eign material followed by embolization into the terminal pulmonary circulation [3, 4, 8]. Examples include fuid silicone, bone marrow, blood and components, autologous fat, calcium replacement therapy, liquid or elemental mercury, “inert” drug excipients or solvents, colony stimulating factors, aprotinin, protamine, gas from hemodialysis machine or from the ECMO setup, fat or lipid excipients (as in propofol, parenteral nutrition or mineral lipids). A comprehensive list is available in Pneumotox [3, 4, 8]. The mechanical consequences of i.v. injection of certain drugs or foreign material include obstruction of the pulmonary circulation to blood fow, traumatic vascular injury from sharp-edged embolized material or crystals, activation of the coagulation cascade, intravascular coagulation, and fuid leakage. Chronic consequences can include severe pulmonary hypertension, interstitial lung disease, and pneumoconiosis. A history of recent injection or infusion of drugs (including drugs of abuse), surgical procedure, liposuction or cosmetic surgery can aid in diagnosing the condition. Telltale signs of surreptitious drug use include venous access (“tracks”) on the forearms or groin, foreign material deposits on fundoscopy, and paraphernalia in their home.

Methylmethacrylate cement embolism is a distinctive complication of vertebroplasty sessions [3, 4]. During kyphoplasty, acrylate cement is injected in the vertebral body [150]. Leakage of cement and bone marrow may occur in up to a quarter of patients so treated and is symptomatic in about 5%. Methylmethacrylate embolism is of interest to the interventional and diagnostic radiologist, orthopedic surgeon, pulmonologist, and cardiologist. On imaging, embolizing or embolized cement is in the form of dense tubular, branching, punctuate or wormlike shadows in paravertebral veins, heart, or pulmonary circulation [151]. This is best viewed on plain chest radiograph and unenhanced CT. High volume acrylate polymerization during transit through the heart or main pulmonary arteries can cause complete hindrance to blood fow and this can be fatal.

Transhepatic chemoembolization sessions may be complicated by vascular dissemination of doxorubicin and/or cyanoacrylate with or without iodized oil (Lipiodol) or radioactive material, causing pulmonary embolism, pleural effusion, acute pulmonary edema, and/or ARDS within hours of the procedure [3, 4].

Acute radiation induced lung injury resulting ARDS has become very unusual following radiation therapy to the chest, particularly since the advent of novel stereotactic techniques and establishment of safer radiation thresholds. The complication is almost exclusively reported in patients who receive concomitant irradiation and chemotherapy or total body irradiation. A single series reported on 15 patients with ARDS developing after administration of the radiochemical 131I for the treatment of hepatocellular carcinoma. The ARDS was lethal in 12 patients (80%) [152].

Drug-Induced/Iatrogenic Airway Emergencies

Airway Obstruction as a Manifestation of Anaphylaxis

Central airway obstruction is common in (drug-induced) anaphylaxis, due to upper airway and laryngeal edema, as found at autopsy [153].

Drug-Induced Angioedema

About 70% of angioedema involving the upper air passages occur as a complication of therapy with drugs (124 are known to cause this condition), with ACEI accounting for 52% of angioedema cases [3, 4, 154]. Angioedema can cause severe upper airway obstruction [3, 4]. Angioedema can also affect the intestine causing relapsing abdominal pain and bowel obstruction. Angioedema typically occurs in isolation in the rst few weeks or later and up to a few years into treatment with the culprit medication, with no clue to predict the development of the condition. Angioedema may develop concomitant with drug-induced anaphylaxis. Drug-induced angioedema can cause rapidly progressive upper airway obstruction and fatal asphyxia [155]. Epidemiological studies disclose an increasing incidence of this complication. Drug-induced upper airway obstruction occurs more often as a complication of chronic treatments with renin-angiotensin system inhibitors including ACEI and angiotensin receptor blockers (ARB) than with any other class of medications [154]. Incidence is less than that of ACEI-induced cough (about 1/30th), and there is no known mechanistic overlap between the two. Among ACEI, incidence is greater with enalapril and lisinopril as compared to captopril. Incidence of ARB-associated UAO is about 1/10th–1/20th compared to ACEI. Mild grades of airway or intestinal angioedema are notoriously underrecognized, and prolonged delays in diagnosis result in continuing exposure to the drug despite repeated episodes of mild lip, tongue, mouth, mouth foor or throat edema puts patients at risk of developing a major or fatal episode of central airway blockage and asphyxia [156]. Risk factors for angioedema include a disproportionate fourfold greater incidence in people of color (african-americans or afro-caribbeans) compared with caucasians. This accounts for a greater incidence of this complication in the US. Airway manipulation and the trauma of intubation are risk factors for acute angioedema. However, UAO can develop unexpectedly with no identi able triggering factor. About 25% of patients give a history of previous spontaneously resolving episodes of mild perioral, oral or palpebral edema that failed to be identi ed and recognized as drug-related by healthcare professionals. Warning symptoms of impending angioedema include sore throat, drooling, dysphagia, pruritus, and the rapid development of edema of the lips, foor of the mouth, tongue and/or larynx. Type 1 angioedema is limited to the face, type 2, to the mouth foor, base of tongue and uvula,

