Case ReportSevere Hypotension Hypoxia and SubcutaneousErythema Induced by Indigo Carmine Administrationduring Open Prostatectomy
Koichiro Nandate1 and Bryan B Voelzke2
1Department of Anesthesiology and Pain Medicine Harborview Medical Center University of Washington 325 Ninth AvenuePO Box 359724 Seattle WA 98104-2499 USA2Department of Urology Harborview Medical Center University of Washington 325 Ninth Avenue PO Box 359868 SeattleWA 98104-2499 USA
Correspondence should be addressed to Koichiro Nandate knandateuwedu
Received 28 April 2016 Accepted 4 July 2016
Academic Editor Giorgio Carmignani
Copyright copy 2016 K Nandate and B B VoelzkeThis is an open access article distributed under the Creative CommonsAttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited
Indigo carmine (also known as 551015840-indigodisulfonic acid sodium salt or indigotine) is a blue dye that is administered intravenouslyto examine the urinary tract and usually is biologically safe and inert Indigo carmine rarelymay cause adverse reactionsWe treateda 66-year-old man who had general anesthesia and radical retropubic prostatectomy for prostate cancer He had a previous historyof allergy to bee sting with nausea vomiting and dizziness Within 1 minute after injection of indigo carmine for evaluation of theureters the patient developed hypotension to 40mmHg severe hypoxia (the value of SpO2 (peripheral capillary oxygen saturation)was 75 on 40 inspired oxygen concentration) poor air movement and bilateral diffuse wheezing on auscultation and markedsubcutaneous erythema at the upper extremities After treatment with 100 oxygen epinephrine (total 15mg) hydrocortisone(100mg) diphenhydramine (50mg) albuterol nebulizer (0083) and continuous infusion of epinephrine (015 120583gkgmin) thevital signs became stable and he recovered completely In summary indigo carmine rarely may cause life-threatening anaphylacticor anaphylactoid reaction that may necessitate rapid treatment to stabilize cardiovascular hemodynamic and pulmonary function
1 Introduction
Indigo carmine (also known as 551015840-indigodisulfonic acidsodium salt or indigotine) is a blue dye that has been used sincethe early nineteenth century to localize the ureteral orificeand identify severed ureters and urinary fistulas [1] Althoughusually safe for clinical use indigo carmine occasionallymay induce severe hypertension and bradycardia possiblyby stimulation of alpha receptors Hypertension after indigocarmine injectionmay occur possibly because of the commonchemical structure between indigo carmine and the neu-rotransmitter serotonin (5-hydroxytryptamine) Serotonindirectly causes vasoconstriction and positive inotropic effectsmediated through the alpha-adrenergic receptor Thereforeadministration of indigo carmine may increase total periph-eral resistance resulting in elevated blood pressure followedby a bradycardic reflex [2ndash4] In addition catastrophic
adverse reactions after intravenous administration of indigocarmine have been reported including critical hypotensionand anaphylactic reaction but the pathologic mechanism isunknown [5ndash7]
We treated a patient who had anaphylactic reaction afteran intravenous injection of indigo carmine during radicalretropubic prostatectomy This reaction is not new and hasbeen already reported However it is worthwhile beingreported again to warn anesthesiologists urologists andgynecologists of life-threatening reaction by indigo carmine
2 Case Presentation
A66-year-oldman presentedwith prostate cancer He did nothave either anymajor medical problems including cardiovas-cular or respiratory diseases history of surgical procedure
Hindawi Publishing CorporationCase Reports in UrologyVolume 2016 Article ID 5237387 3 pageshttpdxdoiorg10115520165237387
2 Case Reports in Urology
or exposure of indigo carmine He had a history of allergicreaction to bee stings associated with nausea vomitingand dizziness which had been treated in the emergencydepartment He was scheduled to undergo elective radicalretropubic prostatectomy with pelvic lymph node dissectionunder general anesthesia
After induction of general anesthesia with midazolamfentanyl and propofol muscle relaxation was achieved withrocuronium and the trachea was intubated An arterial lineand 2 large intravenous catheters were placed according toour routine for patients undergoing radical prostatectomyNo unusual events were noted during general anesthesiainduction and preparation for the surgery
