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- Sulfites -
3/24/05 re: Reactions to sulfites in propofol solution I am a CRNA . Was wondering whether you have found an increase in untoward respiratory effects when propofol with methylbisulfite preservative has been used in asthmatic patients without known sulfite allergy
As you may know, it is the generic formulation of propofol that contains bisulfites as a preservative. The branded product (Diprivan) contains EDTA instead of sulfites as a preservative (see abstract enclosed below). Propofol itself tends to inhibit bronchoconstriction (see enclosed abstract).To help respond to your question. I obtained input from Dr. Ronald Simon of the Scripps Clinic, an authority in the area of adverse reactions to sulfites. His response is enclosed immediately below. My impression from his comments is that the evidence of bronchoconstriction associated with use of generic propofol is mainly anectodal, including some cases where the patient had asthma without known adverse reactions to sulfites. Therefore, it would seem prudent to use Diprivan rather than generic propofol in individuals with pre-existent asthma. The presence of sulfites may also lead to alterations in the propofol molecule, affecting the actions of propofol, as noted below by Dr. Simon.
Dr. Simon's comments:
There have been (anecdotal, but around the country) reports of increased Bronchial reactions to generic propofol. However, such reactions are actually NEVER seen with branded Diprivan.While I believe the sulfite added (in place of EDTA in Diprivan) is related and would cause reactions in those already sulfite sensitive; that's not the (only) possible factor in the reported reactions. I believe it is due to the physiochemical difference in the propofol itself when in a sulfite suspension. There have also been issues of the quality of the anesthetic effect and stability of the product and other issues with the generic propofol. I suggest reading:Am J Anesth, 2000;27. The whole supplement is devoted to this issue. I participated in the preparation of the supplement and authored one of the articles.
Anesth Analg. 2000 Oct;91(4):871-5.
Bisulfite-containing propofol: is it a cost-effective alternative to Diprivan for induction of anesthesia?
Shao X, Li H, White PF, Klein KW, Kulstad C, Owens A.
Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9068, USA.Propofol (Diprivan(TM); AstraZeneca, Wilmington, DE) is a commonly used drug forthe induction of general anesthesia in the ambulatory setting. With the availability of a new bisulfite-containing generic formulation of propofol, questions have arisen regarding its cost effectiveness and safety compared with Diprivan(TM). Two hundred healthy outpatients were randomly assigned, according to a double-blinded protocol, to receive either Diprivan(TM) or bisulfite-containing propofol 1.5 mg/kg IV as part of a standardized induction sequence. Maintenance of anesthesia consisted of either desflurane (4%-8% end- tidal) or sevoflurane (1%-2% end-tidal) in combination with a remifentanil infusion (0.125 microg x kg(-1) x min(-1) IV). Patient assessments included pain on injection, induction time, hemodynamic and bispectral electroencephalographic changes during induction, emergence time, and incidence of postoperative nausea and vomiting. The two propofol groups were comparable demographically, and the induction times and bispectral index values during the induction were alsosimilar. However, the bisulfite-containing formulation was associated with less severe pain on injection (5% vs 11%), with fewer patients recalling pain on injection after surgery (38% vs. 51%, P<0.05). None of the patients manifested allergic-type reactions after the induction of anesthesia. The acquisition cost (average wholesale price in US dollars) of a 20-mL ampoule of Diprivan(TM) was $15 compared with $13 for the bisulfite-containing propofol formulation. Therefore, we concluded that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan(TM) for the induction of outpatient anesthesia. Implications: Bisulfite-containing propofol and Diprivan(TM) (AstraZeneca, Wilmington , DE ) were similar with respect to their induction characteristics; however, the generic formulation was associated with a smaller incidence of injection pain. Assuming that the drug costs are similar, these data suggest that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan(TM)
Anesthesiology. 2001 May;94(5):851-5; discussion 6A.
Comment in: Anesthesiology. 2002 Jun;96(6):1529; author reply 1529-30. Anesthesiology. 2002 Mar;96(3):771-2; author reply 772-3.
Efficacy of propofol to prevent bronchoconstriction: effects of preservative.
Brown RH, Greenberg RS, Wagner EM.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore , Maryland 21205, USA. rbrown@welchlink.welch.jhu.eduBACKGROUND: The authors previously showed that propofol attenuates bronchoconstriction. Recently, a newer formulation of propofol with metabisulfite preservative has been introduced. metabisulfite causes airway narrowing in asthmatics. Therefore, we tested whether the preservative metabisulfite abolishes the ability of propofol to attenuate bronchoconstriction. The authors used a sheep model in which anesthetic agents could be directly administered to the airways via the bronchial artery.
