Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats

BACKGROUND: The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma-lipid emulsion mixture. METHODS: Anesthetized Sprague-Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n = 6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 ml x kg x min(-1) to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n = 6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabeled bupivacaine. RESULTS: Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P < 0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n = 3). CONCLUSIONS: Lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine.     

Acute treatment with corticosteroids decreases IGF-1 and IGF-2 expression in the rat diaphragm and gastrocnemius

Massive doses of methylprednisolone (M) or triamcinolone (T) induced diaphragmatic type IIx/b atrophy, resulting in a leftward shift of the force-frequency curve in rats (). To examine the role of insulin-like growth factors (IGFs) in these changes, IGF mRNA content was measured in costal diaphragm, gastrocnemius, and liver removed from 32 rats treated daily during 5 d either with saline (control, C and pair-fed, PF), M, or T (80 mg/kg). Blood samples were taken to measure IGF-1 serum levels. RNA levels were measured by Northern and dot-blots after hybridization with rat IGF-1 or IGF-2 cDNA probes labeled with alpha-32P. Compared with C (845 +/- 128 ng/ml), IGF-1 serum levels were significantly decreased in M (699 +/- 90 ng/ml, p < 0.001 versus C) and PF animals (505 +/- 33 ng/ml, p < 0.001 versus others) and even more so, in T-treated animals (273 +/- 134 ng/ml, p < 0.001 versus others). Along the same lines, IGF-1 expression in the liver was depressed after corticosteroid treatment and in PF, whereas IGF-2 mRNA content remained unchanged. Compared with C, the relative expression of IGF-1 mRNA in the diaphragm was depressed by 44% and 69% in the M and T groups, respectively (p < 0.0001 versus C), while it was unchanged in PF animals. In the gastrocnemius, IGF-1 expression was reduced after M and T (-51% and -59%, respectively, p < 0.0001 versus C) as well as in PF animals (-40%, p < 0.001 versus C). For IGF-2, a similar pattern of expression was found in the diaphragm and the gastrocnemius. Indeed, IGF-2 mRNA tended to decrease in corticosteroid-treated rats (NS) whereas it was unchanged in PF rats. We conclude that decreased IGF expression after corticosteroid treatment was similar in diaphragm and gastrocnemius and may be responsible for the diaphragmatic changes observed after steroid treatment.     

Chemokine receptor CXCR4 expression in endothelium

The aim of the present study was to study the sensibility in the area of saline-induced muscle pain. In three experiments, ten subjects were exposed to computer-controlled infusion of 0.5 ml isotonic (0.9%) or hypertonic (9%) saline into the anterior tibial muscle. The pain intensity was assessed on a visual analogue scale (VAS). The pain threshold (PT) to pressure and electrical stimulation in muscle and subcutaneous tissues was determined. Three experiments were performed in which infusion of hypertonic saline produced significantly higher VAS scores than isotonic saline. In all three experiments, there was no significant difference in PT obtained after infusion of isotonic saline compared with infusion of hypertonic saline. In experiment 1, the PT was determined at the infusion site and 4 cm from the infusion site. At the infusion site, the pressure PT decreased (-19 +/- 2%) 1, 3, 5, 7 and 9 min after infusion of isotonic and hypertonic saline, but remained unchanged 4 cm from the infusion site. The intramuscular electrical PT at the infusion site and 4 cm from the infusion site increased significantly (29 +/- 6%) 5, 7 and 9 min after saline infusion. In experiment 2, the pressure PT and the intramuscular electrical PT were recorded after two infusions of saline separated by 1 day. The day after the first infusion, the pressure PT was decreased compared with the PT before the first infusion, but the electrical PT was not affected. Moreover, the hypertonic saline infusion given on the second day produced significantly higher (130 +/- 50%) VAS scores than the infusion given on the first day. In experiment 3, the PT was determined in the subcutaneous tissue, but no significant effects of saline infusion were found. The present placebo-controlled experiments failed to show muscular or subcutaneous hyperalgesia after saline-induced muscle pain per se.     

