Differing effects of antihypertensive agents on urinary albumin excretion

Skeletal muscles in an animal model of genetic hypertension (the spontaneously hypertensive rat. SHR) exhibit significant deficits in contractile performance. These deficits appear to be unrelated to the rise in blood pressure. Slow-twitch soleus muscles show a decrease in specific muscle tension and a reduced resistance to muscle fatigue during prolonged contractile activity. We tested the hypothesis that the reduced fatigue resistance occurs as a consequence of an impaired ability to maintain or restore Na+ and K+ balance across the sarcolemma during repeated contractions. This may result from a genetically based increase in the Na+ permeability of SHR muscles, coupled with a reduction Na+, K+ pump capacity as the animals mature. Soleus muscles in adult SHR exhibit a significant increase in intracellular Na+ content and a significant decrease in intracellular K+ content at rest. B6RB+ uptake in Na(+)-loaded hypertensive muscles is 45% less than predicted from the number of ouabain-binding sites available. Activation of Na+, K+ pumps using adrenaline or insulin produces a significantly smaller hyperpolarization in hypertensive soleus than in control muscles. Control soleus muscles are hyperpolarized for at least 10 min after a 4 min period of high-frequency activity, but hypertensive soleus muscles remain at resting polarity. Nonetheless, the number of ouabain-binding sites in hypertensive muscle is significantly greater than in control soleus, and binding affinities are similar. This apparent deficit in pump capacity might lead to a greater and more prolonged increase in extracellular K+ during repetitive contractions,and an associated decline in tension. Recently, we have been able to prevent the abnormal decrease in hypertensive soleus fatigue resistance by long-term treatment (8 weeks) with the Ca2+ blocker amlodipine. The therapy prevented or reversed the contractile deficits, but did not restore the responsiveness of the Na+, K+ pump to hormonal stimulation. The current data suggest that both a reduction in Na+, K(+)-pump capacity and changes in Ca2+ distribution play a role in the development of contractile deficits in hypertensive muscles.     

Endothelial dysfunction in critically ill patients: the effect of haemofiltration

OBJECTIVES: To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients. DESIGN: Observational study. SETTING: University teaching hospital intensive care unit. PATIENTS: 12 critically ill patients with acute renal failure receiving their first episode of CVVH. INTERVENTIONS: Blood samples were collected prior to starting CVVH and at 15 min and 1, 3-4, 8-12, and 24 h, and at 24-h intervals thereafter until the filter clotted. MEASUREMENTS AND RESULTS: Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients. CONCLUSIONS: The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself.     

The effect of total protein and albumin levels in serum on retinal detachment due to EPH-gestosis]

The ob gene product might influence the hypothalamo-pituitary axis and ovarian function directly via specific ovarian receptors. Premenopausal women have higher leptin concentrations compared to postmenopausal controls. In this study, we determined changes in leptin serum concentrations under the influence of supraphysiological estradiol levels during controlled ovarian hyperstimulation. In a prospective study of 20 patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), morning blood samples were collected to determine leptin and estradiol concentrations on day 3 and day 9 of the stimulation cycle and on alternate days until ovulation induction. There was a significant increase in serum leptin concentrations from day 3 to day 9 (9.87 +/- 1.5 ng/ml on day 3 and 13.8 +/- 2.1 ng/ml on day 9 respectively). No further increase in leptin was observed until the day of ovulation induction. These data further underline the role of leptin as a hormone of reproduction.     

The relationship between free and total hydroxyproline concentration in blood serum and urinary excretion of hydroxyproline in healthy individuals

The quantitative measurement of the IgG subclass composition of the sera from sixteen patients with cystic fibrosis has revealed grossly elevated levels of IgG4 in seven patients. The possible significance of this observation is discussed in relation to recent reports of a high incidence of immediate-type hypersensitivity in such patients.     

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.     

