Association between intra-operative cardiac arrest and country Human Development Index status: a systematic review with meta-regression analysis and meta-analysis of observational studies.

Intra-operative cardiac arrests differ from most in-hospital cardiac arrests because they reflect not only the patient's condition but also the quality of surgery and anaesthesia care provided. We assessed the relationship between intra-operative cardiac arrest rates and country Human Development Index (HDI), and the changes occurring in these rates over time. We searched PubMed, EMBASE, Scopus, LILACS, Web of Science, CINAHL and SciELO from inception to 29 January 2020. For the global population, rates of intra-operative cardiac arrest and baseline ASA physical status were extracted. Intra-operative cardiac arrest rates were analysed by time, country HDI status and ASA physical status using meta-regression analysis. Proportional meta-analysis was performed to compare intra-operative cardiac arrest rates and ASA physical status in low- vs. high-HDI countries and in two time periods. Eighty-two studies from 25 countries with more than 29 million anaesthetic procedures were included. Intra-operative cardiac arrest rates were inversely correlated with country HDI (p = 0.0001); they decreased over time only in high-HDI countries (p = 0.040) and increased with increasing ASA physical status (p < 0.0001). Baseline ASA physical status did not change in high-HDI countries (p = 0.106), while it decreased over time in low-HDI countries (p = 0.040). In high-HDI countries, intra-operative cardiac arrest rates (per 10,000 anaesthetic procedures) decreased from 9.59 (95%CI 6.59-13.16) pre-1990 to 5.17 (95%CI 4.42-5.97) in 1990-2020 (p = 0.013). During the same time periods, no improvement was observed in the intra-operative cardiac arrest rates in low-HDI countries (p = 0.498). Odds ratios of intra-operative cardiac arrest rates in ASA 3-5 patients were 8.48 (95%CI 1.67-42.99) times higher in low-HDI countries than in high-HDI countries (p = 0.0098). Intra-operative cardiac arrest rates are related to country-HDI and decreased over time only in high-HDI countries. The widening gap in these rates between low- and high-HDI countries needs to be addressed globally.

Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).

Benfluorex in obese noninsulin dependent diabetes mellitus patients poorly controlled by insulin: a double blind study versus placebo.

Most obese patients with noninsulin-dependent diabetes mellitus (NIDDM) are initially treated with diet, then with oral hypoglycemic agents, eventually with insulin. However several reports indicate that in these patients insulin therapy has little chance to control glucose metabolism, promotes weight gain and arterial hypertension, and is likely to aggravate insulin resistance. In this randomized, double-blind trial vs. placebo (P) we evaluated in 29 obese NIDDM patients poorly controlled by insulin (daily insulin doses 48.7 +/- 4.0 U/day, HbA1c 10 +/- 0.27%, mean daily blood glucose levels 12.3 +/- 0.3 mmol/L, fasting C-peptide 1.8 +/- 0.2, C-peptide after 1 mg iv glucagon 3.2 +/- 0.3 ng/mL, means +/- SE), the clinical and metabolic effects of benfluorex (B), a lipid-lowering drug able to improve insulin sensitivity. After a 2-3 week run-in period (1 tablet P at dinner and diet 800 cal/day to lose 5% of the initial body weight (BWi), patients received a 1000 kcal/day diet and were randomized to B, 150 mg/ tablet, or P (3 tablets/day); the time limit was set at a 10% decrease of BWi or at 90 days. At the end of run-in there was a significant reduction of BWi (P < 0.001), fasting (P = 0.002) and mean daily blood glucose levels (P < 0.001), triglycerides (P = 0.02), cholesterol (P < 0.001) and daily insulin doses (P < 0.001). At the end of the double-blind trial, weight-loss was greater (P < 0.05), faster (P = 0.018), and more frequent (P < 0.05) with B than with P, and systolic blood pressure (P < 0.05) decreased only with B. Considering only patients with a 10% decrease of BWi (B = 15, P = 10), HbA1c (P < 0.001) decreased only with B, while fasting insulin levels decreased with both B (P < 0.01) and with P (P < 0.05). Insulin sensitivity was evaluated by means of a double infusion test (LDIGIT, insulin 25 mU/Kg/h plus glucose 4 mg/kg/min, lasting 150 min) at the end of run-in and at the end of the double-blind trial; at the end of the double-blind trial steady state blood glucose (SSBG, P < 0.05), free fatty acids (FFA, P < 0.05) and blood beta-hydroxybutyrate (P < 0.05) decreased only with B, while blood glycerol decreased both with both P (P < 0.05) and B (P < 0.06). At the end of the double-blind trial, C-peptide release was unchanged with either P or B. In conclusion, benfluorex potentiates the effects of hypocaloric diet on weight loss and on glycemic control in obese NIDDM patients treated with insulin, and this effect seems to be the result of an improved insulin sensitivity.

