Phosphate metabolism in intensive care patients with acute respiratory failure.

OBJECTIVE: To determine the variables predicting the change of plasma phosphate over the first 24 hr period in intensive care in patients with acute respiratory failure. METHODS: Fifty-seven patients were studied prospectively in a university teaching hospital intensive care unit (ICU). Thirty two patients were classified as having acute respiratory failure and a primary respiratory system diagnosis (group I), 10 were classified as having acute cardiogenic pulmonary oedema (group II) and 15 were general ICU patients (group III). Arterial blood specimens at intensive care unit admission (T0) and at 24 hr post-admission (T24) were assayed for multiple plasma biochemical parameters including phosphate (PO4) and red blood cell 2,3-diphosphoglycerate (2,3-DPG). Timed urine collections were used to determine 24 hr urine phosphate loss and renal phosphate threshold concentration (RTP). During the measurement period glucose-free fluids only were infused. RESULTS: Fifty seven patients had a mean (+/- SD) age of 67 +/- 12 years and Apache II score of 22 +/- 6. The plasma PO4 at T0 was 1.55 +/- 0.71 mmol/L and showed a significant 24 hr decrease of 0.55 mmol/L (p < 0.0001) at T24. Hypophosphataemia at T0 was observed in 26% of patients. Red blood cell 2,3-DPG was not elevated at T0 (13.5 +/- 3.3 umol/gHb) and showed a non-significant increment over 24 hr. Urine phosphate loss over the 24 hr period was 21.8 +/- 14.0 mmol with RTP being reduced below the lower reference range limit in groups I (0.65 +/- 0.29 mmol/L) and II (0.57 +/- 0.29 mmol/L). The naive form of phosphate change (PO4T24-PO4T0) was significantly related to initial plasma PO4 and was subject to regression to the mean, which was estimated to have inflated the relationship by 25%. The appropriate form of phosphate change was found to be log ratio T24/T0 phosphate. Independent predictors of log ratio T24/T0 phosphate were 24 hr change (T24-T0) in both 2,3-DPG and arterial pH, RTP, prescription of aminophylline (categorical factor) and the interaction of aminophylline and RTP (R2 = 0.65, ordinary least squares regression). CONCLUSIONS: Twenty-four hour plasma phosphate decrement in intensive care unit patients was multi-factorial and was attended by a lowered renal threshold phosphate concentration.

Interaction of human serum albumin with the electrophilic metabolite 1-O-gemfibrozil-beta-D-glucuronide.

Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to endogenous proteins. Gemfibrozil is a fibrate lipid-lowering agent that is extensively metabolized to an acyl glucuronide conjugate in humans. The aims of this study were to examine the interactions of 1-O-gemfibrozil-beta-D-glucuronide with human serum albumin. The degradation of 1-O-gemfibrozil-beta-D-glucuronide (approximately 200 microM) was examined in vitro during incubations at 37 degrees C with phosphate buffer (pH 7.4 or 9.0), solutions of human serum albumin (pH 7.4), or fresh human plasma (pH 7.4). The effects of diazepam, oxyphenbutazone, and gemfibrozil on the degradation of 1-O-gemfibrozil-beta-D-glucuronide, and its reversible binding to albumin were also studied. A pilot in vivo study was performed on two patient volunteers administered 1 g/day p.o. gemfibrozil. 1-O-Gemfibrozil-beta-D-glucuronide was unstable, with degradation half-lives in buffer of 4.1 hr and 44 hr at pH 9.0 and 7.4, respectively; and 8.5 hr and 5.5 hr in pH 7.4 solutions of human serum albumin or fresh plasma, respectively. Degradation was dependent on pH and the presence of albumin, which seemed to accelerate the intramolecular rearrangement and hydrolysis of the conjugate. 1-O-Gemfibrozil-beta-D-glucuronide was highly reversibly bound to albumin, with a mean unbound fraction of 0.028, and its degradation seemed to be related to the degree of reversible binding. Hydrolysis and covalent binding were associated with the site II binding domain on albumin, because only diazepam inhibited these reactions. However, intramolecular rearrangement was increased when binding to the site I domain was inhibited. Covalent binding was also detected in vivo to human plasma proteins. The half-life of the gemfibrozil-protein adducts was 2.5-3 days. Albumin plays an important role in the disposition of acyl glucuronides by acting as: i) a transporter protein; ii) a potential catalyst for their degradation and, therefore, clearance; and iii) a target for covalent adduct formation.

Total porphyrin and coproporphyrin and uroporphyrin fractions in urine measured by second-derivative spectroscopy.

