Abstract

Patent blue (PB) dye has been successfully used worldwide in breast and cervix surgeries with few complications. Interference of oxyhemoglobin saturation reading by pulse oximetry (SpO₂) and methemoglobinemia, from injection of PB dye, have rarely been reported in breast and cervix surgeries. We report here the first case of interference of SpO₂ reading, advent of methemoglobinemia, and blue urine from the use of PB dye, which occurred concurrently in a female undergoing bilateral modified radical mastectomy. The unexpected events might be a consequence of excessive administration of PB dye. We also reviewed the published discourses in literature on the adverse effects of PB dye.

Keywords

color: blue; coloring agents; methemoglobinemia; oximetry; patent blue dye; urine;

1. Introduction

Patent blue (PB) dye has been widely used for sentinel lymph node (SLN) mapping with rare complications in patients undergoing breast and cervix surgeries. Interference from the PB dye with the accuracy of pulse oximetry reading is a noteworthy adverse effect. PB dye may induce methemoglobinemia which could compromise a patient’s safety.¹ Moreover, anaphylaxis which gives rise to anaphylactic shock after injection of PB dye has been reported.2, 3 We came across a patient who simultaneously experienced sudden oxygen desaturation, blue urine, and positive methemoglobinemia following administration of PB dye for SLN mapping, during a bilateral modified radical mastectomy (MRM). We also reviewed literature on this rare incident.

2. Case report

A 77-year-old female (height = 149 cm; weight = 52 kg) who suffered from bilateral breast cancer, was scheduled for MRM. She reported a history of hypertension without taking any medication. Her systolic blood pressure was kept between 130 and 150 mmHg. She was advised to undergo the surgery under intravenous general anesthesia, with which she complied. Her ASA physical status was class 2. Upon surgery, electrocardiography (lead II), pulse oximetry and non-invasive blood pressure monitors were set for use before induction. Total intravenous anesthesia (TIVA) was made possible with intravenous fentanyl 2 μg/kg, dexamethasone 5 mg, and 2% lidocaine 1.5 mg/kg. Then, continuous infusion of propofol (Fresfol 1%), made possible by the Schnider kinetic model target controlled infusion (TCI) system, was begun with an effect-site concentration (Ce) of 4.0 μg/mL. When the patient lost consciousness, 0.6 mg/kg of IV rocuronium was given for tracheal intubation. Anesthesia was maintained with propofol through TCI, which was adjusted to keep the auditory evoked potential index (AAI) between 15 and 25. Fentanyl 50 μg IV, every 40 minutes, was prescribed for attenuating surgical pain. Ventilation was controlled with an O₂ flow rate of 0.3 L/min at an airway pressure adjusted to maintain the end-tidal carbon dioxide (EtCO₂) pressure of 35–45 mmHg. Rocuronium (10 mg, IV) was given for surgical relaxation under the guidance by train-of-four (TOF) peripheral nerve stimulation. No skin rash or vital sign changes occurred after induction. Five minutes after 2.5% patent blue V dye (Guerbet BP 57400, Roissy, France) (100 mg, 4 mL) was given subareolarly and subdermally for SLN mapping, the pulse oximeter (Datex Satelite; Instrumentrium Corp., Helsinki, Finland) displayed a fall of hemoglobin oxygen saturation (SaO₂) by the right big toe, from 100% to 89%. The connections of the anesthetic-circuit, location of the endotracheal tube, airway pressure and breathing sound were immediately carefully checked. However, no obvious problems were found. At this juncture, the hemodynamic variables had not been interfered with, and the pulse oximetry from the left big toe showed the same reading as from the right big toe. For confirmation, arterial blood was sampled from dorsalispedis for blood gas analysis and hemoglobin analysis using a co-oximeter (ABL520, Radiometer, Copenhagen, Denmark) at instant SpO₂ of 89%. Blood gas analysis revealed that the blood gas condition of the patient was essentially normal (FiO₂ = 1.0, pH = 7.45, PaCO₂ = 35.7 mmHg, PaO₂ = 544.7 mmHg, HC0₃^- = 24.8 mmol/L, SaO₂ = 99.9%), and hemoglobin analysis showed methemoglobin of 3.5%. Therefore, anaphylaxis was unlikely. Two hours after injection of the dye, blue urine from the urinary catheter was noted and the SaO₂ value gradually returned to close to the original value. Thereafter, it was maintained at 95%. Blue discoloration of skin over the patient’s face and neck was observed simultaneously. After successful completion of the surgical procedure, no edema of the larynx and airway was observed, and the patient was hemodynamically stable; the endotracheal tube was removed uneventfully. One day after the breast surgery, the skin discoloration over the face and neck and blue urine gradually faded and the hemoglobin analysis showed methemoglobin of 1.2%. The patient was discharged 3 days later without any sequelae.

