116: Phosphorus

Phosphorus is a nonmetallic element not naturally found in its elemental form; it was isolated from distilled urine by Hennig Brandt in 1669. White phosphorus has been used in munitions (mortar rounds, grenades, artillery shells, bombs) since World War I for its antipersonnel effect as well as its warning, incendiary, and smoke producing properties. It is also used in fireworks made in countries other than the United States and China and for selected chemical synthetic processes (including some pesticides). White phosphorus was used extensively in the past as a rodenticide but is no longer employed for this purpose in the United States. Because of the potential use of red phosphorus for illicit drug manufacture (methamphetamine), its sale is monitored by the US Drug Enforcement Administration, which limits its availability in the United States. Before modern regulation, it was used in scientifically unsubstantiated remedies primarily because its phosphorescent and reactive qualities suggested potency. Its occasional use for homicides was limited by its glowing, smoking qualities. It remains a common method of suicide in some countries.

At the beginning of the 20th century, phosphorus was used in millions of “strike anywhere” matches (lucifers). However, safety concerns with the matches and illnesses in the workers producing the matches prompted a shift from using the more dangerous white phosphorus in the match heads to substituting the safer red phosphorus in the strikers. Workers chronically exposed to white phosphorus developed “phossy jaw,” an illness characterized by disfiguring osteonecrosis of the mandible along with multiple draining abscesses.

Phosphorus, atomic number 15, is in a group of 15 nonmetallic elements sharing chemical properties with nitrogen (above) and arsenic (below) in the periodic table. Elemental phosphorus can exist in several different allotropes (polymorphs); the two common forms considered here are red phosphorus and the highly reactive white phosphorus. The relatively nontoxic and nonreactive black form will not be considered further.

White phosphorus is a waxy whitish to yellow solid with a melting point of 111.4°F (44.1°C). Often there is a small amount of red phosphorus in samples of white phosphorus, resulting in discoloration and explaining the term, “yellow” phosphorus. The word “phosphorus” means light-bearer, which originates from its property of glowing when exposed to air, due to the formation of reactive luminescent phosphorus oxides on its surface. Phosphorus is insoluble in water and often stored under it, but soluble in carbon disulfide and other organic solvents. White phosphorus is very reactive, igniting spontaneously in air at approximately 93°F (34°C), oxidizing to form phosphorus pentoxide (P₄O₁₀), which usually appears as a white fume having a garliclike smell. Phosphorus pentoxide is hydroscopic and reacts with water to form phosphoric acid (H₃PO₄) and reacts with organic molecules in dehydrating reactions.

Red phosphorus is a red powdery compound of limited toxicologic significance. It is not luminescent, it does not combust in air, and its toxicity is orders of magnitude less than that of white phosphorus.

White phosphorus is well absorbed from the intestinal tract, and coingestion with fats, alcohol, and liquids increases toxicity, probably from increased absorption.^6,7 White phosphorus is also well absorbed through the skin, with burns contributing to the absorption; significant morbidity and mortality occurring from large surface area burns. White phosphorus can also be absorbed by inhalation, although this exposure route is rare with current industrial hygiene practices. After ingestion, phosphorus is found in high concentrations within 3 hours in the blood, liver, and kidneys.^4,12

Internally absorbed white phosphorus has significant toxicity. A dose of only about 1 mg/kg in adults is likely to cause significant morbidity, but a lethal dose of 3 mg is reported in a child.³ The mortality from white phosphorus ingestion is difficult to estimate, because the majority of reported cases occurred prior to the development of critical care. Historically, significant ingestions carried a 25% mortality rate.¹⁰

The mechanism of dermal injury from white phosphorus differs significantly from that of ingested white phosphorus. Externally, white phosphorus reacts with oxygen to form phosphorus pentoxide and other phosphorus oxides. Phosphorus pentoxide readily reacts with water in an exothermic reaction, producing corrosive phosphoric acid.¹³ Additionally, phosphorus pentoxide reacts with (dehydrates) some organic molecules. These three mechanisms (exothermic, acid-producing, and dehydrating reactions) all contribute to the tissue injury observed, although the most damaging mechanism is the thermal injury from the heat of the reaction, as evidenced by the relatively short distance of tissue penetration by the acid and the relatively large amount of available water.^5,20 The evidence for describing white phosphorus as a cytoplasmic toxin is mostly derived from electron microscopy, which demonstrates an initial cytoplasmic injury of the rough endoplasmic reticulum rather than initial nuclear or mitochondrial changes; but white phosphorus may also have an effect on mitochondrial energetics.¹¹

Red phosphorus has limited direct toxicological significance. It can cause gastrointestinal (GI) irritation when ingested in significant amounts, but it is orders of magnitude less toxic than white phosphorus.

