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CARDIOVASCULAR ANESTHESIA

Perioperative Melatonin Secretion in Patients Undergoing Coronary Artery Bypass Grafting

Xiangyang Guo, MD PhD^*, Eiko Kuzumi, MD^*, Susan C. Charman, MSc, and Alain Vuylsteke, MD^*

*Anaesthetic Research Unit and Department of Cardiothoracic Anaesthesia, Papworth Hospital; and Medical Research Council, Biostatistics Unit, Cambridge, United Kingdom

Address correspondence and reprint requests to Alain Vuylsteke, MD, Department of Cardiothoracic Anaesthesia, Papworth Hospital, Cambridge, CB3 8RE, UK. Address e-mail to alain.vuylsteke{at}which.net

	Abstract

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Melatonin, a neurohormone, plays an important role in adjusting the "biological clock" in humans. We sought to describe perioperative patterns of melatonin secretion in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass (CPB). After IRB approval and written informed consent, 12 male patients scheduled for elective coronary artery bypass grafting under hypothermic CPB were enrolled in the study. During anesthesia, patients’ eyes were carefully covered to prevent light effects. Blood samples were taken at specific time points during surgery, every 3 h in the immediate postoperative period, and for 24 h from 6:00 PM of Postoperative Day 2 until 6:00 PM of Postoperative Day 3. Plasma melatonin and cortisol concentrations were measured by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. During surgery, plasma melatonin concentrations were below the minimum sensitivity concentration, yet small concentrations, without circadian variation, were detected during the immediate postoperative period. During Postoperative Days 2 and 3, circadian secretion patterns of melatonin were present in 10 patients and showed an inverse correlation with light intensity (r = 0.480; P < 0.01). Plasma cortisol concentrations in the immediate postoperative period were significantly larger than those before the induction of anesthesia (P < 0.01). Only three patients regained circadian secretion of cortisol. We concluded that melatonin and cortisol secretion was disrupted during cardiac surgery with CPB and in the immediate postoperative period. However, circadian rhythms of melatonin were present in most patients from Postoperative Day 2. Only 30% of the patients regained circadian rhythm of cortisol secretion.

IMPLICATIONS: Melatonin is a hormone that plays an important role in adjusting the biological clock in humans and that regulates secretion of various other hormones. We studied melatonin secretion in patients undergoing cardiac surgery with cardiopulmonary bypass. Melatonin secretion was disturbed during and immediately after surgery but had recovered a circadian rhythm 24 h later, raising the question of whether melatonin should be supplemented before cardiac surgery.

	Introduction

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Melatonin is a neurohormone mainly secreted by the pineal gland. It possesses a circadian secretion pattern, with small blood concentrations during the day and large concentrations at night. Physiologically, melatonin plays an important role in human homeostasis and psychiatric behaviors by adjusting the biological clock located at the suprachiasmatic nuclei of the anterior hypothalamus (1,2). Melatonin also exhibits complex effects on neuroimmunomodulation and antioxidant defense systems (3,4). Although the pathophysiologic implications of disturbed melatonin secretion have not been elucidated, clinical studies show that nocturnal secretion of melatonin in patients with Alzheimer’s disease, coronary heart disease, and stroke is decreased (5–7). Deficiency of nocturnal secretion of melatonin has also been documented in patients after gynecological surgery and patients in the respiratory intensive care unit (ICU) (8,9). The disturbance of melatonin secretion has also been linked to sleep deprivation, ICU psychosis, and many other behavioral disorders (10).

An exaggerated endocrine response, including a significant increase of cortisol, catecholamines, and growth hormones after cardiac surgery, has been described (11,12). However, perioperative melatonin secretion has not been fully evaluated. The aim of this study was to describe melatonin circadian secretion profiles both during cardiac surgery and in the postoperative period in patients undergoing coronary artery bypass grafting (CABG). Cortisol circadian secretion profiles are also described.

	Methods

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This observational cohort study was performed during a summer photoperiod (from June to September). After Local Research Ethics Committee approval and written informed consent, 12 male patients scheduled for elective CABG were recruited into the study.