METHODS: After Internal Review Board approval, seven sheep were anesthetized (pentobarbital 20 mg x kg(-1) x h(-1)) and paralyzed (pancuronium 2 mg), and the lungs were ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, propofol with and without metabisulfite, lidocaine (5 mg/ml), or metabisulfite alone (0.125 mg/ml) was infused into the bronchial artery at a rate of 0.06, 0.2, or 0.6 ml/min. After 10 min, airway resistance (Raw) was measured before and after vagal nerve stimulation (30 Hz, 30-ms duration at 30 V for 9 s.) and methacholine challenge (2 microg/ml at 2 ml/min in the bronchial artery). Data were expressed as a percent of maximal response and analyzed by analysis of variance with correction and with significance accepted at P < or = 0.05. RESULTS: Raw at baseline was not significantly different among the four drugs (P = 0.87). Infusion of lidocaine and propofol without metabisulfite into the bronchial artery caused a dose- dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction (P = 0.001). Propofol with metabisulfite had no effect on vagal nerve stimulation- induced bronchoconstriction (P = 0.40). There was a significant difference in the ability of propofol without metabisulfite compared with propofol with metabisulfite to attenuate vagal nerve stimulation-induced (P = 0.0001) and methacholine-induced bronchoconstriction (P = 0.0001).
CONCLUSION: Propofol without metabisulfite and lidocaine attenuated vagal nerve stimulation- induced bronchoconstriction in a dose-dependent fashion. Propofol without metabisulfite also decreased direct airway smooth muscle constriction. The preservative used for propofol can have a dramatic effect on its ability to attenuate bronchoconstriction.
Crit Care Med. 2003 Mar;31(3):787-92. Comment in: Crit Care Med. 2003 Mar;31(3):981-3.
Free radical and drug oxidation products in an intensive care unit sedative: propofol with sulfite.
Baker MT, Gregerson MS, Martin SM, Buettner GR.
Department of Anesthesia, University of Iowa, Iowa City, USA.OBJECTIVES: Some propofol emulsion formulations contain EDTA or sodium metabisulfite to inhibit microbe growth on extrinsic contamination. EDTA is not known to react with propofol formulation components; however, sulfite has been shown to support some oxidation processes and may react with propofol. This study compared the oxidation of propofol and the formation of free radicals by electron paramagnetic resonance analysis in EDTA and sulfite propofol emulsions during a simulated intensive care unit 12-hr intravenous infusion. DESIGN: Controlled laboratory study. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Propofol emulsions (3.5 mL) were dripped from spiked 50-mL vials at each hour for 12 hrs. Two propofol oxidation products, identified as propofol dimer and propofol dimer quinone, were detected in sulfite and EDTA propofol emulsions; however, sulfite propofol emulsion contained higher quantities of both compounds. After initiation of the simulated infusion, the quantities of propofol dimer and propofol dimer quinone increased in the sulfite propofol emulsion, but the lower levels in the EDTA propofol emulsion remained constant. Sulfite propofol emulsion began to visibly yellow at about 6-7 hrs. The EDTA propofol emulsion remained white at all times. The absorbance spectra of the propofol dimer and propofol dimer quinone extracted from sulfite propofol emulsion showed that propofol dimer did not absorb in the visible spectrum, but the propofol dimer quinone had an absorbance peak at 421 nm, causing it to appear yellow. Electron paramagnetic resonance analysis of the propofol emulsion containing metabisulfite revealed that the sulfite propofol emulsion yielded a strong free radical signal consistent with the formation of the sulfite anion radical (SO3*-). The EDTA propofol emulsion yielded no free radical signal above background.
CONCLUSION: Sulfite from the metabisulfite additive in propofol emulsion creates an oxidative environment when these emulsions are exposed to air during a simulated intravenous infusion. This oxidation results in propofol dimerization and emulsion yellowing, the latter of which is caused by the formation of propofol dimer quinone. These processes can be attributed to the rapid formation of the reactive sulfite free radical.1/16/02 re: Reactions to sulfite-free wine and beer Can you recommend an author or journal for me to search re upper respiratory symptom or systemic histamine release following sulfite-free wine and beer?
I have enclosed abstracts of 2 reports describing pulmonary function and symptomatic responses to double-blind challenges with sulfated and low sulfite wines. I do not know of any such challenge studies where levels of allergic mediators were measured before and after challenges with sulfite-free or low-sulfite wines or beers. I discussed your question with Dr. Donald Stevenson of the Scripps Clinic group, one of the leading investigators of food additives (see enclosed abstract). He was unaware of any such challenges in which mediator levels were measured. J Allergy Clin Immunol 1999 Jan;103(1 Pt 1):41-6
Wine-induced asthma: a placebo-controlled assessment of its pathogenesis.
