Discussion
This case report describes accidental bleomycin overdose caused by human error and failure of the system to block the chain of events. The toxicities and clinical management after medication error will be discussed, and a detailed analysis of the chain of events that resulted in the incident will be provided.
After injection, bleomycin is widely distributed throughout the body. Then the bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity (3). Thus, we focused closely on the pulmonary and skin toxicities. According to the instruction, the pulmonary toxicity occurs in approximately 10 % of treated patients and is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. Published articles have shown that the incidence of severe lung toxicity was 0-2 % in the patients exposured to a total dose ≤ 270 USP, the incidence increased to 6-18 % in the patients exposured to a total dose ≥ 360 USP (4-6). In this case, a total dose of bleomycin the patient received was 225 USP due to the medication error. However, we did not observe any pulmonary toxicity during one-year follow-up. The possible reasons are shown as follows: (1) multiple measures were used to protect bleomycin-induced toxicity; (2) the total dose of bleomycin that the patient received was less than 270 USP; (3) the patient was young man aged 25 years, thus the incidence of lung injury was relatively low. Based on the instruction (3), the skin toxicity is a relatively late manifestation usually developing after 150 to 200 USP of bleomycin have been administered and is also related to the cumulative dose. This is consistent with our case that the patient developed a mild rash 10 days after the medication error when the cumulative dose of bleomycin reached 225 USP.
Bleomycin has a renal metabolism with 50 % of dose eliminated in four hours after its administration and 70 % in the next 24 h (7). For this case, the time between the administration of the bleomycin and the detection of the medication error was 22 h. Even though most of the bleomycin had been cleared from the body, intravenous rehydration (3000 ml/m2) combined furosemide 20 mg were used to promote clearance of remaining medication. As the most serious side effects of bleomycin are pulmonary adverse reactions and the most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis, we undertook several approaches to protect the pulmonary toxicity. Up to now, there are no proven efficient to prevent the bleomycin-induced lung injury in humans. Oxidative stress has been implicated as an important factor in the development of bleomycin-induced pulmonary toxicity. A lot of non-clinical studies have reported that N-acetylcysteine amide, a thiol antioxidant, could prevent and ameliorate bleomycin-induced toxicity in human alveolar basal epithelial cells (8, 9). Therefore, the N-acetylcysteine amid was administered via inhalation and intravenous route. In addition, corticosteroids are widely considered to be the standard therapy in symptomatic patients with bleomycin-induced lung injury (10). The dosage of corticosteroids was initially 0.75-1 mg/ (kg·d) of prednison, which was gradually decreased according to the condition of the patients (11). Thus, the equipotent dose of methylprednisone (40 mg) was given initially, and gradually decreased to 4 mg. Luckily, no serious adverse events were observed during the treatment and one-year follow-up period.
Due to the medication error, how the next cycle of chemotherapy was chosen was a matter of further exploration. The medication error occurred in the third cycle of chemotherapy. According to theRAPID (12), CALGB 50604 (13), and RATHL (14) study, PET-CT scan should be performed after 3 cycles of ABVD in patients with newly diagnosed, nonbulky stage I or II Hodgkin lymphoma. The PET 5-point scale (Deauville criteria) of this patient was 2. The further chemotherapy should be one-two cycles of ABVD or four cycles of AVD (12-14). Finally, we choose the four cycles of AVD chemotherapy for the following two reasons. First, the pulmonary toxicity of bleomycin is dose related. Second, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy (14).
The chain of events was initiated by incorrect drug prescription. The doctor explained the error was likely caused by reduced concentration during a routine task combined with the inconsistency in nomenclature of bleomycin. Historically, bleomycin dosage has been described in terms of milligram potency (mg potency), in which 1 mg potency corresponded to 1 unit. In the original preparations 1 mg potency was also equivalent to 1 mg by weight (mg weight). Modifications and improvements in purification over time have meant that ampoules labelled as containing 15 mg—that is, 15 units—contained less than 15 mg weight of bleomycin. In 1995 labelling of bleomycin products in Australia changed from USP units to IU in line with changes in the British Pharmacopoeia and European Pharmacopoeia . The 10 mg vial, formerly labelled as containing 15 USP units, is now labelled as containing 15 000 IU. Therefore, 1.5-2 USP units is equivalent to 1500 IU, which is equivalent to 1 mg (by weight) or approximately 1.5 mg (by potency) (2). Furthermore, the nurses and pharmacists failed to discover the medication error.
In order not to repeat similar medical errors, the following measures were taken in our institution. Firstly, we optimized the hospital information system of prescription pre-checking to intercept the drug overdose. Secondly, lecture series about medication safety of bleomycin were held for doctors, nurses and pharmacists. On top of that, we call the attention to the consistency in nomenclature of bleomycin to prevent wrong-route administration incidents.