postgraduate course 11 sleep and acute respiratory failure ... · th e ers handbook of respiratory...

ERS Annual Congress Munich

6–10 September 2014

Postgraduate Course 11 Sleep and acute respiratory failure (ARF)

Saturday, 6 September 2014 14:00–17:30

Room M-2 (B0)

You can access an electronic copy of these educational materials here:

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Postgraduate Course 11 Sleep and acute respiratory failure (ARF)

AIMS: To revisit sleep-disordered breathing as a possible precipitating cause of respiratory failure, to describe sleep disturbances in patients with ARF, and to analyse the effects of drugs and noninvasive ventilation on sleep. HERMES LINKS ADULT: B.10 Respiratory Failure, B.19 Sleep-related disorders, E.1.6 Treatment modalities and prevention measures, Ventilatory Support (invasive/non-invasive/CPAP). TARGET AUDIENCE: Pulmonologists, respiratory therapists, respiratory physicians, clinical researchers, research fellows, intensivists, nurses, trainees and neurologists. CHAIRS: M.R. Bonsignore (Palermo, Italy), M.W. Elliott (Leeds, United Kingdom). COURSE PROGRAMME PAGE 14:00 Sleep-disordered breathing that leads to severe respiratory failure: mechanisms and clinical presentation 5 O. Marrone (Palermo, Italy) 14:45 Does acute respiratory failure affect sleep? 40 A. Piper (Sydney, Australia) 15:30 Break 16:00 Prevention and treatment of sleep disturbances in acute respiratory failure: the role of drugs 80 C. Gregoretti (Turin, Italy) 16:45 Prevention and treatment of sleep disturbances in acute respiratory failure: the role of noninvasive ventilation 128 M.W. Elliott (Leeds, United Kingdom) Additional course resources 173

Faculty disclosures 174

Faculty contact information 175

Answers to evaluation questions 176

Th e ERS Handbook of Respiratory Sleep MedicineEdited by Anita K. Simonds and Wilfried de Backer

ISBN 978-1-84984-023-1

Th e 8 chapters of the ERS Handbook of Respiratory Sleep Medicine cover all aspects of adult and paediatric respiratory sleep medicine, from physiology and anatomy to diagnosis and treatment. Editors Wilfried de Backer and Anita K. Simonds have brought together leading pulmonologists to produce a thorough yet easy-to-read reference to this important area of respiratory medicine. It is a valuable resource for any practitioner of sleep medicine, whether they come from a respiratory, neurology, cardiology, dental or ENT background.

Accredited by EBAP for 8 hours of European CME credit.

ERSBOOKSHOP.COM

let THE ERS HANDBOOK OFRESPIRATORY SLEEP MEDICINE

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Sleep-disordered breathing that leads to severe respiratory failure: mechanisms and clinical presentation

Dr Oreste Marrone

Institute of Biomedicine and Molecular Immunology National Research Council

Via Ugo La Malfa, 153 90146 Palermo

Italy [email protected]

AIMS • To illustrate through which mechanisms sleep respiratory disorders may lead to CO2

retention. • To describe clinical features of patients with sleep respiratory disorders and severe respiratory

failure, and pathogenetic mechanisms that may lead to acute blood gas deterioration in these patients.

SUMMARY Respiratory disorders during sleep cause transient alterations of oxygen and CO2 tensions. Usually, such alterations have the same duration as each respiratory event. However, some subjects may develop chronic respiratory failure with diurnal hypercapnia after long-term recurrence of sleep respiratory disorders. Severe, life-threatening, respiratory failure may occasionally appear as an effect of precipitating factors, particularly in predisposed subjects [1]. In patients with severe obstructive sleep apnoea (OSA) inadequate ventilatory compensation to CO2 loading after apnoeas, with incomplete recovery of blood gases, can be the first step for the development of diurnal hypercapnia. Ability to generate a high minute ventilation immediately after apnoeas, and duration of interapnoeic periods, concur to the effectiveness of the interapnoeic ventilation. Ventilation between apnoeas may be insufficient in subjects with depressed ventilatory drive, with respiratory mechanical limitations (most often due to coexisting morbid obesity or lower airway obstruction), or with a poor arousability and a consequent short duration of the interapnoeic interval [2]. Prolonged exposure to hypoxia may reduce arousability and could contribute to make interapnoeic ventilation insufficient [3]. Chronically decreased CO2 unloading after sleep apnoeas is believed to buffer cerebrospinal fluid, making central chemoreceptors less responsive to CO2. Chronic CO2 retention may ensue, particularly if kidneys eliminate insufficient amounts of bicarbonates. Similarly to patients with OSA, patients with diseases associated with sleep hypoventilation may develop hypercapnic respiratory failure as an effect of chronic exposure to increased CO2 during sleep. Nocturnal mechanical ventilation, that prevents CO2 rise during sleep and increases ventilatory responsiveness to CO2, helps to relieve diurnal respiratory failure or may delay its onset [4]. Some effect of OSA in decreasing diurnal PaO2 has also been pointed out, which could depend on alterations of mechanical properties of the lung due to recurrence of obstructive apnoeas [5]. Severe respiratory complications have been more rarely described in patients with sleep respiratory disorders.

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The association of COPD with OSA (“overlap syndrome”) makes not only chronic, but also acute life-threatening respiratory failure more likely to occur [6]. In patients with the overlap syndrome, untreated OSA is associated with a higher rate of exacerbations and a higher mortality than in patients with COPD but without OSA [7,8]. Probably, increased risk of infections and pneumonia in the OSA population could enhance exacerbations in the overlap patients [9]. Besides, among patients hospitalised with pneumonia, those who are also affected by OSA more often require transfer to intensive care unit (ICU) and invasive mechanical ventilation [10]. Alcohol abuse, inappropriate oxygen administration, or drugs with depressant respiratory effects may be other causes of severe respiratory failure in OSA patients [11]. A higher incidence of adverse effects with the use of such drugs may be observed in OSA patients than in the general population. Drugs administration, and in particular opioids, may partly explain the high rate of unplanned ICU transfers, respiratory failure and intubations after surgical procedures in patients with OSA [12,13]. Besides, they could importantly contribute to acute blood gas deterioration and sudden death in patients with OSA and psychiatric disorders [14]. Obesity hypoventilation syndrome (OHS) is associated with sleep respiratory disorders. In its most severe form, OHS is recognised in patients hospitalised in ICU for cardiorespiratory failure. If left untreated, OHS is associated with increased mortality, often due to respiratory failure [15]. Recently, a very severe form of OHS has been described, which has been called “Malignant Obesity Hypoventilation Syndrome”, and is characterised by multiple comorbidities and a poor prognosis [16]. In conclusion, sleep-disordered breathing may contribute to the establishment of chronic hypercapnic respiratory failure when it exposes to prolonged periods of hypercapnia. That often occurs in patients with chest wall diseases, or in patients with OSA who are morbidly obese or have coexistent COPD. In such patients respiratory failure may be exacerbated by events like respiratory infections or inappropriate drug administration. Major surgical procedures may put OSA patients at high risk of acute respiratory complications, particularly when opioids are administered. REFERENCES 1. Carr GE et al. Acute cardiopulmonary failure from sleep-disordered breathing. Chest

2012;141:798 – 808. 2. Berger K et al. Obesity hypoventilation syndrome. Semin Respir Crit Care Med 2009;30:253-

61. 3. Hlavac MC et al. Hypoxia impairs the arousal response to external resistive loading and

airway occlusion during sleep. Sleep 2006;29:624-31. 4. Nickol AH et al. Mechanisms of improvement of respiratory failure in patients with

restrictive thoracic disease treated with non-invasive ventilation. Thorax 2005;60:754–60. 5. Fanfulla F et al. The relationship of daytime hypoxemia and nocturnal hypoxia in obstructive

sleep apnea syndrome. Sleep 2008;31:249-255. 6. Fletcher EC et al. "Near miss" death in obstructive sleep apnea: a critical care syndrome. Crit

Care Med 1991;19:1158-64. Eight patients with OSA who presented acute respiratory failure were compared with eight patients with OSA without this complication. The first group more often had COPD with hypercapnia in a clinically stable state, a history of wheezing or prior hospitalisation for respiratory problems. As possible precipitating factors for the acute respiratory failure, lower airway infection, facial trauma and use of narcotics were recognised.

7. Machado MC et al. CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD. Eur Respir J 2010;32:132-7.

8. Marin JM et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010;182:325-31.

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9. Su V et al. Sleep apnea and risk of pneumonia: a nationwide population-based study. CMAJ 2014;186:415-21.

10. Lindenauer P et al. Prevalence, treatment and outcomes associated with obstructive sleep apnea among patients hospitalized with pneumonia. Chest 2014;145:1032-8.

11. Sampol G et al. Acute hypercapnic respiratory failure in patients with sleep apneas. Arch Bronconeumol 2010;46:466-72. Seventy patients with sleep apnea syndrome (SAS) who had survived an episode of acute hypercapnic respiratory failure (AHRF) were prospectively followed for 3 years. Their lung function was worse than in control subjects with SAS but without AHRF, due to either obesity or COPD, but better than in control subjects with COPD but without SAS admitted for AHRF. Alcohol and benzodiazepines consumption, PaO2 and %predicted forced vital capacity measured after the AHRF episode were found independent predictors of AHRF in the SAS patients. Treatment of sleep respiratory disorders resulted in a decrease in hospital admissions in the group with SAS and AHRF; nevertheless, this group of patients had a higher mortality in the three-year period, mainly due to respiratory causes, than the SAS patients who had not experienced AHRF.

12. Memtsoudis S et al. Perioperative pulmonary outcomes in patients with sleep apnea after noncardiac surgery. Anesth Analg 2011;112:113-21.

13. Chung F et al. Factors associated with postoperative exacerbation of sleep-disordered breathing. Anesthesiology 2014;120:299-311.

14. Fleischman J et al. An unexplained death in the psychiatric emergency room: a case of undiagnosed sleep apnea? Gen Hosp Psychiatry 2008;30:83-6.

15. Mokhlesi B et al. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc 2008;5:218–25.

16. Marik PE. The malignant obesity hypoventilation syndrome (MOHS). Obes Rev 2012;13:902–9. The author defines as “Malignant Obesity Hypoventilation Syndrome” (MOHS) the clinical picture of morbid obesity (>40 kg/m2) with hypercapnic respiratory failure, restrictive lung disease due to obesity, type 2 diabetes or metabolic syndrome, and other multisystem organ dysfunction. Among the most common comorbidities, obstructive sleep apnoea, pulmonary and systemic hypertension, right and left ventricular failure, non alcoholic steatohepatitis are observed. Patients with MOHS have frequent hospitalisations, often to ICU for progressive type II respiratory failure, with difficult discharge and a high mortality, and are often mistaken for COPD before hospitalisation.

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EVALUATION 1. Which of these factors is better correlated to CO2 retention in patients with obstructive sleep

apnoea (OSA)? a. Lowest SaO2 during sleep. b. Mean apnoea duration. c. Ratio between apnoea and interapnoeic interval duration. d. Duration of REM sleep.

2. In patients with COPD, OSA is not associated with:

a. Increased severity of lower airway obstruction. b. Increased rate of exacerbations. c. Increased mortality. d. Worse nocturnal desaturations.

3. Pneumonia in patients with OSA, as compared to control subjects, shows:

a. Similar incidence, and similar requirement of ICU care. b. Higher incidence, but similar requirement of ICU care. c. Similar incidence, but higher requirement of ICU care. d. Higher incidence, and higher requirement of ICU care.

4. Which of these factors is not an essential feature of MOHS?

a. BMI>40 kg/m2. b. Thyroid dysfunction. c. Type II respiratory failure. d. Metabolic syndrome or type 2 diabetes.

Please find all answers at the back of your handout materials

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Sleep-disordered breathing that leads tosevere respiratory failure:

Mechanisms and clinical presentation

Oreste MarroneOreste Marrone

National Research CouncilInst. Biomedicine and Clinical Immunology

Palermo, Italy

9

Faculty disclosure

The speaker has no conflict of interest to declare that is related interest to declare that is related

to this presentation

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AIMS

• To illustrate through which mechanims sleep respiratorydisorders may lead to chronic CO2 retention.

• To describe clinical features of patients with sleeprespiratory disorders and severe respiratory failure, andpathogenetic mechanisms that may lead to acute bloodgas deterioration in these patients.