Mechanisms for the paradoxical resistance to d-tubocurarine during immobilization-induced muscle atrophy

This study investigated whether immobilization-induced hyposensitivity to d-tubocurarine (dTC), up-regulation of acetylcholine receptors (AChRs) and changes in fiber size and motor endplate size persist indefinitely and whether they are causally related. Unilateral disuse of the tibialis muscle was produced in adult rats by pinning the knee and ankle joints at 90 degrees flexion. The contralateral unpinned and a separate group of sham-pinned legs served as controls. After 7, 14 or 28 days of disuse, the in vivo dose of dTC that produced 50% depression of nerve-evoked twitch (ED50) in the tibialis muscle increased 3.0-, 3. 2- and 2.1-fold (P < .05), and membrane AChRs increased 6.0- (P < . 05), 6.3- (P > .05) and 1.2-fold (P > .395) relative to control, respectively. Disuse caused muscle fiber atrophy (P < .01) but did not affect endplate size. Hence, the ratio of endplate size to fiber size increased. There was a transient increase in gene expression of all (including de novo expression of the gamma) subunits of the AChR, peaking at day 7 and returning to normal by day 28 of immobilization. The ED50 of dTC correlated directly with AChRs (R2 = 0.51; P < .0001) or the ratio of endplate size to fiber size (R2 = 0. 30; P < .001), and inversely with fiber size (R2 = 0.43, P < .0001). It is proposed that acting together, but not singly, the changes in AChRs, fiber size and relative endplate size contribute to the magnitude and time course of the resistance to dTC produced by chronic disuse.     

Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-I treatment

The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 +/- 8 vs. 123 +/- 16 mg. Muscle weight in the FO + GH/IGF-I group (196 +/- 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 +/- 445 microm2) was increased compared with the Con (2,044 +/- 108 microm2) and FO (2,267 +/- 301 microm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 +/- 15 myonuclei/mm) and FO + GH/IGF-I (217 +/- 23 myonuclei/mm) rats compared with Con (155 +/- 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.     

Intravenous cocaine induces platelet activation in the conscious dog

BACKGROUND: Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo. METHODS AND RESULTS: Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91 +/- 3 to 128 +/- 7 mm Hg [P < .01]) and heart rate (87 +/- 9 to 125 +/- 11 beats per minute [P < .01]). A similar change (P = NS) in mean arterial pressure followed norepinephrine infusion (100 +/- 5 to 137 +/- 13 mm Hg [P < .04]), whereas saline infusion had no effect. Cocaine resulted in a substantial but delayed increase in platelet P-selectin expression (14 +/- 7% [P < .08], 31 +/- 12% [P < .04], and 55 +/- 22% [P < .04] at 17, 22, and 27 minutes after drug infusion, respectively). The magnitude of this increase was similar to that found in blood treated ex vivo with the agonists ADP or PAF (23 +/- 7% and 53 +/- 15%, respectively). No significant increase in P-selectin expression was detected in the blood of animals that received norepinephrine or saline. Serum cocaine concentrations were highest immediately after infusion (538 +/- 55 ng/mL at 2 minutes) but declined rapidly (185 +/- 22 and 110 +/- 25 ng/mL at 17 and 32 minutes after infusion); in contrast, the increase in benzoylecgonine concentrations was delayed (from < 25 ng/mL in all but one animal [34 ng/mL] at 2 minutes to 46 +/- 4 and 71 +/- 11 ng/mL at 17 and 32 minutes, respectively, after infusion). CONCLUSIONS: Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.     

Terazosin in the treatment of hypertension and symptomatic benign prostatic hyperplasia: a primary care trial

In vitro experimental data show that magnesium increases beta-receptor affinity to agonists. We studied the effect of a mild increase in serum magnesium level on the bronchial dose-response curve to salbutamol in six patients with asthma (age 54 +/- 3.6 years, FEV1 49.2 +/- 4.9 per cent of predicted), with a normal serum magnesium level, in a double blind placebo-controlled design. The salbutamol dose-response curve was obtained on two separate days, starting 30 min after an intravenous infusion of saline or MgSO4 (20 mg/kg over 10 min, followed by 10 mg/kg/h). The baseline FEV1 values and the values after 30 min infusion on the two test days were not significantly different. During MgSO4 infusion, the serum magnesium level increased significantly from 0.86 +/- 0.01 to 1.31 +/- 0.19 mmol/litre after 30 min and 1.29 +/- 0.17 mmol/litre at the end of the study. FEV1 values after salbutamol were significantly higher during MgSO4 than during saline infusion at the low doses of salbutamol: 1480 +/- 253 vs. 1368 +/- 212 ml, P < 0.05, after 5 micrograms, and 1596 +/- 585 vs. 1378 +/- 532 ml, P < 0.01, after 10 micrograms of salbutamol. The maximum increase in FEV1 obtained after the maximum dose of salbutamol (400 micrograms) was not significantly different during saline and MgSO4 infusion. In conclusion, a mild sustained increase in serum magnesium level increases the bronchodilating effect of low doses of salbutamol, possibly through an increased beta-receptor affinity. There was no effect on the maximum bronchodilating effect of salbutamol.     

