Phosgene Toxicity Medication

Updated: Jan 30, 2015
  • Author: Paul P Rega, MD, FACEP; Chief Editor: Zygmunt F Dembek, PhD, MPH, MS, LHD  more...
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Medication

Medication Summary

Most of the data regarding medication use in phosgene poisoning are derived either from anecdotal experience in case reports or from studies involving animal models. Case reports are plagued by the absence of a control group and frequently by the lack of any documentation regarding level of phosgene exposure. Animal studies are useful for elucidating pathophysiological mechanisms and providing initial measures of treatment efficacy, but the applicability of such studies to the treatment of human phosgene toxicity is unknown.

Human phosgene toxicity cases occur in too sporadic and sudden a fashion to allow randomized clinical trials. Clearly, intentional exposure of human subjects to phosgene would be unethical.

Multiple authors agree on the need for aerosolized bronchodilator therapy for patients with reactive airway disease or asthma diagnoses prior to phosgene exposure and for patients who are actively wheezing.

Diuretics were recommended for many years, but most recent authors seem disinclined to recommend their use and note that they may actually be harmful in phosgene toxicity. Volume overload is not a feature of phosgene-related noncardiogenic pulmonary edema.

In fact, patients are often hypotensive and intravascularly dry, since they are losing fluid from the vascular space into the lung interstitium due to the breakdown of the alveolar-capillary interface. Positive pressure ventilation may further depress venous return and decrease cardiac preload and may require vigorous support with isotonic crystalloid.

Recommendations for steroid use in phosgene toxicity vary widely. No data support the use of steroids to treat human phosgene exposure, but one animal study demonstrated that intravenous methylprednisolone 30 mg/kg completely blocked pulmonary edema and the associated increased leukotriene synthesis in phosgene-exposed rabbits.

Two caveats about this study are that this protocol involved pretreatment with methylprednisolone before phosgene exposure rather than the postexposure scenario, which practicing clinicians face, and that this study was not designed to test whether the methylprednisolone actually resulted in a survival benefit.

Guidelines from the Centers for Disease Control and Prevention through the Agency for Toxic Substances and Disease Registry recommend intravenous corticosteroids in cases of severe phosgene exposure even if the patient is asymptomatic. [30] Some authors recommend both inhaled and systemic steroids for all phosgene-exposed patients, while others recommend steroids only in patients with pre-existing reactive airway disease. The recommended regimen is methylprednisolone 1 g IV with a taper over the following several days. [31]

Prophylactic antibiotics are not recommended in phosgene-induced pulmonary edema. Antibiotic therapy should be reserved for patients who have clinical findings consistent with pneumonia such as a sputum culture with a likely culprit organism.

A variety of studies have been completed in rabbits and mice using postexposure administration of the following:

  • Intratracheal isoproterenol
  • Parenteral ibuprofen
  • Intratracheal N -acetylcysteine
  • Parenteral aminophylline
  • Subcutaneous terbutaline
  • Colchicine
  • Parental leukotriene receptor blockers

Many of these agents and delivery routes show promise in terms of the following:

  • Decreased pulmonary edema
  • Increased levels of reduced glutathione
  • Decreased production of lipid peroxidation products
  • Decreased leukotriene production
  • Maintenance of tissue cyclic adenosine monophosphate (cAMP) levels

However, these favorable laboratory end points have not necessarily been tied to clinical end points of improved survival. None of these agents has Food and Drug Administration (FDA) approval for treatment of noncardiogenic pulmonary edema associated with toxic inhalations.

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Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune system to diverse stimuli. Whether early administration of corticosteroids can prevent development of noncardiogenic pulmonary edema is unknown. The decision to administer corticosteroids must be made on clinical grounds. Treatment lasting more than 1 week may require a taper to prevent abrupt steroid withdrawal.

Methylprednisolone (Solu-Medrol)

Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear neutrophils (PMNs) and reversing increased capillary permeability.

Beclomethasone (Beclovent, Vanceril)

Beclomethasone inhibits bronchoconstriction mechanisms, producing direct smooth muscle relaxation. It may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Betamethasone (Celestone, Soluspan)

Betamethasone decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability.

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Beta2 Agonists

Class Summary

Patients with hyperactive airways usually benefit from aerosolized bronchodilator therapy.

Albuterol (Proventil, Ventolin)

Albuterol relaxes bronchial smooth muscle by its action on beta 2-receptors. It has little effect on cardiac muscle contractility.

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Vasopressors

Class Summary

Vasopressors are used to treat hypotension, bradycardia, or renal failure.

Dopamine (Intropin)

Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect depends on the dose; lower doses predominantly stimulate dopaminergic receptors that, in turn, produce renal and mesenteric vasodilation. Use low doses to protect renal function; use high doses to combat severe hypotension unresponsive to fluid administration.

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Leukotriene antagonists

Class Summary

These agents reduce the inflammatory response elicited by the leukotriene cascade. Leukotriene antagonists are approved by the FDA only for chronic asthma management.

Zafirlukast (Accolate)

No human studies have evaluated the efficacy and safety of zafirlukast in patients exposed to phosgene. Nevertheless, given the known effects of leukotriene stimulation by phosgene, the results from animal studies, and the drug's safety profile, this agent should be considered for first-line therapy. In the presence of food, bioavailability of oral zafirlukast is decreased by 40%. Administer on an empty stomach.

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