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Features most often observed in OSA patientswith near miss death

COPD, abnormal diurnal ABG,prior hospitalization for respiratory problems

Factors acutely precipitating ABG deterioration

Flu-like syndromes, COPD exacerbations, analgesics/O2

with near miss death

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Surv

ival

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OPIOIDS AND SLEEP DISORDERED BREATHING

fromfromWang D et alChest 2005

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In patients hospitalised with at least one majorrisk factor for ARDS, prior diagnosis of OSA didrisk factor for ARDS, prior diagnosis of OSA didnot independently affect development of ARDS.

Obesity appeared to independently increase therisk of ARDS.

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CAUSE OF SUDDEN DEATH Total (N=100)

Cardiovascular diseases 22

Gas exchange failure 17

Upper airway obstruction 5

Pulmonary embolus 4

Bronchial asthma 2

Pneumonia 2

Respiratory failure NOSa 4

Intracranial events 5

Diabetic ketoacidosis 1

Septic shock 1

Seizure 1

Gastrointestinal bleeding 1

Unknown 52

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CLINICAL PRESENTATIONS OF OBESITY HYPOVENTILATION SYNDROME

1. Patient with suspected OSA and unexpected findingof diurnal hypercapnia. Similar as, or slightly moresevere clinical features than, usual OSA patients.severe clinical features than, usual OSA patients.

2. Patient with acute on chronic respiratory failureoften precipitating a stay in ICU. Obtunded,dyspnoic, edematous (RV failure). Often mistakenfor severe COPD.

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Major Criteria

Minor Criteria

All major criteria + ≥2 minor criteria

• BMI>40• PaCO2>45 and HCO3- >28• Restrictive lung diseases (no COPD or musculoskeletal disease)• Metabolic syndrome / type 2 diabetes

Minor Criteria• Multiple hospital admissions for type II respiratory failure• Sleep disordered breathing (OSA)• Eccentric LV hypertrophy (LVM >47 g/m-1.2.7)• Diastolic LV dysfunction• Systemic hypertension• Chronic renal insufficiency• Non-alcoholic steatohepatitis• Vitamin D deficiency• Elevated C reactive protein

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CONCLUSIONS

• Chronic diurnal hypercapnic respiratory failure mayresult from long-term CO2 loading during sleep

• Severe respiratory failure is unlikely to occur in pureOSA, while it may be observed when OSA is associatedwith morbid conditions, among which the most commonare COPD and morbid obesity, or in case of a majorsurgical procedure

• Inappropriate drug use or acute respiratory infectionsare important factors that may precipitate severerespiratory failure in OSA

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Does acute respiratory failure affect sleep?

Dr Amanda Piper Department of Respiratory and Sleep Medicine

Royal Prince Alfred Hospital Camperdown NSW

Australia [email protected]

AIMS • To outline factors associated with acute respiratory failure that can adversely affect sleep. • To discuss changes in sleep quality and continuity in patient requiring mechanical ventilation

and ICU management and for acute respiratory failure. • To review the potential impact of sleep loss on patient outcome. SUMMARY Acute respiratory failure (ARF) causes changes in breathing pattern, gas exchange and work of breathing all of which have the potential to alter sleep quality. Sleep loss or fragmentation are associated with a range of adverse clinical consequences including fatigue, neurocognitive impairment, reduced immune function and altered respiratory function. These effects have potential implications for weaning and recovery from acute illness in patients with acute respiratory failure (ARF). A number of studies have explored the effect of critical illness and mechanical ventilation on sleep quality and quantity. However, separating the impact ARF directly has on sleep quality from the various interventions and therapies used to manage the presenting medical problem is more challenging. Respiratory disease and sleep quality Many patients with chronic respiratory disease have poor quality sleep and sleep disordered breathing when clinically stable, both of which can worsen considerably during an acute exacerbation. Many features of acute respiratory failure including dyspnea, gas exchange abnormalities, altered pulmonary mechanics, increased sputum load and high work of breathing have the potential to worsen already suboptimal sleep quality. In stable patients with moderate to severe COPD, impaired nocturnal sleep quality appears to be related to dyspnea severity [1], which would likely worsen during acute illness. Increased work of breathing associated with air trapping or increased sputum load could induce more fragmented sleep from respiratory effort-related arousals [2]. Although hypoxia is a poor arousal stimulus [3], hypercapnia alone may induce arousal from sleep [4]. Sleep and the Intensive care environment Patients managed in intensive care units (ICU) display marked alterations in sleep quality and continuity, with a predominance of wakefulness and light sleep (N1 &N2 sleep), and a relative lack of rapid eye movement (REM) and slow wave sleep (N3) [5-7]. These changes in sleep macrostructure have been reported in both ventilated and non-ventilated patients [5,6,8]. Although the total number of hours of sleep recorded over a 24-hour period may be within the normal range, the sleep/wake cycle is often severely disrupted with nearly 50% of sleep occurring during daytime periods [5,7,8]. Significant sleep fragmentation is also present, with an increased number of arousals and awakenings. These objective findings are supported by patients themselves who perceive their sleep in ICU poor, and report sleep deprivation as an important cause of stress and anxiety for them [9,10].

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Restricted or disturbed sleep in patients with acute respiratory illness has significant clinical implications. Sleepiness and cognitive impairment in ambulatory individuals is related to sleep fragmentation, and this may be a contributor to the cognitive decline seen in patients following ICU admission [11]. Delirium is also very common amongst patients managed in ICU and thought by many to be related to sleep deprivation, although these links are not yet firmly established. In patients with acute hypercapnic respiratory failure, delirium is associated with greater circadian sleep-cycle disturbance and less time spent in REM sleep [12]. Weaning from ventilatory support and recovery of respiratory function to baseline levels may also be hampered by sleep loss and fragmentation. Even in healthy subjects, sleep loss has been shown to impair inspiratory muscle endurance [13], spirometry [14] and ventilatory responsiveness to hypercapnia [15,16]. While similar data from patients with acute respiratory failure is unavailable, it would be reasonable to assume that the impact of sleep loss on respiratory function would have at least the same if not a greater impact on those with significantly reduced respiratory reserve. So what is the cause of this sleep disruption? Noise, artificial light and patient care activities were originally believed to be the main factors responsible. However, it now appears that these activities account for only 30% of the arousals and awakenings recorded in intubated patients [7]. Other factors such as pain, discomfort and the severity of the acute illness would also contribute to some of the abnormality seen. More recently, attention has turned to the role mechanical ventilation may play in disrupting sleep, with ventilator mode, settings and patient-ventilator interactions considered to be significant sources of sleep fragmentation. A number of studies have investigated the association between sleep quality and ventilator mode. Several studies have suggested that arousals and awakenings from sleep are higher during pressure support ventilation (PSV) compared to assist control ventilation (ACV) [17, 18]. In contrast, Carbello et al [19] found no difference in sleep duration, sleep architecture or fragmentation index between ACV, clinically-adjusted PSV and an automatically- adjusted PSV, a mode which provides a continuous adaptation of the pressure support level to meet pre-determined ventilation targets based on patient comfort. The results of these studies highlight the importance of producing central events by overventilation as a cause of sleep disruption, especially in patients vulnerable to respiratory instability such as those with heart failure. Poor patient-ventilator interaction has also been identified as a potential source of sleep disruption. In a study comparing PSV to proportional assist ventilation (PAV), a mode designed to adjust flow and volume based on respiratory resistance, elastance, and inspiratory effort, the latter produced fewer asynchronies and better quality sleep in a group of invasively ventilated patients [20]. These findings support the notion that correctly adjusting ventilator settings to avoid hypocapnia or ineffective efforts may be more important in ameliorating sleep fragmentation and improving sleep quality than simply the mode of ventilation used [19,21]. Sleep quality during weaning from ventilation A small amount of data regarding sleep quality during weaning from ventilation is available. Andrejak and colleagues [22] studied 26 patients with COPD and acute on chronic respiratory failure ready for extubation. In a cross over study design, patients were randomised to low PSV (6cmH2O) or pressure control ventilation with inspiratory support pressure and back up rate set to achieve suppression of the respiratory muscles. The study was conducted over a single night, with 4-hrs of recording during each mode. Sleep efficiency was found to be significantly better during PCV, as were the amount of SWS and REM sleep achieved. The authors proposed that the improvements seen may have arisen from respiratory muscle rest with PCV. They speculated that using PCV at night to promote restorative sleep prior to extubation could improve clinical outcomes. Unfortunately, the study was not designed to evaluate the impact of such a strategy on morbidity. In order to assess the impact of ventilation on sleep in patients recovering from acute respiratory failure, Fanfulla and colleagues [23] monitored the 24-hour sleep pattern of patients admitted to a

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sleep down unit. Thirty eight per cent of patients were post-operative, while patients with COPD or restrictive thoracic disorders made up another 38% of the study population. Eleven patients were breathing spontaneously while the remaining 10 still required mechanical ventilation via tracheostomy either continuously (9) or nocturnally (1). Several interesting observations were made. Firstly, sleep variables were similar between mechanically ventilated patients and those who were spontaneously breathing, suggesting that mechanical ventilation was not a major cause of sleep disruption in this population. These findings are similar to another study of tracheostomised patients during recovery from acute respiratory failure and prolonged mechanical ventilation [21]. Secondly, overall sleep quality and quantity was better than that reported in more acutely unwell patients managed in ICU. However, significant abnormalities in sleep architecture were still present in a substantial proportion of patients and were associated with clinical severity and alkalosis. Thirdly, two distinct patterns of sleep were seen. The “long sleepers” had sleep predominantly during the daytime. A positive correlation between sleep quantity and the patient’s clinical status was found, such that patients with a higher clinical severity score slept for longer during the day. The authors suggested this may have reflected sleep recovery in patients moved to a less “intensive” care setting. The other group maintained a more normal wake/sleep cycle but had a highly fragmented sleep pattern. These poor sleepers were characterised by a high pH value, although the mechanism accounting for this association was not readily apparent. Unfortunately, as this was cross-sectional data, no information regarding the evolution of sleep recovery or impact on clinical outcomes was available. Sleep quality and non-invasive ventilation Compared to the data evaluating sleep quality in patients with acute respiratory failure requiring invasive ventilation, fewer studies have looked at the impact of noninvasive ventilation (NIV) on sleep parameters in the acute setting. Ozsancak et al [24] monitored four patients using NIV in the ICU over 24-hr with PSG. As seen in invasively ventilated patients, these patients also demonstrated very fragmented sleep with little or no REM sleep. However, whether this was related to factors associated with acute respiratory failure or failure to provide adequate ventilatory support was not established. In patients with stable chronic respiratory failure, the method of titrating settings for NIV can significantly alter sleep architecture and induce sleep fragmentation [25,26]. In a more recent study, 24 patients with acute hypercapnic respiratory failure using NIV underwent continuous PSG monitoring over a 17-hr period in a medical ICU [27]. Although the total sleep time was similar to that previously reported in invasively ventilated patients (around 6 hrs), the amount of SWS and REM sleep recorded was significantly greater at a median of 30 [Interquartile range: 17-46]% and 11 [5.7-17]%, respectively. In addition, sleep quality during NIV was also significantly better than during unassisted spontaneous breathing, with more SWS and REM sleep and less fragmentation. Sleep quality is an important predictor of NIV outcome [12], with marked sleep disturbance in the presence of an abnormal EEG pattern, a disrupted circadian sleep cycle and reduced REM sleep all associated with NIV failure and delirium [21]. However, the direction of this relationship is still unclear. Sleep quality and its impact on acute respiratory failure Not only will the physiological changes in breathing during acute respiratory failure place the vulnerable patient at risk of sleep loss and fragmentation, sleep deprivation in conjunction with normal sleep physiology may exacerbate respiratory failure, potentially worsening outcomes. A reduction in respiratory muscle endurance and lung function has shown to occur even with short periods of sleep loss in healthy subjects [13,15], with potential implications for patients with chronic respiratory disease recovering from an acute illness or weaning from mechanical ventilation. Reduction in ventilatory chemosensitivity from sleep deprivation [15,16] would be an additional factor contributing to worsening ventilation and gas exchange in acute illness. The upper airway becomes more unstable with sleep deprivation [28], and in some patients acute respiratory failure may develop as a consequence of sleep disordered breathing alone [30].

