Metamizol is a non-narcotic, analgesic and anti-pyretic pyrazolone derivative which belongs to the non-steroidal anti-inflammatory class of drugs. This drug is used in Germany, Spain and Italy, and in many South American countries. It is prohibited in other countries because of its capacity to induce agranulocytosis and aplastic anaemia. In addition to its effects on bone marrow, metamizol may also cause cutaneous reactions, allergic idiosyncratic reactions such a bronchospasm, anaphylactic shock, toxic epidermal necrolysis, hepatitis and severe hypotension [1]. We report here a case of non-oliguric acute renal failure and abortion following the ingestion of an overdose of metamizol in an otherwise healthy girl.
Case. A 14-year-old girl, previously healthy and without history of affective disorder, attempted suicide. She was admitted to our hospital 5 h after ingesting twenty 575 mg metamizol (Nolotil®) capsules (total amount ingested: 11.5 g). At admission, the patient presented with nausea and vomiting. Physical examination revealed a conscious and pale girl. There were no skin eruptions. Weigh was 47 kg, blood pressure was 110/70 mmHg, heart rate was 95 b.p.m., temperature was 36.6°C, and urine output was 100 ml/h. After repeated gastric lavages with medical charcoal, the initial laboratory data showed haematocrit 41%, haemoglobin 14 g/dl, white blood cells 15 500/µl with normal eosinophil count, platelets 237 000/µl, urea 35 mg/dl, glucose 90 mg/dl, creatinine 0.6 mg/dl, sodium 139 mmol/l, potassium 4.2 mmol/l, bicarbonate 24 mmol/l, ionized calcium 5.2 mg/dl and prothrombin time 78%. Eleven hours after admission, the patient was discharged from the hospital and referred to the mental-health unit. She complained of menstrual irregularities and at the time of discharge presented vaginal bleeding. On the second day after metamizol overdose, the patient had persistent vomiting, and was re-admitted to the hospital. Laboratory data showed haematocrit 37%, haemoglobin 12.6 g/dl, white blood cells 11 100/µl, platelets 202 000/µl, urea 41 mg/dl, glucose 96 mg/dl, creatinine 2.2 mg/dl, sodium 139 mmol/l, potassium 3.7 mmol/l, bicarbonate 21.4 mmol/l. Other laboratory data showed aspartate aminotransferase (AST) 9 IU/l, alanine aminotransferase (ALT) 7 IU/l, total bilirubin 0.6 mg/dl and C-reactive protein 4.9 mg/dl (normal 00.5 mg/dl). Urinalysis revealed 75 mg/dl protein and 50 red blood cells/µl in the sediment. A urine pregnancy test was positive [rapid enzyme-linked immunosorbent assay (ELISA)]. Abdominal ultrasonography showed normal sized and symmetric kidneys with increased cortical echogenicity. Transvaginal ultrasonography revealed an empty uterus and a left ovarian cyst. The patient received intravenous (i.v.) normal saline, anti-emetic and omeprazole. Her renal function worsened over the course of the next few days despite the fact that urine output was maintained between 2500 and 3500 ml/day. During the third day in hospital, her serum creatinine and urea levels increased to 3.1 and 67 mg/dl, respectively, her creatinine clearance was 22 ml/min and proteinuria was 0.61 g/day. The haematocrit was 33%, haemoglobin was 11.1 g/dl, and the serum ß-human chorionic gonadotrophin (hCG) level was <1.2 mIU/ml (normal values at 34 weeks of pregnancy, 9130 mIU/ml). The patient was treated with methylprednisolone (0.5 mg/kg/daily) i.v. for 3 days. This therapy was tapered and withdrawn within 12 days. In addition, she received erythropoletin 3000 IU subcutaneously per week (two doses). She recovered renal function rapidly after 3 days of steroid treatment and was discharged 7 days after hospitalization. At that time, her urinalysis was normal, serum creatinine was 0.8 mg/dl and creatinine clearance was 96 ml/min.
Comments. Metamizol can induce two different forms of acute renal failure. In addition to acute renal failure secondary to loss of counter-regulatory prostaglandins during plasma volume contraction, acute tubulointerstitial nephritis is a well recognized side effect of metamizol [24]. Acute tubulointerstitial nephritis has been observed at the usual pharmacological dose of the drug. However, the renal effects may be dose dependent, and large doses of this drug have been associated with acute renal failure in animals. Renal failure may occur because the elimination of this drug and its metabolites is mainly renal or because of acute haemodynamic effects due to inhibition of prostaglandin synthesis [57]. A characteristic feature of this form of presentation is a symptom-free interval of several days [2, 4]. In addition, the effects of metamizol on renal function range from moderate to advanced impairment, with most patients having oliguria.
Our patient presented a severe degree of intoxication to judge by the amount of drug ingested (at least six times the average normal daily dose). She developed non-oliguric acute renal failure after a latent period of 2436 h. Renal damage probably occurred as a result of toxic tubular necrosis, since it was not reversible despite volume repletion. In addition, she also presented microhaematuria and proteinuria, and renal function was rapidly reversible following steroid therapy. Therefore, on the basis of the time course of the disease, we suggest that the renal damage in this patient might be due to a toxic effect producing a tubular lesion and interstitial nephritis.
The mechanism of abortion with this drug is unknown. Metamizol is a prostaglandin synthetase inhibitor and it is advised to be used with caution in pregnancy. Although normal doses of metamizol have been associated with oligohydramnios [8], only in one case report has a high dose of metamizol been implicated in acute renal failure and oligohydramnios [4]. It has been suggested that oligohydramnios could also be a consequence of fetal toxicity due to prostaglandin inhibition [4]. In our patient, the dose of metamizol was very high; part of the drug probably entered the fetal tissues, and might have induced the abortion by direct toxic effect.
In conclusion, overdose of metamizol may induce reversible acute renal failure and abortion in early pregnancy, suggesting that it has toxic effects per se. Although the role of steroid therapy in acute interstitial nephritis has been questioned, it is reasonable to assume that this therapy could have contributed to the subsequent improvement in renal function of our patient. Additionally, menstrual history and test of early pregnancy should be part of the routine follow-up in adolescent girls with drug overdose.
Conflict of interest statement. None declared.
1 Sección de Nefrología and2 Servicio de Medicina Interna Hospital General La Mancha-Centro Alcázar de San Juan Ciudad Real Spain E-mail: cpeces{at}varnet.com
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