Development of a severe mesenteric traction syndrome during major abdominal surgery is associated with increased postoperative morbidity: Secondary data analysis on prospective cohorts.

PURPOSE: MTS is elicited during open abdominal surgery and is characterized by facial flushing, hypotension, and tachycardia in response to the release of prostacyclin (PGI2) to plasma. MTS seems to affect postoperative morbidity, but data from larger cohorts are lacking. We aimed to determine the impact of severe mesenteric traction syndrome (MTS) on postoperative morbidity in patients undergoing open upper gastrointestinal surgery. METHODS: The study was a secondary analysis of data from three cohorts (n = 137). The patients were graded for severity of MTS intraoperatively, and hemodynamic variables and blood samples for plasma 6-keto-PGF1α, a stable metabolite of PGI2, were obtained at defined time points. Postoperative morbidity was evaluated by the comprehensive complication index (CCI) and the Dindo-Clavien classification (DC). RESULTS: Patients undergoing either esophagectomy (n = 70), gastrectomy (n = 22), liver- (n = 23), or pancreatic resection (n = 22) were included. Severe MTS was significantly associated with increased postoperative morbidity, i.e., CCI ≥ 26.2 (OR 3.06 [95% CI 1.1-6.6]; p = 0.03) and risk of severe complications, i.e., DC ≥3b (OR 3.1 [95% CI 1.2-8.2]; p = 0.023). Furthermore, patients with severe MTS had increased length of stay (OR 10.1 [95% CI 1.9-54.3]; p = 0.007) and were more likely to be admitted to the intensive care unit (OR = 7.3 [95% CI 1.3-41.9]; p = 0.027), but there was no difference in 1-year mortality. CONCLUSION: Occurrence of severe MTS during upper gastrointestinal surgery is associated with increased postoperative morbidity as indicated by an increased rate of severe complications, length of stay, and admission to the ICU. It remains to be determined whether inhibition of MTS enhances postoperative recovery.

Venous Cannula Positioning in Arterial Deoxygenation During Veno-Arterial Extracorporeal Membrane Oxygenation-A Simulation Study and Case Report.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is indicated in reversible life-threatening circulatory failure with or without respiratory failure. Arterial desaturation in the upper body is frequently seen in patients with peripheral arterial cannulation and severe respiratory failure. The importance of venous cannula positioning was explored in a computer simulation model and a clinical case was described. A closed-loop real-time simulation model has been developed including vascular segments, the heart with valves and pericardium. ECMO was simulated with a fixed flow pump and a selection of clinically relevant venous cannulation sites. A clinical case with no tidal volumes due to pneumonia and an arterial saturation of below 60% in the right hand despite VA-ECMO flow of 4 L/min was described. The case was compared with simulation data. Changing the venous cannulation site from the inferior to the superior caval vein increased arterial saturation in the right arm from below 60% to above 80% in the patient and from 64 to 81% in the simulation model without changing ECMO flow. The patient survived, was extubated and showed no signs of hypoxic damage. We conclude that venous drainage from the superior caval vein improves upper body arterial saturation during veno-arterial ECMO as compared with drainage solely from the inferior caval vein in patients with respiratory failure. The results from the simulation model are in agreement with the clinical scenario.

Flushing response modifies the association of alcohol consumption with markers of glucose metabolism in Japanese men and women.

