Fig. 15.5.1 Nocturnal hypoventilation: 3 cycles during REM sleep. Transcutanous CO2 (TcCO2) monitoring has been criti- cised in the past, but a variety of ma chines are now in regu- lar use and proving useful, providing the limitations of endtidal C O2 are borne in mind. Transcutaneous measure- ments will always reveal a trend, not breath by breath results, and values are approx 0.5kPa above arterial values. Careful attentions s hould however be paid to calibrating the device with test gas mixtures, skin preparation an d application of the CO2 electrode. A printout of actual data (Fig. 15.5.1) should always b e available rather than sum- mary statistics so that artifacts can be detected and dis- car ded from \201 nal analysis. In Europe polysomnography is rarely used to diagnose nocturna l hypoventilation or other respiratory sleep disorders or to titrate therapy, e.g. deter- m ine NIV settings. Occasionally it may be helpful when problem solving in dif \201 cult cas es, or when treatment is not working optimally. Treatment Asymptomatic mild hypoventilation in a chest wall or neu- romuscular patient does not require treatment, in a chest wall patient, yearly repeat sleep study would be reasona ble although 6-monthly studies preferable in DMD. In Duchenne muscular dystrophy a randomiz ed controlled trial showed no evidence that prophylactic non-invasive ventilation is indica ted. Around a decade ago, consensus conference recommen- dations were that NIV should be us ed once daytime PCO2 exceeds 6kPa. However, the rate of progression of noctur- nal hypovent ilation may be dif \201 cult to predict and as a result many individuals may develop preci pitous daytime ventila- tory failure usually due to a chest infection. In one trial in whic h patients with neuromuscular and chest wall disease were randomized to NIV or control grou p at the onset of Fig. 15.5.2 Cheyne \200\223Stokes ventilation. The two types of central apnoea can easily be differenti- ated by measuring PCO2 level. A f urther learning point is that in some patients with marked respiratory muscle dys- function and obstructive apnoeas, inspiratory muscle A SIMMONDS 376 weakness is insufficient to generate detectable effort (pseudocentral apnoea). Symptomatic nocturnal hypoventilation can be effectively treated with nocturnal NIV which i mproves survival and outcome in chest wall and neuromuscular disease and may help selected COPD patients with marked hyper- capnia or recurrent hypercapnic exacerbations. Sleep disordered breathing in chronic heart failure (CHF) In severe CHF the prevalence of sleep disordered breath- ing (SDB) is at least 10 times gre ater than in the general population, and is associated with an increased risk of mor- talit y. In mild to moderate CHF, it has recently been shown that the prevalence of SDB remains h igh at approximately 50% and about half of these patients have predominantly central sleep apnoea. While treatment of obstructive sleep apnoea in CHF with CPAP is clearly evidence-ba sed, CPAP had not been shown to be beneficial in heart failure patients with central sleep apnoea. In these patients, pre- senting symptoms differ from OSA patients \200\223 sleepin ess is not a major feature, and treatment remains controversial. Oxygen therapy may be help ful but recent work suggests that stabilizing the respiratory pattern by a device that cap- tures ventilation and smoothes the respiratory disturbance may be effective (Autoset CS, R esMed Inc.). This is being tested in a current European randomized controlled trial. Further reading American Thoracic Society Consensus Statement. Respiratory care of the pati ent with Duchenne muscular dystrophy. American Journal of Respir Crit Care Med 2004; 170: 4 56 \200\223465. Consensus Conference. Clinical Indications for Noninvasive Positive Pressure Ventilation in Chronic Respiratory Failure due to Restrictive Lung Disease, COPD, and nocturnal hypoventi lation \200\223 a Consensus conference report. Chest 1999; 116: 521 \200\223534. Mellies U, Ragette R, Schwake C, et al. Long-term noninvasive ventilation in children and a dolescents with neuromuscular disorders. Eur Respir J 2003; 22: 631 \200\223636. Ragette R, Mellies U, Schwake C, et al. Patterns and predictors of sleep disordered breathi ng in primary myopathies. Thorax 2002; 57: 724 \200\223728. Raphael J-C, Chevret S, Chastang C, et al. Randomized trial of preventive nasal ventilation in Duchenne muscular dystrophy. Lancet 1994; 343: 1600 \200\2231604. Takasaki Y, Orr D, Popkin J, et al. Effect of nasal continuous positive airway pressure on sleep apnea in congestive heart failure. Am Rev Respir Dis 1989; 140: 1578 \200\2231584. Key recommendations \200 There should be a high suspicion of nocturnal hypoven- tilation in patients with conditions reducing ventilatory capacity and drive and disorders increasing ventilatory load \200 \223 ask about symptoms of nocturnal hypoventilation, e.g. morning headaches, poor sleep qu ality, waking breathless, vivid dreams. Nocturnal hypoventilation can be diagnosed by over- night oximtry and PCO2 measured continuously with transcutaneous or endtidal CO2 probes. C entral sleep apnoea is caused by either severely reduced ventilatory drive or in conditions that destabi- lise respiratory pattern as a result of enhanced ventila- tory drive, e.g. h eart failure, breathing at high altitude. Teschler H, Dohring J, Wang YM, et al. