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Postoperative delirium and plasma melatonin
Medical Hypotheses (1999) 53(2), 103–106 © 1999 Harcourt Publishers Ltd Article No. mehy.1998.0724
Postoperative delirium and plasma melatonin K. Uchida,1 T. Aoki,1 B. Ishizuka2 1 2
Department of Anesthesiology Department of Obstetrics and Gynecology, St Marianna University School of Medicine, Kawasaki, Japan
Summary The molecular mechanisms of postoperative delirium are not understood in detail yet. This condition is similar to cases of mental symptoms in interferon therapy or hemodialysis. We propose that postoperative delirium is caused by a deficiency of serotonin, an important neurotransmitter, and review the evidence supporting our hypothesis. The serotonin deficiency results from a decrease in tryptophan, the serotonin precursor, and from an increase in melatonin, a serotonin metabolite. Our hypothesis may be applicable to the mechanisms of mental symptoms in interferon therapy and hemodialysis. In addition, we discuss to the relationship between homeostasis and biorhythms because postoperative delirium may be a dysrhythmia. INTRODUCTION Psychiatric complications are sometimes recognized in patients admitted to the intensive care unit after surgery. Postoperative delirium is differentiated from other postoperative complications using the diagnostic criteria shown in Table 1 (1). Although the precise pathophysiology of postoperative delirium is still poorly understood, it has been suggested that impaired cholinergic neurotransmission represents the final common pathway for
the development of delirium. This hypothesis is a considerable oversimplification in that it disregards other important neurotransmitters, notably serotonin and noradrenaline (2). We present a new theory regarding the involvement of serotonin and melatonin in the pathogenesis of postoperative delirium and extend the theory to explain in part complications of hemodialysis and the side-effects of interferon therapy. PERIOPERATIVE PLASMA MELATONIN LEVELS
Table 1 Diagnostic criteria of delirium Reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli. Disordered thinking as indicated by rambling or incoherent speech. At least two of the following: 1. reduced level of consciousness; 2. perceptual disturbance: misinterpretations, illusions or hallucinations; 3. disturbance of the sleep–wake cycle with insomnia or daytime sleepiness; 4. disorientation with regard to time, places, or people; 5. increased or decreased psychomotor activity; 6. memory impairment. Clinical features develop over a short period of time (hours to days) and tend to fluctuate over the course of a day.
Received 12 June 1997 Accepted 5 January 1998 Correspondence to: Kazuhide Uchida PhD, Department of Anesthesiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216, Japan. Phone: +81 44 977 8111; Fax: +81 44 977 8340
We decided to investigate the connection between postoperative delirium and dysrhythmia, because insomnia is seen in this disease (see Table 1). We assessed the changes in the plasma melatonin concentration in 24 patients undergoing cardiac or esophageal surgery (3). Arterial blood was collected at seven time points over 23 hours and the plasma concentration of melatonin was determined by radioimmunoassay. The perioperative plasma melatonin levels of the cardiac group were consistently and significantly higher than those of the esophageal group, whereas the melatonin levels on the morning after surgery were not significantly different. The mean values of the melatonin concentrations of the esophageal group were lower than 25 pg/ml at each tome point, whereas those of the cardiac group were higher than 50 pg/ml with one exception, which was the value on the morning of the day after surgery (Table 2). These findings indicate that the patients in these groups did not have physiological melatonin rhythms. 103
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Table 2 Perioperative plasma melatonin concentrations Sampling time point
Time
Concentration of melatonin (pg/ml) Cardiac group (n=11) Esophageal group (n=13)
Probability
1 2 3 4 5 6 7
0901 ~ 1020 1021 ~ 1130 1131 ~ 1300 1301 ~ 2000 2001 ~ 2230 2231 ~ 0100 0531 ~ 0800
50 ± 31 78 ± 27* 62 ± 20 82 ± 22* 57 ± 29 60 ± 34 41 ± 35
P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.05 N.S.