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Appreciating the role acute respiratory failure plays in worsening sleep quality and the implications of altered sleep duration and quality on respiratory function and recovery is important if we are to develop strategies that make a significant difference to clinical outcomes in vulnerable individuals presenting with acute respiratory failure. REFERENCES 1. Nunes DM et al, Actigraphic assessment of sleep in chronic obstructive pulmonary disease.

Sleep Breath 2013;17:125-132 2. Gleeson K, et al. The influence of increasing ventilatory effort on arousal from sleep. Am Rev

Respir Dis 1990;142:295–300. 3. Berthon Jones M, Sullivan CE. Ventilatory and arousal responses to hypoxia in sleeping

humans.1982; Am Rev Respir Dis; 125:632-639 4. Ayas NT, et al. Hypercapnia can induce arousal from sleep in the absence of altered

respiratory mechanoreception. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1004-8 5. Cooper AB, et al. Sleep in critically ill patients requiring mechanical ventilation. Chest

2000;117:809-18. 6. Freedman NS, et al. Abnormal sleep/wake cycles and the effect of environmental noise on

sleep disruption in the intensive care unit. Am J Respir Crit Care Med 2001;163:51-7. 7. Gabor JY, et al. Contribution of the intensive care unit environment to sleep disruption in

mechanically ventilated patients and healthy subjects. Am J Respir Crit Care Med 2003;167:708-15.

8. Elliott R, et al. Characterisation of sleep in intensive care using 24-hour polysomnography: an observational study. Crit Care 2013;17:R46

9. Little A, et al. A patient survey of sleep quality in the Intensive Care Unit. Minerva Anestesiologica 2012;78:406-14

10. Simini B. Patients' perceptions of intensive care. Lancet. 1999;354(9178):571-2. 11. Ehlenbach WJ, et al. Association between acute care and critical illness hospitalization and

cognitive function in older adults. JAMA. 2010;303:763-770. 12. Roche Campo F, et al. Poor sleep quality is associated with late non-invasive ventilation

failure inpatients with acute hypercapnic respiratory failure. Crit Care Med 2010;38:477-85. 13. Chen H-I, Tang Y-R. Sleep loss impairs inspiratory muscle endurance. Am Rev Respir Dis

1989;140:907-9. 14. Phillips BA, et al. The effect of sleep loss on breathing in chronic obstructive pulmonary

disease. Chest. 1987;91:29-32. 15. Cooper KR, Phillips BA. Effect of short-term sleep loss on breathing. J Appl Physiol

1982;53(4):855-8. 16. White DP, et al. Sleep deprivation and the control of ventilation. Am Rev Respir Dis

1983;128:984-6. 17. Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill patients.

Am J Respir Crit Care Med. 2002; 166:1423–1429. 18. Toublanc B, et al. Assist-control ventilation vs. low levels of pressure support ventilation on

sleep quality in intubated ICU patients. Intensive Care Med 2007;33:1148-54. 19. Cabello B, et al. Sleep quality in mechanically ventilated patients: comparison of three

ventilatory mode. Crit Care Med 2008;36:1749-55. 20. Bosma K, et al. Patient-ventilator interaction and sleep in mechanically ventilated patients:

Pressure support versus proportional assist ventilation. Crit Care Med. 2007;35:1048–1054. 21. Roche Campo F, Thille AW, Drouot X, et al. Comparison of sleep quality with mechanical

versus spontaneous ventilation during weaning of critically-ill tracheotomized patients. Crit Care Med. 2013; 41:

22. Andrejak C, et al. Does using pressure-controlled ventilation to rest respiratory muscles improve sleep in ICU patients? Respir Med. 2013;107(4):534-41

23. Fanfulla F, et al. Sleep disturbances in patients admitted to a step-down unit after ICU discharge: the role of mechanical ventilation. Sleep 2011;34:355-362.

24. Ozsancak A, et al. Sleep and mechanical ventilation. Crit Care Clin. 2008;24:517-31

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25. Fanfulla F, et al. Effects of different ventilator settings on sleep and inspiratory effort in patients with neuromuscular disease. Am J Respir Crit Care Med. 2005;172:619-24

26. Adler D, et al. Polysomnography in stable COPD under non-invasive ventilation to reduce patient-ventilator asynchrony and morning breathlessness. Sleep Breath. 2012;16:1081-90.

27. Cordoba-Izquierdo A, et al. Sleep in hypercapnic critical care patients under noninvasive ventilation: conventional versus dedicated ventilators. Crit Care Med. 2013;41:60-8.

28. Persson HE, Svanborg E. Sleep deprivation worsens obstructive sleep apnea. Comparison between diurnal and nocturnal polysomnography. Chest. 1996;109:645-50.

29. Resta O, et al. Sleep-related breathing disorders in acute respiratory failure assisted by non-invasive ventilatory treatment: utility of portable polysomnographic system. Respir Med. 2000;94:128-34.

EVALUATION 1. Sleep in invasively ventilated patients managed in intensive care is generally characterised by

a. increased N3 (slow wave sleep) and reduced REM sleep b. increased total 24-h sleep duration compared to spontaneously breathing patients c. decreased N1 & N2 (Stage I & II sleep) and increased REM sleep d. decreased N3 and REM sleep

2. During weaning from mechanical ventilation following acute respiratory failure

a. noise from the ventilator is a significant cause of sleep fragmentation b. inappropriately adjusted ventilator settings may generate patient-ventilator asynchrony

and poorer sleep quality c. sleep fragmentation is primarily due to ineffective efforts d. sleep quality is significantly worse than during spontaneous breathing

3. Which of the following statements is correct?

a. Environment factors such as noise, light and patient care account for around 70% sleep arousals and awakenings in the ICU

b. Pressure support ventilation is likely to improve sleep quality by providing better patient-ventilator interactions compared to other ventilation modes

c. Central apnea may occur with mechanical ventilation, and is more likely to be seen in patients with heart failure or with overassistance from ventilatory support

d. EEG abnormalities on polysomnography primarily occur in patients requiring invasive ventilation who are septic

4. Which of the following statements is not correct?

a. Late NIV failure is associated with increased SWS duration b. Sleep disturbance may promote delirium and worse clinical outcomes c. Delirium has been associated with NIV failure d. Delirium is a recognised risk factor for death in patients requiring mechanical ventilation


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DOES ACUTE RESPIRATORY FAILURE AFFECT SLEEP?

AMANDA PIPER PhD

Department of Respiratory and Sleep MedicineRoyal Prince Alfred Hospital

CamperdownWoolcock Institute of Medical Research,

University of Sydney, Australia

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http://www.sswahs.nsw.gov.au/rpa/

http://www.slhd.nsw.gov.au/

Faculty disclosure

•

I have received lecture fees from ResMed, Asia Pacific and Respironics, Australia for educational presentations

•

I have received a grant from The ResMed Foundation to look at optimised therapy in Obesity hypoventilation Syndrome

46

DOES ACUTE RESPIRATORY FAILURE IMPACT ON SLEEP?

Yes!

47

DOES ACUTE RESPIRATORY FAILURE IMPACT ON SLEEP?

AIMS

•

To outline factors associated with ARF adversely affecting sleep

•To discuss changes in sleep quality in patients with ARF–Intensive care setting–During weaning and recovery

•

To review the impact of sleep loss on patient outcome

48

CASE SCENARIO

•

74 year old female, COPD, Gold Stage IV

•

Admitted to a Respiratory Medical ward

–

3 day history ↑

SOB and sputum

–

Sleeping poorly; loss of appetite

•

On examination

–

Resp rate 32 bpm; Accessory resp muscle use

–

0.7/1.7L in clinic 2/12 ago

–

ABG on 3L O2

: pH 7.28; PaCO2

– 65mmHg; PaO2

-

64mmHg

–

BMI 27kg/m2

49

WHAT ASPECTS OF HER ACUTE RESPIRATORY FAILURE COULD AFFECT

SLEEP?

50

NORMAL SLEEP

Normal Sleep

TST (hrs) 7‐10

Sleep Efficiency (%) >80%

N1 (%) 2‐5

N2 (%) 45‐55

N3 (%) 15‐20

REM (%) 20‐25

From Kamdar et al, J Intensive Care Med 2012

SLEEP DURING AN ACUTE RESPIRATORY ILLNESS?

51

Drouot et al, Sleep Med Rev 2008

SLEEP QUALITY IN ICU

Total sleep time ↓

or ↔Sleep Efficiency ↓N1 Sleep ↑N2 Sleep ↑N3 Sleep ↓↓REM sleep ↓↓

or 0

Sleep fragmentation(arousals + awakenings)

↑

•

Poorer sleep quality•

Less consolidated sleep

52

IMPACT OF INFECTIVE EXACERBATION ON SLEEP

Dobbin et al, 2005•20 young CF patients cases with acute infective exacerbation of CF•20 case controls•ABGs in cases: PaO2 –

70mmHg; PaCO2 40mmHg

%

53

IMPACT OF INFECTIVE EXACERBATION ON SLEEP

Dobbin et al, 2005•Less efficient sleep

•Neurocognitive function adversely affected

–

Subjectively

•

More sleepy

•

Increased physical and mental exhaustion

•

Reduced general activation

–

Objectively

•

Reaction speed, concentration and concrete reasoning impaired

54

DISEASE-RELATED FACTORS INFLUENCING SLEEP

•

Underlying disease–

Many chronic respiratory disorders –

subjective poor

sleep (Price et al 2013; Fauroux 2012)

–

PSG:

↓

SE, ↑

N1 and ↓

REM (McSharry et al, 2012)

•

Dyspnea –

Impaired nocturnal sleep (Nunes et al, 2013)

•

Altered blood gases–

Impact of hypoxia and hypercapnia on sleep

•

High work of breathing Effort related arousals

•

Medications–

Steroids: ↑

Wakefulness, ↓

N3 and ↓

REM

•

Pre-existing sleep disordered breathing

55

TREATMENT-RELATED FACTORS AFFECTING SLEEP

•

Location of care–

Intensive care units

–

High dependency or step down units

•

Environmental factors–

Noise, light, patient care activities

•

Types and modes of ventilation•

Medications

56

SLEEP QUALITY IN THE INTENSIVE CARE SETTING

STUDY N MV

typeTST(hrs)

SE% N1 N2 N3 REM Ar/Aw(/h)

NORMAL 7‐10 >80 2‐5 45‐55 15‐20 20‐25 ≈

15

Cooper 2000(24‐h)

20 IMV N: 3.0D: 4.0

N: 38D: 25

N: 40D: 43

N: 40D: 33

N: 0D: 15

N: 10D: 9

22

Freedman 2001(24‐h)

22 IMV 8.8 59 59 26 9 6 12 (Ar)

Carbello 2008*(18‐h)

15 IMV 8.56* 43* 8* 63* 19* 10* 29*

Elliott 2013(24‐h)

53 IMV(28)SB (25)

5.143.37

NRNR

2327

7067

<1<1

42

2029

* Median values

57

•

Loss of normal circadian sleep/wake, night/day cycles

•

50% of sleep during the day

•

Severity of sleep disturbance an indicator of poor patient outcome? (Roche-Campo et al, 2010)

SLEEP QUALITY IN THE INTENSIVE CARE SETTING

(Freedman et al, AJRCCM 2001)

58

CONSEQUENCES OF SLEEP DEPRIVATION

•

Impaired neurocognitive function

•

Impaired immune function

–

Impaired defence mechanisms/increased susceptibility to infection (Spiegel et al, JAMA 2002)

•

Hormonal homeostasis

–

Glucose metabolism (Spiegel et al, Lancet 1999)

–

Cortisol and norepinephrine levels

–

Melatonin (Shilo et al, Am J Med Sci, 1999)

•

Altered respiratory function

–

Reduced resp muscle endurance (Chen & Tang, ARRD 1989)

–

Blunted chemoresponsiveness (White et al, ARRD1983)

59

DELIRIUM AND SLEEP QUALITY

•

Delirium

–

Common in ICU patients

–

Associated with higher mortality (Ely et al, JAMA 2004)

•

Sleep deprivation and loss of circadian rhythm may increase risk of delirium

–

Yet to be confirmed

•

Role of REM sleep?

