a 69-year - old woman with a transitional cell carcinoma in the renal pelvis underwent a laparoscopic nephroureterectomy .
the patient had a history of hypertension , and had no history of allergy or previous exposure to indigo carmine .
anesthesia was induced with thiopental 400 mg and vecuronium 10 mg , and maintained with 2% sevoflurane after tracheal intubation .
a 20-gauge catheter was inserted into her left radial artery to monitor continuous arterial pressure . during the operation ,
the patient 's vital signs were stable , with blood pressure ( bp ) 100 - 130/70 - 95 mmhg , heart rate 62 - 88 bpm , and spo2 98 - 100% .
two hundred minutes after the induction of anesthesia , she received a bolus injection of 40 mg indigo carmine ( sodium indigotindisulfonate ; korea united pharm . ,
one minute later , her bp suddenly decreased from 120/85 mmhg to 50/30 mmhg , but heart rate remained at 80 - 90 bpm .
there was no evidence of massive blood loss or electrocardiographic changes prior to the hypotensive episode , and there were no skin rashes , angioedema , or any sign of bronchospasm during the hypotensive episode .
she was immediately administered ephedrine 20 mg and phenylephrine 0.3 mg , which restored her bp to 120/75 mmhg .
ten days later , a 73-year - old man who underwent a radical retropubic prostatectomy under general anesthesia experienced severe hypotension after administration of indigo carmine .
ninety minutes after anesthesia induction , he received an injection of 40 mg indigo carmine , and then bp decreased from 110/65 mmhg to 60/35 mmhg without any skin rash or urticaria .
he was administered ephedrine 40 mg and phenylephrine 0.3 mg , which restored his bp to the pre - indigo carmine level .
following these adverse events , we decided to dilute indigo carmine in normal saline and to administer it slowly over five minutes .
the patient had a drug allergy to saridon - a ( roche korea , seoul , korea ) , which contains acetaminophen , anhydrous caffeine , and isopropylantipyrine .
two hundred minutes after induction , she was administered 40 mg indigo carmine diluted in 20 ml of saline over five minutes . a sudden drop in bp
was observed ; from 125/72 mmhg to 45/30 mmhg , and injection of ephedrine 30 mg restored her bp within three minutes . following this third episode of hypotension , we suspected a manufacturing error and checked the lot number of indigo carmine .
we discarded all of the indigo carmine with lot number 001 , used in our third patient , and decided to use another lot number , 002 .
two weeks later , two additional patients experienced severe hypotension following administration of indigo carmine .
the first , a 68-year - old man , underwent transurethral bladder tumor resection under general anesthesia .
five minutes later , his bp dropped from 128/75 mmhg to 65/43 mmhg , and injection of phenylephrine 0.3 mg restored his bp .
another patient was a 77-year - old man who underwent transurethral resection of the bladder .
spinal anesthesia was induced with hyperbaric bupivacaine 11 mg at the l4 - 5 level .
after forty - five minutes , he received indigo carmine , and then his bp decreased from 110/65 mmhg to 60/35 mmhg .
after administration of 15 mg ephedrine , his vital signs remained stable throughout the rest of the procedure .
the company 's director informed us that lot numbers 001 and 002 were manufactured with the same raw materials , and the manufacturer provided us with indigo carmine of lot number 906 , which to date has not been associated with any such adverse events .
the raw materials used to manufacture indigo carmines were analyzed , including their crystalline status , thermo - physiochemical properties and particle size distribution , all of which are required analytical criteria for drug manufacture , as determined by the korea food and drug administration .
a comparison of the raw materials used to manufacture lot numbers 002 and 906 showed no differences .
further analysis of the raw materials by liquid chromatography ( lc ) and mass spectrometry ( ms ) showed that , when compared with lot number 906 , lot number 002 had a separated peak on lc and an abnormal fragment peak on ms , suggesting the presence of impurities ( fig .
all indigo carmine numbered as 001 and 002 were recalled and its usage was restricted .