13 ± 6 19 ± 13 20 ± 10* 15 ± 7 22 ± 11* 20 ± 11 17 ± 6
The probability column shows the significant differences between the two groups at each time point. Values are expressed as the mean±SD. *, P < 0.05 versus sampling time point 1 for each group.
Cardiac and esophageal groups of patients had different melatonin levels in the present study. Low night-time melatonin levels in the esophageal group may be due to aging and epidural anesthesia. The patients in the esophageal group were significantly older than those in the cardiac group, and epidural anesthesia was used only for patients in the esophageal group. The nocturnal rise of serum melatonin in elderly people is significantly reduced compared with the rise in the young people (4,5). The local anesthetics used in epidural anesthesia inhibit the activity of protein kinase C (6–8), so potentiation of melatonin biosynthesis through α-receptors (9,10) is suppressed in the mammalian pinealocytes. In fact, subcutaneous administration of local anesthetics significantly decreases the night-time plasma melatonin level in rats (11). High daytime melatonin levels in the cardiac group were not merely attributable to controlled hypothermia and operative stress. The physiological half-life of melatonin has been reported to be as short as 47 min (12). When the metabolism of melatonin is decreased due to hypothermic conditions, it is possible to cause an increase in plasma melatonin concentrations. It has been reported that cold-restrained stress increases the melatonin content of the rat pineal gland (13). In our study, the plasma melatonin levels of the cardiac patients were already high before extracorporeal circulation (time points 1 and 2). Thus, these mechanisms were not involved. In addition, the melatonin concentrations of the esophageal group patients did not increase, even though they experienced the same operative stress of thoracotomy as the cardiac group patients. Our preliminary data suggest that there is no correlation between the plasma concentrations of melatonin and catecholamines, as measured by high performance liquid chromatography in four cardiac and two esophageal patients (data not shown). It has been reported that sympathethic nerve endings in the pineal gland protect against acute stress-induced increases in N-acetyltransferase activity (14). Since the preoperative melatonin values were already high, premedication might have had an activating effect on this enzyme. Atropine Medical Hypotheses (1999) 53(2), 103–106
or scopolamine was given to patients in both the cardiac and esophageal groups. However, nitroglycerin was used only in cases of cardiac surgery. The high levels of plasma melatonin in the cardiac group may be attributable to the effect of nitroglycerin or the interaction of nitroglycerin and muscarinic antagonists. In fact, the simultaneous subcutaneous administration of nitroglycerin and scopolamine significantly increases the daytime plasma melatonin levels of rats (15). Fentanyl, an opioid receptor agonist, was also given to patients in the cardiac group and fentanyl-associated delirium has been reported (16,17). Morphine, an other opioid receptor agonist, increases the activity of N-acetyltransferase in a dose-dependent manner. The stimulatory effect of morphine is inhibited by naloxone, an opioid receptor antagonist (18). The plasma melatonin concentration is increased by intraperitoneal injection of morphine (19). Furthermore, β-endorphin and a Met-enkephalin analogue increase melatonin levels (20,21). These reports support the hypothesis that fentanyl increases the plasma melatonin concentration. INTERACTIONS BETWEEN SEROTONIN AND MELATONIN IN RELATION TO POSTOPERATIVE DELIRIUM It has been suggested that the mental symptoms of post-cardiotomy delirium are caused by a decrease in circulating tryptophan (Trp) availability to the brain, due to a catabolic state (22). The mechanism of the Trp decrease is proposed to be the degradation of Trp by indoleamine-2,3-dioxygenase, which is induced by interferon-γ following immunostimulation (23). These results point to a decrease in the supply of the serotonin precursor. We support and extend this theory. The plasma melatonin level is raised by perioperative drugs (15) or interferon-γ (24–26). Maintenance of a high level of plasma melatonin requires increased availability of serotonin because melatonin is biosynthesized from serotonin. Melatonin is synthesized only in small amounts. However, serotonin is steadily consumed due to the © 1999 Harcourt Publishers Ltd
