Decontamination of the digestive tract and oropharynx in ICU patients.

BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.)

Severe influenza resembling hemorrhagic shock and encephalopathy syndrome.

Influenza-associated encephalopathy is a clinically diverse syndrome and severe cases are not well documented outside Japan. Clinical, pathological and molecular aspects are described of two fatal cases presenting during 2004 and 2005 winter seasons in The Netherlands. Results showed that severe influenza can resemble hemorrhagic shock and encephalopathy syndrome, and proper testing for influenza virus should be considered in similar cases. The failure to detect viral replication in non-pulmonary organs including the brain would support the pathogenesis of this syndrome is based on proinflammatory cytokine responses.

Persistent Acinetobacter baumannii? Look inside your medical equipment.

Two outbreaks of multidrug-resistant Acinetobacter baumannii occurred in our hospital. The outbreak strains were eventually isolated from respiratory ventilators, an apparatus used to cool or warm patients, and four continuous veno-venous hemofiltration machines. Removing dust from the machines and replacing all dust filters brought the outbreaks to an end.

Operations that require supracoeliac aortic cross-clamping: perioperative monitoring with gastric tonometry.

OBJECTIVE: To assess the predictive value of a gastric intramucosal pH of less than 7.35 for mortality in surgical patients after supracoeliac aortic cross-clamping. DESIGN: Open prospective clinical study. SETTING: University hospital, The Netherlands. SUBJECTS: Six patients who required temporary supracoeliac, and four patients who required temporary infrarenal, cross-clamping of the aorta. MAIN OUTCOME MEASURES: Mortality and conventional measures of organ dysfunction correlated with gastric tonometry. RESULTS: All 6 patients who required supracoeliac cross-clamping underwent a steep, and 5 patients a prolonged, decrease in the gastric intramucosal pH. The mean lowest gastric intramucosal pH in the supracoeliac group was 7.05 and in the infrarenal group 7.28. All patients recovered completely. CONCLUSION: A pHig value below 7.35 does not seem to be a marker of mortality in patients who have undergone supracoeliac cross-clamping of the aorta.

[Liver damage attributed to the use of disulfiram]. / Leverbeschadiging toegeschreven aan het gebruik van disulfiram.

In three alcoholic patients, two men aged 30 and 42, and a woman aged 52, hepatitis was diagnosed after the use of disulfiram. In all cases, there was a close temporal relationship between the occurrence of symptoms and disulfiram intake. Other possible causes were excluded. The 30-year-old man died from liver damage. Biopsy showed massive hepatic necrosis without signs of alcoholic hepatitis. In the other patients, symptoms subsided quickly and liver function returned to normal after discontinuation of disulfiram, but there was no confirmation by biopsy. The possibility of drug-induced hepatitis should always be considered in an alcoholic patient treated with disulfiram.

Differential effects of counterregulatory stress hormones on serum albumin concentrations and protein catabolism in healthy volunteers.

Postoperative hypoalbuminemia occurs frequently; however, the cause of this disorder is not clear. In a double-blind, placebo-controlled study we investigated to what extent hypoalbuminemia and protein catabolism are caused by counterregulatory stress hormones, which play an important role in the metabolic changes that follow surgery. We simulated the postoperative endocrine response in healthy volunteers with a cocktail of the counterregulatory hormones epinephrine, glucagon, and hydrocortisone. Saline was infused as a control in a second experiment. Serum albumin and stress hormone concentrations and nitrogen balance were measured for 34 h and were compared with published values for patients after abdominal surgery. Triple-hormone infusion mimicked the endocrine response after abdominal surgery adequately. It caused a negative nitrogen balance comparable with that after moderately severe surgery but no hypoalbuminemia (serum albumin < 35 g/L), although serum albumin was slightly reduced relative to the control group. No net nitrogen loss or hypoalbuminemia occurred after saline infusion. In conclusion, counterregulatory stress hormones do not cause hypoalbuminemia in healthy volunteers, but do produce protein catabolism.

Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD).

Early and late responses to treatment with either oral (600 mg/day) or intravenous (20 mg/day) (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (aminohydroxypropylidene bisphosphonate; APD) were studied in 142 patients with Paget's disease of bone who had not previously been treated with bisphosphonate. The efficacy of three therapeutic regimens was compared: (a) oral aminohydroxypropylidene bisphosphonate given continuously until six months after the serum alkaline phosphatase activity had returned to normal (long term); (b) oral aminohydroxypropylidene bisphosphonate given until urinary hydroxyproline excretion had returned to normal (short term); (c) intravenous aminohydroxypropylidene bisphosphonate for 10 days. With either oral or intravenous treatment the decrease in urinary hydroxyproline excretion was rapid and always preceded the fall in serum alkaline phosphatase activity. Normal urinary hydroxyproline excretion is essential for return of the serum alkaline phosphatase activity to normal. Complete biochemical remission, defined as return of the serum alkaline phosphatase activity to normal, was obtained in 129 patients (91%). The median duration of remission as assessed by actuarial analysis was 2.7 years. This study found no difference in the long term among the three modes of treatment, suggesting that for most patients with Paget's disease a short course of intravenous aminohydroxypropylidene bisphosphonate will produce longlasting, complete remission without need for maintenance treatment.

Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment.

131 patients with osteolytic metastases from breast cancer were randomised to receive long-term oral treatment with aminohydroxy-propylidene-bisphosphonate (APD), 300 mg daily (n = 70), or to act as controls (n = 61) in a multicentre trial. Specific antitumour therapy was at the discretion of the clinician and variable. An interim analysis was made after a median follow-up of 13 months in the APD group and 14 months in the controls. There was a significant reduction in pathological fractures and severe bone pain in the APD group, and hypercalcaemia was prevented. Consequently the necessity for radiotherapy for skeletal complications was more than halved; the number of systemic therapy changes was also reduced. Gastrointestinal side-effects of APD led to a drop-out of 8% of patients. Oral supportive APD therapy is simple and convenient, and significantly reduced skeletal morbidity in advanced breast cancer.

Serum osteocalcin in Paget's disease of bone: basal concentrations and response to bisphosphonate treatment.

Serum osteocalcin concentrations were measured in 42 patients with Paget's disease of bone and elevated serum alkaline phosphatase (AP) levels. High serum osteocalcin levels were found in only 22 patients. Serum osteocalcin was significantly correlated with urinary hydroxyproline excretion (r = 0.747; P less than 0.001) and, to a lesser extent, with serum AP levels (r = 0.483; P less than 0.01). In 23 patients who were followed during treatment with iv (3-amino-1-hydroxypropylidene) 1,1-bisphosphonate (APD) for 10 days, a dissociation among these 3 biochemical parameters was found. Urinary hydroxyproline excretion fell significantly (P less than 0.001), serum AP levels decreased, but not significantly, and serum osteocalcin concentrations increased progressively (P less than 0.001). This increase was greater when initial levels were lower than expected for the activity of the disease. The rise in serum osteocalcin correlated significantly with the concomitant increase in serum 1,25-dihydroxyvitamin D concentrations. Three months after initiation of treatment, all 3 parameters, urinary OHP excretion, serum AP, and serum osteocalcin levels, were near or within the normal range. These results indicate that serum osteocalcin is not a clinically useful parameter for assessment of the activity of Paget's disease. Its basal concentrations lag behind those expected from the activity of the disease, suggesting defective osteocalcin production. It appears that the functions of osteocalcin and AP as well as their initial expression by the osteoblasts are different and that this difference may be important for the quality of bone formed in Paget's disease. APD can modulate the release of osteocalcin, possibly through stimulation of 1,25-dihydroxyvitamin D production, although other factors may be involved.

Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride.

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.

Efficacious management with aminobisphosphonate (APD) in Paget's disease of bone.

The effects of treatment with aminobisphosphonate (APD) have been studied in a large and well-defined group of patients with Paget's disease over a period of seven years. Particular attention is given to the pharmacology of the drug, to methods of assessment of efficacy, and to the quality and the long-term persistence of the treatment results. These studies are compared to previously reported studies on bisphosphonates (P-C-Ps). The data suggest that the efficacy of P-C-Ps in Paget's disease results from a physiologic adaptation of all cellular processes involved in bone metabolism to a primary inhibition of bone resorption. The prolonged persistence of remissions may indicate that this is associated with disappearance rather than suppression of pathogenic material. If the low specific toxicity of the new generations of P-C-Ps is confirmed, it will be possible to induce complete and prolonged remissions through short oral or parenteral treatment courses that are associated with minimal side effects. Early institution of treatment in selected patients may prevent the development of deformity, fracture, and pain.

Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and hypercalcaemic patients treated with APD.

The changes of parathyroid hormone (PTH) and of vitamin D metabolites after intravenous administration of the bisphosphonate APD were studied in ten patients with Paget's disease of bone and in ten patients with tumour-induced hypercalcaemia. After APD all patients with Paget's disease became hypocalcaemic and showed an increase in both N-PTH and C-PTH values. Patients with malignancies had a nearly six-fold greater decrease in serum calcium but rises in N-PTH and C-PTH were observed only in those who developed hypocalcaemia. Overall, a clear rise in PTH was found when serum calcium fell below 2.20 mmol/l. Basal 25-hydroxy- and 24,25-dihydroxyvitamin D concentrations were similar in the two groups and showed no change after APD treatment. Circulating 1,25-dihydroxyvitamin D, however, increased in all patients with Paget's disease and in six of the hypercalcaemic patients. It is concluded that the main regulator of PTH secretion is the concentration of calcium per se rather than the magnitude or the rate of its change. The production of 24,25-dihydroxyvitamin D is not affected by wide variations in serum calcium while that of 1,25-dihydroxyvitamin D is sensitive to these changes.

