C i rca d i a n D y s r h y t h m i a s i n t h e I n t e n s i v e C a re U n i t Martha E. Billings,
a, MD, MSc *,
Nathaniel F. Watson,
MD, MSc
b
KEYWORDS Critical care Mechanical ventilation Circadian rhythm Melatonin KEY POINTS Circadian abnormalities are widespread because of uniform sleep disruption and aberrant sleep architecture in the intensive care unit (ICU). Circadian dysrhythmias develop due to critical illness as well as the ICU environment and therapies (mechanical ventilation [MV], sedation). Sleep and circadian rhythms should be addressed by ICU providers as an aspect of care to restore health and physiologic homeostasis. Changes to the ICU environment, use of natural light, and administration of melatonin in the evening may improve circadian alignment.
INTRODUCTION Circadian Physiology
All physiologic functions have an endogenous rhythm, which is modulated by neuroendocrine signals and is regulated by the circadian clock. The rhythms are entrained to their natural environment by light, feeding, and other social cues with light being the most important factor. The principal clock resides in the suprachiasmatic nucleus (SCN) within the hypothalamus and serves as the master pacemaker for the individual. The SCN not only determines the timing of sleep and wakefulness but also regulates other circadian rhythms that are independent of sleep such as cortisol levels, core body temperature (CBT), and melatonin release.1 The SCN coordinates the peripheral oscillators found in every organ and tissue via neurohormones and aligns these peripheral clocks to the central rhythm (Fig. 1).2 On the cellular level, approximately 15% of gene expression as well as protein and lipid production are under circadian control, which are highly conserved across species.3
Disclosures: The authors report no commercial or financial conflicts of interest relevant to this article. a Division of Pulmonary Critical Care Medicine, UW Medicine Sleep Center at Harborview, University of Washington, 325 Ninth Avenue, Box 359803, Seattle, WA 98104, USA; b Department of Neurology, University of Washington, UW Medicine Sleep Center, Seattle, WA 98104, USA * Corresponding author. E-mail address: [email protected] Crit Care Clin 31 (2015) 393–402 http://dx.doi.org/10.1016/j.ccc.2015.03.006 criticalcare.theclinics.com 0749-0704/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Fig. 1. The SCN is the master clock that regulates peripheral clocks in other organ systems and sets the circadian rhythm of temperature, sleep/wake, and metabolic, neuroendocrine and cardiovascular regulation via the peripheral clock output. (From Griffett K, Burris TP. The mammalian clock and chronopharmacology. Bioorg Med Chem Lett 2013;23:1929–34; with permission.)
Although circadian variation in blood pressure, CBT, urine output, lung function, metabolism, coagulation, and immune response is well established,4 the clinical implications of this on disease manifestation and monitoring have been overlooked. The circadian pattern in heart attacks and asthma flares may reflect circadian changes in immune parameters such as cytokine release, leukocyte tissue migration, and T-helper response. Disease onset may also be timed by increases in sympathetic nervous system output resulting in bronchial constriction and higher blood pressure.5 Asthmatic airways have greater circadian variability in peak flow. Lung inflammatory response to viruses and antigens may also be influenced by circadian factors.6 The circadian nature of physiology has profound implications for critical care. Circadian abnormalities can lead to derangements in physiologic homeostasis and affect critical illness. Patient assessments of temperature, blood pressure, metabolism, and lung function are often made disregarding circadian time, which limits comparability. Drug efficacy may differ depending on the timing of administration because immune response, metabolic function, hormones, and pharmacokinetics have circadian variation.7 The developing field of chronopharmacology addressing this has not yet translated into the ICU. Furthermore, a patient with circadian abnormalities may be at greater risk for delirium, prolonged ICU stay, and morbidity.8 Awareness of the intrinsic circadian rhythm of the patient in ICU has clinical relevance. Circadian Disruption in the Intensive Care Unit
Sleep in the ICU is aberrant in timing, architecture, and amount. Studies using polysomnography (PSG) monitoring in the ICU show an absence of circadian sleep pattern with 50% of sleep in the daytime.9 Perception of sleep by staff is inaccurate and typically grossly overestimated.10 Sleep architecture is aberrant with rapid eye movement (REM) and slow wave (N3) sleep lacking and severe sleep fragmentation common.11,12
Circadian Dysrhythmias in the ICU
This pattern was observed in non–critically ill patients recovering from major noncardiac surgery in the surgical ICU, who underwent 24-h PSG monitoring for 2 to 4 days (Fig. 2).10 This finding was replicated in 22 patients in medical ICU, 20 of whom were on MV but not on sedation.13 This pattern has also been borne out in studies of children in the pediatric ICU, primarily patients with burn.14 Investigating sleep architecture in the ICU is challenging because of the encephalopathic electroencephalographic (EEG) pattern commonly seen in critically ill patients (Fig. 3). Differentiation of wake from sleep and staging sleep is nearly impossible with this pattern.13,15,16 This EEG pattern is more prevalent in sepsis; it may predate septic physiology and resolve with improvement in sepsis.13 Some have attempted alternative methods to stage sleep including spectral analysis of absolute delta activity.15 Others have proposed a new scoring system to classify the atypical EEG patterns common to sedated, critical ill patients including polymorphic delta, burst suppression, and isoelectric pattern.17 Cause of Circadian Dysrhythmias in the Intensive Care Unit
The ICU environment is intrinsically detrimental to natural circadian rhythms (Box 1). Daylight is often obscured by lack of windows, and artificial lighting persists into the night. Studies measuring ambient light exposure do reveal dimness at night in the ICU15 but with large variations as well as nighttime periods with light levels known to impact the circadian pacemaker.18 Noises ranging from staff conversations to ventilator alarms are constant. Studies measuring noise in the ICU found mean levels exceeding Environmental Protection Agency recommendations for both day and night.13 Other social circadian cues are absent, because feedings may be continuous and nursing and respiratory care continues 24 hours a day. Medications commonly administered in the ICU such as sedatives, analgesics, and vasoactive drugs may all affect sleep and circadian rhythms.16,19 Physical symptoms of dyspnea, anxiety, and pain associated with critical illness and postoperative recovery may also compromise circadian rhythms and disrupt sleep (Fig. 4). MV has been attributed to sleep and circadian rhythm disruption. MV ideally allows respiratory muscle rest and recovery by reducing work of breathing, improving gas exchange, and minimizing anxiety associated with dyspnea. However, with ventilator asynchrony and alarms, patients on MV have poor-quality sleep with frequent arousals
Fig. 2. Continuous PSG recording of patients in the surgical ICU showing lack of sleep consolidation, deprivation, and abnormal sleep architecture. (From Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed) 1985;290:1031; with permission.)