Vally H, Carr A, El-Saleh J, Thompson P.
Asthma and Allergy Research Unit, Department of Medicine, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Nedlands, Australia.Background: The sulfite family of food additives has been implicated in the pathogenesis of wine-induced asthma. However, the evidence supporting this is weak, and because wines have many hundreds of components, nonsulfite-associated mechanisms may also play a role. OBJECTIVES: The aim of the study was to assess the potential sensitivity of persons with asthma to nonsulfite components in wine by using low-sulfite wine challenges.
Methods: Sixteen adults with a strong history of wine-induced asthma were challenged with both low-sulfite red and white wines and wine-placebo drinks. Challenges were performed double blind, using a Latin square design, with lung function being assessed before the challenge and at 5, 10, 15, 30, and 60 minutes after the challenge. Subsequently, single-blind challenges with high-sulfite white wine were also completed in 10 individuals whose lack of reactivity to low-sulfite white wine suggested possible reactivity to sulfite additives.
Results: The mean FEV1; forced expiratory flow, mid-expiratory phase; and peak expiratory flow of subjects to low-sulfite red and white wines and red and white placebo wines were not significantly different. Furthermore, with a predetermined criterion of a fall in FEV1 of more than 15% representing a positive challenge, only one individual exhibited a positive reaction in the presence of a negative response to placebo. Only 2 of the 10 test individuals who were challenged with a high-sulfite wine demonstrated a marked and rapid fall in FEV1. Reactivity to low-sulfite wines appears to occur only in a small number of individuals who report sensitivity to wines, suggesting that the sulfite additives may be the major cause of wine-induced asthmatic reactions. However, direct challenge with high-sulfite wine revealed only 2 clear reactions in this asthma cohort.
Conclusion: Wine-induced asthma appears to be a complex phenomenon and may involve several mechanisms that are codependent.
Thorax 2001 Oct;56(10):763-9
Role of sulfite additives in wine induced asthma: single dose and cumulative dose studies.
Vally H, Thompson PJ.
Department of Medicine, The University of Western Australia and the Asthma and Allergy Research Institute Inc, Perth, Western Australia.Background: Wine appears to be a significant trigger for asthma. Although sulfite additives have been implicated as a major cause of wine induced asthma, direct evidence is limited. Two studies were undertaken to assess sulfite reactivity in wine sensitive asthmatics. The first study assessed sensitivity to sulfites in wine using a single dose sulfited wine challenge protocol followed by a double blind, placebo controlled challenge. In the second study a cumulative dose sulfited wine challenge protocol was employed to establish if wine sensitive asthmatics as a group have an increased sensitivity to sulfites.
Methods: In study 1, 24 asthmatic patients with a strong history of wine induced asthma were screened. Subjects showing positive responses to single blind high sulfite (300 ppm) wine challenge were rechallenged on separate days in a double blind, placebo controlled fashion with wines of varying sulfite levels to characterize their responses to these drinks. In study 2, wine sensitive asthmatic patients (n=12) and control asthmatics (n=6) were challenged cumulatively with wine containing increasing concentrations of sulfite in order to characterize further their sensitivity to sulfites in wine.
Results: Four of the 24 self-reporting wine sensitive asthmatic patients were found to respond to sulfite additives in wine when challenged in a single dose fashion (study 1). In the double blind dose-response study all four had a significant fall in forced expiratory volume in one second (FEV(1)) (>15% from baseline) following exposure to wine containing 300 ppm sulfite, but did not respond to wines containing 20, 75 or 150 ppm sulfite. Responses were maximal at 5 minutes (mean (SD) maximal decline in FEV(1) 28.7 (13)%) and took 15-60 minutes to return to baseline levels. In the cumulative dose-response study (study 2) no significant difference was observed in any of the lung function parameters measured (FEV(1), peak expiratory flow (PEF), mid phase forced expiratory flow (FEF(25-75))) between wine sensitive and normal asthmatic subjects.
Conclusions: Only a small number of wine sensitive asthmatic patients responded to a single dose challenge with sulfited wine under laboratory conditions. This may suggest that the role of sulfites and/or wine in triggering asthmatic responses has been overestimated. Alternatively, cofactors or other components in wine may play an important role in wine induced asthma. Cumulative sulfite dose challenges did not detect an increased sensitivity to sulfite in wine sensitive asthmatics and an alternative approach to identifying sulfite/wine sensitive asthma may be required
N Engl Reg Allergy Proc 1988 Mar-Apr;9(2):135-42
Oral challenges to detect aspirin and sulfite sensitivity in asthma.
