Chronobiology and Anesthesia

Received from the Department of Anesthesiology and Intensive Care, Hôtel-Dieu Hospital, Lyon, France.CHRONOBIOLOGY investigates biologic rhythms that are involved in the organization of living organisms. 1Biologic rhythms consist of variations of biologic phenomena that are periodic and foreseeable in time. 2They are genetically determined as indicated by their persistence during constant conditions such as continuous light or darkness. 3Temporal variations in cycles of light-dark, rest-activity, fasting-eating, and other environmental conditions, defined as synchronizers , give the organism temporal markers and thus impose their period on these biologic rhythms. 4These rhythms can therefore be characterized by different periods, leading to the division of circadian (a period of approximately 24 h), ultradian (a cycle that is shorter than 1 day), and infradian (a cycle that may last weeks, months, or seasons). 5These clocks influence how our bodies change throughout the day, affecting blood pressure, activity of the immune system, blood coagulation, and gastric and renal functions. 2,6,7Almost all hormones are regulated by circadian rhythms. 8For example, cortisol naturally decreases to its lowest concentrations at bedtime and reaches its highest concentrations during the early waking hours. 9This variation may be fit to a sinusoidal function by the cosinor method, a linear method of least squares (fig. 1). This function is characterized by parameters such as the midline-estimating statistic of rhythm (MESOR), i.e. , the mean level that is equal to the 24-h average), amplitude (half of the peak-to-trough difference of the fitted cosinus function), and acrophase (the crest time of rhythm given in degrees, where 360° corresponds to a 24-h cycle, or in hours and minutes). 10Other methods, such as Fourier transformation, may be used to detect the periodicity of the rhythm. 11Biologic rhythms are influenced by socioecologic factors, such as jet lag and shiftwork, as well as by illness and drugs. Available clinical data have shown that signs and symptoms are not constant over time and often have cyclic patterns. More strokes and heart attacks occur in the morning compared with any other time of day, and people with osteoarthritis tend to feel less pain in the morning than at night. 12,13Studies also suggest that chemotherapy and treatments for asthma and arthritis may be more effective and less toxic if drugs are administered at carefully selected times. 14,15Taking into account the circadian rhythms for medical treatment by choosing the time of day for drug administration is called chronotherapy . Drug effects can be optimized and side effects can be reduced by basing drug administration on the circadian patterns of a disease.Chronopharmacology is the study of the influence of the moment of administration of a drug (hour, month, and year) on its response according to the temporal structure of the organism receiving it. 16Chronopharmacology also studies the drug-induced alterations of biologic rhythms. Two aspects of chronopharmacology must be distinguished: the time of administration of a drug may determine a different response from a qualitative or a quantitative point of view (chronopharmacodynamics) and/or a different effective drug concentration (chronopharmacokinetics). 17,18Pharmacokinetic parameters are influenced by different physiologic functions displaying circadian rhythm. 19Temporal changes of drug kinetics have been reported in animals and humans for more than a hundred drugs, including anesthetics. 20It has been shown, for example, that despite a constant infusion rate of heparin, the risk of bleeding and the activated partial thromboplastin are higher at night. 21Chronopharmacokinetic data may partly explain chronopharmacodynamic phenomena. 22Knowledge of the influence of the time of administration on the drug kinetics could therefore have implications for its prescription by modulating the distribution of the total daily dose over a 24-h period.The aim of this review is to provide an update on the chronobiologic and chronopharmacologic findings that could have an impact on the daily practice of anesthesiology and/or research in this area.The regulation of rhythmicity necessitates a central pacemaker, input pathways (synchronizers) connecting the clock to the external environment, and output pathways. In mammals, the central circadian pacemaker is located in the suprachiasmatic nucleus of the hypothalamus (fig. 2), and the main synchronizer is light. 23The suprachiasmatic nucleus receives two photic projections. Photoreceptors located in the retina project directly to the suprachiasmatic nucleus through the retinohypothalamic tract. Glutamate is the main signaling molecule at this synaptic connection. Photic information can also indirectly reach the suprachiasmatic nucleus through the intergeniculate leaflet, then through the geniculohypothalamic tract. The γ-aminobutyric acid (GABA) type A and neuropeptide Y act as signaling molecules at this synaptic connection. 24The circadian pacemaker can also be reset by nonphotic synchronizers such as locomotor activity, drugs, and feeding. Serotonergic afferent activity from the raphe nucleus and neuropeptide Y-GABA-mediated (GABAergic) input from the intergeniculate leaflet are involved in these pathways. Acetylcholine, histamine, and serotonin are involved in the control of the suprachiasmatic nucleus.The suprachiasmatic nucleus contains several different peptidergic types of cells, including vasopressin, calretinin, substance P, GABAergic, gastrin-releasing peptide, and somatostatin. 25Recording of electrical activity in the suprachiasmatic nucleus indicates that most of its neurons function as pacemakers. Previous studies have revealed that vasoactive intestinal peptide-expressing cells play a major role in its entrainment by light. 