Inspiratory muscles were affected in the original illness Additional scoliosis due to parav ertebral muscle involvement (in which case vital capacity will be reduced) This may be due to premature ageing of the upper and lower motor neurons due to their \200 \230over-use \200\231. This could follow the original destruction of some of the anterior h orn cells to the inspiratory muscles, and the sub- sequent reinnervation by surviving neuro ns which then have to continu- ously supply more neurons than they were \200\230designed \200\231 for. 2. Weak or mechanically disadvantaged inspiratory muscles with/without secondary reduction of awake ventilatory drive Neuromuscular inspiratory muscle weakness will produce diurnal v entila- tory failure in its own right, particularly when the supine vital capacity falls be low 20% predicted (approximately 1 L). With increasing inspiratory muscle weakness, other accessory inspira- tory muscles are recr uited to maintain ventilation. When this is lost during non-REM sleep, and more so during R EM sleep, ventilation will fall much CAUSES AND CLINICAL FEATURES OF CSA/HYPOVENTILATION 1 585 more than in normal subjects. Whilst metabolic ventilatory drive is reasonably preserved, t his will result in recurrent arousals to \200\230rescue \200\231 the ventilation and conse quent marked sleep disturbance. As ventilatory drive becomes progressively blunted, following the hypo- ventilation forced on the system by weak muscles, extra sleep hypoventi- lation (from loss of \200\230awake \200\231 drive) is tolerated and profound hypoxaemia is observed until there is \201 nall y an arousal that recovers the ventilation and SaO2. The above patients should have a history of a progressive neuromus- cular disorder. Chest wall restrictive diseases, such as scoliosis or post-thoracoplasty patients (p 579), can behave in a similar way with gradual onset of ventilatory failure, particularly when vi tal capacity <1 L. The muscles are not weak, but operating at severe mechanical disadvantag e. The same situation occurs in COPD, when muscles are overloaded and accessory muscles provid e important support, but this too is reduced with non-REM sleep and lost during REM sleep. Again, any secondary reduction in ventilatory drive ampli \201 es the sleep-related falls in SaO2. \200 Chest wall restrictive patients should have an obvious restrictive dis- order with reduced VC to 1 L or below Increasing degrees of COPD will produce increasing degrees of sleep hypo ventilation (p 581) If the awake SaO2 is already low the sleep-related falls in ventilation will produce dramatic dips in SaO2 COPD and OSA together (overlap syndrome, p 570) provoke pro- found nocturnal hypoxic dipping (p 581), and probably a more rapid progression to diu rnal hypoventilation with CO2 retention, due to extra blunting of ventilatory drive (see p 570). The diaphragm is the only respiratory muscle working during REM sleep, as all other postura l muscles are profoundly hypotonic \200 If the diaphragm is paralyzed, then REM sleep is a particularly vulner- able time as there are no muscles of ventilation left working, producing particularly profound falls in SaO2 d uring this period Patients with bilateral diaphragm weakness can present early with no obvi ous weakness elsewhere. Diaphragm weakness is best detected with the patient supine. Inspir ation, particularly on snif \201 ng, will provoke a paradoxical indrawing of the abdominal wall. The vital capacity will also fall on lying down, increasingly with greater degrees o f paralysis (often a >30% fall in VC with complete paralysis). In a progressive neuromuscular disorder, such as motor neuron disease, the above patterns w ill be variable between individuals, but will gradually worsen. Predominant diaphragm weakn ess, as occurs sometimes in motor neuron disease, spinal muscular atrophy, and particularly acid maltase de \201 ciency, can lead to ventilatory failure at a time when the patient i s still ambulant. 586 CHAPTER 47 Sleep apnoea and hypoventilation Causes and clinical features of CSA/ hypoventilation 2 3. Cheyne \200\223Stokes breathing a ssociated with LVF (p 575) The raised left atrial pressure in left heart failure increases ventilatory drive through stimulation of J receptors. This is in addition to ventilatory st imulation due to any hypoxaemia from pulmonary oedema. \200 This ventilatory stimulation lowers the awake PaCO2 producing a respi- ratory alkalosis In addition the use of diuretics may produce a mild metabolic alkalosis, especially if there i s hypokalaemia This extra J receptor ventilatory stimulation appears to reduce at sleep ons et. This, together with the loss of the awake ventilatory drive, allows central hypoventila tion or apnoea to occur This hypoventilation or apnoea will continue until the PaCO2 builds up to drive ventilation again, or until the attendant hypoxaemia causes arousal The return of ventilation itself may provoke arousal too. The arousal itself then injects increased v entilatory drive, reducing the PaCO2 again Sleep returns, and once again the low PaCO2 and alkalosis cause hypoventilation or apnoea Thus a cycle is maintained that involves a \202 uctuating sleep state with arousals, and usually a \202 uctuating SaO2. As with OSA, the patient may be completely unaware of thes e arousals. The delayed circulatory time of left heart failure may compound this instabilit y by introducing a time delay between any change in PaCO2 in the blood leaving the lungs an d its arrival at the carotid body or central chemoreceptors. 