Forearm insulin- and non-insulin-mediated glucose uptake and muscle metabolism in man: role of free fatty acids and blood glucose levels.

Muscle can utilize glucose by two different mechanisms, one non-insulin-mediated and the other insulin-mediated. The aim of this study was to investigate and to quantify the influence of high and low free fatty acids (FFA) levels on muscle non-insulin-mediated glucose uptake (MNIMGU) and muscle insulin-mediated glucose uptake (MIMGU) and on muscle metabolism during euglycemia and hyperglycemia. Six healthy volunteers were submitted, in a random order, to a 2-hour euglycemic clamp (EC) followed by a 2-hour hyperglycemic (11 mmol/L) clamp (HC) under five different conditions: (1) somatostatin infusion (SRIF, 500 micrograms/h); (2) SRIF infusion preceded by a nicotinic acid analogue (acipimox, 250 mg orally, (3) SRIF plus insulin infusion; (4) SRIF plus insulin plus intralipid infusion; and (5) SRIF plus insulin infusion plus acipimox. In the postabsorptive state MNIMGU represented 71% of the total muscle glucose uptake (MGU) and during the EC a sharp reduction of FFA levels increased the MNIMGU by 10% (P less than .05), and an acute increase in FFA levels decreased the MNIMGU by 26% (P less than .05). MIMGU was significantly increased by 103% after acipimox administration (P less than .05) and was decreased by 65% during intralipid infusion (P less than .05). During HC, MNIMGU was not significantly influenced by low or high FFA levels, and MIMGU was not affected by a sharp lowering of FFA levels, but was significantly decreased (85%) during intralipid infusion. There was no significant difference in the lactate, pyruvate, and alanine balance across the forearm during EC and HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Are diabetic metabolic compensation and CA19.9 really correlated?

Diabetes has been claimed to be a risk factor for pancreatic carcinoma, but it is probably a consequence of gland invasion from the neoplastic tissue. A link between diabetes and pancreatic carcinoma was suggested by means of biochemical markers of the diseases, namely glycated hemoglobin and CA19.9. Moreover, CA19.9 was proposed as a sensitive and useful marker of the severity of exocrine damage in diabetes, since the mucin decreased when metabolic compensation improved. We examined 64 diabetic patients (36 insulin dependent, 16 non insulin dependent, 12 treated with diet) by measuring CA19.9 using two different immunometric methods and glycemia and glycated hemoglobin. We observed that a correlation between CA19.9 and biochemical markers of metabolic compensation of diabetes was inexistent and no differences between insulin dependent and non insulin dependent patients were found. A high concentration of CA19.9 in a diabetic patient should be interpreted and evaluated in the same manner as for a non diabetic patient.

Markers of insulin resistance are associated with cardiovascular morbidity and predict overall mortality in long-standing non-insulin-dependent diabetes mellitus.

