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 after destruction of the host suprachiasmatic nucleus. Peripheral tissue clocks have been shown to be directly regulated by light-dark cycles in culture. 31Glucocorticoids can also change per gene expression in peripheral tissues without affecting the suprachiasmatic nucleus. 32In conclusion, current understanding of mammalian circadian rhythms suggests that they are regulated by synchronizers that target signaling pathways in the hypothalamic suprachiasmatic nuclei. The genetic basis of circadian rhythms has been established, and almost every biologic process in cells or in organs seems to be affected at some level by a circadian clock.Anesthesiologists choose a particular local anesthetic in part because of the differences in onset and duration of effect. As for many other drugs, the efficacy and toxicity of local anesthetics depend on the time of administration.Many studies have shown circadian time-dependent changes in acute or chronic toxicity, and data indicating that the circadian susceptibility of mice to local anesthetics is highest during the dark phase (i.e. , the activity period for mice) and lowest during the light phase (i.e. , the resting period for mice). 33A single dose of 65 mg/kg lidocaine given intraperitoneally in mice induces convulsant activity, with a maximal percentage of convulsions (83%) occurring at 21:00 h. 33The lowest concentrations of bupivacaine and mepivacaine inducing 50% of mortality in rodents (LD50, in mg/kg) occurred during the dark period, at 22:00 and 19:00 h, respectively. Mepivacaine values of LD50varied within a 30% range over a 24-h period (100 mg/kg during the day compared with 130 mg/kg at night). 34Latency for lidocaine-induced convulsions was the shortest at the beginning of the night (128 ± 11 s at 23:00 h vs. 177 ± 14 s at 10:00 h), corresponding to the time of maximal mortality. 35In addition, flumazenil influenced lidocaine-induced toxicity in a circadian time-dependent manner because the antagonist activity of flumazenil was only significantly detected during the day and not at night. 35Overall, the results show that the longest duration of anesthesia is at approximately at 15:00 h, whatever the local anesthetic agent (table 1). The longest duration of lidocaine skin anesthesia was found at 15:00 h, with a large peak-trough difference amounting to more than 100% of the 24-h mean. 36Under the conditions of daily dental practice, the duration of mepivacaine or articaine anesthesia was found to be the longest at approximately 15:00 h, and both the onset of pain and the disappearance of numbness followed a similar circadian rhythm 37(fig. 3). The duration of epidural analgesia with ropivacaine during labor was longer in the diurnal period (117 ± 23 min between 13:00 and 19:00 h) than at night (91 ± 23 min between 19:00 and 01:00 h) 38(fig. 4).When intramuscular lidocaine was administered to mice at 16:00 h, its elimination half-life was shorter than when given at 10:00, 22:00, or 04:00 h. The peak drug concentration (Cmax) was the highest (6 μg/ml) at 16:00 h and the lowest (3 μg/ml) at 10:00, 22:00, or 04:00 h. 39These findings could explain, at least in part, that the highest susceptibility of mice to lidocaine was observed in the dark period. 33,35In rats, after a single dose of 20 mg/kg intraperitoneal bupivacaine at 10:00, 16:00, 22:00, or 04:00 h, toxicity was highest at 22:00 h, coinciding with its peak plasma concentration. 40Similar data have been reported on the plasma chronokinetics of etidocaine and mepivacaine in mice. 41A significant circadian variation in the penetration of local anesthetics to heart and brain tissues was also demonstrated, with peak values at 10:00 h in cardiac tissue for bupivacaine, etidocaine and mepivacaine. The maximum penetrations in brain tissue were at 10:00, 16:00, and 22:00 h for bupivacaine, etidocaine and mepivacaine, respectively. 41,42A time dependency in the transcutaneous passage of lidocaine has also been investigated in rats, resulting in significantly higher plasma concentrations after morning application. 43Several human studies have been devoted to chronokinetics of local anesthetics. In one study, four groups of men were injected at 09:30, 12:30, 15:30, and 18:30 h with a single dose of 0.65 mg/kg lidocaine during dental surgical interventions. 44A significant variation of the area under the plasma concentration curves (as much as a 30% difference in plasma concentration) was demonstrated according to the hour of injection, with the area under the curve at its greatest at 15:30 h (table 2).The chronokinetics of bupivacaine were also investigated for postoperative pain relief in patients receiving a constant-rate epidural infusion (0.25 mg · kg−1· h−1for 36 h). 45Bupivacaine plasma concentrations were not constant and in addition never reached toxic plasma concentrations. In spite of the continuous (36 h) and constant infusion rate, the plasma clearance of bupivacaine varied during the 24-h period, with a maximum clearance at 06:30 h (approximately 60% change).The kinetics of the cutaneous application of lidocaine had significantly higher lidocaine plasma concentrations in the evening, with an inverse correlation with pain scores. 43The plasma concentrations of local anesthetics could be affected by the degree of elimination and could therefore be inversely correlated to the amount of the drug applied to the skin. These data obtained in rodents and humans had opposite synchronization, according to phase.Circadian changes in membrane permeability and access to channels may partially explain temporal changes in local anesthetic efficacy and kinetics. Penetration of lidocaine into rat erythrocytes showed circadian variations independently of the circadian variations of total plasma concentrations of lidocaine. 