CONTINUOUS-INFUSION AMPHOTERICIN B REDUCES TOXICITY, RETAINS EFFICACY

Amphotericin B is the mainstay of treatment for immunocompromised patients with life-threatening fungal infections; however, treatment is associated with infusion- and dose-related adverse reactions. Administering amphotericin B by continuous infusion reduces its toxicity without decreasing its effectiveness, say the authors of a prospective, controlled trial from Switzerland.

Eriksson et al randomized 40 patients with refractory fever and suspected or proved invasive fungal infections to a continuous (24-hour) infusion of amphotericin B, and 40 similar patients to rapid (four-hour) infusion. Both groups received a median dose of about 0.96 mg/kg. Thirty-seven and 36 patients, respectively, were severely neutropenic before treatment. The patients were followed for three months after the end of treatment.

The continuous-infusion patients experienced fewer side effects and, therefore, were less likely to be treated for fever or chills after the first day of treatment. C-reactive protein levels, which were similar in the two groups at baseline, rose significantly in the rapid-infusion group at 24 and 48 hours. Creatinine clearance was significantly less impaired in patients undergoing continuous infusion during and at the end of treatment.

Treatment had to be discontinued in two patients in the rapid-infusion group because one had refractory leukemia and the other, severe nephrotoxicity, and in one patient in the continuous-infusion group because of refractory leukemia. Twelve patients in the rapid-infusion arm and four patients in the continuous-infusion group died by three-month follow-up. Seven deaths occurred during the treatment period; all were in the rapid-treatment group.

Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ. 2001;322:579-582.

C PNEUMONIAE INFECTION MAY LIMIT AIRFLOW IN ASTHMATIC PATIENTS

Patients with nonatopic adult-onset asthma may be at risk for persistent airflow limitation due to recurrent or chronic infection with Chlamydia pneumoniae, say the authors of a multicenter, cross-sectional study.

Dutch researchers examined the relationship between loss of lung function and seropositivity to C pneumoniae in 101 patients, ages 18 to 75 years (mean, 46 years), with severe asthma. Fifty-one percent had early-onset asthma (before age 18 years) and 49% had late-onset asthma (18 years or older). Exclusion criteria included current smoking or a smoking history of more than 10 pack-years. Enzyme-linked immunosorbent assay of C pneumoniae–specific serum immunoglobulin (Ig) G and IgA antibodies showed a seroprevalence of 73% and 60%, respectively, with no significant differences overall between those with early- and those with adult-onset asthma.

The annual loss of lung function was determined for various patient subgroups categorized according to age at onset, atopic status, and IgG seropositivity for C pneumoniae. This loss was calculated by dividing the ratio of forced expiratory volume in one second and vital capacity (both expressed as a percentage of predicted) by the duration of asthma.

Patients who were diagnosed with adult-onset nonatopic asthma and positive IgG antibodies to C pneumoniae had about a four times greater loss of lung function than did the other subgroups. However, C pneumoniae IgA seropositivity was not associated with significant differences in lung function in any subgroup.

ten Brinke A, van Dissel JT, Sterk PJ, et al. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol. 2001;107:449-454.

RAPID DIAGNOSIS OF PE BY D-DIMER ASSAY, ALVEOLAR DEAD SPACE

Vascular imaging of patients with suspected pulmonary embolism (PE) is expensive and time-consuming and may expose patients to ionizing radiation. The combination of a negative whole blood agglutination D-dimer assay and a normal alveolar dead-space fraction identifies those patients with a very low probability of PE, report the authors of a prospective, multicenter study.

Kline et al investigated the predictive value of a normal whole blood agglutination D-dimer assay combined with a normal alveolar dead-space fraction (volume of alveolar dead space/tidal volume of 20% or less) in excluding PE in 380 hemodynamically stable emergency department patients 18 years or older. All measurements were made at bedside before the patients underwent pulmonary vascular imaging, either ventilation-perfusion scintillation lung scanning or contrast-enhanced helical computed tomography of the chest. The patients were followed by telephone for six months.

Sixty-four patients (16.8%) were diagnosed with PE. Of these, 20 had an abnormal D-dimer assay result, three had an abnormal dead-space fraction, and 40 had abnormal results in both tests. One patient (one of seven taking warfarin) had normal results in both tests, for a sensitivity of 98.4%. Of the 316 patients without PE, 163 had normal results in both tests, for a specificity of 51.6%.