26The synthesis of melatonin in the pineal gland is one of the rhythms controlled by the suprachiasmatic nucleus. The neuronal input pathway regulating the pineal gland originates in the retina, which projects fibers to the suprachiasmatic nucleus via the retinohypothalamic tract. From the suprachiasmatic nucleus, the signal passes through the paraventricular nucleus, follows the medial forebrain bundle, and ends in the intermediolateral cell column of the upper thoracic spinal cord. From this, there is a projection to the superior cervical ganglion from which sympathetic neurons innervate the pineal gland. 27The signal to the pineal gland is norepinephrine, which is inhibited by light. The synthesis and release of melatonin are therefore stimulated by darkness and inhibited by light. The daily rhythm of melatonin is also controlled by the suprachiasmatic nucleus via GABAergic projections to the paraventricular nucleus.The secretion of cortisol is controlled in the suprachiasmatic nucleus. Basal plasma adrenocorticotropic hormone is rhythmically driven by the suprachiasmatic nucleus, resulting in a peak cortisol concentration in the early hours of the morning, with a minimal concentration around midnight. At least two hypothalamic peptides, corticotropin-releasing hormone and vasopressin, modulate adrenocorticotropic hormone release from the anterior pituitary. The suprachiasmatic nucleus is also directly involved in regulating the sensitivity of the adrenal cortex to adrenocorticotropic hormone. It has been proposed that the suprachiasmatic nucleus uses autonomic neuronal pathways to spread the circadian message to the adrenal gland. 28Clock genes are responsible for circadian rhythm. 24,29,30Their expression is detected in many organs, and expression is not restricted to the central pacemaker. A transcriptional feedback loop is at the center of the clockwork mechanism. CLOCK, BMAL1 and Rev-erbα are transcription factors that drive the expression of two cryptochrome genes (cry1 and cry2) and three period genes (per 1–3). The per and cry proteins block their own synthesis by inhibiting CLOCK and BMAL1. 29,30This feedback is delayed, generating oscillations. The genes that encode this feedback loop respond to synchronizers, of which light is one of the most important. Rhythms are not restricted to the central clock because circadian rhythms have been identified in peripheral organs, such as the heart and the liver, and also in isolated cells. Circadian rhythm persists in cultured suprachiasmatic nucleus neurons, and transplanted suprachiasmatic nucleus cells can restore circadian function of the suprachiasmatic nucleus. clocks have been shown to be directly regulated by cycles in can also change per expression in peripheral affecting the suprachiasmatic nucleus. of circadian rhythms that are regulated by synchronizers that signaling pathways in the hypothalamic suprachiasmatic The of circadian rhythms has been and biologic in cells or in to be at level by a circadian a in because of the in and of for many other drugs, the and of on the time of studies have shown circadian changes in or and data that the circadian of to is highest during the , the activity period for and lowest during the light , the period for dose of given in activity, with a of at lowest concentrations of and of in in during the at and of a over a 24-h period during the day compared with at for the at the of the at at h), to the time of influenced in a circadian because the activity of detected during the day and not at night. the that the of is at approximately at the 1). The of at with a difference to more than of the 24-h the conditions of daily the of or to be the at approximately and the of pain and the of a circadian rhythm The of with during in the period and than at and administered to at its shorter than given at or The peak drug concentration the highest at and the lowest at or findings could at least in that the highest of to in the a dose of at or highest at with its peak plasma data have been reported on the plasma of and in circadian variation in the of to heart and also with peak at in for and The in at and for and time in the of has also been in resulting in higher plasma concentrations morning studies have been to of anesthetics. In one of at and with a dose of during variation of the the plasma concentration as a difference in plasma according to the of with the the at its at of also for pain in receiving a infusion plasma concentrations not constant and in toxic plasma In of the continuous and constant infusion the plasma of during the 24-h with a at kinetics of the of higher plasma concentrations in the with an with pain plasma concentrations of could be by the of and could therefore be to the of the drug to the data in and humans according to changes in and to may explain temporal changes in and of into circadian variations of the circadian variations of total plasma concentrations of circadian variation of also for and with the at for and at for and highest amplitude in the circadian rhythm in into with the most in can also be by circadian variations of and variations in plasma and drug distribution have been for in and and in a temporal the plasma concentrations and the concentrations not the temporal variations of drug in and heart not explain the temporal changes of as drug is to on activity and/or blood on blood for drugs with a such as anesthetics. Circadian variations in blood could therefore explain temporal variations in the of drugs. A clinical study on of in daily variations of blood with higher in the morning (fig. has a impact on studies than on clinical The of of is often by the of a that is controlled by the or The circadian variations of the of of the effects of have not been the of many studies and could be of in studies have reported temporal changes these studies the of the and of the such as and are not in the of studies with have of because of the to drugs. studies circadian changes in the and of these drugs. It that in and are more toxic in the early morning, and is more toxic at of in the also higher at than at The of throughout the day, with from during the day to at night. of by has been to be during