and type 3 to the oropharyngeal, supraglottic and glottic region (though rarely involving the thoracic trachea). The risk of asphyxia is greater in patients with the type 2 or 3 angioedema. These patients are more liable to experience breathing dif culties and require admission to the ICU. It is important to identify and secure the airway early using theberoptic bronchoscope and endotracheal tube, since if the edema progresses, complete airway obliteration may occur. Identi cation of the airway lumen can be problematic and emergent cricothyrotomy or tracheostomy can be perilous in the context of asphyxia and anoxia. Irreversible hypoxic brain damage and death can result [156]. A few angioedema cases were complicated by laryngospasm with consequent negative pressure pulmonary edema or hemorrhage as a “domino” complication. About 40% of patients with drug-­ induced angioedema require admission to the ICU. And 10% of those require mechanical ventilation. Patients need to be monitored for an average of 2 days since rebound angioedema can occur despite drug discontinuation and appropriate management. Corticosteroids and antihistamines have unproven ef cacy. The bradykinin-B2 receptor inhibitor icatibant has met with success in reducing the time to recovery from 33 to 4.4 h [157]. Other therapeutic drugs of interest include ecallantide, fresh frozen plasma, C1-inhibitor, and II-VII-IX-X factor concentrate [158]. Education of patients started on ACEI and ARB is critical, as is regular history taking for the occurrence of mild angioedema episodes anytime a new ACEI prescription is written. Rechallenge with the drug is hazardous, as severe or fatal UAO can recur after variable time on the medication [159]. A few cross-reactions to both ACEI and ARB have been reported in the same individual.

Hematoma Around the Upper Airway

Treatments with vitamin K antagonists, new oral anticoagulants, and exposure to or poisoning with superwarfarins (e.g., brodifacoum) can cause alveolar hemorrhage, hemothorax, hemopericardium, hemomediastinum, hemoptysis or epistaxis [3, 4]. Hematoma can develop in the esophageal wall or around the central airway, which can cause severe upper airway narrowing and obstruction that can be dif cult to diagnose. The hematoma may localize in the neck, tongue, pharyngolarynx, retropharyngeal space or mediastinum in humans as well as in poisoned animals [3, 4]. Hematomas can cause lumenal narrowing and life-threatening airway obstruction. Being deep-seated, hematomas may not cause measurable blood loss and can escape recognition on endoscopy. Anticoagulant-induced esophageal hematomas may compress the tracheal wall [3, 4].

Blood originating from the lung may clot in the large airways and/or the central airway, causing life-threatening or fatal airway obstruction [160].

The “Pill Aspiration Syndrome”

Aspirated drug tablets (e.g., iron sulfate or alendronate pills to name a few) can lodge in the larynx [161], or damage the trachea, and/or large airway walls [162–164], causing unusual but suggestive endoscopic appearances and/or airway obstruction or ulceration that are sometimes mistaken for malignancy [3, 4]. Diagnostic error may occur because the pill or pills may not be longer visible, after being absorbed through the airway mucosa in the interval between aspiration and the time of clinical presentation.

Catastrophic Drug-Induced Bronchospasm

Severe sudden asthma can develop following oral or parenteral exposure to one of the 55 drugs capable of causing the syndrome, including drugs of abuse (cocaine, crack cocaine heroin), adenosine, analgesics, antibiotics, aspirin (salicylate), beta-blocking agents, e-cigarette vapor, lidocaine, and NSAIDs [3, 4]. Most of these drugs are either contraindicated or should be used very cautiously in patients with a history of asthma, particularly if severe or unstable at baseline. These contraindications may be overlooked, causing severe or fatal reactions upon exposure. Drugs cause more severe asthma attacks compared to other triggers. In one study, 8% of acute severe asthma attacks requiring mechanical ventilation in the ICU were triggered by an NSAID [165]. A history of severe, unstable dif cult-to-control, corticosteroid-­dependent asthma, atopy, nasal polyps, drug allergy or prior reaction with the same or drugs or congeners of the same family or class are risk factors. Though catastrophic bronchospasm may develop in a subject with no prior history of asthma (for instance, with nonselective β-blockers) [166], the complication generally occurs in patients with previously diagnosed asthma. Contrasting with drugs to which patients become sensitized upon repeated exposure (for instance, oxaliplatin, neuromuscular blocking agents), aspirin, and NSAID sensitivity/intolerance does not result from acquired sensitization but is rather inherent and constitutional to the patient. Patients may present with the Widal or Samter triad of recalcitrant sinusitis-nasal polyps, intermittent watery nasal discharge, dif cult-to-treat asthma, and intolerance to NSAID of the COX-1 inhibitor family and to aspirin. Exposure to those drugs is followed within minutes to a few hours by an increase in nasal symptoms over baseline, and bronchospasm which can be severe. Avoidance of any COX1 NSAID including aspirin in such patients is essential. Desensitization or a state of tolerance using incremental dosages of the causal drug may be achieved if patients need to be treated again or to use these medications chronically. Importantly, continuous (e.g., daily or thrice weekly) exposure to the drug is necessary for maintenance of the desensitized state, otherwise intolerance returns in a few days and along with it comes the risk of relapse of a severe