–

Trompeo et al, 2011

•

↓REM gp (11%) vs severely ↓REM gp (1%)

•

Delirium in 1/14 in ↓REM gp and 11/15in severely ↓REM gp

–

Roche-Campo et al, 2010

•

greater circadian sleep-cycle disruption & less REM sleep

60

SLEEP QUALITY AND ACUTE ILLNESS

•

Interpreting EEG signals from PSG difficult

–

Usual patterns and sleep markers often absent

–

Loss K complexes and sleep spindles of N2

–

REM atonia

–

Delta waves during wakefulness (Drouot et al, 2008)

•

‘Atypical’

sleep common (Cooper et al, 2000; Freedman et al 2001; Elliott et al 2013; Roche-Campo 2010)

•

Conventional sleep scoring not possible in ≈

30% of patients (Drouot et al, 2012)

•

Cause and association with clinical outcome unclear (Drouot et al, 2012)

61

CAUSES OF SLEEP DISTURBANCE IN ICU

• Environmental factors–

Noise

–

Light–

Patient care activities

•

Accounts for about 30% of sleep fragmentation (Gabor et al, 2003)

• Other causes for poor sleep quality

62

•

Mechanical ventilation as a source of poor quality sleep

–

Endotracheal tube•

Discomfort, suctioning

•

Anxiety (Bergbom-Engberg,1989)

–

Mode of ventilation–

Level of inspiratory support

–

Patient-ventilator asynchrony

SLEEP IN THE INTENSIVE CARE UNIT

63

MODE OF VENTILATION

Parthasarathy & Tobin (2002)•Mode of MV on sleep consolidation•2-h PSV, ACV or PSV with dead space

•Severely fragmented sleep•Development of central apnea•More likely in patients with heart failure

Pressure support versus assist-control ventilation

64

Toublanc et al, 2007

•20 patients with acute on chronic lung disease•Protocol:

65

•

Over whole night, no difference between modes

•

1st

4-h, ACV

–

Less wakefulness, ↑

Stage 1&2

–

No difference SWS or REM

•

2nd

4-h period, ACV

–

SWS achieved 11% cf 0.3% PSV

Toublanc et al, 2007

66

Carbello et al, 2008•ACV vs cPSV vs aPSV•15 conscious intubated pts•PSG over 3 consecutive 6-h periods

Carbello et al, Crit Care Med 2008

•

Sleep duration, sleep architecture and fragmentation not different between modes

Settings used more important than modePSV and impact on sleep/wake ventilation

67

VENTILATOR SETTINGS

Patient-ventilator asynchrony as a source of sleep fragmentation?

Bosma et al, 2007•PSV vs Proportional assist ventilation (PAV)•13 conscious patients•Set to provide 50% respiratory mm unloading compared to SB

68

From Bosma et al, Crit Care Med 2007

VENTILATOR SETTINGS

•

TST not different•

Overall sleep quality better

•

Fewer asynchronies•

Central apnea in 2 pts PSV

•

Correlation btw asynchronies & arousals

Need to target optimal patient-ventilator interactionsSelection of settings to suit breathing pattern and mechanics

69

Andrejak et al, 2013•Impact of respiratory mm rest using PCV on sleep quality•26 COPD patients•Night prior to extubation

SLEEP DURING WEANING AND RECOVERY

Andrejak et al, Respir Med 2013

•

Improved sleep quality with PCV

•

Advantages during weaning period

70

Roche-Campo et al 2013•Medical ICU•16 tracheostomised pts•

>5hrs spont.

breathing


•

Longer sleep duration with MV•

MV has no adverse impact on sleep quality

71


Fanfulla et al, 2011

•Step down unit: tracheal vs spontaneous ventilation•Sleep indices similar between groups•MV group: ineffective effort index 45+66/h

Asynchrony arousal index 3+5/h

STUDY N MV type TST(hrs)

SE% N1 N2 N3 REM Ar/Aw(/h)

Elliott 2013(24‐h)

53 IMV(28)SB (25)

5.143.37

NRNR

2327

7067

<1<1

42

2029

Fanfulla, 2011(24‐h)

1011

Tracheal ventSpont. breath

10.2110.75

NR 1413

5141

2432

1114

2825

•

MV not a significant factor influencing sleep

72

HOW DOES NIV AFFECT SLEEP QUALITY?

•

74 year old female with COPD

–

ABG on 3L O2 –

pH: 7.28; PaCO2

:

65mmHg; PaO2

: 64mmHg

•

High drive•

Dyspnea

•

High WOB•

Anxiety

•

Hypoxia/hypercapnia•

Cough

•

Medications•

Upper airway resistance/OSA

Ozsancak et al, 2008

73

•

N3 sleep preserved compared to ICU studies•

Circadian rhythm relatively maintained–

74% sleep occurred at night

Crit Care Med 2013

74

•

Sleep quality better with NIV

•

Sleep fragmentation:

–

NIV 26/hr vs SB 39/hr

•

PVA caused 19% of arousals

–

50% of which were IE

•

In 8/15 patients, AHI>10 evts/hr

Crit Care Med 2013

75

POOR SLEEP QUALITY AND NIV OUTCOME

Roche-Campo et al, 2010•Relationship between sleep disturbance on NIV and late NIV failure•PSG performed 2nd

– 4th

night NIV

•

Markedly different sleep patterns between groups

•

More sleep-wake cycle disruption NIV failures & reduced REM sleep

•

Subsequent development of delirium

Roche-Campo et al, Crit

Care Med 2010

76

SLEEP AND ACUTE RESPIRATORY FAILURE

ACUTERESPIRATORY

FAILURE

SLEEPPHYSIOLOGY

↓

neural output↓

responsiveness-

chemoreceptors-

mechanoreceptorsChanges lung mechanics

High WOBGas exchangeSleep disruption

SLEEP DISORDERED BREATHING

SLEEP DISORDERED BREATHING

77

CONCLUSION

•

Sleep

quality

is

significantly

altered

by ARF

–

Worsened

by disease

severity

and acuity

–

Markedly

reduced

N3 and REM sleep

–

Altered sleep-wake cycle

•

Cause is

multifactorial

–

Ventilation therapy

a potential

reversible

contributor

•

Difficulties

interpreting

and scoring

EEG signals

•

Abnormal

sleep

quality

–

A predictor

of NIV failure

–

Development

of delirium

78

What hath night to do with sleep? John Milton, Paradise Lost

What hath night to do with sleep? John Milton, Paradise Lost

Impact of abnormal sleep/wake cycles and reduced REM

•

NIV failure•

Development of brain dysfunction/delirium

Greater attention to promoting better sleep opportunities for improved outcomes

79

Prevention and treatment of sleep disturbances in acute respiratory failure: the role of drugs

Dr Cesare Gregoretti

Ospedale Maria Adelaide Lungo Dora Firenze, 87

10153 Turin Italy

[email protected] SUMMARY Many studies conducted over the last years have shown sleep disturbances in critical care area. Patients in the critical care environment experience severe sleep alterations including reductions in sleep stages, marked sleep fragmentation, circadian rhythm disorganization, and daytime sleepiness. Among the numerous sources of these sleep alteration there are both endogenous factors such as patient’s underlying disease severity and exogenous factors such as medications (sedatives, analgesics& other drugs). Prevention of sleep disturbances may include several interventions including use of sleep-promoting pharmacologic agent and minimizing use of pharmacologic agents inhibiting sleep. ICU medications may affect sleep architecture generating sleep disturbances even for 6–12 months after ICU discharge. Opioids Pain disrupts sleep. Although opioids, are considered a mainstay for postoperative and ICU pain they are often mistakenly considered inducers of physiological sleep. Opiods suppress REM and slow waves sleep (SWS) stage. Opioids inhibit sleep, mediated by the mu receptor, at doses of >10 mg/h/d (morphine equivalent) especially SWS and REM sleep without affecting the circadian pacemaker distribution of REM sleep. Withdrawal of REM stage may be associated with high percentage of REM sleep rebound. If opioids are titrated and withdrawn gradually the likelihood of REM rebound should theoretically be less important However taking a message from studies performed outside the ICU pain relief may counterbalance negative effects on sleep disorders. Sedatives Sedation and sleep share similarities: a reversible decrease in vigilance; a reduced metabolic rate and muscle hypotonia. In contrast to sedation, sleep is a spontaneous behavior that can be reversed by external stimuli; is organized in cycles of different depths; tarts and stops in response to endogenous mechanisms; is regulated by complex homeostatic and circadian factors. Benzodiazepine (BZD) and propofol interact with the gamma-aminobutyric acid (GABA) receptor. Dexmedtomidine and clonidine interact with alpha-2 receptors in the locus ceruleus. BZD increase NREM sleep, cause a mild reduction of REM sleep but alter sleep architecture by severely decreasing SWS. BZD have also a delriogenic effect. However In patients whose anxiety might lead to significant sleep disruption, BDZ should be theoretically beneficial (i.e.single shot for night-time sleep) in association with a non-BZD hypnotic agent. Propofol seems not affecting REM sleep leading to a slow wave activity that mimics slow wave sleep. However its effect on REM stage are stiil contradictory. In sleep deprived patients low doses could restore night-sleep with “possible similar” sleep pathway However, propofol may have negative effects on circadian rhythm because circadian variations in core body temperature exert a powerful regulatory effect on sleep rhythms. Sedation with alpha-2 agonists A2A appear to act through the endogenous sleep-promoting pathways differently from that of GABAminergic agents. The locus ceruleus (LC), a modulator of

80

wakefulness, has one of the highest concentrations of the A2A. The REM-suppressant activity of A2A seems to be dose dependent. A2A increases in percentage SWS, and stage II based on an increase in spindle activity. Dexmedetomidine should lead to a state with clinical features similar to natural sleep It seem having less delirioregic effect compared to BZD. Unfortunately, the theoretical advantages have not been demonstrated to improve patients’ perception of their sleep in the ICU Neuromuscular blocking agents There is a paucity of literature on this issue. There are not clear evidence on patients receiving NMBA and sedation on sleep disturbances. Sleep & Typical/Atypical Antipsychotics Haloperidol, has been associated with increased sleep efficiency and stage II sleep with a very small or none effect on SWS in healthy volunteers. Olanzapine and risperidone, are used in the ICU for their sedating effects. They increase total sleep time, sleep efficiency, and SWS in healthy volunteers and schizophrenic patients. Sleep & Sleep promoting agents Zolpidem and zopiclone belonging to Non-BZD hypnotic agents interact with the γ-aminobutyric acid receptor complex at domains close or allosterically coupled to BZD receptors. They little suppress REM sleep and have no effect on SWS. Other medications Inotropic agents, affect sleep quality through their effects on adrenergic receptors. Beta blockers, may cause insomnia and nightmares due to suppressed SWR and REM sleep. High-dose of corticosteroids therapy causes decreased SWS and REM sleep. H2-receptor antagonists and the proton pump inhibitors may cause insomnia. Quinolone antimicrobial agents seems to cause sleep disturbances. A receptor inhibition Tricyclic antidepressants and serotonin reuptake inhibitors prolong SWS and totally or partially abolish REM sleep. Nocturnal melatonin suppression in ICU patients can be influenced by numerous factors such as age, BZD, adrenergic compounds, beta-blockers, opiates, light exposure, sedation, mechanical ventilation and sepsis. There is currently insufficient evidence that exogenous melatonin is effective in preventing or treating postoperative delirium. Conclusions Sedatives and analgesics should be tailored to the perceived patient’s needs or objective scale assessment, according to their PK and PD with attention to the potential causes of sleep disruption. However there has never been a sedation algorithm studied specifically for its effects on sleep. Single dose BZD may favour sleep in anxious patients. Non intubated patients with difficulty sleeping may be able to sleep with the aid of a short-acting hypnotic such as zolpidem or typical/atypical antipsychotics. Propofol has interesting features but caution must be taken in spontaneous breathing patient due to risk of drug accumulation. Dexmedetomidine would also have interesting properties in both intubated and spontaneous patients but further studies are needed. Further investigation may help to elucidate any sedation/analgesia strategy with regard to its effects on sleep. REFERENCES 1. Parthasarathy S, Tobin MJ Sleep in the intensive care unit. Intensive Care Med 2004;30:197–

206. 2. Bourne RS, Sleep disruption in critically ill patients: Pharmacological consideration.