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition

PURPOSE: In a rabbit model, transposition of a muscle pedicle flap to an ischemic hind limb has been shown to result in the development of new blood vessels that connect the arterial circulation of the flap to the circulation of the limb. The hypothesis that exogenous recombinant basic fibroblast growth factor (bFGF) would enhance the development of this new blood supply was examined and the regulation of bFGF in this process was investigated. METHODS: The right common iliac artery was ligated in 12 male New Zealand white rabbits. An abdominal wall muscle flap based on the left inferior epigastric artery was transposed to the right thigh. bFGF in phosphate-buffered saline (PBS) at 3 ng/h (n = 6), or PBS alone (n = 6), was infused for 7 days via mini-osmotic pumps with an infusion catheter positioned at the flap-muscle interface. The flap-muscle interface was immunostained with anti-alpha-actin antibody to determine blood vessel density (number of vessels/mm) and with anti-bFGF antibody to evaluate bFGF distribution. RNA was isolated from these sections, and polymerase chain reaction (PCR) was used to examine endogenous bFGF messenger RNA (mRNA) expression. RESULTS: Blood vessel density was significantly increased in animals receiving exogenous bFGF (22. 0 +/- 10.6 vessels/mm vs. 10.7 +/- 8.8 vessels/mm, P =.009). In the controls, neovessels were arranged in clusters with endogenous bFGF concentrated around these clusters. In bFGF-treated animals, vessels were diffusely scattered throughout the flap-limb interface, corresponding to the distribution pattern of infused bFGF. There was no difference in bFGF mRNA expression between the control and the bFGF-treated groups. CONCLUSION: Exogenous bFGF infusion significantly augmented new blood vessel development at the flap-limb interface. Endogenous bFGF was up-regulated around the newly developed microvessels in control animals, and vessel growth correlated with the diffuse distribution of exogenous bFGF, implicating bFGF as an important factor in angiogenesis. Exogenous bFGF did not affect bFGF mRNA expression, suggesting that the regulation of bFGF is not under autocrine control.     

Scatter rejection in modular gamma cameras for use in dynamic 3D spect brain imaging system

This study examined the effects of Albunex (sonicated 5% human serum albumin) infusion on left ventricular inflow velocity by Doppler echocardiography. Left ventricular pressure and left ventricular inflow velocity were recorded simultaneously under eight different conditions in dogs: 1) baseline 1 (control), 2) Albunex 0.2 ml/kg, 3) baseline 2, 4) Albunex 0.5 ml/kg, infusion of dextran 100 ml, 5) baseline 3, 6) Albunex 0.2 ml/kg, 7) baseline 4, and 8) Albunex 0.5 ml/kg. In the normal state (no dextran), Albunex (0.2 ml/kg) caused no hemodynamic changes or inflow velocity changes. In contrast, infusion of Albunex (0.5 ml/kg) caused time velocity integrals of early filling to increase from the baseline (5.51 +/- 1.13 vs 7.19 +/- 1.14 cm, p < 0.05). After dextran infusion (100 ml), Albunex (0.2 ml/kg) caused peak early filling velocity to increase (62.4 +/- 6.9 vs 67.3 +/- 9.4 cm/sec, p < 0.05), and infusion of Albunex (0.5 ml/kg) also caused peak early filling velocity to increase from baseline (64.6 +/- 8.5 vs 73.7 +/- 14.5 cm/sec, p < 0.05). Infusion of Albunex (0.5 ml/kg) after dextran infusion caused increases in left ventricular pressure at the mitral valve opening (12.7 +/- 3.1 vs 15.2 +/- 3.3 mmHg, p < 0.05) and in left atrial driving force (13.5 +/- 3.6 vs 16.7 +/- 5.9 mmHg, p < 0.05). Clinicians should be cautious about using Albunex at doses of greater than 0.2 ml/kg when evaluating the pressure gradient of the left ventricle in patients with elevated left ventricular diastolic pressure. In patients with normal hemodynamics, Albunex infusion at doses of less than 0.2 ml/kg apparently did not affect the velocity measurement.     

