Krika Duke

Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock.

Background: Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). However, there are few data supporting its use in this condition, and most treatment guidelines have been anecdotally derived. In the present study, the time course of hemodynamic recovery from maximal hypotension was investigated in a canine model of AS in which Epi was administered by the intravenous (IV), subcutaneous (SQ) and intramuscular (IM) routes on different occasions. The findings obtained with Epi treatment were compared to those in a nontreatment study. Methods: Ragweed-sensitized dogs were examined in respective studies approximately 5 weeks apart in which Epi was administered by one of the above routes in a randomized design. Either Epi (0.01 mg/kg) or placebo was administered at maximal hypotension, and hemodynamics were followed for 3 h after shock. The animals were studied while ventilated and anesthetized. Mean arterial pressure (MAP), cardiac output, stroke volume (SV), pulmonary wedge pressure (Pwp) and plasma Epi concentrations were obtained at each measurement interval. Results: In the IV study, Epi produced a transient immediate increase in MAP, SV and Pwp as compared to the nontreatment study (144 vs. 52 mm Hg; 32 vs. 12 ml; 9 vs. 5 mm Hg; p < 0.01), but no differences were observed 15 min after shock. Hemodynamics were not different between Epi and no treatment at any intervals when Epi was given by the SQ and IM routes. AS compared with the placebo study, plasma Epi concentrations were higher in the IV and IM studies, but not in the SQ study. Conclusions: Although higher Epi concentrations were observed in the IM and IV studies, a sustained benefit in hemodynamic recovery was not observed in this anesthetized, ventilated canine model. In AS, when administered during maximum shock after mediators have already been released, a single IM, IV or SQ dose of Epi may have limited utility in the treatment of cardiovascular collapse. Earlier administration of Epi, before maximal hypotension occurs, may produce a more beneficial effect.

Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs

Objective Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). In this condition, most treatment guidelines have been anecdotally derived and no randomized clinical trials have been conducted. In the present study, we examined the time course of haemodynamic recovery in a canine model of AS when Epi was administered at the initiation of allergen challenge before fully developed shock had occurred.

Lysozyme: a mediator of myocardial depression and adrenergic dysfunction in septic shock in dogs

The objective of the present study was to identify the nature of a filterable cardiodepressant substance (FCS) that contributes to myocardial dysfunction in a canine model of Escherichia coli septic shock. In a previous study, it was found that FCS increased in plasma after 4 h of bacteremia (Am J Physiol 1993;264:H1402) in which FCS was identified by a bioassay that included a right ventricular trabecular (RVT) preparation. In that study, FCS was only partially identified by pore filtration techniques and was found to be a protein of molecular weight between 10 and 30 K. In the present study, FCS was further purified by size exclusion high-pressure liquid chromatography, until a single band was identified on one-dimensional gel electrophoresis. This band was then subjected to tandem mass spectrometry and protein-sequencing techniques and both techniques identified FCS as lysozyme c (Lzm-S), consistent with that originating from the canine spleen. Confirmatory tests showed that purified Lzm-S produced myocardial depression in the RVT preparation at concentrations achieved during sepsis in the in vivo preparation. In addition, Lzm-S inhibited the adrenergic response induced by field stimulation and the beta- agonist isoproterenol in in vitro preparations, these results suggesting that Lzm-S may inhibit the sympathetic response in sepsis. The present findings indicate that Lzm-S originating from disintegrating leukocytes from organs such as the spleen contributes to myocardial dysfunction in this model. The mechanism may relate to its binding or hydrolysis of a cardiac membrane glycoprotein thereby interfering with myocardial excitation-contraction coupling in sepsis.

N,n′,n′-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in escherichia coli sepsis in dogs*

