Microalbuminuria and nerve conduction velocity in type-I diabetics during conventional therapy and during continuous I.V. insulin infusion

Summary The objective of this study was to follow the development of microalbuminuria and nerve conduction velocity under continuous i.v. insulin therapy over a limited period of 4 months. For this purpose, 8 labile type I diabetics were selected (age 33±8 years, duration of diabetes 16±9 years) and treated conventionally with two insulin injections daily over 4 months. Afterwards, the same patients were treated with continuous i.v. insulin infusion and finally again with two injections daily over 4 months each. This procedure allowed each diabetic to serve as his own control. HbA₁, microalbuminuria, nerve conduction velocity and relative refractory period of the ulnar nerve were checked at montly intervals. During the continuous i.v. infusion over 4 months, blood sugar values were significantly lower, glucosuria had disappeared almost completely and the glycosylated hemoglobin had fallen to near normal values. The mean rate of albumin excretion was 16±5 μg/min at rest and 76±26 μg/min during exercise (normal: 3.9±0.4 and 4.8±1.2 μg/min, respectively) and did not change significantly. Nerve conduction velocity in the ulnar nerve rose significantly under i.v. insulin therapy from 47.9±0.6 m/sec to 52±0.6 m/sec. Similarly, the relative refractory period of the same nerve fell significantly from 3.7±0.2 to 1.9±0.1 msec (i.e. to within normal range). It is concluded that functional disturbances of peripheral nerve can regress by improved blood sugar control with continuous i.v. insulin infusion over 4 months. On the other hand, incipient microangiopathy measured as microalbuminuria remains unchanged over the same period of time. If an improvement is at all possible, considerably longer periods of euglycemia are likely to be necessary. Supported by Grant No. 3.964-0.80 from the Swiss National Science Foundation.     

Quantitative thallium-201 scintigraphy after dipyridamole infusion combined with low level exercise in healthy volunteers

To establish test specific normal limits for quantitative analysis of uptake and washout of ²⁰¹Tl after dipyridamole infusion combined with low level exercise, 20 healthy volunteers were studied with low likelihood of coronary artery disease (CAD) assessed by a stepwise probability analysis based on age, sex, symptoms, resting electrocardiogram, and exercise electrocardiography. Likelihood of CAD in these volunteers was calculated as 1%. After dipyridamole infusion combined with low level exercise, one volunteer complained of headache; no other side effects were observed. There were no chest pain complaints. Maximal hemodynamic changes were achieved during the 6th and 7th min of the test. No ST segment depression was recorded. Visual analysis of the ²⁰¹Tl scintigrams was normal in all volunteers. Mean regional washout at 4 h was 44.37%±2.11%. The regional washout in the 70° LAO view (46.65%±1.10%) was significantly higher than in the anterior and 30° LAO views (43.44%±1.50% and 43.02%±1.45%, respectively). Profiles of uptake and washout of ²⁰¹Tl were different after dipyridamole infusion combined with low level exercise as compared to maximal exercise. Thus, in quantitative analysis of ²⁰¹Tl scintigraphy after dipyridamole infusion in conjunction with low level exercise as applied in the present study, it is mandatory to use normal limits of uptake and washout of ²⁰¹Tl derived from healthy volunteers who underwent the same combined protocol.     

Adaptive Predictive Control of Arterial Blood Pressure Based on a Neural Network During Acute Hypotension

In acute hypotension, an automated drug infusion system to control mean arterial blood pressure (MAP) has not been previously studied, though many investigations have examined the use of vasodilating drugs to control MAP in postoperative hypertension. Therefore, we examined an automated control of MAP during acute hypotension using a neural network (NN) approach. A proportional-integral-derivative (PID) control, an adaptive predictive control using a NN (APC(NN)), a combined control of APC(NN) and PID (APC(NN-PID)), a fuzzy control, and a model predictive control were tested in computer simulation based on the MAP response to norepinephrine (NE) of 25 microg ml(-1). In six anesthetized rabbits, using the NE of 25 microg ml(-1), the PID control, APC(NN), and APC(NN-PID) prevented severe hypotension compared to an uncontrolled condition. Under PID control, four of the six animals showed MAP oscillation. Using NE of 50 microg ml(-1), the rabbits recovered from acute hypotension for all systems tested but showed sustained MAP oscillation during PID control. In conclusion, utilization of a NN for adaptive predictive control systems could facilitate the development of an automated drug infusion apparatus because it provides robust control even when acute or large perturbations and inter-individual differences in the sensitivity to therapeutic agents occur.     

