Continuing Education Activity

Ammonia toxicity occurs when susceptible individuals suffer exposure to external sources of ammonia via ingestion, inhalation, direct contact with skin, or contact with the eye. Ammonia toxicity has various deleterious acute and chronic effects on the patients. This activity describes the role of an interprofessional team in evaluating, diagnosing, and managing patients presenting with signs and symptoms of ammonia poisoning.

Objectives:

• Identify the etiology of ammonia toxicity.

• Describe the evaluation of a patient presenting with suspected ammonia toxicity.

• Differentiate the management options for ammonia toxicity.

• Summarize interprofessional team strategies for improving care coordination and communication to enhance outcomes for patients affected by ammonia toxicity.

Introduction

Ammonia is a colorless irritant gas with a pungent order readily soluble in water to generate ammonium ions.[1] Ammonia is a natural by-product in the human body as an intermediate in several metabolic reactions primarily involving amino acid synthesis.[2] It also gets produced in the human gut due to various enzymatic actions of bacteria.[3] However, due to the highly toxic nature of ammonia, it is quickly metabolized into urea in the liver by the urea cycle and excreted by the kidneys.[4][5] The blood ammonia level in a healthy adult ranges from 15 to 45 micrograms/dL.[6] Ammonia toxicity occurs when the ammonia content in the blood supersedes the liver’s capacity to eliminate it; this could be a result of either overproduction, such as in congenital hyperammonemia, or under-elimination, such as in liver cirrhosis.[7][8] This topic focuses on the various means by which the human body suffers exposure to external sources of ammonia and the multiple mechanisms of its toxicity.

Injury from ammonia commonly occurs via the following methods:

1. Inhalation of anhydrous ammonia gas or vapors of liquid ammonia
2. Ingestion of ammonia-containing liquids
3. Direct contact of anhydrous ammonia gas with skin or eyes

Etiology

Ammonia is among the most widely produced chemicals in the United States, a majority of which ends up as chemical fertilizers or as animal feeds. Ammonia exposure occurs mainly in the following ways:

1. Gas leaks from the production, storage, or transportation facilities of ammonia. Hence, people who work in such facilities are at an increased risk for inhalational and dermal exposure.[9][10]
2. A high ammonia level may be present in the air after applying ammonia-containing fertilizers in the soil.[11] Hence, the farmers who rely on ammonia-based fertilizers are at an increased risk for inhalational exposure.
3. Household and industrial cleaners contain 5% to 25% of ammonia in dissolved form. Hence, the residents, especially children of such households, are at an increased risk for accidental or suicidal ingestion exposure. The spillage of such products can lead to significant inhalational exposure as well.[12]
4. Ammonia is produced by decaying manure. Hence, farmers working in animal confinement buildings are at an increased risk of inhalation.[13][14]

Epidemiology

The 2017 annual report of the American Association of Poison Control Center’s National Poison Data System reported 1846 single exposures to ammonia with 15 major adverse events and no deaths.[15] They also reported 1366 single exposures to ammonia-containing glass cleaners and 489 single exposures to ammonia-containing all-purpose cleaners, with no reported deaths in either case. Exposure to ammonia is almost always unintentional. Ingestion of ammonia-containing cleaners occurs predominantly in children and is accidental. However, 9.2% of household exposure is intentional and occurs mostly in adults.

Pathophysiology

Anhydrous ammonia, in liquid or gaseous form, reacts readily with water in the human tissue to form ammonium ions. This process is highly exothermic and causes significant thermal injury to the surrounding tissues. Also, the resultant alkaline solution causes liquefaction necrosis to the tissues through protein denaturation and saponification of fats.[16][17] Its extraction of water from the human tissues initiates an inflammatory response.[18] Exposure to liquid anhydrous ammonia, typically stored at -28°F, results in cold-induced thermal injury in addition to the above mechanisms.[19][20] Hence, exposure to gaseous anhydrous ammonia results in corneal injury and burns on the skin. In the respiratory tract, exposure to gaseous ammonia results in injury to the superficial layers of the epithelium, exposing the patient to infection. Injury to the basal layer of epithelium results in irreversible scarring, resulting in chronic lung disease. Ingestion causes injuries along the alimentary canal and can lead to perforation of the hollow viscera. There is little evidence to suggest that exposure to external sources of ammonia can lead to hyperammonemia and manifestations of its systemic toxicity, such as hepatic encephalopathy.