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respira- tion in heart failure and central sleep apnea. Am J R esp Crit Care Med 2001; 164: 614 \200\223619. Tuggey JM, Plant PK, Elliott MW. Domiciliary non-invasive ventila- tion for recurrent acido tic exacerbations of COPD: an economic analysis. Thorax 2003; 58: 867 \200\223871. Ward SA, Chatwin M, Heather S, et al. Randomized controlled trial of non-invasive ventilati on (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients wit h daytime normocapnia. Thorax 2005; 60: 1019 \200\2231024. This page intentionally left blank J PEPPERELL 378 15.6 Cheyne \200\223Stokes respiration associated with left ventricular failure Investigations Con \201 rm LVF with Echo and brain natriuretic peptide. Exclude type II re spiratory failure with ABG sampling. Cheyne \200\223Stokes respiration (CSR) is characterized by the cyclical pattern of smooth crescendo decrescendo periods of hyperventilation with accompanying periods of central apno ea. It is variably called central sleep apnoea and peri- odic breathing. CSR is a respirato ry complication of chronic left ventricular failure (LVF). CSR is important clinically beca use it can cause symptoms, worsens heart failure and is amenable to treatment. Overnight pulse oximetry Approximately half of patients with NYHA class III and IV will hav e an apnoea hypoxia index (AHI) of between 0 \200\22310 per hour on multi channel sleep stu dy. Oximetry is a simple screening tool looking for repetitive desaturations. Compared to O SA, CSR tends to have a longer time period, lower amplitude desaturations through the apnoe a and a slower rise in saturation at end apnoea (Fig. 15.6.1). Pathophysiology CSR results from the following in heart failure: \200 Increased ventilato ry drive/hyperventilation. \200 Low lung volumes and stores of oxygen. \200 Reduced car diac output. \200 Haemodynamic alterations. Hyperventilation is caused by a combination of stimulation of J receptors through increased left atrial pressure and pulmonary oedema, alongside changes in both central and periphera l chemosensitivity. Hyperventilation lowers PaCO2 levels and causes mild res- piratory alka losis (both common in patients with CSR). At sleep onset, cortical input and respiratory dr ive reduce with an increase in apnoea threshold. The PaCO2 from awake hyperventilation fall s below the apnoeic threshold (approx 35mmHg) initiating apnoea. Low cardiac output prolong s circulation time and delays cen- tral perception of the apnoea induced blood gas changes. The long apnoea duration, low lung volumes and oxygen stores contribute to hypoxaemia and hypercapnia. Blood gas derangement may lead to cortical arousal and return of awake ventila tory drive. A period of hyperventilation ensues to restore normal PaO2 and PaCO2 before sle ep resumes and the cycle is repeated. LVF-induced CSR also leads to stimulation of sympathe tic activity, reduced renal blood \202 ow, and sodium and water retention. Vasoconstricti on, increased blood pressure and increased heart rate cause increased myocardial workload w hich further worsens LVF contributing to the poor prog- nosis seen in patients with CSR. De pending on the different respiratory and cardiac compo- nents leading to CSR, it may settle with different sleep stages or spontaneously through the night. Any external arousals, obs tructive events or deep sighs may trigger further episodes. Fig. 15.6.1 Oximetry saturation and pulse rate for CSR, upper panel with reduced amplitude longer cycle length and slower end apnoea saturation rise versus OSA, lower panel. Multichannel sleep studies On full sleep study CSR is distinguished from OSA by the absence of respiratory effort. The gold standard to con \201 rm this, invasive oesophageal pressu re monitoring, is impractical for routine use. Several non-invasive surrogates for respirat ory effort can be used combining abdominal and thoracic inductance bands, the nasal pressur e trace, variations in pulse transit time (PTT, a marker of intrapleural pressure change) o r dyssynchrony between abdominal and thoracic movements. In the examples in Fig. 15.6.2, CS R shows reduced nasal pressure accompanying reduced thoracic and abdominal effort and no sw ing in PTT. Symptoms and signs \200 Poor quality of sleep. \200 Frequent arousals. \200 Choking e pisodes. \200 Nocturnal dyspnoea, arrhythmias or