Hyperglycemic Hyperosmolar State: A Pragmatic Approach to Properly Manage Sodium Derangements.

INTRODUCTION: Although hypovolemia remains the most relevant problem during acute decompensated diabetes in its clinical manifestations (diabetic ketoacidosis, DKA, and hyperglycemic hyperosmolar state, HHS), the electrolyte derangements caused by the global hydroelectrolytic imbalance usually complicate the clinical picture at presentation and may be worsened by the treatment itself. AIM: This review article is focused on the management of dysnatremias during hyperglycemic hyperosmolar state with the aim of providing clinicians a useful tool to early identify the sodium derangement in order to address properly its treatment. DISCUSSION: The plasma sodium concentration is modified by most of the therapeutic measures commonly required in such patients and the physician needs to consider these interactions when treating HHS. Moreover, an improper management of plasma sodium concentration (PNa+) and plasma osmolality during treatment has been associated with two rare potentially life-threatening complications (cerebral edema and osmotic demyelination syndrome). Identifying the correct composition of the fluids that need to be infused to restore volume losses is crucial to prevent complications. CONCLUSION: A quantitative approach based on the comparison between the measured PNa+ (PNa+ M) and the PNa+ expected in the presence of an exclusive water shift (PNa+ G) may provide more thorough information about the true hydroelectrolytic status of the patient and may therefore, guide the physician in the initial management of HHS. On the basis of data derived from our previous studies, we propose a 7-step algorithm to compute an accurate estimate of PNa+ G.

Use, misuse and abuse of diuretics.

Resolution of edema requires a correct interpretation of body fluids-related renal function, to excrete the excess volume while restoring systemic hemodynamics and avoiding renal failure. In heart failure, the intensive diuresis should be matched by continuous fluids refeeding from interstitium to plasma, avoiding central volume depletion. The slowly reabsorbed ascites cannot refeed this contracted volume in cirrhosis: the ensuing activation of intrathoracic receptors, attended by increased adrenergic and Renin release, causes more avid sodium retention, producing a positive fluid and Na balance in the face of continuous treatment. High-dose-furosemide creates a defect in tubular Na causing diuresis adequate to excrete the daily water and electrolyte load in Chronic Renal Failure. Diuretic treatment requires care, caution and bedside "tricks" aimed at minimizing volume contraction by correctly assessing the homeostatic system of body fluids and related renal hemodynamics.

Testosterone Plasma Concentration is Associated with Insulin Resistance in Male Hypertensive Patients.

Background: Low testosterone levels are a common finding among men with Type 2 Diabetes Mellitus (T2DM) and are inversely related to insulin resistance. Whether this relationship holds true in patients with hypertension, but normal glucose tolerance or prediabetes, is unclear. Methods: We recruited 87 male outpatients with essential arterial hypertension, aged 35-70 years. Anthropometric data were collected, an Oral Glucose Tolerance Test (OGTT) performed, and the homeostasis model assessment of insulin resistance (HOMA-IR) score calculated. Follicle-Stimulating Hormone, Luteinizing Hormone, testosterone, Sex Hormone-Binding-Globulin and free-testosterone were measured. The concentrations of sex hormones were compared between normoglucotolerant, prediabetic and diabetic patients. Non-parametric tests were applied as appropriate to verify differences among groups, while multiple linear regression was used to predict the variability of testosterone and free-testosterone. Results: Total serum testosterone concentration was significantly lower in T2DM in comparison to normoglucotolerant subjects (p<0.01) and was inversely related to body mass index (r=- 0.25, p<0.01), waist circumference (r=- 0.27, p<0.01), pre and post-OGTT plasma glucose (r=- 0.4, p<0.0001 and r=- 0.29, p<0.01, respectively), pre and post-OGTT plasma insulin (r=- 0.42, p<0.0001 and r=- 0.42, p<0.0001) and HOMA-IR (r=- 0.46, p<0.0001). Similar associations were observed for free testosterone; HOMA-IR was related to testosterone and free-testosterone even in patients with normal glucose tolerance (r=- 0.47, p<0.01 and r=- 0.34, p<0.05, respectively). At multivariate analysis HOMA-IR was the only variable associated to testosterone (p<0.001) and free-testosterone (p<0.05) plasma concentration. Conclusions: In males with hypertension, the link between insulin sensitivity and hypothalamic-pituitary-gonadal axis is maintained along the entire spectrum of glucose tolerance.