A second-derivative scan of an acidified urine sample allows the amplitude of deflection (delta A) and the minimum wavelength of the trough (lambda min) to determine the correct porphyrin concentration and the coproporphyrin:uroporphyrin (copro:uro) ratio, respectively, from a nomogram constructed from calibrator solutions. We measured 24 urine samples for total porphyrin as coproporphyrin equivalents and adjusted the results with factors from the nomogram. The adjusted results (x) (mean +/- SE, 501 +/- 57 nmol/L) compared favorably with the expected results (y) (514 +/- 57). The regression equation and correlation coefficient were: y = 0.993x - 8.9 (r = 0.998, S(y/x) = 16.2). Results of the copro:uro ratio derived by second-derivative spectroscopy and HPLC showed no significant difference (chi 2-test) from samples with various copro:uro ratios. Recovery studies on four urine samples supplemented with known proportions of coproporphyrins and uroporphyrins gave good agreement between the measured and the expected porphyrin ratios. The overall imprecision (CV) of the assay ranged from 3.6% to 6.0% for coproporphyrin and from 3.2% to 9.1% for uroporphyrin.

Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock.

OBJECTIVE: To characterise the plasma cortisol profile and adreno-cortial responsiveness (short Synacthen test) of patients in septic shock. DESIGN: Retrospective assessment using case-notes and ICU charts. SETTING: University teaching hospital ICU. PATIENTS: 68 septic shock patients with plasma cortisol and/or short Synacthen test measured at ICU-admission or onset of shock post ICU-admission. Patients were identified from a total population of 155 patients who had PCL and/or SST measured over a 4.5 year period. INTERVENTION: None. MEASUREMENTS AND RESULTS: Patients with septic shock had a plasma cortisol ranging from 210-8900 nmol/l and mortality of 56%. There were 22 (32%) below (low) and 46 (68%) above (high) a 'critical' plasma cortisol of 500 nmol/l. Using stepwise logistic regression, mortality was adequately predicted by and increased with, increasing plasma cortisol and onset of shock remote from ICU-admission. Short Synacthen tests were available in 33 patients: 11 responders (cortisol increment > 200 nmol/l above baseline 30 min after 0.25 mg intravenous Synacthen) and 22 hypo-responders. Mortality in patients was adequately predicted by and increased with a decrease in cortisol increment post-Synacthen. Thirteen patients (plasma cortisol 606 +/- [SD] 297 nmol/l) had complete haemodynamic profiles before inotropic therapy; no relationship was demonstrated between plasma cortisol and circulatory variables. Follow-up revealed no cases of Addison's disease. CONCLUSIONS: In septic shock, 'hypocortisolaemia' is not uncommon and does not predict a high mortality; adrenocortical hypo-responsiveness may be associated with poor outcome.

Effect of orally administered beclomethasone dipropionate on calcium absorption from the gut in normal subjects.

BACKGROUND: There is evidence that patients with chronic obstructive airways disease and asthma who take inhaled steroids have a low bone density. As most of a drug given from a metered dose inhaler is actually swallowed, the possibility that swallowed beclomethasone dipropionate acts topically in the gut to impair calcium absorption was investigated. Such an effect, if sustained, may be a causative factor of long term bone loss. METHODS: A two week randomised, double blind, placebo controlled, crossover trial was performed in 12 normal volunteers. Subjects were randomly allocated to swallow beclomethasone dipropionate capsules (500 micrograms twice a day) or placebo for one week. The alternate capsule was given throughout the second week. At the end of each week, calcium absorption was assessed by a strontium absorption test. Serum parathyroid hormone, plasma calcium, and plasma phosphate concentrations were determined on the last two days of each week. Twenty four hour urinary calcium, hydroxyproline, and cortisol concentrations were measured for four successive days in each week. RESULTS: All subjects completed the study. There was a 12% reduction in strontium absorption during the beclomethasone dipropionate ingestion week. There was also a 23% reduction in 24 hour urinary cortisol excretion during the same week. CONCLUSIONS: Calcium absorption (measured by a strontium absorption test) was reduced by oral administration of beclomethasone dipropionate for one week. Decreased calcium absorption due to swallowed corticosteroid may contribute to side effects of inhaled steroids and further long term studies are needed.

Stability of the CK-MB isoenzyme on routine storage.