4. Cheyne \200\223Stokes breathing associated with altitude The acute hypoxia following asc ent to altitude provokes increased ventila- tion. The degree is variable between individual s and hence the degree of hypocapnia and respiratory alkalosis varies (see p 238). With sle ep onset, with a lessening of the hypoxic drive, and removal of the awake drive, an uncompe nsated alkalosis will allow hypoventilation and even apnoea \200\224 similar to the situati on described above for Cheyne \200\223Stokes breathing. Again, ventilation will restart eit her when the PaCO2 rises to a critical level, or the hypoxia provokes arousal. Sleep is fra gmented with complaints of insomnia, but the cause of this is rarely recognized by the suff erer. Skiing in Colorado, altitude 2400 \200\2233400 m (710,000 f), is high enough to provoke sig ni \201 cant periodic breathing in about a \201 fth of individuals. It seems that this \201 fth are the ones with the highest hypoxic ventilatory response. This gives them the l argest respiratory alkalosis and hence the greatest tendency to sleep onset hypoventilation . In addition the tendency to arouse with the resultant extra hypoxaemia may be greater too , thus provoking large increases in ventilation on arousal and greater sleep distur- bance. As the kidney excretes extra bicarbonate and produces a compen- satory metabolic acidosis over a few days, the periodic breathing lessens. CAUSES AND CLINICAL FEATURES OF CSA/HYPOVENTILATION 2 587 Two pharmacological approaches have been taken to reduce this sleep- related periodic breathing. \200 Pre-acclimatization with acetazolamide prior to ascent. This produces a mild metabolic acid osis and maintains the ventilatory drive at sleep onset, thus blocking the hypoventilation. Randomized controlled trials show the ef \201 cacy of this approach with doses between 25 0 and 500 mg/day, 1 \200\2233 days prior to ascent Hypnotics, such as temazepam, can reduce the degree of periodic breathing by reducing the tendency to arousal with each return of v entilation, and thus damping the system. Randomized trials suggest bene \201 t for the ear ly part of the night, with no impairment of nocturnal hypoxaemia or daytime functioning. See also pp 238 \200\22339 (altitude sickness). 588 CHAPTER 47 Sleep apnoea and hypoventilation CSA/hypoventilation: investigations Simple pulmonary function tests will characterize weakn ess of inspiratory muscles. Supine vital capacity is the best predictor of ventilatory fail ure as it incorporates diaphragm weakness that is masked during erect testing. Blood gasses will reveal actual diurnal type II ventilatory failure and, if the base excess is raised w ith a normal PaCO2 (therefore, a mild metabolic alkalosis), then this may indicate nocturna l hypoventilation and incipient ventilatory failure. Sleep study Examples on p 575, 579, 581. Sleep studies in patients with suspected nocturnal hypoventilation or central sleep apnoea are required to con \201 rm the diagnosis and to assess the degree of nocturnal hypoxaemia . Limited sleep studies will reveal falls in SaO2 in association with hypoventilation, but no evidence of obstruc- tion and, in particular, no snoring. Oximetry tracings alone will s how a variety of patterns, often resembling OSA. The pattern in neuromuscular weakness will vary from oscillations all the time (due to recurrent arousal) to just REM sleep-related d ips in SaO2. The same will be true for chest wall restrictive disorders and COPD with only REM dips occurring initially, and more extensive hypoxaemia developing once there is an ele ment of CO2 retention and diurnal hypoxaemia. \200 In OSA there is a slow fall in SaO2 as oxygen is gradually removed from the lung stores, fo llowed by a rapid rise engendered by the \201 rst deep inspiration as the apnoea breaks ( so-called saw tooth pattern), p 571 In Cheyne \200\223Stokes of left heart failure the osci llations in SaO2 are often more sinusoidal than in OSA as the pattern of breathing is usual ly more a symmetrical waxing and waning of ventilation, p 575. However, if each central apn oea is terminated by an arousal, rather