David W. Alling

A Comparison of Amphotericin B Alone and Combined with Flucytosine in the Treatment of Cryptoccal Meningitis

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: Heart rate as an early predictor of prognosis

Forty-eight septic shock patients with positive blood cultures had conventional serial hemodynamic evaluations until recovery or death to identify early cardiovascular variables that predicted outcome. There were 19 (40%) survivors and 29 nonsurvivors. At the initial evaluation, both survivors and nonsurvivors demonstrated an elevated cardiac index (CI), low systemic vascular resistance index (SVRI), and normal stroke volume index. However, only an initial heart rate (HR) less than 106 beat/min significantly predicted survival. Twenty-four hours after the onset of shock, both an HR less than 95 beat/min and an SVRI greater than 1529 dyne.sec/cm5.m2 predicted survival. Comparing the hemodynamic profiles from the initial to the 24 h time point, a decrease in HR greater than 18 beat/min or a decrease in CI greater than 0.5 L/min.m2 predicted survival. Twenty-two deaths occurred in the first week of study, of which 18 (82%) were due primarily to low SVRI and four (18%) to low CI. Seven deaths occurred after 1 wk, all of which were due to multiple organ failure.

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

Pruritus is a distressing and frequent complication of cholestasis [1] that is often difficult to manage. It can lead to severe sleep deprivation and may be an indication for liver transplantation. Because the pathogenesis of this form of pruritus is unknown, there is no sound rationale for its management. Thus, it is not surprising that the many medications and procedures that have been used to manage this condition are largely empirically based [2]. It has recently been proposed that a component of the pruritus of cholestasis may be attributable to increased neurotransmission or neuromodulation mediated by the opioid system in the central nervous system [3, 4]. If this hypothesis is correct, not only would the contribution of at least one class of pruritogenic substances (opioids) involved in the pruritus of cholestasis be apparent, but a rationale would be established for using a specific class of drugs, opiate antagonists, in the treatment of the pruritus of cholestasis. Currently, three lines of evidence support the hypothesis that endogenous opioid agonists contribute to the pruritus of cholestasis: 1) the association of increased opioidergic neurotransmission or neuromodulation induced by opiates (such as morphine) with pruritus of central origin that can be reversed by an opiate antagonist (naloxone) [5-9]; 2) clinical and experimental findings suggesting that cholestasis is associated with increased opioidergic tone [10-12]; and 3) preliminary reports of the amelioration of the perception of the pruritus of cholestasis after the administration of opiate antagonists [10, 13, 14]. These observations led to a controlled, single-blinded trial of naloxone infusions for the pruritus of chronic cholestasis [15]. In eight pruritic patients with primary biliary cirrhosis, scratching activity was 29% to 96% (mean, 50%) less during naloxone infusions than during infusions of a placebo solution. This result required confirmation by a double-blind, controlled study. We report the results of a double-blind, placebo-controlled, crossover trial in which 24-hour naloxone infusions and 24-hour placebo infusions were administered consecutively in random order to 29 cholestatic patients with pruritus. Scratching activity was measured continuously throughout the trial by the use of a monitoring system designed for this purpose [16]. Methods The study protocol was approved by the Clinical Research Subpanel of the National Institute of Diabetes and Digestive and Kidney Diseases. All participating patients signed a written informed consent form. Patients Twenty-nine patients with pruritus and cholestasis associated with a cholestatic liver disease or advanced chronic hepatocellular disease were studied. Needle biopsy of the liver or endoscopy and retrograde cholangiography were done when clinically indicated. In each case, causes of pruritus other than cholestasis, (notably, other general medical and psychiatric disorders and pruritic skin diseases) were systematically excluded by taking a comprehensive medical history, doing a full physical examination, and obtaining results of laboratory tests and procedures relevant to each patients medical status. In addition, the results of a careful evaluation by a dermatologist (MLT) had to be negative for a cause of pruritus other than cholestasis. This skin evaluation included examination of the skin under Woods light when appropriate and photography of skin lesions. In addition, post-trial follow-up of the patients studied for 10 to 32 months did not reveal any cause of pruritus other than cholestasis. Exclusion criteria for the trial were the presence of another condition known to be complicated by pruritus (for example, pregnancy, azotemia, thyroid dysfunction, iron deficiency, malignant diseases, and neurologic disorders) and the occurrence of a gastrointestinal hemorrhage, hepatic encephalopathy, or ascites during the previous 6 months. Diagnoses and demographic characteristics of the patients are shown in Table 1. The duration of pruritus was life-long for the patient with the Alagille syndrome, intermittent in the patients with benign recurrent intrahepatic cholestasis although present for at least 1 month before study entry (range, 1 to 12 months), and from 1 to 15 years in the other patients. Among the patients studied, the severity of the pruritus was considered