Exclusion criteria were exogenous hormone therapy and known endocrine (including diabetes mellitus), renal, hepatic, or central nervous system dysfunction. Patients with multiple myocardial infarctions in the past, a history of valvular disease, previous open-heart surgery, or uncontrolled hypertension (diastolic blood pressure >110 mm Hg) were also excluded. Aspirin and other nonsteroidal antiinflammatory drugs were discontinued 7 days before surgery, but antihypertensive treatment, including ß-blockers and calcium channel blockers, was continued until the morning of surgery.

All recruited patients received the same anesthetic regimen. Anesthesia was started at 8:30 AM. After premedication with IM morphine (10–15 mg) and scopolamine (0.3–0.4 mg), patients received IV midazolam (0.1 mg/kg), and an arterial catheter (Insyte^® Vialonor^®; Becton Dickinson, Franklin Lakes, NJ) was inserted. Anesthesia was induced and maintained with propofol (3 mg · kg^-1 · h^-1) and supplemented with fentanyl (15 µg/kg). Neuromuscular blockade was achieved by the administration of pancuronium (0.15 mg/kg). Intermittent mechanical ventilation was performed with an air/oxygen mixture, during which PaCO₂ was maintained at 35–40 mm Hg. Patients’ eyes were carefully covered throughout the operation with a gauze pad and another layer of tape to avoid light effects.

A standard cardiopulmonary bypass (CPB) technique was used in all patients by use of cold crystalloid cardioplegia (St. Thomas’ Hospital cardioplegia solution) and continuous aortic cross-clamping. Heparin (300 U/kg) was administered before aortic cannulation. The CPB circuit consisted of a hollow-fiber membrane oxygenator (Maxima^®; Medtronic, Anaheim, CA) and a roller pump (Cobe Laboratory, Denver, CO), which was primed with a standard solution consisting of crystalloid (100–1500 mL) and mannitol (350–500 mL). A hard-shell venous reservoir, open to air, was used with an integral cardiotomy reservoir. Nonpulsatile CPB was used with a flow rate of 1.8 L · min^-1 · m^-2. Perfusion pressure was maintained between 50 and 60 mm Hg. PaCO₂ during CPB was controlled with the -stat method (temperature uncorrected). Patients were cooled to a nasopharyngeal temperature of 28°C–32°C immediately after the onset of CPB, the ascending aorta was cross-clamped, and cold, crystalloid cardioplegia solution was administered. Body temperature was restored to 37°C after the distal anastomosis of the last graft.

After surgery, all patients remained intubated and were transported to the same ICU. Artificial ventilation was continued until sufficient spontaneous ventila- tion was regained. During this period, propofol infusion was continued for sedation at 2 mg · kg^-1 · h^-1. Analgesia was achieved with morphine infusion at 0–50 µg · kg^-1 · h^-1. All patients were extubated upon stable cardiovascular and respiratory conditions. Subsequent analgesia was achieved with a morphine infusion at 0–50 µg · kg^-1 · h^-1. Oral paracetamol 1 g and dihydrocodeine tartrate (DF 118 Forte^®, Martindale Pharmaceuticals Ltd., Romford, Essex, UK) 40 mg were started on the morning of Postoperative Day 1, four times daily. From the late morning of Postoperative Day 1 onward, patients with stable hemodynamic and respiratory conditions were transported to a surgical ward for further recovery.

During the day of surgery and the immediate postoperative period, blood samples were taken from the arterial line at the following time points: immediately before the induction of anesthesia but after premedication (T1), 10 min after the induction of anesthesia (T2), just before starting CPB (T3), 30 min after commencement of CPB (T4), 2 min after separation from CPB (T5), at the end of skin closure (T6), and every 3 h for 18 h after arrival in ICU (T7, T8, T9, T10, T11, and T12; clock time 3:00 PM, 6:00 PM, 9:00 PM, midnight, 3:00 AM, and 6:00 AM, respectively). During Postoperative Days 2 and 3, blood samples were taken three times an hour from the central IV line (Multicath^® 9F; Laboratoires Pharmaceutiques Vygon, Ecouen, France) from 6:00 PM on Day 2 until 6:00 PM on Day 3. Each sample was a maximum of 5 mL of blood. Plasma was immediately separated by refrigerated centrifugation at 1500g for 15 min at -4°C. The plasma was stored at -70°C for later analysis.