Efficacy and safety of two different tolvaptan doses in the treatment of hyponatremia in the Emergency Department.

Hyponatremia (plasma sodium concentration or P[Na+] <136 mEq/L) is the most common electrolyte unbalance in clinical practice. Although it constitutes a negative prognostic factor, it frequently remains underdiagnosed and undertreated. Tolvaptan is an oral V2-receptor antagonist which produces aquaresis. Given its emerging role in the treatment of dilutional hyponatremia, we aimed to compare the efficacy and safety of two different doses of this drug in an Emergency Department (ED) setting. Consecutive patients with moderate-severe euvolemic or hypervolemic hyponatremia were sequentially assigned to the 15 mg Group and to the 7.5 mg Group, and were revaluated at 6, 12 and 24 h. Further evaluations and administrations were scheduled daily until P[Na+] correction was achieved or the maximum period of 72 h was exceeded. A 1-month follow-up was performed. Twenty-three patients were enrolled: 12 were included in the 15 mg Group, 11 in the 7.5 mg Group. Both doses significantly elevated the P[Na+] over 24 h, although the 15 mg Group showed faster corrections than the 7.5 mg Group (12 vs 6 mEq/L/24 h; P = 0.025). An optimal correction rate (within 4-8 mEq/L/24 h) was observed in 45.4 % of the 7.5 mg Group against 25.0 % (P n.s.). The standard dose led to dangerous overcorrections (>12 mEq/L/24 h) in 41.7 % of the patients, while the low dose did not cause any (P = 0.037). No osmotic demyelination syndrome was observed. A 7.5 mg tolvaptan dose can be considered both effective and safe in treating hyponatremia in the ED, while a 15 mg dose implicates too high risk of overcorrection.

Adverse effects of drugs on the kidney.

The number of drugs presently marketed is countless, their prescription is relentlessly growing, such that the likelihood of adverse effects is strikingly increasing. As many drugs are cleared by the body through kidney excretion, renal adverse events are likely. In this review we shall concisely describe the pathophysiologic mechanisms of renal damage by drugs, the different clinical presentations outlining renal toxicity in the course of pharmacologic treatment, and the main offending agents.

Sulfonylureas and their use in clinical practice.

Many anti-diabetic drugs with different mechanisms of action are now available for treatment of type 2 diabetes mellitus. Sulfonylureas have been extensively used for treatment of type 2 diabetes for nearly 50 years and, even in our times, are widely used for treatment of this devastating chronic illness. Here, we review some of the available data on sulfonylureas, evaluating their mechanism of action and their effects on glycemic control. We can conclude that sulfonylureas are still the most used anti-diabetic agents: maybe this is due to their lower cost, to the possibility of mono-dosing and to the presence of an association with metformin in the same tablet. However, sulfonylureas, especially the older ones, are linked to a greater prevalence of hypoglycemia, and cardiovascular risk; newer prolonged-release preparations of sulfonylureas are undoubtedly safer, mainly due to reducing hypoglycemia, and for this reason should be preferred.

Oral glucose tolerance test-based calculation identifies different glucose intolerance phenotypes within the impaired fasting glucose range.

