Luigi Severino Brandi

Insulin Resistance in Essential Hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.

Indirect calorimetry in critically ill patients: Clinical applications and practical advice*

Indirect calorimetry is the method by which metabolic rate and substrate utilization are estimated in human beings starting from respiratory gas exchange measurements and urinary nitrogen excretion. This method is based on some models and assumptions that must be known and taken into consideration to correctly interpret the results obtained. Recent advances in technology and the availability of precise and portable metabolic carts have made this technique practical at the beside even in critically ill patients. It must be considered that, particularly in the ICU, there may be several sources of error and many technical difficulties in applying this methodology. Taking into account the relevant clinical studies related to the outcomes of critically ill patient, this article defines when the assessment of energy expenditure by indirect calorimetry may provide useful and valid information. Review of the literature suggests that the clinical application of indirect calorimetry in critically ill patients, although promising, requires further evaluation. Currently, the potential useful clinical applications of indirect calorimetry in this category of patients can be summarized as follows: (1) assessment of energy expenditure in patients who fail to adequately respond to the estimated nutritional needs; (2) assessment of energy expenditure in patients with single- or multiple-organ dysfunction who need prolonged ICU care and artificial nutritional support; (3) assessment of the effects induced by artificial nutrition on the cardiocirculatory and respiratory systems in mechanically ventilated patients with acute respiratory failure; and (4) monitoring of VO2 during weaning from mechanical ventilation.

Effects of chronic angiotensin converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension.

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49 +/- 1 years; body mass index (BMI), 26.1 +/- 0.4 kg/m2) with essential hypertension (blood pressure, 155 +/- 3/105 +/- 1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril, 5 mg/day). Furthermore, a two-step euglycemic insulin clamp was performed after placebo and again at the end of treatment. Blood pressure fell by 7 +/- 4/10 +/- 3 mm Hg (p less than 0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470 pM) whole body glucose use averaged 42.5 +/- 1.6 mumol.min-1.kg-1 before and 43.6 +/- 1.9 after ACE inhibition (p = NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p less than 0.05) improved after treatment (area under OGTT curve (AUC), 240 +/- 24 versus 282 +/- 23 mmol 2 hr.l-1). The latter change was associated with enhanced (+16%, p less than 0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75 +/- 0.05 and 0.92 +/- 0.05 mmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p less than 0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/l, p less than 0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (-22%, p less than 0.01) and ACE inhibition (-21%, p less than 0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r = 0.60, p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)

Operation of Randle's Cycle in Patients With NIDDM

It has been suggested that the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) may be caused by substrate competition between glucose and free fatty acids (FFAs) (Randles cycle). We measured substrate oxidation and energy metabolism in 10 nonobese untreated NIDDM patients with fasting glucose levels of 7–8 mM with indirect calorimetry in the basal state and during an isoglycemic-hyperinsulinemic (∼100 mU/L) clamp without (control) and with a concomitant infusion (∼0.35 mmol/min) of Intralipid, a triglyceride emulsion. In the control study, fasting rates of total glucose turnover ([3−3H]glucose) and glucose and lipid oxidation (9.4 ± 1.4, 7.3 ± 1.3, and 3.0 ± 0.4 μmol · kg−1 · min−1, respectively) were comparable with those of nondiabetic individuals. After insulin administration, lipid oxidation was normally suppressed (to 1.3 ± 0.3 μ · kg−1 · min−1 P < 0.01), as were the circulating levels of FFA, glycerol, and β-hydroxybutyrate, whereas glucose oxidation doubled (14.1 ± 1.8 μmol; · kg−1 · min−1 P <0.01). Because glycemia was clamped at 7.5 mM, endogenous glucose production (EGP) was completely suppressed, and total glucose disposal was stimulated (to 25.7 ± 5.2 μmol · kg−1 · min−1 P < 0.01 vs. baseline), but glucose clearance (3.6 ± 0.8 ml · kg−1 · min−1) was 30% reduced compared with normal. With concomitant lipid infusion, FFA, glycerol, and β-hydroxybutyrate all rose during the clamp; correspondingly, lipid oxidation was maintained at fasting rates (3.6 ± 0.2 μmol · kg−1 · min−1 P < 0.01 vs. control). As a consequence, the insulin-induced increase in glucose oxidation was abolished (7.9 ±1.3 μmol · kg−1 · min−1 P < 0.01 vs. control), and total glucose disposal was inhibited (21.8 ± 4.6 μmol · kg−1 · min−1 P < 0.05 vs. control) by an amount almost equal to the decrement in glucose oxidation. Lipid infusion did not detectably interfere with insulin-induced suppression of EGP. Energy expenditure failed to increase during the control insulin clamp but was significantly stimulated (∼10%, P < 0.01) by concomitant lipid administration (diet-induced thermogenesis). We conclude that in mildly hyperglycemic, nonobese NIDDM patients, excessive fatty substrate oxidation is unlikely to be responsible for the insulin resistance; increased lipid provision, however, enhances lipid oxidation and energy expenditure and inhibits glucose oxidation and total disposal. Thus, in this type of diabetes, Randles cycle does not appear to be spontaneously overactive but can be induced acutely, with metabolic and energetic consequences similar to those observed in nondiabetic subjects.