than a smooth return of ventilation, then the patte rn will look more like OSA. In COPD, the degree of hypoxaemia on the sleep study will depend very much on the awake SaO 2. Because of the shape of the hemoglobin disso- ciation curve, a low awake SaO2 makes it e asier for the SaO2 to fall further with a given reduction in ventilation. Thus during non-R EM, with removal of awake drive, there will be a fairly stable reduction in SaO2, but durin g REM sleep there will be further more dramatic dips. It is important not to diagnose OSA f rom just an oximetry tracing on the basis of SaO2 oscilla- tions in the presence of a low b aseline SaO2 and COPD. In this situation a fuller sleep study is required to provide eviden ce of additional upper airway obstruction. The combination of hypoxic COPD and OSA can prod uce particularly dramatic traces (p 581). Management Intervention in central sleep apnoea o r hypoventilation or periodic breathing, depends on symptoms. Better control of heart failu re may improve Cheyne \200\223Stokes breathing, but often does not. Further treatment will be required for two reasons: either to prevent the cyclical breathing and restore sleep qua lity, or to globaly improve ventilation over- night and reset the respiratory control mecha nisms such that the daytime respiratory failure reverses. CSA/HYPOVENTILATION: INVESTIGATIONS 589 In situations where the hypoxia is playing a part in the pathogenesis (e.g. heart failure) then raising FiO2 can help. There is limited literature on other forms of treatment for the Cheyne \200\223Stokes of heart failure, although acetazolamide and benzodiazepines have be en tried. The unstable breathing in heart failure has been treated with CPAP, however a lar ge RCT has not con \201 rmed long-term bene \201 t. More recently, treat- ment has been t ried with specially designed servo ventilators, but whether these will provide better relie f of symptoms than oxygen is not yet clear, but preliminary evidence suggests they might. T here is some data to suggest that the recurrent arousal in Cheynes \200\223Stokes may raise catecho- lamine levels and provoke deterioration of left ventricular function. Thus, measu res to reduce the arousals may improve cardiac function as well as improve daytime vigilanc e. Sedatives are contraindicated with a raised PaCO2, and extra oxygen may increase the hyperc apnia. In these situations, then overnight non- invasive ventilation, via either nose or fa ce mask, may be appropriate. In slowly progressive neuromuscular disorders, with either sle ep fragmenta- tion or diurnal type II respiratory failure (or both), the symptomatic and ph ysiological response can be dramatic. The use of non-invasive ventilation in more rapidly p rogressive disorders is fraught with potential dif \201 culties and is very much a special ist decision. Increasing dependence on equip- ment, not designed to be immediately life-sus taining, being a particular issue. In scoliosis there is rarely any question that treatment might not be appropriate, and again responses are dramatic. Future developments \200 Treatment of LVF (acute and chronic, no evidence yet for the latter) with overnight CPAP or non-invasive ventilation Introduction of overnight ventilation earlier in the course of a pro- gressive neuromuscular disorder (such as motor neuron disease) to reduce symptoms and possibly prolong life Use of overnight ventilation on patients with stable COPD and hyper- capnia. This may reduce exacerbations, hospital admissions, and prolong life. The evidence is inadequate yet to justify its wide use in this patient group. Further information Lanfranchi PA, Somers VK. Sleep-disordered breathing in heart failure: characteristics and implica- tions. Respir Physiol Neurobiol. 2003; 136: 153 \200\22365. Wuyam B et al. Pathophysiology of central sleep apnea syndrome. Sleep. 2000; 23(suppl. 4): S213 \200\2239. Berry-Kravis EM et al. Congenital central hypoventilation syndrome. Am J Respir Dis Crit Ca re Med 2006; 174: 1139 \200\22344. Gray A etal. Noninvasive ventilation in acute cardiogenic pulmonary edema. NEJM 2008; 359:1 42 \200\22351. BTS sleep training CD. Modular PowerPoint presentations on sleep and its disorders. Availab le from the BTS, +44 (0)2078318778 590 CHAPTER 47 Sleep apnoea and hypoventilation Obesity-related respiratory problems Levels of obesity (BMI>30) are rising in all \200\230 civilized \200\231 societies. In 1993, 13% of men and 17% of women in the UK (21% and 26% i n the USA) had a BMI >30. In 2000 this was 21% and 22% in the UK (29% and 36% in the USA). This also has had many impacts on health care outside of respiratory medi- cine, particular ly the components of the metabolic syndrome. Obesity, particularly in conjunction with OSA and COPD, provokes ven- tilatory failure and cor pulmonale (see p 93). A common clinical