bluuebunny/crossref_metadata_2025 huggingface dataset:
Desflurane Confers Neurologic Protection for Deep Hypothermic Circulatory Arrest in Newborn Pigs
Authors: Dean Kurth C. , Priestley Margaret , Marc Watzman H. , McCann John , Golden Jeff
Published: November 2003

Background

Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), as used for infant heart surgery, carry a risk of ischemic neurologic injury. Volatile anesthetics have neuroprotective properties against both global and focal ischemia at normothermia. The authors examined the hemodynamic and neuroprotective effects of desflurane in a piglet CPB-DHCA model.

Methods

Twenty piglets aged 5-10 days received a desflurane- (6-9% expired) or fentanyl-based anesthetic before and during CPB (before and after DHCA). DHCA lasted 90 min at 19 degrees C brain. Cardiovascular variables (heart rate, arterial pressure, blood gases, glucose, brain temperature) were monitored. On postoperative day 2, neurologic and histologic outcomes were determined.

Results

Cardiovascular variables before, during, and after CPB were physiologically similar between groups. The desflurane group had better neurologic performance (P = 0.023) and greater postoperative weight gain (P = 0.04) than the fentanyl group. In neocortex, the desflurane group had less tissue damage (P = 0.0015) and fewer dead neurons (P = 0.0015) than the fentanyl group. Hippocampal tissue damage was less in the desflurane group (P = 0.05), but overall, neuronal cell counts in the CA1 sector of the right hippocampus were similar to those in the fentanyl group.

Conclusions

Desflurane-based anesthesia yields hemodynamics during CPB with DHCA that are similar to those with fentanyl-based anesthesia. However, desflurane-based anesthesia improves neurologic and histologic outcomes of CPB-DHCA in comparison with outcomes with fentanyl-based anesthesia.
Pain Models Display Differential Sensitivity to Ca2+-Permeable Non-NMDA Glutamate Receptor Antagonists
Authors: Sorkin Linda S. , Yaksh Tony L. , Doom Carmen M.
Published: November 2003

Background

Ca2+-permeable non-N-methyl-D-aspartate receptors are found in the spinal dorsal horn and represent a presumptive target for glutamatergic transmission in nociceptive processing. This study characterized the analgesic profile associated with the blockade of these spinal receptors by intrathecally delivered agents known to act at these receptors, the spider venom Joro toxin (JST) and philanthotoxin.

Methods

Philanthotoxin (0.5, 2.5, or 5 microg) or JST (5 microg) was given spinally before thermal injury to the paw. JST (5 microg) was also given 10 min before subcutaneous formalin injection, after intraplantar administration of carrageenan, and to rats that were allodynic due to tight ligation of spinal nerves. Lower doses of JST (0.25 and 1.0 microg) were given before formalin injection and testing of thermal latencies. Thermal latencies were measured using a Hargreaves box, mechanical thresholds using von Frey hairs, and formalin response by means of counting flinches.

Results

Both agents blocked thermal injury-induced mechanical allodynia. JST (5 microg) given 1 h after carrageenan blocked induction of thermal hyperalgesia and mechanical allodynia. JST (5 microg) had no effect in the formalin test, on allodynia after spinal nerve ligation, or when given 3 h after carrageenan. The lowest dose (0.25 microg JST) at pretreatment intervals of 60-120 min resulted in modest hypoalgesia during phase 1 formalin and thermal testing.

Conclusions

The behavioral effect of intrathecal Ca2+-permeable non-N-methyl-D-aspartate antagonists indicates an important role for this spinal receptor in regulating hyperalgesic states induced by tissue injury and inflammation and reveals an action that is distinct from those observed with other glutamate receptor antagonists.
Influence of Superior Vena Caval Zone Condition on Cyclic Changes in Right Ventricular Outflow during Respiratory Support
Authors: Vieillard-Baron Antoine , Augarde Roch , Prin Sebastien , Page Bernard , Beauchet Alain , Jardin François
Published: November 2003

Background

Adequate fluid resuscitation in critically ill patients undergoing mechanical ventilation remains a difficult challenge, and diastolic and systolic right ventricular (RV) changes produced by positive airway pressure are important to consider in an individual patient with inadequate circulatory adaptation during respiratory support. We hypothesized that insufficient thoracic vena cava filling, predisposing to inspiratory collapse (zone 2 condition), may transiently affect RV outflow.

Methods

We measured beat-to-beat superior vena caval diameter and Doppler RV outflow during a routine transesophageal echocardiographic examination in 22 patients undergoing mechanical ventilation, all of whom required hemodynamic monitoring, and we calculated a collapsibility index for the superior vena cava as maximal expiratory diameter minus minimal inspiratory diameter, divided by maximal expiratory diameter.