angina. \200 Daytime fatigue or sleepi ness. CSR and OSA have been correlated with more severe LV impairment, atrial \201 brillation, ventricular dysrhythmias and earlier mortality in patients with cardiac disease. Fig. 15.6.2 Sleep study of CSR with desaturations (SpO2), following decreased nasal air \202 ow from reduced thoracic and abdominal effort. The PTT channel con \201 rms no intrat horacic pressure swings of respiratory effort. AUTHOR \200\231S TIPS \200 CSR occurs in 50% of NYHA class III or IV heart fail- ure or ejection fraction <45%. CSR is more common in males, the elderly and patients with atrial \201 brillation. CHAPTER 15.6 Cheyne \200\223Stokes respiration associated with left ventricular failure 379 Treatment of heart failure Medical management CSR is related to heart failure severity and pulmonary capillary wedge pressure. Control of heart failure can reduce CSR and all patient s should have their medical treatment optimized. Improve LV function and reduce cir- culato ry time using diuretics, ACE inhibitors, B-blockers and digoxin. Shown to reduce CSR as wel l as mortality. CPAP Nocturnal CPAP can reduce CSR in several ways. By increasing lung volumes and oxygen s tores, decreasing lung water, reducing left ventricular transmural pressure and afterload t o increase cardiac output, or by increasing dead space and CO2 rebreathing. It was hoped th at CPAP would reduce mortality above it improvements in cardiac output and exercise capacit y but this has not been con \201 rmed by a recent large trial. Those patients with cardiac failure with coexisting pre- dominantly obstructive sleep apnoea do benefit from CPAP. Cardiac re-synchronization therapy (CRT) Biventricular pacing can resynchronise myocardial contrac- tion to increase left ventricular ejection fraction, cardiac output and exercise c apacity. Increased cardiac output, reduced circulation time and uncoupling the cardiac and respiratory drive centers may all help stabilize CSR. CRT can be considered in patients wit h the following: \200 \200 \200 Bilevel positive airway pressure There is no evidence that BiPAP is superior to CPAP in CSR . It may indeed lower pCO2 levels leading to vocal cord opposition and arousal at night. Bi PAP is reserved for those who do not tolerate CPAP. NYHA class III or IV. A prolonged QRS of greater than 150ms. Echo evidence of desynchronisa tion. Adaptive servo-ventilation (ASV) ASV ventilators measure breathing frequency and tidal volu me to calculate a minute volume averaged over the preceding 3 minutes. ASV aims to deliver only 90% of this recent minute volume to mimic the usual reduction in ven- tilation during sleep onset allowing pCO2 levels to rise. ASV delivers a stable end expiratory pressure (5 cmH2O) but inspiratory pressure can vary between prede \201 ned lev- els (default 3 \200 \22310 cmH20). ASV predicts breath by breath variations in tidal volume from initial inspir atory effort and provides variable inspira- tory pressure support to maintain target minute ventila- tion. During periods of apnoea ASV provides maximum pressure support at the prece ding spontaneous respira- tory rate. ASV has a number of theoretical advantages to improve cardiac function. In practice it stabilizes CSR over about 10 \200\22320 minutes, reducing AHI and arousals more than oxygen CPAP or BIPAP to improve sleep quality. Small studies hav e shown improvement in daytime somno- lence, quality of life, walking times and ejection fr action, with accompanying reduction in hospital admissions and improvement in survival time . This has not yet been proven in large trials and so although preliminary evidence sug- ge sts that ASV is superior to oxygen or CPAP, it is not yet recommended as \201 rst-line tr eatment. Treatment of CSR The principles of treating CSR which remains after optimis- ing LVF treatm ent are through pharmacological agents, oxygen or ventilation methods aiming to. \200 \200 \200 \200 Alter ventilatory drive. Prevent hypoxaemia. Reduce arousals. Control ventilation. Opiates Opiates decrease the sensitivity of peripheral chemore- ceptors therefore lowering hypoxic ventilatory responses and may reduce arousal and afterload. Theophylline Use of short-term theophylline is associated with signi \201 - cant reduction in the AHI, but no reduction in the fre- quency of arousals or improvement in sleep struct ure or cardiac function. Detrimental effects however, include car- diac dysrhythmias as wel l as increased minute ventilation. Acetazolamide Acetazolamide causes a metabolic acidosis which leads to stimulation of centr al respiratory drive. It also increases the apnoeic threshold for pCO2 thus reducing CSR. E ffects seem to be long-lasting; however it is unlicensed. Metabolic acidosis and hyperventi lation may be detrimental in LVF. Oxygen Low \202 ow nasal oxygen (2 \200\2233L/min) administered at night has been shown i n randomized