BACKGROUND: Influences of alcohol use on glucose metabolism may depend on alcohol flushing response. We investigated the effect of alcohol flushing response on the associations between alcohol consumption and markers of glucose metabolism in Japanese men and women. METHODS: The subjects were 979 employees (885 men and 94 women), aged 18 to 69 years, of a manufacturing company in Japan. Flushing response and alcohol consumption were determined using a self-administered questionnaire. Homeostasis model assessment-insulin resistance (HOMA-IR) and homeostasis model assessment for ß-cell function (HOMA-ß) were computed using fasting plasma glucose and insulin. For each group of flushers and nonflushers, multiple regression analysis was used to estimate means of fasting plasma glucose, hemoglobin A1c (HbA1c), and HOMAs for each category of alcohol consumption, with adjustments for potential confounders. RESULTS: In flushers, alcohol consumption was associated with HbA1c levels in a U-shaped manner, with the lowest HbA1c levels being observed at an alcohol consumption level of 23.0 to <34.5 g ethanol/d (p for quadratic trend = 0.002). In nonflushers, alcohol consumption was linearly and inversely associated with HbA1c levels (p for linear trend = 0.001). Decreases in HbA1c were more evident among flushers compared with nonflushers at moderate alcohol consumption levels (p for interaction = 0.049). An increase of fasting glucose associated with highest alcohol consumption was observed in both flushers and nonflushers. A statistically significant decrease in HOMA-IR with increasing alcohol consumption was observed in flushers (p for trend = 0.007), whereas HOMA-IR levels slightly decreased at higher alcohol consumption in nonflushers. HOMA-ß similarly decreased with increasing alcohol consumption in both flushers and nonflushers (both p for trend < 0.001). CONCLUSIONS: The results suggest that the alcohol flushing response may improve glucose metabolism and insulin resistance at moderate alcohol use levels in apparently healthy Japanese adults.

An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia.

The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.

Investigation of niacin on parameters of metabolism in a physiologic dose: randomized, double-blind clinical trial with three different dosages.

The aim of this double-blind, placebo-controlled cross-over design trial was to assess the safety of a multi-vitamin preparation containing nicotinic acid in a physiological dose. Seventy-two healthy volunteers took part in this trial. At six consecutive time-points, we systematically documented blood pressure, pulse, skin temperature and flushing symptoms after an oral dose of up to 50.1 mg nicotinic acid. The results suggest that nicotinic acid in a dosage of 16.7 mg does not cause flushing symptoms. In higher doses up to 50.1 mg, flushing symptoms are sporadically possible. There was no physiologically relevant change regarding the central metabolic parameters blood pressure, pulse and skin temperature.

An 88-year-old woman with flushing, alopecia and hirsutism and a Sertoli-Leydig cell tumour.

Sertoli-Leydig cell tumour (SLCT) is a rare, androgen-secreting sex cord-stromal tumour of the ovary that usually occurs in young premenopausal women. The major clinical manifestations are virilisation and defeminisation. The following case describes an 88-year-old G1P1 woman, 40 years after menopause, who presented with flushing, hirsutism, voice changes and alopecia along with significantly elevated levels of testosterone. Postoperative report revealed a well-differentiated SLCT in the left ovary. This case is unique in that SLCT is a very rare cancer and even more so in an 88-year-old woman. Taking this case into consideration, it becomes reasonable to check androgen and oestrogen levels in postmenopausal women, not only in patients with signs of virilisation, but also in those with non-classical presentations, such as flushing or heat spells.

Alcohol and coronary artery calcification: an investigation using alcohol flushing as an instrumental variable.

Background: We examined whether alcohol flushing could be used as an instrumental variable (IV) and investigated the effect of alcohol consumption on coronary calcification using alcohol flushing status as an IV. Methods: We analysed cross-sectional data from 24 681 Korean adults (20 696 men and 3985 women) who had been administered a questionnaire assessing alcohol consumption and alcohol flushing, as well as a coronary artery calcium (CAC) measurement. The associations of alcohol flushing status with potential confounders and alcohol consumption were examined. We employed two-stage predictor substitution methodology for the IV analysis. Results: The prevalence of alcohol flushing did not differ depending on gender, education, household income, cigarette smoking or physical activity. Balanced levels of confounders were observed between alcohol flushers and non-flushers. Alcohol flushing was closely related to alcohol consumption and levels of liver enzymes. In men, a doubling in alcohol consumption was associated with increased odds of coronary calcification in both the IV analysis [odds ratio (OR) of CAC scores of 1 or over = 1.11; 95% confidence interval (CI) = 1.03-1.20) and the multivariable regression analysis (OR = 1.04; 95% CI = 1.01-1.07). For cardiovascular risk factors, the IV analysis showed a positive association between alcohol consumption and blood pressure and high-density lipoprotein-cholesterol. Conclusions: Alcohol flushing can be used as an IV in studies evaluating the health impact of alcohol consumption, especially in East Asian countries. Through such an analysis, we found that increased alcohol consumption was associated with an increased risk of subclinical coronary atherosclerosis.

