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2000年の当院麻酔科管理症例のぅち,20歳未満と心臓大血管手術症例を除いた3,432例を対象とし,高血圧の頻度,術前治療の有無と方法,周術期血圧の関連を検討した.高血圧合併頻度は18%,このうち術前治療群は66%であった.治療群の入院時血圧は収縮期140±18mmHg,拡張期80±13mmHgで,両値とも非治療群より有意に低かった.臓器障害/心血管病合併率は治療群が非治療群より有意に高かった.全身麻酔症例では,降圧薬1剤投与群は非治療群より手術室入室時拡張期血圧が有意に低かったが,術中血圧変動や降圧薬投与には差はなかった.高血圧患者の麻酔では,術前治療のいかんにかかわらず,その術中血圧管理に細心の注意を要すると考えられた.

われわれは冠動脈バイパス術後に虚血性腸疾患を合併した3症例を経験した.いずれの症例も重症糖尿病,悪性高血圧など末梢循環不全をきたし得る重篤な基礎疾患を合併した慢性透析の患者であった.3症例とも術直後の経過は順調であり早期にlCU退室となったが,その後腸管虚血をきたして緊急手術が施行された.うち2症例は広範囲にわたる腸管壊死を認め,壊死腸管を切除したにもかかわらず多臓器不全にて死亡した.慢性腎不全を合併した冠動脈バイパス術患者は末梢循環不全をきたしやすく,循環動態の安定化や経口摂取の開始時期等その周術期管理に特に注意を払うことにより,腸管虚血の発症予防と増悪回避に努める必要があると考えられた.

Transesophageal echocardiography is an invaluable hemodynamic monitoring modality. Extended and anatomically based evaluation of cardiac function with transesophageal echocardiography is essential to prompt and accurate decision-making in anesthetic management during cardiac surgery. Fractional shortening and fractional area changes are indices widely used to assess the global systolic performance of the left ventricle. Monitoring regional function using semi-quantitative scoring has been demonstrated to be a more sensitive indicator of myocardial ischemia. Assessment of left ventricular diastolic function should be performed in a systematic way, measuring transmitral flow, pulmonary venous flow, transmitral color M-mode flow propagation velocity, and mitral annulus tissue Doppler imaging. The unique anatomical features of the right ventricle make echocardiographic evaluation complicated and therefore less frequently employed. Right ventricular fractional area change, tricuspid annular plane systolic excursion, maximal systolic tricuspid annular velocity with tissue Doppler imaging, and myocardial performance index are indices successfully incorporated into intraoperative right ventricular assessment. Left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve may develop after cardiac procedures. Transesophageal echocardiography plays a central role in prevention as well as diagnosis of systolic anterior motion. Transesophageal echocardiography is extremely useful not only for detecting and locating intracardiac air, but also for guiding and evaluating the procedures to remove air. Air is likely to persist in the right and left superior pulmonary vein, left ventricular apex, left atrium, right coronary sinus of Valsalva, and ascending aorta. Accurate evaluation of cardiac function depends on performing TEE examination properly and obtaining optimal images.