control trials to reduce CSR, correct hypoxia, improve sleep quality and impro ve daytime cognitive function. CSR is probably reduced by increasing PaO2 and lung oxygen s tores and by suppressing peripheral chemoreceptor drive. Nocturnal oxygen has not yet been shown to improve left ventricular ejection fraction or exercise capacity. AUTHOR \200\231S TIP For CSR causing sleep fragmentation despite optimizing cardiac medicat ions, nocturnal oxygen treatment may stabilize CSR simply prior to trials of CPAP, BiPAP or ASV. Further reading Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pres-sur e for central sleep apnoea and heart failure. N Eng J Med 2005; 353(19): 2025 \200\2232033. Cazeau S, Alonzo C, Jauvert G, et al. Cardiac resynchronization Carbon dioxide Inhaled carbon dioxide can eliminate CSR. By increasing the partial pressure s of carbon dioxide ventilatory drive is maintained during sleep. Similar effects can be se en by increasing dead space ventilation via a facemask. Unfortunately CO2 markedly increase s sympathetic activa- tion, may cause sleep fragmentation and is not recom- mended in the t reatment of CSR. therapy. Europe 2004; 5: S42-S48. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respira- tion in patients with con gestive heart failure. Sleep 1994; 17: 61. Pevernagie D, Janssens JP, DeBacker W, et al. Ve ntilatory support and pharmacological treatment of patients with central apnoea or hypovent ilation during sleep. European Respiratory Review, in press. G ROBINSON 380 15.7 Other causes of sleepiness Overview There are a large number of other causes of sleepiness, the majority of which may be diagnosed with a careful history. True hypersomnolence must be differentiated from fatig ue and tiredness, which are extremely common. The less common pathological causes of sleepi ness will be rarely encountered by the respiratory physician; the parasomnias may be referr ed to a respiratory sleep clinic in the \201 rst instance, and a directed history will en able the appropriate investigation of the majority of disorders. Insomnia is not covered he re. Periodic leg movements in sleep (PLMS) \200 This is the association between stereotyped, repetitive limb movements during REM sleep and daytime hyper- somnolence or frequent nocturnal awakenings. Most commonly patients repeate dly \202 ex and dorsi \202 ex the ankle or great toe, every 20 to 40 seconds. Leg move- ments cause partial brain arousal, sleep fragmentation and thus daytime symptoms. There may be an associa- tion with Parkinson \200\231s disease. The night time syndrome can be assoc iated with daytime restless legs syndrome (RLS), which is the sensation of continually need ing to move the legs, in association with unpleasant parasthesia. The symptoms are relieved by movement. PLMS affects about 50% of individuals aged >65. Mild symptoms of PLMS may be present in up to 15%, but most will be asymptomatic. There may be a genetic basis for the d isorder. RLS can be a feature of diabetic peripheral neuropathy, and is associated with low er leg venous insuf \201 ciency, hypothyroidism, spinal stenosis and excess caffeine intak e. Dopaminergic lower spinal nerve dysfunction is postu- lated as a cause. Most commonly th e disorder is idio- pathic, but there is an association with iron de \201 ciency anemia, e nd stage renal disease (in up to 60%) and the use of tricyclic antidepressants and monoamin e oxide inhibitors. All patients presenting with PLMS should have an FBC 9 iron studies. Tr eatment \200\223 dopamine agonists tend to be more effec- tive than benzodiazepines. Co-be neldopa has been shown to be effective (e.g. as Sinemet CR 1 or 2 tablet nocte). Tachyphy laxis to L-dopa and an earlier onset of symptoms, or increased intensity of symptoms is rec og- nised on L-dopa. Some recommend only intermittent L-dopa for these reasons. Clonazepam 0.5 \200\2232mg nocte may be better tolerated. Dopamine agonists, e.g. prami- pexole 0.125 \200\2230.5mg nocte or pergolide 0.05 \200\2231mg nocte taken about 2 hours before the usua l onset of symptoms may also help. Low potency opioids, e.g. tramadol and codeine, may be u seful. History: key points \200 Sleep hygiene/quality and duration of sleep \200\223 are enough hours being spent in bed, in an environment appropriate for sleep? Insuf \201 cient sleep is a very common cause of hypersomnolence. Associated sleep symptoms \200\223 including dreams and nightmares, and t heir timing (e.g. at sleep onset), sleep paralysis, cataplexy, hypnagogic hallucinations, l eg move- ments or noises during sleep. A collateral history from the bed partner is paramou nt. Past medical history \200\223 including of neurological disease, anxiety/depression, p revious neuro-surgery (especially pituitary surgery), cranial radiotherapy, and visual loss . Drug history \200\223 including prescribed drugs e.g. B-blockers, alcohol, caffeine