Thomas S. Hurst

Neutrophil-mediated acute lung injury after extracorporeal perfusion

A pulmonary injury of varying severity occurs routinely after cardiopulmonary bypass. We studied the pulmonary complications of partial cardiopulmonary bypass in four groups of dogs to better define the injury and to evaluate the efficacy of two interventions (addition of a leukocyte filter or cyclooxygenase inhibition) on preservation of systemic oxygenation. All animals received a standard anesthetic (pentobarbital, morphine, and vecuronium) and, after sternotomy, three groups of animals received 3 hours of partial cardiopulmonary bypass. The animals were randomized to receive partial bypass alone (n = 6), indomethacin and bypass (n = 5), or a leukocyte filter and bypass (n = 5). A fourth group (n = 5) did not receive bypass and served as a time control. We measured blood gases and also obtained histologic samples to assess the degree of lung injury. We found that bypass alone caused a significant reduction (p < 0.05) in arterial oxygen tension 1 hour after the conclusion of bypass (175 +/- 53 mm Hg) compared with prebypass values (357 +/- 41 mm Hg). Pretreatment with indomethacin ameliorated the decrease in arterial oxygen tension from prebypass to postbypass values (477 +/- 50 mm Hg versus 339 +/- 57 mm Hg, respectively). Similarly use of a leukocyte filter reduced the decline in arterial oxygen tension from prebypass to postbypass values (440 +/- 71 mm Hg versus 311 +/- 73 mm Hg, respectively). We believe that indomethacin ameliorates the decline in systemic oxygenation associated with bypass by augmentation of hypoxic pulmonary vasoconstriction and that the leukocyte filter acted to reduce pulmonary edema and thereby minimized intrapulmonary shunt.

Respiratory symptoms and lung function in poultry confinement workers in Western Canada.

OBJECTIVE To determine whether poultry production methods impact respiratory health, and whether poultry farmers have more respiratory symptoms and lower lung function than comparison control groups. DESIGN Cross-sectional study. SETTING Provinces of Saskatchewan, Alberta and Manitoba during the winters of 1997 to 1999. POPULATION Three hundred three poultry workers, 241 grain farmers and 206 nonfarming control subjects were studied. Poultry workers were further classified according to the poultry housing type in which they worked, ie, workers who worked with poultry raised on the floor (floor-based operations), which included broiler/roaster, broiler/breeder and turkey operations (n=181), and workers who worked with poultry raised in a caged setting (cage-based operations), which included egg operations (n=122). INTERVENTIONS Subjects completed a respiratory health questionnaire, which included questions on the poultry operation and work habits, and participated in lung function testing. MAIN RESULTS Overall, this study indicated that poultry workers report greater prevalences of current and chronic respiratory symptoms than control populations, and that the type of production method (cage-based versus floor-based) appears to influence the prevalence of respiratory symptoms and lung function values. Workers from cage-based operations report greater prevalences of current cough and wheeze, as well as lower mean values for forced expiratory volume in the first second (FEV1), forced expiratory flow at 25% to 75% of vital capacity (FEF25-75) and FEV1/FVC than workers from floor-based facilities. Workers from cage-based facilities also reported greater prevalences of current and chronic cough and phlegm, as well as significantly lower FEF25-75 and FEV1/FVC values than nonfarming control subjects. Furthermore, grain farmers had lower FVC and FEV1 values than nonfarmers. CONCLUSIONS The results suggest that the type of poultry production system (ie, floor- versus cage-based) appears to have an effect on the respiratory response of workers from these facilities. Further studies are required to understand the physiological mechanisms of respiratory dysfunction and the relationships concerning workplace exposure among poultry workers.

Depletion of activated neutrophils by a filter during cardiac valve surgery.

