Differential effects of prolonged septicemia on isolated pulmonary arteries and veins from sheep.

Isolated third-order pulmonary arteries and veins from sheep were examined for the effects of septicemia on norepinephrine-induced contractions, nitric oxide (NO)-mediated dilation, and basal cyclic GMP levels. The groups studied were as follows: control sheep (n = 7); sheep given live Pseudomonas aeruginosa (Ps, n = 6) for 48 h; and sheep given NG-mono-methyl-L-arginine during the last 24 h of Ps infusion (Ps-L-NMMA, n = 4). The norepinephrine-induced contractions were significantly greater (p < .05) in arteries from septic (Ps and Ps-L-NMMA) sheep. Basal cyclic GMP levels were similar in all of the arteries. The norepinephrine-induced contractions were significantly depressed (p < .05) in veins from septic (Ps and Ps-L-NMMA) sheep. Basal cyclic GMP levels in veins from Ps sheep were markedly elevated (p < .01). N omega-nitro-L-arginine methyl ester (L-NAME) ex vivo decreased cyclic GMP in both arteries and veins. Removal of endothelium enhanced contractions and decreased cyclic GMP in arteries and veins only from control sheep. The results show that septicemia differently affects the pulmonary artery and vein. The enhanced vasoconstriction of the artery is due to decreased endothelium-dependent NO release; the attenuated vasoconstriction of the vein is associated with NO-mediated increased cyclic GMP levels.

Pulmonary hemodynamics and tissue damage after one lung infusion of Pseudomonas aeruginosa in sheep.

The relative roles of hematogenous mediators and direct bacterial toxicity due to phagocytosis by pulmonary intravascular macrophages were determined by selective bacterial infusion into the left pulmonary artery and comparison of right and left lungs at 24 h. Chronically instrumented sheep received 15-min pulmonary arterial infusions of live Pseudomonas aeruginosa (0.35-2.9 x 10(9), n = 6) or saline (n = 5). The saline group demonstrated stable cardiopulmonary function over time. Left lung blood flow, measured by Doppler flow probe, decreased 15 min into the bacterial infusion, with a concomitant sevenfold increase in left lung pulmonary vascular resistance index. The right lung pulmonary vascular resistance index doubled at 1 h, in association with increased plasma thromboxane B2 levels. An increase in cardiac index and decrease in systemic vascular resistance occurred at 12 h. The wet-to-dry weight ratio of the Pseudomonas-infused left lung was increased compared with that of the sham-infused lung. The tissue count of neutrophils in the lungs was doubled in both sides, but neutrophils on the left were more degranulated. The left lung tissue damage was caused by direct bacterial toxicity, including activation of phagocytic cells. Hematogenous mediators induced pulmonary and systemic hemodynamic changes and right lung neutrophil sequestration, but they did not damage the noninfused lung.

Relaxation by calcitonin gene-related peptide may involve activation of K+ channels in the human uterine artery.

The vasodilatory role of calcitonin gene-related peptide in activating K+ channels was examined in isolated, suffused human uterine arteries. Calcitonin gene-related peptide produced a concentration-dependent relaxation of norepinephrine (1 microM)-induced contractions. Calcitonin gene-related peptide was antagonized by glybenclamide (1-100 microM), an inhibitor of ATP-sensitive K+ channels, but not by tetraethylammonium (1 mM), an inhibitor of calcium(2+)-activated K+ channels. Glybenclamide (10 microM) produced a 6.7 fold and an 11-fold shift to the right of calcitonin gene-related peptide (0.1 to 100 nM) in uterine arteries from pregnant patients (n = 3) and nonpregnant patients (n = 6), respectively. Calcitonin gene-related peptide (10 nM) less effectively (P < 0.05) relaxed contractions produced by KCl (50 mM) (29.4 +/- 1.6%) than by norepinephrine and glybenclamide (10 microM) did not reverse this relaxation (22.2 +/- 6.8%, n = 4 nonpregnant patients). Pinacidil (1 microM), an ATP-sensitive K+ channel opener, relaxed norepinephrine-induced contractions of uterine arteries. Glybenclamide (10 microM) also antagonized pinacidil. These results suggest that calcitonin gene-related peptide relaxes norepinephrine-contracted human uterine arteries, at least in part, by activation of a K+ channel, perhaps of the ATP-sensitive type.

Effect of preexisting inhalation injury on response to bacteremia in sheep.