and illicit drugs. Social history \200\223 current job and pattern of any shift work. Frequent long distance travel. Anything to suggest a neurological disease, e.g. Parkinson \200\231s disease, other movement disorder or muscle weakness. Investigations: key points \200 No further investigations may be needed in patients in whom there is a clear history of sle ep disruption or inadequate sleep duration. Multiple sleep latency testing (MSLT) \200\223 this uses EEG to document the time to fall asleep in a dark and sound- isolated room, on \201 ve naps spaced throughout the day, and can be used to document objective sleepiness. The presence of sleep onset REM (SO-REM), may aid diagno- sis of some parasomnias. An MSLT of <8 minutes is con- sidered abnormal (normal is 10 \200\22315 minutes), though is not ver y speci \201 c. An abnormal MSLT alone is probably enough to diagnose narcolepsy con \201 dently in those with a history of cataplexy and sleepiness. Patients with pathological hyp ersomnolence, in whom no cause is determined from the history, and without snor- ing or cat aplexy, should have an MSLT. If the sleep latency is <10 minutes, further investigation may be warranted. Full polysomnography (including EEG, EOG and EMG, and measurement of respira tory signals and leg move- ments, usually via EMG) may be needed for con \201 dent diagnos is of less common disorders. Parasomnias These are disruptive sleep related disorders, which occur during arousal from R EM sleep, or during partial arousal from non-REM sleep. They are characterized by physical phenomena which include autonomic involvement and/or skeletal muscle involvement. They can occur during speci \201 c sleep stages, or during the sleep-wake transition. The disor- de rs are frequently bizarre, and patients are often labeled as having psychiatric disease. Pa rasomnias are more com- mon in children than adults, and there may be a familial susceptibi lity. There are a number of related conditions; those most likely to be encountered are lis ted. \200 \200 \200 \200 \200 \200 \200 \200 \200 REM behavior disorder. Narcoplepsy. Cataplexy. Sleep walking and sleep terrors. Sleep talki ng. Parasomnia overlap disorder. Nocturnal sleep-related eating disorder. Sleep paralysis. Sleep bruxism. Causes of hypersomnolence Shift work sleep disorder Insufficient or disrupted sleep due to shift work is common, with variable shift patterns causing the most sleep disturbance. Indi viduals tend to become more intolerant of shift work (particularly night shifts) with incre asing age. CHAPTER 15.7 Other causes of sleepiness 381 Moda \201 nil is a non-amphetamine based wakefulness pro- moting agent that probably incre ases dopaminergic signal- ling. 200 \200\223800mg OD, sometimes as a divided dose is effect ive. Moda \201 nil is an enzyme inducer; side effects are uncommon, but include hypertensi on, dry mouth, nausea and diarrhea. Mazidol, methyl-phenidate and selegiline are also used. Drugs increasing noradrenergic and serotinergic signaling suppress REM sleep and therefore reduce REM phenomena such as cataplexy: SSRIs, e.g. venlafaxine and \202 uoxetine, and t ricyclic antidepressants may also be of use. REM behavior disorder This typically occurs in men of late middle age, and involves the act ing out of dreams which are often violent and action-packed. The nocturnal violent behavior is usually out of keeping with the patient \200\231s awake personality. There may be a hig her frequency in individuals who have seen active combat, and an association with the devel opment of Parkinson \200\231s disease in later life. Clonazepam 0.5 \200\2231mg at night, a long with maximizing the safety of the sleep envi- ronment are the usual treatments. Neurological disease associated with hypersomnolence Tumors and infarcts, particularly of t he hypothalamus and upper brain stem, head injury and encephalitis may lead to hypersomnole nce. Parkinson \200\231s disease is associated with hypersomnolence due to sleep disturbanc e, often as a result of dopamine agonists. PMLS is common in Parkinson \200\231s disease, a s are vivid dreams, nightmares and nocturnal tremor, all of which can cause sleep fragmenta tion. Other neurological diseases frequently associated with daytime hypersomnolence are li sted: \200 \200 \200 Narcolepsy This is a disorder of sleep \200\223wake control, characterized by hypersomnolen ce, cataplexy, hypnagogic hallucinations and sleep paralysis. Hypnagogic hallucinations are vivid halluci- nations occurring just before sleep onset, probably due to a mixture of REM sleep and wakefulness. Sleep paralysis is the complete inability to move for up to about 2 minutes after waking. Cataplexy is the sudden onset of loss of vol- untary muscle tone, le ading to partial or complete col- lapse, and may be triggered by emotion, such as laughter, joking or anger. Partial attacks are common, with, for