 – 4 times a week and 5 or more times a week). They used a 27-item self-reporting instrument to measure QOL, with questions on functional status, symptoms, and emotional and social well-being.

Related: Exercise Lowers Risk of Some Cancers

Liver cancer survivors had the poorest QOL in several areas, including the highest level of appetite loss, worst emotional well-being, and worst financial difficulties. Lung cancer survivors reported worse physical functioning than did gynecologic or colorectal cancer survivors, as well as higher scores for dyspnea. Colorectal cancer survivors had the second highest scores on appetite loss and the most serious diarrhea.

However, survivors of all cancer types who engaged in PA reported statistically significant higher scores in physical functioning than did their counterparts. Survivors of lung, gynecologic, and colorectal cancer reported significantly better cognitive functioning. The association was not observed among liver cancer survivors.

Physically active survivors also generally reported lower symptom levels—although only insomnia was significantly lower (among liver cancer survivors). Physically active survivors did not show statistically significant improvements in constipation or diarrhea.

Related: Improving the Quality of Life and Care for Cancer Survivors

Physically active survivors of lung, gynecologic, and colorectal cancer received significantly higher scores on well-being scales. The relationship between PA and QOL was not statistically significant among liver cancer survivors.

The researchers did not observe associations between increased frequency of PA and physical functioning or physical well-being among gynecologic or liver cancer survivors. In fact, gynecologic cancer survivors with more frequent PA reported poorer QOL in role functioning, social functioning, and global health status, as well as lower scores on many symptom scales. The researchers found similar results among colorectal and liver cancer survivors; they say this may be because higher PA frequency is related to poorer QOL conditions for some measures.

Related: The Impact of Obesity on the Recovery of Patients With Cancer

Finally, the researchers were not able to define a statistically significant association between PA frequency and QOL. Based on their findings, they “cautiously advocate” for not “strongly” suggesting a higher frequency of PA to gynecologic, colorectal, or liver cancer survivors.

Source:
Tang F, Wang J, Tang Z, Kang M, Deng Q, Yu J. PLoS ONE. 2016;11(11):e0164971.

Lab mice

Photo by Aaron Logan

Researchers have created a patch designed to monitor a patient’s blood and release heparin as needed to prevent thrombosis.

In mice, the patch successfully released heparin into the bloodstream and proved more effective at preventing thrombosis than an injection of heparin.

Zhen Gu, PhD, of the University of North Carolina at Chapel Hill, and his colleagues developed the patch and described it in Advanced Materials.

“Our goal was to generate a patch that can monitor a patient’s blood and release additional drugs when necessary; effectively, a self-regulating system,” Dr Gu said.

The patch incorporates microneedles made of a polymer that consists of hyaluronic acid (HA) and the drug heparin. The polymer has been modified to be responsive to thrombin.

When elevated levels of thrombin enzymes in the bloodstream come into contact with the microneedle, the enzymes break the amino acid chains that bind the heparin to the HA, releasing the heparin into the bloodstream.

“The more thrombin there is in the bloodstream, the more heparin is needed to reduce clotting,” said study author Yuqi Zhang, a PhD student in Dr Gu’s lab. “So we created a disposable patch in which the more thrombin there is in the bloodstream, the more heparin is released.”

“We will further enhance the loading amount of drug in the patch,” said study author Jicheng Yu, a PhD student in Dr Gu’s lab.

“The amount of heparin in a patch can be tailored to a patient’s specific needs and replaced daily, or less often, as needed. But the amount of heparin being released into the patient at any given moment will be determined by the thrombin levels in the patient’s blood.”

Experiments in mice

The researchers tested the patch in a mouse model of thrombosis. The mice were injected with large doses of thrombin (1000 U kg^-1) to induce an acute thromboembolism, which can lead to death in about 92% of mice.

The mice were then randomized into 5 different treatment groups:

• Intravenous heparin injection
• Empty HA microneedle patch
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch
• Non-responsive HA-heparin microneedle patch (heparin dose: 200 U kg⁻¹).

The mice that received heparin via injection were treated before thrombosis induction. The microneedle patches were applied to the dorsum skin of the mice 10 minutes before the challenge.

All of the mice with the HA microneedle patch or the non-responsive HA-heparin microneedle patch died within 15 minutes of the thrombin injection.

