Tox and Hound – Fellow Friday – Stabilized Chlorine: The Clinical Toxicology of Chlorinated Cyanuric Acids

From Bleached Flour and Canine Hysteria to Mercury, Cl₂, Swimming Pools, Kidney Failure, and Explosions

Steven Curry, M.D.
University of Arizona College of Medicine – Phoenix
Department of Medical Toxicology
Banner – University Medical Center Phoenix
Phoenix, AZ
@SteveCurryMD

Introduction

While it is swimming season pretty much year-round in Phoenix, kids have been jumping into unheated swimming pools for many weeks. The CDC reports that over 4,500 ED visits occur annually from pool chemical injuries. It’s a good time to briefly review the clinical toxicology of stabilized chlorine products used in swimming pools and other applications. The subject matter allows us to explore several topics that are clinically relevant and may appear on toxicology boards, as well as some fascinating history.

In 2019, Andrew Stolbach provided a great review on this site that focused on chlorine chemistry in swimming pools. We will touch on some basic principles Andrew discussed in detail when addressing stabilized chlorine products. But to bring everything together, we need to know a bit about nitrogen trichloride (NCl₃), the manufacture of chlorine and hypochlorite (bleach), the dangers of eating large amounts of flour bleached with “agene” gas, cyanuric acid with its relationship to melamine-induced kidney failure, stabilized chlorine products, and the explosive dangers of mixing pool chemicals that extend far beyond the hazards of simply combining bleach with acid or ammonia. I extend a special thanks to Dr. Michael Worboys, University of Manchester, Sheffield, UK, for providing difficult-to-find historical information on canine hysteria.

After reading this post, medical toxicology fellows should:

• Recognize the explosive nature of NCl₃.
• Understand the historical agene gas process and toxicology associated with it.
• Appreciate the historical occupational hazard associated with the chlor-alkali industry.
• Recognize the potential for alkaline corrosive injury in liquid bleach products.
• Know purpose of cyanuric acid in swimming pool chemistry and relationship to kidney failure.
• Name 2 stabilized chlorine products and recognize their structures.
• List the 3 major hazards of mixing stabilized chlorine products with small amounts of water or with other agents.

Let’s begin with Pierre Louis Dulong.

Pierre Louis Dulong and NCl₃

Pierre Dulong was a French scientist who became especially well-known for his research on the specific heat of gases.

After deciding against a military career, Dulong had entered medical school, but faced financial ruin as a practicing physician. So, he gave up the practice of medicine and turned first to botany and finally to chemistry. Dulong was eventually offered a position in a private laboratory in Arcueil under Claude Louis Berthollet, the famous chemist who was the first to demonstrate the bleaching action of Cl₂, and the first to use sodium hypochlorite solutions for the same purpose.

In October, 1811, Dulong passed Cl₂ through a solution of ammonium chloride (NH₄Cl) without anticipation of the rapid and violent explosion that ensued. Dulong lost at least two fingers and one eye. After a period of some healing, Berthollet and others encouraged him to continue his work, but he found he could not work on the dangerous oil formed in the reaction during summer, since his impure preparations kept violently exploding between 30° and 35°C. In October, 1812, he was again injured in yet another explosion and halted further research. He read his paper on this unknown oil before the Academie Des Sciences on January 7, 1813.

Andre-Marie Ampere learned of Dulong’s research and informed Sir Humphry Davy of the discovery. Davy, a British chemist, had discovered several elements, and we best know him for having experimented with nitrous oxide and writing of its potential as an anesthetic agent.

Ampre had cautioned Davy that Dulong’s heavy oil “detonates with all the violence of fulminating metals by the simple heat of the hand,” and, without providing Dulong’s name, mentioned that the discoverer of the material had lost an eye and several fingers. While that might have encouraged you or me to choose another area of inquiry, Davy moved forward, created his own method of synthesis, and noted that attempts to create and store large quantities of the substance would produce violent explosions, destroying his apparatus. Davy decided to collect the products created during the explosions, and so provided external heat to a curved glass tube sitting over water on which was floating a collection of the oil. You guessed it – an explosion sent glass flying into one eye, temporarily blinding him. Fortunately, by June of 1813 he was able to write, “I recovered the use of my eyes,” and went on to name the compound azotane, which we now know as nitrogen trichloride, or NCl₃.