39,42A circadian variation of erythrocyte penetration was also demonstrated for bupivacaine, etidocaine, and mepivacaine, with the maximum occurring at 04:00 h for bupivacaine and at 10:00 h for etidocaine and mepivacaine. 42,46The highest amplitude in the circadian rhythm in local anesthetic penetration into erythrocytes was observed with the most lipophilic compound, bupivacaine.Differences in chronokinetics can also be explained by circadian variations of distribution, protein binding, and metabolism. Temporal variations in plasma protein binding and drug distribution have been documented for lidocaine in rats and bupivacaine, etidocaine, and mepivacaine in mice. 47However, a temporal relation between the respective free plasma concentrations and the tissue concentrations was not demonstrated. Therefore, the temporal variations of free drug in plasma, brain, and heart do not explain the temporal changes of local anesthetic-induced mortality as previously demonstrated. 48,49Hepatic drug metabolism is generally assumed to depend on liver enzyme activity and/or hepatic blood flow. Metabolism mainly depends on hepatic blood flow for drugs with a high extraction ratio, such as local anesthetics. Circadian variations in hepatic blood flow could therefore explain temporal variations in the clearance of local anesthetic drugs. A clinical study on hepatic clearance of indocyanine green in human volunteers documented daily variations of hepatic blood flow, with higher values occurring in the morning (fig. 5). 50Chronobiology has a greater impact on pharmacokinetic studies than on clinical practice. The duration of effect of local anesthetics is often circumvented by the use of a pump that is controlled by the patient or physician. The circadian variations of the speed of onset of the effects of local anesthetics have not been the object of many studies and could be of practical interest, particularly in obstetric anesthesia.Numerous studies have reported temporal changes among general anesthetic agents. However, these studies were performed before the discovery of the newer anesthetic agents propofol, desflurane, and sevoflurane. Furthermore, some of the older agents, such as ether and althesin, are not currently in use. However, the results of initial chronopharmacokinetic studies performed with older agents have remained of interest because of the possible applicability to newer drugs. Initial studies evaluated circadian changes in the toxicity and efficacy of these drugs. It seems that in mice and rats, barbiturates are more toxic in the early morning, and althesin is more toxic at 10:00 h. 51,52Althesin-induced duration of anesthesia in the rat was also 120% higher at 12:00 h than at 06:00 h. The toxicity of halothane (3.5%) varies throughout the day, with mortality ranging from 5% during the day to 76% at night. 53The duration of sleep produced by 60 mg/kg pentobarbital has been found to be longer during the resting period of mice. 54In rats, the mean duration of anesthesia induced by 35 mg/kg pentobarbital varied from 53 min at 09:00 h to 90 min when the same dose was given at 19:00 h, and the efficacy of pentobarbital was maximal from 17:00 to 20:00 h. 55,56Oral administration of hexobarbital to volunteers was more effective in the evening than in the morning. 57Initial pharmacologic studies showed higher brain pentobarbital or hexobarbital concentrations when mice were injected during the dark phase. 58,59These investigations also showed that endogenous variation in hepatic drug metabolism is correlated to the circadian changes in drug efficacy. Sleeping time for hexobarbital was maximal when activity hexobarbital of the hepatic oxydase was minimal (fig. 6). 60Another explanation for the temporal changes in clinical efficacy could be the existence of diurnal changes in the target receptor for barbiturates. Type A GABAergic and N -methyl-d-aspartate receptors are now considered as important sites for general anesthetic action. 61,62Several studies have produced evidence that postsynaptic type A GABAergic activity is increased during nocturnal hours, 63corresponding to the duration of the maximal efficacy of barbiturates.The influence of the time of day on the sedative or anesthetic properties of benzodiazepines has yet to be well explored. In mice, intraperitoneal diazepam is more toxic during the light phase of the cycle than during the dark phase. 64Pharmacokinetic studies have reported that plasma concentrations of the total diazepam and its metabolite, N-desmethyldiazepam, are lower than predicted between 23:00 and 08:00 h and higher by 09:00 h. 65In contrast, the free fraction of diazepam is at its highest between 23:00 and 08:00 h and lower by 09:00 h. More recently, the elimination half-life of midazolam was found to be at its shortest at 14:00 h and at its longest at 02:00 h (1.26 ± 0.47 vs. 1.57 ± 0.44 h [mean ± SD]). 66A temporal pattern in the sensitivity of the central nervous system to midazolam, as reflected in α wave activity, occurred after short infusion, whereas a circadian fluctuation in the sedative properties of long-term infusion of midazolam (26 h) was not considered to be of clinical significance. 