(Chest. 2004;125:793-795.)
© 2004
American College of Chest Physicians
Toxicity of Food Drug and Cosmetic Blue No. 1 Dye in Critically Ill Patients*
Maria R. Lucarelli, MD;
Mary Beth Shirk, PharmD;
Mark W. Julian, MS and
Elliott D. Crouser, MD
* From the Division of Pulmonary and Critical Care Medicine (Dr. Lucarelli), Department of Pharmacy (Dr. Shirk), The Dorothy M. Davis Heart & Lung Research Institute (Mr. Julian and Dr. Crouser), The Ohio State University Medical Center, Columbus, OH.
Correspondence to: Elliott D. Crouser, MD, Division of Pulmonary and Critical Care Medicine, The Ohio State University Medical Center, 201F Dorothy M. Davis Heart & Lung Research Institute, 473 West Twelfth Ave, Columbus, OH 43210-1252; e-mail: crouser-1{at}medctr.osu.edu
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Abstract
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Food Drug and Cosmetic Blue No. 1 dye (FD&C Blue No. 1) is commonly added to enteral nutrition formulations in order to facilitate the detection of gastric aspirate in tracheal secretions of critically ill patients. However, reports of systemic blue dye absorption and associated adverse outcomes are emerging. We report two cases of abnormal systemic absorption of FD&C Blue No. 1 in critically ill patients who subsequently died of refractory shock and metabolic acidosis. Risk factors and mechanisms of FD&C Blue No. 1 toxicity are discussed, and alternate approaches to gastric aspiration detection in critically ill patients are considered.
Key Words: FD&C Blue No. 1 • blue dye • gastric aspiration • lactic acidosis • mechanical ventilation • mitochondria • sepsis • shock
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Introduction
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The addition of dye, particularly Food Drug and Cosmetic Blue No. 1 (FD&C Blue No. 1), to enteral feedings is commonly employed for the detection of aspiration in the critical care setting.1
However, evidence suggests that this dye is potentially toxic under some clinical conditions. In contrast to early investigations demonstrating limited absorption of FD&C Blue No. 1 when administered to healthy animals,2
significant absorption of the dye has been reported in critically ill patients,3
presumably due to disruption of the integrity of the intestinal barrier. This is a significant concern given the documented cytotoxicity of the dye in vitro,4
5
and could account for adverse outcomes documented in association with blue dye absorption.3
6
7
8
Thus, the utility of this dye for the detection of aspiration events must be considered in context of its potential side effects in critically ill patients.
Here we report two cases of systemic absorption of FD&C Blue No. 1 in patients with sepsis, both of whom died of refractory shock and metabolic acidosis. Blue dye absorption was confirmed quantitatively using spectral analyses of body fluids, a technique that may prove useful in screening for absorption of the dye. The discussion will include a review of the literature relevant to the toxicity of FD&C Blue No. 1 when used to detect aspiration in critically ill patients and will present alternative approaches.
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Case Reports
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Case 1
A 57-year-old man with a history of cadaveric renal transplant was transferred from a nearby hospital with Gram-negative sepsis related to an infected vascular catheter. Despite removal of the catheter and treatment with appropriate antibiotics, the patient exhibited persistent fever, leukocytosis, tachycardia and hypotension, and progressive inflammation, pain, and palpable crepitus in the left hand. Radiographic evaluation of the left arm revealed gas in the soft tissues of the arm consistent with necrotizing fasciitis. The patient was urgently taken to the operating room for surgical debridement and amputation at the left wrist. His condition was further complicated by acute renal failure requiring hemodialysis and respiratory failure.
His condition gradually improved, but he required tracheostomy for failure to wean from the ventilator. Continuous enteral feedings were initiated, but high gastric residual volumes were observed and he was judged to be at high risk for aspiration. As was customary in the surgical ICU, 100 mg of FD&C Blue No.1 was added to 1,000 mL of enteral formula in order to facilitate the detection of gastric aspiration events. The total dose of FD&C Blue No. 1 received did not exceed 0.7 mg/kg/d. On hospital day 32, a bluish discoloration of both the skin and dialysis ultrafiltrate was noted. Spectrophotometric analysis of serum (Fig 1
) and dialysate (not shown) confirmed the presence of FD&C Blue No.1. Enteral feedings were immediately discontinued, but his condition rapidly deteriorated. Despite aggressive volume resuscitation and maximal vasopressor therapy, the patient experienced lactic (metabolic) acidosis, respiratory failure, and refractory shock (Table 1
). No source of infection was identified. Multiple organ failures developed, and the patient died on hospital day 35.