All of the mice that received the heparin injection, heparin microneedle patch, or the thrombin-responsive HA-heparin microneedle patch survived the 15 minutes.

In a second experiment, mice received a thrombin injection 6 hours after treatment, and treatment consisted of:

• Heparin injection
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch.

Fifteen minutes after the thrombin injection, death had occurred in 80% or more of the mice that received the heparin injection and the mice treated with the heparin microneedle patch.

But all of the mice treated with the thrombin-responsive HA-heparin microneedle patch survived.

The researchers also noted that staining of lung sections revealed the “superior anticoagulant capacity” of the thrombin-responsive HA-heparin microneedle patch.

The team observed “insignificant differences” in the lungs of healthy mice and mice treated with the thrombin-responsive HA-heparin microneedle patch.

However, mice that received a heparin injection or treatment with the heparin microneedle patch had intravascular and interstitial hemorrhage, blocked blood vessels, and atelectasis.

“We’re excited about the possibility of using a closed-loop, self-regulating smart patch to help treat a condition that affects thousands of people every year, while hopefully also driving down treatment costs,” Dr Gu said. “This paper represents a good first step, and we’re now looking for funding to perform additional preclinical testing.”

Lab mice

Photo by Aaron Logan

Researchers have created a patch designed to monitor a patient’s blood and release heparin as needed to prevent thrombosis.

In mice, the patch successfully released heparin into the bloodstream and proved more effective at preventing thrombosis than an injection of heparin.

Zhen Gu, PhD, of the University of North Carolina at Chapel Hill, and his colleagues developed the patch and described it in Advanced Materials.

“Our goal was to generate a patch that can monitor a patient’s blood and release additional drugs when necessary; effectively, a self-regulating system,” Dr Gu said.

The patch incorporates microneedles made of a polymer that consists of hyaluronic acid (HA) and the drug heparin. The polymer has been modified to be responsive to thrombin.

When elevated levels of thrombin enzymes in the bloodstream come into contact with the microneedle, the enzymes break the amino acid chains that bind the heparin to the HA, releasing the heparin into the bloodstream.

“The more thrombin there is in the bloodstream, the more heparin is needed to reduce clotting,” said study author Yuqi Zhang, a PhD student in Dr Gu’s lab. “So we created a disposable patch in which the more thrombin there is in the bloodstream, the more heparin is released.”

“We will further enhance the loading amount of drug in the patch,” said study author Jicheng Yu, a PhD student in Dr Gu’s lab.

“The amount of heparin in a patch can be tailored to a patient’s specific needs and replaced daily, or less often, as needed. But the amount of heparin being released into the patient at any given moment will be determined by the thrombin levels in the patient’s blood.”

Experiments in mice

The researchers tested the patch in a mouse model of thrombosis. The mice were injected with large doses of thrombin (1000 U kg^-1) to induce an acute thromboembolism, which can lead to death in about 92% of mice.

The mice were then randomized into 5 different treatment groups:

• Intravenous heparin injection
• Empty HA microneedle patch
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch
• Non-responsive HA-heparin microneedle patch (heparin dose: 200 U kg⁻¹).

The mice that received heparin via injection were treated before thrombosis induction. The microneedle patches were applied to the dorsum skin of the mice 10 minutes before the challenge.

All of the mice with the HA microneedle patch or the non-responsive HA-heparin microneedle patch died within 15 minutes of the thrombin injection.

All of the mice that received the heparin injection, heparin microneedle patch, or the thrombin-responsive HA-heparin microneedle patch survived the 15 minutes.

In a second experiment, mice received a thrombin injection 6 hours after treatment, and treatment consisted of:

• Heparin injection
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch.

Fifteen minutes after the thrombin injection, death had occurred in 80% or more of the mice that received the heparin injection and the mice treated with the heparin microneedle patch.

But all of the mice treated with the thrombin-responsive HA-heparin microneedle patch survived.

The researchers also noted that staining of lung sections revealed the “superior anticoagulant capacity” of the thrombin-responsive HA-heparin microneedle patch.

The team observed “insignificant differences” in the lungs of healthy mice and mice treated with the thrombin-responsive HA-heparin microneedle patch.

However, mice that received a heparin injection or treatment with the heparin microneedle patch had intravascular and interstitial hemorrhage, blocked blood vessels, and atelectasis.