66,67The mechanisms of these circadian variations are probably multifactorial. In the rat, circadian variation in the number and activity of benzodiazepine receptors has been reported, with a higher number during the resting period. peak during the nocturnal hours in postsynaptic type A GABAergic activity has been demonstrated in the cortex of enzyme by and kinetics have been in the circadian of and changes in activity have been reported, whereas reduced activity during of increased circadian in concentrations of Furthermore, the and of midazolam were found to be higher after an dose in the than after a morning The protein binding of diazepam is also to diurnal The rate of of several benzodiazepines and probably also varies over a 24-h period. significant circadian changes in and distribution or the elimination of midazolam were observed in volunteers total plasma clearance was lower during morning activity than during evening activity or morning the duration of after mg/kg or 60 mg/kg was longer during the night than during the circadian rhythm also followed a pattern between in to in This could be to melatonin secretion because these variations were not observed after human study has been performed to a circadian rhythm for studies have shown the existence of a circadian in the expression of N -methyl-d-aspartate receptors in the data are currently circadian changes for or The diurnal changes in the efficacy or toxicity of agents are also explored. The concentration of halothane in the rat was at 12:00 h and increased to at 20:00 h (fig. human study reported that the greatest efficacy of halothane (as by the of the occurred between and 06:00 h. mechanisms of these circadian changes have not been other general circadian rhythmicity in receptor number activity as well in distribution and metabolism could be circadian changes for newer agents, such as and have not been explored. In rats, the activity of was lower during the activity period. by the area under the curve of within min was by at night (fig. This nocturnal was also observed with other drugs, inducing decreases of and in with and respectively. for were higher at 09:00 h than at h during performed in changes in renal elimination and activity could be involved in the circadian changes impact of on the clinical practice of anesthesiology to be However, be considered as any other in pharmacokinetic studies of drugs used in the practice of It be of interest to the impact of on the pharmacokinetic currently proposed in anesthesia for agents such as or response to is not constant over the 24-h period. and the to study the circadian variation in analgesia the showed that the maximal effect of occurred at 21:00 h whereas the minimal effect was obtained at 15:00 h in mice. studies in rodents also showed that the period before a response to a was shorter during the activity period (fig. were at 09:00 and 15:00 h. sensitivity by the in response to in the rat was higher at and early in the morning. has also been shown that the of and N on pain sensitivity is on this circadian rhythm of pain (as much as a 60% change for with these circadian rhythms in pain have been demonstrated in The sensitivity of the to a was maximal at h and reached a peak at h sensitivity was lowest between 15:00 and h, with a peak in pain at 08:00 h pain not the same pattern in all sensitivity to is minimal at h and maximal at 06:00 h. electrical that induced a was least at 01:00 h and reached a peak at 17:00 h In the same study, the of pain to the electrical was higher during the night. rhythms in acute pain have been also such as in dental with a morning peak during the postoperative variation in pain has also been reported after a analgesia The peak of use occurred at 09:00 h and was the least at 15:00 h in patients this study, the rate of was ± compared with ± at night ± The peak for or occurred in the early morning and was lowest during the night in postoperative patients for the peak by a analgesia pump was obtained between 08:00 and 12:00 h difference with the night a pattern was also found in and a peak of was identified between 16:00 and 20:00 h. surgical the for was less in a of patients performed in the morning mg · kg−1· as compared with a mg · kg−1· pain has also been shown to a circadian The greatest pain for arthritis has been reported to occur early in the morning. is most at night for and at 20:00 h as compared with pain at 08:00 h). research has been performed on chronic pain despite the large patient patients showed an evening peak for to studies in humans have shown or findings between with peak pain occurring in the morning and/or the human studies could not show any temporal pattern in pain is important to that many factors influence circadian The which is the main synchronizer of human biologic has been into account in investigations involved than four and not all have been by the type of pain varied throughout studies and the of the was not However, the results depend on the or the response to the that are In addition, a electrical applied to pain the of pain that and the release of Temporal changes to in volunteers and animals can be different than pain in patients with chronic in the of the where are applied may differences in study to a may influence circadian variations in pain many and human studies have indicated a temporal pattern in The results of studies in humans have identified rhythms of a particular period for conditions, different types of and different in the of pain during a 24-h period could in circadian alterations in pain observed in and clinical concentrations of were lower at the of the activity period ± as compared with brain concentrations at the beginning of the period ± circadian rhythm in the of and time-dependent changes in the concentration of and substance in different brain of the rat have been indicating a peak during the activity period. variations of plasma concentrations of have been demonstrated in and with higher values in the morning compared with the morning values of substance and in human have been shown in the effect of melatonin is more at night. data must be with that acute pain produced decreases in melatonin and in melatonin secretion in 11

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