566 CHAPTER 46 Sickle cell disease Sickle cell chronic lung disease Sickle cell chronic lung disease is a poorly described ent ity, charac- terized by progressive breathlessness and abnormal pulmonary function, sometim es with pulmonary hypertension. Thought to follow recurrent epi- sodes of lung infarction/i nfection, although there may not be a history of previous acute chest syndrome. Prevalence in sickle cell disease estimated at 4%. Radiologically, characterized by multifocal interst itial in \201 ltrate. PFTs typically restrictive, although airways obstruction also descri bed. Severe pulmonary hypertension may occur in up to a third of patients with sickle cell disea se. Management is largely as for idiopathic pulmonary arterial hypertension, with anticoagu lation and vasodilators in a specialist center (p 392). Hydroxyurea reduces episodes of acu te chest syndrome and may be of bene \201 t. Inhaled nitric oxide may have a role; studies are ongoing. Pulmonary thromboendarterectomy may be considered in patients with proximal p ulmonary artery occlusion. Further information Siddiqui AK, Ahmed S. Pulmonary manifestations of sickle cell disease. Postgrad Med J 2003; 79: 384 \200\22390. Mak V, Davies SC. Acute chest syndrome of sickle cell anemia. Thorax 2003; 58: 726 \200\223 8. 567 Chapter 47 Sleep apnoea and hypoventilation Obstructive sleep apnoea (OSA) 568 OSA: clinical features 570 OSA: types of sleep study 572 OSA: nasal CPAP 574 OSA: driving advice to patients 576 OSA in children 578 OSA: future de velopments 580 Central sleep apnoea (CSA) and nocturnal hypoventilation 582 Causes and clin ical features of CSA/hypoventilation 1 584 Causes and clinical features of CSA/hypoventilat ion 2 586 CSA/hypoventilation: investigations 588 Obesity-related respiratory problems 590 568 CHAPTER 47 Sleep apnoea and hypoventilation Obstructive sleep apnoea (OSA) De \201 nition and epidemiology OSA, or obstructive sleep a pnoea/ hypopnoea (OSAH) are currently the preferred terms for the problem of dynamic upper airway obstruction during sleep. \200 OSA is part of a spectrum, with trivial snoring at one end and repeti- tive complete obstru ction throughout the night (such that the patient cannot sleep and breathe at the same time ) at the other Along this spectrum is a point at which the degree of obstruction and recove ry fragments sleep enough to cause daytime symptoms Distinction should be made between the sleep study \201 ndings alone (i.e. presence of sleep apnoea episodes), and an abnormal s leep study plus the presence of symptoms (i.e. obstructive sleep apnoea syndrome, OSAS). Thresholds de \201 ning \200\230abnormality \200\231 are arbitrary (e.g. 10 s to de \201 ne an apnoea). Numerical de \201 nitions of OSA, based on counting individual events duri ng a sleep study, are not very helpful. The current de \201 nition of the clinical syndrom e should be: Upper airway narrowing, provoked by sleep, causing suf \201 cient sleep fragmentation to r esult in signi \201 cant daytime symptoms, usually exces- sive sleepiness. Prevalence depends on the chosen thresholds for de \201 ning both an abnormality on the sl eep study, and signi \201 cant symptoms 0.5 \200\2231% of adult men in the UK (and about a \201 fth as many women) have OSA syndrome suf \201 cient to be candidates for treatment with nasal continuous positive airway pressure (CPAP) treatment Prevalence \201 gures de pend on levels of obesity and will be higher in the USA, and probably rise inexorably in th e UK in the future The prevalence in women is thought to be lower due to their different fa t distribution. Upper body obesity (and thus neck obesity) is more a male pattern OSA is th e third most common serious respiratory condition after asthma and COPD. In some respirator y units it has now become the commonest reason for specialist referral Pathophysiology and associated conditions Control of the upper airway musculature is comple x; upper airway patency depends on dilator muscle activity. All postural muscles relax duri ng sleep (including pharyn- geal dilators); some narrowing of the upper airway is normal. E xcessive narrowing with the onset of sleep is due to the following factors. Causes of a small pharyngeal size when awake (such that normal muscle relaxation with sleep is enough to provoke critical narrowing). \200 Fatty in \201 ltration of pharyngeal tissues and external pressure from increased neck fat and/or muscle bulk Large tonsils Subtle \200\230abnormalities \200\231 of craniofacial sh