Notes

Outline

PULMONARY AGENTS

OBJECTIVES Historical perspective General issues related to toxic exposure Agents source mechanism of injury clinical effects therapy

HISTORY 1899  Hague Convention bans CW 1914  WWI begins - August Battle of the Marne - stalemate Both sides explore options to break stalemate Professor Fritz Haber suggests chlorine

22 APRIL 1915 Chlorine gas used by Germany at Ypres, Belgium against the French 6,000 cylinders (168 tons) along a 7,000 m front reported 5,000 casualties both sides unprepared

HISTORY 19 DEC 1915  Phosgene gas by Germany at Ypres, Belgium against the British mass casualties 2 days later 19 MAY 1916  Diphosgene by Germany decomposes to phosgene + chloroform chloroform attacks mask filters

WW I CHEMICAL CASUALTIES Chlorine and Phosgene produced 80% of the fatalities from chemical agent exposure in WW I

RELEVANCE Chlorine, Phosgene - used in industry mass produced and transported industrial accidents domestic terrorism Related compounds organofluoride polymers (PFIB) oxides of nitrogen HC smoke (zinc oxide)

EXPOSURE SURFACE      Route Surface Area Ingestion / parenteral                        --- Ocular 0.0002  m2 Percutaneous 2  m2 Respiratory 50-150  m2

ANATOMY - PHYSIOLOGY Nasopharynx humidifies, filters bypassed when exercise increases MV Central airways  (mouth to 2 mm airways) flow is from smaller to larger area, laminar = QUIET Peripheral airways - (2 mm to alveoli) geometric increase in cross-sectional area Brownian motion

AGENT DISTRIBUTION Aerosols solid particles or liquid droplets suspended in air distribute in lung by particle size produce effects at site of deposition    5 to 30 m - nasopharynx    1 to 5 m - tracheobronchial level (central)    < 1 m  - alveolar level (peripheral)

AGENT DISTRIBUTION Gas/vapor distributes uniformly throughout the lung Effects due to solubility and reactivity High - central effects Low - peripheral effects

PROTECTIVE MECHANISMS Aerosols Solubilized, absorbed, removed by cough, sneeze, specialized cells or mucociliary transport Gases Reactivity - cough and sneeze act as warning Mucociliary damage increases risk of infection

CLINICAL EXAMPLES Site of Action Agent Central Airways Mustard Peripheral Airways Phosgene Combined Chlorine

PHYSICAL ASSESSMENT      SITE           SYMPTOMS            SIGNS Nasopharynx           Sneeze, pain             Erythema Oropharynx           Painful swallow Inflammation Larynx                     Choking Hoarse, stridor Trach/bronchi            Pain, cough          Wheezes, rhonchi Small airways             Dyspnea Rare crackles and alveoli            Tight chest

Clinical Considerations These agents cause pulmonary edema damage alveolar-capillary membrane Latent Period symptom onset may be delayed hours to days objective signs appear later than symptoms Sudden Death may occur laryngeal obstruction (edema/spasm) bronchospasm

Clinical Considerations Infectious Bronchitis / Pneumonitis common usually occurs 3-5 days post-exposure fever, elevated WBC, infiltrates NOT always infection prophylactic antibiotics NOT indicated Effects exacerbated by exertion compensatory mechanisms overwhelmed strict rest, even if asymptomatic No specific therapy exists

CHLORINE - Civilian Uses Chlorinated lime (bleaching powder) water purification disinfection synthesis of other compounds synthetic rubber plastics chlorinated hydrocarbons Don’t try this at home! (bleach + ammonia)

CHLORINE - Physical Properties gas at STP (bp = -34 degrees C) 2.5 times heavier than air green-yellow color acrid, pungent odor

CHLORINE - Mechanism of Injury Reaction 1: generation of HCL Cl2  + H2O        HOCl + HCl Reaction 2: oxygen free radical generation HOCl OCl-  + O2-