Unlike earlier studies on the stability of the CK-MB isoenzyme carried out on control sera and on semi-purified and purified CK isoenzymes, we have studied the stability of CK-MB measured electrophoretically in patient sera under different laboratory storage conditions. The values obtained if the test was done immediately were significantly higher than those done on stored samples. There was no difference between specimens stored at -20 degrees C overnight or kept at room temperature (RT) for a few hours, but values were significantly lower (p less than 0.005) in specimens left at RT for 6 h and then stored overnight at 4 degrees C. To determine the effects of longer storage, further specimens stored either at -20 degrees C or at 4 degrees C for up to 4 days were also tested for CK-MB stability by electrophoresis and by immunoinhibition and immunoenzymetric methods. The immunological methods were included in the study to assess method dependency of CK-MB stability. CK-MB was stable at -20 degrees C by all methods, but at 4 degrees C, CK-MB was stable only by immunological and not by electrophoretic (p less than 0.005) measurement. Specimens stored under adverse conditions (4-6 days at RT) showed 50% deterioration of CK-MB when measured electrophoretically but only about 20% when measured immunologically.

Placebo-controlled trial of dexamethasone for chronic biliary pain after cholecystectomy.

Activation of the sympathetic nervous system appears to be relevant in some patients with unexplained pain after cholecystectomy, particularly those who show increases in plasma transaminase activity after challenge with morphine (morphine responders). In this study, the hypothesis that dexamethasone would improve chronic biliary pain, perhaps by suppressing activation of the sympathetic nervous system, was tested in a double-blind, placebo-controlled, cross-over trial in 20 patients, 10 morphine responders and 10 nonresponders. Before treatment with dexamethasone and placebo, urinary excretion of norepinephrine (NE) was significantly higher (p less than 0.05) in morphine responders than in nonresponders. During treatment with dexamethasone, 1 mg each night for 4 weeks, neither morphine responders nor nonresponders showed a significant improvement in pain or nausea or a significant reduction in sympathoadrenomedullary activity as assessed by urinary excretion of catecholamines. At the dose administered, dexamethasone was unhelpful for chronic pain after cholecystectomy and did not result in suppression of the sympathetic nervous system as assessed by urinary excretion of NE.

Choriogonadotropin-mediated thyrotoxicosis in a man.

A 38-year-old man with a metastatic gonadotropin-secreting tumor of unknown primary origin presented with both clinical and biochemical findings of hyperthyroidism in association with markedly increased concentrations of human choriogonadotropin (hCG) in plasma. After chemotherapy, the concentrations of both hCG and free thyroxin decreased and the patient became euthyroid. We discuss the rare occurrence of this presumably hCG-driven hyperthyroidism in men and compare it with the relatively more common eumetabolic hyperthyroidism associated with choriocarcinoma in women.

Morphine responders with unexplained pain after cholecystectomy may have sympathetic overactivity.

In patients with unexplained pain after cholecystectomy, morphine often induces pain and may increase plasma aspartate aminotransferase activity because of exaggerated or prolonged rises in pressure within the biliary system. Previous studies have demonstrated that patients showing increases in aspartate aminotransferase have increases in plasma concentrations of noradrenaline and dopamine prior to and soon after induction of pain. The purpose of this study was to assess sympathetic activity under basal conditions in patients with (responders) and without (non-responders) increases in aspartate aminotransferase after challenge with morphine. When compared to non-responders, morphine responders had higher plasma concentrations of noradrenaline (p = 0.0001) and dopamine (p = 0.02) and higher urinary excretion of noradrenaline over 24 h (p = 0.03). Plasma and urinary levels of adrenaline were similar in the two groups. These observations indicate higher basal levels of sympathetic activity in the subgroup of patients showing increases in aspartate aminotransferase after challenge with morphine.

Impaired sulphation of phenol by the colonic mucosa in quiescent and active ulcerative colitis.

Substantial amounts of phenols are produced in the human colon by bacterial fermentation of protein. In the colonic mucosa of animals, phenols are inactivated predominantly by conjugation with sulphate. The purpose of this study was to confirm sulphation of phenols by isolated colonocytes from man and to evaluate mucosal sulphation in inflammatory bowel disease using the phenol, paracetamol, in rectal dialysis bags. The incubation of paracetamol with colonocytes isolated from resected colon specimens (n = 7) yielded a mean (SE) value of 7.0 (0.9) mumols/g dry weight of paracetamol sulphate after 60 minutes but virtually undetectable values of paracetamol glucuronide. Paracetamol sulphate was detected in rectal dialysates from all control subjects, with a mean (SE) value of 4.2 (0.8) nmol/hour. Sulphation was significantly impaired (p less than 0.01) in 19 patients with active ulcerative colitis (0.6 (0.2) nmol/hour) and in 17 patients with ulcerative colitis in remission (1.1 (0.4) nmol/hour). Sulphation in eight patients with Crohn's colitis (4.3 (2.1) nmol/hour) was similar to that in control subjects. Impairment of the capacity of the mucosa to sulphate phenols in quiescent and active ulcerative colitis may pose a metabolic burden on colonic epithelial cells, which are continuously exposed to endogenous phenols from the colonic lumen.

