Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial.

OBJECTIVE: To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus. DESIGN: Double-blind, placebo-controlled, crossover trial with four periods. SETTING: Clinical research referral center. PATIENTS: 29 pruritic patients with liver diseases of various causes. INTERVENTION: Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours. MEASUREMENTS: During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously. RESULTS: One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients. CONCLUSIONS: Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.

Is "relative" hypertension a risk factor for vaso-occlusive complications in sickle cell disease?

Supine arterial blood pressure measurements of 89 patients with homozygous sickle cell disease and normal renal function were compared with those of an age-, race-, and sex-matched normal population and with those of individuals who had similar levels of anemia due to beta thalassemia. Consistent with previous reports, sickle cell patients had significantly lower blood pressure than the normal population. However, within most age groups, sickle cell patients tended to have higher than expected blood pressure than individuals with similar or less severe degrees of anemia. Furthermore, the authors have found an association between cerebrovascular accident and elevated blood pressure in men, even in a range of systolic and diastolic pressures that would be considered normal by conventional standards. These results reiterate the intricate relationship that exists between factors governing red cell rheology and microvascular tone. They also raise the possibility that "relative" hypertension may be associated with other vaso-occlusive manifestations of the sickle cell syndromes.

A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.

To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary biliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous (24-hour) IV infusions of naloxone (0.2 micrograms.kg-1.min-1) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed subjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P less than 0.001). These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients.

Application of piezo film technology for the quantitative assessment of pruritus.

A method to quantitate scratching has been developed for assessing the efficacies of interventions purported to ameliorate pruritus. The technique employs a piezo film sensor attached to the finger and the supporting electronics to amplify, transmit, and process the signals generated by the piezo film. The piezo film is essentially a contact microphone on the fingernail of the scratching subject. The method is currently incorporated into clinical trials, and preliminary results are promising.

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

Optical determination of dental pulp vitality.

In this preliminary study, we explored the feasibility of employing photoplethysmography and pulse oximetry to assess the status of the blood circulation in the dental pulp. A simple photometer that measures diffuse light transmission at 575 nm was built to record tooth plethysmograms, and the ability to distinguish vital from surgically devitalized teeth of a dog using plethysmography was demonstrated. As an extension of the photoplethysmographic technique, red-infrared pulse oximetry applied to the measurement of the oxygen saturation (SO2) of blood in the pulp was also examined using an in vitro test setup. Results suggest that the measurement of relative SO2 changes is feasible, but standard dual-wavelength pulse oximetry does not enable determination of SO2 independent of tooth geometry and sensor placement.

Multilayer model of photon diffusion in skin.

A diffusion model describing the propagation of photon flux in the epidermal, dermal, and subcutaneous tissue layers of the skin is presented. Assuming that the skin is illuminated by a collimated, finite-aperture source, we develop expressions relating photon flux density within the skin and intensities re-emitted from the skin surface to the optical properties of the individual layers. Model simulations show that the rate at which re-emitted intensities diminish with radial distance away from the source can provide information about absorption and scattering in underlying tissues. Re-emitted intensities measured from homogeneous and two-layer tissue phantoms compare favorably with model predictions. We demonstrate potential applications of the model by estimating the absorption (sigma a) and transport-corrected scattering (sigma's) coefficients of dermis and subcutis from intensities measured from intact skin and by predicting the magnitude of the optical-density variations measured by a photoplethysmograph.

Food allergy.

Although common, food allergy is vastly overestimated by patients. The main food allergens include cow's milk, eggs, nuts, shellfish and whitefish. Other types of adverse food reactions are numerous; their cause represent a spectrum of toxins, infectious organisms and pharmacologic agents. A definitive diagnosis may be difficult. Recommended measures include prevention through breast feeding, avoidance of known offenders and symptomatic therapy when reactions occur.

The development of a filtration system for evaluating flow characteristics of erythrocytes.

A complete description of the pathophysiology of sickle cell disease requires a physiologically meaningful measurement of red cell deformability. We have designed and built a system which allows one to determine filtration characteristics of erythrocytes. A dilute red cell suspension is forced through a 3.0-micron polycarbonate Nuclepore membrane with a constant positive pressure of 20 mm Hg. Under these conditions blockage of the pores in the polycarbonate membrane is insignificant and flow is linear. We use the relative number of cells filtered through the membrane as a means of approximating the means deformability of cells in the suspension. Using this system we have compared erythrocytes from various mammals and shown that our technique is sensitive in detecting not only differences in cell deformabilities between mammalian species but also changes in cell deformability of human red cells due to exchange transfusion and application of drugs. There was a positive correlation between cell filtrability and percentage cell recovery (coefficient of correlation, 0.65) and a negative correlation between cell size and filtrability (coefficient of correlation, -0.61). The filtrabilities of normal volunteers and sickle cell disease patients were found to be 71.8 +/- 6.6 and 53.6 +/- 5.0%, respectively. This system is sensitive and reliable, and should be useful in evaluating both the contribution of filtrability to the viability of red cells in vivo and potential therapeutic agents for sickle cell disease.

Comparative ocular pressure elevation by medrysone, fluorometholone, and dexamethasone phosphate.

In age-, race-, and sex-matched groups, the relative abilities of medrysone, fluorometholone, and dexamethasone phosphate to elevate intraocular pressure were compared in a masked manner. Compliance was controlled by drops being given by nursing personnel. The 18 male hospitalized volunteers received commercial preparations of one of the corticosteroids to each eye four times a day for six weeks. The relative ability of medrysone, fluorometholone, and dexamethasone phosphate to raise IOP was 1, 4, and 7.6, respectively.