scenario is the obese smoker, with a history of snoring and sleepiness, arriving in A&E with hypercapnia. In addition to apportioning the relative contribution of obesity, COPD, and OSA to the hype rcapnia, and treating accordingly, there are other obesity-related factors to consider:- \200 Intubation The best predictor of a problematic intubation are neck circumference and a Mall ampati score of 3 or more Tracheostomy tubes are often too short and too curved to cope wit h the increased distance between skin and trachea; tubes with adjustable \202 anges that allow customized intra tracheal lengths are useful here Percutaneous dilatational tracheost omy is more dif \201 cult and may have a higher complication rate Low FRCs mean that the o xygen stores are limited, leading to rapid falls in SaO2 during apnoeas of any cause Abdomi nal loading of the diaphragm is increased, but the extra work of breathing can be reduced c onsiderably by tilting the whole bed, head up, by as much as 20 \200\22330 . Abdominal loa ding of the diaphragm reduces basal lung expansion. Resultant basal atelectasis increases t he A \200\223a gradient. Raising the end- expiratory pressure during either invasive or non -invasive ventilation improves this Abdominal loading may increase perioperative risk of as piration DVTs and pulmonary emboli are probably more common in the obese. It is not clear i f DVT prophylaxis regimes need to be modi \201 ed. Some recommend higher doses of low mole cular weight heparin (LMWH), and this higher dose is more effective in patients undergoing bariatric surgery. Weight-based regimes of LMWH for the treatment of DVT and emboli appear satisfactory in the morbidly obese (BMI>40). Increased likelihood of failure to wean: non-i nvasive ventilation (inspira- tory pressure 12, expiratory 4 cmH2O) has been shown to aid w eaning, post-open gastric-bypass surgery for obesity. Possible build-up of sedating anesthe tic agents in fat leading to pro- longed half-life. \200 Further information El-Solh AA. Clinical approach to the critically ill, morbidly obese pat ient. Am J Respir Crit Care Med. 2004; 169: 557 \200\22361. OBESITY-RELATED RESPIRATORY PROBLEMS 591 Class 1 Class 2 Class 3 Class 4 Fig. 47.9 Mallampati index. Simple scoring system for pharyngeal crowding. Affected by cran io-facial shape, tongue size, and obesity. Predicts dif \201 culty of intubation and corre lates with OSA severity. Reproduced with kind permission from Update in Anesthesia; Issue 1 3, 2001. This page intentionally left blank 593 Chapter 48 Toxic agents Drug-induced lung disease: clinical presentations 594 Drug-induced lung disease: examples 1 596 Drug-induced lung disease: examples 2 598 Paraquat poisoning 600 Radiation-induced pul monary disease 601 Inhalational lung injury 1 602 Inhalational lung injury 2 604 Carbon mon oxide poisoning 606 594 CHAPTER 48 Toxic agents Drug-induced lung disease: clinical presentations Introduction A vast number of drugs can d amage the respiratory system, from nose to alveoli. The most complete and useful list (plus ref- erences) is kept at www.pneumotox.com and can be queried by either drug (or drug type ) or clinical/radiological presentation: all agents have equal prominence, but are coded wi th a star rating to indicate likely preva- lence. This chapter describes the commoner drugs that produce respira- tory problems. Commoner presentations of drug-induced lung disease and examples of causative agents \200 Interstitial lung disease, pneumonitis, \201 brosis \200 \200 Acute hypersensitivity pneumonitis (nitrofurantoin, methotrexate) Interstitial pneumonitis 9 eosinophilia (amiodarone, ACE inhibi- tors, sulfasalazine) Chronic organizing pneumonia ( amiodarone, bleomycin) Pulmonary \201 brosis (bleomycin, amiodarone, nitrofurantoin, B bl ockers) Airways disease \200 \200 \200 Pleural changes \200 \200 Bronchospasm (B blockers, contrast media) Obliterative bronchiolitis (busulphan, penicillam ine) Cough (ACE inhibitors) Pleural effusion/thickening (B blockers, nitrofurantoin, metho- trexate, dopamine agonists) Pneumothorax (bleomycin) Vascular changes \200 \200 Thromboembolic disease (phenytoin) Pulmonary hypertension (dexfen \202 uramine, other appe tite sup- pressants) Vasculitis (nitrofurantoin, L-tryptophan) Mediastinal changes \200 \200 Pulmonary oedema (methotrexate, contrast media) Pulmonary hemorrhage (methotrexate, nitrofurantoin, penicillamine, contrast media). Node enlargement (bleomycin, phenytoin) Sclerosing mediastinitis (ergot) \200 This page intentionally left blank 596 CHAPTER 48 Toxic agents Drug-induced lung disease: examples 1 Amiodarone Iodinated benzofuran used to suppress supr a- and ven- tricular tachycardias. Lung toxicity correlates loosely with total dose and the refore usually occurs after a variable number of months. Seen in 10% of subjects on >400 