exam- ple, just the head nodding, o ften with associated facial twitching. Paralysis typically lasts up to 2 minutes, with main - tenance of consciousness. Cataplexy and sleep paralysis are probably due to inappropriate activation of the pathways usually causing muscle paralysis during REM sleep. Narcolepsy h as a prevalence of 25 to 50 per 100,000 (about 1/100th the prevalence of OSA), typically st arting in the teens and early twenties. Only about one-third of patients will have all four classical symptoms. All affected individuals will have daytime hypersomnolence, often fall ing asleep with little warning, so called \200\230sleep-attacks \200\231, and in bizarre s itua- tions, such as eating. The sleepiness of narcoplepsy often resolves after a brief nap , and individuals often feel refreshed in the morning, in comparison to other more common c ause of hypersomnolence. Myotonic dystrophy. Pituitary surgery. Cranial irradiation. Multiple sclerosis \200\223 up to 80% suffer from severe fatigue, and sleep disruption is common, often due to pain or blad- der spasms. There may be associated OSA. Sleep disturban ce related to blindness is due to disruption of the retino-hypothalamic pathways which cue circadian rhythm. Melatonin may be of use. Rare causes of hypersomnolence Delayed sleep phase syndrome This most common in young adult s and is characterized by late sleep onset with late awakening. Treatment is gradual phase advance (by 15 \200\22330 minutes each night), with bright light exposure on wakening. Pathophysiology The disease is thought to be due to loss of neuropeptides orexin (hypocreti n) A and B in the lateral hypothalamus. 90% of patients with narcolepsy have no detectable CSF orexin, due to reduced numbers of hypothalamic orexin- producing neurons. The orexins h ave excitatory post-synaptic effects and are released during wakefulness, increasing the ac tivity of many brain areas involved in the maintenance of wakefulness. Orexins inhibit REM sleep; it is the loss of orexin which promotes the disease speci \201 c REM sleep-related phenom- ena. Narcolepsy is usually sporadic; up to 90% have human leucocyte antigens HLA DR 2 and DQ1. There is a strong association with the DQB1*0602 haplotype. Familial cata- plexy is rare, thus environmental factors must also be important. Kleine Levine Syndrome This rare syndrome is characterized by recurrent episodes of daytime sleepiness in association with bizarre eating pat- terns and hyper-sexuality. \200 Magne sium toxicity. \200 Idiopathic hypersomnolence. \200 Idiopathic stupor. \200 Post-inf ectious hypersomnolence. \200 Post-traumatic hypersmonolence. \200 Limbic encephalitis. Idiopathic insomnia This is a dif \201 culty in maintaining normal sleep which stems from childhood. The etiology is uncertain. Diagnosis This is usually made from the history, with a sleep study off stimulants and anti depressants, to avoid REM rebound. Polysomnography will show REM onset within 15 \200\22320 min- utes of sleep onset (after 80 to 100 minutes is normal), with spontaneous awakenings and reduced sleep ef \201 ciency. MSLT may be useful. Further reading Aldrich MS. Sleep Medicine. Oxford: Oxford University Press, 1999. British Sleep Society http://www.sleeping.org.uk/ contents/homefrm.htm Douglas NJ. Clinician \200\231s Guide to Sleep Medicine, Arnold 2002. Treatment This includes pharmacological therapy for the daytime sleepiness and REM sleep in trusion phenomena, and fre- quent daytime naps. Psychosocial support is important. This page intentionally left blank 383 Chapter 16 Occupation and environment Chapter contents 16.1 Drugs and toxins 384 16.2 Pneumoconiosis 390 16.3 Disability assessme nt 394 16.4 Occupational asthma 398 16.5 The effects of high altitude on the lung 404 16.6 Diving 408 16.7 Occupational chronic obstructive pulmonary disease 412 16.8 Asbestos-relate d diseases (excluding mesothelioma) 414 A MEDFORD 384 16.1 Drugs and toxins Introduction Respiratory disease may be caused by a wide range of drugs and toxins leading to diverse syndromes. Since 1950, knowledge has expanded in this area. It is important for all clinicians to consider, as it is potentially reversible and often forgotten. A few are quite common, most are not but reports are on the increase. Patients may present with prote an symptoms, signs and radiological features to pri- mary care and a variety of specialties including cardiology, oncology and rheumatology. This chapter will outline the commonest p resentation modes and some of the most commonly encountered drugs but is not exclusive: see the online databases. Interstitial disease The pathology can be variable but typically occurs after weeks or mont hs, presenting commonly with dyspnoea, cough and fever. Common agents are shown in Table 16 .1.3 below. Abnormal liver function tests or eosinophilia may be noted. Common causes of eo sinophilia are