Postoperative delirium and plasma melatonin
short half-life of melatonin in the physiologic state. It is unlikely that melatonin alone causes postoperative delirium because considerable side-effects have not been reported in the massive administration of melatonin to humans (27). Indoleamine-2,3-dioxygenase degrades not only Trp but also serotonin and melatonin (28). Although the concentration for serotonin is smaller than that for Trp at the maximum velocity of the enzyme, we must consider the effect of the enzyme in serotonin deprivation. Indoleamine-2,3-dioxygenase catalyzes the oxygenative cleavage of the pyrrole moiety of melatonin yielding N-acetyl-5-methoxyformylkynurenamine. The reaction has been known as the major metabolic pathway of melatonin in the central nervous system (29). In previous reports, high levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, a metabolite of serotonin, were observed in delirious patients during the acute stage (30). It is widely assumed that serotonin turnover is increased by an unknown mechanism. It has been suggested that brain nitric oxide may suppress the central serotoninergic system (31). Our patients received nitroglycerin, which continuously supplies nitric oxide, perioperatively so we think the action of nitric oxide was substantial. The serotonin shortage hypothesis which explains the developmental mechanism of postoperative delirium is shown in Figure 1.
Decrease of tryptophan
Decrease of serotonin
Mechanisms 1. Degradation by catabolism 2. Degradation by indoleamine-2,3-dioxygenase
Increase of melatonin
105
MENTAL SYMPTOMS IN INTERFERON THERAPY OR HEMODIALYSIS Our theory that continuous production of melatonin facilitates the deficiency of an important neurotransmitter, serotonin, in the brain also explains the mental symptoms in conditions other than postoperative delirium. For instance, there are mental symptom side-effects of interferon therapy. When a massive dose or repeated administration of interferon is given to patients with cancer or hepatitis, side-effects such as insomnia and disorientation are experienced. Interferon increases the production of melatonin as mentioned above, so our theory may explain these side-effects. Moreover, when intraoperative immunostimulation is caused by extracorporeal circulation, our theory may partially explain the insomnia and mental symptoms of patients undergoing dialysis. In fact, the melatonin levels of patients with chronic renal failure undergoing hemodialysis treatment are higher than those of patients with the same condition who are not being treated by hemodialysis (32). POSTOPERATIVE DELIRIUM AND DYSRHYTHMIA Although plasma levels of melatonin, a hormone of the pineal gland, showed diurnal rhythm with a night-time surge, postoperative patients who have undergone cardiac surgery lose the rhythmicity (3). These patients also have disturbed body temperature rhythms (33). The occurrence of postoperative delirium is associated with a significant and unusually prolonged postoperative increase in the circulating levels of β-endorphin and cortisol, as well as total disruption of the normal plasma circadian rhythms of β-endorphin and cortisol (34). Moreover, since
Decrease of serotonin
Mechanisms 1. Enhanced biosynthesis induced by interferon-γ 2. Enhanced biosynthesis induced by drugs (e.g. scoplamine and nitroglycerin)
Additional factors
1. Suppression of serotoninergic system by nitric oxide arising from an external donor (e.g. nitroglycerin); 2. Degradation of serotonin by indoleamine-2,3-dioxygenase; 3. Hypermetabolism of serotonin by unknown mechanisms. Fig. 1 The serotonin shortage hypothesis in postoperative delirium. Indoleamine-2,3-dioxygenase is induced by interferon-γ via immunostimulation (e.g. blood transfusion, extracorporeal circulation)
© 1999 Harcourt Publishers Ltd
Fig. 2 The relationship between homeostasis and biorhythms in organisms.
