Severe bradycardia and hypotension in anaesthetized pigs: Possible interaction between octreotide, xylazine, and atropine: A case series

Pigs are common animal models in diabetes research. Streptozotocin-induced destruction of pancreatic β-cells is used to induce diabetes in conscious pigs. However, in short-term non-recovery experiments, suppression of endogenous insulin secretion can be faster and more easily achieved with somatostatin analogues. We report a series of severe and unexpected episodes of severe bradycardia in eight pigs during non-recovery experiments with the original aim of investigating the pharmacokinetics and pharmacodynamics of intraperitoneal hormone delivery. The adverse events occurred four to five hours into the experiments, and we believe that they were caused by an interaction between the somatostatin analogue octreotide, and the sedative drug xylazine and that atropine delayed the time of occurrence

Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism

Background and Objective Artificial pancreases administering low-dose glucagon in addition to insulin have the scope to improve glucose control in patients with diabetes mellitus type 1. If such a device were to deliver both hormones intraperitoneally, it would mimic normal physiology, which may be beneficial. However, the pharmacokinetic properties of glucagon after intraperitoneal administration are not well known. Hence, the current study aims to evaluate the relationship between the amount of intraperitoneally delivered glucagon and pharmacokinetic variables in a pig model. Methods Pharmacokinetic data was retrieved from experiments on 19 anaesthetised pigs and analysed post hoc. The animals received a single intraperitoneal bolus of glucagon ranging from 0.30 to 4.46 µg/kg. Plasma glucagon was measured every 2–10 min for 50 min. Results Peak plasma concentration and area under the time–plasma concentration curve of glucagon correlated positively with the administered dose, and larger boluses provided a relatively greater increase. The mean (standard deviation) time to maximum glucagon concentration in plasma was 11 (5) min, and the mean elimination half-life of glucagon in plasma was 19 (7) min. Conclusions Maximum plasma concentration and area under the time–plasma concentration curve of glucagon increase nonlinearly in relation to the intraperitoneally administered glucagon dose. We hypothesise that the results are compatible with a satiable first-pass metabolism in the liver. Time to maximum glucagon concentration in plasma and the elimination half-life of glucagon in plasma seem independent of the drug dose

Impact of thyrotropin receptor antibody levels on fetal development in two successive pregnancies in a woman with Graves' Disease

Background: Treatment with radioiodine for Graves’ disease regularly increases the level of antithyroid antibodies, and transplacental passage of stimulating thyrotropin receptor antibodies (TRAb) may cause fetal hyperthyroidism. Case presentation: A 21-year-old woman with Graves’ disease received radioiodine treatment to avoid use of antithyroid drugs in pregnancy. She became pregnant 4 months later and was euthyroid during pregnancy. In gestational week (GW) 33, she was admitted with an increased fetal heart rate of 176–180 beats/min. Fetal echocardiography indicated cardiac decompensation. The neonate had severe hyperthyroidism (free thyroxine >100 pmol/l, nv 12.0–22.0), cardiac insufficiency, insufficient weight gain, goiter and considerably accelerated skeletal age. In the mother and neonate, TRAb was >40 IU/l (nv 40 IU/l in the woman, and 18 months later she underwent total thyroidectomy with subsequent decline in TRAb. In her next pregnancy, TRAb fluctuated between 38 and 17 IU/l, and repeated fetal ultrasound showed no goiter or sign of hyperthyroidism. In cord blood, TRAb was 10.9 IU/l, and the neonate had normal thyroid hormone levels. Conclusion: This case report illustrates the impact of maternal TRAb level for neonatal outcome in two successive pregnancies

Physiological effects of intraperitoneal versus subcutaneous insulin infusion in patients with diabetes mellitus type 1: A systematic review and meta-analysis

The intraperitoneal route of administration accounts for less than 1% of insulin treatment regimes in patients with diabetes mellitus type 1 (DM1). Despite being used for decades, a systematic review of various physiological effects of this route of insulin administration is lacking. Thus, the aim of this systematic review was to identify the physiological effects of continuous intraperitoneal insulin infusion (CIPII) compared to those of continuous subcutaneous insulin infusion (CSII) in patients with DM1. Four databases (EMBASE, PubMed, Scopus and CENTRAL) were searched beginning from the inception date of each database to 10th of July 2020, using search terms related to intraperitoneal and subcutaneous insulin administration. Only studies comparing CIPII treatment (≥ 1 month) with CSII treatment were included. Primary outcomes were long-term glycaemic control (after ≥ 3 months of CIPII inferred from glycated haemoglobin (HbA1c) levels) and short-term (≥ 1 day for each intervention) measurements of insulin dynamics in the systematic circulation. Secondary outcomes included all reported parameters other than the primary outcomes. The search identified a total of 2242 records; 39 reports from 32 studies met the eligibility criteria. This meta-analysis focused on the most relevant clinical end points; the mean difference (MD) in HbA1c levels during CIPII was significantly lower than during CSII (MD = -6.7 mmol/mol, [95% CI: -10.3 –-3.1]; in percentage: MD = -0.61%, [95% CI: -0.94 –- 0.28], p = 0.0002), whereas fasting blood glucose levels were similar (MD = 0.20 mmol/L, [95% CI: -0.34–0.74], p = 0.47; in mg/dL: MD = 3.6 mg/dL, [95% CI: -6.1–13.3], p = 0.47). The frequencies of severe hypo- and hyper-glycaemia were reduced. The fasting insulin levels were significantly lower during CIPII than during CSII (MD = 16.70 pmol/L, [95% CI: -23.62 –-9.77], p < 0.0001). Compared to CSII treatment, CIPII treatment improved overall glucose control and reduced fasting insulin levels in patients with DM1