intractable, with severe sleep deprivation, in 6 patients; a major hindrance to regular activities in 20; and tolerable in 3. Serum biochemical profiles on each patient were consistent with cholestasis (median alkaline phosphatase level, 9.67 kat/L [range, 1.3 to 24.4 kat/L; normal, 0.5 to 2.0 kat/L]; median total bilirubin level, 22.3 mmol/L [range, 5.1 to 243 mmol/L; normal, 2.0 to 18 mmol/L]). One patient with chronic hepatitis C had a serum alkaline phosphatase level in the normal range at the time of study. That patient also had a serum bilirubin level of 22.2 mmol/L and fasting and postprandial serum bile acid concentrations that were threefold higher than the upper limit of normal in the absence of features of hepatic decompensation. Table 1. Patient Characteristics In none of the patients was the use of conventional medications for the pruritus of cholestasis associated with clinically acceptable relief from pruritus. Seventeen of the patients had been treated with cholestyramine, antihistamines, or phenobarbital in various combinations. Another patient, who could not tolerate cholestyramine, received antihistamines. One patient with primary biliary cirrhosis had been receiving ursodeoxycholic acid for treatment of cholestasis for 2 years with no apparent effect on pruritus. Therapy with ursodeoxycholic acid, which was not classified as an antipruritic medication, was not discontinued. The patient with the Alagille syndrome had been given rifampicin for pruritus. Therapy with this drug had been discontinued several months before her participation in the trial when the patient developed neuropathy. Study Design Therapy with all antipruritic medications was discontinued 5 days before the study began. During the trial, each patient received four consecutive 24-hour intravenous infusions in an arm vein, with no intervals between infusions. The nursing staff provided conventional maintenance of the intravenous cannula. Two of the infusions consisted of 5% dextrose/0.45% NaCl (placebo), and two contained naloxone (Narcan; DuPont, Manati, Puerto Rico) (0.2 g/kg body weight per minute) in 5% dextrose/0.45% NaCl. The total volume infused during 24 hours was 0.5 L. Each naloxone infusion was preceded by an intravenous bolus injection of 0.4 mg of naloxone in 1 mL of normal saline, and each placebo infusion was preceded by an intravenous bolus injection of 1 mL of normal saline. The order of naloxone and placebo infusions was assigned by balanced randomization. The patients, nursing staff, and clinicians were blinded to the content of the infusions and the bolus injections. Only the statistician (DWA) and the designated pharmacy staff knew of the randomization code. Vital signs were continuously recorded every hour throughout the study by an automated blood pressure monitor (Critikon Corp., Tampa, Florida). Any symptoms or abnormal signs occurring during the infusions, including those compatible with a reaction similar to an opiate withdrawal syndrome, were carefully assessed. Assessment of Pruritus Perception and Scratching Activity Patients were asked to record the severity of their pruritus by making a mark with pen or pencil on a visual analog scale every 4 hours while awake. The scale consisted of a 10-cm horizontal line; 0 cm (the beginning of the scale on the left side) represented no itching and 10 cm (the end of the scale on the right side), the worst itching ever. A visual analog score was the number of centimeters (to the nearest millimeter) between 0 cm and the point on the scale at which the patient made a mark [15, 17]. Scratching activity, independent of limb movements, was continuously recorded during the infusions. The monitoring system used consists of a vibration (scratch) transducer (Piezo Film Division, Altochem Corp., Philadelphia, Pennsylvania), an FM transmitter and receiver (Radio Shack [32-1221]), a custom-made signal processor, and a personal computer. The vibration transducer was taped to the middle fingernail of the dominant hand, and the fingernail was not cut during the study. The transducer consists of a rectangular piece of piezoelectric film, 1 cm2 in area, 28mthick and metallized on both sides with silver ink. It is connected by a thin cable to the transmitter box (2 7 6 cm), which is attached to the same arm by a Velcro cuff. The transducer converts the strain produced by vibrations of the fingernail as it traverses the skin in the act of scratching to an electrical voltage. The electrical signal is transmitted across the room, where it is received, processed, and logged by the personal computer as a scratching activity index in units of counts per unit time (30 seconds). Only signals above a preset threshold and within the frequency band shown by Fourier analysis to be associated with vibrations of the scratching fingernail (50 to 1000 Hz) were recorded [15, 16]. The validity of this index as an accurate quantitative measurement of scratching activity has been confirmed by independent observations and examination of videotapes [16]. Statistical Analysis In this four-period crossover trial [18], each patient was assigned to receive, without interruption, four 24-hour infusions (two of naloxone and two of placebo), the order of which was chosen by balanced randomization from the six possible arrangements. All of the infusion bags and their contents were identical in appearance. Twenty-three patients received all four infusions, four received three, and two received one naloxone infusion and one placebo infusion. The balance achieved in the infusion assignment was as follows: Infus

Antibody to Hepatitis B Core Antigen as a Paradoxical Marker for Non-A, Non-B Hepatitis Agents in Donated Blood