Postresuscitation left ventricular systolic and diastolic dysfunction. Treatment with dobutamine

BACKGROUND: Global left ventricular dysfunction after successful resuscitation is well documented and appears to be a major contributing factor in limiting long-term survival after initial recovery from out-of-hospital sudden cardiac death. Treatment of such postresuscitation myocardial dysfunction has not been examined previously. METHODS AND RESULTS: Systolic and diastolic parameters of left ventricular function were measured in 27 swine before and after successful resuscitation from prolonged ventricular fibrillation cardiac arrest. Dobutamine infusions (10 micrograms.kg-1.min-1 in 14 animals or 5 micrograms.kg-1.min-1 in 5 animals) begun 15 minutes after resuscitation were compared with controls receiving no treatment (8 animals). The marked deterioration in systolic and diastolic left ventricular function seen in the control group after resuscitation was ameliorated in the dobutamine-treated animals. Left ventricular ejection fraction fell from a prearrest 58 +/- 3% to 25 +/- 3% at 5 hours after resuscitation in the control group but remained unchanged in the dobutamine (10 micrograms.kg-1.min-1) group (52 +/- 1% prearrest and 55 +/- 3% at 5 hours after resuscitation). Measurement of the constant of isovolumic relaxation of the left ventricle (tau) demonstrated a similar benefit of the dobutamine infusion for overcoming postresuscitation diastolic dysfunction. The tau rose in the controls from 28 +/- 1 milliseconds (ms) prearrest to 41 +/- 3 ms at 5 hours after resuscitation whereas it remained constant in the dobutamine-treated animals (31 +/- 1 ms prearrest and 31 +/- 5 ms at 5 hours after resuscitation). CONCLUSIONS: Dobutamine begun within 15 minutes of successful resuscitation can successfully overcome the global systolic and diastolic left ventricular dysfunction resulting from prolonged cardiac arrest and cardiopulmonary resuscitation.     

A 26-year-old man with shoulder pain

The acute effects of flumazenil, a benzodiazepine (BZD) receptor antagonist in long-term BZD users were used as a possible test to detect physiological dependence. Thirty-four subjects (20 females, 14 males) aged 26-48 years (mean + SD, 42.4+/-8.5 years), all chronic users of low doses of diazepam (5-20 mg/day, 14.2+/-4.8 mg/day) for 5 to 28 years (10.5+/-6 years), received a single 1-mg i.v. flumazenil dose or saline, infused slowly under double-blind conditions. Physiological dependence was suggested as all patients receiving flumazenil developed an anxiety reaction while the placebo group did not. Flumazenil triggered a qualitatively different reaction amounting to a panic attack during infusion in nine out of 15 patients. These patients had a diagnosis of panic disorder or a history of panic attacks. Caution should be exercised when giving flumazenil to panic patients who are taking BZDs as maintenance treatment.     

Exogenous surfactant and positive end-expiratory pressure in the treatment of endotoxin-induced lung injury

