Postoperative administration of metamizole for one single day: A retrospective cohort study

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Editor,
We read the study by Fieler et al.1 with great interest. Their study addresses an important aspect of postoperative analgesia management. They did not report any cases of agranulocytosis following metamizole administration in more than 1000 children. A single dose of intravenous metamizole for treatment of postoperative pain seems to be well tolerated without adverse events directly related to metamizole administration. We would like to report a retrospective cohort investigation we performed in 2012, on consecutive adult patients, with the aim of investigating whether postoperative intravenous metamizole leads to agranulocytosis. After ethical approval (Medical Ethical Committee of Erasmus University Medical Centre, Rotterdam (Secretary Mrs. W.C.M. Tielemans, BASc, and chairman Prof. Dr H.W. Tilanus) in 2013/2014), we retrospectively included a cohort of 2377 different administrations of metamizole. This study was designed as a hypothesis-generating study for future prospective studies. Our primary outcome was the occurrence of agranulocytosis (defined as a decrease in peripheral granulocytes (neutrophil, eosinophil and basophil) count to less than 0.5 × 109 cells l–1, in accordance with our laboratory standards, or a decrease in the leukocyte count. For our primary analysis, we only used cases with both pre-administrative and post-administrative leukocyte counts to estimate the difference in the leukocyte counts and the percentage change. Exposure status was defined as dose of metamizole - Consumed Daily Dosage (CDD) in grams. As potential confounders, we included age, sex, nephrectomy, and current bone marrow suppressing therapies such as chemotherapy, radiotherapy, brachytherapy or immunosuppressive therapy. Data on metamizole administrations were obtained from the Patient Data Management System (PDMS) and from Electronic Patient Dossier (EPD – Elpado) of the Erasmus University Medical Centre, The Netherlands. The unadjusted and adjusted (corrected for age, sex and chemotherapy) odds ratios were calculated using logistic regression. As a reference category, we used a CDD of 1 g. Ninety-five percent confidence intervals and significance levels were obtained for all values. All analyses were done with IBM SPSS (Statistics for Windows version 21.0; IBM Corp., Armonk, New York, USA).
In our cohort with 2377 administrations of metamizole, 2049 patients (86%) received metamizole for one single day postoperatively. Data on both pre-administrative and post-administrative leukocyte count were available for 449 patients who received metamizole in one single day. When selecting only those who received metamizole for 1 day, mean age was 54 years (SD 16.80). The majority of these patients, 262 (58.6%), received 1 g in 1 day, 149 (33.2%) received 2 g, 18 (4.0%) received 3 grams, 17 (3.8%) received 4 g and two (0.4%) patients received 5 g. Of the 2377 eligible administrations of metamizole, only one case (0.042%) of possible agranulocytosis occurred. This person had a neutropenia (0.31 × 109 l–1) and a leukocyte count of 0.8 × 109 l–1 after using metamizole. Pre-administration, the leukocyte and neutrophil count was 6.00 × 109 l–1 and 4.9 × 109 l–1, respectively. This patient received metamizole together with his seventh RCHOP (Rituximab, Vincristine, Doxorubicine, Cyclofosfamide and Prednison) and intrathecal (Methotrexate and Dexamethasone) chemotherapy for a relapsed testicular B-cell lymphoma with liquor metastases. No complications or diagnostic confirmation of agranulocytosis was registered.
Leukopenia (≤3.4 × 109 cells l–1) occurred in 18 persons (4%) after metamizole. Compared with their pre-administration levels, 236 patients (52.6%) had a drop in their leukocyte count with a mean difference of −0.53 (SD 4.45) × 109 l−1, which represents a −4.73% difference. Patients who received up to 4 g within 1 day had a no significant higher chance of a decreased leukocyte count after administration [adjusted odds ratio (OR) 2.57, 95% confidence interval (95% CI) 0.89 to 7.44, P = 0.083]. For both unadjusted and adjusted analysis, we see a trend of increasing odds for higher dosages, but no significance was reached due to small numbers (see Table 1).
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