the term anaphylaxis has been used for all types of acute life - threatening , generalized hypersensitivity reactions due to abnormal sensitivity to a triggering agent .
although indigo carmine has no known activity in the human body , it has been found to directly activate alpha - adrenergic receptors , which may lead to reflex bradycardia and/or hypertension .
hypotension after indigo carmine administration is an unexpected adverse effect and has been reported in fewer than 10 patients over 80 years of use .
sudden , severe hypotension after indigo carmine administration was first reported in a series of four patients with no known drug allergies who underwent radical prostatectomy under epidural anesthesia . due to the temporal association between indigo carmine injection and the hemodynamic change ,
usually , indigo carmine might cause both stimulant and depressant effects simultaneously , however , those cases could be induced by unopposed depressant component under sympathetic blockade .
severe hypotension , bronchospasm and urticaria after administration of indigo carmine were observed in a patient under general anesthesia .
that patient , who was undergoing transurethral resection of a bladder tumor , manifested the complete spectrum of anaphylaxis five minutes after injection of indigo carmine , including hemodynamic collapse , cutaneous changes , laryngeal edema and bronchospasm . due to a lack of prior allergies or prior exposure to indigo carmine
, their case was thought to be caused by histamine release such as an anaphylactoid reaction .
life - threatening adverse reaction associated with indigo carmine presenting as even asystole was reported .
severe hypotension , bradycardia , hypoxia were observed after indigo carmine injection , and then the patient became asystolic .
following chest compression and intraaortic balloon pump support , the patient 's blood pressure was stabilized .
the patient 's cardiac arrest event was believed to be due to an anaphylactoid reaction in response to indigo carmine .
a diagnosis of anaphylaxis requires evidence of involvement of three or more organs and the detection of specific ige or a positive skin test to the alleged agent .
however , since these reports did not verify these findings , it would be reasonable to diagnose these events as idiosyncratic reactions , including anaphylaxis . compared with the previous reports ,
our patients had somewhat bizarre clinical manifestations . during the period described for all five patients , we used lot numbers 001 and 002 of indigo carmine on 15 patients .
hypotensive episodes in some of the other patients may have been overlooked because their symptoms were mild and they recovered immediately . in all five patients described above , saline replacement was adequate and there was no massive blood loss .
there were no symptoms or signs suggesting anaphylactoid reactions , such as cutaneous changes or wheezing .
two patients who experienced hypotensive episodes were tested for hypersensitivity to indigo carmine of lot number 002 by skin prick tests and intradermal skin tests , and both were negative . although a negative response to a suspected agent is unreliable in ruling out drug hypersensitivity , the clinical manifestations of these patients indicate that drug hypersensitivity or anaphylaxis was unlikely causes .
we focused on the five patients who experienced hypotension serially within a one month period , and suspected that flaws in production were responsible for these adverse reactions . during the manufacturing process
, indigo carmine molecules may be fragmented by accelerated electron beams , and these fragmented ions can be classified by their mass to charge ( m / z ) ratios on ms ( fig .
analysis of the raw materials by lc / ms showed an abnormal peak in lot number 002 that was not present in lot number 906 .
this additional peak contained abnormal amounts of fragmented ions , with m / z = 340 , which had not been filtered out during the manufacturing process .
raw materials , reagents , and degradation during manufacture and storage are all possible sources of impurities in drugs
. these impure drugs may cause various adverse reactions , regardless of their pharmacological effects . determining the lot number of the drug may be helpful in investigating the causes of adverse reactions .
usually , physicians tend to ignore or miss symptoms and signs if they are not critical .
however , practitioners should always pay attention when using drugs and prevent further adverse drug reactions by meticulous monitoring and prompt reporting .
 indigo carmine has been used for eight decades with few adverse effects . 
 several of our patients , however , experienced severe hypotensive episodes after indigo carmine administration within a period of one month . 
 analysis of the raw materials used to formulate the preparation of indigo carmine we used showed that they contained impurities . 
 following recall of these impure materials , none of our patients experienced further hypotensive episodes . 