There is currently accumulating evidence for bidirectional communication between the neuroendocrine and immune systems. Various cytokines have been suggested to be involved in the stimulation of stress hormone secretion during the times of infection and inflammation. To assess the possible involvement and pathophysiologic significance of cytokines in the mechanisms responsible for the perioperative stress response of the hypothalamo-pituitary-adrenal axis, we observed the changes of plasma adrenocorticotropic hormone and cortisol levels together with those of plasma endotoxin and cytokine levels. In patients undergoing pancreatoduodenectomy, perioperative stimulation of adrenocorticotropic hormone and cortisol secretion was accompanied by a significant elevation of plasma cytokine levels. Application of epidural block up to the upper thoracic levels failed to suppress this stress response effectively. In patients undergoing unilateral total hip replacement, the response of plasma hormone levels was smaller and briefer with no significant increase of plasma cytokine levels. Application of epidural block up to the lower thoracic levels suppressed this hormonal response almost completely. In patients undergoing pancreatoduodenectomy, a significant elevation of plasma endotoxin level was followed by a gradual but significant elevation of plasma tumor necrosis factor alpha and interleukin-6 levels. It seems likely that the stimulatory effects of these cytokines on the secretion of adrenocorticotropic hormone and cortisol might be involved in the development of the greater and more prolonged stress response of hypothalamo-pituitary-adrenal axis. Our present study suggests that not only neural input from the surgical wound but also stimulation of cytokine production were responsible for the development of the stress response of the hypothalamo-pituitary-adrenal axis during and after upper abdominal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Using specific antagonists to rat interleukin (IL)-1 alpha and IL-1 beta, the roles of these IL-1s in endotoxin-induced suppression of plasma gonadotropin levels in freely-moving rats were studied. In orchiectomized rats, recombinant rat IL-1 alpha and IL-1 beta administered into the lateral ventricles almost equipotently suppressed plasma LH levels. Twenty five micrograms of bacterial endotoxin or lipopolysaccharide (LPS) administered similarly showed a comparable effect as that of 1 microgram IL-1 alpha or IL-1 beta, and completely lowered plasma LH levels by 60 min after the injection. To examine the roles of endogenous IL-1 alpha and IL-1 beta, anti-rat IL-1 alpha antiserum (anti-IL-1 alpha) and a recombinant human IL-1 receptor antagonist (IL-1ra) were used as specific blockers for IL-1 alpha and IL-1 beta, respectively. Anti-IL-1 alpha (10 microliters) or IL-1ra (10 micrograms) administered intracerebroventricularly (icv) with 25 micrograms LPS, significantly attenuated the LPS-induced effect on plasma LH levels during the first 60 min after LPS infusion, but not during the second 60 min. LPS at a dose of 5 micrograms induced smaller but still significant changes in plasma LH levels compared with 25 micrograms LPS or 1 microgram IL-1 beta. IL-1ra (10 micrograms) completely blocked LH suppression induced by 1 microgram IL-1 beta, but did not completely reverse the changes of LH induced by 5 micrograms LPS. IL-1ra injected iv also significantly attenuated the early suppressive effect of iv administered LPS, but not its late effect on plasma LH levels. However, iv administered IL-1ra had no influence on the effects of icv administered LPS. These data indicate that at least a part of plasma LH suppression caused by icv administered LPS is mediated via IL-1 alpha and IL-1 beta synthesized within the brain, while factor(s) other than IL-1 also participate in the LPS-induced change, particularly during the later period. A similar mechanism may also work peripherally in the case of iv administered LPS-induced plasma LH suppression.

Regulatory mechanisms of the hypothalamo-pituitary-adrenal (H-P-A) axis during and after major abdominal surgery were studied in a group of patients who underwent upper abdominal surgery. We first examined the general profile of the changes of the H-P-A axis from the day before surgery to the seventh day after surgery. On the day of surgery, plasma levels of CRH, ACTH, and cortisol were all significantly elevated after skin incision (phase I). During the next 2 days, plasma cortisol levels remained significantly elevated, and the both plasma CRH and ACTH levels were suppressed below the control levels obtained on the day before surgery (phase II). Several additional studies, carried out to analyze the mechanism that maintains the high plasma cortisol levels, revealed the following features of the H-P-A axis during phase II. Plasma free cortisol levels in this phase were higher than those during the preoperative period. The exogenously administered hydrocortisone clearance rate in phase II did not differ from that observed on the day before surgery. Dexamethasone administration resulted in a decrease in plasma cortisol levels similar to that observed preoperatively. Conversely, the ACTH-stimulated cortisol increase was significantly greater in phase II than that observed preoperatively. These results suggest that during and after major surgical stress, the H-P-A axis undergoes a biphasic change in the pattern of the stress response and during the second phase, not the continuous hypothalamo-pituitary drive but the increased adrenal responsiveness to ACTH is responsible at least in part for maintaining the elevated plasma cortisol level.

The effects of interleukins on adrenal steroidogenesis and their mode of action were studied using cultured rat adrenal cells. The addition of rat interleukin-1 alpha (IL-1 alpha) or rat IL-2 increased corticosterone levels in the medium in a concentration-dependent manner during 24 h of incubation. The minimum, half-maximum, and maximum effective concentrations of both rat IL-1 alpha and rat IL-2 were almost same (approximately 3, 10, and 100 U/ml, respectively). After a latent period, the effect became apparent after 12 h of incubation. Human IL-1 beta and human IL-6 also showed a stimulatory effect on corticosterone production, whereas human IL-2 was inactive in this system. To clarify the cellular mechanism of these stimulatory effects, we measured the levels of prostaglandin E2 (PGE2) and cAMP in the cells and media as well as the corticosterone levels. Corticosterone production stimulated by IL-1 alpha or IL-2 was accompanied by intracellular and extracellular cAMP and PGE2 accumulation. Although the stimulation of both cAMP and corticosterone was observed only after 12 h of incubation, PGE2 levels increased during the first 4 h of incubation. Corticosterone, cAMP, and PGE2 production stimulated by ILs was almost completely blocked by the addition of 0.1 mM aspirin, a cyclooxygenase inhibitor. Lipoxygenase inhibitors, i.e. AA-861, nordihydroguaiaretic acid, and 5,8,11,14-eicosatetrynoic acid, did not abolish corticosterone production stimulated by ILs. Submaximal doses of IL-1 alpha and IL-2 synergistically stimulated PGE2 production, but did not have even additional effects on cAMP and corticosterone levels. On the other hand, submaximal doses of ACTH, which did not significantly affect PGE2 levels, acted synergistically with IL to increase cAMP and corticosterone levels in these cells. These results indicate that 1) IL-1 alpha and IL-2 directly stimulate glucocorticoid synthesis in a dose- and time-dependent manner; 2) a half-maximum effective concentration of ACTH acts synergistically with IL in stimulating glucocorticoidogenesis; 3) the stimulatory process initially requires PGs, followed by the activation of the adenylate cyclase system; 4) although the profiles of steroidogenic action of IL-1 alpha and IL-2 are quite similar, they may exert their effects through different mechanisms in their early steps of PGE2 production; and 5) the low effective concentrations of both cytokines suggest possible physiological or pathophysiological roles of circulating cytokines in the glucocorticoidogenesis under certain conditions.

