a smaller proportion of patients, the histological pattern corresponds to pulmonary edema, acute-NSIP, or pneumonitis with granulomatous, eosinophilic, organizing, brinous organizing, storage-disease-like ILD features, or alveolar hemorrhage. Although distinctive, pathology patterns are rarely speci c for the drug etiology [60], except in the case of amiodarone, which may show evidence for pulmonary storage disease and the presence of foam cells [72] (Table 42.5). When drugs are suspected as the cause of ARDS, examination of the literature, characteristic ndings on imaging (see the eye catcher section in Pneumotox and below) [3, 4], careful medical history and drug history, bronchoalveolar lavage, early urine drug screen for the timely detection of substances of abuse, meticulous exclusion of other causes particularly an infection, response to drug therapy withdrawal, a trial of i.v. corticosteroid therapy and timely discussion of ECMO are indicated. Pneumothorax and/or pneumomediastinum may develop as a consequence of mechanical ventilation [3, 4, 73]. Data in Tables 42.5 and 42.7 provide information about causes of drug-induced or iatrogenic ARDS/DAD and may help deduce appropriate management strategies.

Drug-Induced Noncardiac Pulmonary Edema

Most often, drug-induced pulmonary edema is of the noncardiac type (NCPE) with normal left ventricular function andlling pressure, normal ejection fraction, brain natriuretic peptide (BNP) levels, and pulmonary capillary wedge pressure, when measured. Drug-induced NCPE may escape recognition and diagnosis. The time from the rst exposure to the drug and full-blown pulmonary edema can be very rapid or delayed. For instance, pulmonary edema in the form of lobular shadowing and septal lines on CT images occurred in 25 s after administration of radiocontrast material in one case [46] or minutes in the case of fash pulmonary edema [e.g., from radiocontrast media, epinephrine (adrenaline) or intravenous heroin], often within hours days or more with salicylate or hydrochlorothiazide. Noncardiogenic pulmonary edema may evolve into acute respiratory failure and a fully developed ARDS picture. Cardiac ultrasound, urine drug screen (depending on context and extrapulmonary signs and symptoms), and naloxone reversal test are indicated. Acute drug-induced noncardiogenic pulmonary edema can develop following deliberate (suicidal) or inadvertent overdose of such drugs as salicylate, adrenaline, tricyclic antidepressants, calcium channel blocking drugs (amlodipine, chlordiazepoxide, nicardipine, nifedipine, verapamil), carbamates, carbamazepine, colchicine, dibenzazepine, haloperidol, insulin, naloxone, phenothiazines, propoxyphene, salicylate, zolpidem or drugs of abuse (heroin, amphetamines, cocaine, codeine, fentanyl). Drug-induced NCPE can develop following oral, parenteral or topical administration of drugs including epinephrine (adrenaline), ATRA, arsenic trioxide

(As2O3), CSFs, hydrochlorothiazide, lidocaine, naphazoline, opiates, propofol; tocolytic agents, chemo drugs (gemcitabine, methotrexate, mitomycin C, taxanes), and radiocontrast agents, among 219 causal drugs or agents (up from 171 in the earlier edition of this chapter) [3, 4]. DI-NCPE can develop following even one tablet of the offending drug. Pulmonary edema can also be a manifestation of drug-­ induced (DI) anaphylaxis. The diagnosis is sometimes raised by patient or family who astutely observe the temporal relationship between exposure and onset of symptoms with rechallenge at home. Abrupt onset in seconds, minutes or in a few hours with resolution in hours or days upon drug stoppage are suggestive of DI pulmonary edema. There may be a stepwise increase in edema severity concomitant with each inadvertent readministration of the causal drug [74]. Severe pulmonary edema in drug abusers may be heralded by a plume of pink protein-rich (plasma to edema fuid protein ratio >0.7) and frothy sputum at the mouth [75]. Fever, hypotension, shock, and hemoconcentration concomitant with pulmonary in ltrates characterize those cases with hydrochlorothiazide pulmonary edema. Transient pulmonary in l- trates waning in a few hours have been noted after exposure to crack cocaine, hydrochlorothiazide, nitrofurantoin, and anti-thymocyte globulin [3, 4]. Drug-induced pulmonary in ltrates may be indicative of feeting pulmonary edema or DAD, and a few case reports support that contention [76]. Imaging ndings can also include diffuse haze, ground-glass shadows, septal line thickening (consistent with excess fuid in lung), and sometimes pleural fuid is present as an associated feature. There is typically little or no enlargement of the cardiac silhouette or vascular pedicle on chest imaging [77] in NCPE, since alveolar fooding is caused by increased vascular permeability. Unless overzealous resuscitation with fuids leads to volume overload pulmonary edema [78]. On pathological examination, interstitial congestion and alveolar lling with acellular proteinaceous fuid are noted in NCPE [61]. Hyaline membranes, alveolar brin, and resolving DAD are found in cases with overlapping features of DAD or acute brinous organizing pneumonia (AFOP) [60, 61]. Some DI-NCPE cases present with DAH [79]. Diuretics are generally considered of uncertain bene t in DI-NCPE, as intravascular volume may be on the low side due to fuid extravasation to the lung and other tissues. Care should be taken to avoid drug re-exposure in cases of DI-NCPE, as severe relapses may follow [80]. Mortality in DI-NCPE can be as high as 5–20% (extracted from reference in [3, 4]).

The respiratory manifestations of salicylate poisoning are worthy of special mention because of the prevalence of aspirin overdoses. Salicylate-induced pulmonary edema can occur in both acute and chronic users, with a predilection for the aged and patients with renal dysfunction [81]. Patients may present with fever, systemic, and neurologic symptoms including obtundation and anion-gap metabolic acidosis. A