also shown in Table 16.1.3. Risk factors include multiple drugs at the same time. Bronchoscopy and BAL may reveal lymphocytosis but is helpful to exclude infection or cancer. Lung function is restrictive with impaired gas transfer as expected. High- resoluti on computed tomography (HRCT) is not speci \201 c, and increased uptake may be noted on Ga llium scanning. Transbronchial biopsy (TBB) is not speci \201 c and a surgical lung biopsy may sometimes be needed. The drug must be stopped but steroids may be needed if there is e xtensive radiological change and impaired lung function. Diagnosis Diagnosis of drug-induced lung disease requires a number of criteria to be satis \201 ed as shown in Table 16.1.1. Table 16.1.3 Common drugs causing interstitial lung disease and pulmonary eosinophilia Table 16.1.1 Diagnostic criteria Correct identi \201 cation Harder if occurs after drug stopped or multiple exposures Interstitial lung disease Eosinophilia Bleomycin Busulphan Chlorambucil Cyclophosphamide Methotrexate* Amiodarone* Nitrofurantoin* Sulphasalazine* Aspirin Isoniazid Penicillin Sulphonamides Timing consistent Improvement on stopping Recurrence with re-challenge Characteristic features Clinical Imaging Broncho-alveolar lavage (BAL) Histology Exclusion of common causes Infection Oedema Underlying lung condition Denotes also causes eosinophilia. Drug-induced lupus pleuritis Lung involvement may occur in 50% of cases of drug- induced lu pus, manifesting as pleuritis. Features discrimi- nating it from spontaneous lupus are show n in Table 16.1.4. Delayed metabolism (slow acetylation) is important in the pathogenesis o f two of the commonest drugs. Treatment may include nonsteroidal anti-inflammatory drugs (N SAIDs) and anti-malarials for musculoskeletal symp- toms. Corticosteroids have been used fo r serositis. The three commonest drugs are discussed here: Presentation modes The commonest modes of presentation are shown in Table 16.1.2 Table 16.1.2 Modes of presentation Interstitial lung disease Pneumonitis Fibrosis Eosinophilia Organizing pneumonia Acute respiratory distress syndrome (ARDS) Procainamide Drug-induced lupus often occurs in almost all after 2 years treatment but can occur in up to 33% after 1 year, especially in slow acetylators. Genetic factors have been implicated. Pleural disease Thickening Pleuritis Effusion Pneumothorax Pneumomediastinum Hydralazine Drug-induced lupus occurs in 5 \200\22310%, especially in those >200mg/day, cum ulative dose >100g, female, slow acetyla- tors and having a low C4 complement. Genetic fact ors have also been implicated. Airway disease Direct injury Obliterative bronchiolitis Bronchospasm Bronchial hyper-reactivity (BHR) Pulmonary vascular disease Hemorrhage Infarction Thrombo-embolism Pulmonary hypertension Minocycline Drug-induced lupus often occurs in young women on minocycline for acne. Fever a nd rashes are more common than with other drug-induced cases. Anti-histone Abs are often ab sent (<13%), although p-ANCA (anti-neutrophil cytoplasmic antibodies) may be positive in up to 85%. Infection Pneumonia Aspiration Tuberculosis (TB) CHAPTER 16.1 Drugs and toxins 385 symptoms were not increased lung term or quantities of inhaled B-agonists. Carvedilol has a lso shown to be well tolerated (in terms of FEV1, FEF25-75 and VO2 max) despite being a non -selective B-blocker, possibly because of mild broncho-dilation from its alpha (A)-blocking activity. B-blockers have other (less well known) lung toxicities other than broncho-const riction including pulmonary in \201 l- trates with eosinophilia, hypersensitivity pneumoni tis, organizing pneumonia, \201 brosis, pleural thickening/effusion and drug-induced lupu s. NSAIDs cause bronchoconstriction in 5% of asthmatics by driving cysteinyl leukotriene pr oduction and inhibiting cyclo-oxygenase-1 (COX-1). Key points \200 If both anti-histone Abs and p-ANCA are absent, this makes drug-induced lupus very unlikely . This diagnosis is often forgotten in patients investigated several times for pulmonary em bolism (with negative \201 ndings) and ongoing unexplained pleuritis. If considering hydr alazine-induced lupus, check ANCA as atypical p-ANCA (anti-elastase, not anti-MPO (mye- lop eroxidase)) is speci \201 c for hydralazine-induced vascu- litis and may require immunosup pressant treatment. Table 16.1.4 Discriminating features for drug-induced lupus Drug-induced lupus ACE inhibitors Angiotensin converting enzyme (ACE) inhibitors (ACEI) cause dry nocturnal co ugh in 20% via bradykinin release, normally metabolized by ACE in the lungs. There is a poo r dose response relationship and it usually occurs within 1 month but may take at least 3 m onths to subside after cessation of the drug. The main differentials are usually asthma and heart failure. Gender No female predominance Onset Abrupt Organs involved Less for skin, renal and central nervous system