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Fig. 3. Example 30-second epoch of encephalopathic EEG pattern seen in critically ill patients, typically with sepsis and on sedation. (From Weinhouse GL, Watson PL. Sedation and sleep disturbances in the ICU. Crit Care Clin 2009;25:539–49, ix; with permission.)
as well as nonconsolidated and fragmented sleep.20 Patients on MV also had much more daytime sleep, less slow wave sleep, and more fragmented sleep than healthy subjects in the same environment. In patients on MV, ICU factors such as noise and patient care did not seem to be major contributors to sleep disruption (17% noise arousal in patients on MV vs 68% in healthy subjects monitored in the ICU for 24 hours).9 Multiple studies have investigated the impact of the mode of MV on sleep and circadian rhythm.21–24 Pressure support (PS) mode during sleep was found to contribute to sleep disruption by causing relative hyperventilation and precipitating central apneas; this was reduced by adding dead space.24 Proportional assist ventilation (PAV) was found to be preferable to PS because it improved patient-ventilator synchrony.22 As both PAV and PS can induce periodic breathing, most recommend resting on assist control at night to improve sleep quality and reduce arousals from central apneas.20 For patients off sedation who have a tracheostomy in place with prolonged weaning, MV during the night improved sleep quantity versus spontaneous breathing.21 Thus respiratory support that does not induce hyperventilation or hypoventilation may improve sleep quality and help restore natural circadian sleep rhythm. In addition, MV and/or tracheostomy can treat any underlying obstructive sleep apnea that may disrupt sleep. MV may not be the culprit of circadian misalignment. In long-term acute care facilities (LTACs), where residents are typically on long-term ventilator weans, abnormalities in circadian rhythm have not been observed. One study of 15 patients in LTAC recovering from critical illness found a normal circadian activity pattern via actigraphy, which was in phase with environmental cues and light level variation.25 The
Box 1 Factors contributing to circadian disruption in the ICU Excessive artificial light/lack of natural light Noise Ventilator asynchrony and mode Patient care activity Psychosocial stress and physical pain Critical illness Medications
Circadian Dysrhythmias in the ICU
Fig. 4. Schematic of the effects of the ICU environment and illness on circadian alignment. (From Brainard J, Gobel M, Bartels K, et al. Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions. Semin Cardiothorac Vasc Anesth 2015;19:54; with permission.)
environmental factors disrupting circadian rhythms in the ICU may not be present in LTACs. These patients are on MV, but typically have tracheostomies, do not receive continuous sedation, and have much lower nursing care needs than in the ICU. These patients are also not otherwise critically ill and may be able to participate in rehabilitation and be active in the daytime. The improved zeitgebers (eg, stimulus or cue that synchronizes the internal pacemaker) in LTACs, which include timed meals, rehabilitation therapy, light, and other social cues (and the patient’s ability to respond to them), likely hasten the recovery from critical illness. Abnormalities in Melatonin
Further circadian disruption may result from the intrinsic effects of critical illness, ICU medications, and environment on melatonin release. Circadian melatonin patterns have been noted to be abnormal in multiple studies in the ICU.15,26–29 Most demonstrate a lack or attenuation of melatonin acrophase (peak) during the night compared with the day. Abolished serum circadian melatonin patterns, measured every 2 hours, were seen in 24 critically ill patients on continuous sedation; it was more pronounced in those with brain injury.28 In a seminal study by Mundigler and colleagues,29 septic patients in the ICU were found to lack a circadian pattern to melatonin secretion compared with nonseptic patients in the ICU. Melatonin levels as measured by 6-sulfatoxymelatonin (aMT6) excretion in the urine every 4 hours did not have a circadian rhythm in 16 of 17 septic patients compared with 7 nonseptic patients in the ICU, both groups receiving sedation. A more recent study investigating mechanically ventilated patients in the ICU did not replicate this finding among septic patients. However, investigators did find that most patients in the ICU had circadian
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melatonin misalignment. Patients exhibited primarily a phase delay pattern of their aMT6 excretion, which was not aligned with slow wave activity on EEG spectral analysis.15 These studies were small observational studies (less than 25 patients) and subject to many potential confounders including use of sedation, vasoactive medications, type of illness and its severity, and light exposure. There are also many methodological differences in melatonin assays, sampling frequency, and duration perhaps accounting for the differences in results. Critical illness and sepsis with the resulting neurohormonal dysregulation may also contribute to circadian dysrhythmias in the ICU. In a small study of 24 critically ill patients, researchers found no circadian pattern to cortisol release or cardiovascular parameters.28 This result was not replicated in a much larger study that modeled circadian rhythm using ICU physiologic data from 14,705 patients. Variations in blood pressure and heart rate were found, although attenuated. However, this rhythm was lost in sepsis nonsurvivors, indicating that circadian cardiovascular variation is a potential biomarker of ICU survival in this group.30 CBT reaches its nadir in a circadian manner in the early morning.1 The pattern persists even with febrile illness. CBT nadir can be used to identify the end of circadian night, and in patients in the ICU, the degree of CBT displacement from early morning is associated with illness severity.31 These derangements in circadian rhythm are seen in experimental models of sepsis in humans and rats.32,33 Furthermore, experimental response to endotoxin is modulated by circadian time.34 Molecular studies demonstrate a link between immune response and circadian rhythm, with disruptions associated with disease.35 Management Goals