ape, e.g. minor micrognathia or retrognathia Extra submucosal tissue, e.g. myxoedema, mucop olysaccharidoses \200 OBSTRUCTIVE SLEEP APNOEA 569 Causes of excessive narrowing of the airway occurring with muscle relaxation at sleep onset \200 Mass loading from an obese or muscular neck may simply \200\230overwhelm \200\231 residual dilator action, as well as reduce the starting size Neuromuscular diseases with pharyngeal involvement may lead to greater loss of dilator muscle tone, e.g. stroke, myotonic dystrop hy, Duchenne dystrophy, motor neuron disease Muscle relaxants, such as sedatives and alcoho l Increasing age \200 Predisposing conditions OSA is found more commonly in certain condi- tions, such as acromeg aly and hypothyroidism, but the reasons are not well understood. It is unclear whether ther e need to be any other non- anatomical factors (such as unstable ventilatory control, or ph aryngeal sensory abnormalities) to provoke OSA. Most associated abnormalities that have bee n described are likely to be secondary to long periods of snoring and OSA, rather than prim ary causal factors. Short-term consequences of OSA In severe OSA, repetitive collapse of the upper airway, with arousal required to re-activate the pharyngeal dilators, occurs approximately every minute throughout the sleeping period (60 events/h, or over 400 per night); they are usually atte nded by hypoxia and hypercapnia that are corrected during the inter-apnoeic hyperventilator y period. Obstructive events short of complete obstruction also provoke arousal, as it is u sually the compensatory re \202 ex increase in inspiratory effort, rather than the blood g as deterioration directly, that wakens the brain. In this situation the drops in oxygen sat uration may be very much less and, in younger thinner individuals, almost imperceptible on oximetry tracings. This is because the compensation afforded by the increased inspiratory e ffort may be adequate, and the bigger oxygen stores in the lungs of the less obese will buf fer any brief hypoventilation. \200 \200 \200 Recurrent arousals lead to highly fragmented and unrefreshing sleep Excessive daytime sleep iness results The correlation between the sleep fragmentation and the resultant degree of s leepiness is not tight, with some patients being sleepy with low levels of fragmentation, a nd vise versa This is thought to result partly from inter-individual differences in sensi- tivity to the effects of sleep fragmentation With every arousal there is a rise in blood pr essure, often over 50 mmHg. It is unclear if these BP rises do any damage to the cardio- va scular system. There is also a carry-over of hypertension (average of 3 mmHg) into the waki ng hours which falls after treatment at 1 month There is true nocturia, mechanism unclear; there may be raised atrial natriuretic peptide (ANP) levels from increased central blood vo lume, brought about by the subatmospheric intrathoracic pressures during the obstructed bre athing; or it may be simply a re \202 ection of highly frag- mented sleep preventing the n ormal reduction in urine \202 ow associated with sleep. 570 CHAPTER 47 Sleep apnoea and hypoventilation OSA: clinical features Chapter 14 (p 85) covers many of the essential features in the histo ry and discusses the differential diagnosis of excessive daytime sleepiness. Most patients present with: \200 Excessive sleepiness, measured using the Epworth Sleepiness Scale; >9 is considered abnorma lly sleepy (p 89) Loud snoring, and apnoeic episodes recognized by the bed partner The pati ent recognizes that he wakes up choking from time to time Poor concentration Unrefreshing s leep and waking unrefreshed Nocturia (true nocturia with reversal of the usual day/night ra tio) \200 \200 \200 \200 Less often there will be: \200 Nocturnal sweating \200 Reduced libido \200 Oesophagea l re \202 ux \200 Increasingly common are patients arriving with spouses worried by the apnoeic pauses they have observed Sleepiness \200 Sometimes dif \201 cult to assess: failure by the patient to recognize the problem, or den ial due to concerns over driving and licensing The Epworth scale (p 89) assesses tendency t o fall asleep, rather than perceived sleepiness per se, as some patients may regard their s ituation as normal It is important to separate the symptom of tiredness from sleepiness (p 86), the latter being much more typical of OSA, although sometimes complained of (rather th an sleepiness) by women with OSA Examination and investigations The examination (often