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G. J. McHugh
Anaphylactoid reaction to pentastarch Accepted: 17 May 1999 Sir: The recent report of an anaphylactoid reaction to pentastarch (Kannan S, Milligan KR. Intensive Care Med 1999; 25: 220±222) has piqued my interest for several reasons. Firstly because I have previously encountered such a reaction to pentastarch [1], albeit a pentastarch with slightly different characteristics (weight-average MW 250,000/degree of substitution 0.45 versus 200,00/0.5). This, together with an earlier description of a reaction to a 10 % pentastarch (200,000/0.5) [2], devalues the primacy of their report. The French multicentre report [3] also includes reactions to starch solutions of MW 200,000, although the degree of substitution is not recorded. Kannan and Milligan appear to be the first to report a reaction to 6 % pentastarch, but not to pentastarch per se. This leads to my second point of interest. The taxonomy of intravenous starch solutions can create confusion and begs the question of when is a pentastarch not a pentastarch? This has been less of a problem here in New Zealand where only two hydroxyethyl starch (HES) solutions have been available. Only one of these is a pentastarch, presented as a 10 % solution in 0.9 % saline (250,000/0.45; Pentaspan, DuPont Pharmaceuticals), the other a 6 % hetastarch in 0.9 % saline (480,000/0.7; Hespan, DuPont Pharmaceuticals). The former tends to be referred to locally as the lower MW preparation, but given the diversity of HES products available worldwide, it is perhaps wiser to adopt a classification as shown by Dieterich et al [4]. They classify HES according to both weight-average molecular weight (MW) and degree of substitution (DS) thus: low MW/low DS, medium/low, medium/high, high/high. Pentaspan and 6 % Haes-steril would both fit into the medium/low group. The classification offered by Warren and Durieux [5] is simpler, perhaps reflecting the HES products available in their marketplace. They characterize pentastarches as having MW of 280,000 and DS of 0.5. Neither Pentaspan nor Haes-steril 6 % fit into this classification, yet both are pentastarches. Admittedly the particular HESclassification has no bearing on the nature of the reaction described. Finally I am interested in the reported tryptase assays. The two-hour level rose above their stated normal range, but it was not greatly elevated. In keeping with an
anaphylactic process, it decreased over time. The normal range of tryptase is ordinarily reported as only an upper level [6], variously < 3 mg ´ 1 1 or < 5 mg ´ 1 1. These values may however alter according to the particular assay process. Above these thresholds, there is an intermediate range, and beyond this the tryptase is regarded as unequivocally elevated. The normal range given by Kannan and Milligan thus seems unusual, and further comment upon interpretation of the measured tryptase level would have been useful. The anaphylactoid reaction previously reported from this institution did not yield an elevated serum tryptase although possible shortcomings with blood sampling are acknowledged [1]. The minimal elevation in tryptase recorded by Kannan and Milligan may lend further support to the supposition that IgE-mediated mast cell degranulation is not a feature of HES-related anaphylactoid reactions [2, 4], no matter what their MW or their DS.
References 1. McHugh GJ (1998) Anaphylactoid reaction to pentastarch. Can J Anaesth 45: 270±272 2. Kreimeier U, Christ F, Kraft D et al (1995) Anaphylaxis due to hydroxyethylstarch-reactive antibodies. Lancet 345: 49±50 3. Laxenaire MC, Charpentier C, Feldman L, et le Groupe Francais d'Etude de la Tolerance des Substituts Plasmatiques (1994) Reactions anaphylactoides aux substituts colloidaux du plasma: incidence, facteurs de risque, mecanismes. Enquete prospective multicentrique francaise. Ann Fr Anesth Reanim 13: 301±310 4. Dieterich HJ, Kraft D, Sirtl C, Laubenthal H, Schimetta W, Polz W, Gerlach E, Peter K (1998) Hydroxyethyl starch antibodies in humans: incidence and clinical relevance. Anesth Analg 86: 1123±1126 5. Warren BB, Durieux ME (1997) Hydroxyethyl starch: safe or not? Anesth Analg 84: 206±212 6. Fisher MM, Baldo BA (1998) Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 80: 26±29
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G. J. McHugh ( ) Department of Anaesthesia and Intensive Care, Palmerston North Hospital, PO Box 11036, Palmerston North, New Zealand email:
[email protected] Tel. + 64 6 3 50 85 65 Fax + 64 6 3 50 85 66
S. Kannan K. R. Milligan
Reply Accepted: 17 May 1999 Sir: We thank Dr. McHugh for his interest in our case report. Since acute adverse reactions to a couple of other formulations of pentastarch had already been reported in the literature, we had specifically emphasized the weighted average molecular weight (WAMW), degree of substitution and the percentage formulation in our report. We did not claim that we were the first to report an adverse reaction to pentastarch per se. We do agree that there is a degree of confusion surrounding the nomenclature of the various intravenous starch solutions. Although Warren and Durieux [1] had characterized pentastarch as compounds with a WAMW of 280,000, Prough and Kramer [2] considered compounds with the same WAMW to be pentafraction. Conversely, the former characterized compounds with WAMW of 264,000 as pentafraction whereas the latter considered the same to represent pentastarch. Although Traylor and Pearl [3] also classified pentastarch as compounds with a WAMW of 280,000, they considered pentafraction to have a higher WAMW of 350,000. As mentioned by Dr. McHugh, it is debatable whether the nature of the reaction would differ based on minor differences in WAMW or the degree of substitution. However, in addition to the fact that such a reaction was not previously reported with the use of the type of pentastarch described in our report, our emphasis was on the reaction occurring in a patient being treated for acute severe asthma. The mast cell tryptase was assayed using a commercial radio-immunoassay (UniCAP tryptase fluoroenzyme immunoassay ± Pharmacia & Upjohn Diagnostics, Sweden). The normal range of levels was based on the company's manual for the assay instrument [4]. In a study [4] on 129 apparently healthy children and adults without evidence of mast cell stimulation, it was found that the mean value of mast cell tryptase was 5.6 mg ´ l±1 with the 90th and 95th upper percentile values of 9.8 and 13.5 mg ´ l±1, respectively. Fisher and Baldo [5] assayed the mast cell tryptase levels in a large study using the same equipment and considered a concentration of more than 3 mg ´ l±1 to be elevated. This was well below our peak value of 16.1 mg ´ l±1. As pointed out by Dr. McHugh, the increased levels of
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mast cell tryptase at 2 h but not at 4 h along with the normal IgE and complement levels in our report lends credence to a non-immune basis for the reaction.