When treating patients in the ICU, providers should seek to enable consolidated sleep and restoration of circadian rhythm to both central and peripheral clocks. Primary to that goal is awareness of circadian rhythms including absence and misalignment. Unfortunately, evaluating sleep and circadian alignment is currently not feasible in the ICU outside of the research setting. Future investigation is needed to allow critical care teams to assess and enhance circadian alignment. Efforts should be made to enhance natural zietgebers (daylight, daytime activity off sedation, feeding, and other cues) to maintain rhythm entrainment and nighttime sleep. Pharmacologic Strategies
Melatonin Sedation minimization Melatonin secretion is abnormal in timing and amplitude, with a blunting because of circadian rhythm derangement in the ICU. It is postulated that abnormalities in melatonin (as well as concomitant sleep deprivation) may contribute to ICU delirium.36 Recent studies have assessed administering melatonin to help enhance circadian alignment and improve sleep. A small randomized control trial of patients undergoing tracheotomy in the ICU (nonsedated) showed improved nocturnal sleep with melatonin administration.37 Melatonin has also been shown in animals to modulate immune response to endotoxemia, a model of sepsis.38,39 Thus melatonin may be an underused tool in the ICU to promote healthy circadian rhythms with the potential to improve innate immunity. Sedation, although it generates a state similar to sleep, is not equal to natural sleep, lacking circadian and ultradian pattern. Sleep provides a restorative function, essential for life. Benzodiazepines and opioids are known to reduce REM sleep and slow wave
Circadian Dysrhythmias in the ICU
sleep (N3), the most restorative form of sleep.19 Studies have found a lack of slow wave (N3) and REM sleep and only 2 to 3 hours of light sleep in patients in the ICU on continuous sedation who seemed to be sleeping.40 Excess sedation may actually result in sleep deprivation and worsen circadian abnormalities. Excess sedation, primarily with anticholinergic agents and benzodiazepines, is associated with delirium, prolonged ICU length of stay, and prolonged days on MV. The effect of sedating medications in further reducing restorative slow wave (N3) sleep and REM sleep may augment this effect by contributing to relative sleep deprivation.8,41 Consensus statements recommend minimizing sedation, eliminating continuous sedation to reduce delirium, and improve outcomes.42 Allowing natural sleep and daytime alertness by reducing sedation may also improve circadian alignment. Nonpharmacologic Strategies
Diurnal daylight/blue light exposure Noise minimization, especially at night Meal time feeding/noncontinuous feeds Light, blue spectrum (459–483 nm), is the most powerful entrainment signal, aligning intrinsic rhythm to the environment. Light can acutely suppress melatonin, regulate cortisol rhythm, and elevate body temperature and heart rate. Light has subjective benefits of improving alertness, improving mood and performance, and decreasing daytime sleepiness.43 Exposure to daylight was found to reduce the odds of delirium among patients in the ICU.44 Postoperative patients recovering from spinal surgery required less opioids in bright sunny rooms compared to dim rooms.45 In a natural experiment, patients in the cardiac care unit recovering from myocardial infarction in sunny rooms had a shorter length of stay and lower mortality than those in dull rooms.46 This result was not replicated in a study of patients with subarachnoid hemorrhage.47 A recent larger study investigating the effect of light in the ICU found that outdoor light intensity did not affect measured light intensity at the ICU bed. Even in rooms with windows, there was limited diurnal variation and an overall low light intensity.48 The hospital built environment, designing ICU rooms to allow exposure to natural daylight and window views from bed, may be another avenue to enhance circadian alignment. Further study on the effect of blue spectrum light on ICU outcomes is warranted. Reducing nighttime noise that may disrupt sleep and further erode circadian rhythm may be another necessary ICU environment change. A simple intervention, using ear plugs, was found to reduce ICU delirium. Patients were randomized to wear ear plugs at night or not. Those wearing ear plugs had a lower odds of developing delirium and had subjectively better sleep.49 White noise, acoustic foams to absorb noise in neonatal incubators, and implementing quiet times are other methods that have been shown to improve sleep.50 The impact of noise reduction on circadian rhythm has not been evaluated. Finally, implementing consistent meal times may improve circadian rhythm. Digestion, lipid metabolism, as well as liver and pancreatic function all have an intrinsic circadian rhythm. Traditional continuous tube feeds and parenteral nutrition abolish these natural rhythms and variations in bile acid synthesis, insulin secretion, and glycogen production, which typically occur primarily in the daytime. Nighttime is a period of fasting with gluconeogenesis and lipid catabolism. Circadian realignment may be enhanced by time-restricted feeding that parallels natural meal time during the day and fasting during the night. Time-restricted feeding may enhance peripheral metabolic entrainment.2
