Comment
Human beings, like almost all animals, are subject to endogenous rhythms that are largely modulated by light and darkness. These circadian rhythms comprise biochemical and behavioural cycles of between 22 h and 25 h. Circadian rhythms are synchronised with daytime and night-time through specialised retinal cells.1 A central oscillator located in the suprachiasmatic nucleus of the hypothalamus controls several peripheral oscillators and thereby regulates most, if not all, physiological functions in relation to the environment, and particularly light. Darkness triggers melatonin release from the pineal gland. Concentrations of this hormone peak at around 2300 h and cause organ activity to slow. About 3 h after sleep onset, concentrations of cortisol start to increase and peak at around 0900 h. During the day cortisol levels decline progressively, reaching a nadir around midnight. Thus, transitioning light, especially from darkness to light, seems to be an important factor for the circadian rhythm of cortisol concentration.2 Stress can lead to misalignment of circadian rhythms, causing altered function in various body systems, including the cardiovascular, respiratory, endocrine, metabolic, and immune systems. Loss of circadian rhythms and sleep disruption are thought to be the hallmarks of critical illness, and have been associated with various factors related to disease and the environment in intensive-care units (ICUs).3 Systemic inflammation, particularly during sepsis, is strongly associated with disruption of internal cycles. Artificial light, noise, mechanical ventilation, and painful procedures are the most frequent ICU-related factors that affect chronobiology. Alterations to the central or peripheral oscillators, or both, might contribute to altered immune response in patients with critical illness and cognitive dysfunction. Interventions that might restore normal biological rhythms include drug and physical therapies. Small trials have suggested that oral melatonin has favourable effects on sleep quality in critically ill patients,4,5 although results are inconclusive for patient-centred outcomes, such as mortality, length of hospital stay, or post-traumatic stress disorders. In The Lancet Respiratory Medicine, Koen Simons and colleagues6 investigated whether dynamic high-intensity light in the daytime could reduce the risk
of ICU-acquired delirium in 734 critically ill adults. Over a 2-year period, patients admitted to the ICU of one hospital were randomly assigned the dynamic lighting application (bluish-white light up to 1700 lux) or normal lighting for the duration of their stay. No evidence was found of an effect on delirium, which occurred in 137 (38%) of 361 patients in the dynamic light and 123 (33%) of 373 in the normal light group (odds ratio 1·24, 95% CI 0·92–1·68, p=0·16). Likewise, dynamic light therapy had no significant effect on length of stay or survival in hospital. No differences were seen in circadian rhythm, but this was measured in only a small subgroup of 20 patients, and, therefore, it is unclear whether internal cycles were affected by light therapy. In the study of Simons and colleagues, patients were enrolled at the early phase of critical illness and a large proportion of them were sedated. Inappropriate population and timing may have accounted for the lack of benefit from light therapy. First, light needs to reach specific short-wavelength photopigments in the retina to modulate hypothalamic neurons and suppress melatonin secretion.7 Patients’ eyes must, therefore, be open for substantial amounts of time during exposure to light therapy. Second, the initial response to acute stress includes attenuation of circadian rhythms to allow control of homeostasis. Sustained disruption to internal cycles, however, might contribute to loss of organ function and poor outcomes.3 Restoration of normal chronobiology might, therefore, favourably affect the chronic rather than the acute trajectory of critical illness. Retinal ganglion cells expressing melanopsin are directly connected to the hypothalamic and other structures of the limbic systems to modulate the central oscillator in mammals.8 These cells are maximally sensitive to blue light, which indicates the relevance of light wavelength. Evidence suggests that simulation of dawn with artificial light starting 30 min before and ending 20 min after wake-up time improves cognitive function and mood.9 These data support the importance of transitioning light, particularly from darkness to light, in the restoration of body homoeostasis. In view of all these confounders, I suggest that future trials of ICU light therapy should enrol patients in the chronic phase of critical illness, when attempts are being made to wean them off life-supporting therapies and
www.thelancet.com/respiratory Published online February 16, 2016 http://dx.doi.org/10.1016/S2213-2600(16)00055-2
George Mattei/Science Photo Library
Light therapy and chronobiology in critical illness
Lancet Respir Med 2016 Published Online February 16, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)00055-2 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(16)00025-4
1
Comment
organs are healing. The therapy should comprise blue light and dawn simulation and continue beyond ICU discharge. Cognitive function in the long term would be a feasible main outcome. Djillali Annane
I declare no competing interests.