There were no issues during the operation until thesurgical team requested the anesthesia team to give 5mlof indigo carmine (08 sodium indigotindisulfonate USPsolution America Regent Company Shirley NY USA) intra-venously to ensure that neither ureter was injured duringprostatectomy By this time estimated surgical blood loss was1500mL and the patient had been given 2 units of red bloodcells 3500mL crystalloid and low doses of vasopressors(phenylephrine 01microgramkgmin) to stabilize the vitalsigns Hematocrit was 31Within 1 minute after administra-tion of indigo carmine the vital signs deteriorated suddenlySystolic blood pressure dropped from 110 to 40mmHgbut the heart rate remained at 60 beatsmin The patientbecame hypoxic (oxygen saturation decreased from 99 to75 on 40 inspired oxygen concentration) Auscultationshowed poor air movement and bilateral diffuse wheezingMarked cutaneous erythema was observed at the upperextremities
The anesthesia team requested the surgical team tosuspend surgery temporarily until the patient became stableThe patient immediately was given 100oxygen epinephrine(total 15mg) hydrocortisone (100mg) diphenhydramine(50mg) albuterol nebulizer (0083) and continuous infu-sion of epinephrine (015 120583gkgmin) and the vital signsbecame stable Emergency transesophageal echocardiogra-phy was performed and there was no evidence of myocardialinfarction or pulmonary embolism The diagnosis of ana-phylactic reaction due to indigo carmine was made on thebasis of the sudden decrease in blood pressure respiratoryproblems and subcutaneous lesions immediately after theadministration of indigo carmine
After the vital signs were stabilized the surgery wasresumed and completed uneventfully The patient remainedon a continuous infusion of epinephrine (01 120583gkgmin) andwas transferred to the surgical critical care unit for closemonitoring without emerging from general anesthesia Thepatient was released from the critical care unit to the wardafter 48 hours and discharged from the hospital on post-operative day 7 without any further complications Duringthe patientrsquos stay in the hospital we seriously consideredinvestigating the serum activity of tryptase histamine andimmunoglobulin E but could not achieve the patient and thefamily agreement
3 Discussion
The present patient had an anaphylactic reaction man-ifested by hypotension hypoxia bilateral wheezing andsubcutaneous erythema after intravenous injection of indigocarmine
In a previous report of 4 patients who were treated within6 weeks for severe hypotension none of the patients hada history of allergy previous exposure to indigo carmineor anaphylactic signs such as cutaneous erythema laryngealedema or bronchospasm the authors were unable to linkthe hypotensive reaction to an anaphylactic reaction andwarned about the possibility of drug lot impurity [5] Weexamined the lot impurity of indigo carmine which we gaveto the patient but it was far before the expired date In twoother previous case reports themarked hypotensive responsenoted immediately after intravenous administration of indigocarmine was due to anaphylactic reaction [6 7] In one ofthese case reports the patient had the complete spectrum ofanaphylaxis but did not have a history of allergies or previousexposure of indigo carmine and the authors suggested thatindigo carmine directlymay have triggered histamine releaseconsistent with an anaphylactoid reaction associated withsevere hypotension bronchospasm and urticaria [6] In theother case report the patient did not have a previous historyof allergy or skin symptoms but he had severe hypotensionand hypoxia with wheezing that progressed to cardiac arrest[7]
The present patient had a history of bee sting allergyand he developed hypotension wheezing and subcutaneouserythema within several minutes after the administrationof indigo carmine It may be difficult to prove whether hehad a life-threatening anaphylactic reaction in response toindigo carmine The only proven method to evaluate thepatientrsquos allergic response to indigo carmine is skin testingWe seriously considered performing the skin testing but thepatient refusedTherefore anaphylactic reaction usually maybe diagnosed on the basis of a previous history of allergy andthe clinical presentationThe clinical condition of the presentpatient satisfied the clinical criteria for a life-threateningreaction due to anaphylactic response by the World AllergyOrganization [8]
In summary indigo carmine may be used in routineclinical practice in urology or gynecology because of thesafety profile of the dye compared with methylene blue [9]However physicians should be aware that indigo carminerarely may cause a major life-threatening anaphylactic reac-tion
Competing Interests
The authors declare that there are no competing interestsregarding the publication of this paper
References
[1] W W Lacy C Ugaz and E V Newman ldquoThe use of indigocarmine for dye dilution curvesrdquo Circulation Research vol 3no 6 pp 570ndash574 1955
Case Reports in Urology 3
[2] D L Jeffords P H Lance and W C Dewolf ldquoSevere hyper-tensive reaction to indigo carminerdquo Urology vol 9 no 2 pp180ndash181 1977