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SUMMARY/DISCUSSION
The literature supports significant alteration in circadian rhythm in the ICU. There is evidence of misalignment, from the reduction in amplitude of melatonin acrophase and other circadian biomarkers to abolishment of rhythm. The evidence suggests some association between the degree of circadian pathology and critical illness severity. This result parallels that of animal model work showing circadian variation in immunity and response to illness. It is currently unclear if the circadian dysrhythmia is primarily intrinsic to critical illness or is a consequence of treatments including MV, sedative and vasoactive drugs, and the ICU environment. Most likely it is a combination of these factors. The research is still in its infancy because studies are just beginning to illuminate the role of circadian physiology on critical illness and recovery. Future research is required to enable clinicians to evaluate their patients’ circadian rhythm or lack thereof at the bedside. Further investigations are needed to evaluate the efficacy of any interventions in improving circadian rhythm and the impact on ICU outcomes and longterm morbidity. REFERENCES
1. Hastings M, O’Neill JS, Maywood ES. Circadian clocks: regulators of endocrine and metabolic rhythms. J Endocrinol 2007;195:187–98. 2. Sunderram J, Sofou S, Kamisoglu K, et al. Time-restricted feeding and the realignment of biological rhythms: translational opportunities and challenges. J Transl Med 2014;12:79. 3. Dallmann R, Viola AU, Tarokh L, et al. The human circadian metabolome. Proc Natl Acad Sci U S A 2012;109:2625–9. 4. Chan MC, Spieth PM, Quinn K, et al. Circadian rhythms: from basic mechanisms to the intensive care unit. Crit Care Med 2012;40:246–53. 5. Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol 2013;13:190–8. 6. Durrington HJ, Farrow SN, Loudon AS, et al. The circadian clock and asthma. Thorax 2014;69:90–2. 7. Dallmann R, Brown SA, Gachon F. Chronopharmacology: new insights and therapeutic implications. Annu Rev Pharmacol Toxicol 2014;54:339–61. 8. Weinhouse GL, Schwab RJ, Watson PL, et al. Bench-to-bedside review: delirium in ICU patients - importance of sleep deprivation. Crit Care 2009;13:234. 9. Gabor JY, Cooper AB, Crombach SA, 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. 10. Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed) 1985;290:1029–32. 11. Hilton BA. Quantity and quality of patients’ sleep and sleep-disturbing factors in a respiratory intensive care unit. J Adv Nurs 1976;1:453–68. 12. Broughton R, Baron R. Sleep patterns in the intensive care unit and on the ward after acute myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45: 348–60. 13. Freedman NS, Gazendam J, Levan L, 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;163:451–7. 14. Kudchadkar SR, Aljohani OA, Punjabi NM. Sleep of critically ill children in the pediatric intensive care unit: a systematic review. Sleep Med Rev 2014;18:103–10.
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15. Gehlbach BK, Chapotot F, Leproult R, et al. Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation. Sleep 2012;35:1105–14. 16. Weinhouse GL, Watson PL. Sedation and sleep disturbances in the ICU. Crit Care Clin 2009;25:539–49, ix. 17. Watson PL, Pandharipande P, Gehlbach BK, et al. Atypical sleep in ventilated patients: empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria. Crit Care Med 2013;41:1958–67. 18. Pulak LM, Jensen L. Sleep in the intensive care unit: a review. J Intensive Care Med 2014. [Epub ahead of print]. 19. Weinhouse GL. Pharmacology I: effects on sleep of commonly used ICU medications. Crit Care Clin 2008;24:477–91, vi. 20. Ozsancak A, D’Ambrosio C, Garpestad E, et al. Sleep and mechanical ventilation. Crit Care Clin 2008;24:517–31, vi–vii. 21. Roche-Campo F, Thille AW, Drouot X, et al. Comparison of sleep quality with mechanical versus spontaneous ventilation during weaning of critically ill tracheostomized patients. Crit Care Med 2013;41:1637–44. 22. Bosma K, Ferreyra G, Ambrogio C, et al. Patient-ventilator interaction and sleep in mechanically ventilated patients: pressure support versus proportional assist ventilation. Crit Care Med 2007;35:1048–54. 23. Cabello B, Thille AW, Drouot X, et al. Sleep quality in mechanically ventilated patients: comparison of three ventilatory modes. Crit Care Med 2008;36:1749–55. 24. Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill patients. Am J Respir Crit Care Med 2002;166:1423–9. 25. Koldobskiy D, Diaz-Abad M, Scharf SM, et al. Long-term acute care patients weaning from prolonged mechanical ventilation maintain circadian rhythm. Respir Care 2014;59:518–24. 26. Frisk U, Olsson J, Nylen P, et al. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci (Lond) 2004;107:47–53. 27. Shilo L, Dagan Y, Smorjik Y, et al. Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci 1999;317:278–81. 28. Paul T, Lemmer B. Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury. Chronobiol Int 2007;24: 45–61. 29. Mundigler G, Delle-Karth G, Koreny M, et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med 2002;30:536–40. 30. George ZC, Zhengbo Z, Mohammad G, et al. Modeling Circadian Rhythm Variations During Sepsis. B105 Sepsis: Care Models And Outcomes: American Thoracic Society 2014;189:A3795. [abstract]. 31. Gazendam JA, Van Dongen HP, Grant DA, et al. Altered circadian rhythmicity in patients in the ICU. Chest 2013;144:483–9. 32. Baracchi F, Ingiosi AM, Raymond RM Jr, et al. Sepsis-induced alterations in sleep of rats. Am J Physiol Regul Integr Comp Physiol 2011;301:R1467–78. 33. Li CX, Liang DD, Xie GH, et al. Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients. Mol Med Rep 2013;7:1117–22. 34. Alamili M, Bendtzen K, Lykkesfeldt J, et al. Pronounced inflammatory response to endotoxaemia during nighttime: a randomised cross-over trial. PLoS One 2014;9: e87413.