Inhalation injury increases the likelihood of sepsis. We tested the hypothesis that preexisting inhalation injury would diminish bacterial clearance across the pulmonary vasculature and induce greater hemodynamic response. Live Pseudomonas aeruginosa were infused centrally for one hour in three groups of awake sheep. Inh + Ps (n = 10), with a seven to 10-day-old inhalation injury; Ps-LOW (n = 8) both received 10(7) Ps/min; and Ps-HI (n = 9) received 5 x 10(7) Ps/min. for one hour. Pulmonary hypertension was more severe in Ps-HI and Inh + Ps. A hyperdynamic response with high cardiac index and low mean arterial pressure developed in Inh + Ps and Ps-HI from six to 18 hr, while Ps-LOW, only the cardiac index was elevated at six to eight hr. The Inh + Ps and Ps-LOW groups had equivalent pulmonary artery and aortic bacterial levels, while Ps-HI had levels approximately five times higher. All groups removed bacteria efficiently in the lungs. However, preexistent inhalation injury exaggerated the pulmonary and systemic hemodynamic response.

Intravascular macrophages in pulmonary capillaries of humans.

Pulmonary intravascular macrophages reside in the pulmonary capillaries and phagocytize bacteria and particulates. These cells are prominent in several animals species, but they have not been described in humans. Samples of lung tissue from patients undergoing thoracotomies for excision of noninfectious diseases were examined with transmission electron microscopy to determine if pulmonary intravascular macrophages are present in humans. The macrophages, with cytoplasm closely adjacent to the capillary and with an irregular contour, were seen in specimens from all patients. The morphologic features of human pulmonary intravascular macrophages resemble the appearance of these cells in animals. The potential significance of pulmonary intravascular macrophages is discussed with regard to sepsis-induced acute respiratory failure.

Postoperative opisthotonus and torticollis after fentanyl, enflurane, and nitrous oxide.

Most drug-induced extrapyramidal symptoms are due to blockade of dopaminergic receptors and are treated with anticholinergic drugs. We report a patient with severe postoperative extrapyramidal symptoms which responded to physostigmine and indicated a different aetiology. A young, healthy female outpatient developed severe extrapyramidal symptoms after an uneventful 50 min anaesthetic with thiopentone, fentanyl (100 micrograms), enflurane, and nitrous oxide. Although the trachea was not extubated until she obeyed commands, the patient developed opisthotonus, which resolved initially after treatment with thiopentone (40 mg), diazepam (5 mg), and diphenhydramine (50 mg). The opisthotonus recurred approximately 25 min later, in association with torticollis, obtundation, and periodic apnoea. A tentative diagnosis of central anticholinergic syndrome was proposed, and fentanyl was considered to have been responsible. Naloxone (0.4 mg) induced no improvement, but physostigmine (2 mg) reversed the dystonic symptoms and periodic apnoea and improved her mental status. The response to physostigmine may have been due specifically to increased levels of acetylcholine at the cholinergic receptors, or to a nonspecific analeptic effect.

Cardiopulmonary changes occurring with pulmonary intravascular clearance of live bacteria in sheep.

Sheep were infused with live bacteria to determine if the bacteria are phagocytized in the pulmonary circulation and to study the associated cardiopulmonary changes. Unanesthetized animals (n = 9) with chronic hemodynamic and pulmonary lymph catheters received a 1 hr central venous infusion of live Pseudomonas aeruginosa (5 x 10(7) Ps./minute) and were compared to a sham group (n = 7). The pulmonary arterial levels of bacteria were five to 100 times higher than the aortic levels. Pulmonary intravascular clearance rates were 79-91%. Electron microscopy of the lungs 24 hr after the bacterial infusion showed that pulmonary intravascular macrophages and neutrophils phagocytosed the bacteria. Severe initial and mild persistent pulmonary hypertension occurred. The pulmonary lymph flow was elevated, initially from hydrostatic pressure and later from increased permeability. A hyperdynamic circulation occurred from 6 to 18 hr, with elevated cardiac index and lowered systemic vascular resistance and mean arterial pressure, mimicking cardiopulmonary changes seen in clinical sepsis. The removal of bacteria in the lungs may contribute to the injury in sheep.

Complement depletion in a porcine model of septic acute respiratory disease.