Energy expenditure and severity of injury and illness indices in multiple trauma patients.

OBJECTIVE To determine whether the energy expenditure of mechanically ventilated multiple trauma patients correlates with the severity of injury and illness indices before important systemic infection has complicated the clinical course, and to compare the energy expenditure with the energy expenditure expected from the Harris-Benedict equation adjusted with correction factors for trauma. DESIGN Prospective, clinical study. SETTING General intensive care unit of a university teaching hospital. PATIENTS Immediate multiple trauma adult patients who required mechanical ventilation. INTERVENTIONS Metabolic cart connected to the ventilator. MEASUREMENTS AND MAIN RESULTS Data on admission to the emergency department and during the first 24 hrs of intensive care unit admission were collected for computation of severity of injury and illness indices, respectively. Resting and total energy expenditures were derived at least 48 hrs after intensive care unit admission by continuous indirect calorimetry. Predicted basal energy expenditure was obtained using the Harris-Benedict equation and predicted total energy expenditure was calculated using the Harris-Benedict value adjusted with correction factors for trauma. Twenty-six multiple trauma adult patients completed the study. No statistically significant correlations were observed between both the resting energy expenditure and the total energy expenditure and the Injury Severity Score, Revised Trauma Score, Simplified Acute Physiologic Score II, Acute Physiology and Chronic Health Evaluation II score, and Glasgow Coma Scale score. A regression model of total energy expenditure was developed with the following variables: Harris-Benedict equation, heart rate, and minute ventilation (p = .01; r2 = .74). The resting energy expenditure/predicted basal energy expenditure ratio was 1.17+/-0.2 and the total energy expenditure/predicted total energy expenditure ratio was 0.76+/-0.1. CONCLUSIONS In mechanically ventilated multiple trauma patients the energy expenditure is not correlated to the severity of injury and illness indices but is dependent on the Harris-Benedict equation in addition to heart rate and minute ventilation. Furthermore, this patient population is characterized by a moderate state of hypermetabolism, and the Harris-Benedict prediction modified with correction factors for trauma systematically overestimates the total energy expenditure.

Effects of ventilator resetting on indirect calorimetry measurement in the critically ill surgical patient.