CHLORINE - Tissue Effects Topical rather than systemic In central airways - from HCl necrosis, sloughing In peripheral airways oxygen free radicals react with sulfhydryl groups, disulfide bonds damage to alveolar-capillary membrane

CHLORINE - Clinical Effects Mild Exposure suffocation, choking sensation ocular, nasal irritation chest tightness, cough exertional dyspnea Moderate Exposure above sx + hoarseness, stridor pulmonary edema within 2-4 hours

CHLORINE - Clinical Effects Severe Exposure severe dyspnea at rest may cause pulmonary edema within 30-60 min copious upper airway secretions sudden death may occur from laryngospasm

CHLORINE - Therapy Supportive care only oxygen positive pressure ventilation with PEEP to keep PaO2 > 60 torr bronchodilators Bacterial superinfection common (3-5 days out) follow serial cultures prophylactic antibiotics not indicated No long-term sequelae (uncomplicated cases)

CHLORINE EXPOSURE 36 y/o female 2 hrs post exposure resting dyspnea diffuse crackles PaO2  32 torr (room air) CXR: diffuse edema w/o cardiomegaly

PHOSGENE - Uses/Sources Chemical industrial production isocyanates (foam plastics) herbicides, pesticides aniline dyes Combustion of chlorinated hydrocarbons plastics Carbon tetrachloride Methylene chloride (paint stripper) degreasers

PHOSGENE - Physical Properties Cl Gas at STP (bp =7.6 deg C) 3.4 times heavier than air      C = O colorless odor of new mown hay Cl carbonyl chloride

PHOSGENE - Mechanism of Injury Reaction 1: hydrolysis, generation of HCl     CG + H2O       CO2 + 2HCl  -central effect -laryngospasm Reaction 2: acylation, X = NH, NR, O, S      CG + X       COX2 + 2HCl -peripheral effect -edema

PHOSGENE - Clinical Effects Mild Exposure mild cough dyspnea chest tightness Moderate Exposure above symptoms ocular irritation, lacrimation smoking tobacco produces bad taste

PHOSGENE - Clinical Effects Severe Exposure severe cough, dyspnea onset of pulmonary edema within 4 hours may produce laryngospasm Latent Period s/s onset more rapid with higher exposures Exacerbated by exercise

PHOSGENE - Therapy Supportive care strict bed rest O2, PPV with PEEP to maintain PaO2 IV fluids for hypotension (3rd spacing) bronchodilators for bronchospasm surveillance cultures antibiotics when indicated No long-term sequelae (uncomplicated)

PHOSGENE - Case 1 40 y/o male 2 hrs post exposure mild dyspnea normal physical exam PaO2 88 torr (room air) CXR: normal

PHOSGENE - Case 1 7 hrs post exposure mod. dyspnea at rest few crackles PaO2 64 torr (room air) CXR: mild interstitial        edema survived w/o sequelae

PHOSGENE - Case 2 42 y/o female 2 hrs post exposure rapidly inc. dyspnea PaO2 40 torr (room air) CXR: infiltrates - perihilar fluffy diffuse interstitial death 6 hrs post exp.

PFIB Organofluoride Polymers polytetrafluoroethylene (“Teflon”) many commercial uses used in armored vehicles, aircraft Toxic Combustion By-Products perfluoroisobutylene (PFIB) pulmonary edema similar to phosgene

Teflon Pyrolysis - Clinical Effects Teflon Pyrolysis at 450 degrees C symptoms mimic influenza “polymer fume fever” fever (104 degrees F) chills, malaise, sore throat, chest tightness spontaneous resolution no sequelae

PFIB - Clinical Effects Teflon Pyrolysis at >800 degrees C liberates PFIB 10X more toxic than phosgene latent period of 1-4 hours followed by increasing dyspnea s/s of pulmonary edema usually recover within 72 hours, w/o sequelae

PFIB - Therapy Supportive Care similar to treatment of phosgene

HC SMOKE Obscurant smoke Zinc Oxide + Hexachloroethane Combustion Products: zinc chloride phosgene chlorine carbon tetrachloride hydrogen chloride ethyl tetrachloride carbon monoxide hexachloroethane hexachlorobenzene