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35. Arjona A, Silver AC, Walker WE, et al. Immunity’s fourth dimension: approaching the circadian-immune connection. Trends Immunol 2012;33:607–12. 36. Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth 2012;108:572–80. 37. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008;12:R52. 38. Alamili M, Klein M, Lykkesfeldt J, et al. Circadian variation in the response to experimental endotoxemia and modulatory effects of exogenous melatonin. Chronobiol Int 2013;30:1174–80. 39. Alamili M, Bendtzen K, Lykkesfeldt J, et al. Melatonin suppresses markers of inflammation and oxidative damage in a human daytime endotoxemia model. J Crit Care 2014;29:184.e9–13. 40. Andersen JH, Boesen HC, Skovgaard Olsen K. Sleep in the intensive care unit measured by polysomnography. Minerva Anestesiol 2013;79:804–15. 41. Watson PL, Ceriana P, Fanfulla F. Delirium: is sleep important? Best Pract Res Clin Anaesthesiol 2012;26:355–66. 42. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306. 43. Castro R, Angus DC, Rosengart MR. The effect of light on critical illness. Crit Care 2011;15:218. 44. Van Rompaey B, Elseviers MM, Schuurmans MJ, et al. Risk factors for delirium in intensive care patients: a prospective cohort study. Crit Care 2009;13:R77. 45. Walch JM, Rabin BS, Day R, et al. The effect of sunlight on postoperative analgesic medication use: a prospective study of patients undergoing spinal surgery. Psychosom Med 2005;67:156–63. 46. Beauchemin KM, Hays P. Dying in the dark: sunshine, gender and outcomes in myocardial infarction. J R Soc Med 1998;91:352–4. 47. Wunsch H, Gershengorn H, Mayer SA, et al. The effect of window rooms on critically ill patients with subarachnoid hemorrhage admitted to intensive care. Crit Care 2011;15:R81. 48. Castro RA, Angus DC, Hong SY, et al. Light and the outcome of the critically ill: an observational cohort study. Crit Care 2012;16:R132. 49. Van Rompaey B, Elseviers MM, Van Drom W, et al. The effect of earplugs during the night on the onset of delirium and sleep perception: a randomized controlled trial in intensive care patients. Crit Care 2012;16:R73. 50. Xie H, Kang J, Mills GH. Clinical review: the impact of noise on patients’ sleep and the effectiveness of noise reduction strategies in intensive care units. Crit Care 2009;13:208.
a, MD, MSc *,
Nathaniel F. Watson,
MD, MSc
b
KEYWORDS Critical care Mechanical ventilation Circadian rhythm Melatonin KEY POINTS Circadian abnormalities are widespread because of uniform sleep disruption and aberrant sleep architecture in the intensive care unit (ICU). Circadian dysrhythmias develop due to critical illness as well as the ICU environment and therapies (mechanical ventilation [MV], sedation). Sleep and circadian rhythms should be addressed by ICU providers as an aspect of care to restore health and physiologic homeostasis. Changes to the ICU environment, use of natural light, and administration of melatonin in the evening may improve circadian alignment.
