REACTIONS TO LEPIRUDIN

Lepirudin is an anticoagulant used in patients with heparin-induced thrombocytopenia. In 2002, three patients with potential allergic reactions to lepirudin were identified by Schering AG, the drug’s manufacturer. Greinacher et al used Schering’s pharmacosurveillance system to assess the risk of allergic and anaphylactic reactions caused by lepirudin. The researchers found that although the drug can cause fatal reactions in some patients, its benefits are still substantial.

All cases reported to the manufacturer as anaphylactic or severe allergic reactions were included in the study. In addition, the investigators screened the adverse event database for 289 terms that could be related to allergy, anaphylaxis, or shock. This yielded 345 reports, which were evaluated for cases involving possible anaphylactic reactions.

Nine cases were identified as severe allergic reactions to lepirudin; all had occurred within minutes of treatment initiation. In four of these cases, the patients had previously been treated with the drug uneventfully but experienced reactions during reexposure to lepirudin one to 12 weeks later. All four died shortly after onset of the reaction. The other five patients survived.

Greinacher et al calculated that the risk for severe reactions during initial lepirudin treatment is about five in 32,500 and during reexposure, four in 2,500. The authors stressed that the death rate in patients with heparin-induced thrombocytopenia was more than 20% before the introduction of lepirudin. It is now less than 10%.

Thus, the drug plays an important role in the management of this condition; however, they suggested that alternative treatments be considered before patients are reexposed to lepirudin.

Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation. 2003;108:2062-2065.

ANABOLIC STEROIDS HAVE A POSITIVE EFFECT IN COPD

Patients with COPD often have dyspnea and impaired exercise performance that persist despite medication. Diminished muscle function is partially due to muscle wasting and possibly a decrease in anabolic hormones. In addition, systemic corticosteroids are known to contribute to respiratory and peripheral muscle weakness in COPD patients. Theoretically, therefore, anabolic steroids could be used to enhance the response to pulmonary rehabilitation.

To test this hypothesis, Creutzberg et al studied the effects of a short course of anabolic steroids in 63 male COPD patients who were undergoing pulmonary rehabilitation. The drug had an overall positive effect on lung and muscle function, health status, and erythropoietic parameters.

The men were randomized to receive either 50 mg nandrolone decanoate (ND) intramuscularly every two weeks for eight weeks or placebo. They also continued their regular therapy. Lung function measurements were performed at baseline and end of study. Body composition, muscle function, exercise capacity, and health status were also assessed.

At baseline, all patients had severely impaired lung function and decreased exercise capacity. Thirty-one were receiving oral corticosteroids as maintenance medication at a mean dosage of 7.5 mg/d.

There was a significantly greater increase in fat-free mass and intracellular mass in the treatment group. Both groups experienced increases in muscle strength, peak workload, and peak oxygen consumption. However, in the ND group, there were also marked improvements in maximal inspiratory mouth pressure (PImax), maximal isokinetic work of the lower extremities, peak lactate/peak workload ratio, and peak oxygen pulse. In addition, the ND group had a significant increase in erythrocyte count and a tendency toward increases in hematocrit, hemoglobin, and erythropoietin levels.

The benefit of anabolic steroids was particularly dramatic in the patients who had received corticosteroids as maintenance therapy (Figure 1). Both PImax and peak workload rose substantially among the ND recipients in this group, but neither variable changed significantly from baseline in the placebo cohort. This suggests that ND treatment counteracts the corticosteroid-induced disturbances in intrinsic muscle oxidative capacity.

Creutzberg EC, Wouters EFM, Mostert R, et al. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest. 2003;124:1733-1742.

PREDICTING SURVIVAL WITH NSCLC TUMORS SMALLER THAN 2 CM

In patients with stage IA non–small cell lung cancer (NSCLC), five-year survival is about 60% to 80%. It has been clearly shown that outcomes are better in patients with tumors that are 3 cm or less in size than in those with larger tumors. But whether even smaller tumor sizes can help predict prognosis has not been studied.

Thus, Port et al conducted a retrospective study of patients with resected tumors to determine whether tumor size smaller than 2 cm is predictive of survival. They found that within stage IA NSCLC, five-year survival is markedly higher in patients whose tumors are no more than 2 cm in size than in patients with larger neoplasms, and thus they recommend that screening to detect small tumors be considered.

During the study, which was conducted between January 1990 and December 2001, 244 patients underwent surgery for NSCLC. The overall five-year survival was 71.1%. Survival for patients with tumors 2 cm or smaller was 77.2%, and for patients with larger tumors, it was 60.3%.

The overall five-year disease-specific survival was 74.9%. However, disease-specific survival, which was 81.4% in patients with tumors 2 cm or smaller, dropped to 63.4% for patients with larger tumors. The differences in both overall and disease-specific survival were significant.

Although the current lung-cancer staging system recognizes a survival difference for tumors larger or smaller than 3 cm, the authors suggested a further substaging of stage IA lesions to include tumors smaller than 2 cm.