On the relationship between methylnicotinate-induced skin flush and fatty acids levels in acute psychosis.

Vasodilation induced by methylnicotinate, a fatty acid- and cyclooxygenase-dependent process, is reduced or absent in patients with schizophrenia. This phenomenon has been suggested to be useful as a diagnostic test for the illness. To determine whether reduced flushing is specific to schizophrenia and is caused by a deficiency in membrane fatty acids, the extent of topically applied methylnicotinate-induced vasodilation was measured in 23 subjects with schizophrenia, 20 subjects with bipolar disorder and 34 healthy volunteers along with red cell fatty acid concentrations and measures of clinical severity. Although there was a significant decrease in an estimate of vasodilation (erythema) compared with healthy volunteers in both schizophrenia and bipolar groups, the schizophrenia group responded significantly less than subjects with bipolar disorder. The reduction in the bipolar group was partly due to a delayed vasodilatory reaction, an effect not observed in subjects with schizophrenia. In subjects with schizophrenia, there were no significant correlations between methylnicotinate response and fatty acid concentrations. The authors conclude that the methylnicotinate procedure can differentiate schizophrenia from other serious mental illness. The methylnicotinate insensitivity in schizophrenia, however, is likely to be due to a deficiency in the fatty acid precursors required for the vasodilatory reaction.

Degrees of alcohol intoxication in 117 hospitalized cases.

The correlation among degrees of alcohol intoxication, facial flushing, blood alcohol concentration (BAC) and blood acetaldehyde level was studied in 117 male alcoholic patients who underwent various tests to assess alcohol influence. Blood samples were collected and alcohol and acetaldehyde levels were determined. BACs ranged from 29 to 577 mg/dl in all patients and from 200 to 299 mg/dl in 48 of them. Fifty-one patients could stand erect (mean BAC [+/- SD] = 189 +/- 80 mg/dl), while 48 showed apparently normal reaction to a walking and turning test (mean BAC = 192 +/- 78 mg/dl). Some of the cases having BACs over 300 mg/dl could still stand and walk while others with BACs under 100 mg/dl already showed psychomotor impairment. Facial flushing was recognized in 75% of the subjects. Acetaldehyde concentrations in 27 patients ranged from 24 to 147 micrograms/dl. Appearance of facial flushing was correlated with relatively high concentrations of blood acetaldehyde. Seven out of 10 healthy volunteers given 1.6 to 2.0 g/kg of alcohol as a control could do nothing but sleep after reaching peak BAC (mean = 232 +/- 21 mg/dl). These findings are taken to indicate a great difference in response to alcohol between alcoholics and healthy men. This study is the first to report the occurrence of facial flushing and raised blood acetaldehyde concentration among Japanese alcoholics.

Hot flushes in men with pituitary adenoma.

BACKGROUND: Hot flushes are common in menopausal women and also in men made acutely hypogonadal after orchiectomy or testicular injury. It is, however, an unusual symptom in patients with hypogonadism secondary to pituitary tumors. METHODS: In evaluating the histories of men with hypogonadal state associated with nonfunctioning pituitary macroadenoma we were struck by the presence of hot flushes in four of them. RESULTS: All four of the patients were hypogonadal with sexual dysfunction preoperatively. All had low gonadotropins and low testosterone levels with varying degrees of panhypopituitarism. All had successful transsphenoidal removal of tumors. None had endocrine improvement following surgery. All patients had improvement in sexual function and the hot flushes with administration of testosterone postoperatively. CONCLUSIONS: Hot flushes are an uncommon presentation in men with pituitary adenoma. Perhaps the symptom will become more prominent if it is specifically questioned. We postulate that the cause of the flushing is related to nonsuppressed pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus.