Intraperitoneal insulin administration in pigs: Effect on circulating insulin and glucose levels

Introduction The effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses. There is a lack of studies comparing the insulin appearance in the systemic circulation after intraperitoneal compared with subcutaneous insulin delivery. Thus, we also aimed for a comparison with the subcutaneous route. Research design and methods Eight anesthetized, non-diabetic pigs were given three different intraperitoneal insulin boluses (2, 5 and 10 U). The order of boluses for the last six pigs was randomized. Endogenous insulin and glucagon release were suppressed by repeated somatostatin analog injections. The first pig was used to identify the infusion rate of glucose to maintain stable glucose values throughout the experiment. The estimated difference between insulin boluses was compared using two-way analysis of variance (GraphPad Prism V.8). In addition, a trial of three pigs which received subcutaneous insulin boluses was included for comparison with intraperitoneal insulin boluses. Results Decreased mean blood glucose levels were observed after 5 and 10 U intraperitoneal insulin boluses compared with the 2 U boluses. No changes in circulating insulin levels were observed after the 2 and 5 U intraperitoneal boluses, while increased circulating insulin levels were observed after the 10 U intraperitoneal boluses. Subcutaneously injected insulin resulted in higher values of circulating insulin compared with the corresponding intraperitoneal boluses. Conclusions Smaller intraperitoneal boluses of insulin have an effect on circulating glucose levels without increasing insulin levels in the systemic circulation. By increasing the insulin bolus, a major increase in circulating insulin was observed, with a minor additive effect on circulating glucose levels. This is compatible with a close to 100% first-pass effect in the liver after smaller intraperitoneal boluses. Subcutaneous insulin boluses markedly increased circulating insulin levels

The Artificial Pancreas: A Dynamic Challenge

In patients with diabetes mellitus type 1, the pancreatic insulin production ceases, causing raise in blood glucose level (BGL) and potentially severe long-term complications. The “holy grail” of diabetes treatment is the artificial pancreas (AP), a closed-loop control system that regulates the user’s BGL by infusing insulin, and possibly glucagon. Numerous attempts have been largely unsuccessful, mainly due to slow dynamics that make it difficult to avoid unwanted BGL excursions. System performance has been improved through improved sensor technology and faster-acting insulin types, but the risk of hypoglycemia is still significant unless the glucose setpoint is unnaturally high. We argue that this problem can be circumvented by choosing appropriate sites for glucose measurement and insulin infusion. While intravascular measurement and infusion provides the fastest dynamics and thus the best conditions for closed-loop control, it is only viable in inpatients mainly due to danger of infections and limited sensor durability. On the other extreme, state-of-the-art subcutaneous systems exhibit significant time delays and diffusion dynamics, yielding poor BGL control in the event of disturbances like meals and physical activity. Avoiding dangerous hypoglycemia therefore comes at the expense of daily episodes of elevated BGL (typically 10–15 mmol/L) that increase the risk of long-term complications. Furthermore, slow insulin uptake from subcutis remains as a major challenge. Hence we advocate the double intraperitoneal (IP) AP. Here, insulin is released into the abdominal cavity (peritoneum) through a semi-permanent port, which also allows access for IP glucose sensing. This improves both sensing and absorption dynamics. Thus the closed-loop control may be significantly tighter, allowing a setpoint closer to the healthy normal BGL of approximately 4.5 mmol/L whilst potentially improving system safety. These statements are supported by results from our own research and the literature

Why intraperitoneal glucose sensing is sometimes surprisingly rapid and sometimes slow: A hypothesis

The artificial pancreas requires fast and reliable glucose measurements. The peritoneal space has shown promising results, and in one of our studies we detected glucose changes in the peritoneal space already at the same time as in the femoral artery. The peritoneal lining is highly vascularised, covered by a single layer of mesothelial cells and therefore easily accessible for proper sensor technology, e.g. optical technology. We hypothesize that the rapid intraperitoneal glucose dynamics observed in our study was possible because the sensors were located directly at the peritoneal lining, at the point where the glucose molecules entered the peritoneal space. Glucose travels slowly in fluids by diffusion, and a longer distance between the sensor and the peritoneal lining would consequently result in slower dynamics. We therefore propose to place the glucose sensor in an artificial pancreas as closely to the peritoneal lining as possible, or even utilize appropriate sensor technology to measure glucose in the peritoneal lining itself

A Review of the Current Challenges Associated with the Development of an Artificial Pancreas by a Double Subcutaneous Approach

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Seniority rules, worker mobility and wages : evidence from multi-country linked employer-employee data

We construct multi-country employer-employee data to examine the consequences of last-in, first-out rules. We identify the effects by comparing worker exit rates between different units of the same firms operating in Sweden and Finland, two countries that have different seniority rules. We observe a relatively lower exit rate for more senior workers in Sweden in the shrinking firms and among the low-wage workers. These empirical patterns are consistent with last-in, first-out rules in Sweden providing protection from dismissals for the more senior workers among the worker groups to whom the rules are most relevant. Similarly, we observe a steeper seniority-wage profile in Sweden, suggesting that last-in, first-out rules may also be beneficial for more senior workers in terms of compensation.peerReviewe