ObjectiveReversible myocardial depression in sepsis has been ascribed to the release of inflammatory mediators. We recently found that lysozyme c (Lzm-S), consistent with that originating from the spleen, was a mediator of myocardial depression in an Escherichia coli model of septic shock in dogs. We further showed in a right ventricular trabecular (RVT) preparation that Lzm-S’s depressant activity could be blocked by N,N′,N’ triacetylglucosamine (TAC), a competitive inhibitor of Lzm-S. We hypothesized that Lzm-S binds to or cleaves a cardiac membrane glycoprotein, thereby interfering with myocardial contraction in sepsis. In the present study, we examined whether TAC could prevent myocardial depression in an in vivo preparation and whether other related N-acetylglucosamine (NAG) structures could also inhibit Lzm-S’s effect in RVT. DesignRandomized experimental study. SettingUniversity laboratory. SubjectsAnesthetized, mechanically ventilated dogs. InterventionsWe produced sepsis by infusion of E. coli over an approximately 6-hr period. Measurements and Main ResultsWe examined the effect of TAC on stroke work, our primary index of myocardial function, when treatment was administered before sepsis (pretreatment) and after 1.5 hrs (early treatment study) and 3.5 hrs of sepsis (late treatment study; LTS). In the pretreatment study and early treatment study, myocardial depression would have not yet occurred but would have already been present in the late treatment study. In RVT, we assessed the effect of other NAG oligosaccharides and variants to the NAG structure on Lzm-S’s depressant activity. In pretreatment and the early treatment study, TAC prevented the reduction in stroke work observed in nontreated septic groups but did not reverse the reduction found in the late treatment study. In RVT, of the compounds tested, only N,N′-diacetylglucosamine showed an inhibitory effect. ConclusionsWe found that TAC, a competitive inhibitor of Lzm-S, prevented myocardial depression in experimental sepsis. Only specific NAG structures are inhibitory to Lzm-S’s depressant activity. TAC may be useful in attenuating cardiovascular collapse in sepsis.

Characterization of membrane N-glycan binding sites of lysozyme for cardiac depression in sepsis.

Purpose In sepsis, reversible myocardial depression has been ascribed to the release of mediators of inflammation. We previously found that lysozyme released from leukocytes from the spleen and other organs mediated myocardial depression in an Escherichia coli model of septic shock in dogs. We hypothesize that lysozyme binds to or cleaves a cardiac surface membrane N-glycoprotein to cause depression. The objectives of the present study were: 1) to determine whether the binding of lysozyme is reversible; 2) to assess the N-glycan structure to which lysozyme binds; 3) to examine whether nonenzymatic proteins, termed lectins, with a binding specificity similar to that of lysozyme could also cause depression; and 4) to assess whether the membrane to which lysozyme binds is affected by the enzymes protease type XIV and collagenase A, that are used to prepare single cell myocyte experiments.Methods We measured isometric contraction in a right ventricular trabecular preparation.Results We found that lysozyme binds in a reversible manner to the Man β(1–4) GlcNAc β(1–4)GlcNAc moiety in the tri-mannosyl core structure of high mannose/hybrid and tri-antennary carbohydrate classes where GlcNAc is N-acetylglucosamine and Man is mannose. Lectins with a specificity similar to that of lysozyme also caused depression, and lysozyme’s depressant activity was eliminated by protease type XIV and collagenase A.Conclusions These results indicate that lysozyme reversibly binds to a membrane glycoprotein to cause myocardial depression in sepsis. We further localize its binding site to a variant of the chitotriose structure in the tri-mannosyl core of the membrane glycoprotein.

Role of autacoids in cardiovascular collapse in anaphylactic shock in anesthetized dogs

OBJECTIVE In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins (prost), and leukotrienes (leuk) on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. METHODS In randomized design, we investigated whether blockade of histamine H1, H2, and H3 receptors or inhibition of the cyclooxygenase (cyclo) and lipoxygenase pathways (lipox) prevented AS in ragweed sensitized dogs. Seven dogs were studied under pentobarbital anesthesia in which the treatment studies were approximately 2 weeks apart. RESULTS During H1 receptor blockade, the decreases in blood pressure and cardiac output otherwise observed in AS were attenuated (P < 0.05) and the release of prost, thromboxanes, and leuk were reduced as compared with nontreatment studies. Cyclo inhibition also attenuated cardiovascular collapse and mediator release in AS, but the other treatments showed no effects. CONCLUSION H1 receptor blockade and cyclo may attenuate cardiovascular shock in AS. These agents inhibit autacoid release from mast cells in addition to any specific receptor blocking and pathway inhibition effects.

Effect of histamine H3 receptor blockade on venous return and splanchnic hemodynamics in experimental bacteremia