In a porcine model of severe septic acute respiratory failure produced by continuous infusion of live Pseudomonas aeruginosa, the role of the complement system was studied by pretreating animals with cobra venom factor (CVF) to deplete C3. Three groups of spontaneously breathing animals were monitored with Swan-Ganz and arterial thermodilution catheters. Group I was pretreated with 80 U/kg of CVF iv 16-18 hours before testing. Group II received Ps. aeruginosa iv (2 X 10(8)/20 kg/minute). Group III was pretreated with CVF and later given the Pseudomonas infusion. The CH50 as a measure of complement activity was less than 7% of normal level in Groups I and III. No changes in respiratory variables occurred in Group I. In Group II, the mean pulmonary artery pressure doubled, intrapulmonary shunt fraction (Qs/Qt) increased, PaO2 decreased, and extravascular lung water doubled in 4 hours. In Group III, the pulmonary hypertension, hypoxemia, increase in Qs/Qt, and increase in EVLW were all significantly less than in Group II. Neutropenia occurred with the Pseudomonas infusion in Groups II and III.

Indomethacin improvement of septic acute respiratory failure in a porcine model.

The effects of indomethacin, a prostaglandin synthesis blocker, were tested in a porcine model of septic acute respiratory failure (ARF) produced by continuous infusion of live Ps. aeruginosa. Control groups received either indomethacin boluses (2 mg/kg) intravenously at 20 and 210 minutes or Ps. aeruginosa infusion (2 X 10(8) CFU/20 kg/min). The treatment group received both continuous Ps. aeruginosa infusion and indomethacin. Indomethacin alone transiently but significantly decreased cardiac indices, heart rate, and PaCO2. With Ps. aeruginosa infusion, significant pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, and systemic hypotension occurred. In this porcine model of septic ARF, indomethacin doubled the survival period and improved cardiopulmonary parameters.

Prostacyclin in experimental septic acute respiratory failure.

Manipulation of prostaglandins (PG) in animal models of sepsis and acute respiratory failure (ARF) is promising. Prostacyclin (PGI2), a short-acting vasodilator, was evaluated in a porcine model of ARF produced by continuous infusion of live Pseudomonas aeruginosa (Ps.). Cardiopulmonary parameters were monitored in three groups of spontaneously breathing animals that received 0.1 micrograms PGI2/kg/min begun 20 min after baseline (Group I); 2 X 10(8) Ps./20 kg/min (Group II); identical Ps. infusion and then PGI2 begun at 20 min (Group III). The decrease in mean arterial blood pressure and cardiac index with Ps. infusion was improved by PGI2 treatment. In Groups II and III, mean pulmonary artery pressure (PAP) doubled (P less than 0.005) and pulmonary vascular resistance (PVR) tripled (P less than 0.01) by 15 min. Both PAP and PVR were decreased significantly with PGI2 treatment. In both Ps. groups, significant hypoxemia occurred. PGI2 improves cardiac output and acts as a pulmonary vasodilator, but does not improve oxygenation in this porcine model of severe ARF.

Comparison of live bacteria infusions in a porcine model of acute respiratory failure.

Acute respiratory failure (ARF) related to sepsis continues to have a high mortality and uncertain pathogenesis. With a reproducible live Pseudomonas aeruginosa infusion pig model, the gas exchange, hemodynamics, and pulmonary clearance of this organism were compared with live Staphylococcus aureus and Escherichia coli. Lightly anesthetized, male, mixed-breed pigs, 15-30 kg, were intubated, allowed to breathe spontaneously, and had femoral artery, central venous, and Swan-Ganz catheterization through cutdowns. After baseline data were collected, approximately 1 X 10(9) organisms/20 kg/min were infused into a central vein for 4 hr with frequent monitoring of the variables. Immediate autopsies were done for related quantitative tissue culture studies. S. aureus pigs maintained a high rate of lung bacterial clearance with pulmonary hypertension, a nonsignificant decrease in PaO2, and relatively normal lungs at autopsy. Ps. aeruginosa and E. coli animals developed systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, hypoxemia, and decreased pulmonary clearance. Their lungs had gross congestion and edema. These studies confirm the suitability of E. coli and Ps. aeruginosa infusion into pigs as a model of sepsis-induced ARF in man. The findings also indicate that neither pulmonary hypertension nor bacterial clearance by the lungs is sufficient to cause ARF.

Exaggerated cardiopulmonary response after bacteremia in sheep with week-old thermal injury.

