To the Editor:—

I read with interest the elegant study by Veien et al. , 1“Mechanisms of Nonimmunological Histamine and Tryptase Release from Human Cutaneous Mast Cells,” in which the authors examine the release of histamine and tryptase by nonimmunologic stimuli. This in vitro  study represents an important addition to our understanding of nonimmunologic histamine release. As the authors noted, some of their findings disagree with those in our clinical study published previously in this journal. 2In that study, we demonstrated that rapid infusion of vancomycin was accompanied by significant increases in plasma histamine without increases in plasma tryptase concentration. The difference between the two studies is more than academic because clinicians may be able to use plasma tryptase to distinguish between immunologic and nonimmunologic reactions.

There are several possible reasons for the differences between the results of our clinical studies and the in vitro  studies presented by Veien et al.  1The most obvious explanation is the difficulty in extrapolating the results from infant foreskin mast cells to measurements in human plasma. As acknowledged by the authors, there is remarkable heterogeneity between mast cells of different tissues, with regard both to their susceptibility to release and to what is released. Cutaneous mast cells may not be a good model for generalized release, 3as may be reflected by the somewhat higher than normal doses of releasing agents (10–1,000×) required in the infant foreskin preparation. In our vancomycin infusion studies, the mean peak plasma concentration was 37 × 106m, while the mast cell preparation was exposed to 3 × 103m vancomycin. Another explanation for the difference between results is that plasma concentrations of histamine and tryptase almost certainly reflect overflow from tissues rather than direct release into the circulation. Analogous observations regarding release of norepinephrine and dopamine-β-hydroxylase (DBH) release were made more than two decades ago. Norepinephrine and DBH, which are contained in adrenergic vesicles, are released in exocytosis. However, attempts to correlate plasma DBH concentrations with plasma norepinephrine concentrations have been largely unsuccessful. 4Concentrations of plasma catecholamines often correlate well with acute hemodynamic perturbations, but the plasma half-life of DBH, like tryptase, is several hours, and plasma DBH concentrations often may not be increased in short-term release. Given its long half-life, nonsustained chemically mediated release of tryptase would be expected to generate only small changes in plasma concentrations. On the other hand, sustained release, such as what may occur during anaphylactic reactions, might result in increased plasma tryptase. This explanation seems all the more plausible because increases in tryptase do not always occur, even in documented immunologic anaphylaxis. 5 

Finally, the clinical studies cited as supporting evidence for the in vitro  studies support our conclusions. The retrospective study by Fisher and Baldo 6shows that 125 of 130 patients (96%) with increased tryptase had immunologic evidence (immunoglobulin E antibodies), whereas 130 of 137 patients (95%) without tryptase increases did not. The conclusions of one article that proposes a possible immunologic origin of contrast reactions 7are reinterpreted by Veien et al . 1Aside from our study on vancomycin-induced release, 2the prospective, randomized, clinical trials that we and the authors have used previously to assess nonimmunologic histamine release have not been performed with tryptase. 8,9 

The observations of Veien et al.  1on human foreskin mast cells contribute greatly to our understanding of the mechanisms of histamine release, but these in vitro  observations should be translated into clinical practice with caution.

Veien M, Szlam F, Holden JT, Yamaguchi K, Denson DD, Levy JH: Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000; 92: 1074–81
Renz C, Laroche D, Thurn J, Finn H, Lynch J, Thisted R, Moss J: Tryptase levels are not increased during vancomycin-induced anaphylactoid reactions. Anesthesiology 1998; 89: 620–5
Barrett KE, Pearce FL: Heterogeneity of mast cells, Histamine and Histamine Antagonists. Edited by Uvnäs B. Berlin, Springer-Verlag, 1991, p 93
Lake CR, Ziegler MG: Effect of acute volume alterations on norepinephrine and dopamine-beta-hydroxylase in normotensive and hypertensive subjects. Circulation 1978; 57: 774–8
Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H: Biochemical markers of anaphylactoid reactions to drugs. Anesthesiology 1991; 75: 945–9
Fisher MM, Baldo BA: Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 1998; 80: 26–9
Laroche D, Gastin-Aimone I, Dubois F, Huet H, Gerard P, Vergnaud MC, Mouton-Faivre C, Gueant JL, Laxenaire MC, Bricard H: Mechanism of severe, immediate reactions to iodinated contrast material. Radiology 1998; 209: 183–90
Levy JH, Davis GK, Dugan J, Szlam F: Determination of the hemodynamics and histamine release of rocuronium (Org 9426) when administered in increased doses under N2O/O2-sufentanil anesthesia. Anesth Analg 1994; 78: 318–21
Levy JH, Pitts M, Thanopoulos A, Szlam F, Bastian R, Kim J: The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anesthesia. Anesth Analg 1999; 89: 290–5