3. Discussion

SLN mapping by injection of PB dye around a tumor is becoming an essential element in surgical strategies. From the point of view of anesthesia, the PB dye, which interferes with the accuracy of pulse oximetry reading, is a matter of concern. It is a serious problem, because it could jeopardize the patient’s safety during surgery.¹ Moreover, anaphylaxis from PB dye has been reported.² Many dyes used during operations may interfere with the work of a pulse oximeter, which uses two wavelengths (660 nm and 940 nm) to differentiate between oxygenated and deoxygenated hemoglobin. Dyes that can absorb the light of wavelengths near to either of the above, will potentially interfere with the readings of pulse oximetry.⁴ PB dye has a maximum absorbance of light at 640 nm and its presence in blood leads to increased absorbance of the light of 660 nm wavelength emitted by the pulse oximeter. Thus, falsely low pulse oximetric readings are caused.⁵ There are different reasons which might explain why PB dye injection caused blue face and neck, blue urine, methemoglobinemia and low pulse oximetric readings in this case. Firstly, when we retrospectively traced the event, it was found that the time of emergence of the low SpO₂ reading was within 5 minutes of injection of the PB dye. Secondly, the surgeons used excessive PB dye (total 4 mL, 100 mg) for SLN mapping. Thirdly, the drugs used in anesthesia that could cause methemoglobinemia are prilocaine, benzocaine, amyl nitrite, nitroglycerine, phenacetin, and sulfonamides.⁶ These drugs were not used in this surgical procedure, save PB dye. Finally, some PB dye might have been injected intravascularly during SLN mapping, which could have caused the lingering low SpO₂ reading, blue face and neck and blue urine. To the best of our knowledge, no other drug induced the blue face and neck and blue urine in this anesthesia or the surgical procedure, save PB dye.

In our patient, PB dye also led to methemoglobinemia, with a concentration greater than 3%, as determined by co-oximetry. Methemoglobin forms when the Fe ion in the hemoglobin is oxidized from ferrous (Fe²⁺) to ferric (Fe³⁺). In healthy adults, methemoglobin levels remain below 1%. Methemoglobin cannot carry oxygen, leading to tissue hypoxia. At methemoglobin levels below 15%, patients do not show clinical symptoms if the hemoglobin level is adequate and cardiac output is sufficiently preserved. When methemoglobin levels are 15–20%, black-brown blood and cyanosis occur. Higher levels (20–45%) cause headaches, somnolence, tachycardia, lethargy, and dizziness. When levels are ≥45%, respiratory difficulty, acidemia, arrhythmia, heart failure, and seizures occur. At levels >70%, there is a high risk of death.⁶ So far, there is no satisfactory solution for detecting methemoglobinemia due to blue dye.¹

Interference of SpO₂ readings from injection of PB dye has been reported by certain authors.1, 5, 7, 8, 9, 10, 11, 12, 13 Some presented their observations of methemoglobinemia in cervix and breast surgeries.1, 9, 10, 13 In the literature, there are no reports on interference of SpO₂ readings, methemoglobinemia, and blue urine concurrently occurring from administration of PB dye in a bilateral MRM. Our case differs from previous reports in that our patient received more PB dye than usual in her bilateral breast cancer. A salient and interesting feature in our case was that she displayed blue discoloration over the face and neck rather than over the trunk or four limbs,5, 9 which largely differed from other reported cases. We suspected that the mechanism by which her face and neck discolored might be due to an excessive intravascular injection of PB dye. Urinary excretion of PB after intradermal injection has been reported in the literature.¹⁴ This is consistent with what had happened in our patient. We summarized some published documents of adverse effects of PB dye in Table 1.

Table 1. Summary of known adverse effects of patent blue.

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In conclusion, intraoperative use of PB dye may interfere with pulse oximetry readings and measurement of methemoglobin. Blue urine may be observed simultaneously. Anesthesia providers should be aware of this potential risk and be capable of dealing with it. Furthermore, surgeons should beware of excessively dosing PB dye, should avoid intravascular injection and should adequately communicate with anesthetists when they are performing SLN mapping. It is advisable to monitor arterial PO₂ in these patients to ensure appropriate levels of oxygenation. However, there is no satisfactory solution for early detection of methemoglobinemia due to PB dye. This bottleneck merits further study for a solution.