The aim of this study was to evaluate the influence of endogenous insulin levels and of insulin administration on coronary heart disease (CHD) and on mortality in a cohort of patients with long-standing non-insulin-dependent diabetes mellitus (type 2). In a cross-sectional study, 93 patients (known duration 17 +/- 8 years, mean+/-SD) with poor metabolic control (glycosylated hemoglobin, HbA1C 9.3%+/-2.09%) were evaluated for CHD, for insulin release (C-peptide), for clinical and metabolic parameters including body mass index (BMI), smoking habits, arterial blood pressure (BP), blood lipids, kidney function, and proteinuria. Life status was ascertained 5 years later by direct examination or through death certificates. At entry, 54 out of 93 patients had CHD; after 5 years, 25 patients had died. Comparisons performed on patients of the same age range showed that patients with CHD (34 vs 24) had a greater BMI, higher diastolic BP, higher creatinine, triglyceride and uric acid levels, and higher fasting and i.v. glucagon-stimulated C-peptide release. By logistic stepwise regression analysis, fasting C-peptide and triglycerides were independently associated with CHD. In the follow-up study, surviving patients (39 vs 19) showed at baseline lower triglyceride and creatinine levels, were less frequently affected by CHD, and received lower doses of insulin; by logistic stepwise regression analysis, presence of CHD, dose of insulin, and creatinine levels were independent risk factors for mortality. These data indicate that in patients with long-standing type 2 diabetes mellitus and poor metabolic control, CHD and overall mortality are related to insulin release and to insulin administration, suggesting that markers of insulin resistance represent additional risk factors for CHD and for mortality. Reduction of insulin resistance, together with achievement of good metabolic control, might prevent morbidity and mortality in long-standing type 2 diabetes mellitus.

Effects of hyperglycaemia on visual evoked potentials in insulin-dependent diabetic patients.

Multimodality evoked potentials frequently reveal subclinical involvement of the central nervous system in patients with insulin-dependent diabetes mellitus. We devised this study to evaluate the possible effects of acute hyperglycaemia on visual evoked potential (VEP) parameters in type 1 diabetic patients. A hyperglycaemic clamp (250 mg/dl for 180 min) was performed in ten patients. Monocular pattern reversal VEPs (check size 15', contrast 50%) were recorded before, and every 30 min after the start of the clamp. Basal VEP latencies and amplitudes were normal bilaterally in nine patients. No significant changes in pattern reversal and flash VEP parameters were observed after the induction or during the clamp period. None of the neurophysiological parameters evaluated during the test was related to the duration of the disease, the basal VEP latency or amplitude or the presence of retinopathy. Our data suggest that the neurophysiological abnormalities detected in insulin-dependent diabetic patients are due to structural involvement of the central nervous pathways and not to functional damage induced by acute short-term hyperglycaemia.

Weight loss reverses secondary failure of oral hypoglycaemic agents in obese non-insulin-dependent diabetic patients independently of the duration of the disease.

The aim of the present study was to evaluate whether reduction of body weight is able to restore sensitivity to oral hypoglycaemic agents in obese non-insulin-dependent diabetic patients with secondary failure of to the anti-diabetic drugs. 80 obese patients (BMI approximately 30 kg/m2) with Type 2 diabetes lasting 1-30 years and showing hyperglycaemia for at least 3 months (51 on insulin, 29 on oral drugs) received an 800 kcal diet for 20-24 days, lost about 6.3% BMI, and returned to euglycaemia; 22 obese euglycaemic Type 2 diabetes patients (9 on insulin, 13 on oral therapy) underwent the same treatment, and lost approximately 8.3% BMI. As a result insulin could be withdrawn in 18 out of 60 patients and reduced (from 0.5 to 0.2 U.kg day) in the remaining patients. Oral therapy could be withdrawn in 17 out of 42 cases and reduced (from 12.1 to 8.6 mg glibenclamide/day) in the remaining cases. As a control group, 20 non obese (BMI < 24.0 kg/m2) hyperglycaemic Type 2 diabetic patients (10 on oral hypoglycaemic agents, 10 on insulin) with Type 2 diabetes lasting 1-26 years, underwent the same dietary regimen, lost about 3.2% of body weight, but could not withdraw insulin, which had to be started in 6 previously oral hypoglycaemic drugs treated patients. Systolic and diastolic blood pressure and serum cholesterol and triglyceride levels also decreased in obese, but not in non-obese Type 2 diabetes patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The hypotonic effect of intranasal and intravenous glucagon in gastrointestinal radiology.

In the present study, following a double-blind, double placebo protocol vs. placebo, we compared the hypotonic effect of intranasal and intravenous glucagon during a double-contrast barium meal examination of the stomach. We found a statistically significant difference between placebo and intranasal or intravenous glucagon in inducing gastric hypomotility, with no significant differences between IN and IV glucagon. The intranasal administration of glucagon has the advantage of being noninvasive and well tolerated by the patients, and might be a valuable aid in upper gastrointestinal examination as well as in CT scan or magnetic resonance imaging of the abdomen.