OBJECTIVE: To evaluate the efficacy of treating endotoxin-induced lung injury with single dose exogenous surfactant and positive end-expiratory pressure (PEEP). DESIGN: Prospective trial. SETTING: Laboratory at a university medical center. SUBJECTS: Nineteen certified healthy pigs, weighing 15 to 20 kg. INTERVENTIONS: Pigs were anesthetized and surgically prepared for hemodynamic and lung function measurements. Animals were randomized into four groups: a) Control pigs (n = 4) received an intravenous infusion of saline without Escherichia colilipopolysaccharide (LPS); b) the LPS group (n = 5) received an intravenous infusion of saline containing LPS (100 microg/kg); c) the PEEP plus saline group (n = 5) received an intravenous infusion of saline containing LPS. Two hours after LPS infusion, saline was instilled into the lung as a control for surfactant instillation, and the animals were placed on 7.5 cm H2O of PEEP; d) the PEEP plus surfactant group (n = 5) received an intravenous infusion of saline containing LPS. Two hours following LPS infusion, surfactant (50 mg/kg) was instilled into the lung and the animals were placed on 7.5 cm H2O of PEEP. PEEP was applied first and surfactant or saline was instilled into the lung while maintaining positive pressure ventilation. All groups were studied for 6 hrs after the start of LPS injection. At necropsy, bronchoalveolar lavage was performed and the right middle lung lobe was fixed for histologic analysis. MEASUREMENTS AND MAIN RESULTS: Compared with LPS without treatment, PEEP plus surfactant significantly increased PaO2 (PEEP plus surfactant = 156.6 +/- 18.6 [SEM] torr [20.8 +/- 2.5 kPa]; LPS = 79.2 +/- 21.9 torr [10.5 +/- 2.9 kPa]; p<.05), and decreased venous admixture (PEEP plus surfactant = 12.5 +/- 2.0%; LPS = 46.9 +/- 14.2%; p< .05) 5 hrs after LPS infusion. These changes were not significant 6 hrs after LPS infusion. PEEP plus surfactant did not alter ventilatory efficiency index (VEI = 3800/[peak airway pressure - PEEP] x respiratory rate x PacO2), or static compliance as compared with LPS without treatment at any time point. Cytologic analysis of bronchoalveolar lavage fluid showed that surfactant treatment significantly increased the percentage of alveolar neutrophils as compared with LPS without treatment (PEEP plus surfactant = 39.1 +/- 5.5%; LPS = 17.4 +/- 6.6%; p< .05). Histologic analysis showed that LPS caused edema accumulation around the airways and pulmonary vessels, and a significant increase in the number of sequestered leukocytes (LPS group = 3.4 +/- 0.2 cells/6400 micro2; control group = 1.3 +/- 0.1 cells/6400 micro2; p < .05). PEEP plus saline and PEEP plus surfactant significantly increased the total number of sequestered leukocytes in the pulmonary parenchyma (PEEP plus surfactant = 8.2 +/- 0.7 cells/6400 micro2; PEEP plus saline = 3.9 +/- 0.2 cells/6400 micro2; p <.05) compared with the control and LPS groups. CONCLUSIONS: We conclude that PEEP plus surfactant treatment of endotoxin-induced lung injury transiently improves oxygenation, but is unable to maintain this salutary effect indefinitely. Thus, repeat bolus dosing of surfactant or bolus treatment followed by continuous aerosol delivery may be necessary for a continuous beneficial effect.     

Acute adenosine treatment is effective in augmentation of ischemic tolerance in muscle flaps in the pig

The objective of the present project was to investigate the efficacy and mechanism of acute (10-minute) adenosine treatment for augmentation of ischemic tolerance in muscle flaps in pigs. Varying doses of adenosine were infused into 28 latissimus dorsi muscle flaps through the axillary artery (0, 0.5, or 2.0 mg per flap) and 22 gracilis muscle flaps through the medial circumflex femoral artery (0, 10, or 20 mg per flap) over 10 minutes. Ten minutes after adenosine infusion, these muscle flaps were subjected to 4 hours of sustained warm global ischemia. In addition, one group of latissimus dorsi muscle flaps (n = 6) received a 10-minute intraarterial adenosine infusion (0.5 mg) at the beginning of reperfusion. Muscle biopsies (n = 4 or 5) for adenosine triphosphate (ATP) analysis were obtained before and after adenosine infusion and at the end of 4 hours of ischemia. The extent of muscle infarction was assessed at 48 hours of reperfusion by the tetrazolium dye staining technique. Muscle blood flow in latissimus dorsi muscle flaps was measured at the end of adenosine infusion (0 or 0.5 mg per flap, n = 8) by the radioactive microsphere (15-microns) technique. It was observed that adenosine, at all doses tested, significantly (p < 0.05) reduced the extent of muscle infarction in latissimus dorsi muscle flaps (control, 40.3 +/- 2.2 percent; 0.5 mg, 20.6 +/- 1.6 percent; 2.0 mg, 18.2 +/- 1 percent) and gracilis muscle flaps (control, 31.0 +/- 1.5 percent; 10 mg, 14.3 +/- 3 percent; 20 mg, 11.6 +/- 1.2 percent). Preischemic adenosine treatment (0.5 mg per flap) was associated with maintenance of a significantly (p < 0.05) higher muscle content of ATP in latissimus dorsi muscle flaps at the end of 4 hours of ischemia compared with saline-treated ischemic controls. Postischemic adenosine treatment did not protect latissimus dorsi muscle flaps against infarction. Furthermore, adenosine treatment did not have any significant effect on mean systemic arterial blood pressure or muscle blood flow in latissimus dorsi muscle flaps. It is concluded that acute (10-minute) preischemic adenosine treatment is effective in augmentation of ischemic tolerance in muscle flaps and that this protective effect of adenosine may be, at least in part, the result of slowing muscle ATP depletion during sustained ischemia. The possible mechanisms of this adenosine-induced energysparing effect are discussed.     