We examined the adrenocorticotropic hormone-releasing activities of several human interleukin-1 beta analogues that have markedly reduced pyrogenic activities in rats. Among the analogues tested, [Gly4]-, [Leu93]- and [1-148]-interleukin-1 beta increased the plasma adrenocorticotropic hormone level to almost that induced by authentic human interleukin-1 beta. Modifications of the N-terminus of the authentic molecule, i.e., [7-153]- and [Des-Ala1, Asp4]-interleukin-1 beta, significantly reduced the hormone-releasing activity. These data suggest that the adrenocorticotropic hormone-releasing activity of human interleukin-1 beta resides in the N-terminal structure of the authentic peptide and can be separated from its pyrogenic activity.

To assess the chronic effects of interleukin-1 (IL-1) and IL-2 on the hypothalamo-pituitary-adrenal axis in vivo, we administered recombinant human (rh) IL-1 alpha, rhIL-1 beta or rhIL-2 (2.0 micrograms/day) repetitively to adult male rats for 10 days. In rhIL-1 beta-treated rats, adrenocorticotropic hormone-like immunoreactivity (ACTH-LI) of the anterior pituitary appeared to increase first on day 3 followed by an increase of corticotropin-releasing hormone (CRH)-LI both in the hypothalamus and in the adrenal gland after day 7. At the end of the 10-day treatment, wet weights of the adrenal glands of rhIL-1 beta-treated rats increased significantly compared with those of control rats. Plasma ACTH levels in rhIL-1 beta-treated rats at the sampling time continued to be elevated throughout the experimental period. Under the same experimental design, rhIL-1 alpha increased plasma ACTH levels at the sampling time without changes in adrenal weight or in the peptide contents investigated. The same amount of rhIL-2 had no effect on these measured variables during the 10-day treatment. These data indicate that the repetitive administration of IL-1 beta resulted in chronic effects in the hypothalamo pituitary-adrenal axis to increase the activities in these organs during the treatment and, moreover, IL-1 possibly has a positive direct effect on the CRH-containing cells in the adrenal glands.

The levels of immunoreactive corticotropin-releasing hormone (ir-CRH) were measured in discrete hypothalamic nuclei and the median eminence of obese Zucker rats and their lean littermates. More than 90% of total hypothalamic ir-CRH was detected in the median eminence in both obese and lean rats. Though ir-CRH levels in the paraventricular nucleus of obese rats tended to be lower than those of their lean littermates, no significant difference of ir-CRH levels was observed in any hypothalamic nuclei studied between obese and lean rats. However, ir-CRH levels in the median eminence of obese rats were significantly lower than those of their lean littermates (5263 +/- 438 pg/tissue vs. 7050 +/- 473 pg/tissue, P < 0.05). These results suggest that the hypoactive hypothalamic CRH tonus would play some role in the phenotypic expression of obesity in the genetically obese Zucker rats.

Publisher Summary Cytokines, which were originally isolated from lymphocytes and monocytes and identified as immunomediators, have a broad spectrum of actions as factors involved in various kinds of cell-to-cell communication. Among the cytokines identified so far, interleukin lα (IL-lα), interleukin lβ (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interferons have been reported to be major cytokines induced during the early inflammatory processes and affecting various neuroendocrine functions, especially the stimulation of activities in the hypothalamic-pituitary-adrenal (HPA) axis. These cytokines are, therefore, presumed to be the mediators of acute-phase responses to infectious challenge. In in vivo experiments, a cascade of events induced by cytokines must be carefully considered because neuroendocrine functions may be modified as a second effect. Data acquired by in vitro (artificial) systems should also be assessed carefully as to their physiological significance. This chapter describes the in vivo and in vitro systems that have been used to the study of the effects of several cytokines on pituitary hormone secretion, especially that of adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP), and oxytocin (OT), and also to present some data obtained using these methods as examples.