Histopathology

Histopathologic examination of lung tissue after acute exposure to ammonia demonstrates acute pulmonary congestion edema and desquamation of the bronchial epithelium.[21] Significant lower airway obstruction results from the debris of epithelial cells, red blood cells, and dust cells.

Toxicokinetics

The pungent smell of ammonia in the air is detectable at concentrations as low as 5 ppm. Hence, significant exposure to ammonia in the air without the patient’s knowledge is rare. Ammonia concentrations of up to 100 ppm in the air are tolerated well for up to several hours.[22] At 1700 ppm, the glottic region's coughing, laryngospasm, and edema start. Concentrations of 2500 to 4500 ppm can be fatal in approximately 30 minutes, and concentrations above 5000 ppm usually produce rapid respiratory arrest. Anhydrous ammonia in concentrations above 10000 ppm is sufficient to evoke skin damage.[23] The US National Institute of Occupational Safety and Health recommendations state that the maximum permissible time-weighted average exposure of anhydrous ammonia for an 8-hour workday of 40 hours per week is 25 ppm.[24] The short-term exposure limit, or the concentration at which exposure of longer than 15 minutes is potentially dangerous, is 35 ppm. The concentration at which the gas is immediately harmful to life or health is 300 ppm.

There is minimal ammonia absorption into the systemic circulation if there is short-term (under 120 seconds) inhalational exposure.[25] However, long-term inhalational exposure results in some absorption into the systemic circulation.[26] Most of the inhaled ammonia gets dissolved in the mucus of the upper respiratory tract, and 70% to 80% gets excreted in the exhaled air. Ingested ammonia readily absorbs into the bloodstream, and the liver plays a significant role in its elimination.[27] Quantitative data on the metabolism of exogenous ammonia in humans is not available. However, studies in rats show that most exogenous ammonia converts into glutamate and urea within 30 minutes.[28] Orally ingested ammonia is almost completely converted into urea in the liver and excreted via the kidneys as urinary urea, with 25% excreted within the first 6 hours and 72% within 3 days. However, oral ingestion rarely raised the levels high enough to cause signs of systemic toxicity.[29] Currently, no evidence suggests that dermal exposure to ammonia results in systemic absorption.

History and Physical

History

Following an inhalational injury, the patients generally present with rhinorrhea, scratchy throat, chest tightness, cough, dyspnea, and eye irritation. Since ammonia is a gas with a strong, pungent odor, the onset of symptoms is generally preceded by the patient identifying the smell, and people capable of escaping this environment are not subject to prolonged exposures. Prolonged or severe exposure to the gas results in full-thickness skin burns. Following ingestion injury, the patients present with oropharyngeal, epigastric, and retrosternal pain. Abdominal pain and similar gastrointestinal symptoms follow if there is perforation of a viscus; this can occur as late as 24 to 72 hours after ingestion. More often than not, there is a preceding history of accidental or suicidal ingestion of ammonia-containing products, commonly household ammonia-based cleaners. 

Physical Examination

After securing the airway, breathing, and circulation, a brief physical examination should be performed to establish the extent of the exposure. Start by assessing the level of consciousness. Examine the head, ears, eyes, nose, and throat for signs of facial and oral burns, ulcerations, or edema. Examine the respiratory system and evaluate for respiratory rate, oxygen saturation, stridor, drooling, cough, wheezing, rhonchi, and decreased air entry. Completely expose the patient and examine the skin for signs of burns. Special attention should be given to the eye examination since ammonia can cause severe damage to the cornea and lens and may even lead to globe perforation. Abdominal examination may delineate epigastric tenderness and peritoneal signs in patients with perforation. Since this can be a late sign, the clinician should repeat the abdominal examination periodically.

