A B S T RA C T Measurement of urine to blood (U-B) carbon dioxide tension (Pco2) gradient during alkalinization of the urine has been suggested to assess distal H+ secretion. A fact that has not been considered in previous studies dealing with urinary Pco2 is that dissolution of HCO3 in water results in elevation of Pco2 which is directly proportional to the HCO3 concentration. To investigate the interrelationship of urinary HCO3 and urinary acidification, we measured U-B Pco2 in (a) the presence of enhanced H+ secretion and decreased concentrating ability i.e., chronic renal failure (CRF), (b) animals with normal H+ secretion and decreased concentrating ability, Brattleboro (BB) rats, and (c) the presence of both impaired H+ secretion and concentrating ability (LiCl treatment and after release of unilateral ureteral obstruction). At moderately elevated plasma HCO3 levels (30-40 meq/liter), normal rats achieved a highly alkaline urine (urine pH > 7.8) and raised urine HCO3 concentration and U-B Pco2. At similar plasma HCO3 levels, BB rats had a much higher fractional water excretion and failed to raise urine pH, urine HCO3 concentration, and U-B Pco2 normally. At a very high plasma HCO3 (>50 meq/liter), BB rats raised urine pH, urine HCO3 concentration, and U-B Pco2 to the same levels seen in normals. CRF rats failed to raise urine pH, urine HCO3, and U-B Pco2 normally at moderately elevated plasma HCO3 levels; at very high plasma HCO3 levels, CRF rats achieved a highly alkaline urine but failed to raise U-B Pco2. Dogs and patients with CRF were also unable to raise urine pH, urine HCO3 concentration, and U-B Pco2 normally at moderately elevated plasma HCO3 levels. In rats, dogs, and man, U-B Pco2 was directly related to urine HCO3 concentration and inversely related to fractional water excretion. At moderately elevated plasma HCO3 levels, animals with a distal acidification defect failed to raise U-B Pco2; increasing the plasma HCO3 to very high levels resulted in a significant increase in urine HCO3 concentration and U-B Pco2. The observed urinary Pco2 was very close to the Pco2 which would be expected by simple dissolution of a comparable amount of HCO3 in water. These data demonstrate that, in highly alkaline urine, urinary Pco2 is largely determined by concentration of urinary HCO3 and cannot be used as solely indicating distal H+ secretion.

Pituitary-thyroid function was assessed in 40 patients with chronic renal failure undergoing regular maintenance hemodialysis and in 35 normal subjects. Serum thyroid hormone levels were significantly lower in the dialysis patients than in the normal subjects (P less than 0.001) and were in the hypothyroid range in a high proportion of dialysis patients (total T3, 25%; free T3, 45%; total T4, 55%; free T4, 45%; and free T4 index, 38%). The reduced free thyroid hormone levels could not be explained by currently recognized assay artefacts. Serum TSH levels were higher than in the normal subjects (P less than 0.01), but still within the normal range for most (35 of 40) dialysis patients and did not correlate significantly with total or free thyroid hormone concentrations in either group. These results suggest some impairment in the thyroidal response to TSH and impaired pituitary response to low serum thyroid hormone levels, the latter implying resetting of the normal feedback mechanism such that diminished thyroid hormone production evokes a smaller than normal increase in TSH secretion. This diminished thyrotroph sensitivity to reduced serum thyroid hormone levels may be beneficial in severe nonthyroidal illness.

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The safety and efficacy of cefepime empiric monotherapy compared with standard broad-spectrum combination therapy for hospitalized adult patients with moderate to severe community-acquired bacterial infections were evaluated. In an open-label, multicenter study, 317 patients with an Acute Physiology and Chronic Health Evaluation (APACHE II) score ranging from >5 to =19 were enrolled with documented pneumonia (n=196), urinary tract infection (n=65), intra-abdominal infection (n=38), or sepsis (n=18). Patients were randomly assigned 1:1 to receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin, cephalothin, or ceftriaxone ± aminoglycoside therapy for 3 to 21 days. For both treatment groups, metronidazole, vancomycin, or macrolide therapy was added as deemed necessary. The primary efficacy variable was clinical response at the end of therapy. Two hundred ninety-six (93%) patients met evaluation criteria and were included in the efficacy analysis. Diagnoses included the following: 180 pneumonias (90 cefepime, 90 comparator), 62 urinary tract infections (29 cefepime, 33 comparator), 37 intra-abdominal infections (19 cefepime, 18 comparator), and 17 sepses (8 cefepime, 9 comparator). At the end of therapy, overall clinical success rates were 131/146 (90%) for patients treated with cefepime vs 125/150 (83%) for those treated with comparator (95% confidence interval [CI]: -2.6% to 16.3%). The clinical success rate for patients with community-acquired pneumonia, the most frequent infection, was 86% for both treatment groups. Among the patients clinically evaluated, 162 pathogens were isolated and identified before therapy. The most commonly isolated pathogens were Escherichia coli (n=49), Streptococcus pneumoniae (n=29), Haemophilus influenzae (n=14), and Staphylococcus aureus (n=11). Bacteriologic eradication/presumed eradication was 97% for cefepime vs 94% for comparatortreated patients. Drug-related adverse events were reported in 16% of cefepime patients and 19% of comparator patients. In conclusion, cefepime had higher cure rates compared with broad-spectrum combination therapy as an initial empiric treatment for hospitalized patients with moderate to severe community-acquired infections, including urinary tract infections, intra-abdominal infections, and sepsis. Key Words: Cefepime, ampicillin, caphalotin, ceftriaxone, aminoglycoside, urinary tract infections, intra-abdominal infections, sepsis. The initial selection of an empiric antimicrobial regimen for the treatment of hospitalized patients with serious community-acquired infections requires the use of broadspectrum antibiotics. It has been common practice to treat presumed bacterial infections (e.g. pneumonia, urinary tract infection, sepsis) with combination antibiotic therapy, such as a β-lactam plus an aminoglycoside, in order to cover likely Gram-positive and Gram-negative organisms. In addition, combination therapy is prescribed to provide synergy against difficult-to-treat pathogens or ones that are likely to emerge resistant (e.g...