Insulin requirement in elderly patients with non-insulin dependent diabetes mellitus (NIDDM).

Diabetes mellitus in the elderly is mainly of the non-insulin dependent type (NIDDM). A large proportion of such patients are treated with insulin, after many years of therapy with oral hypoglycemic agents (OHA), on the assumption that these lose their efficacy with time. Moreover, many such patients are obese and show preserved insulin release. In the present study 45 obese subjects with NIDDM (14 under good metabolic control and 31 who presented hyperglycemia for at least 3 mo prior to testing) were placed on a strictly hypocaloric diet (800 Kcal/d) for 20 to 24 d. All of these patients had preserved insulin release. At the end of the trial, all the patients presented a significant reduction in body weight and a near normalization of the blood glucose profile, as well as a significant decrease both in the serum cholesterol and triglyceride levels and in the systolic blood pressure. On the basis of these results, insulin and OHA could be reduced in all the patients and suspended in some of these. The decrease in blood glucose levels was the same in all the patients regardless of the length of time that each had suffered from NIDDM. Five non-obese patients were placed on the same regimen, but the daily insulin dose could not be reduced. These data indicate that the majority of obese elderly patients with NIDDM are unnecessarily treated with insulin or with OHA, while diet alone would be sufficient to keep them under good metabolic control.

Association of obesity and type II diabetes mellitus as a risk factor for gallstones.

Age, female sex, and obesity are well-known risk factors for gallstones; in contrast the possible role of type 2 diabetes mellitus (type-2 DM) is controversial. One reason for this discrepancy might be that type 2 DM is often accompanied by obesity. Therefore, the aim of this study was to evaluate the importance of obesity and of type 2 DM, separately and together, as risk factors for gallstones. In all, 203 obese patients with normal glucose tolerance (obese NGT), 446 obese patients with type 2 DM (obese type 2 DM), 269 lean patients with type 2 DM (lean type 2 DM) and 250 lean subjects with a normal glucose tolerance (lean NGT) were evaluated by ultrasonography for the presence of gallstones. At univariate analysis patients with gallstones (177) were older and were more frequently affected by both obesity and type 2 DM, and had higher triglycerides and fasting blood glucose levels. At multiple logistic regression analysis, only age and obesity, both in the presence or in absence of type 2 DM, were strongly associated with gallstones (P < 0.001); diabetes alone had a lower level of statistical significance (P = 0.07). These data suggest that obesity is a stronger risk factor for gallstones than type 2 DM.

Pirenzepine decreases basal and stimulated GH secretion in patients with type 2 (non-insulin-dependent) diabetes mellitus.

Growth hormone (GH) hypersecretion has been described in diabetes mellitus and seems to be involved in the pathogenesis of diabetes complications. As pirenzepine (PZ), a cholinergic muscarinic antagonist, is able to inhibit GH hypersecretion in insulin-dependent diabetes mellitus (IDDM), we investigated whether PZ is also able to inhibit spontaneous and stimulated GH-release in non-insulin-dependent diabetes mellitus (NIDDM). Ten non-obese well-controlled patients with NIDDM underwent in random order the following three double-blind one week treatments: placebo (PL), PZ at low dose (PL in the morning plus PZ 50 mg at 22 h) or high dose (PZ 50 mg at 8 h plus 100 mg at 22 h). Pirenzepine administration significantly (p < 0.05) decreased nocturnal GH release after both low and high dose (AUC, PL vs PZ: 107.3 +/- 26.5 vs 48.3 +/- 10.5 and 57.6 +/- 9.6 micrograms/L/h, respectively). The GH response to arginine infusion was significantly inhibited by PZ at high dose (AUC, 147.1 +/- 48.8 vs 444.7 +/- 194.3 micrograms/L/h, p < 0.01), but not at low dose. Glucose, insulin, glucagon and somatostatin responses to arginine infusion were not changed by pirenzepine treatment. In conclusion, the muscarinic blockade by PZ is able to inhibit the spontaneous and stimulated GH secretion also in NIDDM without affecting insulin secretion.