NCl₃ is a yellow oily liquid at room temperature that is insoluble in cold water and very volatile, rapidly evaporating into air.

It decomposes in hot water and explodes above about 93°C, but because of intense reactivity, will react with explosive force at much lower temperatures when mixed with various agents or when impurities are present. It decomposes to N₂ and Cl₂. In air, where oxygen is present, decomposition produces nitrogen oxides (NOx), as well.

Canine hysteria, agene, and methionine sulfoximine

What do you do with something like NCl₃, given difficulty in making, storing, and using such a reactive substance? Even today it is mainly used for research purposes as a chlorinating agent. But it was found that relatively low concentrations of the gas could be used for bleaching substances, including wheat flour. Agents that had been used to bleach flour included gases such as nitrogen peroxide, Cl₂, nitrosyl chloride, and chlorine dioxide. But the agene gas method of improving and bleaching flour was used for as much as 90% of production by the mid 1940s. Agene consisted of about 1% NCl₃ in air saturated with water vapor. The gas was created by mixing appropriate quantities of Cl₂, water, and NH₄Cl. Air and the gas were then mixed and brought into contact with flour through an agitator.

Meanwhile, beginning about 1916, a disease in dogs had appeared in the southern U.S. and subsequently was recognized in England about 1924. The illness was called canine hysteria or fright disease, and the distribution and incidence of the disorder increased progressively over the next 20 years.

Dogs were described as having seen ghosts. They snapped at imaginary objects, howled, ran around wildly as though in great fear, attempted to climb walls, and sometimes experienced generalized seizures. Some would run until they died of hyperthermia. Theories abounded on the etiology, including infections such as distemper, worms, or bacterial pathogens. One author proposed the disorder resulted from inhalation of gases released from stale dog urine.

Eventually it was recognized that dogs would usually recover rather quickly if their diet was changed. This observation led to numerous investigations. Sir Edward Mellanby, for whom the Mellanby effect of ethanol is named, reported that the disease resulted from consumption of dog food/treats containing flour bleached with agene (NCl₃), but not from untreated flour.

Use of agene was quickly banned in Europe and the U.S. The potential for a human counterpart of canine hysteria was of concern, but never recognized.

Subsequent experiments led to the identification of the toxic agent responsible for the disease as being methionine sulfoximine, formed from a reaction between NCl₃ and protein.

When pure methionine sulfoximine was fed to animals, there was variability in toxic doses on a per Kg basis, and dogs were among the most sensitive, with non-human primates being among the least. Humans did not consume enough flour in their diet to approach that required to produce recognized toxicity. However, when Krakoff administered up to 400 mg of pure methionine sulfoximine in capsules daily to patients with advanced incurable cancer, he found the substance produced hallucinations, agitation and disorientation that resolved over 1 to 3 days after discontinuation. Co-administration of methionine prevented toxicity in man and animals. We now recognize methionine sulfoximine as a suicidal inhibitor of glutamine synthetase. Which pharmacologic action(s) produces encephalopathy remains to be clarified, as synthetase inhibition can be demonstrated during protective co-administration of methionine. Data suggest that it may mimic the actions of glutamate at glutamate receptors.

The banning of agene for treatment of flour ended most use of NCl₃. But its relevance to our discussion of stabilized chlorine products will resurface later.

Swimming pool chlorine and hypochlorite

Various swimming pool chlorine products are used to chlorinate pool water. Chlorine, itself, is a strong oxidant and both hypochlorous acid (HOCl) and Cl₂ are effective as algaecides and disinfectants. Chlorine products are used not only to maintain Cl₂ concentration in water in an effective but safe range for swimming, but also are added to water in larger amounts intermittently to acutely raise the chlorine level to several times greater than normal to “shock” the pool. As discussed in detail by Andrew, Cl₂ in water exists in an equilibrium with hypochlorous (HOCl) and hydrochloric acid (HCl). HCl, of course, completely dissociates at any pH found in swimming pools, while the dissociation of hypochlorous acid to a proton and hypochlorite (OCl^–) exists with a pKa of 7.54. (Figure 11) Cl₂ dissolved in water is in equilibrium with Cl₂ gas released from the water.

