Deborah J. Dehring

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.

Tricyclic antidepressants in treatment of depression and chronic pain: analysis of the supporting evidence.

There is now sufficient scientific evidence to indicate that chronic pain and depression share in common certain neurochemical abnormalities (1). With this interrelationship, it is not surprising that the tricyclic antidepressants have proven effective not only in the treatment of depression, but also in treating chronic pain. Most anesthesiologists are aware of the potential cardiac toxicity associated with the tricyclic antidepressants (2-8). Several reports have warned of tachycardia and deleterious arrhythmias in patients taking tricyclic antidepressants when given halothane and pancuronium during general anesthesia (9,lO). In contrast, the psychotropic and analgesic properties of the tricyclic antidepressants are less well known to many anesthesiologists. This review is oriented to the anesthesiologist interested in the management of chronic pain. It discusses depression and pain as concurrent disorders, the biomolecular mechanisms that control mood and pain, the usefulness of tricyclic antidepressants in chronic pain, and the direction for future studies. The juxtaposition of pain and depression and their treatment with tricyclic antidepressants also provides valuable insight into the neural abnormalities that occur during a chronic pain disorder.

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.

Sulfite Supported Lipid Peroxidation in Propofol Emulsions

Background Sodium metabisulfite is added to a commercial propofol emulsion as an antimicrobial agent. The sulfite ion (SO3−2) is capable of undergoing a number of reactions, including autooxidation and the promotion of lipid peroxidation. This study evaluated sulfite reactivity in propofol emulsions by determining thiobarbituric acid reacting substances (TBARS), sulfite depletion, and emulsion pH in emulsions containing sulfite or EDTA. Methods Commercial EDTA and sulfite propofol emulsions were compared, and 10% soybean oil emulsion containing various additives were evaluated for TBARS, sulfite, and pH. TBARS were analyzed with a modified thiobarbituric acid method. Sulfite was analyzed by the reaction of sulfite with 5,5′-dithiobis(2-nitrobenzoic acid). pH was measured by glass electrode methodology. Results Thiobarbituric acid reacting substances were detectable in commercial sulfite propofol emulsions in concentrations ranging from 0.02 to 0.22 &mgr;g/ml based on malondialdehyde. No TBARS were detected in EDTA propofol emulsions. Incubation (37°C, up to 6 h) of sulfite propofol emulsions in air resulted in further increases in TBARS (35–160%). No increases occurred in incubated EDTA propofol emulsions. Metabisulfite (0.25 mg/ml) alone added to 10% soybean oil resulted in large increases in TBARS that were inhibited in part by propofol (10 mg/ml) and completely by ascorbic acid (0.05 mg/ml). Soybean oil emulsion pH declined rapidly on the addition of metabisulfite (0.25 mg/ml). The addition of propofol (10 mg/ml) partially inhibited the decline in pH and ascorbic acid (0.05 mg/ml) completely inhibited it. Conclusion These results show that sulfite supports the peroxidation of lipids in soybean oil emulsions and propofol functions to partially inhibit these processes.

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.

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.

Postoperative opisthotonus and torticollis after fentanyl, enfiurane, 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 μg), 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.RésuméLa plupart des symptômes extrapyramidaux reliés à l’usage de médicaments sont causés par un blocage des récepteurs dopaminergiques et répondent bien aux anticholinergiques. Nous avons observé en postopératoire desmanifestations extrapyramidales répondant à l’usage de physostigmine, ce qui trahit une étiologie différente. Suite à une anesthésie de 50 minutes au thiopental, fentanyl (100 μg), enflurane et protoxyde d’azote et la détubation de la trachée après retour de la conscience, une jeune femme présenta un opisthotonos. Quarante mg de thiopental, 5 mg de diazépam et 50 mg de diphenhydramine parvinrent à contrer l’opisthotonos qui réapparu 25 minutes plus tard associé cette fois à un torticolis, de la stupeur et des pauses respiratoires. Avec un diagnostic présomptif de syndrome anticholinergique central attribuable au fentanyl, on essaya sans résultat 0,4 mg de naloxone. Deux mg de physostigmine suffirent à faire disparaître la dystonie et les pauses respiratoires et à améliorer l’état de conscience de la patiente. Cette réponse à la physostigmine peut être attribuable à une augmentation la quantité d’acétylcholine sur les récepteurs cholinergiques ou à un effet analeptique non-spécifique.

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.

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 (107P. 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. (Crit Care Med 1993; 21:88–893)

Amelioration of pulmonary pathophysiology of adult respiratory distress syndrome by sulindac, a cyclo-oxygenase inhibitor

The effects of sulindac, a cyclo-oxygenase inhibitor, were tested in a bacteremic porcine model of acute respiratory failure produced by a continuous infusion of live Pseudomonas aeruginosa. Control groups received either a single intravenous dose of sulindac (6 mg/kg) 20 minutes after baseline determinations or a continuous infusion of Ps. aeruginosa (10(7) CFU/kg/min) beginning at time 0. The experimental group received both. Sulindac alone had no effect on any hemodynamic or gas exchange parameter. Ps. aeruginosa infusion caused pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, systemic hypotension, and increased extravascular lung water. Sulindac treatment reversed the pulmonary hypertension, hypoxemia, and increased intrapulmonary shunting, prevented the systemic hypotension, but had no effect on the rising extravascular lung water.