INTRODUCTION Circadian Physiology
All physiologic functions have an endogenous rhythm, which is modulated by neuroendocrine signals and is regulated by the circadian clock. The rhythms are entrained to their natural environment by light, feeding, and other social cues with light being the most important factor. The principal clock resides in the suprachiasmatic nucleus (SCN) within the hypothalamus and serves as the master pacemaker for the individual. The SCN not only determines the timing of sleep and wakefulness but also regulates other circadian rhythms that are independent of sleep such as cortisol levels, core body temperature (CBT), and melatonin release.1 The SCN coordinates the peripheral oscillators found in every organ and tissue via neurohormones and aligns these peripheral clocks to the central rhythm (Fig. 1).2 On the cellular level, approximately 15% of gene expression as well as protein and lipid production are under circadian control, which are highly conserved across species.3
Disclosures: The authors report no commercial or financial conflicts of interest relevant to this article. a Division of Pulmonary Critical Care Medicine, UW Medicine Sleep Center at Harborview, University of Washington, 325 Ninth Avenue, Box 359803, Seattle, WA 98104, USA; b Department of Neurology, University of Washington, UW Medicine Sleep Center, Seattle, WA 98104, USA * Corresponding author. E-mail address: [email protected] Crit Care Clin 31 (2015) 393–402 http://dx.doi.org/10.1016/j.ccc.2015.03.006 criticalcare.theclinics.com 0749-0704/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Fig. 1. The SCN is the master clock that regulates peripheral clocks in other organ systems and sets the circadian rhythm of temperature, sleep/wake, and metabolic, neuroendocrine and cardiovascular regulation via the peripheral clock output. (From Griffett K, Burris TP. The mammalian clock and chronopharmacology. Bioorg Med Chem Lett 2013;23:1929–34; with permission.)
Although circadian variation in blood pressure, CBT, urine output, lung function, metabolism, coagulation, and immune response is well established,4 the clinical implications of this on disease manifestation and monitoring have been overlooked. The circadian pattern in heart attacks and asthma flares may reflect circadian changes in immune parameters such as cytokine release, leukocyte tissue migration, and T-helper response. Disease onset may also be timed by increases in sympathetic nervous system output resulting in bronchial constriction and higher blood pressure.5 Asthmatic airways have greater circadian variability in peak flow. Lung inflammatory response to viruses and antigens may also be influenced by circadian factors.6 The circadian nature of physiology has profound implications for critical care. Circadian abnormalities can lead to derangements in physiologic homeostasis and affect critical illness. Patient assessments of temperature, blood pressure, metabolism, and lung function are often made disregarding circadian time, which limits comparability. Drug efficacy may differ depending on the timing of administration because immune response, metabolic function, hormones, and pharmacokinetics have circadian variation.7 The developing field of chronopharmacology addressing this has not yet translated into the ICU. Furthermore, a patient with circadian abnormalities may be at greater risk for delirium, prolonged ICU stay, and morbidity.8 Awareness of the intrinsic circadian rhythm of the patient in ICU has clinical relevance. Circadian Disruption in the Intensive Care Unit
Sleep in the ICU is aberrant in timing, architecture, and amount. Studies using polysomnography (PSG) monitoring in the ICU show an absence of circadian sleep pattern with 50% of sleep in the daytime.9 Perception of sleep by staff is inaccurate and typically grossly overestimated.10 Sleep architecture is aberrant with rapid eye movement (REM) and slow wave (N3) sleep lacking and severe sleep fragmentation common.11,12
Circadian Dysrhythmias in the ICU
This pattern was observed in non–critically ill patients recovering from major noncardiac surgery in the surgical ICU, who underwent 24-h PSG monitoring for 2 to 4 days (Fig. 2).10 This finding was replicated in 22 patients in medical ICU, 20 of whom were on MV but not on sedation.13 This pattern has also been borne out in studies of children in the pediatric ICU, primarily patients with burn.14 Investigating sleep architecture in the ICU is challenging because of the encephalopathic electroencephalographic (EEG) pattern commonly seen in critically ill patients (Fig. 3). Differentiation of wake from sleep and staging sleep is nearly impossible with this pattern.13,15,16 This EEG pattern is more prevalent in sepsis; it may predate septic physiology and resolve with improvement in sepsis.13 Some have attempted alternative methods to stage sleep including spectral analysis of absolute delta activity.15 Others have proposed a new scoring system to classify the atypical EEG patterns common to sedated, critical ill patients including polymorphic delta, burst suppression, and isoelectric pattern.17 Cause of Circadian Dysrhythmias in the Intensive Care Unit
The ICU environment is intrinsically detrimental to natural circadian rhythms (Box 1). Daylight is often obscured by lack of windows, and artificial lighting persists into the night. Studies measuring ambient light exposure do reveal dimness at night in the ICU15 but with large variations as well as nighttime periods with light levels known to impact the circadian pacemaker.18 Noises ranging from staff conversations to ventilator alarms are constant. Studies measuring noise in the ICU found mean levels exceeding Environmental Protection Agency recommendations for both day and night.13 Other social circadian cues are absent, because feedings may be continuous and nursing and respiratory care continues 24 hours a day. Medications commonly administered in the ICU such as sedatives, analgesics, and vasoactive drugs may all affect sleep and circadian rhythms.16,19 Physical symptoms of dyspnea, anxiety, and pain associated with critical illness and postoperative recovery may also compromise circadian rhythms and disrupt sleep (Fig. 4). MV has been attributed to sleep and circadian rhythm disruption. MV ideally allows respiratory muscle rest and recovery by reducing work of breathing, improving gas exchange, and minimizing anxiety associated with dyspnea. However, with ventilator asynchrony and alarms, patients on MV have poor-quality sleep with frequent arousals
Fig. 2. Continuous PSG recording of patients in the surgical ICU showing lack of sleep consolidation, deprivation, and abnormal sleep architecture. (From Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed) 1985;290:1031; with permission.)