Anaesthesia 2004; 59:374 –384 3. Lydic R, Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state

control. Anesthesiology 2005; 103:1268–95

81

4. Hardin KA, Seyal M, Stewart T, et al: Sleep in critically ill chemically paralyzed patients requiring mechanical ventilation. Chest 2006; 6:1468–1477

5. Bourne at al Melatonin: possible implications for the postoperative and critically ill patient 6. Intensive Care Med 2006; 32:371–379 7. Drouot X, Belen CabelloB, d’Ortho MP, Brochard L Sleep in the intensive care unit Sleep

Medicine Reviews 2008; 12:391-403 8. Friese RS Sleep and recovery from critical illness and injury: A review of theory, current

practice, and future directions. Crit Care Med 2008; 36:697–705 9. Bonafide PB, Aucutt-Walter N, Divittore N et al Remifentanil Inhibits Rapid Eye Movement

Sleep but Not the Nocturnal Melatonin Surge in Humans Anesthesiology 2008; 108:627–33 10. Weinhouse GL, Watson PL Sedation and sleep disturbances in the ICU. Crit Care Clin 2009:

25:539–549. 11. Frank L, Tourtier JP, Libert N, Grasser L, Auroy Y How did you sleep in the ICU? Crit Care

2011;5:408. EVALUATION 1. Do opioids supress REM sleep?

a. Never b. Only when sedatives are associated c. Only in elderly people d. Yes in a dose dependent way

2. Is there a rationale for using propofol in an intubated patient with sleep deprivation?

a. Yes b. Never c. Only in young people d. Only if a benzodiazepine is associated

3. Is there a rationale for using small dose of haloperidol in a non invasive ventilated patient

complaining of sleep deprivation? a. Yes if there are not contraindications b. Never c. Yes always d. Only if a benzodiazepine is associated

4. Do benzodiazepines alter slow waves sleep (SWS)?

a. Yes b. Never c. Only at very high dosage d. Only if an opioid is associated


82

PREVENTION AND TREATMENT OF SLEEP DISTURBANCES IN ACUTE

RESPIRATORY FAILURE: ROLE OF DRUGS

C. Gregoretti (Turin, Italy)

83

Faculty disclosure

• Received fee for consultancy

or lectures by:• Covidien• Breas (GE)• ResMed • Philips• Smiths Medical Ind

84

IntroductionAIMS

• Aim 1: analysing and understanding the effects of Analgesics & Sedatives & neuromuscular blocking agents (NMBA) on sleep

• Aim 2 : analysing and understanding the effects of other medications on sleep

85

CLINICAL SCENARIO

A

18‐year 70 Kg immunosuppressed man is admitted to the ICU with an ARDS consecutive to bacterial pneumonia.

He is rapidly noninvasively ventilated Two hours after he is complaining for discomfort and he feels

uneasy and agitated. Midazolam is started at 0.015 mg/kg /h targeted to a RASS 0/‐

1

The day after he is complaining for not being able to fall

asleepMidazolam is increased night time at 0.03 mg/kg /h The morning after the patient is drowsy (RASS ‐3).At noon he is intubated

86

CLINICAL SCENARIO

A 58‐year 68 Kg man is admitted to the ICU with an exacerbation of COPD & bacterial pneumonia.

NIV fails and he is orally intubated Propofol 1 mg/kg /h is started with morphine 0.015mg/kg/htargeted to a RASS ‐1The day after the nurse reported an agitated night (RASS +1) with

the patient not being able to fall asleepThe morning after Midazolam is added at 0.015mg/kg/hTwo day later the patient has a CAM‐ICU positive for delirium

87

• Analgesic request not yielding to the expected pain relief

Simini B (1999) Lancet : 354: 571-572

94 %

63 %• Anxiety

• Isolation

• Pain

• Lack of information

62 %

46 %

43 %

33 %

• Sleep deprivation

ICU & Sleep

88

• Sleep deprivation may be pathogenically involved in the development of delirium Elyy W Jama 2004; Helton MC, Heart Lung 1980; Heller SS. N Engl J Med 1970., Figueroa- Ramos M Intensive Care Med 2009; Weinhouse GL, Watson PL Crit Care 2009; Sanders RD Can J Anesth 2011;

• Benzodiazepines may induce deliriumPandharipande P et al..Anesthesiology 2006

• ICU medications may affect sleep architecture generating sleep disturbances even for 6–12 months after ICU discharge. Weinhouse GL, Watson PL Crit Care 2009; Frank L, et al Crit Care 2011 Parthasarathy S, Tobin MJ Care Med 2004 ;Eddleston JM et al. Crit Care Med 2000

ICU & Sleep

89

REM, SWS

NE

REM, SWS

REM

TST, SE

Insomnia, REM, SWS

Insomnia, REM, SWS

Insomnia, REM, Nightmares

Nightmares

Insomnia, REM, SWS

Insomnia, REM, SWS, TST, SE

Insomnia

REM

REM, TST, SE

Sleep Fragmentation

REM

REM

Benzodiazepines

Propofol

Opioids

Clonidine

Non steroidal anti-inflammatory ag.

Norepinephrine ⁄

Epinephrine

Dopamine

b-Blockers

Amiodarone

Corticosteroids

Aminophylline

Quinolones

Tricyclic antidepressants

Selective serotonin reuptake inhib.

Phenytoin

Phenobarbital

Carbamazepin

Υ

aminobutyric acid type A receptor stimulation

Υ

aminobutyric acid

μreceptor stimulation

a2 receptor stimulation

Prostaglandin synthesis inhibition


D2 receptor stimulation ⁄


Central nervous system b-blockade

Unknon mechanism

Reduced melatonin secretion

Adenosine receptor antagonism

Υ

aminobutyric acid type A receptor inhibition

Antimuscarinic activity and a1 receptor stimulation

Increased serotonergic activity

Inhibition of neuronal calcium influx

Increased gamma aminobutyric acid type A activity

Adenosine receptor stimulation and ⁄

or serotonergic activity

Drug Class or Individual Drug Sleep Disorder Induced or Reported Possible Mechanism

Modified by Bourne RS et al Anaesthesia, 2004, 59: 374–384

SLEEP & MEDICATIONS

90

Sleep & ICUPrevention of its disturbance

● Noise reduction ● Diurnal lighting practices ● Use of sleep-promoting pharmacologic agent ● Minimizing use of pharmacologic agents inhibiting sleep ● Uninterrupted time for adequate sleep ● Appropriate physiologic support ● Active promotion of patient orientation ● Patient-ventilator synchrony ● Relaxation techniques

Parthasarathy S, Tobin MJ Intensive Care Med 2004 30:197–206. Friese RS Crit Care Med 2008; 36:697–705

91

• Pain disrupts sleep.Cohen MJM Rev Psychiatry 2000;12:115–27; Pilowsky IPain 1985;23:27–33;

Roehrs T, Roth T. Semin Neurol 2005; 25:106–16; Sabatowski R, Pain 2004; 109:26–35; Power JD. Arthritis Rheum 2005; 53:911–9; Friese RS, J Trauma. 2007;63:1210–1214.

• Poor sleep leads to a more painful procedures the following day Raymond et al. Pain 2001;92:381–8.

• Opioids, are a mainstay for treating pain in the postoperative and ICU setting but are often mistakenly considered inducers of physiological sleep.

Lydic R Anesthesiology 2005; 103:1268–9; Friese RS Crit Care Med 2008; 36:697–705

Sleep & Analgesics

92

• Analgesic request not yielding to the expected pain relief

Simini B Lancet 1999; 354: 571-572

94 %

63 %• Anxiety

• Isolation

• Pain

• Lack of information

62 %

46 %

43 %

33 %

• Sleep deprivation

Sleep & Analgesics

93

• Opioids inhibit sleep, mediated by the mu receptor, at doses of >10 mg/h/d (morphine equivalent) especially SWS and REM sleep without affecting the circadian pacemaker distribution of REM sleep

• Opioids act on the ponto-thalamic arousal pathway most active in REM generation rather than the hypothalamic pathway more affected by the GABA agonists.

Saper CB et Nature 2005;437:1257–63; ;Keifer JC, et al Anesthesiology 1992;77:973–8; . Dimsdale JE,et al.. J Clin Sleep Med 2007;3:33–6 ; Kay DC Psychopharmacologica (Berl) 1968; 14:404–16

Sleep & Opioids

94

Sleep & Opioids • Is opioid administration or opioid withdrawal that

affects sleep ?• Hypothesis: an overnight infusion of remifentanil (0.01–0.04 mcg .kg

.m) inhibits REM sleep

Bonafide et al Remifentanil Inhibits Rapid Eye Movement Sleep but Not the Nocturnal Melatonin Surge in Humans Anesthesiology 2008; 108:627–33

Remifentanil reduced by 53% SWS and by 72% REM sleep time.

95

• In a RCT , in Patients with osteoarthritis and pain, opioids were able to improve sleep quality, including subjects’ overall perception of sleep quality.

Caldwell JR, et al. J Pain Symptom Manage 2002;23:278–91.

• In a RCT randomized patients who receive either fentanyl or bupivacaine through an epidural catheter found no statistically significant differences between subjects’ sleep quality between the two drug

Cronin AJ et al.. Sleep 2001;24:39–44.

Sleep & Opioids

• Is opioid administration able to ameliorate patient’s subjective perception of sleep quality outside the ICU ?

96

TAKE HOME MESSAGE • Opiods suppress REM stage and SWS in a dose dependent

way

• Withdrawal of REM stage may be associated a REM sleep rebound

• If opioids are carefully used, titrated and withdrawn gradually the likelihood of REM rebound should theoretically be less important

• Taking a message from patients treated with opioids outside the ICU, pain relief may counterbalance negative effects of opioids on sleep architecture

97

• Sedation and sleep share similarities:– a reversible decrease in vigilance,– a reduced metabolism, – muscle hypotonia. • In contrast to sedation, physiologic sleep:

– can be reversed by external stimuli.– is organized in well defined cycles – starts and stops in response to endogenous mechanisms,– is regulated by complex homeostatic and circadian factors.

Lydic R, Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 2005; 103:1268–95.

SLEEP & SEDATIVES

98

They exert their sedative effect on the a-1-GABAA receptor subunit inducing :

1.a dose-dependent increase in NREM sleep,

2. a mild reduction of REM sleep, a potent suppression of slow waves sleep (SWS)

Borbely AA, Hum Neurobiol 1985; Aeschbach D et al 1994;; Billard V Clin Pharmacol Ther 1997; Tan X, Psychiatry Clin Neurosci 86. 2003;Bourne RS Anaesthesia 2004;

Sleep & Benzodiazepine

99

• Hypothesis: Daily Sedation (DSI) Interruption may affects sleep characteristics.

• 22 MV pts under midazolam infusion were randomly assigned to DSI or Continuous Sedation (CS) (target Ramsey night‐time 4 to 5)

• All mechanically ventilated patients demonstrated abnormal sleep architecture, but, compared with CS, DSI increased the amount of slow wave sleep and rapid eye movement sleep

Oto et a lEffect of daily sedative interruption on sleep stages

of mechanically ventilated patients

receiving midazolam by infusion. Anaesth Intensive Care. 2011 ;39:392‐400.

Sleep & Benzodiazepine• Does BDZ blood concentration influence sleep ?

100

Benzodiazepines & Delirium

MICU/SICU patientsventilated and sedated

Controllorazepam (GABA)± fentanyl

Interventiondexmedetomidine (α2)

± fentanyl

Duration of Dexmedetomidine infusion up to 5 days or 120 hours

Doses of Dexmedetomidine up to 1.5 mcg/kg.hr

Pandharipande et a l JAMA, 2007101

TAKE HOME MESSAGE

• BZD increase NREM sleep but severely decrease in a dose dependent way SWS with a mild reduction in REM stage

• Benzodiazepines have a deliriogenic effect

• However In patients whose anxiety might lead to significant sleep disruption, BDZ should be theoretically beneficial (i.e. single shot for night-time sleep) in association with a non-BZD hypnotic agents,

102

• Propofol binds to the GABAA receptor at a site distinct from the benzodiazepines’ binding site

• Propfol leads to slow wave activity that mimics slow wave sleep

• Propofol seems not affecting REM sleep but results are contradictory

Sleep & Propofol

Hales TG, Lambert JJ. Br J Pharmacol 1991;104:619–28.; Kuizenga K, et al Br J Anaesth 2001;86:354–60; Ozone M,, et al. Clin Neurosci 2000;54:317–8; Koskinen M et al . Clin Neurophysiol 2005;116:2069–76; Drouot X et al Sleep Medicine Reviews 2008 ;12:391-403 Rabelo FA et al Laryngoscope. 2013 ;123:2300-5.; Kondili E et al Intensive Care Med 2012; 38:1640–1646

103

• Objective: to assess and compare the impact of overnight sedation with midazolam or propofol on anxiety and depression levels, as well as sleep quality,.