As pH decreases, more OCl^– in the water becomes HOCl, which in turn, dissociates to form Cl₂, increasing available, potentially free chlorine. (Figure 12)

One option to chlorinate pool water, then, would be to bubble Cl₂ into the water, maintaining pH about 7.5 or so, until the free Cl₂ concentration was in a desired range after equilibrium, though this is uncommonly done for most pools. But a good question for Med Tox fellows is, how does industry make Cl₂?

The major way Cl₂ is manufactured is using the chlor-alkali process. An electric current is sent through salt (NaCl) water, which generates Cl₂, H₂, and NaOH. The name, chlor-alkali, represents that both Cl₂ and NaOH are produced. Of course, if a different salt is used, other alkalis such as KOH can be made. The main reason the chlor-alkali process is historically important with regard to medical toxicology is that the anodes commonly were made from elemental mercury. (Figure 13) Chronic elemental mercury poisoning was a well-known occupational hazard in days gone by for chlor-alkali workers. Today virtually all mercury cell chlor-alkali production in Europe and the U.S. has been converted to a membrane cell process that does not involve mercury.

Of course, the inhalation of Cl₂ is irritating since the Cl₂ immediately dissolves in airway and mucosal water to form hydrochloric and hypochlorous acid. Onset of symptoms is immediate, typical of highly water soluble irritants.

Back to methods of chlorinating pool water. A second option would be to simply add a solution of sodium hypochlorite (NaOCl), a.k.a. bleach, and this is commonly done. After multiple equilibriums between Cl₂, HOCl, H₂O, HCl, and NaOH, the hypochlorite will, in part, form hypochlorous acid which will equilibrate with Cl₂. (Figure 14)

Now, how is bleach made? Bleach is made commercially by mixing Cl₂ with dilute solutions of caustic soda (aqueous NaOH), which produces NaCl, NaOCl, and H₂O. Bleach solutions are kept alkaline by maintaining residual amounts of NaOH in the product in order to keep the chlorine in the form of hypochlorite.

If pH falls by mixing bleach with any acid, then Cl₂ gas will be liberated. (Figures 11 & 12) The ingestion of a bleach solution not only represents oxidant injury, but also potentially an alkaline corrosive injury. The pH of household bleach commonly ranges from 11 to 13, though I have seen some products as low as 9.5. While household bleach is about 5.25% NaOCl, the “liquid chlorine” solutions sold for pool chlorination commonly contain about 10% to 12% NaOCl.

As an illustration of the potential corrosive nature of pool bleach, Rao and Hearn reported on a man pinned under a truck with a ruptured tank of 14.5% NaOCl at pH 13.5 used for pool water chlorination. Bleach poured onto his legs at about 5 gallons per minute and pooled around his torso. He could not be rapidly extricated and died within 10 minutes. His body continued to erode after death. The photo below shows the victim on his side, from behind, knees to the right.

Calcium hypochlorite is another salt that can be used for pool chlorination, though it is more commonly used to shock pools intermittently since it increases hardness of the water. We’ll return to Ca(OCl)₂ later. It is most commonly available in granules at a concentration of about 65 to 68 percent, dramatically higher than liquid NaOCl solutions.

Cyanuric acid, melamine and kidney failure

Ultraviolet (UV) light and heat rapidly degrade HOCl in pool water to HCl and O₂. Thus, when a pool is freshly filled, such as after replastering, cyanuric acid, known as a stabilizer, is added to water to protect from UV light. Cyanuric acid exists in several tautomers, though the keto form is found at the highest concentration at pool water pHs. Cyanuric acid combines with HOCl in a reversible reaction.

Melamine is a related compound of historical and toxicologic interest and is used in various plastic items, laminates, soundproofing, insulation and other products. (Figure 21) Like cyanuric acid, it is commercially synthesized from urea, and the final step of synthesis involves condensation of cyanuric acid with ammonia to form melamine.

In 2004, an outbreak of canine kidney failure associated with pet food was recognized in Asia. In 2007, the US FDA recalled some pet foods after cats and dogs became ill; many died from kidney failure. Vegetable protein products from China, labeled wheat gluten, had been adulterated with melamine and cyanuric acid to raise measured total nitrogen content, which was used as a surrogate for protein content. Both substances are filtered and excreted in urine, where cyanuric acid and melamine would combine via hydrogen bonds to form crystalline complexes that deposited in renal tubules and the urinary collecting system/bladder. (Figure 22) Cyanuric acid and melamine exhibited low LD₅₀, separately, but when given together, produced kidney injury and death at much lower doses.