A resurgence of toxicity and human injury indirectly related to red phosphorus has resulted from the increase in North American domestic methamphetamine production. Red phosphorus is used in conjunction with elemental iodine to produce hydroiodic acid, the ultimate reducing agent required to convert ephedrine to methamphetamine. In this situation, red phosphorus contributes to human injury by causing fire due to its unintentional conversion to highly flammable white phosphorus. ­Additional pathology occurs because during heating, the reaction products of iodine and red phosphorus often generate phosphine (PH₃), a pulmonary irritant and metabolic inhibitor gas (Chap. 124). Phosphine is only produced in significant amounts during an active methamphetamine “cook” using the red phosphorus method. This gas most likely contributes to some of the pulmonary effects occurring with chronic exposures in methamphetamine laboratories, as well as several of the deaths resulting from performing the synthesis in an area with limited ventilation in order to hide the characteristic odors.²¹ Unless specifically stated, all further references to phosphorus in this chapter refer to white phosphorus.

General

The clinical manifestations of oral phosphorus poisoning are classically described in three stages. The initial effects may be delayed for a few hours, and the degree of delay depends on the dose. During the first phase, patients experience vomiting, hematemesis, and abdominal pain, with hypotension and death occurring within 24 hours after large ingestions.⁷ During the second stage, there is transient resolution of the toxic effects. During the third stage, the patient develops hepatic injury with coagulopathy and jaundice and acute kidney injury with oliguria and uremia. Mental status changes and seizures (independent of electrolyte changes) are also reported. However, clinical experience demonstrates that three distinct phases are the exception rather than the rule, with significant overlap or absence of the “quiescent” second stage and death potentially occurring within hours of ingestion.^6,15 In the first 6 hours postexposure, poor prognostic signs include altered sensorium, cyanosis, hypotension, metabolic acidosis, elevated prothrombin time, and hypoglycemia.⁶ Survival to 3 days serves as a good prognostic sign. However, deaths occur later in the clinical course.⁷ Recovery usually occurs over 1 to 2 weeks.

Gastrointestinal

Initial symptoms after ingestion of phosphorus include nausea, vomiting, and abdominal pain. Both diarrhea and constipation are reported but are much less common. The breath and vomitus are sometimes described as having a garlic or musty sweet odor. The vomitus and diarrhea are sometimes luminescent and smoking, but this specific finding occurs infrequently. The smoking material is caused by the combustion of phosphorus upon its reexposure to air after being eliminated from the GI tract. Phosphorus causes an inflammatory injury to the GI tract characterized by local hemorrhage and hematemesis, but generally perforation does not occur. Massive GI bleeding may occur later in the clinical course, particularly when hepatic failure and coagulopathy are present.¹⁰

Renal/Electrolytes

In a rat model of dermal burns from phosphorus, an initial diuresis occurs followed by acute kidney injury manifested by hyperkalemia, hyponatremia, and hyperphosphatemia.¹ Renal cell swelling and necrosis with vacuolar degeneration of proximal convoluted tubules was also observed.¹ Poisoned patients demonstrated an increase in urinary white and red blood cells with casts and proteinuria.³ In humans, acute kidney injury from phosphorus is most likely acute tubular necrosis resulting from hypotension, salt and water depletion, and a direct toxic effect.⁷

Significant electrolyte disturbances may result from both ingestion and dermal absorption of phosphorus. Hypocalcemia is common, but ­hypercalcemia is also occasionally reported.¹³ Hyperphosphatemia may accompany the hypocalcemia but is not universal and can occur at any time in the clinical course.³ The hyperphosphatemia is partially due to the conversion of absorbed phosphorus to phosphate. In an animal model, those that died had increased concentrations of phosphorus, decreased concentrations of ­calcium, and hyperkalemia as early as one hour postexposure.² ­Hyperkalemia is occasionally reported in humans and may be secondary to tissue injury and acute kidney injury.¹ The electrolyte disturbances are likely a leading cause of early mortality from phosphorus.