unrewarding) and the investigations a re detailed in Chapter 14 (p 88). Look for the presence of additional lower airways obstruc tion, with associated CO2 retention, so-called \200\230overlap syndrome \200\231. CO2 rete ntion in pure OSA is very uncommon (except in the very, very obese). It appears that the ad ditive effect of some lower airways obstruc- tion (often not enough in its own right to pre cipitate CO2 retention) is required, which perhaps limits the inter-apnoeic hyperventilatio n and thus gradually encourages tolerance to raised levels of CO2. The majority of patients with signi \201 cant OSA are male, tend to have a combination of upper body obesity (neck circumference >17 in), and a relatively undersized or set back mandible. Airway size can b e assessed with scoring systems, e.g. p 591. Sleep study The sleep study assesses if there is anything likely to be the cause of the pat ient \200\231s symptoms. The considerable gray area between normality and abnormality means that sometimes it is unclear whether the symptoms can be blamed on the sleep study \201 ndings. There is also considerable night- to-night variation in sleep study indices that fu rther blurs the distinction between normality and abnormality. In this situation it may be necessary to undertake a therapeutic trial of nasal CPAP and let the patient decide if the bene \201 ts of treatment outweigh the disadvantages. OSA: CLINICAL FEATURES 571 Fig. 47.1 Normal overnight oximetry. Normal baseline and a few dips. Vertical axis, 70-100% SaO2 for each panel; horizontal axis, 60 minutes each panel. Fig. 47.2 Severe OSA. Large numbers of regular dips, sawtooth shaped (faster rise in SaO2 t han fall). 572 CHAPTER 47 Sleep apnoea and hypoventilation OSA: types of sleep study \200 \200 Overnight oximetry alone More than just oximetry, with other channels such as snoring, body movement, heart rate, oronasal air \202 ow, chest and abdominal movements, leg movements: so-called \200\230limited \200\231 sleep studies, or \200\230respiratory PSG \200\231 Fu ll polysomnography, with EEG, EOG, and EMG, to stage sleep elec- trophysiologically, in add ition to the channels listed above There is no evidence that OSA diagnosis needs full polysomnography (PSG with EEG) and it is not indicated for most patients. Oximetry will identify most cases, allowing onward referr al for CPAP treatment. False- positive oximetry occurs with Cheyne \200\223Stokes breathing (heart failure, post-stroke) and when there is a low baseline SaO2 (e.g. COPD); this allow s the SaO2 to oscillate more, with small changes in PaO2 due to the increasing steepness of the Hb dissociation curve at lower SaO2. False negatives, discussed earlier, can occur wit h younger and thinner patients. With appropriate expertise, and recognition of its limitations, oximetry alone is a very va luable tool in the diagnosis and management of OSA. Limited sleep studies (respiratory PSG) are the usual routine investiga- tion. Different un its have expertise in interpreting different sorts of sleep studies. Experience is more imp ortant than the particular sleep study equipment used. Any system should assess the degree of sleep fragmenta- tion and the degree of upper airway narrowing: this can be done using m any different direct and indirect techniques. Management Not all patients need treatment. The evidence for signi \201 cant treatment ben e \201 ts rests on symptoms, which drive treatment, rather than the degree of OSA on a sle ep study. Treatment decisions require a close dialog between physician and patient. Key features in making a treatment choice \200 How sleepy is the patient? Does it affect quality of life? Is it critical to the patient \200\231s livelihood (e.g. HGV driving)? Are they motivated to do anything about it? Has th e patient underestimated the impact of their sleepiness or misled the doctor because of con cerns over driving issues? Is there any evidence of the \200\230overlap \200\231 syndrome, where additional lower airways obstruction has contributed to pushing the patient into typ e II ventilatory failure? If so, is this a stable state or part of an acute decline with a respiratory acidosis? Is obesity the dominant risk factor or is there a surgically remediab le component (e.g. tonsillar hypertrophy)? There is no RCT evidence that CVD, nocturnal angina, or poorly con- trolled hypertension sh ould in \202 uence the decision to treat. Many, however, would lower the treatment thresho ld. There is some evidence that treating OSA when