In 2008 infant formulas containing melamine were recognized in Asia. An estimated 294,000 infants became ill and there were 51,900 hospitalizations. 99% of affected children were younger than 3 years of age and had ingested adulterated formula for 3 to 6 months as their only or major food source. Six children died. No co-contamination with cyanuric acid was evident, but stones were deposited in kidneys, collecting systems, and urinary bladders.

Analysis showed that melamine, in human cases, complexed with uric acid to produce deposits, again, through extensive hydrogen bonding. (Figure 24) Infants excrete several times more uric acid per day than adults, on a weight basis.

Neither melamine nor cyanuric acid are approved food additives. The amount of cyanuric acid ingested while swimming is tiny compared to amounts ingested by animals who coingested melamine and became ill from adulterated food. Cyanuric acid in swimming pools is not considered a toxic threat; concentrations in water are typically 30 to 150 ppm.

Stabilized chlorine products

If stabilizer is added only once to a pool after being filled with water, concentrations will gradually fall over time as water is removed from the pool (e.g., backwashing filter systems). Thus, “stabilized chlorine” products that release both cyanuric acid (stabilizer) and hypochlorous acid at the same time are used. There are two stabilized chlorine products in common use, and they are available in granular form to shock pools, or in tablet form for gradual release over several days. These same products are used as disinfectants, dry bleaches, in large cafeteria dishwashers, and for other purposes, as well.

Dichloroisocyanuric acid is usually available as the sodium salt. (Figure 25) Synonyms for this compound include dichlor, sodium dichloro-s-triazinetrione, Na-DCCA, and NaDCC. This product is usually found as granules for shocking pools, given its rapid dissolution in water.

Trichloroisocyanuric acid is also known as trichlor, TCCA, trichloro-s-triazinetrione, and TST (among others). It is commonly available in granular and tablet forms. (Figures 27 & 28)

Stabilized chlorine products react with water to release hypochlorous acid, which is in equilibrium with Cl₂. (Figure 29) Using trichlor as an example:

The above reaction is an abbreviated summation that includes intermediate steps in which trichlor goes to dichlor + HOCl, then to monochloroisocyanuric acid + HOCl, and then to cyanuric acid + HOCl. You get the idea.

Acute oral ingestions of solid stabilized chlorine products in quantities large enough to produce toxicity have not been described in the human literature and these products are generally of low oral toxicity in animals (e.g., ~ 600 to 1500 mg/Kg LD₅₀ in rats). These products are weak acids, and toxicity would be from gradual release of hypochlorous acid. Of course, aspiration of granules into the trachea or around vocal cords would be anticipated to produce airway problems. Overall, these products are very safe when they are stored and used correctly.

However, dichlor and trichlor are strong oxidants and highly reactive with other substances, with potential for 3 main hazards: 1) release of Cl₂ (commonly through generation of HOCl); 2) release of NCl₃ leading to explosions and Cl₂ release; and 3) oxidation of organic substances to produce ignition and fire. Mixing pool chemicals or other agents with stabilized chlorine is especially dangerous and potentially lethal. Let’s look at some common examples. I’ll include 3 cases from our toxicology service as illustrations.

Stabilized chlorine + calcium hypochlorite

Mixing trichlor and Ca(OCl)₂ results in release of large amounts of Cl₂ and production of heat. On top of this, NCl₃ formation can lead to explosion, with additional liberation of Cl₂. Martinez and Long reported on two patients who experienced Cl₂ inhalation injury from such mixing. One of the patients was also involved in an explosion (presumably NCl₃), and he died from his injuries. Our group has cared for a man who lost two fingers and experienced Cl₂ inhalation with pneumonitis after mixing granular trichlor with calcium hypochlorite in a bucket of water to clean mold off of walls of restaurant that was being remodeled. As yet another example, this household explosion in Indiana appeared to have resulted from mixing of these two products.

Stabilized chlorine + sodium hypochlorite solution (bleach)

Alkalinity found in liquid bleach solutions drives release of hypochlorous acid from stabilized chlorine (acids) and, thus, of Cl₂, despite higher and higher pKa values found as trichlor is converted to cyanuric acid.