Development of multielectrode impedance plethysmography

The feasibility of simultaneous independent measurements of impedance variations in the right and left apex and base of the lungs using the technique of multielectrode impedance plethysmography (MIPG) was investigated. To obtain independent impedance measurements in each region, high impedance sensitivity areas must be localised by weighting the impedance sensitivity distribution. 12 planar coaxial-type electrodes were attached on the right and left upper, middle and lower sites of the anterior and posterior chest walls. Currents of identical absolute values and differing polarities were simultaneously applied to neightbouring electrodes and voltage measurements were carried out sagittally at the right and left upper and lower sites of the chest walls. The effect of weighting the impedance sensitivity distribution was verified through experimental studies on mongrel dogs. The methods utilised for the induction of regional physiological conductivity changes were selective ventilation and selective indicator infusion into the pulmonary vasculature. The detected impedance variation showed reasonably indenpendent responses which were consistent with our expectations from the results of the computer simulation.     

Power spectral analysis of the electroencephalographic and hemodynamic correlates of propofol anesthesia in the rat: Intravenous infusion

Based on the tail-flick response to noxious thermal stimuli, we determined in the present study that effective antinociception could be achieved in adult male Sprague-Dawley rats 15 min after intravenous infusion of propofol at 60 mg/kg/h. Simultaneous power spectral analysis of the electroencephalographic (EEG) and systemic arterial pressure signals further revealed a concomitant depression of the activity of all EEG frequency bands (δ, θ, , β), alongside hypotension, negative inotropic and chronotropic actions, and attenuated baroreceptor reflex and vasomotor activity. These effects were congruent with a plasma concentration of propofol in the arterial blood of 1.70 ± 0.13 μg/ml, as determined by high-performance liquid chromatography.     

Vagal mediation of the cholecystokinin satiety effect in rats

Central (intracerebroventricular) and peripheral (intraperitoneal) injections of the octapeptide of cholecystokinin (CCK-8) were compared to determine the most effective route of administration to elicit satiety for food intake in the rat. Subdiaphragmatic bilateral vagotomy and spinal cordotomy (T2-T3) were also performed to investigate the importance of visceral nerves for the satiety effect. CCK-8 suppressed feeding and elicited satiety resting behavior when injected peripherally but it was less effective when injected centrally. The satiety effect of CCK-8 or CCK-33 following peripheral injections was blocked by vagotomy whereas spinal cordotomy had no effect. The results indicate that some component of the vagus is required to mediate the peripherally induced cholecystokinin satiety effect, but the splanchnic nerves are not necessary. The weak effect of CCK-8 following ventricular administration is additional evidence suggesting that cholecystokinin of intestinal origin acts in the periphery rather than directly on the brain to elicit its typically rapid satiety effect in rats.     

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high-field 19F-NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