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Figure 1.. Blue dye measurements in blood samples from septic patients. A linear standard curve is derived from the absorbance characteristics (629 nm) of known concentrations of FD&C Blue No. 1. Actual absorbance spectra of each standard sample are depicted in the inset. The concentrations of blue dye in plasma samples derived from case 1 (red "X") and case 2 (green "X") fell between 4 µg/mL and 10 µg/mL and exhibit a light green appearance in a serum sample (arrow). AU = arbitrary units.
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Case 2
A 78-year-old woman was admitted to our institution with symptomatic atherosclerotic coronary artery disease, acute right heart failure, and tricuspid regurgitation. She subsequently underwent coronary artery bypass and repair of the tricuspid valve. Her postoperative course was complicated by acute renal failure, which was managed with hemodialysis. After initial improvement in her condition, on hospital day 28 she acquired respiratory failure and shock secondary to pneumonia.
Her condition subsequently improved on appropriate antibiotics, but she was slow to wean from ventilator support and her gastric motility was impaired. As the patient was considered to be at high risk for aspiration, FD&C Blue No. 1 was added to the enteral formula, and pulmonary secretions were monitored. The dose of FD&C Blue No. 1 did not exceed 2 mg/kg/d. On hospital day 44, her hemodialysate was noted to be green in color. No skin discoloration was appreciated. Spectrophotometric analysis of serum and dialysate (Fig 1)
confirmed the presence of FD&C Blue No. 1. Enteral feedings were discontinued; however, lactic acidosis and refractory shock developed (Table 1)
, leading to death within 24 h. No obvious source of infection was identified in the perimortem period.
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Discussion
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Bedside techniques for detecting aspiration in patients receiving mechanical ventilation and enteral feedings are commonly employed in critical care units. The addition of various amounts of FD&C Blue No. 1 to enteral formulas is the technique most commonly employed. Currently, no consensus exists for the administration of the dye, and recommendations vary considerably, ranging from routine additions of 5 mL (100 mg) of dye per 250 mL of enteral formula,9
to dose titrations to achieve perceptible discoloration of feedings without affecting the color of the patient’s stool.10
The lack of regulation or conformity relating to the use of the dye is likely a reflection of the perceived safety profile of the dye, which is based on studies showing minimal absorption11
and no toxicity at doses up to 12 mg/kg/d in healthy animals (ie, the maximum enteral dose recommended by the US Food and Drug Administration).2
However, these cases and other reports3
6
7
cast serious doubt on the safety of FD&C Blue No. 1, and other food dyes, in critically ill patients and patients with impaired GI barrier function.8
The full extent of the problem is unclear and is obscured by the poor outcome of septic patients in general and a lack of awareness of the potential for dye-related toxicity.
There is reason to incriminate FD&C Blue No. 1 as a potential cause of metabolic derangement or even death in patients with sepsis. In vitro analyses demonstrate dose-dependent inhibition of mitochondrial oxidative phosphorylation by FD&C Blue No. 1,4
an effect that would, like other mitochondrial poisons (eg, cyanide), lead to increased reliance on anaerobic metabolism for the formation of adenosine triphosphate required for normal organ function. As such, systemic absorption of the dye is expected to cause metabolic (lactic) acidosis and undermine the function of vital organs. It follows that the toxic effects of FD&C Blue No. 1 would be amplified in the context of an underlying metabolic derangement, such as has been observed during sepsis.12
This hypothesis may explain the sudden, fatal decompensation of the septic patients presented herein.
Given the observed propensity for dye absorption in the critically ill and the potentially lethal implications, alternative approaches should be considered and glucose measurement in tracheal aspirates appears the most promising. This technique utilizes glucose oxidase reagent strips to detect increases in glucose concentrations in tracheal secretions attendant to aspiration of enteral nutritional formula. Clinical trials comparing enteral food dye administration and glucose testing of tracheal secretions demonstrate the latter to have better sensitivity.13
14
15
However, glucose detection in tracheal secretions also carries limitations, including false-positive readings in the presence of blood and reduced sensitivity in formulas containing lower concentrations of glucose.16
These limitations of the glucose oxidase technique for the detection of aspiration are obviated by adjusting for the glucose concentrations of enteral formulas and by performing serial glucose measurements.13
The reports of systemic dye absorption, its toxic implications, and its lack of sensitivity for the detection of pulmonary aspiration bring attention to the need for further investigation and regulation of the technique. It is evident that safety standards derived from healthy humans or animals cannot be translated to critically ill patients. For instance, the patients reported herein were estimated to have received approximately 1 mg/kg/d of FD&C Blue No. 1, well below the limit set by the US Food and Drug Administration (ie, 12 mg/kg/d), and both patients exhibited profound metabolic derangements prior to death. As such, it remains unclear what level of absorption, if any, can be considered safe, particularly in patients with underlying metabolic derangements or impaired GI barrier function, such as occurs during sepsis. Thus, new dosing safety standards must now be developed. Furthermore, rather than relying on changes in skin coloration, a development commonly associated with profound toxicity, more sensitive screening techniques such as quantitative spectrophotometric analysis of body fluids, including serum and urine, are needed if the use of food dyes is to be used for the detection of aspiration in critically ill patients.