mg /day. Rare if <300 mg/day. Risk factors \200 \200 \200 \200 \200 Daily dose >400 mg Increasing age of patient Use for more than 2 months Pre-existing lung d isease (although not a contraindication to its use) Recent surgical intervention or lung in fection. Diagnosis is usually one of exclusion, and response to cessation of drug (which can take mo nths). In \201 ltrative lung disease varying from acute respiratory distress (rare) throug h to COP (cough, pleuritic pain, fever, dyspnoea, asymmetric patchy in \201 ltrates, effus ion), and the most indolent, chronic interstitial pneumonitis (cough, dyspnoea, weight loss , diffuse and/ or focal opacities). On CT the liver, thyroid, and lungs will usually show increased attenua- tion, indicating a signi \201 cant amiodarone load. A baseline CXR is useful. Lung biopsie s exclude other diagnoses and provide compatible \201 ndings, but there is dissent as to how diagnostic they are (except for the \201 nding of foamy macrophages in the airspaces, \201 lled with amiodarone \200\223phospholipid complexes, but may occur in absence of lu ng toxicity). Mechanisms of toxicity are unclear, and there are features to suggest hyperse nsitivity and direct toxic damage. Treatment Steroids are effective and required in severe disease. The half- life of amiodarone in the tissues is in excess of a month and response t o stopping the drug may be slow. Prognosis is good in the majority. Anti-TNF agents (in \202 iximab and etanercept) represent a large step forward in the trea tment of rheumatoid arthritis and Crohn \200\231s disease. However, there is a small but im portant risk of reactivating TB, commonly extrapulmonary - see p 512. Pneumonia and develop ment of antibodies are also more common; SLE develops only rarely. Azathioprine Extensively used as an immunosuppressant but has remarkably little pulmonary toxicity other than via o pportunistic lung infection. Case reports of pneumonitis only. Bleomycin DNA-damaging glyco peptide used in the treatment of lym- phomas, germ cell tumors, squamous carcinomas (cervix , head, neck, and esophagus). Pulmonary \201 brosis occurs in about 10%. Risk factors \200 Older age \200 Those receiving total dose of >300,000 international u nits (1000 inter- national units [or 1 old/USB unit] = 1.5-2.0 mgs) Increased FiO2, probabl y via increased superoxide/free radical forma- tion. Pneumonitis may be precipitated by sup plementary oxygen for some time after drug administration \200\224warn anesthetist if surge ry DRUG-INDUCED LUNG DISEASE: EXAMPLES 1 597 planned in patients who have received bleomycin in previous 6-12 months Pulmonary irradiati on, not just in the irradiated \201 eld Renal failure decreases drug elimination and thus toxicity Associated use of cyclophosphamide. \200 \200 Symptoms (cough, dyspnoea, chest pain, fever) develop 1 \200\2236 months after bleomycin. T here is hypoxia and a restrictive defect. Progressive basal subp- leural shadowing, small l ungs, and blunting of costophrenic angles. Histology shows a dominant subpleural distributi on of damage and repair with \201 brosis; this appearance is non-diagnostic and common to many drugs/disorders. Toxicity is probably due to DNA damage or oxidative injury, with int erindividual variation occurring due to differing activity of the enzyme bleomycin hydrolas e; only low levels of this enzyme exist in the lung (and skin). A rare acute hypersensitivi ty form comes on within days of administration. Other unusual presentations include pulmona ry nodules or organizing pneumonia. Treatment \200 Bleomycin must be stopped on suspicion of damage, and some units use lung function tests (k CO) to detect early damage Steroids are used, but there is little evidence they alter long- term prog- nosis (in the acute hypersensitivity subgroup there is a clear bene \201 cial e ffect) Use the minimum FiO2 to maintain an adequate SaO2 (85-90%) Over 50% may experience a relentless decline in lung function. \200 Busulphan DNA alkylating, myelosuppressive, agent mainly used to treat chronic myeloid leuk emia, and prior to bone marrow transplanta- tion, with a low rate of lung toxicity (4 \200 \22310%) due to \201 brosis. Risk factors \200 \200 \200 Cumulative doses over 500 mg (mostly over 120 days) Concurrent administration of other alky lating agents Pulmonary irradiation. Presents with cough and progressive SOB, often years after exposure (usually about 4). CXR is typically unremarkable. Reduced kCO and restrictive defect. Diagnosis is usually by excl usion. The place of steroids is unproven. Chlorambucil DNA alkylating agent mainly used to treat chronic lymphocytic leukemia, lymphomas, and ovarian cancer. It has additional immuno suppressive actions, and is also used in conditions such as rheuma- toid arthritis. Low ris k (1%) of pulmonary toxicity and con \201 ned to those who have received >2 grams. Similar ly to busulphan, presentation may be many years later. Presents with cough, dyspnoea, weigh t loss, and basal crackles. CXR shows diffuse basal reticular shadowing. Non-speci \201 c his- tology. On suspicion, chlorambucil should be stopped; use of steroids is unproven. Pro gnosis is poor (50% fatal). 