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Fig. 3. Example 30-second epoch of encephalopathic EEG pattern seen in critically ill patients, typically with sepsis and on sedation. (From Weinhouse GL, Watson PL. Sedation and sleep disturbances in the ICU. Crit Care Clin 2009;25:539–49, ix; with permission.)
as well as nonconsolidated and fragmented sleep.20 Patients on MV also had much more daytime sleep, less slow wave sleep, and more fragmented sleep than healthy subjects in the same environment. In patients on MV, ICU factors such as noise and patient care did not seem to be major contributors to sleep disruption (17% noise arousal in patients on MV vs 68% in healthy subjects monitored in the ICU for 24 hours).9 Multiple studies have investigated the impact of the mode of MV on sleep and circadian rhythm.21–24 Pressure support (PS) mode during sleep was found to contribute to sleep disruption by causing relative hyperventilation and precipitating central apneas; this was reduced by adding dead space.24 Proportional assist ventilation (PAV) was found to be preferable to PS because it improved patient-ventilator synchrony.22 As both PAV and PS can induce periodic breathing, most recommend resting on assist control at night to improve sleep quality and reduce arousals from central apneas.20 For patients off sedation who have a tracheostomy in place with prolonged weaning, MV during the night improved sleep quantity versus spontaneous breathing.21 Thus respiratory support that does not induce hyperventilation or hypoventilation may improve sleep quality and help restore natural circadian sleep rhythm. In addition, MV and/or tracheostomy can treat any underlying obstructive sleep apnea that may disrupt sleep. MV may not be the culprit of circadian misalignment. In long-term acute care facilities (LTACs), where residents are typically on long-term ventilator weans, abnormalities in circadian rhythm have not been observed. One study of 15 patients in LTAC recovering from critical illness found a normal circadian activity pattern via actigraphy, which was in phase with environmental cues and light level variation.25 The
Box 1 Factors contributing to circadian disruption in the ICU Excessive artificial light/lack of natural light Noise Ventilator asynchrony and mode Patient care activity Psychosocial stress and physical pain Critical illness Medications
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Fig. 4. Schematic of the effects of the ICU environment and illness on circadian alignment. (From Brainard J, Gobel M, Bartels K, et al. Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions. Semin Cardiothorac Vasc Anesth 2015;19:54; with permission.)
environmental factors disrupting circadian rhythms in the ICU may not be present in LTACs. These patients are on MV, but typically have tracheostomies, do not receive continuous sedation, and have much lower nursing care needs than in the ICU. These patients are also not otherwise critically ill and may be able to participate in rehabilitation and be active in the daytime. The improved zeitgebers (eg, stimulus or cue that synchronizes the internal pacemaker) in LTACs, which include timed meals, rehabilitation therapy, light, and other social cues (and the patient’s ability to respond to them), likely hasten the recovery from critical illness. Abnormalities in Melatonin
Further circadian disruption may result from the intrinsic effects of critical illness, ICU medications, and environment on melatonin release. Circadian melatonin patterns have been noted to be abnormal in multiple studies in the ICU.15,26–29 Most demonstrate a lack or attenuation of melatonin acrophase (peak) during the night compared with the day. Abolished serum circadian melatonin patterns, measured every 2 hours, were seen in 24 critically ill patients on continuous sedation; it was more pronounced in those with brain injury.28 In a seminal study by Mundigler and colleagues,29 septic patients in the ICU were found to lack a circadian pattern to melatonin secretion compared with nonseptic patients in the ICU. Melatonin levels as measured by 6-sulfatoxymelatonin (aMT6) excretion in the urine every 4 hours did not have a circadian rhythm in 16 of 17 septic patients compared with 7 nonseptic patients in the ICU, both groups receiving sedation. A more recent study investigating mechanically ventilated patients in the ICU did not replicate this finding among septic patients. However, investigators did find that most patients in the ICU had circadian
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melatonin misalignment. Patients exhibited primarily a phase delay pattern of their aMT6 excretion, which was not aligned with slow wave activity on EEG spectral analysis.15 These studies were small observational studies (less than 25 patients) and subject to many potential confounders including use of sedation, vasoactive medications, type of illness and its severity, and light exposure. There are also many methodological differences in melatonin assays, sampling frequency, and duration perhaps accounting for the differences in results. Critical illness and sepsis with the resulting neurohormonal dysregulation may also contribute to circadian dysrhythmias in the ICU. In a small study of 24 critically ill patients, researchers found no circadian pattern to cortisol release or cardiovascular parameters.28 This result was not replicated in a much larger study that modeled circadian rhythm using ICU physiologic data from 14,705 patients. Variations in blood pressure and heart rate were found, although attenuated. However, this rhythm was lost in sepsis nonsurvivors, indicating that circadian cardiovascular variation is a potential biomarker of ICU survival in this group.30 CBT reaches its nadir in a circadian manner in the early morning.1 The pattern persists even with febrile illness. CBT nadir can be used to identify the end of circadian night, and in patients in the ICU, the degree of CBT displacement from early morning is associated with illness severity.31 These derangements in circadian rhythm are seen in experimental models of sepsis in humans and rats.32,33 Furthermore, experimental response to endotoxin is modulated by circadian time.34 Molecular studies demonstrate a link between immune response and circadian rhythm, with disruptions associated with disease.35 Management Goals