Anxiogenic and stress-inducing effects of peripherally administered acetaldehyde in mice: similarities with the disulfiram-ethanol reaction.

UNLABELLED: Peripheral accumulation of acetaldehyde, the first metabolite of ethanol, produces autonomic responses in humans called "flushing". The aversive characteristics of flushing observed in some populations with an isoform of aldehyde dehydrogenase (ALDH2) less active, are the basis for treating alcoholics with disulfiram, an ALDH inhibitor. Although ethanol and centrally formed acetaldehyde have anxiolytic effects, peripheral accumulation of acetaldehyde may be aversive in part because it is anxiogenic. OBJECTIVES: We investigated the effect of direct administration of acetaldehyde on behavioral measures of anxiety and on hormonal markers of stress in mice. The impact of disulfiram on the anxiolytic actions of ethanol was evaluated. Acetate (a metabolite of acetaldehyde) was also studied. METHODS: CD1 male mice received acetaldehyde (0, 25, 50, 75 or 100 mg/kg) at different time intervals and were assessed in the elevated plus maze and in the dark-light box. Corticosterone release after acetaldehyde administration was also assessed. Additional experiments evaluated the impact of disulfiram on the anxiolytic effect of ethanol (0 or 1 mg/kg), and the effect of acetate on the plus maze. RESULTS: Direct administration of acetaldehyde (100 mg/kg) had an anxiogenic effect at 1, 11 or 26 min after IP administration. Acetaldehyde was ten times more potent than ethanol at inducing corticosterone release. Disulfiram did not affect behavior on its own, but blocked the anxiolytic effect of ethanol at doses of 30 and 60 mg/kg, and had an anxiogenic effect at the highest dose (90 mg/kg) when co-administered with ethanol. Acetate did not affect any of the anxiety parameters. CONCLUSIONS: Peripheral administration or accumulation of acetaldehyde produces anxiogenic effects and induces endocrine stress responses. This effect is not mediated by its metabolite acetate.

Unpredictable endocrinology of the menopause transition: clinical, diagnostic and management implications.

The approach to menopause can be divided into the early (E) and late (L) menopausal transitions (MT) on the basis of menstrual irregularity (EMT) and subsequent observation of at least one episode of 60 or more days amenorrhoea (LMT). In total, 40-60% of cycles in the LMT are anovulatory, often with low oestradiol (E2) and high follicle-stimulating hormone concentrations. The ovulatory cycles have variable endocrine characteristics, none of which is specific to EMT or LMT. Hormonal measurements of FSH and E2 are thus of little diagnostic value because of their unpredictable variability. Symptoms during the transitions may result from high or low E2 and can often be satisfactorily managed with low-dose oral contraceptives, which suppress pituitary-ovarian function.

Alterations of niacin skin sensitivity in recurrent unipolar depressive disorder.

INTRODUCTION: Skin flushing after niacin (methylnicotinate, vitamin B(3)) stimulation is a biological marker of availability of polyunsaturated fatty acids (PUFA). Decreased PUFA levels have been reported in depressive disorder, while add-on supplementation of omega-3 PUFA has been suggested to improve depressive symptoms. This study aimed to clarify whether a disturbance of niacin skin flushing occurs also in depression, and to identify patient characteristics for those who might benefit from PUFA supplementation. METHOD: We studied 30 patients with recurrent unipolar depressive disorder during a major depressive episode (treated with antidepressants), and 30 healthy volunteers matched for age and gender. Aqueous methylnicotinate was applied in three dilution steps (0.001M, 0.01M, and 0.1M) onto the inner forearm skin. Skin flushing was assessed in three-minute intervals over 15min using optical reflection spectroscopy. RESULTS: While there was no overall difference in skin flushing between patients and controls, niacin sensitivity was inversely correlated with severity of symptoms, and flush deficits were significantly associated with depressed mood, feelings of anxiety and somatic symptoms (loss of appetite and weight loss). CONCLUSION: Results are suggestive of a subgroup of depressive patients characterised by a specific symptom cluster and disturbed niacin skin flushing.

Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk.

OBJECTIVES: To investigate the effect of low-dose aspirin administered in the morning or evening on the rate of discontinuation of prolonged-release nicotinic acid (Niaspan) due to flushing in patients at elevated cardiovascular risk. RESEARCH DESIGN AND METHODS: This was an observational, non-interventional study in patients at elevated cardiovascular risk due to cardiovascular disease or type 2 diabetes. Patients received prolonged-release nicotinic acid and aspirin under the usual care of their physician for 15 weeks. MAIN OUTCOME MEASURES: The main outcome measure was the rate of treatment discontinuation for flushing. Other adverse drug reactions (ADRs) were also recorded. Lipid parameters were also measured. RESULTS: The patient population included 539 subjects (70% male); 36% had type 2 diabetes, 80% had prior cardiovascular disease, and 37% had a family history of cardiovascular disease. The rate of treatment discontinuation due to flushing did not differ (p = 0.3375) between the morning aspirin group (10.6%) and the evening aspirin group (13.8%). The overall incidence of flushing was 57%. Most flushes were of mild or moderate severity and decreases occurred over time in both frequency and intensity. ADRs unrelated to flushing occurred in 6.6% of the morning aspirin group and 7.4% of the evening aspirin group. HDL-cholesterol increased by +21.3% in the overall population, together with moderate improvements in other lipid parameters. CONCLUSIONS: Flushing was the most common ADR with prolonged-release nicotinic acid treatment, as expected. The timing of aspirin administration did not influence the rate of treatment discontinuations for flushing. Marked increases in HDL-cholesterol were observed.

Influence of drinking alcohol on atherosclerotic risk in alcohol flushers and non-flushers of Oriental patients with type 2 diabetes mellitus.

AIMS: Facial flushing caused by alcohol drinking is a typical symptom of high sensitivity to alcohol in orientals. We investigated whether drinking alcohol influences atherosclerotic risk factors in alcohol flushers and non-flushers in patients with diabetes mellitus. METHODS: A cross-sectional study was performed using 225 subjects with type 2 diabetes. Sensitivity to alcohol was surveyed by a questionnaire on facial flushing. Subjects were divided into three groups by average amount of alcohol drinking (non-drinkers; light drinkers: <140 g/week; heavy drinkers: 140 g/week or more). RESULTS: Systolic blood pressure and blood HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. There were no significant differences in body mass index, blood pressure, blood total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid levels in flushers and non-flushers. In alcohol flushers, diastolic blood pressure and HDL cholesterol in heavy drinkers were significantly higher than those in non-drinkers, and systolic blood pressure was significantly higher in heavy drinkers than in non-drinkers and light drinkers. On the other hand, blood pressure and HDL cholesterol in non-flushers were not significantly different among non-, light and heavy drinkers. Serum total cholesterol was not significantly different among the three drinking groups both in flushers and non-flushers. CONCLUSIONS: Blood pressure and HDL cholesterol are more prone to be affected by drinking in flushers than in non-flushers, suggesting that alcohol sensitivity evaluated by flushing response due to drinking alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in oriental patients with type 2 diabetes mellitus.

Acetaldehyde syndrome after celiac plexus alcohol block.

In the course of celiac plexus alcohol block, facial flushing, palpitations, and hypotension are occasionally incurred in some patients. We hypothesized that the phenomenon represents acetaldehyde syndrome, not response to increased blood levels of ethanol as might be supposed. In order to prove our hypothesis, we selected five patients scheduled to undergo celiac plexus alcohol block, and, with their consent, we measured blood concentration of ethanol and acetaldehyde before and for 6 hr after the block. We also determined the phenotypes of aldehyde dehydrogenase (ALDH) in their hair roots. We found that "flushers" are found exclusively among subjects without ALDH I, and that their blood levels of acetaldehyde were significantly higher than those of "non-flushers" within 10 min after the block. The flushers also gave histories of facial flushing after ingestion of small amounts of ethanol. On the basis of such histories one can anticipate whether acetaldehyde syndrome is likely or unlikely to accompany the block.