HC SMOKE - Clinical Effects Mild Exposure dyspnea lab findings normal (monitor x 4-6 hours) Moderate Exposure initial severe dyspnea, resolves spontaneously in 4-6 hrs return of symptoms within 24-36 hours CXR initially clear, later - dense infiltrates hypoxia bronchopnuemonia may lead to interstitial fibrosis

HC SMOKE - Clinical Effects Severe Exposure rapid onset, severe dyspnea paroxymal cough with bloody sputum hemorrhagic ulceration of upper airway rapid onset pulmonary edema may have rapid onset laryngeal edema/spasm, death

HC SMOKE - Therapy Supportive care of acute tracheobronchitis pulmonary edema Steroids probably useful (acutely) for inflammatory fibrotic changes long-term PFT follow-up 10-20% develop interstitial fibrotic changes

HC SMOKE EXPOSURE 60 y/o male 8 hrs post exposure mod. severe dyspnea diffuse crackles PaO2 41 torr (room air) CXR: dense peripheral infiltrates

HC SMOKE EXPOSURE 3.5 months later persistent, moderate dyspnea at rest PaO2 = 61 mmHg (room air) biopsy: diffuse interstitial fibrosis

NITROGEN OXIDES Nitrogen Dioxide (NO2, N2O4) high temp combustion arc welding nitrate-based explosives enclosed spaces diesel engine exhaust

NOx - Clinical Effects Symptoms similar to HC exposure may remit spontaneously exacerbated by exertion Long Latent Period may be asymptomatic for 2-5 weeks Fibrotic changes may occur PFTs may show chronic airway obstruction

NITROGEN OXIDES - Therapy Supportive Care similar to HC exposure steroids may be beneficial

CG - EXPOSURE February 3, 1917 - A chemist was working on a new chemical product.  A syphon of phosgene, required for the synthesis of this substance, burst on his table at 1:00 p.m.  A yellowish cloud was seen by a second person in the room to go up close to the chemist’s face, who exclaimed, “I am gassed,” and both hurried out of the room.  Outside, the patient sat down on a chair, looking pale and coughing slightly.

CG - EXPOSURE 2:30 p.m. -  In bed at hospital, to which he had been taken in a car, having been kept at rest since the accident.  Hardly coughing at all, pulse normal.  No distress or anxiety and talking freely to friends for over an hour.  During this time he was so well that the medical officer was not even asked to see the patient upon admission to the hospital.

CG - EXPOSURE 5:30 p.m. -  Coughing, with frothy expectoration, commenced, and the patient was noticed to become bluish about the lips; his condition now rapidly deteriorated.  Every fit of coughing brought up large quantities of clear, yellowish frothy liquid, of which about 80 ounces were expectorated in 1 and 1/2 hours.  His face became of a gray, ashen color, never purple, though the pulse remained fairly strong.

CG - EXPOSURE He died at 6:50 p.m. without any great struggle for breath.  The symptoms of irritation were very slight at the onset; there was then a delay of at least 4 hours, and the final development of serious edema up to death took little more than an hour though the patient was continually rested in bed.     Official History of The War (1914-1918)

CG - EXERCISE PROHIBITION “… men who have passed through a gas attack and have subsequently complained of only slight cough, nausea and tightness of the chest whilst resting in the trenches, have collapsed and even died abruptly some hours later on attempting to perform some vigorous muscular effort.”                Medical Manual of Chemical Warfare

SUMMARY Inhaled toxic agent effects may be Central, peripheral, or combined Latent period - “dose” dependent Onset of effect Symptoms occur before signs < 4 hours - severe, often lethal exposure > 4 hours - lethality less likely

SUMMARY - Therapy Terminate exposure Resuscitate - ABCs Maintain strict bed rest Assess immediately and at 4 hours If abnormal, assess for additional 24 to 36 hrs

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