When treating patients in the ICU, providers should seek to enable consolidated sleep and restoration of circadian rhythm to both central and peripheral clocks. Primary to that goal is awareness of circadian rhythms including absence and misalignment. Unfortunately, evaluating sleep and circadian alignment is currently not feasible in the ICU outside of the research setting. Future investigation is needed to allow critical care teams to assess and enhance circadian alignment. Efforts should be made to enhance natural zietgebers (daylight, daytime activity off sedation, feeding, and other cues) to maintain rhythm entrainment and nighttime sleep. Pharmacologic Strategies
Melatonin Sedation minimization Melatonin secretion is abnormal in timing and amplitude, with a blunting because of circadian rhythm derangement in the ICU. It is postulated that abnormalities in melatonin (as well as concomitant sleep deprivation) may contribute to ICU delirium.36 Recent studies have assessed administering melatonin to help enhance circadian alignment and improve sleep. A small randomized control trial of patients undergoing tracheotomy in the ICU (nonsedated) showed improved nocturnal sleep with melatonin administration.37 Melatonin has also been shown in animals to modulate immune response to endotoxemia, a model of sepsis.38,39 Thus melatonin may be an underused tool in the ICU to promote healthy circadian rhythms with the potential to improve innate immunity. Sedation, although it generates a state similar to sleep, is not equal to natural sleep, lacking circadian and ultradian pattern. Sleep provides a restorative function, essential for life. Benzodiazepines and opioids are known to reduce REM sleep and slow wave
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sleep (N3), the most restorative form of sleep.19 Studies have found a lack of slow wave (N3) and REM sleep and only 2 to 3 hours of light sleep in patients in the ICU on continuous sedation who seemed to be sleeping.40 Excess sedation may actually result in sleep deprivation and worsen circadian abnormalities. Excess sedation, primarily with anticholinergic agents and benzodiazepines, is associated with delirium, prolonged ICU length of stay, and prolonged days on MV. The effect of sedating medications in further reducing restorative slow wave (N3) sleep and REM sleep may augment this effect by contributing to relative sleep deprivation.8,41 Consensus statements recommend minimizing sedation, eliminating continuous sedation to reduce delirium, and improve outcomes.42 Allowing natural sleep and daytime alertness by reducing sedation may also improve circadian alignment. Nonpharmacologic Strategies
Diurnal daylight/blue light exposure Noise minimization, especially at night Meal time feeding/noncontinuous feeds Light, blue spectrum (459–483 nm), is the most powerful entrainment signal, aligning intrinsic rhythm to the environment. Light can acutely suppress melatonin, regulate cortisol rhythm, and elevate body temperature and heart rate. Light has subjective benefits of improving alertness, improving mood and performance, and decreasing daytime sleepiness.43 Exposure to daylight was found to reduce the odds of delirium among patients in the ICU.44 Postoperative patients recovering from spinal surgery required less opioids in bright sunny rooms compared to dim rooms.45 In a natural experiment, patients in the cardiac care unit recovering from myocardial infarction in sunny rooms had a shorter length of stay and lower mortality than those in dull rooms.46 This result was not replicated in a study of patients with subarachnoid hemorrhage.47 A recent larger study investigating the effect of light in the ICU found that outdoor light intensity did not affect measured light intensity at the ICU bed. Even in rooms with windows, there was limited diurnal variation and an overall low light intensity.48 The hospital built environment, designing ICU rooms to allow exposure to natural daylight and window views from bed, may be another avenue to enhance circadian alignment. Further study on the effect of blue spectrum light on ICU outcomes is warranted. Reducing nighttime noise that may disrupt sleep and further erode circadian rhythm may be another necessary ICU environment change. A simple intervention, using ear plugs, was found to reduce ICU delirium. Patients were randomized to wear ear plugs at night or not. Those wearing ear plugs had a lower odds of developing delirium and had subjectively better sleep.49 White noise, acoustic foams to absorb noise in neonatal incubators, and implementing quiet times are other methods that have been shown to improve sleep.50 The impact of noise reduction on circadian rhythm has not been evaluated. Finally, implementing consistent meal times may improve circadian rhythm. Digestion, lipid metabolism, as well as liver and pancreatic function all have an intrinsic circadian rhythm. Traditional continuous tube feeds and parenteral nutrition abolish these natural rhythms and variations in bile acid synthesis, insulin secretion, and glycogen production, which typically occur primarily in the daytime. Nighttime is a period of fasting with gluconeogenesis and lipid catabolism. Circadian realignment may be enhanced by time-restricted feeding that parallels natural meal time during the day and fasting during the night. Time-restricted feeding may enhance peripheral metabolic entrainment.2
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SUMMARY/DISCUSSION
The literature supports significant alteration in circadian rhythm in the ICU. There is evidence of misalignment, from the reduction in amplitude of melatonin acrophase and other circadian biomarkers to abolishment of rhythm. The evidence suggests some association between the degree of circadian pathology and critical illness severity. This result parallels that of animal model work showing circadian variation in immunity and response to illness. It is currently unclear if the circadian dysrhythmia is primarily intrinsic to critical illness or is a consequence of treatments including MV, sedative and vasoactive drugs, and the ICU environment. Most likely it is a combination of these factors. The research is still in its infancy because studies are just beginning to illuminate the role of circadian physiology on critical illness and recovery. Future research is required to enable clinicians to evaluate their patients’ circadian rhythm or lack thereof at the bedside. Further investigations are needed to evaluate the efficacy of any interventions in improving circadian rhythm and the impact on ICU outcomes and longterm morbidity. REFERENCES
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