The authors emphasize that while the alveolar dead-space fraction enhances the diagnostic accuracy of the D-dimer assay, the fraction was normal in almost one third of the patients with PE. Thus, the dead-space measurement should not be used as the only screening test for PE.

Kline JA, Israel EG, Michelson EA, et al. Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study. JAMA. 2001;285:761-768.

AN OBJECTIVE METHOD FOR SCORING BURN-RELATED ORGAN DYSFUNCTION

Readily available objective clinical and laboratory data can be used to gauge the extent of burn-related organ dysfunction, according to the authors of a prospective study from Texas. These data may also be used as evidence of treatment effectiveness.

Cumming et al assessed organ dysfunction, organ failure, and sepsis in 85 patients hospitalized during a single year with total body surface area burns of at least 20%. Organ dysfunction and the severity of sepsis were determined by a modified version of the multiple organ dysfunction (MOD) score, which excludes the central nervous system component but retains the pulmonary, renal, cardiovascular, hepatic, and hematologic systems.

Of the 85 patients, only 32 (37.6%) had no evidence of organ dysfunction. Fifteen patients (17.6%) had dysfunction in two or more organ systems; 24 (28%) had severe MOD (defined as a MOD score of 6 or greater).Sepsis occurred in 43 patients (50.6%); 12 patients (14.1%) had severe sepsis or septic shock.

The risk for MOD correlated with age and total body surface area burned. MOD occurred more commonly in men than in women. In patients with and without severe MOD, mortality was 29.2% and 9.8%, respectively. Age and larger burn area were the most important factors associated with the development of severe sepsis/septic shock. Both severe MOD and severe sepsis/septic shock were related to male gender, as well as to prolonged intensive care unit stays and prolonged mechanical ventilation.

Cumming J, Purdue GF, Hunt JL, O’Keefe GE. Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma. J Trauma. 2001;50:510-515.

ARGATROBAN: ALTERNATIVE THERAPY FOR HEPARIN-INDUCED THROMBOCYTOPENIA

The onset of heparin-induced thrombocytopenia (HIT) mandates heparin discontinuation, but what should be done for patients who need continued anticoagulation? The direct thrombin inhibitor argatroban is an acceptable alternative, say the authors of a multicenter, prospective, historical controlled study.

Lewis et al evaluated the effectiveness of argatroban as an anticoagulant in 160 patients who had HIT and 144 who had HIT with thrombosis syndrome (HITTS); 252 (83%) of the original 304 patients completed treatment. The mean dose of argatroban administered was about 2.0 µg/kg/min; therapy was given for about five to six days. The historical controls included 147 patients with HIT and 46 with HITTS. The primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis within 37 days of the start of treatment.

Among subjects with HIT, the incidence of the composite end point was 25.6% in the argatroban-treated patients and 38.8% in the controls—a significant difference. Among those with HITTS, the corresponding figures were 43.8% and 56.5%, respectively; however, this difference did not reach significance. Among both groups of patients, argatroban administration was associated with a significant decrease in the number of deaths caused by thrombosis and in the percentage of patients with new thrombosis. Argatroban therapy resulted in adequate anticoagulation in at least 83% of patients, usually within four to five hours of treatment onset. There were no differences in the rate of major bleeding between the argatroban-treated patients and controls. The most common adverse events were diarrhea (11%) in the HIT group and pain (9%) in the HITTS group.

Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001;103:1838-1843.

IL-8 COMPLEXES PROVIDE CLUES TO ARDS PROGRESS

Although the presence of interleukin 8 (IL-8) in bronchoalveolar lavage (BAL) fluid is not a reliable predictor of the onset of acute respiratory distress syndrome (ARDS), the presence of autoimmune IL-8 antibody (anti–IL-8):IL-8 complexes in those same fluids may be an important prognostic indicator for patients who have ARDS.

IL-8 is a major attractant of neutrophils in ARDS, which is characterized by dramatically elevated proportions of such proteins in BAL fluids; these proteins are believed to contribute to tissue injury in alveolar spaces. Kurdowska et al therefore examined BAL fluids from 64 patients (19 patients at risk for ARDS and 45 patients with ARDS) at various stages of the syndrome’s progress. They found that IL-8 is biologically inactive when bound with anti–IL-8 but that the exact role of such complexes in the course of ARDS was difficult to determine.