2
2
4
5
6
General intensive care unit, Raymond Poincaré Hospital (AP-HP), Laboratory of Inflammation and Infection, U1173, INSERM and University of Versailles SQY, 92380 Garches, France [email protected] 1
3
7
8
Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N Engl J Med 1983; 309: 469–76. Law R, Hucklebridge F, Thorn L, Evans P, Clow A. State variation in the cortisol awakening response. Stress 2013; 16: 483–92.
9
Oldham MA, Lee HB, Desan PH. Circadian rhythm disruption in the critically ill: an opportunity for improving outcomes. Crit Care Med 2016; 44: 207–17. 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. Mistraletti G, Umbrello M, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol 2015; 81: 1298–310. Simons KS, Laheij RJF, van den Boogaard M, et al. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial. Lancet Respir Med 2016; published online Feb 16. http://dx.doi.org/10.1016/S2213-2600(16)00025-4. Thapan K, Arendt J, Skene DJ. An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J Physiol 2001; 535: 261–67. Sand A, Schmidt TM, Kofuji P. Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res 2012; 31: 287–302. Gabel V, Maire M, Reichert CF, et al. Effects of artificial dawn and morning blue light on daytime cognitive performance, well-being, cortisol and melatonin levels. Chronobiol Int 2013; 30: 988–97.
www.thelancet.com/respiratory Published online February 16, 2016 http://dx.doi.org/10.1016/S2213-2600(16)00055-2
Human beings, like almost all animals, are subject to endogenous rhythms that are largely modulated by light and darkness. These circadian rhythms comprise biochemical and behavioural cycles of between 22 h and 25 h. Circadian rhythms are synchronised with daytime and night-time through specialised retinal cells.1 A central oscillator located in the suprachiasmatic nucleus of the hypothalamus controls several peripheral oscillators and thereby regulates most, if not all, physiological functions in relation to the environment, and particularly light. Darkness triggers melatonin release from the pineal gland. Concentrations of this hormone peak at around 2300 h and cause organ activity to slow. About 3 h after sleep onset, concentrations of cortisol start to increase and peak at around 0900 h. During the day cortisol levels decline progressively, reaching a nadir around midnight. Thus, transitioning light, especially from darkness to light, seems to be an important factor for the circadian rhythm of cortisol concentration.2 Stress can lead to misalignment of circadian rhythms, causing altered function in various body systems, including the cardiovascular, respiratory, endocrine, metabolic, and immune systems. Loss of circadian rhythms and sleep disruption are thought to be the hallmarks of critical illness, and have been associated with various factors related to disease and the environment in intensive-care units (ICUs).3 Systemic inflammation, particularly during sepsis, is strongly associated with disruption of internal cycles. Artificial light, noise, mechanical ventilation, and painful procedures are the most frequent ICU-related factors that affect chronobiology. Alterations to the central or peripheral oscillators, or both, might contribute to altered immune response in patients with critical illness and cognitive dysfunction. Interventions that might restore normal biological rhythms include drug and physical therapies. Small trials have suggested that oral melatonin has favourable effects on sleep quality in critically ill patients,4,5 although results are inconclusive for patient-centred outcomes, such as mortality, length of hospital stay, or post-traumatic stress disorders. In The Lancet Respiratory Medicine, Koen Simons and colleagues6 investigated whether dynamic high-intensity light in the daytime could reduce the risk