• Design: Open, comparative, prospective, randomised study.

• Patients: 40 conscious patients expected to stay in the ICU for at least 5 days who were admitted following trauma or elective orthopaedic, thoracic or abdominal surgery.

• Methods The bolus was given at 10.00 p.m. on the day of admission and the continuous infusion was stopped at 6.00 a.m., for 5 consecutive nights. The infusion rate were adjusted to maintain a Ramsay 3 scoreMorphine was given intravenously or provided via an extradural catheter

Sleep & Propofol

Treggiari-Venzi M et al Intensive Care Med 1996; 22:1186-1190

104

Midazolam (0.01 -0.07 mg/kg) plus IV a continuous infusion at a 0.03-0.2mg/kg/h) Propofol (0.2-0.3 mg/kg) plus IV continuous infusion at a rate of 0.3- 3 mg/kg /h).

•Conclusions The beneficial effects of sedation on sleep quality were comparable for midazolam and propofol, regardless of a lack of improvement in anxiety and depression.

Sleep & Propofol

Treggiari-Venzi M et al Intensive Care Med 1996; 22:1186-1190

105

• In healthy humans, a 1-h propofol infusion at 2.00 p.m.(during TIVA ) increased sleep latency during the subsequent night compared to a control but distributions of stage 3 and 4 and the rapid eye movement and 'REM' stage were not changed.

• This suggests that propofol sedation may subserve a function that overlaps with sleep

Sleep & Propofol

Ozone M et al. Changes in subjective sleepiness, subjective fatigue and nocturnal sleep after anaesthesia with propofol. Psychiatry Clin Neurosci 2000;54:317–8.

106

RC double-blinded trial evaluating sleep quantity and ìquality in ICU patients receiving either propofol (continuous infusion at 2 mg/kg/h) or flunitrazepam as a bolus dose (0.015 mg/kg)

Engelmann C et al Propofol versus flunitrazepam for inducing and maintaining sleep in postoperative ICU patients Indian J Crit Care Med. 2014; 18: 212–219.

Propofol for promoting and maintaining night sleep in ICU patients who are not analgo- sedated was superior to flunitrazepam regarding sleep quality and sleep structure.

Sleep & Propofol

107

Kondili et al Effects of propofol on sleep quality in mechanically ventilated critically ill patients: a physiological study Intensive Care Med 2012; 38:1640–1646

Sleep & PropofolRC cross-over trial to assess sleep in 12 mechanical ventilated (MV) ICU patients patients with or without propofol)

Propofol administration to achieve the recommended level of sedation (ramsay 3) su pressed the REM sleep stage and further worsens the poor sleep quality of these patients.

108

•RCT , double‐blind, placebo‐controlled (103 pts with chronic primary insomnia (CPI)

•Hypothesis

: propofol anaesthesia is beneficial in restoring sleep •The Leeds Sleep Evaluation Questionnaire and PNS were used for sleep

assessment •A 2‐h continuous IV of propofol for 5 consecutive nights improved the

subjective and objective assessments of sleep in 64 patients. This improvement occurred immediately after the therapy and persisted

for

6 months. No serious adverse events were noticed

Xu Z et al Propofol‐induced sleep: efficacy and safety in patients withrefractory chronic primary insomnia Cell Biochem Biophys. 2011l;60:161‐6

Sleep & PropofolTake a a message from outside the ICU & animal studies

109

• Rats sedated with propofol during normal sleep time did not show signs of sleep deprivation

Sleep & Propofol

Tung A et al Prolonged sedation with propofol in the rat does not result in sleep deprivation. Anesth Analg 2001;92:1232–6.

• After 24 hours of sleep deprivation, recovery sleep was no different infusing 6 h of propofol compared with normal recovery

sleep, indicating that the normal homeostatic control of sleep may occur.

Tung A, et al Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology 2004;100:1419–26.

• Sleep deprivation in rodents not only potentiates anesthesia but also delays recovery.

Tung A, et a lSleep deprivation potentiates the onset and duration of loss of righting reflex induced by propofol and isoflurane. Anesthesiology 2002;97(4):906–11

110

TAKE HOME MESSAGE

• Propofol seems not to alter SWS and . Effect on REM sleep is still not well defined

• In sleep deprived patients low doses could restore night‐sleep with “possible similar”

sleep pathway

• However , propofol may have negative effects on circadian rhythm because circadian variations in core body temperature exert a

powerful regulatory effect on sleep rhythms Challet E, eta lNeuropsychopharma‐cology 2007;32:728–35;. Gilbert SS, Sleep Med Rev 2004;8:81–93.

111

• Sedation with A2A appear to act through the endogenous sleep- promoting pathways on locus ceruleus (LC) which reduces norepinephrine release and thereby disinhibits the ventrolateral preoptic area (VLPO ) neurons that inhibit the arousal pathways

• NREM sleep : A2A increases in percentage SWS, and stage II based on an increase in spindle activity.

• REM sleep: the REM-suppressant activity of A2A seems to be dose dependent

Sleep & Apha2‐agonist (A2A

)

Autret A Eur J Clin Pharmacol. 1977 ;12:319-22 Carskadon MA. Sleep. 1989 ;12:338-44; Gentili A Eur J Clin Pharmacol. 1996;50(463-5. Nelson LE , et al..Anesthesiology 2003;98:428–36; ;Coull et al. Neuroimage 2004 Mallick BN Brain Res. 2005 Mar 7;158:9-21;; 52: 289-9 Maksimow et al. Acta Anaesthesiol Scand 2007; 51: 22-30;; 22:315-22; Huupponen et al. Acta Anaesthesiol Scand 2008

112

Sleep & Apha2‐agonist (A2A

)

Analysis of sleep spindles shows that dexmedetomidine produces a state closely resembling physiological S2 sleep in humans, which gives further support toearlier experimental evidence for activation of normal NREM -promoting pathways

Huupponen E Acta Anaesthesiol Scand 2007113

Oto J et al Sleep quality of mechanically ventilated patients sedated with dexmedetomidine Intensive Care Med 2012, 38:1982–1989

SLEEP & APHA2‐AGONIST (A2A

)

In mechanically ventilated patients, nighttime infusion of dexmedetomidine preserved the day‐night cycle of sleep but induced severely disturbed sleep

architecture without evidence of SWS or REM sleep.

114

TAKE HOME MESSAGE

• Dexmedetomidine interacts with the natural sleep pathway at a site farther upstream than the GABA agonists and should

lead to

a state with clinical features similar to natural sleep

• Dexmedetomidine seems having less delirioregic than BDZ Pandharipande et al JAMA, 2007

• Unfortunately, the teoretical advantages have not been demonstrated to improve patients’

perception of their sleep in

the ICU

• Further studies need to confirm these data

115

Sleep & NMBA

Hardin K et al: Sleep in critically ill chemically paralyzed patients requiring mechanical ventilation. Chest 2006; 6:1468 –1477

•18 pts were classified into three groups based on medication regimen determined a priori: 1) intermittent sedation (IS): 2) continuous sedation (CS) and 3) CS and an NMBA.

•Although patients receiving NMBA were sedated, they were shown to be awake by EEG criteria 22% of the time.

•REM sleep could not be detected in the patients receiving NMBAs and was reduced in the other two groups (3.5%).

116

• Haloperidol, has been associated with increased sleep efficiency and stage II sleep with little or none effect on

SWS in healthy volunteers.

• Olanzapine and risperidone increase total sleep time, sleep efficiency, and SWS in healthy volunteers and

schizophrenic patients

Pandharipande P et al. Anesthesiology 2006;104:21–6; Akerstedt T, et al J Sleep Res 1997;6:221–9; Gimenez S et al. Psychopharmacology 2007;190:507–16. .

TYPICAL/ATYPICAL ANTIPSYCHOTICS

SLEEP & OTHER MEDICATIONS

117

SLEEP & SLEEP PROMOTING AGENTS

• Non-BZD hypnotic agents (zolpidem & zopiclone) interacting with the γ-aminobutyric acid receptor complex at domains close or allosterically coupled to BZD receptors, do not affect SWS (even increase) and have a less suppressive effect on REM sleepMerlotti L, et al:. J Clin Psychopharmacol 1989; 9:9 –14


• Zolpidem has been found to decrease the number of nocturnal awakenings, decrease sleep latency, increase total sleep time, and improve sleep qualityHerrmann W, al. J Int Med Res 1993;21:309–22; Maarek L et al.. J Int Med Res 1992;20:162–70

118

Armour et al A Randomized, Controlled Prospective Trial of Zolpidem and Haloperidol for Use as Sleeping Agents in Pediatric Burn Patients(J Burn Care Res 2008;29:238–47

Zolpidem minimally increased the proportion of 3/4 and REM but not TST Haloperidol significantly increased and stage 2 sleep vs control nights. Although sleep was somewhat improved by each tested drug, there were no statistically significant differences between the two drugs

RCT

zolpidem (0.5 mg/kg, to a maximum of 20 mg) or haloperidol (0.05 mg/kg to a maximum

of 5 mg)

SLEEP & OTHER MEDICATIONSSLEEP PROMOTING AGENTS

119

Bourne at al Melatonin: possible implications for the postoperative and critically ill patient ntensive Care Med (2006) 32:371–379

MELATONIN• Nocturnal suppression in ICU patients can be influenced by

numerous factors such as age, BZD, adrenergic compounds, beta‐ blockers, light exposure, sedation, MV and sepsis. .

Mundigler G,. Crit Care Med 2002;30:536–40; Frisk U, Clin Sci (Lond) 2004;107:47–53; Claustrat B, Brun J. Sleep Med Rev 2005;9(1): 11–24; Karkela J et al . Acta Anaesthesiol Scand 2002; 46:30–6; Olofsson K,. Acta Anaes thesiolScand 2004;48:679–84; Hu et al. Critical Care 2010, 14:R66


Drug group/drug

Proposed mechanism

Effect on melatonin

serum concentration

Local anaesthesics

Inhibition of protein kinase COpioids

Opioid‐mediated increase in NATBeta‐blockers

CNS β1

‐receptor blockadeBenzodiazepines

GABA receptor agonismCorticosteroids

Decreased NAT activityCalcium channel blockers (dihydropyridine)

Decreased NAT activityNonsteroidal anti‐inflammatory drugs

Inhibition of prostaglandin synthesisClonidine

α2

receptor agonismSodium valproate

Increased GABA levels

120

Bonafide e tal Remifentanil Inhibits Rapid Eye Movement Sleep but Not the Nocturnal Melatonin Surge in Humans Anesthesiology 2008; 108:627–33

• Hypothesis: an overnight infusion of remifentanil (0.01–0.04 mcg .kg .m) inhibits REM sleep and melatonin secretion.

• Administration of melatonin did not ameliorate the opioid induced sleep disturbance.

MELATONIN


121

• Shilo et al. assessed melatonin excretion and and exogenous administration carrying out an actigraphic sleep analysis Compared with controls (GW), the nocturnal peak of melatonin secretion was absent in ICU patients. Treatment group improved both the duration and quality of sleep

Shilo L et al (1999). Am J Med Sci 317:278–281 Shilo L, et al (2000) Chronobiol Int 17:71–76

• Melatonin given at 10-mg may produce supra-physiological morning plasma levels in ICU patients, possibly negating some of the phase-advancing effects of nocturnal administration.

Bourne RS. Crit Care 2008;12:R52.

MELATONIN


122

SLEEP & OTHER MEDICATIONS• Inotropic agents, affect sleep acting on adrenergic receptors

• B‐blockers, may tsuppresse SWR and REM ( (inmsomnia &nightmares)

• H2 antagonists and the proton pump inhibitors can cause insomnia. • Corticosteroids at high‐dose ,cause decreased SWS and REM sleep

• Quinolone antimicrobial agents have been reported to cause sleep• disturbances via Υ‐aminobutyric acid type A receptor inhibition

• Tricyclic antidepressants and serotonin reuptake inhibitors prolong slow wave sleep and totally or partially block REM sleep

Bourne RS, Anaesthesia 2004; 59:374 –384 Cove-Smith JR Eur J Clin Pharmacol 1985; 28:69 –72 Unseld E et al: Br J Clin Pharmacol 1990; 30:63–7 Wilson S,Drugs 2005;65(7): 927–47.