Determinations of ethanol, acetaldehyde and acetate in blood and urine during alcohol oxidation in man.

Blood and urine samples were analyzed for ethanol, acetaldehyde and acetate during alcohol oxidation in Japanese men by head space gas chromatography, following the consumption of 16 ml/kg of beer during a 20 min period. The maximum level of blood/urine ethanol was found to be 15-17 mM (20-22 mM), while that of acetaldehyde in a flusher and in non-flushers was 20 microM (52 microM) and 2-5 microM (10-13 microM), respectively. Acetate levels in these groups ranged from 0.2 mM (0.1 mM) to 0.8 mM (1.0 mM). Blood ethanol levels were dose dependent, whereas acetaldehyde and acetate levels reflected individual metabolic rates. The relative concentrations of ethanol and acetaldehyde in blood and that of acetate in alcohol metabolism could be summarized as follows: 7500 (15 mM): 1-3 (2-5 microM); 250-400 (0.5-0.8 mM) for non-flushers; and 7500 (15 mM): 5-10 (10-20 microM): 250-400 (0.5-0.8 mM) for a flusher.

Hemoglobin-acetaldehyde adducts in human volunteers following acute ethanol ingestion.

Rabbit antibodies against albumin-acetaldehyde adduct were used in an enzyme-linked immunosorbent assay to detect acetaldehyde-hemoglobin condensates from the blood of 12 volunteers following ingestion of 1.3 to 2.9 g of ethanol per kg body weight during 8 hr. Blood samples were drawn before drinking and between 2 to 46 hr after starting the drinking session. While there were no significant increases in blood acetaldehyde levels in these samples, acetaldehyde-hemoglobin adducts were significantly increased in the samples drawn after ethanol had been eliminated from the body. Administration of ethanol (0.1 g/kg) to an Oriental flusher resulted in an increase both in blood acetaldehyde and the hemoglobin-acetaldehyde adduct levels. These results suggest that acetaldehyde-hemoglobin condensates are formed in vivo following acute ethanol ingestion. Such condensates may be of value to mark alcohol consumption.

Biophysical and endocrine-metabolic changes during menopausal hot flashes: increase in plasma free fatty acid and norepinephrine levels.

Thermocutaneous, vascular, metabolic and hormonal changes were investigated during 11 hot flashes from 6 postmenopausal women. The first detectable change was an increase in finger blood flow with a concomitant enhancement of skin conductance. The increase in skin conductance was followed rapidly by a sharp rise in finger temperature. The main endocrine-metabolic changes associated with the above phenomena were a sharp increase in plasma free fatty acids (approximately 65%), norepinephrine (approximately 100%) and LH (approximately 20%) levels. Plasma glucose and cortisol tended to be increased but did not reach statistical significance; on the other hand, plasma insulin, glucagon, growth hormone, epinephrine and dopamine remained unchanged.

Histamine in carcinoid syndrome.

The exact etiology of carcinoid flushing remains unknown, but the symptoms are probably mediated through release of one or several humoral substances. Flushing seen in fore-gut carcinoids (gastric carcinoids) has been ascribed to excessive histamine release, whereas flushing seen in mid-gut carcinoids (ileal carcinoids) tentatively has been ascribed to excessive release of serotonin, bradykinin, substance P, substance K or eledoisin. In this study plasma histamine was measured in 8 patients with mid-gut carcinoids and carcinoid syndrome using an enzymatic isotopic method in order to evaluate histamine as the vasoactive agent in patients with ileal carcinoid tumours and carcinoid syndrome. All patients had raised plasma histamine values. In patients with mid-gut carcinoids histamine may be one of the substances mediating flushing.