Indocyanine green (ICG) has long been used in various clinical settings including cardiac output measurements, liver function studies, and ophthalmological angiographic procedures.1–3 A microscopic-integrated ICG videography for intraoperative assessment of blood flow during aneurysm surgery was described and compared with standard angiographic techniques.4 The simplicity and timeliness of the information provided by this technique has led to increasing intraoperative use of ICG during a variety of neurovascular procedures. ICG is generally considered safe and has a very low incidence of complications.5 The reactions to ICG are well known to those specialists who regularly use ICG; however, this is not the case for most anesthesiologists. The occurrence of adverse reactions due to ICG administered during surgical procedures under general anesthesia has not been reported. We report a case of severe hypotension after ICG administration during general anesthesia for intracranial aneurysm clipping, and a similar episode that occurred during a surgical procedure for moyamoya disease.
We did not receive informed patient consent for publication of this article. Our IRB does not require consent for unique case reports that contain no identifying patient information. The cases occurred at Stanford Hospital (Stanford, CA), with the first case in 2010 and the second case in 2012.
FIRST CASE REPORT
A 69-year-old, 80-kg woman with an unruptured basilar tip aneurysm was scheduled for craniotomy and clipping of the aneurysm under mild hypothermia. Her medical history included gastrointestinal reflux disorder, hyperlipidemia, and migraine headache. She had no history of cardiac or respiratory illness, and baseline investigations including a 12-lead electrocardiogram (ECG) were normal. There was no history of any allergy to drugs, food, or contrast media. The patient was taking omeprazole, simvastatin, estradiol, medroxyprogesterone, cyclobenzaprine, and multivitamins. The patient received 2 mg IV midazolam before transport to the operating room. Anesthesia was induced with divided doses of fentanyl (total: 750 μg) and propofol (total: 100 mg). Rocuronium (50 mg) was given to facilitate tracheal intubation. Anesthesia was maintained with oxygen–nitrous oxide (1:1 ratio), isoflurane (end-tidal concentration = 0.6 %), and remifentanil infusion (0.05–0.1 μg/kg/min). Monitoring included a 20-gauge left radial artery catheter, a triple-lumen left subclavian central venous catheter, electroencephalography (EEG), and somatosensory evoked potentials. Baseline blood gas analysis with electrolytes and glucose measurements done at the commencement of surgery were within normal limits. After an uneventful surgical exposure and initial aneurysm clip placement, the surgeon requested ICG injection for video angiography. Five milligrams of ICG (IC-GREEN™, Akorn, Inc., Lake Forest, IL) diluted in 2 mL sterile water was injected through the central venous catheter. There was no change in the monitored variables after this initial injection. On the request of the surgeon, a second dose (5 mg) of ICG was injected centrally approximately 8 minutes after the initial dose. Within 2 minutes of the second injection her systolic blood pressure decreased 95 to 55 mm Hg with a proportionate decrease in the mean and diastolic blood pressures but without any compensatory change in the heart rate (Fig. 1). No change in the mean airway pressure, lung/chest wall compliance, end-tidal carbon dioxide (ETCO2), or hemoglobin oxygen saturation occurred during this hypotensive event. EEG and evoked potentials remained unaffected. Her chest was clear to auscultation. Since the patient was covered with surgical drapes, much of the skin could not be examined for rash, but the skin of the distal part of the extremities appeared normal. Treatment of this hypotensive event required two 5 mg doses of ephedrine and two 100 μg doses of phenylephrine given through the central venous catheter. Her arterial blood pressure recovered to the pre-ICG level within 10 minutes and remained stable thereafter. The rest of the intraoperative and postoperative periods were uneventful.
SECOND CASE REPORT
A 56-year-old, 60-kg woman with a history of bilateral watershed infarcts, secondary to moyamoya disease, scheduled for craniotomy and external-carotid to internal-carotid bypass under mild hypothermia. We routinely use mild hypothermia for its potential neuroprotective properties in neurovascular surgeries that involve placement of temporary arterial clips, or have the potential for such placement. Her medical history was significant for hyperlipidemia and a 30 pack-year smoking history. She had no history of cardiac disease or significant pulmonary disease. Her baseline laboratory studies and ECG were within normal limits. The patient’s allergies included simvastatin and contrast dye, which caused mild symptoms consisting of hives and urticaria. At home, she was prescribed clopidogrel and aspirin. Additionally, she took 50 mg prednisone and 50 mg diphenhydramine before receiving contrast for radiology studies.