Results

In 15 patients (group 1), the collapsibility index was low (17 +/- 7%) and was associated with a moderate inspiratory decrease in RV outflow (25 +/- 17%). However, in seven patients (group 2), we observed a high collapsibility index (71 +/- 7%), which was associated with a major inspiratory decrease in RV outflow (69 +/- 14%) combined with a reduced pulmonary artery flow period. A rapid volume expansion, only performed on group 2, markedly and significantly reduced both the collapsibility index (15 +/- 12%) and the inspiratory decrease in RV outflow (31 +/- 20%).

Conclusion

A major inspiratory decrease in RV outflow associated with a reduced pulmonary artery flow period in a patient undergoing mechanical ventilation reflected a high collapsibility index of the thoracic vena cava, suggesting a zone 2 condition, and may be corrected by blood volume expansion.
Pharyngeal Function and Airway Protection During Subhypnotic Concentrations of Propofol, Isoflurane, and Sevoflurane
Authors: Sundman Eva , Witt Hanne , Sandin Rolf , Kuylenstierna Richard , Bodén Katarina , Ekberg Olle , Eriksson Lars I.
Published: November 2003

Background

Anesthetic agents alter pharyngeal function with risk of impaired airway protection and aspiration. This study was performed to evaluate pharyngeal function during subhypnotic concentrations of propofol, isoflurane, and sevoflurane and to compare the drugs for possible differences in this respect.

Methods

Forty-five healthy volunteers were randomized to receive propofol, isoflurane, or sevoflurane. During series of liquid contrast bolus swallowing, fluoroscopy and simultaneous solid state videomanometry was used to study the incidence of pharyngeal dysfunction, the initiation of swallowing, and the bolus transit time. Pressure changes were recorded at the back of the tongue, the pharyngeal constrictor muscles, and the upper esophageal sphincter. After control recordings, the anesthetic was delivered, and measurements were made at 0.50 and 0.25 predicted blood propotol concentration (Cp50(asleep)) for propofol and 0.50 and 0.25 minimum alveolar concentration (MAC)(awake) for the inhalational agents. Final recordings were made 20 min after the end of anesthetic delivery.

Results

All anesthetics caused an increased incidence of pharyngeal dysfunction with laryngeal bolus penetration. Propofol increased the incidence from 8 to 58%, isoflurane from 4 to 36%, and sevoflurane from 6 to 35%. Propofol in 0.50 and 0.25 Cp50(asleep) had the most extensive effect on the pharyngeal contraction patterns (P < 0.05). The upper esophageal sphincter resting tone was markedly reduced from 83 +/- 36 to 39 +/- 19 mmHg by propofol (P < 0.001), which differed from isoflurane (P = 0.03). Sevoflurane also reduced the upper esophageal sphincter resting tone from 65 +/- 16 to 45 +/- 18 mmHg at 0.50 MAC(awake)(P = 0.008). All agents caused a reduced upper esophageal sphincter peak contraction amplitude (P < 0.05), and the reduction was greatest in the propofol group (P = 0.002).

Conclusion

Subhypnotic concentrations of propofol, isoflurane, and sevoflurane cause an increased incidence of pharyngeal dysfunction with penetration of bolus to the larynx. The effect on the pharyngeal contraction pattern was most pronounced in the propofol group, with markedly reduced contraction forces.
Effect of Volatile Anesthetics on the Force–Frequency Relation in Human Ventricular Myocardium
Authors: Schotten Ulrich , Greiser Maura , Braun Volker , Karlein Christian , Schoendube Friedrich , Hanrath Peter
Published: November 2003

Background

In human ventricular myocardium, contractile force increases at higher stimulation frequencies (positive force-frequency relation). In failing hearts, the force-frequency relation (FFR) is negative. Data on the effect of volatile anesthetics on FFR are very limited.

Methods

The authors obtained left ventricular tissue from 18 explanted hearts from patients undergoing cardiac transplantation and tissue of 8 organ donors. The negative inotropic effect of halothane, isoflurane, and sevoflurane on isometric force of contraction of isolated muscle preparations at a stimulation frequency of 1 and 3 Hz and the effect of each anesthetic on the FFR were studied. Ryanodine and verapamil were studied for comparison. In addition, the effect of the anesthetics on Ca(2+)-dependent (3)H-ryanodine binding was investigated.