PurposeTo determine whether inclusion of a neutrophil-specific filter into the extracorporeal circuit during open heart valve surgery alters postoperative outcomes.MethodsConvenience sampling of 24 patients undergoing elective open heart valve surgery between July 1993 and June 1994. Patients were randomized to a neutrophil-specific filter (n= 11) or to a standard blood filter (n= 13) during cardiopulmonary bypass.ResultsNeutrophil-specific filter diminished (P < 0.02) the expression of CD 18, a neutrophil surface adhesion molecule, at 1 (84.5 ± 4.2 vs 94.8 ± 3.8%). 4 (80.0 ± 4.2 vs 95.1 ± 3.9%) and 24 hr (75.2 ± 4.2 vs 98.2 ±3.9%) post-operatively compared with standard filter. Total white blood cell count, neutrophil count, and proinflammatory cytokmes (IL-6, IL-8) were similar between groups at all times. Measured outcomes including: PaO2, cardiac index, ejection fraction, haemodynamic variables, use of motropes, spirometry (FEV FVC). and hospitalization duration were similar between groups.ConclusionsInclusion of the neutrophil filter during open heart valve surgery selectively depletes activated neutrophils. There were no other detectable differences between the two groups and the use of a neutrophilspecific filter in routine clinical practice for patients undergoing open heart valve surgery is not supported.RésuméObjectifDéterminer si l’ajout au circuit extracorporel d’un filtre spécifique aux neutrophiles pendant une chirurgie valvulaire modifiait les résultats de l’interventionMéthodesUn échantillonnage de 24 patients subissant une intervention valvulaire à coeur ouvert entre juillet 1993 et juin 1994. Les patients ont été répartis aléatoirement à un circuit extracorporel incluant un filtre spécifique aux neutrophiles (n= 11) ou un filtre standard (n= 13).RésultatsLe filtre spécifique aux neutrophiles a diminué l’expression de CD 18. une molécule adhésive de sur face, une heure (84.5 ± 4.2 vs 98.8 ± 3.8%), quatre heures (80 ± 4,2 vs 95.1 ± 3,9%) et 24 heures (75.2 ± 4,2 vs 98.2 ± 3.9%) après l’opération comparativement au filtre standard. Le décompte total des globules blancs, des neutrophiles et des cytokines pro-inflammatoires (IL-6. IL8) étaient à tous les moments identiques entre les groupes. Les mesures de résultats incluant la PaO2, l’index cardiaque, la fraction d’éjection, les données hémodynamiques, l’utilisation d’inotropes, la spirométne (VEMS, CVF) et la durée du séjour hospitalier étaient identiques entre les groupes.ConclusionL’ajout d’un filtre spécifique aux neutrophiles pendant la chirurgie à coeur ouvert épuise sélectivement les neutrophiles activés. Aucune autre différence n’est discernable entre les groupes. L’utilisation courante de filtres spécifiques aux neutrophiles en clinique chez des patients soumis à une chirurgie valvulaire à coeur ouvert n’est pas justifiée.

Lazaroid pretreatment preserves gas exchange in endotoxin-treated dogs☆

PURPOSE The lazaroids are a new class of potent free-radical scavengers. We tested whether U-74389G, a lazaroid, could attenuate some of the adverse cardiopulmonary effects of sepsis. METHODS Dogs were randomized to receive either 10 mg/kg U-74389G (n = 10), or a saline control (n = 11). After baseline measurements of hemodynamics and gas exchange, they were then randomized to receive either 0.2 mg/kg endotoxin or a saline infusion. Measurements of hemodynamics and gas exchange were repeated. The study was concluded 70 minutes after endotoxin infusion and the lungs were then removed for histologic evaluation. RESULTS In endotoxin-treated control animals, PO2 decreased (278 +/- 123 mm Hg to 67 +/- 13 mm Hg, P < .05) and intrapulmonary shunt increased (12.9% +/- 1.1% to 28.2% +/- 11.4%, P < .05) after endotoxin. Pretreatment with U-74389G attenuated the decrease in PO2 (476 +/- 61 mm Hg to 226 +/- 143) and the increase in intrapulmonary shunt (12.6% +/- 6.1% to 14.3% +/- 6.8%) observed after endotoxin. The extent of lung injury and systemic hemodynamics were similar between control or U-74389G-treated dogs. CONCLUSIONS A free-radical-scavenger can attenuate the gas exchange defect commonly associated with endotoxin but it does not improve the derangement of systemic hemodynamics.

Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury

BackgroundAlthough mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses.ResultsMechanical function and gas exchange parameters improved following treatment with doxycycline in the high volume ventilated group as compared to the placebo group. Nine pulmonary proteins have shown significant changes between the two biochemically analysed (high volume ventilated) groups. Treatment with doxycycline resulted in a decrease of pulmonary MMP-9 activity as well as in an increase in the levels of soluble receptor for advanced glycation endproduct, apoliporotein A-I, peroxiredoxin II, four molecular forms of albumin and two unnamed proteins. Using the pharmacoproteomic approach we have shown that treatment with doxycycline leads to an increase in levels of several proteins, which could potentially be part of a defense mechanism.ConclusionAdministration of doxycycline might be a significant supportive therapeutic strategy in prevention of VILI.

Excess Longitudinal Decline in Lung Function in Grain Farmers

ABSTRACT Workers in intensive agricultural operations are exposed to dust and endotoxin that are associated with respiratory effects. The authors investigated the longitudinal changes in lung function in male grain farmers. In this study, male grain farmers (n = 263) and male nonfarming control subjects (n = 261) studies initially in 1990/91 were followed-up in 1994/95 and 2003/04. After controlling for potential confounders, grain farmers had an excess annual decline of 9.2 ml/year (95% confidence interval [CI]: 2.7, 15.8, p = .006) in forced vital capacity (FVC) in comparison to control. Long-term exposure to grain dust and other substances in lifetime grain farmers results in progressive loss in lung function.

Augmentation of hypoxic pulmonary vasoconstriction by NG-L-methyl-arginine in a rabbit model of thermal injury☆

We tested deeply anesthetized rabbits to determine if a burn acutely diminished the strength of hypoxic pulmonary vasoconstriction (HPV) and if this could be augmented by L-NMMA, a nitric oxide synthase inhibitor. We induced a burn using water heated to 75 degrees C and assessed the strength of HPV as the difference in pulmonary vascular resistance during 100% and 13% O2 ventilation. The rabbits then were randomized to receive 10 mg/kg L-NMMA (n = 8) or a placebo (n = 8). The strength of HPV decreased from 0.42 +/- 0.11 mm Hg/mL/min preburn to 0.22 +/- 0.11 mm Hg/mL/min postburn (P <.05). L-NMMA administration augmented HPV to a postburn value of 0.48 +/- 0.014 mm Hg/mL/min (P <.05). We speculate that the loss of HPV following a burn could worsen ventilation to perfusion mismatch and thereby aggravate the hypoxia associated with burns. Augmentation of HPV might be a short-term goal during the acute stabilization of hypoxic burn patients.