Differential sensitivity of prolactin release to dopamine and thyrotrophin-releasing hormone in intact and pituitary stalk-sectioned rhesus monkeys

The effects of dopamine and thyrotrophin-releasing hormone (TRH) on prolactin release was studied in 14 intact and six pituitary stalk-sectioned (SS) female rhesus monkeys (Macaca mulatta). Baseline prolactin values were ninefold higher in SS animals (149+/-16 ng/ml) than in intact animals (16+/-1 ng/ml). Prolactin release after intravenous administration of TRH in doses of 0, 125, 250, 500 and 1000 ng revealed that SS monkeys were more sensitive to the prolactin-releasing activity of this tripeptide than were intact animals. A significant (P less than 0.05) increment in serum prolactin was observed in SS animals after injection of 125 ng TRH whereas 250 ng was required to raise prolactin levels in the circulation of intact animals significantly (P less than 0.05). Furthermore, at each comparable dose level of TRH, the increment in serum prolactin was distinctly greater in SS animals than in intact monkeys. Infusion of dopamine at the rate of 10 microgram/kg body weight per min significantly (P less than 0.05) lowered prolactin levels within 60 min in intact animals and no further decline was observed with 20 or 40 microgram dopamine. Serum prolactin concentrations were not affected by saline infusion or by 5 microgram dopamine. Infusion of dopamine at the rate of 10 microgram/kg body wt per min also resulted in significant (P less than 0.01) suppression of serum prolactin in SS animals. This prolactin decrease was apparent within 40 min. Prolactin release after 500 ng TRH was less in these dopamine-treated SS monkeys than after an infusion of saline. Higher doses of dopamine (20 and 40 microgram) did not cause a further decrease in basal serum prolactin concentrations, but these two dopamine treatments blocked the increase in prolactin elicited by 500 ng TRH. The results suggest that the removal of hypothalamic influence, possibly related to the effects of dopamine, renders the pituitary gland more sensitive to the prolactin-releasing action of TRH.     

The effect of a lesion of the subcortical conducting pathways on the electrical activity of the human cerebral cortex

We studied whether monophosphoryl lipid A (MLA), an endotoxin derivative, protected the heart from planned ischemia in hypercholesterolemic conscious rabbits. Normal and hypercholesterolemic (8-week exposure to 1.5% cholesterol-enriched diet) conscious rabbits with right ventricular electrode and left ventricular polyethylene catheters were subjected to ventricular overdrive pacing (VOP: 500 beats/min over 10 min = control VOP). The resulting intracavitary ST-segment elevation, increase in left ventricular end-diastolic pressure (LVEDP), and a reduction of ventricular effective refractory period (VERP) were measured. Three days later the animals were given a single intravenous bolus of 10 or 30 microg/kg MLA or its solvent or both, and a second VOP (test VOP) was applied 24 h later. MLA decreased ST elevation and LVEDP increase from 2.1 +/- 0.16 to 1.27 +/- 0.25 and 0.97 +/- 0.13 mV and 14.6 +/- 1.2 to 11.1 +/- 1.0 and 12.4 +/- 1.2 mm Hg in normal animals and from 2.55 +/- 0.14 to 1.31 +/- 0.12 and 0.96 +/- 0.30 mV and from 21.0 +/- 1.6 to 11.7 +/- 1.3 and 12.4 +/- 1.3 mm Hg in atherosclerotic animals after 10- and 30-microg/kg doses, respectively (p < 0.001 for each). VOP-induced VERP reduction was also significantly alleviated by both MLA doses; nevertheless, 30-microg/kg MLA significantly prolonged resting VERP with a slight VERP reduction in response to pacing in both normal and atherosclerotic animals. We conclude that MLA produces a delayed antiischemic effect in both normal and hypercholesterolemic/atherosclerotic conscious rabbits.     