AIMS/INTRODUCTION: The conventional oral glucose tolerance test (OGTT) cannot detect future diabetics among isolated impaired fasting glucose (is-IFG) nor normal glucose tolerant (NGT) groups. By analyzing the relationship between fasting (FPG) and 2-h plasma glucose (2hPG), the present study identifies is-IFG subjects liable to worsening glucose homeostasis. MATERIALS AND METHODS: Oral glucose tolerance test was carried out in 619 patients suffering from obesity, hypertension or dyslipidemia, whose FPG was in the 100-125 mg/dL range. We calculated the percentage increment of 2hPG with respect to FPG (PG%) in these patients using the formula: ([2hPG - FPG] / FPG) × 100. Differences in ß-cell function within is-IFG patients were assessed by estimated insulin sensitivity index (EISI), first-phase insulin release (1stPH) and 1stPH/1/EISI (1stPHcorrected). RESULTS: Diabetes was diagnosed in 69 patients (11.2%), combined IFG/impaired glucose tolerance (IGT) in 185 patients (29.9%) and is-IFG in 365 patients (58.9%). Is-IFG was subdivided into PG% tertile groups: the percentage of females increased from 25% in the lowest to 45.2% in the highest tertile (χ(2) = 18.7, P < 0.001). Moving from the lowest to the highest PG% tertile group, insulin and 2hPG concentrations rose, whereas FPG, EISI, and 1stPHcorrected decreased progressively and significantly. Furthemore, PG% correlated inversely with EISI (r = -0.44, P < 0.0001) and 1stPHcorrected (r = -0.38, P < 0.0001). CONCLUSIONS: Oral glucose tolerance test does differentiate the great heterogeneity in metabolic disorders of patients with FPG 100-125 mg/dL. Furthermore, PG% can expand the diagnostic power of OGTT in the is-IFG range by distinguishing metabolic phenotypes very likely to herald different clinical risks.

Sex differences in lipid profiles in relation to the progression of glucose abnormalities.

BACKGROUND: In the present study, we investigated the role of changes in blood lipids in the abolition of the lower cardiovascular risk associated with the female gender in individuals with type 2 diabetes mellitus (T2DM). METHODS: An oral glucose tolerance test (OGTT) was performed in 1091 consecutive patients (478 men and 613 women) and patients were divided into groups as follows: (i) those with normal glucose tolerance (NGT; n = 589); (ii) those with pre-diabetes (pre-T2DM), who were further divided into those with impaired fasting glucose (IFG; n = 212), impaired glucose tolerance (IGT; n = 84), and both IFG and IGT (IFG/IGT; n = 102); and (iii) those with T2DM (n = 104). Total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein (apo) A-I, apoB, and the apoB:apoA-I ratio were determined in each patient. Differences in lipids between the different groups were assessed using Student's t-test. RESULTS: Significantly higher triglyceride levels and an apoB:apoA-I ratio were found in NGT men (P < 0.0001), along with lower HDL-C and apoA-I (P < 0.0001). Men in the pre-T2DM group maintained a higher apoB:apoA-I ratio (P < 0.05) and lower HDL-C (P < 0.0001) compared with women. In the T2DM group, only HDL-C was lower in men compared with women (P < 0.05). CONCLUSIONS: The progression of glucose intolerance from NGT to pre-T2DM and T2DM exhibits striking sex differences regarding the lipid profile. The data demonstrate a worsening of plasma lipid composition in women who become diabetic. This could explain, at least in part, the loss of the more favorable cardiovascular risk normally associated with NGT women.

Treating high blood pressure: is reaching the target more important than the means? Yes, the target is more important.