the period of the mean of by from at to the dose given at and the of from to administration of to more effective in the than in the studies higher or concentrations during the also that variation in drug is to the circadian changes in drug time for activity of the minimal (fig. for the temporal changes in clinical could be the of changes in the for A GABAergic and are as for studies have that type A GABAergic activity is during to the of the of influence of the time of day on the or of has to be well In is more toxic during the light of the cycle than during the studies have reported that plasma concentrations of the total and its are than and and higher by the of is at its highest and and by More the of to be at its at and at its at temporal in the sensitivity of the central to as in activity, a circadian in the of infusion of not to be of clinical of these circadian variations are In the circadian variation in the and activity of has been with a higher during the peak during the hours in type A GABAergic activity has been in the cortex of by and kinetics have been in the circadian of and changes in activity have been reduced activity during of circadian in concentrations of the and of to be higher an dose in the than a morning The of is also to The rate of of several and also over a 24-h circadian changes in and distribution or the of in total plasma during morning activity than during activity or morning the of or during the than during the circadian rhythm also a in to in This could be to melatonin secretion because these variations not study has been to a circadian rhythm for studies have shown the of a circadian in the expression of in the data are circadian changes for or The changes in the or of are also The concentration of in the at and to at (fig. study reported that the of by the of the and of these circadian changes have not been other circadian rhythmicity in activity as well in distribution and could be circadian changes for such as and have not been In the activity of during the activity by the the of by at (fig. This also with other drugs, decreases of and in with and for higher at than at during in changes in renal and activity could be involved in the circadian changes impact of on the clinical practice of anesthesiology to be be as any other in studies of drugs used in the practice of It be of to the impact of on the proposed in for such as or response to is not constant over the 24-h and the to study the circadian variation in the that the of at the minimal at in studies in also that the period a response to a shorter during the activity period (fig. at and sensitivity by the in response to in the higher at and early in the has also been shown that the of and on pain sensitivity is on this circadian rhythm of pain as a change for with these circadian rhythms in pain have been in The sensitivity of the to a at and a peak at sensitivity lowest and with a peak in pain at pain not the in all sensitivity to is minimal at and at electrical that a least at and a peak at In the the of pain to the electrical higher during the night. rhythms in pain have been also such as in with a morning peak during the variation in pain has also been reported a The peak of at and the least at in this the rate of compared with at The peak for or in the early morning and lowest during the in for the peak by a and difference with the a also in and a peak of identified and the for less in a of in the morning as compared with a pain has also been shown to a circadian The pain for arthritis has been reported to occur early in the is most at for and at as compared with pain at research has been on pain despite the an peak for to studies in humans have shown or findings with peak pain in the morning and/or the studies could not any temporal in pain is to that many factors influence circadian The which is the main synchronizer of biologic has been into account in involved than and not all have been by the type of pain throughout studies and the of the not the on the or the response to the that are In a electrical to pain the of pain that and the release of changes to in and animals can be different than pain in with in the of the where are may in study to a may influence circadian variations in pain many and studies have indicated a temporal in The of studies in humans have identified rhythms of a period for conditions, different types of and different in the of pain during a 24-h period could in circadian alterations in pain in and clinical concentrations of at the of the activity period as compared with concentrations at the of the period circadian rhythm in the of and changes in the concentration of and substance in different of the have been a peak during the activity variations of plasma concentrations of have been in and with higher in the morning compared with the morning of substance and in have been shown in the of melatonin is more at night. data must be with that pain decreases in melatonin and in melatonin secretion in drugs and are to many have shown that these drugs may have a circadian the that and side these drugs are often used during the studies have shown that the of are not constant throughout the plasma at for change for the peak concentration and change for the the and and higher concentrations change for the peak for given at and at other of the day or (fig. and morning has also been with and rate and of of release of in at than at time to peak the for not has been shown that of and the of chronobiologic variations in chronobiologic data are the circadian changes in the of are to alterations in drug In the plasma concentrations and the at distribution and total higher than during for is than that at night. blood to the in the morning, renal and plasma could also explain circadian changes in studies have on temporal changes in pain data are the of In a for administered has been concentration and the higher at at these temporal changes not in an treatment In two of with cell circadian changes in drug with an that shorter and total that during the night. to