there is left heart failure improves ejec tion fraction and possibly survival. OSA: TYPES OF SLEEP STUDY 573 Simple approaches \200 Weight loss. This is dif \201 cult; slimming clubs have the best record for non-surgical a pproaches Reduce evening alcohol consumption Sleep decubitus, rather than supine, and with the bedhead elevated \200 For snorers and mild OSA \200 \200 Mandibular advancement devices, assuming adequate dentition Pharyngeal surgery as a last re sort (poor RCT data and what there is suggests poor outcomes) For signi \201 cant OSA \200 \200 \200 \200 Nasal continuous positive airway pressure therapy (CPAP) Bariatric surgery (e.g. gastroplas ty or gastric bypass operations) Tracheostomy (rarely indicated) Mandibular/maxillary advan cement surgery in highly selected cases Severe OSA with CO2 retention \200 May require a period of non-invasive positive pressure ventilation (NIPPV) prior to CPAP if acidotic Compensated CO2 retention may reverse with CPAP alone If there are large tonsils then their removal may be appropriate, although this seems to be much more successful in children than in adults. In reality pharyngeal surgery is a poor o ption for either snoring or OSA; what little evidence there is suggests that the outcomes a re little better than placebo. There is no place for alerting agents (such as moda \201 ni l) in the routine management of sleepiness in OSA. It is unclear if these drugs help; they may reduce the perception of sleepiness more than the sleepiness itself, and have only been studied in the residual sleepiness sometimes found in patients, even when treated successf ully with nasal CPAP. Mandibular advancement devices \200 Worn in the mouth at night, holding the lower jaw forward: similar to \200\230jaw thrust \200\231 in an unconscious patient Many designs, but essentially one half clips to the uppe r teeth and the other half to the lower, and connected together with the lower jaw misalign ed forward by 5 \200\22310 mm Some give adjustable forward displacement; some are \201 xe d They need to be customized to match the patient \200\231s dentition, which usually requir es the services of a dentist DIY devices exist that are heated and molded to the teeth dire ctly Control snoring and OSA at the milder end of the spectrum Side-effects include tooth p ain and jaw ache, which often lessen with time Long-term use may be associated with movemen t of the teeth and alterations to the bite The initial cost (usually over 300) is similar to that of a CPAP machine ( 250) and they usually only last about a year. \200 \200 \200 574 CHAPTER 47 Sleep apnoea and hypoventilation OSA: nasal CPAP Nasal CPAP consists of a blower/pressure generator that sits by the patient \200\231s bed and is connected to a mask by a length of large-bore tubing. The masks are u sually just nasal, but nose and mouth masks are also used. The blower raises the pressure a t which the patient is breathing (to about 10 cmH2O) and splints open the pharynx, preventi ng its collapse, sleep frag- mentation, and the consequent daytime sleepiness. Nasal CPAP i s a highly effective therapy with resolution of the sleepiness and large gains in quality o f life. It is a suf \201 ciently curious and initially uncomfortable therapy to require a careful induction program. Without this, the take-up and compliance rates are poor. Most ce nters have found that a dedicated CPAP nurse or technician is required. Many centers use sp ecial patient education aids, such as video presentations, and provide help lines manned by previous patients established on CPAP. The best method of establishing a patient on CPAP a nd deriving the required mask pressure is not known, and many different approaches appear t o work. Recent innovations include CPAP machines that automatically hunt for the required p ressure, and do not require a formal overnight titration with a technician present. New mas k designs appear at regular intervals with a slow improvement in their comfort and \201 t (impor- tant to prevent air leaks). Patients require subsequent long-term follow-up to mai ntain their CPAP equipment and attend to problems. The commonest problems encountered include: \200 Mouth leaks lead to increased air through the nose and out of the mouth, with excessive dry ing of the mucosa, nasal congestion, rhinitis, and sneezing. Use either a chin support to c lose the mouth or the addi- tion of a heated humidi \201 er Pain and ulceration of the ski n on the nasal bridge. Try different masks or patient \200\230interfaces \200\231 Claustro phobia. This usually settles but may require a different interface Temporary nasal congesti on, usually during a cold. Try nasal deconges- tants for these short periods only, such as xylometazoline \200 Alternative diagnoses Most patients who snore, are sleepy, and have an abnormal sleep study , will have ordinary obstructive sleep apnoea and respond to nasal CPAP. Sometimes, differe ntiating obstructive sleep apnoea from central apnoeas (p 582) can be dif \201 cult becaus e some patients with Cheyne \200\223Stokes breathing, for example, may have a few obstructe d breaths at the end of each apnoeic cycle, even though the problem is primarily central. P oor response to CPAP should at least prompt a reappraisal of the diagnosis. Not all obstruc tive sleep apnoea is due to pharyngeal collapse; a very small number of patients have laryn geal closure. This can occur with: \200 Shy \200\223Drager syndrome (multisystem atrophy). This causes laryngeal abductor weakness with laryngeal closure during sleep, with stridulous obstruction rather than the usual nois e of snoring Rheumatoid arthritis can damage the larynx with resultant OSA Arnold \200\223C hiari malformation can compress the brainstem and interfere with the control of the larynx and pharynx, as well as the control of ventilation, with mixed \201 ndings on the sleep s tudy These forms of obstruction also respond to nasal CPAP therapy as the larynx is also \200\230blown open \200\231 by raising airway pressure. \200 OSA: NASAL CPAP 575 Fig. 47.3 Sleep onset periodic ventilation. Short bursts of dipping, otherwise normal. Fig. 47.4 Cheyne \200\223Stokes ventilation. Prolonged periods of dipping, often sinusoidal rather than sawtooth. 576 CHAPTER 47 Sleep apnoea and hypoventilation OSA: driving advice to patients In UK law one is responsible for one \200\231s vigilance le vels while driving. We know when we are sleepy and should stop driving. Driving while sleep y has been likened to driving whilst drunk, and a prison sentence can result from sleep-rel ated accidents on the road. No one should drive while they are sleepy, and the same applies to pathological causes of sleepiness. Advice to all patients with OSA. Do not drive while sleepy; stop and have a nap. On diagnos is, patients with OSA syndrome (i.e. with daytime hyper- somnolence) should notify the DVLA who will send them a questionnaire. If they admit to excessive daytime sleepiness their li cense is revoked. If already treated and the sleepiness has resolved, then the license is n ot revoked. It is the doctor \200\231s duty to tell the patient of the diagnosis of OSAS an d of the requirement to inform the DVLA. Patients who are not sleepy and only have OSA on t heir sleep study do not have OSA syndrome (OSAS), and thus do not need to inform the DVLA. According to US epidemiological studies, 1/20 men have OSA on a sleep study, which would ra ther overwhelm the DVLA. The doctor can advise the patient whether they should stop driving entirely (wise if the pa tient is very sleepy and/or drives a heavy goods vehicle or public service vehicle \200\224 class 2 license holders), or to continue driving only with extreme caution for short distan ces. The advice given to the patient should be recorded in the notes. Driving can be restarted as soon as the sleepiness has resolved and been con \201 rmed by medical opinion, but in the case of class 2 license holders the success of the treatment mu st be veri \201 ed by a specialist clinic. This means a normal ESS and evidence of adequat e nasal CPAP usage from the hour meters built into most nasal CPAP machines. A minimum usa ge has not been de \201 ned, but 3 h per night on average is often the arbitrary threshold used. Non-usage for even one night can lead to a return of sleepiness, so patients have to continue to act responsibly. This page intentionally left blank 578 CHAPTER 47 Sleep apnoea and hypoventilation OSA in children Adult respiratory physicians interested in sleep apnoea may be asked to inv estigate children with OSA due to poor sleep services for children. \200 Mainly due to enlarged tonsils and adenoids; varying degrees of OSA are present in up to 4% of children around the age of \201 ve; prevalence tails off as tonsils atrophy These chi ldren present with snoring, restless sleep, and different daytime symptoms to those of adul ts. Obvious sleepiness is less common Sleep-deprived children tend to become hyperactive wi th reduced attention spans, and be labeled as dif \201 