Cardiovascular

Death within 24 hours of the ingestion is likely the result of cardiovascular collapse. One series of 41 patients who attempted suicide demonstrated a variety of initial electrocardiographic (ECG) abnormalities. T wave changes predominated in 24 patients, and there were also two cases of ventricular fibrillation. An increasing number of ECG abnormalities occurred in patients with larger ingestions, although the electrolyte abnormalities were not described in many patients.⁷ An animal model of phosphorus exposure demonstrated prolonged QT interval and ST segment changes along with electrolyte abnormalities, suggesting that many of the ECG changes might be due to electrolyte abnormalities.² A small study of phosphorus exposure in rats observed a decrease in amino acid uptake in myocytes suggesting a direct toxic effect. Human autopsies of several poisoned patients demonstrated fatty degeneration of the myocardium and vacuolated cytoplasm many hours postingestion.¹⁹

Hepatic

Phosphorus is a potent hepatotoxin. Increase in prothrombin time, hyperbilirubinemia, and hypoglycemia usually occur within 3 days, with earlier signs of hepatic failure such as jaundice and coagulopathy indicative of a poor prognosis.^7,14 The increase in hepatic aminotransferases occurs over several days, usually peaking at or below 1000 IU/L and almost invariably less than 3000 IU/L.¹⁰ Other biochemical effects demonstrated by experimental phosphorus toxicity include an increase in glucose-6-phosphate activity and impairment of triglyceride metabolism and protein synthesis. When death occurs after several days (as opposed to within 24 hours), hepatic injury is usually implicated. If survival occurs, the hepatic damage usually resolves over several months, although persistent periportal fibrosis is reported.¹⁴

With absorption of sufficient quantities, phosphorus causes a dose-related zone 1 or periportal hepatic injury, in contrast to the centrilobular pattern (zone 3) that occurs with other hepatotoxins, such as acetaminophen and carbon tetrachloride (Chap. 23). Fatty degenerative changes and fatty infiltrates are also observed within 6 hours of ingestion.⁶ Other histological changes include acute necrosis with large vacuoles and inflammatory changes. Electron microscopy in a rat model demonstrated an increase in the rough endoplasmic reticulum and an increase in the cytoplasmic fat without initial mitochondrial or nuclear injury.¹¹ Although the early pathological effects appear to be predominantly cytoplasmic, the formation of nuclear vacuoles can occur.¹⁴

Nervous System

Central nervous system effects include headache, altered mental status, coma, and rarely seizures. The altered mental status is probably due partially to the presence of other organ dysfunction and shock; one example of the former is the encephalopathy secondary to hepatic injury. Patients with initial alterations in mental status or coma have an increased mortality rate independent of the presence of any electrolyte abnormalities.¹⁵

Dermal/Mucous Membranes

Dermal phosphorus exposure causes extensive burns, and this occurs most frequently in the military setting. The burns are described as emitting a garlic odor and displaying a yellow color that fluoresces under ultraviolet light. Necrosis of the wounds is common when wound decontamination is incomplete. Depending on the release conditions, white phosphorus can be a solid or liquid. Liquid white phosphorus splatters and can penetrate clothing; burning clothing commonly exacerbates the burn area.^13,16 Dermal penetration may be partially due to its lipophilicity and a compromised dermal barrier caused by the burn injury. The smoke produced by burning white phosphorus contains phosphorus pentoxide and is irritating to the conjunctiva and mucosa of the oropharynx and lungs.

Following a large burn, systemic illness manifested by electrolyte, cardiovascular, and hepatic abnormalities may result from absorbed phosphorus.^1,2 A 12% to 15% body surface area burn in a rat was lethal 50% of the time; human morbidity from large skin burns is similarly high. Rats with dermal burns from phosphorus subsequently developed kidney and liver injury. Healing time from phosphorus burns is prolonged when compared with thermal burns.⁷

Serum elemental phosphorus concentrations are not clinically available, and a serum phosphate concentration does not reflect the serum elemental phosphorus concentration.The diagnosis of phosphorus poisoning must rely on the history and physical examination. However, for optimal supportive care of the patient, many laboratory factors must be monitored such as ECG, electrolytes, serum pH, hepatic function, glucose, renal function, and coagulation parameters.