Differential response of arteries and vein grafts to blood flow reduction

BACKGROUND: Because the relative efficacy of antiarrhythmic agents on halothane-epinephrine arrhythmias has not been well characterized, this study was undertaken to comparatively evaluate the antiarrhythmic action of Na(+)-, K(+)- and Ca(2+)-channel blockers on epinephrine-induced ventricular arrhythmias during halothane anesthesia in rats. METHODS: Rats were anesthetized at random with either halothane (1.5%), isoflurane (2.0%), or pentobarbital (50 mg/kg intraperitoneally), and the lungs were mechanically ventilated with oxygen. The rats were studied in three consecutive protocols. Protocol I determined the arrhythmogenic thresholds of epinephrine during the three types of anesthesia in 33 rats. Protocol II determined the arrhythmogenic thresholds of epinephrine during halothane anesthesia in 64 rats receiving saline (control) or one of five antiarrhythmic agents. Protocol III measured the duration of epinephrine-induced arrhythmias during halothane anesthesia in 42 rats receiving saline (control) or one of five antiarrhythmic agents. RESULTS: In protocol I, the arrhythmogenic doses of epinephrine during halothane, isoflurane, or pentobarbital anesthesia were 1.7 +/- 3.2, 11.1 +/- 0.6, and 39.0 +/- 3.9 micrograms/kg, respectively, and the corresponding plasma concentrations were 4.3 +/- 0.8, 103.7 +/- 9.2, and 246.7 +/- 28.9 ng/ml, respectively. In protocol II, the arrhythmogenic doses were similar in rats receiving saline and in those receiving lidocaine. The arrhythmogenic doses in rats receiving verapamil, flecainide (Na(+)- and K(+)-channel blocker), E-4031 (K(+)-channel blocker), or amiodarone(K(+)-channel blocker with Na(+)-, Ca(2+)-, and beta-blocking activity) increased significantly, i.e., 4.2, 4.2, 5.5, and 31.7 times control (P < 0.01). In protocol III, lidocaine had no effect on the duration of arrhythmias. Flecainide, E-4031, and verapamil markedly reduced the duration of arrhythmias induced by epinephrine, 8 micrograms/kg intravenously (P < 0.01), whereas only amiodarone markedly reduced the duration of arrhythmias induced by epinephrine, 16 micrograms/kg intravenously (P < 0.01). CONCLUSIONS: It was concluded that agents with K(+)-channel blocking properties were the most effective in preventing halothane-epinephrine arrhythmias in rats.     

Effects of the stable prostacyclin analogue iloprost on mesenteric blood flow in porcine endotoxic shock

OBJECTIVE: To determine the effects of the stable prostacyclin analog, iloprost, in a porcine model of endotoxin-induced mesenteric ischemia. DESIGN: Prospective, experimental, randomized, controlled study. SETTING: Animal research laboratory at a university medical center. INTERVENTIONS: Pigs were randomized to receive a constant infusion of iloprost (0.18 microg/kg/min) or an equivalent amount of carrier solution (normal saline) 30 mins before being infused with endotoxin (100 microg/kg over 1 hr). The infusion with iloprost or carrier solution was continued for the duration of the experiment. MEASUREMENTS AND MAIN RESULTS: Twelve pigs (six per group), weighing between 20 and 22 kg, underwent laparotomy during which a magnetic flowprobe was placed around the superior mesenteric artery and an ileal tonometer was inserted. Thirty minutes before they were infused with endotoxin, the animals were randomized to receive intravenous iloprost or normal saline. Endotoxin was infused centrally over a 60-min period. Animals received normal saline at a rate of 1.2 mL/kg/min which was begun at the start of the endotoxin infusion. Data were measured at the end of the endotoxin infusion (E60) and 1 hr later (E120). Mean arterial pressure was not affected by the dosage of iloprost used in this experiment. After resuscitation, the cardiac output returned to baseline in the iloprost-treated group but remained decreased in the control group (2.6 +/- 0.5 vs. 1.6 +/- 0.4 L/min). Superior mesenteric blood flow increased 34% above baseline levels in animals pretreated with iloprost (from 363 +/- 85 to 485 +/- 81 mL/min). The superior mesenteric PCO2 was significantly higher (53 +/- 9 vs. 40 +/- 5 torr; 7.1 +/- 1.2 vs. 5.3 +/- 0.7 kPa) and the ileal intramucosal pH was significantly lower (7.07 +/- .28 vs. 7.44 +/- .23) in the control group than in the iloprost-treated group. CONCLUSIONS: Pretreatment with intravenous iloprost effectively increased intestinal blood flow in this model of endotoxin-induced mesenteric ischemia. This action of the drug resulted in an attenuation of ileal intracellular acidosis. Since low-dose iloprost had no effect on mean arterial pressure, it may be a useful adjunct in the treatment of sepsis and septic shock.     