The patient received 2 mg midazolam before entering the operating room. Anesthesia was induced with divided doses of fentanyl (500 μg) and propofol (100 mg). Rocuronium (50 mg) was used to aid tracheal intubation. Anesthesia was maintained with oxygen–nitrous oxide (1:1 ratio), isoflurane (end-tidal concentration = 0.5 %), and remifentanil infusion (0.05–0.1 μg /kg/min). Monitoring included a 20-gauge right radial artery catheter, a triple-lumen left subclavian central venous catheter, EEG, and somatosensory and motor evoked potentials. Baseline blood gas analysis with electrolytes and glucose measurements done at the commencement of surgery were within normal limits. The patient received 1 g ceftriaxone and 8 mg dexamethasone before incision. After uneventful dissection of the superficial temporal artery and subsequent anastomosis to an appropriate distal middle cerebral artery branch, the surgeon requested ICG injection for video angiography. Two and a half milligrams of ICG diluted in 10 mL sterile normal saline was injected through the central venous catheter. Within minutes, her arterial blood pressure decreased from 117/60 (mean arterial blood pressure [MAP] 84 mm Hg) to 86/45 (MAP 62 mm Hg). Heart rate was unchanged at 51 bpm. The blood pressure had been supported with a phenylephrine infusion at 0.1 μg/kg/min. No changes were made to the phenylephrine infusion rate before or during the hypotensive episode. No measurable change occurred to the mean airway pressure, lung/chest wall compliance, ETCO2, or oxygen saturation during this episode. EEG and evoked potentials remained unaffected. The skin on her distal extremities appeared normal. The patient had previously demonstrated a high sensitivity to vasopressors. As a result, 1 mg ephedrine was administered to restore hemodynamics. Within 5 minutes, her blood pressure was restored to 110/57 (MAP 79 mm Hg). At the time of the hypotensive event, the patient’s core temperature measured 33.2°C. The rest of the intraoperative and postoperative periods were uneventful. The patient returned 1 week later for surgery on the contralateral side. Again, she underwent general anesthesia with isoflurane (end-tidal concentration = 0.5%) and remifentanil infusion (0.05–0.1 μg/kg/min), except this time 50 μg/kg/min of propofol was substituted for nitrous oxide due to significant postoperative nausea after the first surgery. Once again, the patient’s blood pressure required a phenylephrine infusion of 0.1 μg/kg/min. However, this time difficulty with the surgical anastomosis required 3 injections of ICG. Each dose was 2.5 mg. No appreciable change to the patient’s blood pressure occurred with each ICG injection. The rest of the intraoperative period was uneventful.
ICG is a low molecular weight (775 g/mol), water soluble, and iodide-containing tricarbocyanine dye that fluoresces when exposed to infrared light. It rapidly binds to plasma proteins, has no significant organ or tissue uptake, does not undergo any enterohepatic circulation, is not metabolized, and is eliminated unchanged by billiary excretion, with a plasma half-life of approximately 3 to 4 minutes.6 Because of these favorable characteristics, it has been used in a wide variety of circumstances, in both diagnostic and research applications, for >50 years.5
With the advent of improved ICG videography, the intraoperative administration of ICG during general anesthesia is now routinely used for neurovascular cases such as aneurysm clippings and external-carotid to internal-carotid bypass for moyamoya disease7 (Fig. 2).
In both cases, our patients had been hemodynamically stable throughout the case preceding the ICG injections. Hypotension occurred rapidly after ICG injection. This event was not associated with significant blood loss, any change in the ECG morphology, or respiratory variables (lung/chest wall compliance, airway pressure, ETCO2 or oxygen saturation [SpO2]). In both cases, the anesthetic drug levels had been stable for hours with no change to drug infusions, and no other drug or agent was administered within 30 minutes preceding the hypotensive event. No surgical manipulations were occurring at the time of the events. It is unlikely that stable, mild hypothermia could have caused this transient episode of hypotension. These observations make other causes of hypotension including myocardial ischemia, tension pneumothorax, pulmonary embolism, drug reaction, anesthetic drugs, hypothermia, blood loss, and surgical manipulation unlikely.