Protection of Health Care Workers

Caution should be exercised in decontamination and subsequent storage of contaminated clothing. Vomitus and diarrhea must be considered potentially hazardous due to fire risk and should be carefully handled. Any phosphorus fragments removed from the patient as well as all potentially contaminated clothing items should be kept under water. Fires and explosions are reported during GI decontamination efforts, and the smoke from burning white phosphorus is irritating to the eyes and pulmonary system.¹⁷

General

General supportive care is the mainstay of treatment. Cardiac monitoring; frequent analysis of calcium, phosphate, and potassium concentrations, and serial ECGs are essential for patients with a history of significant ingestion or overt toxicity as dysrhythmias may occur rapidly.⁷ Electrolyte disturbances such as hyperkalemia, hypocalcemia, and hypercalcemia should be corrected. With significant exposure to phosphorus, hepatic injury will occur, and thus directed supportive care should be provided such as fresh-frozen plasma and vitamin K, when indicated. Adequate serum glucose concentrations are required to provide reducing equivalents through glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) pathways, especially when there is evolving hepatic injury. Increased glucose concentrations may also theoretically offer protection by competing with phosphorus reuptake in the kidney, but the contribution to human morbidity is unclear. Corticosteroids have not been shown to improve outcome following ingestions of white phosphorus.¹⁴ Direct contact of phosphorus with the eye can result in serious ophthalmic injury. Immediate copious ophthalmic decontamination with water rather than with copper sulfate is recommended (see Dermal Exposure).¹⁸ A careful examination should be conducted by an ophthalmologist whenever possible.

Dermal Exposure

Initial treatment is to halt continuing injury by extinguishing combustion of the phosphorus. This is performed by submerging the affected area in cool water or, more practically, covering any areas with clean materials soaked in water or a 0.9% sodium chloride solution to limit the white phosphorus contact with atmospheric oxygen. Decontamination is undertaken by removing clothing and using large amounts of cool water to remove any phosphorus fragments. In the past, sodium bicarbonate decontamination solution was recommended, but because the tissue injury is not due to the production of acid and because no clinical benefit was demonstrated, there is no current role for specific neutralization fluids.^5,20 Water dilutes any phosphoric acid present and reacts with the phosphorus pentoxide to limit the damaging dehydrating reactions.

Careful débridement is the next critical step as wounds that have not undergone adequate decontamination heal poorly, requiring additional débridement. Smoking pieces of phosphorus are not necessarily hot enough to cause thermal burns, but the oxidation process must be arrested. Fragments of phosphorus from the wound should be placed under water to prevent a fire hazard. Particles of phosphorus can be visualized by using a Woods lamp as the chemical burns have a yellowish fluorescence. One author recommends turning off the lights to look for the glow of the phosphorescent particles; presumably this will work only if there has not been any copper or silver metal wash solution used, but others have questioned if the amount of glow will be enough to locate fragments under real world conditions (see following paragraphs).⁸ Because of the increased solubility of phosphorus in hydrophobic solvents, it is important not to use ointments until the wound is completely decontaminated.

A copper (II) sulfate solution was previously recommended for “decontamination.” Copper sulfate reacts with phosphorus to produce copper phosphide, a dark compound that is much more easily visualized in the tissues. This dark material coats the particle, but the entire particle is not converted to copper phosphide. Additionally, this coating decreases the reaction of phosphorus with oxygen for a limited time. The use of high concentrations of copper sulfate solutions on exposed human flesh is no longer recommended because of potential systemic toxicity such as hemolysis caused by the copper (Chap. 95).¹⁸ This is especially concerning in patients at increased risk for oxidant injury, such as those with G6PD deficiency. The solutions of copper sulfate historically used ranged from 2% to 5% and were applied for several hours to the wounds, resulting in substantial amounts of copper absorption and morbidity.

However, copper sulfate solutions still may have a role in the complete approach to the treatment of phosphorus wounds. A dilute copper sulfate solution (0.5%–1.0%) applied once to the wound and then rinsed off with water may not result in the morbidity that occurs with the more concentrated rinses and may provide temporary neutralization of the outer surface of the phosphorus. This approach may assist in identification of the small pieces of phosphorus that are difficult or impossible to visualize by darkening the fragments, especially in those with less experience débriding these wounds. Wounds that are not treated with a copper solution may be at greater risk of requiring repeat débridement because of the persistence of small phosphorus particles missed during the initial decontamination efforts. Animal models have suggested improved healing from the initial treatment with a dilute copper solution, but a relatively large human case series did not find a difference in those who were treated with copper sulfate compared with those who were not.⁵ The copper phosphide–coated particles must be removed as they still react slowly and can cause toxicity. It is important to remember that the dilute copper sulfate solution is not a decontamination therapy but a temporizing treatment that allows for better visualization for physical débridement, and this solution must be rinsed away immediately after application.⁸ The use of pads soaked in copper ­sulfate is not recommended.