OBJECTIVE To evaluate the effect of acute changes in minute ventilation (VE) on oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient, and energy expenditure during volume-controlled mechanical ventilation in the critically ill surgical patient. The effects on some oxygen transport variables were assessed as well. DESIGN Prospective, randomized clinical study SETTING Adult surgical intensive care unit of a university teaching hospital. PATIENTS Twenty adult critically ill surgical patients were studied during volume-controlled mechanical ventilation. INTERVENTIONS After a basal period of stability (no changes over time in body temperature, energy expenditure, blood gases, acid-base status, cardiac output, and ventilatory parameters), VE was then randomly either increased or reduced (+/-35%) by a change in tidal volume (VT), while respiratory rate and inspiratory/expiratory ratio were kept constant. Settings were then maintained for 120 mins. During the study, patients were sedated and paralyzed. MEASUREMENTS AND MAIN RESULTS VO2, VCO2, and respiratory quotient were measured continuously by a Nellcor Puritan Bennett 7250 metabolic monitor (Nellcor Puritan Bennett, Carlsbad, CA). Hemodynamic and oxygen transport parameters were obtained every 15 mins during the study. Despite large changes in VE, VO2 and energy expenditure did not change significantly either in the increased or in the reduced VE groups. After 15 mins, VCO2 and respiratory quotient changed significantly after ventilator resetting. VCO2 increased by 10.5 +/- 1.1% (from 2.5 +/- 0.10 to 2.8 +/- 0.12 mL/min/kg, p< .01) in the increased VE group and decreased by 12.4 +/- 2.1% (from 2.7 +/- 0.17 to 2.4 +/- 0.16 mL/min/kg, p< .01) in the reduced VE group. Similarly, respiratory quotient increased by 16.2% +/- 2.2% (from 0.87 +/- 0.02 to 1.02 +/- 0.02, p< .01) and decreased by 17.2% +/- 1.8% (from 0.88 +/- 0.02 to 0.73 +/- 0.02, p< .01). VCO2 normalized in the reduced VE group, but remained higher than baseline in the increased VE group. Respiratory quotient did not normalize in both groups and remained significantly different from baseline at the end of the study. Cardiac index, oxygen delivery, and mixed venous oxygen saturation increased, while oxygen extraction index decreased significantly in the reduced VE group. Neither of the mentioned parameters changed significantly in the increased VE group. CONCLUSIONS We conclude that, during controlled mechanical ventilation, the time course and the magnitude of the effect on gas exchange and energy expenditure measurements caused by acute changes in VE suggest that VO2 and energy expenditure measurements can be used reliably to evaluate and quantify metabolic events and that VCO2 and respiratory quotient measurements are useless for metabolic purposes at least for 120 mins after ventilator resetting.

Energy metabolism of surgical patients in the early postoperative period: a reappraisal.

Energy metabolism was measured at the bedside in 22 uncomplicated surgical patients in the early (24 to 48 h) postoperative period with the use of continuous computerized indirect calorimetry with a canopy system. Energy production rates were higher than those predicted by the Harris-Benedict formula both in absolute value (1516 +/- 61 vs. 1387 +/- 49 kcal/day, p less than .05) and when normalized by body weight (BW; 23.5 +/- 0.5 vs. 21.7 +/- 0.5 kcal/day.kg BW, p less than .01) or by lean body mass (LBM; 32.8 +/- 0.8 vs. 30.2 +/- 0.9 kcal/day.kg LBM, p less than .01). Furthermore, surgical patients had higher energy production rates than those measured in 22 overnight fasted, resting healthy subjects matched for age, sex, and body size (23.5 +/- 0.5 vs. 21.8 +/- 0.6 kcal/day.kg BW, p less than .05). In both the patients and the control group, measured energy production bore a direct relation to LBM. We conclude that the early postoperative period of uncomplicated surgery is associated with a small (about 7%) but consistent increase in energy metabolism above the level observed in the overnight fasted, resting healthy individual. This increase appears to be an effect of surgery itself, and is not predicted by Harris-Benedict equations.