Results

In nonfailing myocardium, halothane was the strongest negative inotropic compound, and the positive FFR was not affected by either drug. In failing myocardium, halothane also showed the strongest negative inotropic effect, but the positive shape of FFR was restored by halothane and ryanodine. In contrast, isoflurane, sevoflurane, and verapamil did not change FFR. Only halothane shifted the Ca(2+)-dependent (3)H-ryanodine binding curve toward lower Ca(2+) concentrations.

Conclusion

In nonfailing human myocardium, none of the anesthetics affect FFR, but halothane is the strongest negative inotropic compound. In failing myocardium, halothane, but not isoflurane or sevoflurane, restores the positive shape of FFR. Both the more pronounced negative inotropic effect of halothane and the restoration of the positive shape of FFR in failing myocardium in the presence of halothane can be explained by its interaction with the myocardial sarcoplasmic reticulum calcium-release channel.
Effects of Inverse Ratio Ventilation versus Positive End-expiratory Pressure on Gas Exchange and Gastric Intramucosal Pco2and pH under Constant Mean Airway Pressure in Acute Respiratory Distress Syndrome
Authors: Huang Chung-Chi , Shih Mei-Ju , Tsai Ying-Huang , Chang Yu-Chen , Tsao Thomas C. Y. , Hsu Kuang-Hung
Published: November 2003

Background

In patients with acute respiratory distress syndrome, whether inverse ratio ventilation differs from high positive end-expiratory pressure (PEEP) for gas exchange under a similar mean airway pressure has not been adequately examined. The authors used arterial oxygenation, gastric intramucosal partial pressure of carbon dioxide (PiCO(2)), and pH (pHi) to assess whether pressure-controlled inverse ratio ventilation (PC-IRV) offers more benefits than pressure-controlled ventilation (PCV) with PEEP.

Methods

Seventeen acute respiratory distress syndrome patients were enrolled and underwent mechanical ventilation with a PCV inspiratory-to-expiratory ratio of 1:2, followed by PC-IRV 1:1 initially. Then, they were randomly assigned to receive PC-IRV 2:1, then 4:1 or 4:1, and then 2:1, alternately. The baseline setting of PCV 1:2 was repeated between the settings of PC-IRV 2:1 and 4:1. Mean airway pressure and tidal volume were kept constant by adjusting the levels of peak inspiratory pressure and applied PEEP. In each ventilatory mode, hemodynamics, pulmonary mechanics, arterial and mixed venous blood gas analysis, PiCO(2), and pHi were measured after a 1-h period of stabilization.

Results

With a constant mean airway pressure, PC-IRV 2:1 and 4:1 decreased arterial and mixed venous oxygenation as compared with baseline PCV 1:2. Neither the global oxygenation indices with oxygen delivery and uptake nor PiCO(2) and pHi were improved by PC-IRV. During PC-IRV, applied PEEP was lower, and auto-PEEP was higher.

Conclusion

When substituting inverse ratio ventilation for applied PEEP to keep mean airway pressure constant, PC-IRV does not contribute more to better gas exchange and gastric intramucosal PiCO(2) and pHi than does PCV 1:2 for acute respiratory distress syndrome patients, regardless of the inspiratory-to-expiratory ratios.
Sevoflurane Inhibits Unstimulated and Agonist-induced Platelet Antigen Expression and Platelet Function in Whole Blood In Vitro
Authors: Horn Nicola A. , de Rossi Lothar , Robitzsch Tilo , Hecker Klaus E. , Hutschenreuter Gabriele , Rossaint Rolf
Published: November 2003

Background

Previous studies have reported conflicting results about the effect of sevoflurane on platelet aggregation. To clarify this point, we investigated the effects of sevoflurane on platelet antigen expression and function in vitro.

Methods

Human whole blood was incubated for 1 h with 0.5 and 1 minimum alveolar concentration sevoflurane, 21% O(2), and 5% CO(2). A control sample was kept at the same conditions without sevoflurane. After stimulation with adenosine diphosphate or thrombin receptor agonist peptide 6, samples were stained with fluorochrome conjugated antibodies, and the expression of platelet glycoproteins GPIIb/IIIa, GPIb, and P-selectin, as well as activated GPIIb/IIIa, were measured with two-color flow cytometry. In addition, platelet function was assessed by means of thromboelastography and using the platelet function analyzer 100.

Results

Already in subanesthetic concentrations, sevoflurane inhibits unstimulated and agonist-induced GPIIb/IIIa surface expression and activated GPIIb/IIIa expression on platelets in whole blood. The agonist-induced redistribution of GPIb into the open canalicular system was also impaired by sevoflurane, whereas no effect on P-selectin expression in activated platelets could be found. Sevoflurane significantly reduced the maximum thromboelastographic amplitude. Furthermore, platelet function analyzer 100 closure times were significantly prolonged.