Medical Hypotheses (1999) 53(2), 103–106
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Uchida et al.
postoperative delirium involves in insomnia, the disease is considered to be a dysrhythmia. Both homeostasis and biorhythms are maintained on the basis of crosstalk between the nervous, endocrine and immune systems (35,36). The relationship between homeostasis and biorhythms in mammals is similar to the connection between the wave and corpuscular theories of light, in that both states are essential but are not consistent with each other (Fig. 2). Although many people know that a collapse of homeostasis causes disease, only a minority of reseach workers and clinicians pay attention to the relationship between a disease and nonphysiological changes in the patient’s biorhythms. We probably should be more aware of the fact that dysrhythmia is causally related to many pathological states.
REFERENCES 1. Parikh S. S., Chung F. Postoperative delirium in the elderly. Anesth Analg 1995; 80: 1223–1232. 2. O’Keeffe S. T., Chonchubhair A. N. Postoperative delirium in the elderly. Br J Anaesth 1944; 73: 673–687. 3. Uchida K., Aoki T., Takahashi K., Iigo M., Hattori A., Suzuki T. Perioperative plasma melatonin levels in patients with cardiac surgery. St Marianna Med J 1995; 23: 353–360. 4. Iguchi H., Kato K., Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 1982, 55: 27–29. 5. Touitou Y., Fevre M., Bogdan A. et al. Patterns of plasma melatonin with ageing and mental condition: stability of nyctoheneral rhythms and differences in seasonal variations. Acta Endocrinol 1984; 106: 145–151. 6. Oyama Y., Sadoshima J., Tokutomi N., Akaike N. Some properties of inhibitory action of lidocaine on the Ca2+ current of single isolated frog sensory neurons. Brain Res 1988; 442: 223–228. 7. Tomoda M., Ueda W., Tsuchiya M., Hirakawa M. Effects of lidocaine on stimulation-coupled responses of neutrophils and protein kinase C activity. Jpn J Anesth 1992; 41: 369–375. 8. Mori T., Takai Y., Minakuchi R., Yu B., Nishizuka Y. Inhibitory action of chlorpromazine, dibucaine, and other phospholipiddependent protein kinase. J Biol Chem 1980; 255: 8378–8380. 9. Klein D. C., Sugden D., Weller J. Postsynaptic α-adrenergic receptors potentiate the β-adrenergic stimulation of pineal N-acetyltransferase. Proc Natl Acad Sci USA 1983; 80: 599–603. 10. Sugden D., Weller J., Klein D. C., Kirk K. L., Creveling C. R. Alpha-adrenergic potentiation of beta-adrenergic stimulation of rat pineal N-acetyltransferase. Biochem Pharmacol 1984; 33: 3947–3950. 11. Uchida K., Aoki T., Sato H. et al. Effects of local anesthetics, carbachol, 4-aminopyridine and neostigmine administered at nighttime on plasma concentrations of melatonin in rats. St Marianna Med J 1995; 23: 1030–1034. 12. Webley G. E., Leidenberger F. The circadian pattern of melatonin and its positive relationship with progesterone in women. J Clin Endocrinol Metab 1986; 63: 323–328. 13. Oxenkrug G. F., McIntyre I. M. Stress–induced synthesis of melatonin: possible involvement of the endogenous monoamine oxidase inhibitor (tribulin). Life Sci 1985; 37: 1743–1746. 14. Parfitt A. G., Klein D. C. Sympathetic nerve ending in the pineal gland protect against acute stress-induced increase in N-
Medical Hypotheses (1999) 53(2), 103–106