Effects of acute hypercarnitinemia during increased fatty substrate oxidation in man

To test whether carnitine availability is rate-limiting for fat oxidation under conditions of augmented oxidative use of fatty substrates, two series of studies were performed. In study no. 1, L-carnitine (1 g + 0.5 g/h intravenously [i.v.]) or saline was given to eight volunteers during a 4-hour infusion of a 10% triglyceride emulsion, thereby increasing plasma free-carnitine levels from 38 +/- 4 to 415 +/- 55 mumol/L. Fat infusion increased plasma triglyceride levels (80%) and lipid oxidation (30%), and decreased (28%) carbohydrate oxidation (as measured by indirect calorimetry); hypercarnitinemia had no influence on these responses. In study no. 2 in 12 healthy subjects a bolus of L-carnitine (3 g) or saline was administered 40 minutes before aerobic exercise (bicycling for 40 minutes at 60 W), followed by 2 minutes of anaerobic exercise (250 W) and 50 minutes of recovery. Oxygen consumption (VO2), increased to 18.3 +/- 0.7 mL.min-1 x kg-1 during aerobic exercise, reached a maximum of 46.0 +/- 0.8 mL.min-1 x kg-1 during the anaerobic bout, and returned to baseline within a few minutes, with no difference between control and carnitine. At virtually identical mean energy expenditure rates (196 +/- 7 v 197 +/- 7 J.min-1 x kg-1, saline v carnitine), after carnitine administration the entire exercise protocol was sustained by a lower mean carbohydrate oxidation rate (42.1 +/- 3.6 v 36.5 +/- 2.3 mumol.min-1 x kg-1, P < .03) and a higher mean lipid oxidation rate (6.7 +/- 1.0 v 8.3 +/- 0.7 mumol.min-1 x kg-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Inadvertent Catheterization of the Internal Thoracic Vein Mimicking Pulmonary Embolism: A Case Report

Although aberrant locations are typical complications of central venous catheterization, the right internal thoracic vein (mammary vein) is an exceptional one. A case of this unusual aberrant location occurring after right internal jugular venous cannulation for total parenteral nutrition, is described. This aberrant position caused signs and symptoms resembling pulmonary embolism. This is the first known description of the symptoms induced by the infusion of parenteral solution into the right internal thoracic vein.

Comparison between cardiac output measured by thermodilution technique and calculated by O2 and modified CO2 Fick methods using a new metabolic monitor.

Abstract Objective: To calculate cardiac output from dual oximetry with carbon dioxide production (VCO2) and oxygen consumption (VO2) measured by a new metabolic monitor, and to compare these values with measurements made simultaneously using the thermodilution method during the steady state condition. Design: Prospective, comparative clinical study. Setting: The adult postsurgical intensive care unit (ICU) of a University Hospital. Patients: Twenty mechanically ventilated postsurgical patients (70.7 ± 7.8 years of age; range 50–84). Measurements and results: A new metabolic monitor (Puritan-Bennett 7250, Carlsbard, USA) connected to a ventilator (Puritan-Bennett 7200) was used to measure VCO2 and VO2. Measurements of arterial (SaO2) and mixed venous (SvO2) oxygen saturations were made using pulse and venous fiberoptic oximeters. Cardiac output starting from VCO2 (COVCO2) was obtained according to Mahuttes formula: COVCO2 = VCO2/[k (SaO2− SvO2)], where k represents a constant. The value for each patient was determined from the initial measurements of thermodilution cardiac output (COtd), VCO2, SaO2 and SvO2. COVCO2 calculated from the previous equation was compared to the COtd. Cardiac output calculated from the traditional O2 Fick equation (COVO2) was compared to the COtd. All patients were studied over a period of 120 min at 15-min intervals in reasonably stable conditions. COVCO2 was closely related to COtd (r = 0.94; SEE = 0.79; p = 0.0001; n = 180) with a bias of − 0.10 and a precision of 0.45 l/min. The mean percent difference between the two methods was − 2.2 ± 8.3 %. COVO2 was related to COtd (r = 0.77; SEE = 0.79; p = 0.0001; n = 180) with a bias of − 0.57 and precision of 0.86 l/min. The mean percent difference between the two methods was − 10.8 ± 16.0 %. Conclusions: In stable patients, cardiac output measurements obtained from dual oximetry with VO2 and VCO2 measured by this new metabolic monitor, show good correlation with measurements made using the thermodilution method. The values of cardiac output calculated from VCO2 are more accurate and precise than values from VO2. The validity of these measurements in hemodynamically unstable patients and during various modes of mechanical ventilation seems warranted.