Relation between signs and symptoms in Paget's disease of bone.

The relation between signs and symptoms of Paget's disease of bone was studied in 180 patients consecutively submitted for treatment. In these patients 826 lesions were identified by scintigraphy. The intensity of scintigraphic uptake was correlated with long-term calcium uptake in bone. The frequency distribution of lesions over the patients was compatible with a 65 per cent chance of local disease once the patient had been exposed to an extraneous agent. The spatial distribution within a skeleton was related to the local density of the osteoclast population. The particular frequency distribution resulted in a log-normal distribution diagram for anatomical spread. Within lesions, increases in numbers of osteoclasts and osteoblasts were proportional and these too had a log-normal distribution. Increases of alkaline phosphatase levels and hydroxyproline excretion were closely related and reflected anatomical spread on the one hand and local activity on the other. They were also closely correlated with overall calcium fluxes. It was shown that alkaline phosphatase is the more sensitive and hydroxyproline the more accurate of the biochemical signs. Maximum values, corresponding to total skeletal disease, were approximately 25 times the upper limit of normal. Equilibrium between bone formation and resorption was not always maintained. There were, indeed, wide variations of urinary calcium, which were significantly related to the difference between bone formation and resorption, but the extracellular calcium homeostasis was generally maintained. This may explain the frequent occurrence of normocalcaemic and hypercalcaemic hyperparathyroidism. The hypercalciuria constitutes an additional risk for urolithiasis in men. The most frequent complaint was pain (86 per cent). Extent of lesions was important, but a major decisive factor was the specific nature of the bone affected. The findings allowed assessment of the relative importance of the various signs, symptoms and locations as criteria of disease severity and as indications for treatment.

Quantitative bone scintigraphy in Paget's disease treated with APD.

Half-yearly bone scintigrams of 27 patients with Paget's disease, who were treated with the bisphosphonate APD, were evaluated. Uptake of 99Tcm-Sn-EHDP was determined by computer analysis. All patients reached clinical and biochemical remission, usually within 6 months. The scintigraphic uptake dropped steeply during the first 6 months and only slightly during the second 6 months. The decrease in uptake was proportional to the original uptake and averaged 80% of this value. The residual 20% persisted, although clinical and biochemical remission were attained. The scintigraphic results obtained with APD agree with our earlier findings for patients in remission after treatment with a combination of calcitonin and EHDP. Eight patients suffered a recurrence after discontinuation of APD. In all cases scintigraphic deterioration also occurred, usually simultaneously or 6 months before the recurrence. In two patients with scintigraphic deterioration a recurrence could not be confirmed during this study. The scintigraphic deterioration presented as one of the three patterns seen after combination therapy.

Apparent mineralocorticoid excess and deficient 11 beta-oxidation of cortisol in a young female.

A 19-year-old female, known to have had hypertension and hypokalemic alkalosis since the age of 9 months, was found to have suppressed renin, negligible plasma and urinary aldosterone and low plasma levels of other known sodium-retaining steroids. Despite the normal plasma cortisol the urinary excretion of 17-oxosteroids and 17-oxogenic steroids was low as was the cortisol secretion rate, suggesting a diminished metabolic clearance of cortisol. This was confirmed by the demonstration of a prolonged t 1/2 of 14C-cortisol. The abnormally high urinary excretion ratios of cortisol to cortisone, tetrahydracortisol to tetrahydrocortisone and 11-hydroxy-aetiocholanolone to 11-oxy-aetiocholanolone indicate that the diminished cortisol breakdown is the result of deficient 11 beta-oxidation. Moreover, the urinary excretion of free cortisol was elevated, probably due to diminished tubular reabsorption of cortisol. Hypokalemic alkalosis did not respond to spironolactone, but was partly corrected by amiloride. No response to dexamethasone was observed, but dexamethasone combined with aminogluthetimide normalized blood pressure and serum K. These findings support the involvement of a sodium-retaining, kaliuretic steroid in this rare syndrome.

Photon-deficient bone scan lesion as a precursor of active Paget's disease.

A case is presented in which a Pagetoid lesion was demonstrated as a photon-deficient area (cold spot) on the bone scan. This area changed into a hot spot 3 years after its discovery. Clinical and radiological observations provide evidence that a scintigraphically photon-deficient area may represent a precursor of active Paget's disease.