A Sprague-Dawley rat model with DS sarcoma transplanted in the thigh was used to compare transcatheter locoregional i.a. and systemic i.v. administration of 5-fluorouracil (FU) at 12 dose-rate schedules: 25, 50 and 100 mg/kg; bolus, 1, 5 and 24 h infusions. In experiment A tumor (62/67 animals) as well as liver and kidney (56/67 animals) were excised 1 h after a single bolus or 1 h infusion or at the end of 5 and 24 h infusions. (19)F-NMR spectroscopy at 11.7 T was used to quantitate FU and its metabolites in ca. 1 g of tissue at 4 degrees C. In experiment B analogous FU treatments were repeated for 5 days (rats 80+11 controls). Tumor volumes vs time, various blood parameters and survival times were recorded, and a log growth rate parameter log GR, a response index RI, and a toxicity index TI were calculated. The i.a. vs i.v. ratios for tumor concentrations of FU and total anabolites (F-Nucl) were >1 for nearly all treatments and increased with infusion time at the higher doses. F-Nucl in tumor correlated linearly with total fluorine concentration (Tot. F range 30-1100 nmol/g) over all treatments (r=0.92, slope=0.45, p<0.0001). For non-bolus i.v. treatments [FU+F-Nucl] decreased linearly with decreasing FU dose rate (r(2)=0.74, zero intercept), while i.a. treatments showed non-linear behavior. For non-bolus treatments the mean log GR per treatment group showed a negative correlation (r=-0.87) with log[F-Nucl]. The most effective non-toxic treatments were 25 mg/kg over 5 or 24 h; the i.a. route was superior to i.v. on the basis of [FU+F-Nucl], RI, the reduction in log GR, and Kaplan-Meier survival statistics. For liver and kidney Tot. F (>83% FU catabolites) reached ca. 3-4 and 6-7 micromol/g, respectively, at the highest dose rates for either route; F-Nucl were detected only for Tot. F>500 nmol/g and increased exponentially as Tot. F increased (toxic treatments). The concentrations of the main catabolite (alpha-fluoro-beta-alanine, FBAL) in tumor did not correlate with Tot. F but rather with FBAL levels in kidney (r=0.90, all treatments), indicating that uptake of liver-derived FBAL from the circulation is the major source of FBAL in tumor.     

Nutrient composition: effects on appetite in monkeys with oral factors held constant

The effects of macronutrients on appetite and total caloric intake in monkeys (Macaca mulatta) was studied using a new feeding and infusion system which yoked intragastric infusion of various nutrients to oral ad lib intake and removed the confounding factor of palatability from the assessment of nutrient effects on feeding behavior. A suction-activated liquid diet feeding system provided free access to a nutritionally complete diet, with 1 ml of diet delivered orally by pump with each discrete suck by the monkey. A second pump was yoked to the oral feeding pump and delivered various nutrients directly into the stomach via an implanted intragastric cannula. Thus, while oral diet composition remained constant, the net diet reaching the stomach varied over ranges of 28 to 77% carbohydrate, 16 to 65% fat and 7 to 36% protein. No significant differences in total caloric intake were observed between intakes of diets with net composition of high carbohydrate or high fat. When protein was increased to 36%, total caloric intake was generally reduced, and this effect was sustained for at least 3 weeks. Therefore, protein appears to have an increased specific satiating effect beyond the caloric content, when compared to carbohydrate or fat.     

Spread of epidural analgesia following a constant pressure injection

(1) The spread of epidural analgesia following injection of 15ml of 2% mepivacaine was 17.3 ± 0.6, 14.3 ± 0.4, and 13.3 ± 0.7 spinal segments in cervical, thoracic, and lumbar epidural analgesia, respectively. The patients age showed significant correlation with the spread of epidural analgesia in cervical (r = 0.5776, p < 0.001), thoracic (r = 0.3758, p < 0.01), and lumbar area (r = 0.8195, p < 0.001). The spread of cervical epidural analgesia was more caudad than cephalad (p < 0.05), but in lumbar epidural analgesia it was more cephalad than caudad (p < 0.05). There was no difference between the cephalad and caudad spread in thoracic epidural analgesia.(2) The epidural pressure immediately after injection of 15ml of 2% mepivacaine into the lumbar epidural space at a constant pressure (80mmHg) correlated to the patients age (r = –0.5714, p < 0.001) and the spread of analgesia (r = –0.3904, p < 0.05). The lower epidural pressure associated with higher age, the wider spread of analgesia. There was no significant correlation between the residual pressure at 60 seconds and the age or the spread of analgesia.(Hirabayashi Y et al.: Spread of epidural analgesia following a constant pressure injection: an investigation of relationships between locus of injection, epidural pressure and spread of analgesia. J Anesth 1: 44–50, 1987)