acetyltransferase activity. Endocrinology 1976; 99: 840–851. 15. Uchida K. Effects of several drugs used during perioperation on plasma melatonin concentrations in daytime in rats. St Marianna Med J 1996; 24: 50–57. 16. Crawford R. D., Baskoff J. D. Fentanyl-associated delirium in man. Anesthesiology 1980; 53: 168–169. 17. Steinberg R. B., Gilman D. E., Johnson F. III. Acute toxic delirium in a patient using transdermal fentanyl. Anesth Analg 1992; 75: 1014–1016. 18. Govitrapong P., Pariyanonth M., Ebadi M. The presence and action of opioid receptors in bovine pineal gland. J Pineal Res 1992; 13: 124–132. 19. Esposti D., Esposti G., Lissoni P., Parravicini L., Fraschini F. Action of morphine on melatonin release in the rat. J Pineal Res 1988; 5: 35–39. 20. Gaffori O., Geffard M., van Ree J. M. des-Tyr1-γ-Endorphin and haloperidol increase pineal gland melatonin levels in rat. Peptides 1983; 4: 393–395. 21. Lissoni P., Esposti D., Esposti G. et al. A clinical study on the relationship between the pineal gland and the opioid system. J Neural Transm 1986; 65: 63–73. 22. van der Mast R. C., Fekkes D., Moleman P., Pepplinkhuizen L. Is postoperative delirium related to reduced plasma tryptophan? Lancet 1991; 338: 851–852. 23. Weiss G., Werner E. R., Werner-Felmayer G., Wachter H. Postoperative delirium and plasma tryptophan. Lancet 1991; 338: 1078. 24. Withyachumnarnkul B., Nonaka K. O., Santana C., Attia A. M., Reiter R. J. Interferon-γ modulates melatonin production in rat pineal gland in organ culture. J Interferon Res 1990; 10: 403–411. 25. Withyachumnarnkul B., Nonaka K. O., Attia A. M., Reiter R. J. Changes in indole metabolism in organ cultured rat pineal glands induced by interferon-γ. J Pineal Res 1990; 8: 313–322. 26. Finocchiaro L. M. E., Arzt E. S., Fernandez-Castelo S., Criscuolo M., Finkielman S., Nahmod V. E. Serotonin and melatonin synthesis in peripheral blood mononuclear cell: stimulation by interferon-γ as part of an immunomodulatory pathway. J Interferon Res 1988; 8: 705–716. 27. Voordouw B. C. G., Euser R., Verdonk R. E. R. et al. Melatoninprogestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab 1992; 74: 108–117. 28. Hayaishi O. Properties and function of indoleamine 2,3-dioxygenase. J Biochem 1976; 79: 13p–21p. 29. Hirata F., Hayaishi O., Tokuyama T., Senoh S. In vitro and in vivo formation of two new metabolites of melatonin. J Biol Chem 1974; 249: 1311–1313. 30. Koponen H. J., Lepola U., Leinonen E. A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium. Eur Arch Psychiatry Clin Neurosci 1994; 244: 131–134. 31. Squadrito F., Calapai G., Altavilla D. et al. Food deprivation increases brain nitric oxide synthase and depresses brain serotonin levels in rats. Neuropharmacology 1994; 33: 83–86. 32. Viljoen M., Steyn M. E., van Rensburg B. W., Reinach S. G. Melatonin in chronic renal failure. Nephron 1992; 60: 138–143. 33. Narumi J., Suma K., Kaneko H. et al. Postoperative deep body temperature rhythm. Jpn J Surg 1987; 17: 209–212. 34. McIntosh T. K., Bush H. L., Yeston N. S. et al. Beta-endorphin, cortisol and postoperative delirium: a preliminary report. Psychoneuroendocrinology 1985 10: 303–313. 35. Kordon C., Bihorean C. Integrated communication between the nervous, endocrine and immune systems. Horm Res 1989, 31: 100–104. 36. Homo-Delarche F., Dardenne M. The neuroendocrine–immune axis. Springer Semin Immunopathol 1993; 4: 221–238.