The relationship between the presence of antibody to hepatitis B core antigen (anti-HBc) in donor blood and the development of hepatitis in recipients of that blood was studied in 6293 blood donors and 481 recipients who were followed for 6 to 9 months after transfusion. Of 193 recipients of at least 1 unit of blood positive for anti-HBc, 23 (11.9%) developed non-A, non-B hepatitis compared with 12 (4.2%) of 288 recipients of only anti-HBc-negative blood (p less than 0.001). Donor anti-HBc status was not significantly associated with the development of hepatitis B in the recipient and was negatively associated with the development of cytomegalovirus hepatitis. The relationship of donor anti-HBc status and the development of non-A, non-B hepatitis in the recipient was independent of transfusion volume and elevated donor transaminase level. Although 88% of anti-HBc-positive blood units were not associated with recipient non-A, non-B hepatitis, calculation of maximal corrected efficacy predicted that exclusion of anti-HBc-positive donors might have prevented 43% of the cases of non-A, non-B hepatitis with a donor loss of 4%. Because of the serious chronic consequences of non-A, non-B hepatitis, surrogate tests for non-A, non-B virus carriers must be seriously considered.

Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir

We studied 35 otherwise healthy adults with frequently recurring genital herpes (greater than or equal to 1 episode per month), in a double-blind trial comparing oral acyclovir with placebo capsules for suppression of recurrent infection. The patients were treated for 125 days unless herpes recurred. Among 32 evaluable patients, there were significantly fewer recurrences during acyclovir treatment (4 of 16) than during placebo treatment (16 of 16, P less than 0.001). The mean duration of therapy was significantly longer for patients receiving acyclovir than for those receiving placebo (114.9 vs. 24.8 days, P less than 0.001). Of 19 patients who had recurrences in the blind trial, only 2 had recurrences when given acyclovir in a second, open-study phase. All patients had recurrences after completing acyclovir treatment. The therapy was well tolerated, with minimal gastrointestinal upset and one hypersensitivity reaction. Studies of the viral isolates demonstrated that lesions developing in patients receiving acyclovir contained drug-resistant virus. Later recurrences in these patients were associated with drug-sensitive virus. We conclude that oral acyclovir suppresses genital herpes in patients with frequent recurrences, but the potential for problems with drug resistance and the long-term safety need to be more fully explored.

A prospective trial of colchicine for primary biliary cirrhosis.

Abstract We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminot...

Colchicine therapy for familial mediterranean fever. A double-blind trial.

Abstract Eleven patients with long standing familial Mediterranean fever were studied in a double-blind trial using daily colchicine or placebo. During 60 courses of placebo, 38 attacks of familial...

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.

Prevention of catheter-associated urinary tract infections: Efficacy of daily meatal care regimens

To evaluate the efficacy of daily cleansing of the urethral meatus-catheter junction in preventing bacteriuria during closed urinary drainage, randomized, controlled trials of two widely recommended regimens for meatal care were completed. In 32 (16.0 percent) of 200 patients given twice daily applications of a povidone-iodine solution and ointment bacteriuria was acquired, as compared with 24 (12.4 percent) of 194 patients not given this treatment. In 28 (12.2 percent) of 229 patients given once daily meatal cleansing with a nonantiseptic solution of green soap and water bacteriuria was acquired, as compared with 18 (8.1 percent) of 23 patients not given special meatal care. There was no evidence in either trial of a beneficial effect of meatal care. Moreover, each of four different statistical methods indicated that the rates of bacteriuria were higher in the treated groups than in the untreated groups. In subsets of female patients at high risk in both studies significantly higher rates of bacteriuria were noted in the treated groups than in the untreated groups. Current methods of meatal care appear to be hazardous, as well as expensive, and cannot be recommended as measures to control infection.

Heterogeneity of immunoregulatory T-cell subsets in systemic lupus erythematosus: Correlation with clinical features

Immunoregulatory T-cell subsets as defined by differentiation antigens were studied in 32 patients with systemic lupus erythematosus (SLE) and 16 healthy persons using the monoclonal antibodies OKT 3 or anti-Leu 4 (T cells), anti-Leu 2a (suppressor/cytotoxic cells) and anti-Leu 3a (helper/inducer cells). Compared with the 95 percent confidence limits in control subjects, decreases or increases of Leu 3a+ cells were observed in 23 patients, whereas abnormal percentages of Leu 2a+ cells were observed in only 10 patients (p less than 0.002). The ratio of Leu 3a+ to Leu 2a+ cells varied over a much broader range (0.31 to 4.14) in patients with SLE than in control subjects (95 percent confidence limit 1.04 to 2.20). Furthermore, the helper:suppressor ratio correlated significantly (p less than 0.001) with a numerical clinical characterization of the patients. A low helper: suppressor ratio was observed in patients with severe renal disease, thrombocytopenia and onset of SLE by 20 years of age. Patients with a high helper:suppressor ratio had multisystem disease including lymphadenopathy, but only rarely SLE renal disease. Patients with a normal helper:suppressor ratio had the most widespread multisystem disease, often involving the kidneys and the central nervous system. The ratio was not correlated with duration of illness, disease activity or corticosteroid dosage in the patients examined. The study suggests that SLE is not one disease entity, but rather a symptom complex with different immunoregulatory abnormalities and associated manifestations.