“We’re excited about the possibility of using a closed-loop, self-regulating smart patch to help treat a condition that affects thousands of people every year, while hopefully also driving down treatment costs,” Dr Gu said. “This paper represents a good first step, and we’re now looking for funding to perform additional preclinical testing.”

Lab mice

Photo by Aaron Logan

Researchers have created a patch designed to monitor a patient’s blood and release heparin as needed to prevent thrombosis.

In mice, the patch successfully released heparin into the bloodstream and proved more effective at preventing thrombosis than an injection of heparin.

Zhen Gu, PhD, of the University of North Carolina at Chapel Hill, and his colleagues developed the patch and described it in Advanced Materials.

“Our goal was to generate a patch that can monitor a patient’s blood and release additional drugs when necessary; effectively, a self-regulating system,” Dr Gu said.

The patch incorporates microneedles made of a polymer that consists of hyaluronic acid (HA) and the drug heparin. The polymer has been modified to be responsive to thrombin.

When elevated levels of thrombin enzymes in the bloodstream come into contact with the microneedle, the enzymes break the amino acid chains that bind the heparin to the HA, releasing the heparin into the bloodstream.

“The more thrombin there is in the bloodstream, the more heparin is needed to reduce clotting,” said study author Yuqi Zhang, a PhD student in Dr Gu’s lab. “So we created a disposable patch in which the more thrombin there is in the bloodstream, the more heparin is released.”

“We will further enhance the loading amount of drug in the patch,” said study author Jicheng Yu, a PhD student in Dr Gu’s lab.

“The amount of heparin in a patch can be tailored to a patient’s specific needs and replaced daily, or less often, as needed. But the amount of heparin being released into the patient at any given moment will be determined by the thrombin levels in the patient’s blood.”

Experiments in mice

The researchers tested the patch in a mouse model of thrombosis. The mice were injected with large doses of thrombin (1000 U kg^-1) to induce an acute thromboembolism, which can lead to death in about 92% of mice.

The mice were then randomized into 5 different treatment groups:

• Intravenous heparin injection
• Empty HA microneedle patch
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch
• Non-responsive HA-heparin microneedle patch (heparin dose: 200 U kg⁻¹).

The mice that received heparin via injection were treated before thrombosis induction. The microneedle patches were applied to the dorsum skin of the mice 10 minutes before the challenge.

All of the mice with the HA microneedle patch or the non-responsive HA-heparin microneedle patch died within 15 minutes of the thrombin injection.

All of the mice that received the heparin injection, heparin microneedle patch, or the thrombin-responsive HA-heparin microneedle patch survived the 15 minutes.

In a second experiment, mice received a thrombin injection 6 hours after treatment, and treatment consisted of:

• Heparin injection
• HA microneedle patch encapsulating free heparin
• Thrombin-responsive HA-heparin microneedle patch.

Fifteen minutes after the thrombin injection, death had occurred in 80% or more of the mice that received the heparin injection and the mice treated with the heparin microneedle patch.

But all of the mice treated with the thrombin-responsive HA-heparin microneedle patch survived.

The researchers also noted that staining of lung sections revealed the “superior anticoagulant capacity” of the thrombin-responsive HA-heparin microneedle patch.

The team observed “insignificant differences” in the lungs of healthy mice and mice treated with the thrombin-responsive HA-heparin microneedle patch.

However, mice that received a heparin injection or treatment with the heparin microneedle patch had intravascular and interstitial hemorrhage, blocked blood vessels, and atelectasis.

“We’re excited about the possibility of using a closed-loop, self-regulating smart patch to help treat a condition that affects thousands of people every year, while hopefully also driving down treatment costs,” Dr Gu said. “This paper represents a good first step, and we’re now looking for funding to perform additional preclinical testing.”

NCCN Guidelines for Patients®:

Nausea and Vomiting

©NCCN® 2016

The National Comprehensive Cancer Network (NCCN) has released new educational materials designed to help cancer patients combat nausea and vomiting.

The NCCN Guidelines for Patients® for Nausea and Vomiting and NCCN Quick Guide™ for Nausea and Vomiting are the first patient resources from NCCN to focus specifically on supportive care.

The resources are available on NCCN.org/patients and via the NCCN Patient Guides for Cancer mobile app.