© 1999 Harcourt Publishers Ltd
Postoperative delirium and plasma melatonin K. Uchida,1 T. Aoki,1 B. Ishizuka2 1 2
Department of Anesthesiology Department of Obstetrics and Gynecology, St Marianna University School of Medicine, Kawasaki, Japan
Summary The molecular mechanisms of postoperative delirium are not understood in detail yet. This condition is similar to cases of mental symptoms in interferon therapy or hemodialysis. We propose that postoperative delirium is caused by a deficiency of serotonin, an important neurotransmitter, and review the evidence supporting our hypothesis. The serotonin deficiency results from a decrease in tryptophan, the serotonin precursor, and from an increase in melatonin, a serotonin metabolite. Our hypothesis may be applicable to the mechanisms of mental symptoms in interferon therapy and hemodialysis. In addition, we discuss to the relationship between homeostasis and biorhythms because postoperative delirium may be a dysrhythmia. INTRODUCTION Psychiatric complications are sometimes recognized in patients admitted to the intensive care unit after surgery. Postoperative delirium is differentiated from other postoperative complications using the diagnostic criteria shown in Table 1 (1). Although the precise pathophysiology of postoperative delirium is still poorly understood, it has been suggested that impaired cholinergic neurotransmission represents the final common pathway for
the development of delirium. This hypothesis is a considerable oversimplification in that it disregards other important neurotransmitters, notably serotonin and noradrenaline (2). We present a new theory regarding the involvement of serotonin and melatonin in the pathogenesis of postoperative delirium and extend the theory to explain in part complications of hemodialysis and the side-effects of interferon therapy. PERIOPERATIVE PLASMA MELATONIN LEVELS
Table 1 Diagnostic criteria of delirium Reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli. Disordered thinking as indicated by rambling or incoherent speech. At least two of the following: 1. reduced level of consciousness; 2. perceptual disturbance: misinterpretations, illusions or hallucinations; 3. disturbance of the sleep–wake cycle with insomnia or daytime sleepiness; 4. disorientation with regard to time, places, or people; 5. increased or decreased psychomotor activity; 6. memory impairment. Clinical features develop over a short period of time (hours to days) and tend to fluctuate over the course of a day.
Received 12 June 1997 Accepted 5 January 1998 Correspondence to: Kazuhide Uchida PhD, Department of Anesthesiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216, Japan. Phone: +81 44 977 8111; Fax: +81 44 977 8340
We decided to investigate the connection between postoperative delirium and dysrhythmia, because insomnia is seen in this disease (see Table 1). We assessed the changes in the plasma melatonin concentration in 24 patients undergoing cardiac or esophageal surgery (3). Arterial blood was collected at seven time points over 23 hours and the plasma concentration of melatonin was determined by radioimmunoassay. The perioperative plasma melatonin levels of the cardiac group were consistently and significantly higher than those of the esophageal group, whereas the melatonin levels on the morning after surgery were not significantly different. The mean values of the melatonin concentrations of the esophageal group were lower than 25 pg/ml at each tome point, whereas those of the cardiac group were higher than 50 pg/ml with one exception, which was the value on the morning of the day after surgery (Table 2). These findings indicate that the patients in these groups did not have physiological melatonin rhythms. 103
104
Uchida et al.
Table 2 Perioperative plasma melatonin concentrations Sampling time point
Time
Concentration of melatonin (pg/ml) Cardiac group (n=11) Esophageal group (n=13)
Probability
1 2 3 4 5 6 7
0901 ~ 1020 1021 ~ 1130 1131 ~ 1300 1301 ~ 2000 2001 ~ 2230 2231 ~ 0100 0531 ~ 0800
50 ± 31 78 ± 27* 62 ± 20 82 ± 22* 57 ± 29 60 ± 34 41 ± 35
P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.05 N.S.
13 ± 6 19 ± 13 20 ± 10* 15 ± 7 22 ± 11* 20 ± 11 17 ± 6
The probability column shows the significant differences between the two groups at each time point. Values are expressed as the mean±SD. *, P < 0.05 versus sampling time point 1 for each group.