Systemic thermal injury in anesthetized rabbits causes early pulmonary vascular injury that is not ablated by lazaroids

PurposeTo study the effects of a systemic thermal injury on the pulmonary vasculature with and without inhibitors of lipid peroxidation (U74389G).MethodsIn a prospective, placebo control, randomized, and blinded multi-group study, bum shock was induced by scalding thermal injury (65C) to 35% body surface area in rabbits (n=28). Hemodynamics and gas exchange were followed for 240 min post bum in four groups; No Burn, Burn-Control, Burn-U74 (10 mg·Kg−1 U74389G), No Burn-U74 (10 mg·Kg−1 U74389G).ResultsScald resulted in early pulmonary injury as measured by increased pulmonary vascular resistance in the pooled Burn group compared with the No Burn groups (942 ± 358 vs 605 ± 255 dynes-sec−1·cm−5 respectively, P < 0.05). These pulmonary changes were associated with alveolar sequestration of leukocytes (4.8 ± 2.9 vs 17.7 ± 6.0 cells × 109·L−1,P < 0.05) in the No Burn and Burn groups respectively. Histological evidence of decreased neutrophil sequestration after scald injury was present in U74 treated animals (3+ vs 2+,P < 0.05 in the Burn and No Burn groups respectively and 2+ vs 2+,P > 0.05 in the Burn-U74 and No Burn-U74 groups respectively) although bronchial alveolar lavage still demonstrated neutrophil sequestration (5.3 ±2.5 vs 12.2 ±3.3 cell 109L−1,P < 0.05 in No Burn-U74 and Burn-U74 groups respectively). Similarly, circulating white blood cells were increased in the Burn group but not Burn-U74 group four hours post burn. The increase in pulmonary vascular resistance after bum was not altered by administration of U74.ConclusionsSystemic burn results in early pulmonary vascular changes associated with leukocyte sequestration. After scald injury administration of lazaroids (U744389G) did not lessen pulmonary vascular resistance changes but did reduce neutrophil sequestration.RésuméObjectifÉtudier les effets d’une lésion thermique généralisée, associée ou non à des inhibiteurs de peroxydation lipidique (U74389G), sur le système vasculaire pulmonaire.MéthodeDans une étude multigroupe contre placebo, prospective, randomisée et à l’insu, le choc des brûlés a été induit par un ébouillantement traumatique (65C) sur 35 % de la surface corporelle de lapins (n = 28). Les caractéristiques hémodynamiques et les échanges gazeux ont été enregistrés pendant 240 min après la brûlure dans quatre groupes: Non brûlés, Brûléstémoins, Brûlés-U74 (10 mg·Kg−1 U74389G), Non brûlés- U74 (10 mg·Kg−1 U74389G).RésultatLe fait d’ébouillanter a produit une lésion pulmonaire précoce prouvée par l’accroissement de la résistance vasculaire pulmonaire dans les groupes Brûlés comparés aux groupes Non brûlés (942 ± 358 vs 605 ± 255 dynes·sec−1·cm−5 respectivement,P < 0,05). Ces changements pulmonaires étaient associés à une séquestration alvéolaire de leucocytes (4,8 ± 2,9 vs 17,7 ± 6,0 cellules × 109·L−1,P < 0,05) dans les groupes Non brûlés et Brûlés respectivement. Après le traumatisme thermique, une évidence histologique de la baisse de la séquestration des polynucléaires neutrophiles était présente chez les animaux traités au U74 (3+ vs 2+,P < 0,05 chez les Brûlés et les Non brûlés respectivement et 2+ vs 2+,P > 0,05 chez les Brûlés-U74 et les Non brûlés-U74 respectivement, bien que le lavage broncho-alvéolaire indiquait toujours la séquestration des polynucléaires neutrophiles (5,3 ± 2,5 vs 12,2 ± 3,3 cellules 109L−1,P < 0,05 chez les Non brûlés-U74 et les Brûlés-U74, respectivement). De même, après les brûlures, les leucocytes circulants ont augmenté dans le groupe d’animaux Brûlés, mais non dans celui des Brûlés-U74, et ce, pendant quatre heures. L’augmentation de la résistance vasculaire pulmonaire après une brûlure n’était pas changée par l’administration de U74.ConclusionUne brûlure généralisée provoque des changements vasculaires pulmonaires hâtifs associés à une séquestration de leucocytes. Après le traumatisme thermique, l’administration de lazaroïdes (U74389G) n’a pas diminué les changements de résistance vasculaire pulmonaire, mais a réduit la séquestration de polynucléaires neutrophiles.