Na, Wang, and colleagues described 61 patients who experienced Cl₂ inhalation at a swimming pool when trichlor was mixed with a solution of about 9% sodium hypochlorite, typical of liquid pool chlorinating compounds. The medical consequences included pneumonitis and pulmonary edema.

Stabilized chlorine + algaecides with or without copper

Algaecides used in swimming pools commonly contain various alkyl ammonium or amine compounds. Some also contain copper. (Figure 31)

Mixing stabilized chlorine with alkyl ammonium algaecides and/or copper results in immediate generation of NCl₃, with explosions and liberation of Cl₂, N₂, and NO_x. To emphasize the danger of such mixtures, below is a short video created for public education in which a fire department poured white, granular stabilized chlorine into a barrel, followed by the addition of liquid algaecide. All activities were controlled remotely, about 200 feet away. The immediate formation and explosion of NCl₃ resulted in release of N₂, NO_x, and Cl₂ (green). Readers should NEVER, NEVER, EVER attempt this.

Our group admitted a woman from a suburb of Phoenix who mixed trichlor with an algaecide in a bucket to clean swimming pool walls. There was an immediate explosion and she was covered head-to-toe in white granular unreacted stabilized chlorine. Severe respiratory distress was immediate, but she eventually recovered from Cl₂-induced ARDS and perforated tympanic membranes.

Stabilized chlorine + small amounts of water

If these products simply get damp and are not completely immersed in water in areas with stagnant air, NCl₃ can be released and accumulate. This can make fighting fires in structures where large quantities of these products are stored particularly difficult. During the fire, exposed stabilized chlorine products may become wet from hoses or sprinkler systems, which can actually increase risk of explosions as NCl₃ reacts with nearby substances or is heated from flames. As oxidants, the trichlor and dichlor make other things burn better, as well. Thus, exposed products should be deluged with copious amounts of water.

In a final patient example, we cared for a man who placed trichlor in a closed, obstructed pool skimmer basket filled with wet leaves and debris, with a low water level in the pool. Trichlor became damp but was not immersed in water. Later he returned and opened the top of the skimmer. Upon removing the skimmer basket, a small explosion occurred, resulting in mild chlorine-pneumonitis from which he quickly recovered. The occurrence of a skimmer basket explosion must be extremely rare, given that tablets (which should not be placed in baskets in the first place) are usually immersed in water, and air flow (with water) into and out of the skimmer normally would prevent accumulation of NCl₃. But the example demonstrates the principle. (In Arizona, we are usually more concerned about rattlesnakes getting into pool skimmer baskets.)

Stabilized chlorine + ammonia or inorganic ammonium compounds

Such a mixture can immediately produce NCl₃ and explosion with release of Cl₂ and NO_x. This explosive and potentially fatal reaction is in contrast to mixing 5% or 10% sodium hypochlorite (NaOCl) with ammonia, which results in production of irritating chloramine gas (as was described by Andrew in more detail).

On September 21, 2001, an enormous explosion of ammonium nitrate occurred at a fertilizer plant in a suburb of Toulouse, France, killing 30 and injuring 2442 persons. A crater about 7m deep was created below the shed that exploded.

An investigation led to the theory that a few dozen kilograms of sodium dichloroisocyanurate (dichlor) had mixed with ammonium nitrate about 20 minutes prior to the explosion. Experiments performed scaled up to 30 Kg in size showed that contact with granular dichlor at moderate humidity, producing NCl₃, resulted in full detonations of ammonium nitrate. However, the exact cause of the disastrous explosion could not be proved with complete certainty.

Stabilized chlorine + organic matter, including hydrocarbons

Like other oxidizers, stabilized chlorine products mixed with hydrocarbons (e.g., turpentine, oil) can produce ignition and fire in seconds to minutes. Similarly, if these products are left in contact with dried leaves, old rags, etc., fire may result. The same is true for calcium hypochlorite solid products, though reactions may not occur as quickly in all instances.

Conclusion

Stabilized chorine products present hazards well beyond those of simply mixing sodium hypochlorite with acid to generate Cl₂, or ammonia to form chloramine. The potential for NCl₃ formation from stabilized chlorine products can lead to serious explosions and Cl₂ generation, reminiscent of experiments performed by Dulong and Davy. Play it safe and never mix stabilized chlorine products with other substances. If your dog develops hysteria, and you’re sure it’s not rabies, change their diet.