the time of in concentration and the for and its shown in a at at and effects and in the to in this difference to be to changes in drug plasma concentrations (fig. information is the for used during infusion over not any circadian change in receiving a constant data has been or in a study reported the of circadian variation in the distribution of in drug with a risk in the hours chronobiologic of the of on has been with a more at in with chronobiologic data are at this time for other drugs used as such as and these data that circadian effects in on pain have different patterns that are is that the time of day on the of pain and that the of to the of research on the aspects of and studies different pain the time of is by the pineal gland at or in a an melatonin and melatonin have been used to such as and jet have that their reported less pain and at night. The effects of melatonin occur at and are by the circadian rhythm in melatonin may and also and the and of several with a involved in several central physiologic including blood and regulation and several such as and as well as are in the in and may be to the of the circadian secretion of melatonin or to a drug-induced in circadian rhythm. circadian melatonin secretion has been to during the 24 findings are in with reported where the of the circadian of melatonin secretion not on the type of i.e. , or changes in melatonin secretion not in plasma melatonin concentrations a in plasma melatonin concentrations in with studies have shown that on and concentrations of the other a dose of melatonin the of by in a clinical of melatonin as a has been reported in one study that with melatonin or with a in and an in of nonphotic including can the of the circadian pacemaker. is a major in the and of have been shown to circadian rhythms in activity in by approximately and also of activity these The indicated that circadian rhythms by its effects on than by a on the circadian pacemaker. the of several circadian including and heart in not circadian rhythm in melatonin the and of and has also has a role in the regulation of circadian which are often in and has been proposed as a The of melatonin as an in humans must be of have for for and asthma with of and and morning administration of has to be is to the role of in and of the of clinical is to in to drugs. to and the time of drug effects physiologic and conditions, including the The effects of on the parameters of and are often by the of that are identified are and physiologic is not often into account because the that studies are are of the involved in the of drugs are to circadian circadian variations in of plasma rate of of and have been is on blood which has been shown to by to during a 24-h in blood concentrations of drugs with a such as and could be to a in drugs used in are by the A of data that studies be carefully at different of is given by the chronopharmacology of for constant of also reported in the study an of and a of these findings are for studies restricted to morning data could to an or of compared with and for the A chronopharmacologic provide in studies of than the which not The influence of time of administration on the of side effects is also of for of on physiologic such as blood pressure, and may be influenced by circadian At the cell activity, and expression are also by 24-h in blood pressure, heart and output to In renal as by is during the day than at all such as and and and heart rate A 24-h rhythm of the in a circadian with a at an amplitude of and acrophase at variation in has been with a morning at compared with in the and in the and circadian rhythms in people and in to is more and and as compared with at and in the and circadian patterns. the dose of at different of the day, in and higher at and at of the 24-h changes in the of are in morning hours of the day are with higher blood concentrations of factors, activity, and an in The and and and are and concentrations of activated and 1 at as compared with plasma concentrations at and the plasma concentrations of higher at than the at concentrations at a at and a of the at studies have shown that the effects of or on on the time the The sensitivity of to or is not the throughout the effective concentrations for and at and The also a temporal with a at compared with many of these circadian changes are and may the of clinical or in and in study the time of the day in the The of any that time of the day be as a that could have an impact on the impact of may be of physiologic where early alterations can be detected in of changes in rhythm It may be to symptoms and there is and heart rate in and their highest during the day, by a and an early morning In this is or in blood Two risk with in the risk of are circadian a characterized by an circadian amplitude of blood pressure, and alterations in heart rate of blood and heart rate provide information the risk of in heart must be to are at the highest risk of or heart rate is with an in the risk of an circadian blood amplitude is with an in the risk of of such a to detect at risk for during the period is to be of pain has been over the has on the of drugs and on the of of studies have also on circadian changes in The have to a with in the morning or in the of cyclic variations in pain may changes in for a type of could be by of the of drug This is by studies resulting from the and of of or at a constant and continuous temporal variation in the of pain and a of chronobiologic studies the influence of biologic rhythms on the of information is on the of circadian rhythm and the influence of such rhythms on the and of drugs. the sensitivity of many drugs, and variations in pain are to the daily practice of pain for information circadian rhythms for and of in the of has for the of clinical or temporal patterns of drug or the of in the of research could have a impact on the and be controlled The impact of on the clinical practice of is less or on the influence of circadian rhythms on and is of for in the of the

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