123

TAKE HOME MESSAGE

•Avoid whenever possible inotropic agents as well as corticosteroids and beta-blockers

•Typical and Atypical antipsychotics have been used off-label to promote sleep . However the latter have not been tested in the critically ill and the adverse effect and safety profiles of all antipsychotics must be

taken into

account

•Zolpidem could be an interesting agent to promote sleep in ICU in conscious not intubated patients patients

•There is currently insufficient evidence that exogenous melatonin is effective in preventing sleep disturbances in ICU

Bourne RS Intensive Care Med (2006) 32:371–379 ;;Bellapart J British Journal of Anaesthesia 2012; 108 (4): 572–80

124

CLINICAL SCENARIO 1

Midazolam is increased night time at 0.03 mg/kg /h Why do not try to switch from midazolam to dexmedetomidine or use propofol

just night time (ie from 10 pm to 6 am) ? Why do not try to use night time zolpidem ?

CLINICAL SCENARIO 2

Midazolam is added at 0.015mg/kg/h Why increase midazolam day time ? Why do not simply increase propofol from 10 pm to 6

am ?

Why do not use a small dose of haloperidol (i.e at 10 am) if not contraindicated ?

125

CONCLUSION 1

• Sleep disturbances include also exogenous factors such as medications, sedatives and analgesics.

• Sedatives and analgesics should be tailored to the perceived patient’s needs or objective scale assessment , according to their PK and PD with attention to the potential causes of sleep disruption

• However there has never been a sedation algorithm studied specifically for its effects on sleep.

126

CONCLUSION 2• BZD may disrupt sleep and cause delirium but a single

dose of short-acting BZD may favour sleep in anxious patients

• Non intubated

patients sleep may be theoretically facilitated with the aid of a short-acting hypnotic such as zolpidem

or a typical/atypical antipsychotics

• Propofol

has interesting features but its effect on REM sleep is still debated

• Dexmedetomidine

would also have interesting properties in both intubated

and not intubated

patients but further

studies are needed127

Prevention and treatment of sleep disturbances in acute respiratory failure: the role of noninvasive ventilation

Dr Mark W. Elliott

Respiratory Medicine St James’s University Hospital

Beckett Street Leeds LS9 7TF

United Kingdom [email protected]

AIMS To understand • How application of NIV might impact upon sleep quality • Why this might be important • Taking application of NIV in the (acute) situation to the next level SUMMARY Disrupted and restricted sleep adverse effect of well-being and predispose to chronic medical problems. It has long been recognised that critically ill patients, particularly those undergoing mechanical ventilation, have poor sleep quality. Sleep deprivation may have a number of adverse consequences, which theoretically could impact upon ICU outcome. For instance broken sleep architecture may be associated with delirium and this may have an adverse effect upon the application of non-invasive ventilation (1). There are number of factors which may adversely affect sleep quality in acutely ill patients. General ward noise associated with the care of other patients, regular sleep disruption for the delivery of nursing care, including monitoring, disruption to the day / night routine, medication and illness severity. This presentation will focus upon how the application of mechanical ventilation may impact upon sleep quality. Patients presenting to hospital with acute on chronic respiratory failure are often chronically sleep deprived. In some patients once effective ventilation is applied, and the effort of breathing against an increased load reduced, patients quickly fall asleep. Theoretically this could have an adverse effect on ventilation as REM rebound may occur, leading to increased upper airway obstruction, reduced inspiratory drive to breathe and facial atonia, leading to mouth leak. Assisted ventilation may affect sleep quality through a number of mechanisms: patient ventilator asynchrony, central apnoeas due to over ventilation, inadequate ventilatory support and air leaks. Noise from the machine and due to airflow through and around the interface, may also be disruptive. Different factors to be considered include ventilator mode, settings and interface issues. Fanfulla et al (2) compared two groups of patients on a respiratory step down unit. Patients underwent 24-hour EEG recording. Sleep amount of quality was no different in those admitted for monitoring (breathing spontaneously) and those receiving tracheostomy ventilation. A significant proportion however had reduced sleep efficiency. Total sleep time and efficiency was reduced in those with more severe illness and a higher pH was correlated with reduced sleep quantity and quality. Mechanical ventilation per se did not appear to be a primary cause of sleep impairment. Patient ventilator asynchrony is known to reduce the tolerance and effectiveness of ventilation both invasive and non-invasive. It prolongs weaning and is associated with impaired sleep quality. Causes are multifactorial including ineffective efforts, prolonged cycling and auto triggering and each can lead to discomfort during wakefulness and arousal from sleep. Crescimanno et al (3) showed that asynchrony is correlated to leak with auto triggering, followed by ineffective efforts

128

being the most common. Asynchrony occurred more often in non-REM than REM sleep. Although asynchrony rate correlated with arousals and awakenings only 13% of arousals or were due to patient ventilator asynchrony. Fanfulla et al (4) investigated the effects of different ventilator settings on sleep and inspiratory effort in patients with neuromuscular disease. They compared usual settings with those determined physiologically aimed to reduce the tidal swing of trans-diaphragmatic pressure by between 40 and 80% and to avoid any positive deflection in oesophageal pressure during expiration. They showed that physiological settings resulted in a significant improvement in gas exchange, sleep efficiency and percentage of REM sleep. This was significantly correlated with a reduction in ineffective efforts. A small number of patients develop severe breathlessness on discontinuing non-invasive ventilation in the morning, "deventilation dyspnoea" Adler et al (5) showed that by identifying respiratory abnormalities during nocturnal polysomnography and making appropriate changes to ventilator settings this could be markedly reduced. The predominant cause was an increased number of ineffective efforts, which could be reduced by decreasing the level of pressure support, primarily by reducing the level of IPAP, but in some by increasing EPAP, or by increasing backup rate, inspiratory flow rate and adjusting TI Max to achieve an I: E ratio of 1 to 2.5 - 3. As well as reducing morning dyspnoea there was a subjective improvement in patient perception of asynchrony and leaks and an improvement in sleep quality. High intensity ventilation with high inflation pressures and backup rates is advocated by some; comparable sleep quality has been shown between high and low ventilation strategies (6). The above findings suggest that the high backup rate may be important in reducing patient ventilator asynchrony, which can be worsened if high inflation pressures lead to an increase in intrinsic PEEP. Leak, either from around the interface or through the mouth, when a nasal mask is utilised, reduces ventilator efficiency, increases asynchrony and also compromises sleep quality. Meyer et al (7) showed that while oxygenation was maintained during leak it was associated with frequent arousals. Patients used a combination of active and passive manoeuvers to reduce leak. Teschler et al (8) showed that mouth leak could be reduced by taping the lips shut and that this improved carbon dioxide elimination and reduced the arousal index. The percentage of time in REM sleep was also increased. The role of different modes of ventilation upon sleep quality has also been investigated. Tuggey and Elliott (9) showed no difference in sleep quality in stable patients with restrictive chest wall disease receiving pressure or volume ventilation in a crossover trial. Importantly there were no differences in various neuropsychological tests, performed during the day, which might have been expected to have shown differences if there were differences in sleep quality. In the acute setting ICU type ventilators are commonly used to deliver non-invasive ventilation; in one study (10) although slight differences in patient ventilator synchrony were observed there were no differences in sleep quality. Non-invasive ventilation sessions did not prevent patients sleeping but rather aided sleep, compared with spontaneous breathing. Noise from the ICU ventilators contributed to arousals. The ability of a ventilator to meet the patient’s inspiratory demands is key to patient comfort and prevention of arousals. Two innovative modes have been developed to match the patient's respiratory demands more closely, proportional assist and neurally adjusted ventilation; neither has gained widespread clinical acceptance though both have been shown to improve comfort, reduce patient ventilator asynchrony and proportional assist ventilation to improve some measures of sleep quality (11, 12). More recently volume assured modes have been introduced to ensure adequate control of nocturnal hypoventilation and while these have not been shown in most studies to be superior to "expertly" initiated NIV one study showed a subjective benefit in terms of improved sleep quality but in another (13) volume assured ventilation, because of increased leak was associated with increased dyssynchrony.

129

Finally it is important to realise that factors other than the ventilator may be important. Leak from around the interface has already been mentioned but in addition the high gas flows necessary for some interfaces, for instance the helmet (14), generate considerable noise and while this has not been studied during sleep the effects of noise are obvious. Patients receiving NIV are usually in a higher dependency area and the noise generated by other patients, their nursing care, ventilator alarms etc going off will also contribute to sleep disruption. NIV, in common with all critical illness, requires monitoring further interrupting sleep; a decision should be made as to whether the patient being allowed to sleep is more important than the need for clinical data. This must be determined on a case by case basis but "routine" monitoring at the expense of sleep should be avoided. In conclusion differences in the way that NIV is applied have been shown to have an impact upon sleep quality. There is however, to date, no evidence that this in impacts upon outcome. On purely pragmatic grounds however it is reasonable to address these issues if no other reason that patient comfort is improved. Finally it is worth taking the opportunity to remember that sleep is important to us all and that many things can be done simply to improve the quality of sleep for patients receiving NIV. REFERENCES 1. Charlesworth M, Elliott MW, Holmes JD. Noninvasive Positive Pressure Ventilation for

Acute Respiratory Failure in Delirious Patients: Understudied, Underreported, or Underappreciated? A Systematic Review and Meta-analysis. Lung. 2012;190(6):597-603. Epub 2012/07/12.

2. Fanfulla F, Ceriana P, D'Artavilla LN, Trentin R, Frigerio F, Nava S. Sleep disturbances in patients admitted to a step-down unit after ICU discharge: the role of mechanical ventilation. Sleep. 2011;34(3):355-62.

3. Crescimanno G, Canino M, Marrone O. Asynchronies and sleep disruption in neuromuscular patients under home noninvasive ventilation. Respiratory medicine. 2012;106(10):1478-85.

4. Fanfulla F, Delmastro M, Berardinelli A, Lupo NDA, Nava S. Effects of Different Ventilator Settings on Sleep and Inspiratory Effort in Patients with Neuromuscular Disease. Am J Respir Crit Care Med. 2005;172(5):619-24.

5. Adler D, Perrig S, Takahashi H, Espa F, Rodenstein D, Pepin JL, et al. Polysomnography in stable COPD under non-invasive ventilation to reduce patient-ventilator asynchrony and morning breathlessness. Sleep & breathing = Schlaf & Atmung. 2012;16(4):1081-90. Epub 2011/11/05.

6. Dreher M, Ekkernkamp E, Walterspacher S, Walker D, Schmoor C, Storre JH, et al. Non-invasive ventilation in COPD: Impact of inspiratory pressure levels on sleep quality: A randomized cross-over trial. Chest. 2011.

7. Meyer TJ, Pressman MR, Benditt J, McCool FD, Millman RP, Natarajan R, et al. Air leaking through the mouth during nocturnal nasal ventilation: effect on sleep quality. Sleep. 1997;20:561-9.

8. Teschler H, Stampa J, Ragette R, Konietzko N, Berthon-Jones M. Effect of mouth leak on effectiveness of nasal bilevel ventilatory assistance and sleep architecture. European Respiratory Journal. 1999;14:1251-7.

9. Tuggey JM, Elliott MW. Randomised crossover study of pressure and volume non-invasive ventilation in chest wall deformity. Thorax. 2005;60(10):859-64.

10. Cordoba-Izquierdo A, Drouot X, Thille AW, Galia F, Roche-Campo F, Schortgen F, et al. Sleep in hypercapnic critical care patients under noninvasive ventilation: conventional versus dedicated ventilators. Crit Care Med. 2013;41(1):60-8.

11. Beck J, Campoccia F, Allo JC, Brander L, Brunet F, Slutsky AS, et al. Improved synchrony and respiratory unloading by neurally adjusted ventilatory assist (NAVA) in lung-injured rabbits. Pediatr Res. 2007;61(3):289-94. Epub 2007/02/23.

130

12. Crisafulli E, Manni G, Kidonias M, Trianni L, Clini EM. Subjective Sleep Quality During Average Volume Assured Pressure Support (AVAPS) Ventilation in Patients with Hypercapnic COPD: A Physiological Pilot Study. Lung. 2009;187(5):299-305.

