Wayne Kepron

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.

A canine model for reaginic hypersensitivity and allergic bronchoconstriction

Immunization of neonatal dogs with a conjugate of 2,4-dinitrobenzene and ovalbumin (DNP2-OA), using aluminum hydroxide as the adjuvant, elicited long-lasting (over 30 wk) anti-DNP and anti-OA IgE antibody responses of high titers as determined by homologous passive cutaneous anaphylaxis. Low antigen doses of 10 or 50 mug were more effective than the higher doses of 250 or 1,250 mug in inducing high IgE antibody levels. However, this method of immunization failed to elicity any detectable IgE antibody response in adult dogs. Bronchoprovocation with antigen of sensitized animals having IgE antibody titers in excess of 64 resulted in a marked increase in airflow resistance, which could be corrected by the administration of nebulized isoproterenol. On the other hand, sensitized animals with IgE antibody titers in the order of 64 did not manifest significant bronchoconstriction on inhalation challenge but developed anaphylaxis following intravenous injection of the antigen.

Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients

BACKGROUND Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality following lung transplantation, is defined as an irreversible decline in forced expiratory volume in 1 s (FEV1). Previous studies using azithromycin for BOS in lung transplant patients have demonstrated a potential reversibility of the decline in FEV1. OBJECTIVES To examine whether initiating azithromycin reverses decline in FEV1 in lung transplant recipients with established BOS of at least three months. METHODS Pulmonary function tests were performed every three months in seven lung transplant recipients with established BOS of at least three months. FEV1 was recorded at six and three months before initiation, at time of initiation, and three, six, nine and 12 months postazithromycin initiation. The primary end point was change in FEV1. During the study, no immunosuppressive medication changes or acute rejection episodes occurred. RESULTS Mean time from transplant to azithromycin initiation was 64 months (range 17 to 117 months). Mean time from BOS diagnosis to azithromycin initiation was 22 months (range three to 67 months). Rate of FEV1 decline from six months before azithromycin initiation, and rates of FEV1 increase from initiation to three and 12 months post-treatment initiation, were not statistically significant (P=0.32, P=0.16 and P=0.18, respectively). Following a trend toward improvement in the first three months after treatment initiation, FEV1 tended to stabilize. DISCUSSION Although several studies address the possible benefit of maintenance azithromycin in lung transplant patients with BOS, the role of the drug remains unproven in these patients, and would best be addressed by a large randomized controlled trial.

Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock

OBJECTIVE Epinephrine (Epi) is considered to be the drug of choice for anaphylactic shock (AS). However, the benefit of this drug on improving systemic hemodynamics in AS has never been shown. We used a canine ragweed model of AS to determine if an intravenous bolus of Epi hastened the recovery of hemodynamics and modified mediator release (Med) compared with no treatment (NT). METHODS In one protocol (n = 8), the effects on hemodynamics of two intravenous doses of Epi (0.01 and 0.025 mg/kg) were examined for 3 h postshock in respective studies approximately three weeks apart under pentobarbital anesthesia in the same animal. In five other dogs, left ventricular (LV) mechanics were additionally determined by sonomicrometric techniques to determine changes in contractility as defined by the preload recruitable stroke-work (SW) relationship. RESULTS Compared with NT values, Epi treatments produced only transient increases in mean arterial pressure (MAP) and cardiac output (CO) post-challenge. By 20 min postshock, CO in the Epi studies were generally lower (p < 0.05) and BP was not different from NT values. With Epi treatment, SW was reduced for a given LV end-diastolic volume compared with the control study. Epi treatments also caused relatively higher plasma thromboxane B2 concentrations postshock. CONCLUSION Our findings indicate that, when given immediately postshock, bolus-Epi did not hasten recovery and caused impairment in LV mechanics in canine AS.

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.

Increased ATPase Activity and Myosin Light Chain Kinase (MLCK) Content in Airway Smooth Muscle from Sensitized Dogs

The bronchial hyperreactivity associated with acute asthma appears to be a manifestation of alterations in the regulatory pathways governing airway smooth muscle function (Stephens et al., 1988; Jiang et al., 1990; Kong et al., 1990). We have developed a canine model of asthma (Kepron et al., 1977), in which newborn dogs are sensitized to ragweed pollen using an intraperitoneal immunization regime.

Effects of tolerogenic conjugates in a canine model for reaginic hypersensitivity: I. Suppression of hapten-specific IgE antibody response

Intraperitoneal administration to dogs of conjugates consisting of the 2,4-dinitrophenyl (DNP) groups coupled to nonimmunogenic macromolecules such as the copolymer of D-glutamic acid and D-lysine (DNP16-DGL) prior to sensitization with DNP2-ovalbumin led to the development of hapten-specific tolerance with respect to the IgE antibody response. Administration of these same conjugates to sensitized dogs resulted in complete abrogation of the ongoing anti-DNP IgE antibody production. A similar hapten-specific suppression of the ongoing anti-DNP response was also observed using the conjugates of DNP9-canine gamma globulins, and the tolerogenic effect was dose-dependent. The state of hapten-specific immunosuppression induced by these two types of tolerogenic conjugates was maintained despite repeated booster injections of the sensitizing antigens at biweekly inervals.

Isotonic Shortening Parameters but not Isometric Force Development are Altered in Ragweed Pollen Sensitized Canine Bronchial Smooth Muscle

Studies on airway smooth muscle can serve two major purposes. First, the elucidation of basic mechanisms and properties of smooth muscle contraction and its regulation can be obtained. The trachealis, for example, provides a plentiful source of relatively pure smooth muscle tissue for studies at biochemical and molecular levels. In addition, both tracheal and bronchial smooth muscles furnish us with an optimal preparation for studying mechanical properties because their respective muscle fibers are oriented in a parallel fashion. The second purpose in studying airway smooth muscle is in characterizing the pathophysiology of asthma with hopes of advancing disease management. On this tack, we have a canine model of the disease (Kepron et al., 1977), in which dogs are immunized from birth with ragweed pollen. These animals demonstrate a generalized sensitization of their smooth muscles to the pollen antigen (Antonissen et al., 1979; Antonissen et al., 1980; Kong and Stephens, 1983; Wang et al., 1990). Concomitantly, they produce high IgE anti-ragweed antibody titers and show marked increases in airflow resistance upon aerosolized, specific antigen bronchoprovocation (Becker et al., 1989).

A canine model for the study of hapten-specific suppression of IgE-mediated bronchoconstriction and anaphylaxis.

Newborn mongrel dogs were sensitized with conjugates of ovalbumin (OA) and 2,4-dinitrophenol (OA-DNP3) in the presence of Al(OH)3 to produce high levels of anti-OA and anti-DNP IgE antibody. At 4-6 months of age, when anti-DNP and anti-OA antibody levels reached titers of 64 by passive cutaneous anaphylaxis, the dogs underwent separate inhalation and intravenous challenges with conjugates of DNP and bovine gamma globulin (DNP15-BGG) and OA. Inhalation challenge with DNP15-BGG and OA resulted in 5- and 10-fold increases in airflow resistance, respectively. Intravenous challenge with either DNP15-BGG or OA produced profound anaphylaxis with 60-80% decreases in blood pressure, cardiac output and regional blood flows in the carotid, superior mesenteric and renal arteries, and the distal aorta. Treatment of sensitized dogs with 5 doses of 20 mg of conjugates of DNP and polyvinyl alcohol (DNP2-PVA) on alternate days resulted in suppression of anti-DNP IgE antibody production; abrogation of established airway and vascular anaphylactic sensitivities; no change in regional blood flows, and no effect on sensitivities to challenge with OA.