References 1. Warren BB, Durieux ME (1997) Hydroxyethyl starch: safe or not? Anesth Analg 84: 206±212 2. Prough DS, Kramer G (1994) Medium starch, please. Anesth Analg 79: 1034±1035 3. Traylor RJ, Pearl RG (1996) Crystalloid versus colloid versus colloid: all colloids are not created equal. Anesth Analg 83: 209±212 4. UniCAP Tryptase Fluoroenzyme immunoassay ± Diagnostics product information. Internal data (1997) Pharmacia & Upjohn Diagnostics, Sweden 5. Fisher MM, Baldo BA (1998) Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 80: 26±29
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S. Kannan ( ) ´ K. R. Milligan Department of Anaesthetics, Altnagelvin Area Hospital, Londonderry BT47 1SB, UK e-mail:
[email protected] Tel.: + 44-15 04-3 45 1 71 Ext. 3594 Fax: + 44-15 04-6 11 2 72
T. Vassilakopoulos S. Zakynthinos
Can dynamic PEEPi be greater than static PEEPi? Accepted: 17 May 1999 Sir: In the March issue, Fujino et al. [1] compared static and dynamic PEEPi in sedated and paralyzed mechanically ventilated rabbits and, contrary to the relevant literature, found that PEEPidyn was higher than PEEPistat under all conditions tested. This is a ªchallengingº and unexpected finding. However, from a physiological standpoint, we think that there is an alternative way to interpret these findings, along the lines of the viscoelastic model used to assess the mechanical properties of the respiratory system [2]. This model consists of a resistance (R) in parallel with a standard elastance (Est) and a series spring-and-dashpot body (Evisc and Rvisc), representing viscoelastic (stress adaptation) units [2]. The authors state that ªthe value of PEEPidyn . ..may not necessarily represent the mechanical characteristics of the lungº. Nevertheless, by definition PEEPi dyn is the airway pressure at the point of zero flow before the beginning of inspiration and, thus, it represents the mechanical characteristics of the lung at this point. In fact, according to the model, it is the sum of the static recoil pressure and the viscoelastic pressure of the respiratory system (i. e. the pressure across the spring-and-dashpot body) and is, of course, equal in the alveoli and the airways, since flow is zero at this point [3]. The explanation that ªthere is a time delay for the expiratory flow to return to zero at the alveoli after Paw at the airway opening reaches the PEEPi level because of inertia of gasº is not completely satisfactory, since this provides no rationale for the fact that the alveolar pressure at the point of zero flow before the beginning of inspiration (i. e. PEEPidyn) was higher than the static recoil pressure of the respiratory system (PEEPistat) at the same moment (end of expiration) and lung volume. The only way that PEEPidyn can be higher than PEEPistat is by operating at lung volumes where the viscoelastic pressure is positive and not negative, and it is thus added to the static recoil pressure of the respiratory system (PEEPistat). This explanation is supported by the volume dependence of the difference PEEPidyn±PEEPistat reported by Fujino et al. [1], and the fact that the ani-
mals were rather significantly hyperinflated. In fact, Schuessler et al. [3, Fig. 10] have theoretically shown that (even in COPD patients) whereas PEEPidyn is lower than PEEPistat at low lung volumes (which means that the viscoelastic pressure is negative), when the lung volume increases PEEPidyn equals PEEPistat (which means that the viscoelastic pressure is zero). Accordingly, it can be theoretically predicted that further hyperinflation would cause the viscoelastic pressure to become positive and, thus, the PEEPidyn greater than the PEEPistat. However, it should be stated that the above-mentioned explanation can only be valid in normal lungs, in the absence of significant inhomogeneity of time constants and expiratory flow limitation [3].
References 1. Fujino Y, Nishimura M, Uchiyama A, Taenaka N, Yoshiya I (1999) Dynamic measurement of intrinsic PEEP does not represent the lowest intrinsic PEEP. Intensive Care Med 25: 274±278 2. Bates JHT, Brown KA, Kochi T (1989) Respiratory mechanics in the normal dog determined by flow interruption. J Appl Physiol 67: 2276±2285 3. Schuessler TF, Gottfried SB, Bates JH (1997) A model of the spontaneously breathing patient: applications to intrinsic PEEP and work of breathing. J Appl Physiol 82: 1694±1703
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T. Vassilakopoulos ( ) ´ S. Zakynthinos Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, 45±47 Ipsilandou Street, GR-10 675 Athens, Greece Tel.: + 30-1-7243320 Fax: + 30-1-7 21 65 03