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Conclusions
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Based on the cases presented here and reports by others,3
6
7
8
the routine use of FD&C Blue No.1 in enteral feedings for the detection of aspiration in the critically ill is questioned. Patients with suspected metabolic derangements, including those with sepsis, or with disruption of the intestinal barrier appear to be at particularly high risk for toxicity. It is possible that improved techniques for the detection of blue dye absorption, such as quantitative spectrophotometric analyses of body fluids, and additional testing in relevant human cohorts to identify patients at risk of dye absorption, may improve the safety of the enteral dye technique. Until that time, we recommend that alternative approaches to gastric aspiration detection, such as serial glucose measurements in pulmonary secretions, should be employed in critically ill patients and other patients with suspected intestinal barrier dysfunction.
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Footnotes
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Abbreviation: FD&C Blue No. 1 = Food Drug and Cosmetic Blue No. 1
Support was provided by National Institutes of Health grant HL04335.
Received for publication May 28, 2003.
Accepted for publication September 5, 2003.
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References
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- Metheny, NA, Aud, MA, Wunderlich, RJ (1999) A survey of bedside methods used to detect pulmonary aspiration of enteral formula in intubated tube-fed patients. Am J Crit Care 8,160-167[Abstract]
- Food and Drug Administration. FD&C Blue No. 1. 47 Federal Register 42563–42566 (1982)
- Maloney, JP, Halbower, AC, Fouty, BF, et al Systemic absorption of food dye in patients with sepsis. N Engl J Med 2000;343,1047-1048[Medline]
- Reyes, FG, Valim, MF, Vercesi, AE Effect of organic synthetic food colours on mitochondrial respiration. Food Addit Contam 1996;13,5-11[Medline]
- Noda, K, Yoshimoto, M, Hatano, S, et al Effect of coal tar dyes on oxygen uptake in mitochondria isolated from rat liver. J Food Hygiene Soc Japan 1985;26,203-207
- Czop, M, Herr, DL Green skin discoloration associated with multiple organ failure. Crit Care Med 2002;30,598-601[CrossRef][ISI][Medline]
- Carpenito, G, Kurtz, I Green urine in a critically ill patient. Am J Kidney Dis 2002;39,E20[CrossRef][Medline]
- Ehrig, F, Waller, S, Misra, M, et al A case of ‘green urine.’ Nephrol Dial Transplant 1999;14,190-192[Abstract/Free Full Text]
- AACN procedure manual for critical care. 3rd ed. 1993 WB Saunders. Philadelphia, PA:
- Davis, AE, Arrington, K, Fields-Ryan, S, et al Preventing feeding-associated aspiration. Medsurg Nurs 1995;4,111-119[Medline]
- Hess, S, Fitzhugh, O Absorption and excretion of certain triphenylmethane colors in rats and dogs. J Pharmacol Exp Ther 1955;114,38-42[Abstract/Free Full Text]
- Brealey, D, Brand, M, Hargreaves, I, et al Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002;360,219-223[CrossRef][ISI][Medline]
- Potts, RG, Zaroukian, MH, Guerrero, PA, et al Comparison of blue dye visualization and glucose oxidase test strip methods for detecting pulmonary aspiration of enteral feedings in intubated adults. Chest 1993;103,117-121[Medline]
- Montejo-Gonzalez, JC, Perez-Cardenas, MD, Fernandez-Hernandez, AI, et al Detecting pulmonary aspiration of enteral feeding in intubated patients. Chest 1994;106,1632-1633[Medline]
- Liu, D, McIntyre, R, Watters, J Pulmonary aspiration in critically ill patients receiving enteral feedings [abstract]. Clin Invest Med 1989;22(suppl),B19
- Potts, RG, Zaroukian, MH Glucose content of tracheal aspirates. Crit Care Med 1995;23,1451-1453[CrossRef][ISI][Medline]
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Abstract
Introduction