Plasma concentrations of melatonin were measured in duplicate by using radioimmunoassay (Stockgrand, Guildford, UK) (13). The analytical detection limit of the assay for melatonin was 12.1 ± 5.2 pmol/L. The intraassay coefficient of variation was 6.7%.

Plasma concentrations of cortisol were measured by the enzyme-linked immunosorbent assay (Boehringer Mannheim Immunodiagnostics, East Sussex, UK) by using the ES700 (Boehringer-Mannheim Biochemica, Mannheim, Germany) automated immunoassay analyzer. The lower detection limit of cortisol was 27.6 nmol/L. The intraassay coefficient of variation of the assay was 5.6% at 67 nmol/L and 2.9% at 800 nmol/L. The interassay coefficient of variation was 11.5% at 67 nmol/L and 5.5% at 800 nmol/L. Both melatonin and cortisol values were corrected for hemodilution by using concurrent hematocrit values (14).

After the patients were transported to the ICU, light intensities were measured with a digital light meter (RS Components Ltd., Taiwan) at the same time the blood samples were drawn. Meter readings of ambient light were recorded at the eye level close to the patient’s head. It was measured without awakening or disturbing the patient.

The data were analyzed with the SPSS package (version 10.0; SPSS, Inc., Chicago, IL). Nonparametric analysis of variance (Friedman test) was used to compare sequential alterations in plasma melatonin and cortisol with baseline values (data collected before the induction of anesthesia served as controls for the rest of the data obtained during the day of surgery, and data collected at 6:00 PM on Day 2 served as controls for the analysis of the series of data from Postoperative Days 2 and 3). Data are expressed as minimum, maximum, median, 25th percentile, and 75th percentile values. To adjust for multiple comparisons, a P < 0.01 for post hoc comparison (Wilcoxon’s signed rank test) was considered significant. Spearman’s rank test served to analyze the correlation between melatonin and light.

To establish whether melatonin or cortisol exhibited circadian rhythm, a cosinor analysis was completed (15). A cosine function of the form f(t)= M + A cos(t + ) was fitted for each patient for time points T13 (6:00 PM Day 2) to T21 (6:00 PM Day 3). In the previous equation, f(t) is melatonin (or cortisol) at time t, and is fixed and depends on the period of the function (24 h in this case). The variables M, A, and are estimated by least squares and are interpreted as follows: M is the estimated mean (mesor) value over the 24-h period, the amplitude (A) is the estimated maximal deviation from the mean, and the acrophase indicates where in the time frame the maximum occurs. We can conclude that the cosine curve is better than a straight line, thus implying rhythmicity, if A is significantly different from 0 (P < 0.05).

	Results

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Demographic and perioperative data are described in Table 1. The list of perioperative medication that may theoretically affect melatonin secretion is presented in Table 2. All patients took oral ß-blockers, and five patients received calcium channel blockers on the morning of surgery, but these drugs were not restarted before the end of the study period. One patient asked to be withdrawn from the study at 9:00 PM on Day 2.

View larger version (14K): [in this window] [in a new window]   Figure 1. Plasma levels of melatonin (A) and light intensity (B) during surgery and in the immediate postoperative period. The box represents the 25th–75th percentiles; the middle line is the median; the extended bars represent the 10th–90th percentiles; and circles represent values outside this range. ICU = intensive care unit. T values are sample times: T1 = before the induction of anesthesia; T2 = 10 min after the induction of anesthesia; T3 = before starting cardiopulmonary bypass (CPB); T4 = 30 min after the commencement of CPB; T5 = 2 min after separation from CPB; T6 = at the end of skin closure. T7 to T12 are 3-h interval samples taken for 18 h from arrival in the ICU.

View larger version (17K): [in this window] [in a new window]   Figure 2. Plasma levels of melatonin (A) and light intensity (B) from 6:00 PM of Postoperative Day 2 to 6:00 PM of Postoperative Day 3. The box represents the 25th–75th percentiles; the middle line is the median; the extended bars represent the 10th–90th percentiles; and the circles represents values outside this range. *P < 0.01 versus the value tested at 6:00 PM on Day 2.