[3] T Y Ng T D Datta and B I Kirimli ldquoReaction to indigocarminerdquo Journal of Urology vol 116 no 1 pp 132ndash133 1976
[4] T Harioka H Mori and K Mori ldquoHypertensive reaction toindigo carmine during transurethral resection of a bladdertumorrdquo Anesthesia amp Analgesia vol 66 no 10 p 1049 1987
[5] Y Shir and SN Raja ldquoIndigo carmine-induced severe hypoten-sion in patients undergoing radical prostatectomyrdquoAnesthesiol-ogy vol 79 no 2 pp 378ndash381 1993
[6] J Naitoh and B M Fox ldquoSevere hypotension bronchospasmand urticaria from intravenous indigo carminerdquo Urology vol44 no 2 pp 271ndash272 1994
[7] A E Gousse M H Safir S Madjar F Ziadlourad and S RazldquoLife-threatening anaphylactoid reaction associatedwith indigocarmine intravenous injectionrdquo Urology vol 56 article 5082000
[8] F E R Simons L R F Ardusso M B Bilo et al ldquoWorld allergyorganization guidelines for the assessment and management ofanaphylaxisrdquo World Allergy Organization Journal vol 4 no 2pp 13ndash37 2011
[9] M M Mahadevan G A Weitzman S Hogan S Breckinridgeand M M Miller ldquoMethylene blue but not indigo carmine istoxic to human luteal cells in vitrordquoReproductive Toxicology vol7 no 6 pp 631ndash633 1993
or exposure of indigo carmine He had a history of allergicreaction to bee stings associated with nausea vomitingand dizziness which had been treated in the emergencydepartment He was scheduled to undergo elective radicalretropubic prostatectomy with pelvic lymph node dissectionunder general anesthesia
After induction of general anesthesia with midazolamfentanyl and propofol muscle relaxation was achieved withrocuronium and the trachea was intubated An arterial lineand 2 large intravenous catheters were placed according toour routine for patients undergoing radical prostatectomyNo unusual events were noted during general anesthesiainduction and preparation for the surgery
There were no issues during the operation until thesurgical team requested the anesthesia team to give 5mlof indigo carmine (08 sodium indigotindisulfonate USPsolution America Regent Company Shirley NY USA) intra-venously to ensure that neither ureter was injured duringprostatectomy By this time estimated surgical blood loss was1500mL and the patient had been given 2 units of red bloodcells 3500mL crystalloid and low doses of vasopressors(phenylephrine 01microgramkgmin) to stabilize the vitalsigns Hematocrit was 31Within 1 minute after administra-tion of indigo carmine the vital signs deteriorated suddenlySystolic blood pressure dropped from 110 to 40mmHgbut the heart rate remained at 60 beatsmin The patientbecame hypoxic (oxygen saturation decreased from 99 to75 on 40 inspired oxygen concentration) Auscultationshowed poor air movement and bilateral diffuse wheezingMarked cutaneous erythema was observed at the upperextremities
The anesthesia team requested the surgical team tosuspend surgery temporarily until the patient became stableThe patient immediately was given 100oxygen epinephrine(total 15mg) hydrocortisone (100mg) diphenhydramine(50mg) albuterol nebulizer (0083) and continuous infu-sion of epinephrine (015 120583gkgmin) and the vital signsbecame stable Emergency transesophageal echocardiogra-phy was performed and there was no evidence of myocardialinfarction or pulmonary embolism The diagnosis of ana-phylactic reaction due to indigo carmine was made on thebasis of the sudden decrease in blood pressure respiratoryproblems and subcutaneous lesions immediately after theadministration of indigo carmine
After the vital signs were stabilized the surgery wasresumed and completed uneventfully The patient remainedon a continuous infusion of epinephrine (01 120583gkgmin) andwas transferred to the surgical critical care unit for closemonitoring without emerging from general anesthesia Thepatient was released from the critical care unit to the wardafter 48 hours and discharged from the hospital on post-operative day 7 without any further complications Duringthe patientrsquos stay in the hospital we seriously consideredinvestigating the serum activity of tryptase histamine andimmunoglobulin E but could not achieve the patient and thefamily agreement
3 Discussion
The present patient had an anaphylactic reaction man-ifested by hypotension hypoxia bilateral wheezing andsubcutaneous erythema after intravenous injection of indigocarmine