Conclusion

The results show that sevoflurane significantly impairs platelet antigen expression in vitro. It is especially the inhibition of GPIIb/IIIa expression and activation that impairs bleeding time as reflected in thromboelastographic measurements and platelet function analyzer 100 closure times. The exact inhibitory mechanism remains unclear.
Mechanisms of Direct Inhibitory Action of Propofol on Uterine Smooth Muscle Contraction in Pregnant Rats
Authors: Tsujiguchi Naoki , Yamakage Michiaki , Namiki Akiyoshi
Published: November 2003

Background

Although propofol directly inhibits uterine smooth muscle contraction, the mechanisms of this effect are still unknown. The current study aimed to clarify the mechanisms of the inhibitory effect of propofol on oxytocin-induced uterine smooth muscle contraction by measuring (1) the concentration of intracellular free Ca(2+) ([Ca(2+)](i)) simultaneously with muscle tension, (2) the amount of intracellular inositol 1,4,5-triphosphate ([IP(3)](i)), and (3) voltage-dependent Ca(2+) channel (VDCC) activity.

Methods

Uterine smooth muscle tissues were obtained from pregnant rats (in late gestation). [Ca(2+)](i) with isometric tension was monitored by the 500-nm light emission ratio of preloaded Ca(2+) indicator fura-2. [IP(3)](i) and VDCC activity were measured by radioimmunoassay and patch clamp techniques, respectively. The uterine smooth muscle was stimulated by 20 nm oxytocin and exposed to propofol (10(-7) approximately 10(-4) m).

Results

Propofol had significant inhibitory effects on oxytocin-induced uterine smooth muscle contraction and increased [Ca(2+)](i) in pregnant rats in a dose-dependent manner, without affecting the agonist-receptor binding affinity. Propofol inhibited the increase in [IP(3)](i) induced by oxytocin. Propofol also inhibited VDCC activity in both activated and inactivated states. The solvent Intralipid had no effects on these parameters.

Conclusions

Propofol inhibits oxytocin-induced uterine smooth muscle contraction, at least in part, by decreasing [Ca(2+)](i) without affecting agonist-receptor binding; the inhibitory effect of propofol on [Ca(2+)](i) might be mediated both by a decrease in [IP(3)](i) and by inhibition of VDCC activity.
Systemic Toxicity of Levobupivacaine, Bupivacaine, and Ropivacaine during Continuous Intravenous Infusion to Nonpregnant and Pregnant Ewes
Authors: Santos Alan C. , DeArmas Pedro I.
Published: November 2003

Background

Levobupivacaine, the single levorotatory isomer of bupivacaine, is now available for clinical use. This study was undertaken to determine whether pregnancy affects the systemic toxicity of levobupivacaine and to compare the systemic toxicity of levobupivacaine with that of bupivacaine and ropivacaine.

Methods

Chronically prepared nonpregnant and pregnant sheep were randomized to receive an intravenous infusion of 0.52% levobupivacaine, 0.52% bupivacaine, or 0.50% ropivacaine at a constant rate of 0.1 ml x kg(-1) x min(-1) until circulatory collapse. The investigators were blinded to the identity of the local anesthetic. Physiologic parameters, including cardiac rhythm, were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations. These were analyzed for total and free serum drug concentrations as well as arterial blood pH and gas tensions.

Results

The doses of all three drugs required to produce convulsions were lower in pregnant than nonpregnant animals. However, as the infusion continued, there were no significant differences between pregnant and nonpregnant ewes in the dose of drug required to produce more advanced manifestations of toxicity: hypotension, apnea, and circulatory collapse. The mean cumulative dose and serum concentration at each toxic manifestation was lowest for bupivacaine, intermediate for levobupivacaine, and highest for ropivacaine in both pregnant and nonpregnant animals. For all three local anesthetics, there were no significant differences between pregnant and nonpregnant ewes in total and free serum drug concentrations, except that at circulatory collapse, these were higher in pregnant animals.