598 CHAPTER 48 Toxic agents Drug-induced lung disease: examples 2 Cyclophosphamide DNA alkylating agent mainly used to treat chronic lymphocytic leukemia, small cell lung cancer, and other solid tumors. Particu larly useful as an immunosuppressive agent in certain vasculitides and nephropathies. Lung toxicity is rare. Risk factors \200 \200 \200 Pulmonary irradiation Oxygen therapy Concurrent drugs causing pulmonary toxicity, e.g. bleo mycin. Clinical presentation is usually within 6 months, with a short duration of fever, cough, an d fatigue. Reticular shadowing with ground-glass appearance on CT. Later onset progressive pulmonary \201 brosis can also develop insidi- ously in those on therapy for many months with progressive SOB and dry cough. The histology of the more acute type can be similar to any of the acute interstitial pneumonias (e.g. COP, diffuse alveolar damage), whereas the m ore chronic form is indistinguishable from UIP. Cyclophosphamide is not itself toxic to the lung, but its metabolites are. There appears to be genetic variation to susceptibility, as there is no obvious dose \200\223response relationship. Cessation of drug and steroid ther apy is used successfully in the acute form, but the chronic form seems to progress inexorab ly, in a similar manner to UIP. Lung transplantation is an option. Note increased risk of P CP whilst taking cyclophosphamide. Gold Used in rheumatoid arthritis, >500 mg cumulative dose can produce pneumonitis (possibl y COP, obliterative bronchiolitis) with cough, dysp- noea, and basal crackles. Rare (1%), b ut associated with certain HLA types and distinctive histological feature of alveolar septa l in \202 ammation. Good prognosis following drug cessation; poor evidence for steroids. Methotrexate Folic acid derivative, inhibiting cell division by blocking dihydrofolate redu ctase and nucleic acid production. Mainly used in leukemia and as an immunosuppressive, e.g . rheumatoid arthritis and psoriasis. Commonly (4 \200\22310%) causes a variety of lung pat hologies, not associated with folic acid de \201 ciency. Risk factors \200 \200 \200 \200 \200 \200 \200 Hypoalbuminaemia Diabetes Previous use of drugs that modify disease progress in rheumatoid Rheumatoid or other lung/pleural disease Not particularly dose-related; can occur at doses of <20 mg per week Daily rather than intermittent (weekly) therapy >60 years. Presents both acutely (interstitial pneumonitis, fever, and eosinophilia) and over very lon g time periods; however, the subacute form (within a year, dys- pnoea, fever, cough, hypoxi a, basal crackles, restrictive defect, and reduced kCO) is commoner. Bilateral diffuse pulm onary in \201 ltrates or mixed pattern with alveolar shadowing on CXR, occasional effusion s. DRUG-INDUCED LUNG DISEASE: EXAMPLES 2 599 Histology more useful than in other drug toxicities, shows alveolitis, inter- stitial pneum onitis, epithelial cell hyperplasia, eosinophilic in \201 ltration, and granuloma formatio n in the more acute, hypersensitivity, form, and more UIP-like changes in indolent form. Me chanism of damage unknown but likely to be multifactorial. Treatment consists of drug withdrawal and unproven use of steroids. Anecdotal reports suppo rt use of steroids in the more acute, hypersensi- tivity form. Other methotrexate-related l ung diseases include opportun- istic lung infection (including PCP) and non-Hodgkin \200 \231s B-cell lymphoma, which may regress with drug withdrawal, and may be associated with E pstein \200\223Barr virus. Nitrofurantoin is used commonly for long-term prophylaxis agains t urinary tract infections (UTIs). Acutely nitrofurantoin causes a hypersen- sitivity vascu litis, and, much less frequently, a chronic interstitial \201 brosis. Most patients are w omen due to their much higher prevalence of chronic UTIs. The acute form presents abruptly with fever, dyspnoea, dry cough, rash, chest pain, hypoxia, crackles, and eosinophilia with in a week or two of starting, and is dose-independent. Lower zone diffuse patchy in \201 l trates and sometimes unilateral effusions on CXR. Lung biopsy reveals vascu- litis, eosinop hilia, reactive type II pneumocytes, focal hemorrhage, and some interstitial in \202 ammat ion. Treatment consists of discontinuation and improvement begins rapidly. Prognosis is goo d with or without steroids. Oxygen Prolonged 80 \200\223100% oxygen therapy can provoke lun g damage. Penicillamine Used in the treatment of rheumatoid arthritis, peni- cillamine may increase the prevalence of obliterative bronchiolitis. This is dose-related but rare, with a subacute onset (after several months) of dyspnoea and cough. There is a progressive obstr uctive pattern without bronchodilator response. 