The effectiveness of hypertension treatments is attributed either to the change in blood pressure, independent of the means used, or to an important contribution of appropriate drug selection: this debate probably stems from an inappropriate comparison. Treating essential hypertension in relatively healthy patients without advanced vascular disease and co-morbidities affords cardio-vascular protection by the lowering of the mechanical shear stress determined by blood pressure per se: thus, lowering blood pressure is the critical step, while the methods used can only differ through side effects. This treatment is, in fact, a lifetime prophylaxis, as hypertension, rather than a disease, is a symptom affecting one tail of the Gaussian distribution of blood pressure across the normal population. Treating hypertension in the context of diseases, like diabetes mellitus, congestive heart failure, left ventricular hypertrophy, and advanced atherosclerosis, would be improper if focused on just one symptom, while the appropriate treatment must include options which exhibit a more extended profile to include effectiveness on cardiac hypertrophy, insulin resistance, cardiac output, and systemic hemodynamics: thus, drugs may be different in their effectiveness and in the cardio-vascular protection afforded, even though the trials quoted in favour of this thesis were designed to compare drugs in their ability to lower blood pressure rather than in improving the overall complex clinical derangements. In conclusion, while the answer to the question is a sharp YES when dealing with primary prevention, it might be a NO, still clouded by contradictory and inconclusive evidence when dealing with secondary prevention and/or treatment of complex disease conditions and co-morbidities.

Computation of the excess glucose and Na deficit of hypo-osmolar hyponatremic hyperglycaemia.

Exact computations of glucose accumulation (GA, mM) and Na anions deficit (DeltaNa, mEq) can be obtained in hypo-osmolar hyponatremic hyperglycaemia (HHH), where plasma osmolality (POsm) is lower than normal. In this condition, GA - DeltaNa = POsm x TBW (total body water). GA is given by plasma glucose concentration (PG(1)) times extra-cellular volume (ECV), calculated as TBW - ICV (the known intra-cellular volume). The changes in solute content can then be computed from their concentrations. This model was verified on computer-simulated patients to whom GA was added in variable amounts, lower than those of DeltaNa subtracted, generating known ICV, ECV, PNa(1), and PG(1). True computer-generated values were identical (the correlation coefficient R(2) = 1, p < 0.0001) to those computed from solute concentrations with our formulas. These same calculations were applied to patients with HHH, using exclusively the measured PNa(1) and PG(1) to compute solute and solvent changes. The results were significantly correlated to true data obtained by balance studies (R(2) = 0.89, p < 0.001). The mathematical model correctly computes DeltaNa and GA in HHH, where patients can therefore benefit from accurate replacement strategies.

New method to compute mixed water and electrolyte changes in hyponatremia: a preliminary report.

BACKGROUND: We developed a new method that diagnoses when either Na or water alone are altered during electrolyte abnormalities. The aim of this study is to describe the preliminary report of an original method which can give exact or useful calculations even in mixed disorders. METHODS: when NaCl is lost, the plasma Cl (PCl) to plasma Na (PNa) ratio falls from 0.75 (the normal value) toward zero, the ratio of plasma anions other than Cl (POAN) to PNa rises toward unity and POAN/PPCl toward infinity. With subscript 0 or normal values and subscript 1 for those during derangement, PCl1/PCl0 falls below unity, while POAN 1 /POAN 0 rises above unity in these hyponatremic disorders. Based on these changes, we developed exact mathematical formulas to compute alterations in solvent and solutes. The boundary conditions of applicability were computer modeled. RESULTS: regression coefficients between true data fed oo the computer and those calculated with our formulas were 1.00 when the boundary conditions were entirely met (R2=1.00, <0.0001) and 0.93-0.96 (R2>0.94<0.99, <0.001) when the boundary conditions were allowed to extend beyond their limits of exclusive mathematical validity. The method was extended to patients whose data satisfied the boundary conditions. The results show that the computations satisfactorily predict the exact measurements obtained by the change in body weight (R2=0.61, <0.001). CONCLUSIONS: This new method represents useful adjunct in evaluating and treating hyponatremias. Although its validity is limited to rather strict boundary conditions, it represents an original way to evaluate mixed solvent/solute derangements.

Hyperosmolar coma due to exclusive glucose accumulation: recognition and computations.