Cardiac and esophageal groups of patients had different melatonin levels in the present study. Low night-time melatonin levels in the esophageal group may be due to aging and epidural anesthesia. The patients in the esophageal group were significantly older than those in the cardiac group, and epidural anesthesia was used only for patients in the esophageal group. The nocturnal rise of serum melatonin in elderly people is significantly reduced compared with the rise in the young people (4,5). The local anesthetics used in epidural anesthesia inhibit the activity of protein kinase C (6–8), so potentiation of melatonin biosynthesis through α-receptors (9,10) is suppressed in the mammalian pinealocytes. In fact, subcutaneous administration of local anesthetics significantly decreases the night-time plasma melatonin level in rats (11). High daytime melatonin levels in the cardiac group were not merely attributable to controlled hypothermia and operative stress. The physiological half-life of melatonin has been reported to be as short as 47 min (12). When the metabolism of melatonin is decreased due to hypothermic conditions, it is possible to cause an increase in plasma melatonin concentrations. It has been reported that cold-restrained stress increases the melatonin content of the rat pineal gland (13). In our study, the plasma melatonin levels of the cardiac patients were already high before extracorporeal circulation (time points 1 and 2). Thus, these mechanisms were not involved. In addition, the melatonin concentrations of the esophageal group patients did not increase, even though they experienced the same operative stress of thoracotomy as the cardiac group patients. Our preliminary data suggest that there is no correlation between the plasma concentrations of melatonin and catecholamines, as measured by high performance liquid chromatography in four cardiac and two esophageal patients (data not shown). It has been reported that sympathethic nerve endings in the pineal gland protect against acute stress-induced increases in N-acetyltransferase activity (14). Since the preoperative melatonin values were already high, premedication might have had an activating effect on this enzyme. Atropine Medical Hypotheses (1999) 53(2), 103–106
or scopolamine was given to patients in both the cardiac and esophageal groups. However, nitroglycerin was used only in cases of cardiac surgery. The high levels of plasma melatonin in the cardiac group may be attributable to the effect of nitroglycerin or the interaction of nitroglycerin and muscarinic antagonists. In fact, the simultaneous subcutaneous administration of nitroglycerin and scopolamine significantly increases the daytime plasma melatonin levels of rats (15). Fentanyl, an opioid receptor agonist, was also given to patients in the cardiac group and fentanyl-associated delirium has been reported (16,17). Morphine, an other opioid receptor agonist, increases the activity of N-acetyltransferase in a dose-dependent manner. The stimulatory effect of morphine is inhibited by naloxone, an opioid receptor antagonist (18). The plasma melatonin concentration is increased by intraperitoneal injection of morphine (19). Furthermore, β-endorphin and a Met-enkephalin analogue increase melatonin levels (20,21). These reports support the hypothesis that fentanyl increases the plasma melatonin concentration. INTERACTIONS BETWEEN SEROTONIN AND MELATONIN IN RELATION TO POSTOPERATIVE DELIRIUM It has been suggested that the mental symptoms of post-cardiotomy delirium are caused by a decrease in circulating tryptophan (Trp) availability to the brain, due to a catabolic state (22). The mechanism of the Trp decrease is proposed to be the degradation of Trp by indoleamine-2,3-dioxygenase, which is induced by interferon-γ following immunostimulation (23). These results point to a decrease in the supply of the serotonin precursor. We support and extend this theory. The plasma melatonin level is raised by perioperative drugs (15) or interferon-γ (24–26). Maintenance of a high level of plasma melatonin requires increased availability of serotonin because melatonin is biosynthesized from serotonin. Melatonin is synthesized only in small amounts. However, serotonin is steadily consumed due to the © 1999 Harcourt Publishers Ltd
Postoperative delirium and plasma melatonin
short half-life of melatonin in the physiologic state. It is unlikely that melatonin alone causes postoperative delirium because considerable side-effects have not been reported in the massive administration of melatonin to humans (27). Indoleamine-2,3-dioxygenase degrades not only Trp but also serotonin and melatonin (28). Although the concentration for serotonin is smaller than that for Trp at the maximum velocity of the enzyme, we must consider the effect of the enzyme in serotonin deprivation. Indoleamine-2,3-dioxygenase catalyzes the oxygenative cleavage of the pyrrole moiety of melatonin yielding N-acetyl-5-methoxyformylkynurenamine. The reaction has been known as the major metabolic pathway of melatonin in the central nervous system (29). In previous reports, high levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, a metabolite of serotonin, were observed in delirious patients during the acute stage (30). It is widely assumed that serotonin turnover is increased by an unknown mechanism. It has been suggested that brain nitric oxide may suppress the central serotoninergic system (31). Our patients received nitroglycerin, which continuously supplies nitric oxide, perioperatively so we think the action of nitric oxide was substantial. The serotonin shortage hypothesis which explains the developmental mechanism of postoperative delirium is shown in Figure 1.