of ICU-acquired delirium in 734 critically ill adults. Over a 2-year period, patients admitted to the ICU of one hospital were randomly assigned the dynamic lighting application (bluish-white light up to 1700 lux) or normal lighting for the duration of their stay. No evidence was found of an effect on delirium, which occurred in 137 (38%) of 361 patients in the dynamic light and 123 (33%) of 373 in the normal light group (odds ratio 1·24, 95% CI 0·92–1·68, p=0·16). Likewise, dynamic light therapy had no significant effect on length of stay or survival in hospital. No differences were seen in circadian rhythm, but this was measured in only a small subgroup of 20 patients, and, therefore, it is unclear whether internal cycles were affected by light therapy. In the study of Simons and colleagues, patients were enrolled at the early phase of critical illness and a large proportion of them were sedated. Inappropriate population and timing may have accounted for the lack of benefit from light therapy. First, light needs to reach specific short-wavelength photopigments in the retina to modulate hypothalamic neurons and suppress melatonin secretion.7 Patients’ eyes must, therefore, be open for substantial amounts of time during exposure to light therapy. Second, the initial response to acute stress includes attenuation of circadian rhythms to allow control of homeostasis. Sustained disruption to internal cycles, however, might contribute to loss of organ function and poor outcomes.3 Restoration of normal chronobiology might, therefore, favourably affect the chronic rather than the acute trajectory of critical illness. Retinal ganglion cells expressing melanopsin are directly connected to the hypothalamic and other structures of the limbic systems to modulate the central oscillator in mammals.8 These cells are maximally sensitive to blue light, which indicates the relevance of light wavelength. Evidence suggests that simulation of dawn with artificial light starting 30 min before and ending 20 min after wake-up time improves cognitive function and mood.9 These data support the importance of transitioning light, particularly from darkness to light, in the restoration of body homoeostasis. In view of all these confounders, I suggest that future trials of ICU light therapy should enrol patients in the chronic phase of critical illness, when attempts are being made to wean them off life-supporting therapies and
www.thelancet.com/respiratory Published online February 16, 2016 http://dx.doi.org/10.1016/S2213-2600(16)00055-2
George Mattei/Science Photo Library
Light therapy and chronobiology in critical illness
Lancet Respir Med 2016 Published Online February 16, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)00055-2 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(16)00025-4
1
Comment
organs are healing. The therapy should comprise blue light and dawn simulation and continue beyond ICU discharge. Cognitive function in the long term would be a feasible main outcome. Djillali Annane
I declare no competing interests.
2
2
4
5
6
General intensive care unit, Raymond Poincaré Hospital (AP-HP), Laboratory of Inflammation and Infection, U1173, INSERM and University of Versailles SQY, 92380 Garches, France [email protected] 1
3
7
8
Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N Engl J Med 1983; 309: 469–76. Law R, Hucklebridge F, Thorn L, Evans P, Clow A. State variation in the cortisol awakening response. Stress 2013; 16: 483–92.
9
Oldham MA, Lee HB, Desan PH. Circadian rhythm disruption in the critically ill: an opportunity for improving outcomes. Crit Care Med 2016; 44: 207–17. 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. Mistraletti G, Umbrello M, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol 2015; 81: 1298–310. Simons KS, Laheij RJF, van den Boogaard M, et al. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial. Lancet Respir Med 2016; published online Feb 16. http://dx.doi.org/10.1016/S2213-2600(16)00025-4. Thapan K, Arendt J, Skene DJ. An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J Physiol 2001; 535: 261–67. Sand A, Schmidt TM, Kofuji P. Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res 2012; 31: 287–302. Gabel V, Maire M, Reichert CF, et al. Effects of artificial dawn and morning blue light on daytime cognitive performance, well-being, cortisol and melatonin levels. Chronobiol Int 2013; 30: 988–97.
www.thelancet.com/respiratory Published online February 16, 2016 http://dx.doi.org/10.1016/S2213-2600(16)00055-2