Silver nitrate has been suggested as a potential solution to replace the use of copper sulfate. It forms an insoluble, minimally reactive silver phosphide. Its use and preparation is similar to that described above and as such silver nitrate (1%–2% solution) should be considered as a temporary neutralization tool and not a decontamination therapy. It does not have the detrimental physiologic effects that internalized copper ions cause. However, there is very limited experience with this approach and no detailed human data. Silver forms an insoluble precipitate with chloride and cannot be combined with 0.9% sodium chloride solutions; therefore, the amount of soluble silver ion that reaches the imbedded phosphorus may be more limited than with copper because of the presence of relatively large amounts of chloride ion in living tissues.²²

A reasonable approach is to begin by decontaminating the wound using a Woods lamp and or a darkened room looking for phosphorescence. Only then applying a transient dilute copper sulfate or silver nitrate wash as described above is indicated to improve visualization and possibly neutralize very small phosphorus particles. After decontamination, good wound care and burn management is required, because these burns (like other chemical burns) can require an extended period of time to heal. As discussed, incomplete decontamination is a common reason for delayed wound healing. For significant burns, the patient should be admitted to a burn intensive care unit for close monitoring of cardiovascular, renal, and electrolyte status for several days at the minimum. Because of the potential instability of these patients, it is important to weigh the risk-to-benefit ratio of transfer to a specialized center. The experience of the receiving center with phosphorus burns in addition to the acuity and severity of the injury are important factors in making this decision.

Gastrointestinal Exposure

There is no evidence that GI decontamination or antidotal therapy following phosphorus ingestion is efficacious. In the past, several different lavage fluids were recommended, ranging from the mostly benign (sodium bicarbonate) to the potentially dangerous (potassium permanganate). Milk might also be potentially harmful because of its lipophilic components. Some authors postulate better outcome with earlier GI decontamination, but no reliable studies are available.¹⁴ Activated charcoal may bind to white phosphorus and could be considered, although there are no human data to support its use. However, despite the lack of data of efficacy, given the poor outcome of patients with large ingestions of phosphorus, decontamination efforts should be strongly considered. If lavage is considered, a nasogastric tube would not be expected to remove substantial quantities due to the insoluble, solid nature of phosphorus. The tissue injury caused by phosphorus is not expected to cause early esophageal perforation, and the use of an orogastric (OG) tube would therefore be best. Caution to protect caregivers should be exercised with any lavaged material. Due to the risk of fire and explosion, one author recommends keeping the free end of the OG tube under water while inserting and instilling small amounts of water (not air) to check for proper placement.¹⁷

It appears that the hepatic injury is much more likely with ingested phosphorus exposure than following dermal exposure. N-acetylcysteine (NAC) is suggested as a potential adjunct in the treatment of phosphorus toxicity. Although NAC was used in a limited human series, the numbers were small.¹⁰ The use of superoxide dismutase in an animal model suggested benefit but did not limit morbidity, and a separate animal model suggested benefit from glutathione; therefore, limiting oxidant injury may play a role in treatment.⁹ There is no theoretical harm in using NAC for phosphorus toxicity, and so it should be added to the treatment regimen. Methionine was used many years ago in the treatment of a few patients, but the number of treated patients was too few to draw any conclusions.⁶ When liver transplantation was performed for phosphorus induced hepatic failure outcomes have been suboptimal, likely due to toxicity occurring in the central nervous and cardiovascular systems.

• White phosphorus was most commonly used in warfare, causing morbidity through dermal burns.

• These burns require large amounts of water irrigation and adequate débridement while protecting health care workers.

• Following ingestion, typically in suicide attempts, morbidity remains quite high, and treatment options are limited to unproven decontamination therapies.

• Signs and symptoms of white phosphorus toxicity include vomiting, abdominal pain, confusion, dysrhythmias, hepatic injury, and acute kidney injury.

• As early mortality is believed to be due to electrolyte abnormalities and cardiac dysrhythmias, vigilant critical care is the mainstay of therapy.

• NAC may be used, but it has not been shown to alter human outcomes.

Acknowledgments

Heikki E. Nikkanen, MD, and Michele M. Burns, MD, contributed to this chapter in previous editions.

References