cult or disruptive Symptoms will \202 uctuate with the size of the tonsils and this depends on the presence of upper respira tory infections Mild intermittent sleep disturbance may not matter, but every-night sleep f ragmentation for months interferes with development in a variety of ways The clinical decis ion is mainly whether to recommend removal of tonsils, or a wait and see policy, rememberin g that there is a signi \201 cant morbidity from adenotonsillectomy, and even the occasion al death A halfway house is the use of nasal steroids, which can reduce tonsillar size suf \201 ciently to improve symptoms until natural tonsillar atrophy occurs. OSA IN CHILDREN 579 Fig. 47.5 REM sleep hypoventilation in scoliosis. Substantial dips, in bursts, compatible w ith the occurrence of REM periods. Fig. 47.6 Moderate OSA with many <4% dips in SaO2. 580 CHAPTER 47 Sleep apnoea and hypoventilation OSA: future developments The old view that sleep apnoea requires polysomnography to diagnos e is rapidly being replaced with a more pragmatic and evidence-based approach using simpler equipment. Simpler ways to establish patients on CPAP are also evolving that will bring do wn costs further. Obesity surgery is improving and in appropriate cases may become the trea tment of choice. Appetite suppressants are being developed that will greatly reduce the pre valence of obesity and hence OSA. Pharmacological agents are being tried that attempt to pr event the loss of tone in the pharyngeal dilators during sleep, mainly serotonergic agents, although progress in this area is slow (e.g. mirtazapine reduces OSA, but unfortunately ca uses sedation and weight gain!). New pharyngeal operations are being devised all the time, but none have been very effective when investigated properly: ran- domized controlled trial s with objective outcome data are badly needed in this area. Whether OSA is truly an independent risk factor for vascular disease (e.g. MI, strokes etc. ) is hotly debated. Cross-sectional and non-randomized data suggest so. However, it is dif \201 cult to adequately control for con- founding variables, such as visceral obesity, and non-randomized studies carry important bias. RCTs show small bene \201 ts to BP of treati ng OSA with CPAP. Further information Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002; 360: 237 \200\22345. Robinson GV et al. OSA/H syndrome and hypertension. Thorax 2004; 59: 1089 \200\22394. Sleep Apnoea Trust, Patients association, www.sleep-apnoea-trust.org. SIGN/BTS guidelines (2003), http://www.sign.ac.uk/pdf/sign73.pdf. NICE technology appraisal of CPAP for OSA, www.nice.org.uk/guidance/index.jsp?action= downl oad&0=38198 Cochrane database on CPAP. Continuous positive airways pressure for obstructive sleep apnoe a in adults. http://www.cochrane.org/reviews/en/ab001106.html. Interventions to improve compliance with continuous positive airway pressure for obstructiv e sleep apnoea. http://www.cochrane.org/reviews/en/ab003531.html. American commercial website showing all the CPAP equipment, www.cpapman.com Main American Sleep Information website, www.sleephomepages.org. American website with patient information on a variety of sleep disorders (simple), www.nlm .nih. gov/medlineplus/tutorials/sleepdisorders/nr249101.html. Source of DIY dental device www.oscimedsa.com. OSA: FUTURE DEVELOPMENTS 581 Fig. 47.7 Nocturnal hypoxia in COPD. Low baseline SaO2, with more dramatic falls (often qui te prolonged) during periods compatible with the occurrence of REM. Fig. 47.8 Overlap syndrome \200\224OSA and COPD. Low baseline SaO2. Some periods with typic al sawtooth dipping; other periods with prolonged falls in SaO2. 582 CHAPTER 47 Sleep apnoea and hypoventilation Central sleep apnoea (CSA) and nocturnal hypoventilation De \201 nition and epidemiology \200\230Central sleep apnoea/hypopnoea \200\231, or \200\230hypoventilation \200\231, or \200\230periodic breathing \200\231 are said to occur when there is no evidence of upper ai rway obstruction as the cause for the reduced ventila- tion during sleep. Compared with OSA it is much less common. \200 Central sleep apnoea tends to be used as a term when there are actual apnoeas, and referred to as Cheyne \200\223Stokes breathing when there is regular symmetrical waxing and waning, usually in the context of left heart failure Periodic breathing is an alternative and can be used to describe regular \202 uctuations in breathing, with or without actual apnoeas The description nocturnal hypoventilation tends to be