Auto-antibodies 95% anti-histone antibody (Ab) positive Double-stranded deoxyribonucleic acid (dsDNA) Ab ra rely positive AUTHOR \200\231S TIPS \200 Complement Normal B-blockers can be cautiously trialed in mild \200\223moderate reversible obstructive lung d isease. Cardio-selective B-blockers are preferable (atenolol, metoprolol) or combined A- an d B-blockers (carvedilol). Remember other lung toxicities of B-blockers, if bron- cho-const riction does account for the symptoms. Give it 3 months since stopping the ACEI, before ref er- ring or investigating for other causes of chronic cough. Pleural eosinophilia Pleural eosinophilia (>10%) can be due to air or blood in the pleural space, asbestos-related effusion, parasitic infec- tions, but also drugs as listed in Table 16.1.5 below. Table 16.1.5 Common drugs causing pleural eosinophilia. Pleural eosinophilia Nitrofurantoin* Isotretinoin Non-cardiogenic pulmonary oedema ARDS has been associated with a variety of drugs. In over- dose, it has been described with aspirin, cocaine (see later), opioids, phenothiazines and tricyclic antidepressants. At normal doses, nitrofurantoin (see later), protamine and cert ain radiographic contrast media have been implicated. Dantrolene Valproate Propylthiouracil Bromocriptine* Denotes discussed later. AUTHOR \200\231S TIP In ARDS of uncertain etiology, consider drug-related causes especially if psychiatric issues are a possibility AUTHOR \200\231S TIPS \200 The presence of co-existing parenchymal in \201 ltrates would support nitrofurantoin- or b romocriptine-induced lung toxicity amongst this select group of drugs. Concurrent periphera l blood eosinophilia would sup- port nitrofurantoin, dantrolene or valproate-induced lung d isease among this group. Pulmonary arterial hypertension (PAH) PAH has been described in relation to use of anorecti c agents (fex \202 enuramine, dex \202 en \202 uramine) and stimulants including ampheta mines and cocaine. In case control stud- ies, odds ratios of 3 \200\2236 are reported with these agents. The mechanism is uncertain. The anorectics may block potas- sium channels lea ding to calcium in \202 ux increasing pulmo- nary vascular tone. Other studies have report ed a higher prevalence of bone morphogenic protein receptor 2 (BMPR2) mutations in PAH due to anorectic agents. Airway disease b-blockers B-blockers (including eye drops) and cholinergic drugs (e.g. pyri dostigmine) cause bronchoconstriction via bronchial M2-receptor blockade and muscarinic M1 and M3 receptor activation. However, a meta-analysis in reversible obstructive lung dis- ea se has con \201 rmed no evidence of long-term decline in lung function with cardio-selecti ve B-blockers (atenolol, metoprolol). A short-term decline of 8% in FEV1 was seen, but this was not sustained and reversibility of bronchodila- tor increased to about 7%. In addition , respiratory AUTHOR \200\231S TIP In unexplained PAH, drugs must be considered Individual drugs and toxins Amiodarone Amiodarone is one of the commonest drugs implicated ( 5% of patients). Pneumotoxicity is more likely in males, with pre-existing lung disease, at daily doses \211 200mg A MEDFORD 386 (5 \200\22315% chance at \211 400mg), > 2 months treatment, or cumulative doses >150g. The drug is directly cytotoxic but an immunological hypersensitivity also occurs. It has a lon g half-life ( 45 days) and a high af \201 nity for lung tissue. It presents insidiously mo st often as non-speci \201 c interstitial pneumonitis but can present as an organizing pne umonia (25% of cases) or less often (but life threatening) ARDS and rarely as a solitary pu lmonary mass. Foamy lipid macro- phages are present in the airspaces and may be evident on BAL or biopsy but indicate exposure not injury. Lung func- tion is as expected for intersti tial lung disease. There are no predictors for who will develop lung toxicity. Clinical fea tures include dyspnoea, fever, malaise, weight loss with crackles and a high erythrocyte se dimentation rate (ESR), lactate dehydrogenase (LDH) and leucocytosis. Wheeze, pleuritic che st pain and a friction rub may occur. The CXR may show interstitial or alveolar shadowing b ut not pleural effusions. An alternative drug should be used to control arrhythmias if poss ible or reduce dose with steroid cover (prednisolone 40 \200\22360mg od tapering over 2 \200\2236/12). If not, 80% will improve but up to 20% die with respiratory failure. If ARDS devel- ops, mortality is 50%. seen on biopsy. 10% of pneumonitis progresses to pulmo- nary \201 brosis. AUTHOR \200\231S TIPS \200 Exclude infection especially Pneumocystis jiroveci (PCP), cytomegalovirus, fungi, TB and no n-tuberculous myco- bacterium before steroid treatment. Methotrexate lung toxicity is favor ed over rheuma- toid arthritis (RA) itself if biopsy shows granulomas rather than usual int erstitial pneumonia (UIP) and if arthritis quiescent.