50% mortality. Sulphasalazine Used extensiv ely in treatment of in \202 ammatory bowel disease (mainly ulcerative colitis). Rarely cau ses side effects but can cause new onset dyspnoea and pulmonary in \201 ltrates after any period of use. Cough, fever, lung crackles and blood eosinophilia is the usual presenta- ti on. Prior allergy history, rash and weight loss also seen with eosinophilic pneumonia the u sual pathology. Withdrawal of drugs is usually successful within weeks, and recovery can be hastened by steroids. Rare deaths when the histology is more like usual interstitial pneum onitis and may be more related to the condition requiring sulphasalazine. Talc is commonly used for pleurodesis (p 776). Talc particles may be small enough to enter the circulation a fter intrapleural instillation, being found throughout the body at post mortem. They appear to provoke a systemic reaction with fever, raised in \202 ammatory markers, and hypoxia s uggestive of an ARDS-like pathology. Occasional deaths after talc pleurodesis have been rep orted. Re \201 ned talc with fewer smaller particles seems less toxic. 600 CHAPTER 48 Toxic agents Paraquat poisoning De \201 nitions Paraquat (Weedol , Pathclear , Gramoxone ) and relat ed bipyridyl com- pounds are used as contact herbicides. They kill plants by inhibiting NAD P reduction during photosynthesis, which involves the production of super- oxide radicals. The toxicity of paraquat in animals is also believed to be due to the production of damagin g superoxides. Most cases of poisoning are deliberate, and the treatment should be commence d as soon as possible. Serious poisoning is usually by ingestion (although paraquat is abso rbed through the skin and mucous membranes, including the conjunctiva and bronchial mucosa) . \200 \200 \200 \200 More than 6 g is always fatal Less than 1.5 g is rarely fatal Between 1.5 and 6 g, the mort ality is 60 \200\22370% A mouthful of 20% Gramoxone liquid (10 g/50 mL) is almost certain ly fatal Less than 1 sachet of Weedol granules (1.4 g paraquat/57 g sachet) is unlikely t o cause death Usually fatal if blood level >0.2 mg/mL at 24 h. Clinical features \200 Oral and oesophageal ulceration shortly after contact, with later for- mation of a pseudome mbrane Renal failure (reversible) within a few days, but delayed excretion of paraquat prev ents falls in blood levels Pulmonary oedema early on, evolving into \200\230acute respirat ory distress syndrome \200\231 Death usually occurs within 1 to 2 weeks Pulmonary \201 br osis if the patient survives, with varying degrees of recovery. \200 22 Management \200 Gastric lavage with Fuller \200\231s earth/bentonite/activated charcoal/ sodium resonium to reduce absorption Haemoperfusion (haemodialysis less effective) to reduce blood levels Low est inspired oxygen tension possible (high concentrations prob- ably increase superoxide fo rmation) Supportive measures which may require intubation and ventilation Other treatments (e.g. immunosuppression, NO) are experimental. \200 \200 RADIATION-INDUCED PULMONARY DISEASE 601 Radiation-induced pulmonary disease Manifestations of lung injury following radiotherapy in clude: Radiation pneumonitis \200 Often asymptomatic, although may cause dyspnoea and chronic ventila- tory failure Radiograp hic abnormalities more common than clinical disease. Characteristically straight margins on CT in \201 ltrate Pathological feature is of diffuse alveolar damage, with vascular intim al \201 brosis Typically follows lung radiotherapy Treatment of symptomatic disease is wi th steroids (1mg/kg daily), although minimal evidence to support their use. Amifostine or p ent- oxifylline (used in the treatment of extrapulmonary manifestations of radiation-induce d tissue damage) may be of bene \201 t, although unproven. \200 Radiation-induced organizing pneumonia \200 Often presents with cough (rather than breathlessness, which is more suggestive of radiatio n pneumonitis) Characterized by migratory patchy consolidation which always extends beyond radiation \201 eld on CT Typically follows breast radiotherapy Treatment is with steroids ; often long courses are needed. Macrolides may have a role. \200 Radiation-induced chronic eosinophilic pneumonia \200 Possible association; few cases reported. 602 CHAPTER 48 Toxic agents Inhalational lung injury 1 De \201 nition Agents damaging the lung and airways through dir ect tox- icity. Much of the acute damage is common to many toxic agents including pneumonit is/pulmonary oedema, mucosal damage/sloughing/airway debris. Secondary infection is common due to breached defenses. 