However, the researchers did discover that the number of anti–IL-8:IL-8 complexes was significantly higher in BAL fluids at ARDS onset. Although this count did not indicate which patients would survive, anti–IL-8:IL-8 complex levels decreased over time in the patients who did not die. Complex levels remained high in nonsurvivors.

Kurdowska A, Noble JM, Steinberg KP, et al. Anti–interleukin 8 autoantibody:interleukin 8 complexes in the acute respiratory distress syndrome: relationship between the complexes and clinical disease activity. Am J Respir Crit Care Med. 2001;163:463-468.

AN ALTERNATIVE TO OZONE-DEPLETING MDIs

Albuterol delivered by means of a metered-dose inhaler (MDI) that contains chlorofluorocarbon (CFC) propellants is the most commonly prescribed treatment for asthma; however, CFC propellants have been associated with depletion of the ozone layer. Albuterol, delivered via an MDI formulated with the propellant hydrofluoroalkane (HFA) 134a, is as safe and effective as the drug delivered through a CFC-propelled MDI, report the authors of a multicenter, double-blind, placebo-controlled, randomized trial.

Lumry and associates compared the effectiveness of 12 weeks of treatment with CFC-propelled albuterol, HFA-propelled albuterol, or placebo in 313 asthma patients. After a three-week run-in period during which all subjects received the CFC-propelled drug (180 µg four times daily), 108 patients were randomized to continue this regimen, 101 were assigned to treatment with HFA-propelled albuterol at the same dosage, and 104 were given placebo.

After the first dose of medication on day 1 and at weeks 6 and 12, both actively treated groups had comparable mean values for forced expiratory volume in one second (FEV1); in addition, these groups experienced significantly greater improvement in FEV1 from baseline than did the placebo controls.

Both actively treated groups were also similar in the percentage of patients who responded to treatment, the maximum response to treatment, and time-to-onset and duration of response.

Patient-completed diaries showed a similar frequency of adverse events (ie, upper respiratory infection, throat irritation, viral respiratory infections, and upper respiratory inflammations) in all groups: 59% for CFC-propelled albuterol, 66% for HFA-propelled albuterol, and 69% for placebo. Asthma exacerbations occurred in 5%, 4%, and 8% of patients, respectively. There were no clinically significant changes in electrocardiographic or Holter findings, vital signs, or laboratory test results among patients.

Lumry W, Noveck R, Weinstein S, et al. Switching from Ventolin CFC to Ventolin HFA is well tolerated and effective in patients with asthma. Ann Allergy Asthma Immunol. 2001;86:297-303.

G6PD DEFICIENCY PREDISPOSES TO SEPSIS AFTER SEVERE INJURY

The type A–glucose-6-phosphate dehydrogenase (G6PD) deficiency, which occurs in about 10% of African Americans, increases a patient’s risk for sepsis after severe trauma, a prospective cohort study has found.

After screening 467 male African American trauma patients, Spolarics et al identified 44 with type A–G6PD deficiency; 43 other patients, who were matched for age, injury severity, and type of trauma but who did not have G6PD deficiency, served as controls. Eight of the G6PD-deficient patients and 16 of the nondeficient patients had suffered major trauma (as indicated by an Injury Severity Score of 16 or above); 36 and 27 patients, respectively, from each group had had moderate trauma (Injury Severity Score below 16).

Among the patients with major trauma, sepsis (including positive bacterial blood cultures) developed in four (50%) of the G6PD-deficient patients but in only one (6%) of the nondeficient controls. Sputum cultures were positive in six (75%) and five (31%) patients, respectively. In comparison to the controls, the G6PD-deficient patients also had a longer average duration of the sepsis syndrome (3.7 vs 0.5 days) and of the systemic inflammatory response syndrome (SIRS, 15.8 vs 5.6 days). Antibiotics were required by these patients for an average of 24 and nine days, respectively. All of these differences were statistically significant.

Among the patients who had moderate trauma, none experienced sepsis or the sepsis syndrome, and none had positive sputum cultures. The average duration of SIRS was 1.1 days in these G6PD-deficient patients and 1.7 days in the nondeficient patients; antibiotics were required for an average of 2 and 5 days, respectively. Neither of these differences was significant.

Spolarics Z, Siddiqi M, Siegel JH, et al. Increased incidence of sepsis and altered monocyte functions in severely injured type A–glucose-6-phosphate dehydrogenase–deficient African American trauma patients. Crit Care Med. 2001;29:728-736.

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