Evaluation

There are no reliable laboratory tests that can assess the extent of systemic ammonia toxicity. In patients with preserved liver function, serum ammonia levels do not correlate with the extent of external exposure and are of little diagnostic utility.

The following investigations are routine in patients presenting with exposure to ammonia:

• Complete blood count
• Blood urea nitrogen and creatinine
• Serum lactic acid levels
• Kidney function tests
• Serum electrolytes
• Prothrombin time, international normalized ratio
• Blood type and cross-matching
• Urine output monitoring

In patients with suspected respiratory injury:

• Pulse oximetry
• Cardiac monitoring
• Serial blood gases
• Chest radiography
• Pulmonary function tests
• Bronchoscopy in suspected severe acute inhalation
• Ventilation-perfusion scan

In patients with suspected ingestion:

• Abdominal series to rule out perforation following ingestion
• Early endoscopy (within 12 hours) in patients with stridor, drooling, dysphagia, or significant oral burns. Endoscopy is a safe procedure for these patients.[30] Please note that the absence of oral burns does not reliably rule out esophageal injury; hence, early endoscopic evaluation is indicated for most of these patients. 

In patients with suspected exposure to the eye:

• Slit-lamp examination with fluorescein staining
• Tonometry
• Conjunctival pH measurement

Treatment / Management

Since systemic toxicity with external exposure to ammonia is rare, there are no systemic antidotes for the management of ammonia poisoning. Management is largely supportive. Remove the patient from the source and decontaminate the patient. Start by supporting the airway, breathing, and circulation.

After a quick physical examination, assess the need for an advanced airway. Indications for an advanced airway include the following:

• Depressed mental status
• Deep burns in the face or proximal airway
• Hoarseness or stridor
• Severe respiratory distress

Supplement the patient with warm, humidified oxygen. Liberal fluid resuscitation should be avoided as these patients seldom have acute lung injury. Follow standard burn management if skin burns are identified during the physical examination. Irrigate the burns with tepid water for at least 15 minutes, followed by frequent irrigation for at least 24 hours. Avoid using any medications or dressing, as this prevents the natural elimination of ammonia by vaporization. If an eye injury is suspected, irrigate the eye with tepid water for at least 30 minutes or until the conjunctival pH reaches 6.8 to 7.4. Consult ophthalmology early, as ammonia exposure can lead to permanent eye damage. If oral ingestion is suspected, then dilute the ingestion with water or milk. Arrange an early gastroenterology consult for endoscopic evaluation. Do not induce emesis, as this incurs further injury by the second pass of the toxin. The patient should be kept nil per oral until the completion of an assessment of the need for surgical management. Early surgical management is associated with improved patient outcomes in those patients with an identified impending perforation.[31] In patients who present with dysphagia, a follow-up endoscopy and barium swallow should be performed several weeks later to rule out stricture formation.

The evidence for corticosteroid use in managing ammonia toxicity is conflicting and should be avoided. Steroids may be beneficial in those patients who are exhibiting signs of airway edema and airway hyperreactivity after exposure to ammonia. The majority of the patients who present with ammonia exposure can be safely discharged from the emergency department after 6 hours of observation, after ruling out significant injury, and if the patient can tolerate oral feeding. Some of the indications for hospital admission include persistently symptomatic patients and those with endoscopically demonstrated burns. Patients with respiratory distress or abnormalities in laboratory values attributable to ammonia exposure should also be admitted for further evaluation.

Differential Diagnosis

Inhalation of high water-soluble, high irritative gases presents a similar effect to ammonia inhalation in that they predominantly affect the upper airway.[32] These gases include acrolein, ethylene oxide, formaldehyde, hydrogen chloride, and sulfur dioxide. When exposure is severe, the patient presents with symptoms of respiratory distress. Hence, other causes of acute respiratory distress, such as status asthmaticus, anaphylaxis, and foreign body aspiration, should merit consideration. Ammonia inhalation also results in severe eye irritation. Acute onset eye pain and irritation should be differentiated from angle-closure glaucoma, impacted foreign body, and corneal abrasions without a well-defined history of ammonia exposure. Ammonia ingestion presents similar to other caustic substance ingestions. Since there is an overlap in their management, differentiation of the specific substance may not be necessary for immediate management.[30] Ammonia exposure on the skin presents similar to other chemical and thermal burns caused by sodium hydroxide, potassium hydroxide, and calcium hydroxide.