Reliability of the porphobilinogen screening assay.

A survey conducted by the Australian Association of Clinical Biochemists Porphyrin Working Party on urinary porphobilinogen screening showed good sensitivity (75-97.5%). This is contrary to reports in the literature and to our own observations. We therefore assessed a widely used screening method (Watson-Schwartz) and found poor sensitivity (40-69%), and even less sensitivity (28-53%) when the urine samples were normally coloured or concentrated. Thus the results obtained by the Working Party might mislead one to infer that the Watson-Schwartz method is reliable.

Relationship between morphine responses and sphincter of Oddi motility in undefined biliary pain after cholecystectomy.

In 150 patients with undefined biliary pain after cholecystectomy, responses to morphine were compared with responses to morphine combined with neostigmine. The relationship between rises in plasma levels of aspartate aminotransferase (AST) after morphine or morphine-neostigmine and sphincter of Oddi motility as assessed by endoscopic manometry was also examined. When compared with morphine-neostigmine, patients given morphine alone showed a similar frequency (30% versus 33%) of increases in plasma levels of AST (greater than twice the upper limit of the reference range) but had less abdominal pain and a lower frequency of similar increases in plasma levels of amylase (4% versus 25%). Of 92 patients who consented to endoscopic manometry of the sphincter of Oddi, satisfactory manometric records were obtained in 84, 31 with and 53 without increases in AST after morphine or morphine-neostigmine. Those showing rises in AST had a higher frequency of abnormal manometric records (81% versus 57%, P = 0.025), higher basal pressures in the sphincter of Oddi (P = 0.0001) and higher pressures within ducts (P = 0.02). There was a significant correlation between sphincter basal pressures and intraduct pressures (r = 0.51, P less than 0.001). Rises in plasma AST after morphine are similar to those after morphine-neostigmine and are influenced by, or linked to, factors which determine sphincter basal pressures and intraduct pressures.

Do nonesterified fatty acids displace thyroxin from its plasma binding sites in severe nonthyroidal illnesses?

Severe nonthyroidal illnesses have been associated with increases in nonesterified fatty acids (NEFA) and the dialyzable fraction of thyroxin (T4) in plasma. We have further investigated their possible relationship in severe nonthyroidal illnesses as well as in induced in vivo and in vitro situations involving increased NEFA. We demonstrate that there is no relationship between NEFA and the dialyzable fraction of T4, either in severe nonthyroidal illnesses or in the other situations, unless plasma NEFA concentrations exceed 5 mmol/L in normal persons or 1.7 mmol/L in nonthyroidal illnesses, and that this concentration was not reached in the patients we studied, with one exception. We conclude that NEFA are unlikely to contribute to an inhibition of the binding of T4 to the binding proteins that might be present in plasma of patients with severe nonthyroidal illnesses unless their NEFA concentrations are very high.

Evaluation of evoked potentials and cerebrospinal fluid analysis in the differential diagnosis of multiple sclerosis.

During the 6 years to December 1988, 191 patients underwent evoked potential (EP) studies and cerebrospinal fluid (CSF) analysis for oligoclonal bands at the Queen Elizabeth Hospital, for the differential diagnosis of multiple sclerosis (MS). Clinical data at the time of study separated patients into 3 groups, as follows: (i) multiple sclerosis (n = 90) - McDonald and Halliday Classification, 1977, (ii) other neurological disease (n = 82) and (iii) no neurological disease (n = 19). In cases of clinically definite MS, visual evoked potentials (VEPs) were abnormal and oligoclonal bands were detected in 64% and 59% of cases, respectively. However, only 15% of patients with suspected MS had abnormal VEPs, and only 23% had oligoclonal bands. Other studies have shown figures differing from these, though not necessarily significantly. We found a substantial number of EP (20%) but few CSF (4%) abnormalities in disorders other than MS, and no abnormalities in cases without neurological disease. The various figures for abnormal results in cases assessed for the differential diagnosis of MS are influenced not only by laboratory methods, but by the degree of clinical suspicion in relation to the cases selected, as well as by differences in populations from which cases are derived. Long-term prospective studies of diagnostically indeterminate cases are still required to determine the diagnostic weighting that can be applied on the basis of abnormal investigational results. Magnetic resonance imaging will not resolve these questions since it has limitations of its own, particularly with regard to specificity.