22 Management of inhalational lung injury \200 \200 \200 \200 Following acute exposure, supportive therapy is critical Look for respiratory failure, stri dor, or distress; may occur hours later CXR (poor sensitivity until pulmonary oedema develo ps) May need intubating/tracheostomy to bypass oedematous and sloughing upper airway mucosa Humidi \201 ed oxygen: \200 Raise SaO2 into low/mid 90s (higher levels may contribute to oxidative damage) Raise PaO2 a s high as possible if CO poisoning suspected Treat cyanide poisoning if suspected (dicobalt edetate, little evidence) Bronchodilators Ne bulized dilute heparin/acetylcysteine \200\224variable opinions on value Steroids and proph ylactic antibiotics \200\224variable opinions on value Mechanical ventilation (low volume/p ressure, permissive hypercapnia) Fluid replacement, but not excessive as encourages pulmona ry oedema Enteral feeding. \200 \200 \200 \200 \200 Examples of toxic agents, listed alphabetically Aldehydes (acetaldehyde, formaldehyde) \200 \200 \200 Chemical and plastics industry, used for disinfection Highly irritant to mucosal membranes Acute damage \200 Chronic effects \200 Pneumonitis and pulmonary oedema Rhinitis/asthma Ammonia \200 \200 \200 Fertilizer and plastics production, used in many chemical industries Highly irritant to muc osal membranes Acute damage \200 \200 Chronic effects \200 Upper airway obstruction from secretions and mucosal oedema Lung damage and secondary infec tion Airways obstruction and bronchiectasis described Chlorine \200 \200 Extensive use in the chemical industry, bleaching agent Acute damage \200 \200 Chronic effects (e.g. from repeated accidental exposure) \200 Overwhelming toxicity producing rapid hypoxia Pneumonitis and pulmonary oedema Airways obstruction; sometimes reversible INHALATIONAL LUNG INJURY 1 603 Cocaine (when smoked) \200 \200 \200 \200 Pneumothorax/pneumomediastinum Pulmonary hemorrhage Pulmonary oedema Allergic responses (as thma, pulmonary eosinophilia, hypersensitivity pneumonitis) Metals and metal compounds (as fumes or nebulized solutions) \200 \200 Mainly used in the chemical industry Acute damage \200 \200 Chronic effects \200 Some speci \201 c effects such as: \200 \200 \200 Mucosal irritation Pulmonary oedema Pneumoconiosis Sarcoid-like reaction to beryllium Asthma/from cobalt, chromium, nickel, vanadium Fibrosing alveolitis from cobalt and zinc fumes Methyl isocyanate (Bhopal disaster: 3800 dead, 170 000 injured) \200 \200 Chemical industry, carbamate pesticides Acute damage \200 \200 Chronic effects \200 \200 \200 Pneumonitis and pulmonary oedema Secondary infection Airways obstruction Bronchiolitis obliterans Pulmonary \201 brosis Hydrocarbons/mineral oils \200 \200 Used as lubricant and cooling agent Acute damage Pneumonitis \200 Chronic effects Pneumon itis \200 Fibrosis \200 Asthma \200 Nitrogen dioxide \200 \200 \200 \200 Chemical industry (explosives) Agricultural silos Odorless and therefore high doses inhaled without knowing Acute damage (several hours after exposure) \200 Later effects \200 \200 Silo \201 llers lung (pneumonitis/pulmonary oedema) Secondary pulmonary oedema 2 \200\2238 weeks after exposure Steroid responsive, needs 2 mon ths therapy after exposure. 604 CHAPTER 48 Toxic agents Inhalational lung injury 2 More examples of toxic agents Ozone \200 \200 \200 \200 Bleaching agent Product of welding Similar to NO2 Both immediate and late effects of pneumo nitis/pulmonary oedema Phosgene \200 \200 \200 Chemical warfare, chemical industry, chlorination Released from heated methylene chloride ( paint stripper) Acute damage \200 \200 Pneumonitis and pulmonary oedema Produces COHb; breath CO therefore re \202 ects degree of exposure Smoke \200 \200 Most smoke injury is due to heat damage to upper airway Hypoxia, vaporized toxins (e.g. for maldehyde, chlorine), systemic agents (e.g. CO and cyanide) Acute damage \200 Look out fo r: \200 \200 \200 \200 \200 \200 Mucosal oedema and sloughing with airway blockage Peri-oral burns Black sputum Altered voice Respiratory distress Stridor (rapid inspiration to accentuate) Additional CO and/or cyanide poisoning Sulfur dioxide \200 \200 \200 Used as a fumigant, and bleaching agent in the paper industry Very irritant as dissolves to form sulphuric acid Acute damage \200 \200 Chronic effects \200 Sloughing of airway mucosa Pneumonitis and haemorrhagic pulmonary oedema Airways obstruction Welding fumes \200 \200 Many agents released Speci \201 c examples: Cadmium \200\224pneumonitis \200 Zinc \200 \224 \200\230metal fume fever \200\231 \200 Several agents may cause airways obstruction/ COPD \200 Siderosis (welders lung) non- \201 brogenic pneumoconiosis \200 Iron deposits in lung producing small rounded opacities This page intentionally left blank 606 CHAPTER 48 Toxic agents Carbon monoxide poisoning De \201 nition and epidemiology \200 