NCCN Guidelines for Patients are patient-friendly translations of the NCCN Clinical Practice Guidelines in Oncology. Each resource features guidance from US cancer centers designed to help people living with cancer talk with their physicians about the best treatment options for their disease.

NCCN Quick Guide™ sheets are 1-page summaries of key points in the patient guidelines. They include elements such as “questions to ask your doctor,” a glossary of terms, and medical illustrations of anatomy, tests, and treatments.

The NCCN Guidelines for Patients for Nausea and Vomiting:

• Explain how these side effects are related to cancer treatment
• List cancer treatments that can cause nausea and vomiting
• Detail methods of preventing and treating these side effects
• Outline methods of coping with nausea and vomiting
• Provide a list of resources for information and support.

“At NCCN, our mission is to improve the lives of patients with cancer, and we are excited to be able to provide the information that will help patients better understand this common side effect of cancer treatment,” said Marcie R. Reeder, executive director of the NCCN Foundation.

“The NCCN Guidelines for Patients for Nausea and Vomiting are the first of a highly anticipated library of supportive care resources that provide patients with the same information their doctors use.”

NCCN Guidelines for Patients®:

Nausea and Vomiting

©NCCN® 2016

The National Comprehensive Cancer Network (NCCN) has released new educational materials designed to help cancer patients combat nausea and vomiting.

The NCCN Guidelines for Patients® for Nausea and Vomiting and NCCN Quick Guide™ for Nausea and Vomiting are the first patient resources from NCCN to focus specifically on supportive care.

The resources are available on NCCN.org/patients and via the NCCN Patient Guides for Cancer mobile app.

NCCN Guidelines for Patients are patient-friendly translations of the NCCN Clinical Practice Guidelines in Oncology. Each resource features guidance from US cancer centers designed to help people living with cancer talk with their physicians about the best treatment options for their disease.

NCCN Quick Guide™ sheets are 1-page summaries of key points in the patient guidelines. They include elements such as “questions to ask your doctor,” a glossary of terms, and medical illustrations of anatomy, tests, and treatments.

The NCCN Guidelines for Patients for Nausea and Vomiting:

• Explain how these side effects are related to cancer treatment
• List cancer treatments that can cause nausea and vomiting
• Detail methods of preventing and treating these side effects
• Outline methods of coping with nausea and vomiting
• Provide a list of resources for information and support.

“At NCCN, our mission is to improve the lives of patients with cancer, and we are excited to be able to provide the information that will help patients better understand this common side effect of cancer treatment,” said Marcie R. Reeder, executive director of the NCCN Foundation.

“The NCCN Guidelines for Patients for Nausea and Vomiting are the first of a highly anticipated library of supportive care resources that provide patients with the same information their doctors use.”

NCCN Guidelines for Patients®:

Nausea and Vomiting

©NCCN® 2016

The National Comprehensive Cancer Network (NCCN) has released new educational materials designed to help cancer patients combat nausea and vomiting.

The NCCN Guidelines for Patients® for Nausea and Vomiting and NCCN Quick Guide™ for Nausea and Vomiting are the first patient resources from NCCN to focus specifically on supportive care.

The resources are available on NCCN.org/patients and via the NCCN Patient Guides for Cancer mobile app.

NCCN Guidelines for Patients are patient-friendly translations of the NCCN Clinical Practice Guidelines in Oncology. Each resource features guidance from US cancer centers designed to help people living with cancer talk with their physicians about the best treatment options for their disease.

NCCN Quick Guide™ sheets are 1-page summaries of key points in the patient guidelines. They include elements such as “questions to ask your doctor,” a glossary of terms, and medical illustrations of anatomy, tests, and treatments.

The NCCN Guidelines for Patients for Nausea and Vomiting:

• Explain how these side effects are related to cancer treatment
• List cancer treatments that can cause nausea and vomiting
• Detail methods of preventing and treating these side effects
• Outline methods of coping with nausea and vomiting
• Provide a list of resources for information and support.

“At NCCN, our mission is to improve the lives of patients with cancer, and we are excited to be able to provide the information that will help patients better understand this common side effect of cancer treatment,” said Marcie R. Reeder, executive director of the NCCN Foundation.

“The NCCN Guidelines for Patients for Nausea and Vomiting are the first of a highly anticipated library of supportive care resources that provide patients with the same information their doctors use.”

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.