OBJECTIVE: To determine if thermal injury impairs pulmonary intravascular clearance of bacteria and therefore leads to exaggerated cardiopulmonary dysfunction in sheep, since endotoxin infusion has been previously shown to induce more severe pulmonary injury after thermal injury. DESIGN: Prospective, unblinded, randomized, controlled trial. SETTING: Laboratory at a large university medical center. INTERVENTIONS: Chronically instrumented, anesthetized sheep received a 40% total body surface area, third-degree thermal injury. Live Pseudomonas aeruginosa (10(7) P. aeruginosa/min for 1 hr; n = 6) were infused 7 to 10 days after thermal injury. Similarly prepared noninjured sheep received the same pseudomonas infusion (n = 7) or saline (n = 7). MEASUREMENTS AND MAIN RESULTS: Bacterial clearance, which measures phagocytosis by the pulmonary intravascular macrophages, was equally efficient in intact sheep and sheep with thermal injury. Pulmonary hypertension persisted for 18 hrs after thermal injury, compared with 8 hrs in noninjured sheep. Lung lymph flow significantly increased from 6 to 8 hrs in only the thermal injury group. Both bacteremic groups developed a hyperdynamic circulation from 6 to 8 hrs, but cardiac index was 1 to 1.5 L/min/m2 higher in thermally injured sheep. Total peripheral resistance index decreased significantly from 6 to 24 hrs in thermally injured sheep and from 6 to 12 hrs in intact bacteremic sheep. Mean arterial pressure of thermally injured sheep was increased at baseline and for the first 6 hrs compared with noninjured animals. Mean arterial pressure decreased from 6 to 24 hrs in sheep with thermal injury but did not change in intact bacteremic sheep. CONCLUSIONS: Bacterial clearance was not impaired by preceding thermal injury in sheep. Bacteremia in the presence of a preexisting thermal injury led to more persistent pulmonary hypertension and an exaggerated hyperdynamic circulation.

Changes in regional hemodynamics after nitric oxide inhibition during ovine bacteremia.

We studied the action of nitric oxide synthase (NOS) inhibition on changes in regional blood flow during a continuous infusion of live bacteria. Eighteen ewes were chronically instrumented. After a 7-day recovery period, an infusion of 10(6) colony-forming units/min Pseudomonas aeruginosa was begun. At 24 h, cardiac output increased significantly above baseline in all groups (5.9 +/- 0.4 vs. 8.2 +/- 0.6 l.min 1.m-2), systemic vascular resistance decreased (1,362 +/- 120 vs. 821 +/- 145 dyn.g.cm-5.m-2), and cerebral, cephalic mesenteric, and hindlimb blood flows increased. The animals were then equally and randomly assigned to a bolus of a NOS inhibitor, either 25 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) or 20 mg/kg N omega-monomethyl-L-arginine (L-NMMA), followed by a continuous infusion of 7 mg.kg-1.min-1 L-NMMA or saline. After NOS inhibition, cardiac index decreased [5.6 +/- 0.1 (L-NAME) and 5.5 +/- 0.4 l.min-1.m-2 (L-NMMA)] and remained significantly decreased for 12 h. 1-NAME decreased carotid and mesenteric blood flows to 64% of the preseptic baseline, and they remained below baseline for 20 h. L-NMMA decreased blood flows only to preseptic baseline values. NOS inhibitors may affect blood flows independently of their hemodynamic effects.

Hydroxyethyl starch pretreatment in bacteremic sheep.

Live bacteria were infused in a chronic ovine lung lymph model to determine if a preceding infusion of the colloid, hydroxyethyl starch (HES), exaggerated the cardiopulmonary dysfunction or impaired removal of bacteria by macrophages in the pulmonary circulation. HES was infused (3 mL/kg/hr; n = 6) from 24 to 12 hr before the bacteria and decreased plasma protein content and increased pulmonary lymph to plasma protein concentration because of its oncotic properties. Ringer's lactate (2 mL/kg/hr) was given after stopping HES and also to the control group (n = 6). Infusion of live Ps. aeruginosa (2.5 x 10(8) Ps./min for approximately 30 min) induced equivalent pulmonary hypertension, increased pulmonary microvascular permeability, and cardiovascular depression in the two groups. The removal of bacteria in the lungs was not affected, indicating that this measurement of the function of the mononuclear phagocytic system was not impaired by the preceding HES.