used when the hypoventilation and hyp oxaemic dips are not particularly periodic in nature. However, these terms are imprecise an d sometimes mixed indiscriminately. Pathophysiology Central sleep apnoea, or hypoventilation, or periodic breathing, can occur in a number of settings with different aetiologies (see also Chapter 15, p 92). At one end of a spectrum is pure loss of ventilatory drive, while at the other is pure loss of the abi lity to expand the chest adequately, with dependence on accessory muscles of respiration. M any clinical presenta- tions are mixtures of these two. Patients with reduced ventilatory drive (e.g. following brainstem damage) can often maintai n adequate, or near adequate, ventilation whilst awake as there is a non-metabolic \200 \230awake \200\231 ventilatory drive equivalent to about 4 or 5 L/min. During non-REM sleep , this awake drive is lost and ventilation becomes dependent on PaO2 and PaCO2. During REM sleep, an \200\230awake- like \200\231 drive sometimes returns partially and ventilation c an improve again (seen in congenital forms of absent drive where REM sleep can tempo- raril y restore SaO2 levels). In patients with impaired mechanical ability to ventilate, accessory muscles of respiration become critically supportive (e.g. in many neuromuscular disorders and obstructive/restric tive respiratory conditions). However, during non-REM sleep, this re \202 ex recruitment o f accessory muscles is attenuated and hypoventilation follows. During REM sleep the physiol og- ical paralysis of all postural muscles (REM atonia) can remove all com- pensatory mecha nisms, leaving only the diaphragm working, and produce profound hypoventilation or apnoea. Chronic hypoventilation, often secondary to poor respiratory function (e.g. as evidenced by CO2 retention in some patients with COPD or chest wall restrictive disorders) can eventual ly force resetting of ventilatory control mechanisms. This is an acquired blunting of venti latory drive and leads to sleep-related changes in ventilation, similar to those described in the paragraphs above. CENTRAL SLEEP APNOEA/NOCTURNAL HYPOVENTILATION 583 Unstable ventilatory control can lead to regular oscillations in ventilation, e.g. as occur s in heart failure and at altitude. During REM sleep it is normal to have \202 uctuations in ventilation, sometimes with complete apnoeas. Sometimes sleep studies can be misinterpreted and apnoeas, really of obstructive origin, ar e mistakenly labeled as central. For example, if inspira- tory muscles are very weak, their poor efforts during obstructive apnoeas may be missed. 584 CHAPTER 47 Sleep apnoea and hypoventilation Causes and clinical features of CSA/ hypoventilation 1 Although there are many different ca uses, only four relatively common clinical scenarios occur (but with overlap). 1. Absent or reduced ventilatory drive Brainstem involvement from strokes, tumors, syringob ulbia, surgical damage, post-polio syndrome, congenital (Ondine \200\231s curse \200\224usu ally presents soon after birth, can be later, abnormalities of neural crest development due to increased number of \200\230alanine repeats \200\231 in one of the homeobox genes \200 \224 PHOX2B). Presents clinically with unexplained ventilatory failure, much worse during s leep when the \200\230awake \200\231 drive is lost. May be recognized early, cyanosis, mor ning confusion, ankle oedema. May be recognized late, loss of consciousness and an emergenc y admission to ITU for ventilation. Lung function is often normal, with no evidence of respiratory muscle weakness, indicating normal innervation from the voluntary motor system. Arnold \200\223Chiari malformation with brainstem compression can present like this, but there is usually involvement of surroundi ng structures such as the lower cranial motor nuclei supplying the larynx and pharynx (with associ- ated obstructive sleep apnoea, p 570). These patients will have no apparent neuromuscular or respiratory cause for their hypoventi lation, but may have a previous history of brainstem stroke (or other form of brain damage) . The congenital form presents shortly after birth when the amount of REM sleep reduces and is replaced by non-REM. Post-polio syndrome is: \200 \200 \200 Ill de \201 ned syndrome \200\224decline in function, decades after initial illness Return of weakness in previously affected areas (mechanism unclear) Late development of ventilato ry failure is more likely if: \200 \200 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).