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.