View larger version (29K): [in this window] [in a new window]   Figure 3. Individual patient’s graphs showing the actual plasma concentrations of melatonin (+ + +), the fitted cosine function for melatonin (——), and the fitted cosine function for light ( · · · · ) during the second study period, from 6:00 PM on Day 2 to 6:00 PM on Day 3. The fitted line is the result of a cosinor analysis (see text for details).

No significant alteration in plasma cortisol concentration was observed during surgery. However, in the immediate postoperative period, cortisol concentrations at 6:00 PM, midnight, 3:00 AM, and 6:00 AM were significantly larger than those before the induction of anesthesia (P < 0.01). During Postoperative Days 2 and 3, no significant difference of cortisol concentrations was detected if compared with the baseline value. There was a circadian secretion pattern in 3 of the 12 patients (Table 4).

	Discussion

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Our data are inconsistent with previous reports that observed the melatonin profile in patients receiving gynecological surgery. Reber et al. (17) studied the effect of isoflurane and propofol, as well as darkness, in gynecological patients. They reported increased plasma melatonin concentrations that persisted in the recovery period in patients anesthetized with isoflurane, whereas melatonin concentrations decreased gradually during the recovery period in patients anesthetized with propofol. They also reported in the same study that plasma melatonin concentrations were significantly smaller in both groups after premedication with an oral benzodiazepine. This is in agreement with reports showing that benzodiazepines inhibit melatonin secretion by acting on the -aminobutyric acid receptor complex (18). This may account for the absence of melatonin at the start of surgery in all the patients participating in this study, because all received midazolam before radial artery catheterization. Other reports have also shown that ß-blockers are another class of drug that may suppress nocturnal melatonin secretion by inhibiting pineal -adrenergic receptors (19). In this study, all patients received ß-blocker treatment in the morning before surgery. Other therapies, such as calcium channel blockers (20) and nonsteroidal antiinflammatory drugs, may also inhibit melatonin secretion (21). However, there are drugs that can enhance melatonin secretion, and there is also evidence that in patients with coronary artery disease who already demonstrate a marked decrease in nighttime melatonin synthesis without receiving ß-blocker treatment, the introduction of a ß-blocker (atenolol or metoprolol) does not induce further significant suppression of nocturnal melatonin production (7). Morphine can stimulate the release of melatonin, as shown in animal studies (22), and this might explain the sporadic melatonin secretion detected at the end of surgery that coincided with the commencement of a morphine infusion. However, the effect of premedication with morphine and the administration of fentanyl during anesthesia on melatonin secretion was not observed in this study.

Light is a strong timekeeper for human circadian rhythm and influences several endocrine and neuroendocrine functions. In this study, melatonin concentrations showed inverse correlation with light intensity, and these results are in accordance with the unequivocally demonstrated fact that nocturnal light exposure inhibits nighttime secretion of melatonin (23–25).

It is interesting to note that during the immediate postoperative period, disrupted melatonin secretion accompanied significantly larger concentrations of cortisol. High-level cortisol inhibits melatonin secretion (26,27), but it has also been demonstrated that melatonin regulates other hormone secretion by acting on melatonin receptors in the suprachiasmatic nuclei, the internal biological clock, the pituitary gland, and the adrenal gland (2). In addition, melatonin possesses both hypnotic and analgesic effects (28). Therefore, small melatonin secretion may in itself exaggerate the stress response. Although use of melatonin as a therapeutic drug remains controversial in terms of safety and is not approved for use by the Food and Drug Administration, preliminary reports on melatonin toxicology in volunteers (29), efficacy as a premedication before surgery (30), and treatment in critically ill patients for sleep deprivation in the ICU (31) are encouraging. However, the timing and dosage of administration of melatonin should be well designed according to the endogenous melatonin secretion status, particularly during the postoperative period, hence the importance of continuing such studies.

In summary, we demonstrated that perioperative melatonin and cortisol secretions in patients undergoing CABG surgery with CPB were disturbed in our study population. A circadian secretion pattern for melatonin, but not for cortisol, was, however, present on Postoperative Day 2 in most of the patients.

	Acknowledgments

 
Xiangyang Guo, MD, PhD, was sponsored by the Royal Society Fellowship Program, UK.

	Footnotes

 
Presented in part at the autumn meeting of the Association of Cardiothoracic Anaesthetists of Great Britain and Ireland, Cumbria, UK, November 3, 2000.

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