Prognosis

There were no recorded deaths resulting from exposure to ammonia in the United States in 2017.[15] However, 1 in every 125 patients suffered from a major adverse event following ammonia exposure. Mild ammonia exposures are largely self-limiting conditions. The absence of symptoms within 24 hours of exposure essentially rules out injury. However, severe or prolonged exposures require hospitalization and may even result in death.[10][33] Clinical observation is that in patients presenting with acute ammonia inhalation, the chest physical examination findings on admission are the best predictor of long-term morbidity and mortality.[33][34] In patients presenting with dermal exposure, the extent and depth of burns are the best tools for prognosis. In patients presenting with ingestion, the extent and depth of upper GI burns visible on endoscopy predict the prognosis and direct subsequent management.[35]

Complications

Since ammonia gas erodes the superficial layers of pulmonary epithelium, this predisposes the patient to develop super-added bacterial or fungal infections. Acute respiratory distress syndrome and acute lung injury are also common complications. Chronic inhalation of mild to moderate levels of ammonia may lead to the development of obstructive airway disease.[36] Severe acute exposure, when it damages the basal layers of the pulmonary epithelium, can lead to chronic lung disease and may even necessitate a lung transplant.[37][38] Following ingestion injury, 83.7% of patients did not develop any long-term complications.[30] Common acute complications include aspiration, altered mental status, and perforation of the viscera. The most likely long-term complication is the development of esophageal stricture.[39][40] Hence, follow-up with serial endoscopy is the recommended approach in these patients.

Deterrence and Patient Education

The Agency for Toxic Substances and Disease Registry provides the following recommendations to the general public for avoiding ammonia exposure:

• Ammonia-based household cleaner use requires well-ventilated rooms.
• Avoid storing ammonia-based cleaners in glass bottles, as breakage could lead to severe exposure.
• Wear proper clothing and use eye protection while using ammonia-based cleaners.
• Keep ammonia-based cleaners out of reach of children.
• Avoid visiting farming areas where ammonia-based fertilizers are applied immediately after their application.
• Avoid visiting animal confinement buildings without the use of proper personal protective equipment.

They also recommend that workers who use or apply ammonia in farming always follow proper safety precautions mentioned on the equipment and use personal protective equipment wherever necessary.

Enhancing Healthcare Team Outcomes

The paramedical team and the emergency department play a major role in diagnosing and managing these patients. Timely interventions are key to managing ammonia exposure and reducing long-term sequelae. The EMS team can obtain valuable insights into the exposure environment and may provide the first clue to ammonia poisoning. They can initiate decontamination before arriving in the emergency department. After primary and secondary surveys, the emergency clinician should initiate early consultation for ophthalmology, gastroenterology, a burn nurse, and plastic surgery, depending on the need. Early specialist intervention improves patient outcomes.

Based on the exposure portal, the patient may need long-term follow-up care. Follow-up with a pulmonologist may be necessary for patients with severe acute inhalation, as the development of chronic lung disease is common. Long-term follow-up with a gastroenterologist may be necessary for patients with ingestion to screen for stricture development. In patients with intentional or suicidal exposure, psychiatric consultation may be advisable early in the management of such cases. Nurses provide inpatient care and monitoring, evaluate the patient's progress on follow-up outpatient visits, and report their findings to the treating clinician. Ammonia toxicity requires an interprofessional team approach, including primary clinicians, specialists (based on exposure type), and specialty-trained nurses, all collaborating across disciplines to achieve optimal patient results. Most evidence on ammonia poisoning is from case studies, case series, and systematic reviews.