Predictability of creatinine clearance estimates in critically ill patients

OBJECTIVES: a) To evaluate the predictive ability of different creatinine clearance methods as compared with the criterion standard, inulin clearance; and b) to determine which of the predictive methods yields the most accurate estimation of creatinine clearance. DESIGN: Prospective study. SETTING: Medical intensive care unit (ICU) of a university-affiliated tertiary care hospital. INTERVENTIONS: Glomerular filtration rate was measured by the criterion standard, inulin clearance. PATIENTS: Twenty mechanically ventilated adults. MEASUREMENTS: Renal function was assessed by the following procedures: inulin clearance using a standard protocol, 30-min creatinine clearance, 24-hr creatinine clearance, and creatinine clearance estimates by the Cockcroft-Gault equation. Ideal body weight, total body weight or lean body mass with actual serum creatinine or serum creatinine concentration corrected to 1 mg/dL (85 mumol/L) in cachectic patients were sequentially incorporated into the Cockcroft-Gault equation. RESULTS: The Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration, was the best predictor of inulin clearance with the smallest bias (9.7 +/- 8.6, 95% confidence interval 5.7 to 13.8). The bias encountered with the 30-min creatinine clearance was not different from that value with the 24-hr creatinine clearance (21.6 +/- 33.0, 95% confidence interval 6.2 to 37.1 vs. 25.4 +/- 28.3, 95% confidence interval 11.8 to 42.9). Good correlations existed between inulin clearance and the Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration (r2 = .81; p = .0001), as well as between inulin clearance and the Cockcroft-Gault equation, using the lower of ideal or total body weight and the higher of the actual serum creatinine concentration or corrected serum creatinine (r2 = .75; p = .0001). The 30-min creatinine clearance and the 24-hr creatinine clearance had poorer agreement with inulin clearance. The incorporation of a corrected serum creatinine value into the Cockcroft-Gault equation consistently led to better predictions and higher correlation coefficients. CONCLUSIONS: The utilization of the Cockcroft-Gault equation as used clinically (the lower of ideal or total body weight and the higher of actual serum creatinine or corrected serum creatinine concentration to 1 mg/dL [85 mumol/L]) results in more accurate predictions of glomerular filtration rate in the medical, critically ill patient than urine creatinine clearance measures. If creatinine clearance measures are used, the 30-min collection provided results not different from those results obtained with 24-hr urinary collections.     

Relationship between serum 1,5-anhydroglucitol and urinary excretion of N-acetylglucosaminidase and albumin determined at onset of NIDDM with 3-year follow-up

A nonsense codon suppression technique was employed to incorporate ortho-nitrobenzyl tyrosine, "caged tyrosine," in place of tyrosine at any of three positions (93, 127, or 198) in the alpha subunit of the muscle nicotinic ACh receptor (nAChR) expressed in Xenopus oocytes. The ortho-nitrobenzyl group was then removed by 1 ms flashes at 300-350 nm to yield tyrosine itself while macroscopic currents were recorded during steady ACh exposure. Responses to multiple flashes showed (1) that each flash decages up to 17% of the tyrosines and (2) that two tyrosines must be decaged per receptor for a response. The conductance relaxations showed multiple kinetic components; rate constants (<0.1 s(-1) to 10(3) s(-1)) depended on pH and the site of incorporation, and relative amplitudes depended on the number of prior flashes. This method, which is potentially quite general, (1) provides a time-resolved assay for the behavior of a protein when a mutant sidechain is abruptly changed to the wild-type residue and (2) will also allow for selective decaging of sidechains that are candidates for covalent modification (such as phosphorylation) in specific proteins in intact cells.     