Effects of erythromycin on the rabbit pleura: its potential role as a pleural sclerosant

Tetracycline (TCN) has been considered the agent of choice for pleurodesis in patients with symptomatic malignant pleural effusions and recurrent pneumothoraces. However, the intravenous form of TCN used for pleurodesis is no longer available. Erythromycin, like TCN, often produces irritation when administered intravenously. In view of these irritant properties, we tested the effect of erythromycin as a pleural sclerosant in rabbits as compared with TCN. Normal saline was used as a control. Adult rabbits weighing 2.5 to 3.0 kg underwent sterile placement of a silastic pleural tube in the right pleural space. Erythromycin (n = 17) or TCN (n = 6), each in doses of 35 mg/kg in 2 ml saline, was administered via the tube. Control animals (n = 6) received 2 ml saline. The chest tubes were left in place for removal of pleural fluid and to maintain lung expansion. Animals were killed 8 d after receiving the various treatments, and their pleural surfaces were examined grossly and histologically. Numerous adhesions were present between the visceral and parietal pleurae in all animals receiving erythromycin and TCN, but not in those receiving saline. On light microscopy, pleurae treated with erythromycin or TCN were histologically identical, showing inflammation, edema, and fibroblast proliferation in the submesothelial tissues. The saline-treated animals had a normal pleura. Because erythromycin produced pleural inflammation and adhesions within 8 d of treatment, we propose that it may have a potential role as a pleural sclerosant.     

Infusion of hot crystalloid during operative burn wound debridement

BACKGROUND: Hypothermia exacerbates coagulopathy and is thus a potentially devastating morbidity during operative debridement of burn wounds. Current techniques for maintaining body temperature include warming intravenous fluids at 38 degrees C. The purpose of this study was to assess the safety of infusing saline heated to 55-60 degrees C. METHODS: Using a modified fluid warmer, saline heated to 60 degrees C was infused through central venous access in eight adult patients undergoing debridement of burn wounds. The temperature of the saline actually entering the patient was measured by a thermocouple attached at the connection to the central line catheter. RESULTS: The actual infusate temperature was 54.0 +/- 1.2 degrees C. Over the first hour, 1,100 mL of hot saline was given, thus delivering 17.6 kcal more heat than fluid warmed to the traditional 38 degrees C. Core temperature measured via esophageal and Foley catheters had an insignificant trend toward increase during the operative procedure. There was no evidence of intravascular hemolysis or coagulopathy. CONCLUSION: This pilot study suggests that infusion of hot crystalloids given via central venous access is safe and may be an acceptable adjuvant in attenuating hypothermia during operative procedures.     

Emotional stress and blood melatonin levels

Blood serum melatonin concentrations were measured in male Wistar rats exposed to acute water-immersion emotional stress (ES) during intraperitoneal injections of physiological saline or different doses of melatonin. ES increased blood melatonin levels in rats receiving physiological saline 1 hour before or just after ES. When physiological saline was administered just ES, blood melatonin concentrations remained unchanged. The blood levels of melatonin both in control and stressed animals injected with exogenous melatonin were higher than those in rats given physiological saline alone. Immersion ES decreased blood melatonin concentrations in rats receiving different exogenous melatonin doses just before ES. However, in rats given melatonin, 1.0 mg/kg, after ES, its blood levels after ES was higher than those in the animals unexposed to stress. The findings suggest that it is just exogenous rather than endogenous melatonin that is consumed in rats injected with its different doses just prior to immersion ES.