Port JL, Kent MS, Korst RJ, et al. Tumor size predicts survival within stage IA non–small cell lung cancer. Chest. 2003;124:1828-1833.

A SIX-MONTH INTERVENTION HAS LASTING BENEFITS FOR ASTHMA PATIENTS

More than four fifths of the resources for asthma in this country are used by the 20% of patients who frequently need asthma-related health care. A study of such patients by Castro et al found that a six-month, nurse-focused intervention resulted in dramatic reductions in both hospitalizations and health care costs.

Ninety-six patients (predominantly young African-American women) who were admitted to the study hospital for asthma and had a history of one or more hospitalizations in the past year took part in the study. Participants were randomized to receive either usual care or the intervention. The intervention was provided by a nurse and consisted of asthma education appropriate to the patient’s education level, motivations, and cultural beliefs; completion of a daily asthma care flow sheet during hospitalization; psychosocial support and patient screening for professional counseling; establishment of an individualized asthma self-management plan; consultation with social service professionals to help plan for hospital discharge; and outpatient follow-up for six months, including telephone calls, home visits, and physician appointments. Both groups of patients were then observed with no intervention given to either for an additional six months.

During the initial six months of the study, the intervention group had a 60% reduction in hospital readmissions compared with the control group. In the intervention group, 21 readmissions were due to asthma, versus 42 in the control group. In the six months after the intervention, the lower readmission rate was sustained in the intervention group.

The average total health care costs per patient in the control group were $12,188, compared with $5,726 in the intervention group. Lower indirect health care costs in the intervention group resulted in an additional cost savings of $2,220 per patient. These lower indirect costs were mostly due to a 76% reduction in lost workdays in the intervention group.

The authors observed that the short-term intervention had long-term effects. They suggested that the intervention may have given patients greater knowledge and self-management skills, as well as an improved sense of control over health.

Castro M, Zimmermann NA, Crocker S, et al. Asthma intervention program prevents readmissions in high healthcare users. Am J Respir Crit Care Med. 2003;168:1095-1099.

POLYMORPHISMS OF ADAM33 DIFFER WITH ETHNIC GROUP

ADAM33 (a disintegrin and metalloprotease 33) was recently identified as a gene involved in airway remodeling and asthma susceptibility. Because the specific polymorphism responsible for the increased risk remains unknown, Howard et al studied four asthma populations of different ethnicity and tested each of them for eight single nucleotide polymorphisms (SNPs) of ADAM33. Their findings confirm that the gene is important in the development of asthma and atopy, but no single SNP could be found that was common to all patient groups.

African-American, US white, US Hispanic, and Dutch asthma patients and their families were studied. A significant association with asthma susceptibility was observed in each population for at least one polymorphism, but no single SNP was associated with a specific asthma phenotype across all groups. Similarly, at least one SNP was associated with skin test responsiveness or IgE levels in each group, but there was no single polymorphism to which these characteristics could be attributed.

The authors suggested two explanations for their results. An as yet undiscovered SNP or haplotype could be linking differently within each group and thus could be responsible for the varying effects of the SNPs. Alternatively, the different ethnic groups could have different genetic backgrounds or specific environmental exposures.

Howard TD, Postma DS, Jongepier H, et al. Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol. 2003;112:717-722.

ICU MORTALITY LOW WHEN ACUTE RESPIRATORY FAILURE OCCURS ALONE

If acute respiratory failure (ARF) is not complicated by dysfunction of other organ systems, ICU survival is above 95%. However, more than 20% of patients die within 90 days of ARF onset, usually because of their underlying disease. When ARF is complicated by other types of organ dysfunction, rates of both ICU and 90-day mortality rise markedly (Figure 2).

ARF is the most common type of organ failure in the ICU. Because most estimates of its mortality rate have included patients with other types of organ dysfunction, Flaatten et al studied 529 patients who were admitted to the ICU with ARF or who developed ARF while in the ICU. At admission, 137 patients had single-organ ARF and 255 had ARF plus one or more additional organ failures. In addition, 19 patients developed single-organ ARF and 118 developed multiorgan failure while in the ICU.

The ICU, hospital, and 90-day mortality rates were lowest in patients who had ARF as the only type of organ failure; there was no difference in outcome between those who had single-organ ARF on admission and those who developed it in the ICU. Mortality increased sequentially with the number of additional organ failures. Overall, mortality at 90 days was 35.7% higher in the group with multiple-organ failure than in the patients with single-organ ARF.

Of the 151 patients with single-organ ARF who survived their ICU stay, 29 had died by 90-day follow-up. These patients died of their underlying disease.

Flaatten H, Gjerde S, Guttormsen AB, et al. Outcome after acute respiratory failure is more dependent on dysfunction in other vital organs than on the severity of the respiratory failure. Crit Care. 2003;7:R72-R77.