Associations of urinary albumin excretion rate with vascular disease in europid nondiabetic subjects

Microalbuminuria and its association with vascular disease has previously been reported in nondiabetic individuals. The aims of this study were to determine whether there is a cross-sectional relationship between urinary albumin excretion rate and cardiovascular disease in nondiabetic subjects and to investigate hereditary predisposition to microalbuminuria by studying offspring of the main study population. Europid patients, aged 40-70 years, were randomly selected from a large inner-city general practice; there was a 62.6% attendance rate, and a study population of 959 remained after exclusions. Blood pressure, ankle systolic pressure, height, and weight were measured. Albumin excretion rate was calculated from overnight and morning urine collections. Venous blood was taken for lipids, fibrinogen, and factor VII; and resting electrocardiograms were carried out. Offspring (aged 15-40 years) of those found to be microalbuminuric were invited to attend for the same tests, and controls were selected by age and sex matching the parents. There was no association between parents' albumin excretion rate with that of their offspring, and there were no significant differences in albumin excretion rate between offspring subjects and their controls. There were no statistically significant associations of prevalent coronary heart disease (CHD) with albumin excretion rate or microalbuminuria in either sex [CHD in women: odds ratio (OR) 1.85; 95% confidence interval (CI) 0.19,9.0] [CHD in men: OR 2.13; 95% CI (0.64, 6.59)]. In women, there were significant associations between albumin excretion rate and peripheral vascular disease (positive) and fibrinogen (negative). Because established risk factors may not be as strongly associated with CHD in cross-sectional studies, we intend to follow this group prospectively.     

Comparison of gastric mucosal pH and clinical judgement in critically ill patients

OBJECTIVES: To compare gastric tonometry (pHi) with estimates of pHi in ill injured patients, and to correlate pHi with haemodynamic variables. DESIGN: Prospective, non-interventional study. SETTING: ICU of Level I trauma centre, USA. MAIN OUTCOME MEASURES: 154 gastric tonometry measurements were compared with physicians' estimates of adequacy of resuscitation. Resuscitation was categorised as inadequate (pHi < 7.35) or adequate (pHi> or = 7.35). Measured and estimated pHi were also compared with oxygen delivery, oxygen consumption, cardiac index, mixed venous O2 saturation, and critical illness scores. RESULTS: Estimated pHi was often higher than measured pHi in the judgement of all four surgical intensive care physicians. Measured pHi correlated positively with mixed venous O2 tension (r = 0.21). There were significant negative correlations between measured pHi and both oxygen delivery (r = -0.25) and oxygen consumption (r = 0.28). Estimated pHi correlated positively with mean arterial pressure (r = 0.21) and hospital day (r = 0.26); it correlated negatively with pulmonary arterial elastance (r = -0.35). CONCLUSION: Experienced intensive care physicians tended to overestimate visceral perfusion, which suggests that gastric tonometry adds useful information over and above routine haemodynamic indices. Arterial blood pressure and mixed venous oxygen saturation correlated better with measured pHi than with other indices of perfusion.     

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P less than 0.05). Two major conclusions of this study are at variance with those of previous investigators; (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.     

Usefulness of transesophageal echocardiography in the treatment of critically ill patients

To evaluate the usefulness of transesophageal echocardiography (TEE) in the treatment of critically ill patients, 80 patients (51 male and 29 female; mean age, 53 years) undergoing both transthoracic echocardiography (TTE) and TEE were studied in a 2-year period. Of these, 48 patients were studied in the ICU, while the other 32 patients were directly referred from the emergency departments. Indications for the study included suspected aortic dissection (34 patients), hemodynamic instability (22 patients), suspected cardiac source of embolism (11 patients), evaluation of the severity of mitral regurgitation (7 patients), and suspected infective endocarditis (6 patients). The probe was passed successfully in 78 of 80 attempts (98 percent). No significant complications were recorded during the transesophageal echocardiographic study. Transesophageal echocardiography provided critical information that was not obtained by TTE in 39 of 78 studies (50 percent, p < 0.005). Cardiac surgery was prompted by TEE findings in 14 patients (18 percent) and these findings were all confirmed at operation. Transesophageal echocardiography was a safe, well-tolerated, and valuable diagnostic approach for the rapid detection of specific cardiac abnormalities in patients with critical illness; TEE should be considered in the treatment of critically ill patients especially when TTE provided inadequate information.     