OBJECTIVE In the heart, histamine H3 receptors may function as inhibitory presynaptic receptors that decrease adrenergic neural norepinephrine release in conditions of enhanced sympathetic tone. In a previous study, we found that H3 receptor blockade improved cardiac contractility and systemic hemodynamics in experimental bacteremia in dogs. Because histamine H3 receptors have been found in the splanchnic circulation in other animal models, it was not clear the extent to which H3 receptor blockade may have altered splanchnic hemodynamics, and variables of venous return, that in turn contributed to the overall improvement in systemic hemodynamics observed in the previous experiment. In the present study, we examined splanchnic hemodynamics in the presence of H3 receptor blockade in a canine model of Escherichia coli bacteremia. DESIGN Bacteremia was produced by intravenous infusion of live E. coli administered throughout the experiment. Variables of venous return included mean systemic pressure, resistance to venous return, and mean right atrial pressure. Splanchnic measurements included hepatic and portal pressures and flows. Measurements were obtained before and after H3 receptor blockade with thioperamide maleate. The animals were studied while ventilated and anesthetized. RESULTS H3 receptor blockade caused a decrease in mean right atrial pressure from 5.9 mm Hg pretreatment to 3.5 mm Hg posttreatment (p < .05), although it did not affect mean systemic pressure or resistance to venous return. There were no changes in portal or hepatic flows after H3 receptor blockade. The cardiac function curve after H3 receptor blockade was shifted upward and to the left compared with the pretreatment curve. CONCLUSIONS The results showed that the primary effect of H3 receptor blockade in experimental bacteremia was attributable to an increase in inotropy. There was no evidence to indicate that H3 receptor activation contributed to altered splanchnic hemodynamics in this model.

Effect of bumetanide in capillary permeability pulmonary oedema

To determine if bumetanide, like furosemide, improves shunt through pulmonary vasoactivity, 20 dogs with unilobar oleic acid pulmonary oedema were studied. Fractional perfusion and intrapulmonary shunt of the oedematous lobe were measured at: baseline, 11/2 hours after oleic acid infusion, 15 minutes later after either 0.1 mgkg-1 of bumetanide in ten dogs (Bumetanide Group) or without bumetanide in ten dogs (Control Group), and 21/2 hours after the oleic acid, the bumetanide being administered immediately after the 11/2 hours post-oleic acid measurements. Lobar shunts for the Bumetanide Group were: 9.3 ± 4.0, 54.3 ± 13.6, 54.7 ± 13.6, 38.6 ± 12.0 per cent and for Controls: 8.7 ± 1.6, 45.1 ± 8.8, 48.3 ± 7.8, 70.4 ± 6.2 per cent. Fractional perfusions of the oedematous lobe were: 29.9 ± 1, 14.7 ± 1.1, 14.6 ± 0.7, 19.3 ± 1.9 per cent in the Bumetanide Group and 28.6 ± 2.1, 14.2 ± 1.1, 14.2 ± 1.5, and 9.9 ± 1.1 per cent in Controls. Oedema (wet to body weight ratio) was less (p < 0.05) in the contralateral lobe (2.5 ± 0.2 vs 2.9 ± 0.3) and the oedematous lobe (4.7 ±0.4 vs 6.0 ± 0.5) after bumetanideinduced diuresis. We conclude that bumetanide decreases shunt by decreasing oedema and not through pulmonary vasoactivity.RésuméAfin de déterminer si la bumétanide, comme la furosémide, améliore le shunt à travers une vasoactivité pulmonaire, 20 chiens dont un lobe pulmonaire est rendu oedématié par ľacide oléique ont été étudiés. La perfusion régionale et le shunt intrapulmonaire du lobe oedématié ont été mesurés aux temps suivants: contrôle, une heure et demie après la perfusion ďacide oléique, 15 minutes plus tard après injection soit de 0.1 mg.kg-1 de bumétanide chez dix chiens (groupe Bumétanide) ou sans injection de bumétanide chez dix chiens (Groupe contrôle), et deux heures et demie après ľacide oléique. La bumétanide étant administrée immédiatement après les mesures faites une heure et demie après ľinjection ďacide oléique. Les shunts lobaires pour le groupe bumétanide étaient: 9.3 ± 4.0, 54.3 ± 13.6, 54.7 ± 13.6, 38.6 ± 12.0 pour cent et pour le groupe contrôle: 8.7 ± 1.6, 45.1 ± 8.8, 48.3 ± 7.8, 70.4 ± 6.2 pour cent. La perfusion régionale des lobes oedématiés étaient de: 29.9 ± 1, 14.7 ± 1.1, 14.6 ± 0.7, 19.3 ± 1.9 pour cent pour le groupe bumétanide et de 28.6 ± 2.1,14.2 ± 1.1,14.2 ± 1.4, et 9.9 ± 1.1 pour cent pour le groupe contrôle. Ľoedème (rapport poids frais sur poids corporel) était moindre (p < 0.05) dans le lobe contralatéral (2.5 ± 0.2 vs2.9± 0.3) et pour le lobe oedématié (4.7 ± 0.4 vsô.0 ± 0.5) après diurèse induite par la bumétanide. On conclut que la bumétanide diminue le shunt en diminuant ľoedème et non par son action sur la vasoactivité pulmonaire.