AIM: To avoid electrolyte derangements during correction of hyperosmolar coma (HC), PNa(PREDICTED) at the end of correction is presently estimated from plasma glucose (P(G), mM/L). When the rise in plasma osmolality (Posm) is entirely due to glucose addition (G(A), mM) to the extracellular volume (ECV), this PNa prediction can be improved by correctly estimating G(A) and any associated water loss (DeltaV), while excluding any concomitant Na loss (DeltaNa). METHODS: Indicating with (0) the normal conditions, with (1) the HC,DeltaPosm=P(G1)xECV1 establishes an exclusive G(A) accumulation. We derived the equations for computing G(A), DeltaV and PNa(PREDICTED). Computer simulations of HC were performed by adding the known G(A) while subtracting the known DeltaV and DeltaNa in different combinations, obtaining exact values of PNa(1) and P(G1). Applying our formulas, we recognized and discarded all cases with concomitant DeltaNa, and we computed G(A), DeltaV and PNa (PREDICTED) from PNa(1) and P(G1), as if they had been measured in patients. We extended these same calculation algorithms to 68 patients with HC. RESULTS: In computer simulations, true and calculated G(A), DeltaV and PNa(PREDICTED) were identical, such that regression and correlation coefficients were 1 (P < 0.0001). Out of the 68 patients recruited, 13 fulfilled the boundary conditions of an exclusive G(A) addition. The true values, obtained by balance studies performed on these patients, were not different from and significantly correlated with the calculated data (R(2) = 0.99, P < 0.001). CONCLUSION: Our new model system for HC and the new formulas improve to near exactness the accuracy in estimating PNa(PREDICTED), helping the physician to avoid unwanted electrolyte derangements during treatment.

In vitro effect of cyclosporine-A on angiotensins secretion by glomerular cells.

AIM: Cyclosporine-A (CyA) is used to control transplant rejections and to treat autoimmune diseases. We investigated the possibility that changes induced by CyA on endothelin 1 (ET), angiotensin I (AI) and angiotensin II (AII) concentrations recognize a common pathway through which different mechanisms operate. METHODS: We measured ET, AI and AII concentrations, before and after either ET or CyA addition to the incubation medium of glomeruli of pig kidneys, isolated in vitro. The measurements were carried out with or without selective (ET(A) and ET(B)) or unselective ET(A)-ET(B) receptor inhibitors. RESULTS: In the presence of CyA, AI and ET are positively correlated either when ET(B) receptors are blocked, or when both receptors are free, while this correlation becomes negative when ET(A) receptors alone are blocked. Adding ET to the medium, the correlations between AI and ET are negative when either ET(A), or ET(B) or both are blocked. The effects of CyA and ET are significant only during the first 2 h of incubation. CONCLUSION: Cyclosporine-A recruits angiotensins and ET through ET(A) receptors, a mechanism possibly responsible of glomerular damage. This stimulation is time-dependent. Prevention of the renal damage from CyA should require selective ET(A) receptor blockade.

An improved method to compute the solute and water derangements of hyperglycaemia.

Evaluation and treatment of hyperglycaemic hyponatremia, being quantitatively inaccurate, is open to new advancements. We herein describe the improvement of previous calculations of glucose appearance (G(A)), solute and solvent changes. From G(A) we derive the predicted plasma sodium concentration (PNa(G)), assuming no change in total body water (TBW), but only water shift from cells to the extracellular space (ECV). This assumption is validated by the respective solute ratios (PCl/PNa) unchanged from normal values, as well as the ratios between actual and normal solute concentrations (PNa(1)/PNa(0), PCl(1)/PCl(0)), identical for all solutes. When the assumption is met, G(A) can be exactly calculated. When the ratios are different from normal, they indicate the presence of a mixed abnormality due to a loss either of sodium, or sodium and water. These are estimated by computing the difference between PNa(G) and the actual PNa measured (PNa(1)). PNa(1) approximately equal PNa(G) if TBW and Na are unchanged, PNa(1) < PNa(G) in the presence of prevalent Na depletion, PNa(1) > PNa(G )when volume depletion prevails. In the first circumstance the ECV expansion is exactly established by appropriate mathematical formulas, in the latter conditions either Na or volume depletion are empirically estimated with algebric expressions. These equations were validated on computer-simulated models, and applied to 49 subjects with plasma glucose concentration >15 mM/L. G(A) and PNa(G) were computed, and, with the same formulas used in computer-simulated experiments, we calculated water and Na deficits. The PNa measured after correction of hyperglycaemia was correctly predicted (R(2) = 0.63, P < 0.0001). This method provides a firm ground to select the correct equation to accurately estimate the initial conditions of hyperosmolar hyperglycaemia, significantly improving its quantitative correction.