Effect of antihypertensive treatment on urinary albumin excretion, glomerular filtration rate, and renal plasma flow in patients with essential hypertension

In 20 patients with essential hypertension the urinary albumin execretion, glomerular filtration rate (GFR),and renal plasma flow (RPF) were examined before and after antihypertensive treatment. Albumin excretion measured by radioimmunoassay was increased before treatment, and there was a significant fall during treatment. In patients responding well to therapy (diastolic pressure below 100 mm Hg), albumin excretion was significantly lower than in patients responding poorly to therapy. There was a positive correlation between albumin excretion before treatment and diastolic pressure during treatment, indicating that the albumin excretion rate may be used to predict the result of antihypertensive treatment. Patients with excretion rates below 25 mug/min generally respond well to the treatment used. No definite changes in GFR and RPF were found during treatment, and there was no correlation between albumin excretion and GFR and RPF. It is suggested that the increased albumin excretion in essential hypertension is due both to functional and morphological alterations in the glomerulus, namely increased glomerular filtration pressure and vascular damage.     

Aminoglycoside volume of distribution and illness severity in critically ill septic patients

The volume of distribution of amikacin and the APACHE II score were determined in 42 critically ill patients being treated for a gram-negative infection. The mean volume of distribution (Vdt) was 0.41 +/- 0.12 l/kg with a wide range (normal of 0.25 l/kg). There was a good relationship between the Vdt and illness severity as measured by the APACHE II score (r = 0.70; P < 0.001). Critically ill patients should receive larger loading doses of aminoglycosides in order to achieve therapeutic blood levels. The aminoglycoside Vdt may be useful in determining the degree of capillary leak and tissue oedema that accompanies sepsis.     

Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients

BACKGROUND: Airway obstruction after anesthesia may be caused or exaggerated by residual neuromuscular block, with loss of muscle support for collapsible upper airway structures. METHODS: Six male volunteers were studied before treatment, during stable partial neuromuscular block with vecuronium at a mean train-of-four (TOF) ratio of 50% (95% CI, 36-61%), and after reversal by neostigmine. Catheter-mounted transducers were placed in the pharynx and esophagus to estimate, respectively, the upper airway resistance, and the work of breathing (calculated as the time integral of the inspiratory pressure developed by the respiratory muscles, esophageal pressure time product) during quiet breathing, during breathing 5% carbon dioxide, and while breathing with an inspiratory resistor. Breathing with pressure at the airway opening held at pressures from -5 to 40 cm H2O were also tested to assess airway collapsibility. RESULTS: Although breathing through a resistor increased upper airway resistance from 1.2 (0.67, 1.72) cm H2O x l(-1) x s to 2.5 (1.32, 3.38) cm H2O x l(-1) x s, and carbon dioxide stimulation reduced resistance to 0.8 (0.46, 1.33) cm H2O x l(-1) x s, no effect of partial neuromuscular block (mean TOF ratio, 52%) on upper airway properties could be shown. CONCLUSIONS: Neuromuscular block with a TOF ratio of 50% can be present yet clinically difficult to detect in patients recovering from anesthesia. This degree of block has no effect on airway patency in volunteers, even during challenge. Airway obstruction during recovery from anesthesia thus is more likely to be caused by residual effects of general anesthetic agents or centrally acting analgesics, either alone or perhaps in concert with residual neuromuscular block.     

Quantification of the determinants of arterial hypoxemia in critically ill patients

A quantification of the determinants of arterial hypoxemia was performed in 376 cardiorespiratory measurements obtained from 180 critically ill patients. Statistical analysis showed that pulmonary venous admixture (Qsp/Qt) could explain only 48% of the PaO2 variability in the sample of measurements taken (r2 = 0.48), while the effect of central venous O2 tension (PVO2) brought the total explained PaO2 variability up to 82% (total r2 = 0.82). These findings imply that pulmonary function is not the only determinant of PaO2; the PVO2-mediated effect of other cardiovascular and metabolic determinants must be recognized in the clinical setting.     

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.