Decrease of tryptophan
Decrease of serotonin
Mechanisms 1. Degradation by catabolism 2. Degradation by indoleamine-2,3-dioxygenase
Increase of melatonin
105
MENTAL SYMPTOMS IN INTERFERON THERAPY OR HEMODIALYSIS Our theory that continuous production of melatonin facilitates the deficiency of an important neurotransmitter, serotonin, in the brain also explains the mental symptoms in conditions other than postoperative delirium. For instance, there are mental symptom side-effects of interferon therapy. When a massive dose or repeated administration of interferon is given to patients with cancer or hepatitis, side-effects such as insomnia and disorientation are experienced. Interferon increases the production of melatonin as mentioned above, so our theory may explain these side-effects. Moreover, when intraoperative immunostimulation is caused by extracorporeal circulation, our theory may partially explain the insomnia and mental symptoms of patients undergoing dialysis. In fact, the melatonin levels of patients with chronic renal failure undergoing hemodialysis treatment are higher than those of patients with the same condition who are not being treated by hemodialysis (32). POSTOPERATIVE DELIRIUM AND DYSRHYTHMIA Although plasma levels of melatonin, a hormone of the pineal gland, showed diurnal rhythm with a night-time surge, postoperative patients who have undergone cardiac surgery lose the rhythmicity (3). These patients also have disturbed body temperature rhythms (33). The occurrence of postoperative delirium is associated with a significant and unusually prolonged postoperative increase in the circulating levels of β-endorphin and cortisol, as well as total disruption of the normal plasma circadian rhythms of β-endorphin and cortisol (34). Moreover, since
Decrease of serotonin
Mechanisms 1. Enhanced biosynthesis induced by interferon-γ 2. Enhanced biosynthesis induced by drugs (e.g. scoplamine and nitroglycerin)
Additional factors
1. Suppression of serotoninergic system by nitric oxide arising from an external donor (e.g. nitroglycerin); 2. Degradation of serotonin by indoleamine-2,3-dioxygenase; 3. Hypermetabolism of serotonin by unknown mechanisms. Fig. 1 The serotonin shortage hypothesis in postoperative delirium. Indoleamine-2,3-dioxygenase is induced by interferon-γ via immunostimulation (e.g. blood transfusion, extracorporeal circulation)
© 1999 Harcourt Publishers Ltd
Fig. 2 The relationship between homeostasis and biorhythms in organisms.
Medical Hypotheses (1999) 53(2), 103–106
106
Uchida et al.
postoperative delirium involves in insomnia, the disease is considered to be a dysrhythmia. Both homeostasis and biorhythms are maintained on the basis of crosstalk between the nervous, endocrine and immune systems (35,36). The relationship between homeostasis and biorhythms in mammals is similar to the connection between the wave and corpuscular theories of light, in that both states are essential but are not consistent with each other (Fig. 2). Although many people know that a collapse of homeostasis causes disease, only a minority of reseach workers and clinicians pay attention to the relationship between a disease and nonphysiological changes in the patient’s biorhythms. We probably should be more aware of the fact that dysrhythmia is causally related to many pathological states.
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