In a previous report of 4 patients who were treated within6 weeks for severe hypotension none of the patients hada history of allergy previous exposure to indigo carmineor anaphylactic signs such as cutaneous erythema laryngealedema or bronchospasm the authors were unable to linkthe hypotensive reaction to an anaphylactic reaction andwarned about the possibility of drug lot impurity [5] Weexamined the lot impurity of indigo carmine which we gaveto the patient but it was far before the expired date In twoother previous case reports themarked hypotensive responsenoted immediately after intravenous administration of indigocarmine was due to anaphylactic reaction [6 7] In one ofthese case reports the patient had the complete spectrum ofanaphylaxis but did not have a history of allergies or previousexposure of indigo carmine and the authors suggested thatindigo carmine directlymay have triggered histamine releaseconsistent with an anaphylactoid reaction associated withsevere hypotension bronchospasm and urticaria [6] In theother case report the patient did not have a previous historyof allergy or skin symptoms but he had severe hypotensionand hypoxia with wheezing that progressed to cardiac arrest[7]
The present patient had a history of bee sting allergyand he developed hypotension wheezing and subcutaneouserythema within several minutes after the administrationof indigo carmine It may be difficult to prove whether hehad a life-threatening anaphylactic reaction in response toindigo carmine The only proven method to evaluate thepatientrsquos allergic response to indigo carmine is skin testingWe seriously considered performing the skin testing but thepatient refusedTherefore anaphylactic reaction usually maybe diagnosed on the basis of a previous history of allergy andthe clinical presentationThe clinical condition of the presentpatient satisfied the clinical criteria for a life-threateningreaction due to anaphylactic response by the World AllergyOrganization [8]
In summary indigo carmine may be used in routineclinical practice in urology or gynecology because of thesafety profile of the dye compared with methylene blue [9]However physicians should be aware that indigo carminerarely may cause a major life-threatening anaphylactic reac-tion
Competing Interests
The authors declare that there are no competing interestsregarding the publication of this paper
References
[1] W W Lacy C Ugaz and E V Newman ldquoThe use of indigocarmine for dye dilution curvesrdquo Circulation Research vol 3no 6 pp 570ndash574 1955
Case Reports in Urology 3
[2] D L Jeffords P H Lance and W C Dewolf ldquoSevere hyper-tensive reaction to indigo carminerdquo Urology vol 9 no 2 pp180ndash181 1977
[3] T Y Ng T D Datta and B I Kirimli ldquoReaction to indigocarminerdquo Journal of Urology vol 116 no 1 pp 132ndash133 1976
[4] T Harioka H Mori and K Mori ldquoHypertensive reaction toindigo carmine during transurethral resection of a bladdertumorrdquo Anesthesia amp Analgesia vol 66 no 10 p 1049 1987
[5] Y Shir and SN Raja ldquoIndigo carmine-induced severe hypoten-sion in patients undergoing radical prostatectomyrdquoAnesthesiol-ogy vol 79 no 2 pp 378ndash381 1993
[6] J Naitoh and B M Fox ldquoSevere hypotension bronchospasmand urticaria from intravenous indigo carminerdquo Urology vol44 no 2 pp 271ndash272 1994
[7] A E Gousse M H Safir S Madjar F Ziadlourad and S RazldquoLife-threatening anaphylactoid reaction associatedwith indigocarmine intravenous injectionrdquo Urology vol 56 article 5082000
[8] F E R Simons L R F Ardusso M B Bilo et al ldquoWorld allergyorganization guidelines for the assessment and management ofanaphylaxisrdquo World Allergy Organization Journal vol 4 no 2pp 13ndash37 2011
[9] M M Mahadevan G A Weitzman S Hogan S Breckinridgeand M M Miller ldquoMethylene blue but not indigo carmine istoxic to human luteal cells in vitrordquoReproductive Toxicology vol7 no 6 pp 631ndash633 1993
[2] D L Jeffords P H Lance and W C Dewolf ldquoSevere hyper-tensive reaction to indigo carminerdquo Urology vol 9 no 2 pp180ndash181 1977
[3] T Y Ng T D Datta and B I Kirimli ldquoReaction to indigocarminerdquo Journal of Urology vol 116 no 1 pp 132ndash133 1976
[4] T Harioka H Mori and K Mori ldquoHypertensive reaction toindigo carmine during transurethral resection of a bladdertumorrdquo Anesthesia amp Analgesia vol 66 no 10 p 1049 1987
[5] Y Shir and SN Raja ldquoIndigo carmine-induced severe hypoten-sion in patients undergoing radical prostatectomyrdquoAnesthesiol-ogy vol 79 no 2 pp 378ndash381 1993
[6] J Naitoh and B M Fox ldquoSevere hypotension bronchospasmand urticaria from intravenous indigo carminerdquo Urology vol44 no 2 pp 271ndash272 1994
[7] A E Gousse M H Safir S Madjar F Ziadlourad and S RazldquoLife-threatening anaphylactoid reaction associatedwith indigocarmine intravenous injectionrdquo Urology vol 56 article 5082000
[8] F E R Simons L R F Ardusso M B Bilo et al ldquoWorld allergyorganization guidelines for the assessment and management ofanaphylaxisrdquo World Allergy Organization Journal vol 4 no 2pp 13ndash37 2011
[9] M M Mahadevan G A Weitzman S Hogan S Breckinridgeand M M Miller ldquoMethylene blue but not indigo carmine istoxic to human luteal cells in vitrordquoReproductive Toxicology vol7 no 6 pp 631ndash633 1993