A variety of adverse reactions including death have been reported after the use of ICG in patients with and without any previous exposure5,8–16 (Table 1). The most commonly reported adverse reactions were typically mild and included pruritus, shortness of breath, and nausea. Less commonly reported events include bronchospasm, laryngospasm, hypotension, and cardiac arrest. No adverse reaction to ICG administered during general anesthesia has been reported. This may be explained by the fact that major adverse reactions are quite rare and that the routine intra-anesthetic use of ICG is a recent development. In a study of 1923 ICG video angiography tests involving 1226 consecutive conscious patients for various ophthalmologic procedures, Hope-Ross et al.13 reported the incidence of mild, moderate, and severe reactions to be 0.15%, 0.2%, and 0.05%, respectively. But in this series, 2 of the patients had fainting attacks (1 of them was associated with severe hypotension) without any other signs or symptoms of allergic reaction. It is not clear whether these reactions were because of the ICG or a vasovagal response to the procedure itself. Severe syncopal attacks and cardiac arrests have been reported with the simple placement of IV needles.17,18 There are reports of severe reactions after ICG administration in patients who had previously received the dye without any problem. In the series of complications reported by Speich et al.,11 1 of the patients developed an anaphylactoid reaction to ICG after a previously uneventful injection. Okuda et al. were reported by Obana et al.14 to have had a case where the patient developed “shock” during IV ICG administration for a liver function study. This patient had previously undergone the same procedure 4 times without complication. Benya et al.5 have pointed out that in these previously exposed patients, it was not known whether they had experienced any mild reaction during their initial exposure to ICG. For a possible explanation for the absence of any signs or symptoms after the first injection of ICG, Bunya et al.5 suggest that the dose may have been subthreshold for an adverse effect or that mild signs or symptoms could have been masked by general anesthesia. The subsequent dose could have resulted in a cumulative ICG level that was severe enough to cause hypotension. A similar pattern of adverse reaction to ICG has been reported by Michie et al.8 who described the occurrence of adverse reactions after administration of ICG given to 4 uremic patients undergoing hemodialysis. One of their patients developed severe generalized pruritus, weakness, and diaphoresis after the first dose (5 mg), which progressed after the second dose (5 mg) to agitation and syncope. Another patient in their series had a similar reaction sequence while undergoing a cardiac output study. After the first injection of ICG (5 mg) the patient developed moderate hypotension, agitation, and headache which progressed to profound hypotension after the second injection (5 mg) given a few minutes later. In another series of patients with end-stage renal disease, 1 patient developed a sore throat during the initial injection (5 mg) but then became severely hypotensive after he received the second injection (5 mg) a few minutes later.10
The exact mechanisms responsible for adverse reactions after ICG administration are not known. ICG formulations contain 5% to 9% sodium iodide, which has the potential to bind with proteins to form a protein-hapten complex that may induce anaphylactic or anaphylactoid reactions. Adverse reactions noted in patients with iodide sensitivity have been attributed to the iodide component of the preparation. However, an iodide-free preparation of ICG has also been associated with the occurrence of severe adverse reactions;16 thus it has been argued that iodide sensitivity may not be a significant predictor of ICG sensitivity. Speich et al.11 have reported that the adverse effects of ICG are dose dependent with a much more frequent incidence when doses exceed 0.5 mg/kg. In a survey of complications associated with ICG angiography during ophthalmic procedures comprising the data from 2918 ICG injections, Obana et al.14 did not find any relationship between ICG dosage and frequency of hypotensive reaction, although the frequency of mild reactions did increase with increasing dosage. They reported an overall adverse reaction incidence of 0.103%, with hypotension occurring in 0.034% of cases. In a survey done by Takemoto as reported by Obana et al.,14 comprising 57,471 patients from 100 institutions in Japan adverse reactions occurred with frequency of 0.12%.
The studies by Michie et al.8 have suggested that adverse reactions to ICG are most likely due to a nonimmunologic histamine release rather than an antigen-antibody reaction. Bonte et al.16 reported that a patient with a negative skin prick test developed flushing of the prefrontal and periocular areas with local skin redness and swelling after subsequent intradermal injections of ICG. They suggested that milder ICG reactions may be the result of a nonimmunologic pseudoallergic phenomenon whereas more severe reactions are the result of a truly allergic (anaphylactic) reaction. In the survey reported by Obana et al.,14 1 of the patients who had a negative test to an extremely low dose of IV ICG, subsequently developed diaphoresis, tremor, and hypotension after IV administration of 75 mg ICG. They found that only 3 patients (0.103%) in 2918 tests had any reaction after IV low dose testing, while no patient reacted to subcutaneous testing. The efficacy of skin or IV testing of ICG before full dose administration has not been established. It is not clear why our patients had a reaction to ICG, or why a reaction did not occur every time. Since the mechanism is uncertain, and there is the possibility that a reaction can occur with any exposure to ICG, it is imperative that the anesthesiologist have awareness of this rare, but potentially significant drug reaction.
In conclusion, we describe 2 cases of significant intraoperative hypotension after ICG injection for video angiography under general anesthesia. Although we believe that ICG can be used safely in most surgical patients, a severe hypotensive reaction can occur after its use. Anesthesiologists and surgeons are increasingly likely to encounter or request the intraoperative administration of ICG, and they need to be aware of this potential for adverse reaction, particularly with the repeated doses. Anesthesia and other intraoperative conditions may mask the mild adverse reactions usually associated with ICG. Unfortunately, there appears to be no way to predict which patients are likely to develop severe reactions to ICG.
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