Estimating excess glucose, sodium and water deficits in non-ketotic hyperglycaemia.

BACKGROUND: The treatment of solute addition, Na and water losses in hyperglycaemic hyponatraemia is guided by clinical judgement rather than by a quantitative assessment. METHODS: We devised an iteration method to compute glucose appearance (G(A)) within the extracellular space, to obtain the PNa (plasma sodium concentration) expected by glucose addition only (PNa(G)). The difference between this and the actual measurement (PNa(1)) was used to compute the attending Na and/or volume depletion, and the PNa expected during correction. The equations were validated on computer-built models, where the electrolyte derangements were simulated, generating true values of plasma glucose (P(G)) and Na concentrations, from which surfeit and deficits were back-calculated with our formulas. We also computed G(A) and PNa(G) on 43 patients who were stratified into a group with normal hydration (PNa(1) = PNa(G)), one with prevalent Na depletion (PNa(1) < PNa(G)), and one with prevalent volume depletion (PNa(1) > PNa(G)). The volume conditions established by our computations were compared by logistic regression analysis with those assessed from clinical laboratory data. RESULTS: The computer simulations demonstrated that the method gave exact results when only one variable changed, clinically useful estimates in the presence of mixed volume and sodium deficits. There was a strongly significant concordance between the clinical and the quantitative method (P < 0.001). The latter predicted the PNa measured after correction of hyperglycaemia (P < 0.001). CONCLUSION: This new method more accurately computes the initial conditions, resulting in a useful stratification of patients which improves the quantitative evaluation and treatment of hyperosmolar coma.

The significance of the furosemide test for predicting ascites control by diuretics in cirrhotics: a comparison with volume expansion and octreotide infusion.

To verify prospectively the usefulness of the furosemide-induced natriuresis test in predicting ascites control by medical treatment, 15 stable cirrhotics (9 male) with ascites were studied. Sodium excretion was measured after this test and after volume expansion with saline associated with intravenous infusion of octreotide; 6 months later, response to medical treatment was rated as good (N=9) or poor (N=6). Patients with poor ascites control had lower sodium excretion with the furosemide-induced natriuresis test (median, 88 vs 201 mmol; P < 0.01). Poor control was observed in four of four patients with sodium excretion < or =125 mmol, and good control in six of six patients with sodium excretion >175 mmol (P < 0.002). Volume expansion was followed by limited natriuresis (median, 20 mmol), in inverse relationship with plasma active renin concentration (P < 0.001). In conclusion, long-term ascites control is well predicted by the furosemide-induced natriuresis test.

A malignant fibroleiomyoma of the testis.

The patient described has a 2-cm, hard, painless nodule close to an atrophic testis that had been present for > 10 years, suggesting inactive disease, recently associated with fever of undetermined origin with constitutional symptoms. Extensive examinations of pleural, spinal, and bronchoalveolar fluids; bacterial and mycobacterial cultures; bone biopsies; and computed tomography scans were inconclusive. Orchiectomy demonstrated an angiotropic large B-cell lymphoma (CD19+CD20+CD79a+) in the context of a benign fibroleiomyoma. The symptoms abated after the first of 4 rituximab injections. Reports suggest that benign tumors can be harbingers of angiotropic lymphoma or facilitate its onset. To date, no testicular or epididymal primary site has been reported for angiotropic lymphoma.