Postscript

Here are a couple questions for medical toxicology fellows:

• The billions of neutrophils in a human body excel at producing hypochlorous acid, which dissociates to Cl₂. What is the enzyme responsible for this reaction, and how is hydrogen peroxide involved?
• What role does the above enzyme play in DRESS syndrome from sulfonamides and other drugs?
  

Selected References

1. Ashmore, P. Explosions in Mixtures of Hydrogen, Chlorine and Nitrogen Trichloride. Nature 172, 449–450 (1953). https://doi.org/10.1038/172449a0
2. Dalal RP, Goldfarb DS. Melamine-related kidney stones and renal toxicity. Nat Rev Nephrol. 2011 May;7(5):267-74. doi: 10.1038/nrneph.2011.24. Epub 2011 Mar 22. PMID: 21423252.
3. Dechy N, Bourdeaux T, Ayrault N, Kordek MA, Le Coze JC. First lessons of the Toulouse ammonium nitrate disaster, 21st September 2001, AZF plant, France. J Hazard Mater. 2004 Jul 26;111(1-3):131-8. doi: 10.1016/j.jhazmat.2004.02.039. PMID: 15231358.
4. French Ministry of Sustainable Development. Explosion in the AZF fertilizer plant September 21st, 2001 Toulouse France. April 4, 2024. https://www.aria.developpement-durable.gouv.fr/wp-content/files_mf/FD_21329_TOULOUSE_DP_JLC_GB_29072013.pdf
5. Guan N, Fan Q, Ding J, Zhao Y, Lu J, Ai Y, Xu G, Zhu S, Yao C, Jiang L, Miao J, Zhang H, Zhao D, Liu X, Yao Y. Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J Med. 2009 Mar 12;360(11):1067-74. doi: 10.1056/NEJMoa0809550. Epub 2009 Feb 4. PMID: 19196669.
6. Krakoff IH. Effect of methionine sulfoximine in man. Clin Pharmacol Ther. 1961 Sep-Oct;2:599-604. doi: 10.1002/cpt196125599. PMID: 13753895.
7. Martinez TT, Long C. Explosion risk from swimming pool chlorinators and review of chlorine toxicity. J Toxicol Clin Toxicol. 1995;33(4):349-54. doi: 10.3109/15563659509028921. PMID: 7629902.
8. Mellanby E. Diet and canine hysteria; experimental production by treated flour. Vet Rec. 1947 Jan 11;59(2):13-5. PMID: 20279656.
9. Na W, Wang Y, Li A, Zhu X, Xue C, Ye Q. Acute chlorine poisoning caused by an accident at a swimming pool. Toxicol Ind Health. 2021 Sep;37(9):513-519. doi: 10.1177/07482337211019180. Epub 2021 Aug 3. PMID: 34342256.
10. New Jersey Department of Health: Trichloroisocyanuric acid hazardous substance fact sheet. https://www.nj.gov/health/eoh/rtkweb/documents/fs/1892.pdf
11. Proler M, Kwlleway P. The methionine sulfoximine syndrome in the cat. Epilepsia. 1962 Mar;3:117-30. doi: 10.1111/j.1528-1157.1962.tb05237.x. PMID: 14488947.
12. Rao VJ, Hearn WL. Death from pool chlorine–an unusual case. J Forensic Sci. 1988 May;33(3):812-5. PMID: 3385386.
13. Skinner CG, Thomas JD, Osterloh JD. Melamine toxicity. J Med Toxicol. 2010 Mar;6(1):50-5. doi: 10.1007/s13181-010-0038-1. PMID: 20195812; PMCID: PMC3550444.
14. Sun N, Shen Y, He LJ. Histopathological features of the kidney after acute renal failure from melamine. N Engl J Med. 2010 Feb 18;362(7):662-4. doi: 10.1056/NEJMc0909177. PMID: 20164495.
15. UN Environment Programme. Mercury cell chlor-alakli production. https://www.unep.org/globalmercurypartnership/what-we-do/mercury-cell-chlor-alkali-production
16. Wang IJ, Chen PC, Hwang KC. Melamine and nephrolithiasis in children in Taiwan. N Engl J Med. 2009 Mar 12;360(11):1157-8. doi: 10.1056/NEJMc0810070. Epub 2009 Feb 4. PMID: 19196667.