Stevenson DD.
Allergy & Immunology Fellowship Program, Scripps Clinic Medical Institutions, La Jolla, California 92037."Oral challenge with aspirin, or potential cross-reacting substances, is an effective method for establishing the presence of these sensitivities in asthmatic subjects. However, in patients with concomitant active irritable airways, testing is inaccurate and potentially dangerous. Strategies for dealing with these problems and other details important in conducting oral challenges are outlined. Sulfite challenges are conducted in a different manner and there has not been cross-sensitivity established between sulfite sensitive and aspirin sensitive asthmatics. However, many of the same problems created by heightened airway activity interfere with the accuracy of sulfite challenges. A special obstacle in interpreting the results of sulfite challenges is the issue of specificity. Oral challenges with solutions of sulfite improve sensitivity of the challenge procedure. But only low dose sulfite solutions (50 mg/ml or less) and capsules of sulfite salts are specific provoking substances for sulfite sensitivity."
2/4/00 re: Sulfate sensitivity testing How does one test for sulfite allergy? Please refer to lab where I can get this test performed. Please refer to my response to a previous similar question about testing for sulfite sensitivity in this Ask the Expert section (dated 9/14/99). As noted in my response, there there is not one generally agreed upon method to do sulfite challenge testing. However, a very reasonable challenge approach is described in the reference given. To my knowledge, there is no reliable in vitro test for sulfite allergy In response to your question about experts to whom patients can be referred for sulfite testing, I would recommend (among others): 1) Dr. Robert Bush, of the Allergy Division, University of Wisconsin in Madison, WI (a co-author of the chapter reference in my previous response) or 2) Dr. Donald Stevenson of the Scripps Clinic in La Jolla, CA.. Because there is no reliable in vitro test, one cannot simply send a serum specimen to these investigators.
9/14/99 re: Correct protocol for sulfite challenge I am a board certified allergist practicing in California and am in the process of initiating Sulfite Challenge testing in my medical office. What method (i.e. skin testing, oral-capsules etc) is recommended for optimal results. What is the standard protocol - lowest dose to start testing on patient.? As pointed out by Bush and Taylor in their very good chapter (Chap. 84) in the current (5th) Edition of the "Allergy, Principles and Practice" text, there is no standardized protocol for doing sulfite challenges. The nature of the challenge material may depend on the circumstances in which the individual patient reported a possible reaction (e.g. - ingestion of solid foods vs ingestion of wine). For more details, I recommend that you read the relevant portions of Bush and Taylor's chapter (page 1193 and particularly the outlines in Box 84-1 and Box 84-2 on page 1186). 8/7/98 re: sulfite sensitivity A 51-year-old gentleman with myasthenia gravis and IDDM has been having episodes of anaphylaxis involving facial and oropharyngeal swelling every two to three months despite 30 mg of prednisone daily and h1 and h2 blockers. I performed the usual work-up for anaphylaxis/ angioedema including tryptase, complement studies, and even some food testing. My question is, has "idiopathic" anaphylaxis been described in these patients related to their underlying myasthenia? Might this be amenable to plasmapharesis? Almost all reported adverse reactions to sulfites are respiratory, presumably due to the effects of the sulfites themselves or of SO2 resulting from sulfite catabolism, on reactive airways. It is not known why only a small percentage of asthmatics are so reactive to sulfites. There have been occasional case reports of angiodema (periorbital) ascribed to sulfites, but these do not appear to be confirmed in double-blind challenges. If the patient can tolerate
sizable portions of dried fruits (e.g.,-apricots), which contain sizable amounts of sulfites, these agents are not the problem.
I think that the offender in the case you describe may more likely be tyramines. These agents are generally present in higher concentrations in red rather than white wines (particularly those of the Bordeaux type, although the amount varies considerably from bottle to bottle, depending on the wine preparation method). Although tyramines usually cause headaches and flushing in reactive individuals, swelling has also been reported. Unfortunately, the tyramine content of individual wines is not listed on the bottle. I am not aware of high histamine levels in commercial red wines. If one wishes to explore this further, one could do a cautious challenge with tyramine itself, under close observation.In response to your second question, I am not aware of systemic anaphylactoid reactions to sulfites present in small amounts in epinephrine for injection. However, preservatives present in medications for inhalation have been incriminated in worsening of existent asthma, a factor prompting the use of single dose units of such medications not containing preservatives.