Furosemide increases urinary acidification in control subjects and in certain patients with normokalemic or hypokalemic distal renal tubular acidosis (RTA). We studied the effect of furosemide in 14 patients with hyperkalemic distal RTA. In a group of patients with pure selective aldosterone deficiency, furosemide increased net acid and K excretion in a fashion indistinguishable from controls. This effect of furosemide was observed both in the presence and in the absence of acute mineralocorticoid administration. In another group of patients with hyperkalemic distal RTA, furosemide failed to decrease urine pH and to increase net acid excretion despite acute mineralocorticoid administration. Plasma aldosterone was variable in this group in that some patients had appropriate levels of aldosterone for the degree of hyperkalemia, whereas in the other patients the levels were low. The failure of these patients to respond to furosemide, despite pharmacologic doses of mineralocorticoid, suggests that these patients had a defect in H+ secretion other than that attributable to aldosterone deficiency alone. To gain insight into the mechanism whereby furosemide increases urinary acidification, we studied control and amiloride-treated rats pretreated with mineralocorticoid. In response to furosemide, control rats had a significantly lower urine pH and higher net acid and K excretion than that observed in amiloride-treated rats. These data suggest that furosemide increases H+ and K excretion, at least in part, by creating a favorable electric gradient for secretion of these ions since these effects were blunted in presence of inhibition of distal Na transport by amiloride.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of parathyroid hormone (PTH) administration on urinary acidification was studied in intact and thyroparathyroidectomized dogs. PTH administration resulted in a significant increase in urine pH and HCO3 excretion. In dogs with maximally acid urine caused by Na2SO4 infusion PTH administration also led to a significant increase in urine pH and to a decrease in ammonium excretion. To examine the effect of PTH on H+ secretion in the distal nephron we measured the urine-blood (U-B) PCO2 gradient in dogs with maximally alkaline urine (urine pH greater than 7.8) before and after PTH administration. After infusion of the hormone, HCO3 excretion increased significantly but the U-B PCO2 gradient remained unchanged. The effects of PTH infusion on urinary acidification in animals with distal renal tubular acidosis caused by LiCl administration were also studied. PTH administration to these dogs increased HCO3 excretion to the same level seen in normal dogs. These data suggest that PTH does not inhibit distal H+ secretion but increases HCO3 excretion by depressing proximal HCO3 reabsorption.

The phosphaturic effect of parathyroid hormone (PTH), cyclic adenosine monophosphate (cAMP), acetazolamide (Az), and HCO3 loading was studied in normal, thyroparathyroidectomized (TPTX), and Li-treated dogs. PTH administration to normal animals markedly increased fractional excretion (F) of PO4 but had a blunted effect on FPO4 in the Li-treated animals. Cyclic AMP likewise markedly increased FPO4 in the normal animals but had a markedly blunted effect in the Li-treated animals. Az led to a significant increase in FNa, FHCO3, and FPO4 in the normal animals. In the Li-treated dogs, Az induced a significant natriuresis and bicarbonaturia but failed to increase phosphaturia. HCO3 loading in normal dogs caused a significant phosphaturia while having little effect on FPO4 in Li-treated dogs. HCO3 loading to TPTX dogs was associated with a lower FPO4 as compared to normal HCO3-loaded animals. These data suggest that Li administration not only blocks the adenyl cyclase-cAMP system in the renal cortex, but it may also interfere with a step distal to the formation of cAMP, since the phosphaturic effect of both PTH and cAMP was markedly diminished in Li-treated animals.

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