It is well known that surgical invasion activates the hypothalamo-pituitary-adrenal (H-P-A) axis and induces marked elevation in plasma adrenocorticotropic hormone (ACTH) and Cortisol levels during and after surgery. The stress response of plasma ACTH and Cortisol levels cannot be totally suppressed by epidural [1] or subarachnoid anesthesia [2], especially in upper abdominal surgery [3], which suggests the involvement of some factor(s) other than afferent neural output arising from the injury site [4]. Some cytokines have recently been suspected to play important roles in the activation of the H-P-A axis at the times of infectious challenge and other stressful conditions [5–7]. To assess the possible involvement and role of cytokines in the stress response of the H-P-A axis during surgical procedures, we observed changes in the levels of plasma ACTH, Cortisol, endotoxin, tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in patients undergoing upper abdominal surgery. We then investigated the ACTH-releasing activities of these cytokines using an in vivo experimental system.

We have studied immunoreactive corticotropin-releasing hormone (CRH) levels in the hypothalamus of female Wistar fatty rats, a strain with the fa gene transferred from the Zucker rat to the Wistar Kyoto rat, in an attempt to understand the role of CRH in the development of obesity. A study was conducted with 5-week- and 12-week-old female Wistar fatty rats and lean littermates. There was no significant difference in hypothalamic CRH levels between lean and obese rats at the age of 5 weeks (1887 +/- 99.6 vs. 1767 +/- 124 pg/tissue; mean +/- S.E.M.). Hypothalamic CRH immunoreactivities, however, were significantly lower in 12-week-old obese rats (2361 +/- 132 pg/tissue) than those in lean littermates (2992 +/- 118 pg/tissue; P less than 0.05). The difference of CRH contents between the lean and obese group becomes apparent as they grow up and develop obesity.

To elucidate whether interleukins are involved in vasopressin or oxytocin release during cytokine-related stressful conditions, we examined the effects of human interleukin-1 beta and interleukin-6 on plasma vasopressin and oxytocin levels in rats. Interleukin-1 beta administrated intravenously stimulated both the vasopressin and oxytocin secretion in dose-dependent manners. Neither hormone release was observed following interleukin-6 administration. Pretreatment with aspirin significantly attenuated the effects of interleukin-1 beta on both the vasopressin and oxytocin levels. SC-19220, a prostaglandin E2 receptor antagonist, did not affect the interleukin-1 beta-induced increase of plasma oxytocin levels, but almost completely abolished its effect on plasma vasopressin levels. These results suggest that under certain stressful conditions which accompany the stimulation of cytokine production, interleukin-1 is involved in the increase of plasma vasopressin and oxytocin levels and, moreover, different kinds of prostaglandins are suggested to participate in these interleukin-1-induced hormone release.

We compared adrenocorticotropin-releasing activities of several interleukins in a homologous or heterologous in vivo system. Intravenous injection of rat interleukin-1 α significantly increased plasma adrenocorticotropin in conscious, freely-moving rats 30 min after the injection, and the effect was 10 times greater than that of human interleukin-1 α. Rat interleukin-2 affected plasma adrenocorticotropin in a much slower manner and increased its levels significantly 120 min after the injection. Human interleukin-2 had no effect on plasma adrenocorticotropin. Thus, species difference in the experimental system should be considered to assess the physiological significance of cytokines in the neuroendocrine system.

Therapeutic applications of hypothalamic hypophysiotropic hormones were discussed. Pulsatile administration of gonadotropin-releasing hormone (Gn RH) is effective to maintain menstrual cycles and ovulation in female patients with hypothalamic gonadal dysfunction and testicular function in male patients. On the other hand, continuous administration of Gn-RH or its analog is able to suppress gonadal function and thereby gonadal hormonedependent activities effectively. Application of this medical gonadectomy includes treatments for excessive menstrual bleeding, endometriosis, prostatic cancer and benign prostatic hypertrophy. Thyrotropin-releasing hormone has been applied in patients with spinocerebellar degeneration or some kinds of consciousness disturbance and somatostatin analog has benn tried to treat acromegaly. Corticotropin-releasing hormone and growth hormone-releasing hormone have also therapeutic potentials. We believe that many-sided research trials, which include development of new potent analogs, new effective drug delivery systems and further elucidation of physiology and pathophysiology about the functions of the hypothalamic hormones, are inevitable to materialize therapeutic potentials of these hormones.

A case of juvenile angina pectoris probably due to congenital syphilis was reported. Both coronary ostial narrowing could be only presumed in usual physical and laboratory examination. And then aortitis and both coronary ostial stenosis demonstrated in vivo by aortography and selective coronary arteriography. The progress of this case has been observed at present with internal treatments, but surgical repair will be necessary in the near future.