13. Crescimanno G, Marrone O, Vianello A. Efficacy and comfort of volume-guaranteed pressure support in patients with chronic ventilatory failure of neuromuscular origin. Respirology. 2011;16(4):672-9.

14. Cavaliere F, Conti G, Costa R, Proietti R, Sciuto A, Masieri S. Noise exposure during noninvasive ventilation with a helmet, a nasal mask, and a facial mask. Intensive Care Med. 2004;30(9):1755-60. Epub 2004/06/09.

EVALUATION 1. Sleep may worsen effectiveness of NIV acutely because

a. REM sleep is reduced b. Facial atonia can increase leak around the mask c. Respiratory drive is reduced d. Mouth leak increases e. Patient ventilator asynchrony is increased

2. The following modes have been shown to be superior to pressure ventilation in terms of sleep

quality as determined by EEG a. neurally adjusted ventilation b. proportional assist ventilation c. volume ventilation d. volume assured ventilation e. ICU ventilators

3. The following are causes of patient ventilator assynchrony

a. Auto triggering b. Failed triggering c. Shortened expiration time d. Prolonged inspiration time e. Prolonged expiration time in assisted modes

4. Critically ill patients may have compromised sleep because

a. they are cared for on ICU b. of the severity of the underlying illness c. drugs d. monitoring e. of other patients


131

Dr Mark Elliott Dr Mark Elliott [email protected]@doctors.org.uk

St. JamesSt. James’’s University Hospitals University Hospital

Prevention and treatment of sleep disturbances in acute respiratory failure: the role of noninvasive

ventilation

132

Disclosure

• I have received honoraria, subsistence and payment for attendance on expert panels from manufacturers of ventilators

133

Aims

• To understand –How application of NIV might

impact upon sleep quality

–Why this might be important

–Taking application of NIV in the (acute) situation to the next level

134

Effect of Sleep deprivation

• Respiratory

• Cognitive (delirium)

• Cardiovascular

• Endocrine

• Immune

• Patient acceptance of NIV

135

Potential disadvantages of effective NIV

• Patients chronically sleep deprived• Sleep once established on NIV• REM rebound

– Upper airway obstruction– Reduced respiratory drive

• Apnoeas• Less patient contribution to inspiration

– Facial atonia => mouth leak

136

How may assisted ventilation affect sleep quality?

• Patient ventilator asynchrony

• Central apnoeas due to over ventilation

• Inadequate ventilatory support

• Air leaks

137

Factors that may impact upon sleep during NIV

• Ventilator mode

• Ventilator settings

• Interface issues–Leak

–Noise

138

IE = ineffective effortsPC = Prolonged cyclingAT = auto triggering

Types of patient ventilator asynchrony

144

Arousals and awakenings associated with PVA but only 12.7% of arousals and awakenings due to PVA

146

Main change was to decrease number of unrewarded inspiratory efforts•PSV 13.6 to 10.3 cm H2O•IPAP decr 1 to 5 cm H2O in 7•EPAP incr by 1 to 4 cm H2O in 4•Back up rate increased in 4•Time to peak slightly increased in all•Timax adjusted to achieve I:E 1 to 2.5 to 3

149

Effect of deliberate mouth leak

157

Modes

158

D NIV Higher VT may have contributed to PVAICU NIV more noise related fragmentation

165

Crit Care Med 2007; 13:1048-54166

Crit Care Med 2007; 13:1048-54167

Subjective Sleep Quality During Average Volume Assured Pressure Support (AVAPS) Ventilation in Patients with

Hypercapnic COPD: A Physiological Pilot Study

• AVAPs v Pressure support

• N=9 stable COPD patients

• Baseline (T0) and after three (T1) and five (T2) nights

• PaCO2 and comfort VAS similarly improved for both modalities

• Perceived sleep efficiency score significantly improved at T2 with AVAPS (from 5.1 +/- 2.0 to 4.1 +/- 2.2, P = 0.001) but not with PS (from 5.1 +/- 1.7 to 4.7 +/- 1.3, P = 0.219).

• No difference in mean usage.

Crisafulli et al Lung 2009; 187:299-305169

• Not just about the ventilator–Other patients and activity on the

ward

–Alarms

–Monitoring• Bloods including arterial blood gases

• Blood pressure etc

–Ward staff are at work

171

Conclusion

• Differences in way NIV applied affect sleep quality

• No evidence that this impacts upon outcome• The issues raised are worthy of consideration in

improving delivery of NIV on pragmatic grounds alone

• Consider the patient’s need for sleep in hospital– Think about the other things – they may be easier to

identify and change!

172

Additional course resources Readings and guidelines

1. Roche Campo F, Drouot X, Thille AW, et al. Poor sleep quality is associated with late noninvasive ventilation failure in patients with acute hypercapnic respiratory failure. Crit Care Med 2010; 38: 477-485.

2. Córdoba-Izquierdo A, Drouot X, et al. Sleep in hypercapnic critical care patients under noninvasive ventilation: conventional versus dedicated ventilators. Crit Care Med 2013; 41: 60-8.

3. Fanfulla F, Ceriana P, D'Artavilla Lupo N, et al. Sleep disturbances in patients admitted to a step-down unit after ICU discharge: the role of mechanical ventilation. Sleep 2011; 34:355-362.

4. Ozyilmaz E, Ugurlu AO, Nava S. Timing of noninvasive ventilation failure: causes, risk factors, and potential remedies. BMC Pulm Med. 2014;14:19. doi: 10.1186/1471-2466-14-19.

5. Struik FM, Lacasse Y, Goldstein RS, et al. Nocturnal noninvasive positive pressure ventilation in stable COPD: a systematic review and individual patient data meta-analysis. Respir Med 2014; 108: 329-337.

6. Dreher M, Ekkernkamp E, Walterspacher S, et al. Noninvasive ventilation in COPD: impact of inspiratory pressure levels on sleep quality. Chest 2011; 140: 939-945.

7. Piper AJ. Obesity hypoventilation syndrome--the big and the breathless. Sleep Med Rev 2011; 15: 79-89.

8. Ojeda Castillejo E, de Lucas Ramos P, López Martin S, et al. Noninvasive mechanical ventilation in patients with Obesity Hypoventilation Syndrome. Long-term outcome and prognostic factors. Arch Bronconeumol 2014 Apr 2. pii: S0300-2896(14)00088-X. doi: 10.1016/j.arbres.2014.02.015.

E-learning resources

1. Simonds A. Respiratory Failure. HERMES Summer School 2014, Educational material: http://www.ers-education.org/Media/Media.aspx?idMedia=238625

2. Try the NIV simulator. Search for ‘Skills based Simulator training in Non-Invasive ventilation’ on the ERS e-learning webpage: http://www.ers-education.org/home.aspx

3. Go to ERS e-learning resources and search by topic ‘Respiratory failure’ for particular sub-area study. http://www.ers-education.org/search/quick-search.aspx

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Faculty disclosures Dr Mark W. Elliott has received honoraria, subsistence and payment for attendance on expert panels from manufacturers of ventilators. Dr Cesare Gregoretti has received fee for consultancy or lectures from Covidien, Breas (GE), ResMed, Philips and Smiths Medical Ind. Dr Amanda Piper has received lecture fees from ResMed, Asia Pacific and Respironics, Australia for educational presentations. She has also received a grant from The ResMed Foundation to look at optimised therapy in Obesity hypoventilation Syndrome.

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Faculty contact information Prof. Maria R. Bonsignore Pneumology Biomed. Dept. of Internal and Specialistic Med. University of Palermo Via Trabucco 180 90146 Palermo ITALY [email protected] Dr Cesare Gregoretti Ospedale Maria Adelaide Lungo Dora Firenze, 87 10153 Turin ITALY [email protected] Dr Amanda Piper Department of Respiratory and Sleep Medicine Royal Prince Alfred Hospital Camperdown NSW AUSTRALIA [email protected]

Dr Mark W. Elliott Respiratory Medicine St James’s University Hospital Beckett Street Leeds LS9 7TF UNITED KINGDOM [email protected] Dr Oreste Marrone Institute of Biomedicine and Molecular Immunology National Research Council Via Ugo La Malfa, 153 90146 Palermo ITALY [email protected]

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Answers to evaluation questions

Please find all correct answers in bold below Sleep-disordered breathing that leads to severe respiratory failure: mechanisms and clinical presentation – Dr Oreste Marrone

1. Which of these factors is better correlated to CO2 retention in patients with obstructive sleep apnoea (OSA)? a. Lowest SaO2 during sleep. b. Mean apnoea duration. c. Ratio between apnoea and interapnoeic interval duration. d. Duration of REM sleep.

2. In patients with COPD, OSA is not associated with:

a. Increased severity of lower airway obstruction. b. Increased rate of exacerbations. c. Increased mortality. d. Worse nocturnal desaturations.

3. Pneumonia in patients with OSA, as compared to control subjects, shows:

a. Similar incidence, and similar requirement of ICU care. b. Higher incidence, but similar requirement of ICU care. c. Similar incidence, but higher requirement of ICU care. d. Higher incidence, and higher requirement of ICU care.

4. Which of these factors is not an essential feature of MOHS?

a. BMI>40 kg/m2. b. Thyroid dysfunction. c. Type II respiratory failure. d. Metabolic syndrome or type 2 diabetes.

Does acute respiratory failure affect sleep? – Dr Amanda Piper

1. Sleep in invasively ventilated patients managed in intensive care is generally characterised by a. increased N3 (slow wave sleep) and reduced REM sleep b. increased total 24-h sleep duration compared to spontaneously breathing patients c. decreased N1 & N2 (Stage I & II sleep) and increased REM sleep d. decreased N3 and REM sleep

2. During weaning from mechanical ventilation following acute respiratory failure

a. noise from the ventilator is a significant cause of sleep fragmentation b. inappropriately adjusted ventilator settings may generate patient-ventilator

asynchrony and poorer sleep quality c. sleep fragmentation is primarily due to ineffective efforts d. sleep quality is significantly worse than during spontaneous breathing

3. Which of the following statements is correct?

a. Environment factors such as noise, light and patient care account for around 70% sleep arousals and awakenings in the ICU

b. Pressure support ventilation is likely to improve sleep quality by providing better patient-ventilator interactions compared to other ventilation modes

c. Central apnea may occur with mechanical ventilation, and is more likely to be seen in patients with heart failure or with overassistance from ventilatory support

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d. EEG abnormalities on polysomnography primarily occur in patients requiring invasive ventilation who are septic

4. Which of the following statements is not correct?

a. Late NIV failure is associated with increased SWS duration b. Sleep disturbance may promote delirium and worse clinical outcomes c. Delirium has been associated with NIV failure d. Delirium is a recognised risk factor for death in patients requiring mechanical ventilation

Prevention and treatment of sleep disturbances in acute respiratory failure: the role of drugs – Dr Cesare Gregoretti

1. Do opioids supress REM sleep? a. Never b. Only when sedatives are associated c. Only in elderly people d. Yes in a dose dependent way

2. Is there a rationale for using propofol in an intubated patient with sleep deprivation?

a. Yes b. Never c. Only in young people d. Only if a benzodiazepine is associated

3. Is there a rationale for using small dose of haloperidol in a non invasive ventilated patient

complaining of sleep deprivation? a. Yes if there are not contraindications b. Never c. Yes always d. Only if a benzodiazepine is associated

4. Do benzodiazepines alter slow waves sleep (SWS)?

a. Yes b. Never c. Only at very high dosage d. Only if an opioid is associated

Prevention and treatment of sleep disturbances in acute respiratory failure: the role of noninvasive ventilation – Dr Mark W. Elliott

1. Sleep may worsen effectiveness of NIV acutely because a. REM sleep is reduced b. Facial atonia can increase leak around the mask c. Respiratory drive is reduced d. Mouth leak increases e. Patient ventilator asynchrony is increased

2. The following modes have been shown to be superior to pressure ventilation in terms of sleep

quality as determined by EEG a. neurally adjusted ventilation b. proportional assist ventilation c. volume ventilation d. volume assured ventilation e. ICU ventilators

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3. The following are causes of patient ventilator assynchrony

a. Auto triggering b. Failed triggering c. Shortened expiration time d. Prolonged inspiration time e. Prolonged expiration time in assisted modes

4. Critically ill patients may have compromised sleep because

a. they are cared for on ICU b. of the severity of the underlying illness c. drugs d. monitoring e. of other patients

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