Conclusions

Pregnancy increases the risk of convulsions but not of more advanced manifestations of local anesthetic toxicity. The risk of toxicity is greatest with bupivacaine and least with ropivacaine. However, in actual clinical practice, the risk of systemic toxicity may also be affected by the relative potency and effectiveness of these drugs.
The Transfer Half-life of Morphine-6-glucuronide from Plasma to Effect Site Assessed by Pupil Size Measurement in Healthy Volunteers
Authors: Lötsch Jörn , Skarke Carsten , Schmidt Helmut , Grösch Sabine , Geisslinger Gerd
Published: November 2003

Background

Clinical and experimental data suggested a long delay between the plasma concentration versus time course of morphine-6-glucuronide and the time course of its central opioid effects. This study was aimed at the quantification of the transfer half-life (t(1/2,ke0)) of this delay.

Methods

Pupil size was used as a measure of central opioid effect. Eight healthy volunteers (four men, four women) participated in that single-blind randomized crossover study. Median dosages administered intravenously were 0.5 mg morphine as loading dose followed by 10.7 mg given as infusion over a period of 4.7 h, and 10.2 mg M6G as loading dose followed by 39.1 mg M6G given over a period of 3.7 h. The duration of the infusion was tailored to achieve submaximum pupil constriction. The pupil diameter was assessed every 20 min for approximately 18 h. Values of t(1/2,ke0) were obtained by semiparametric pharmacokinetic-pharmacodynamic modeling.

Results

The estimated median t(1/2,ke0) of M6G was 6.4 h (range, 2.9-16.2 h), and that of morphine was 2.8 h (range, 1.8-4.4 h). The individual t(1/2,ke0) of M6G was always longer than that of morphine. Judged by the concentration at half-maximun effect (EC50) values of the sigmoid pupil size at maximum constriction (Emax) model describing concentration-response relation, M6G was apparently 22 times less potent than morphine (EC50 = 740.5 nm [range, 500-1,520 nm] for M6G and 36.2 nm [range, 19.7-43.3 nm] for morphine). The steepness of the sigmoid Emax model did not significantly differ between morphine and M6G (gamma = 1.9 and 2.6, respectively). To produce similar pupil effects, the M6G dose had to be 2.8 times greater than the morphine dose.

Conclusions

The reported numerical value of the t(1/2,ke0) of M6G in humans obtained after direct administration of M6G is a step toward a complete modeling approach to the prediction of the clinical effects of morphine. The study raises questions about the high interindividual variability of the transfer half-life between plasma and effect site (ke0) values and the apparent low potency of M6G.
Adaptive Support Ventilation for Fast Tracheal Extubation after Cardiac Surgery
Authors: Sulzer Christopher F. , Chioléro René , Chassot Pierre-Guy , Mueller Xavier M. , Revelly Jean-Pierre
Published: November 2003

Background

Adaptive support ventilation (ASV) is a microprocessor-controlled mode of mechanical ventilation that maintains a predefined minute ventilation with an optimal breathing pattern (tidal volume and rate) by automatically adapting inspiratory pressure and ventilator rate to changes in the patient's condition. The aim of the current study was to test the hypothesis that a protocol of respiratory weaning based on ASV could reduce the duration of tracheal intubation after uncomplicated cardiac surgery ("fast-track" surgery).

Methods

A group of patients being given ASV (group ASV) was compared with a control group (group control) in a randomized controlled study. After coronary artery bypass grafting during general anesthesia with midazolam and fentanyl, patients were randomly assigned to group ASV or group control. Both protocols were divided into three predefined phases, and weaning progressed according to arterial blood gas and clinical criteria. In phase 1, ASV mode was set at 100% of the theoretical value of volume/minute in group ASV, and synchronized intermittent mandatory ventilation mode was used in group control. When spontaneous breathing occurred, ASV setting was reduced by 50% of minute ventilation (phase 2) and again by 50% (phase 3), and the trachea was extubated. In group control, the ventilator was switched to 10 cm H2O inspiratory pressure support (phase 2), then to 5 cm H2O (phase 3) until extubation.

Results

Forty-nine patients were enrolled. Sixteen patients completed the ASV protocol, and 20 the standard protocol; 7 patients were excluded in group ASV and 6 in group control according to explicit, predefined criteria. There were no differences between groups in perioperative characteristics or in the doses of sedation. The primary outcome of the study, that is, the duration of tracheal intubation, was shorter in group ASV than in group control (median [quartiles]: 3.2 [2.5-4.6] vs. 4.1 [3.1-8.6] h; P < 0.02). Fewer arterial blood analyses were performed in group ASV (median number [quartiles]: 3 [3-4] vs. 4 [3-6]), suggesting that fewer changes in the settings of the ventilator were required in this group.

Conclusions

A respiratory weaning protocol based on ASV is practicable; it may accelerate tracheal extubation and simplify ventilatory management in fast-track patients after cardiac surgery. The evaluation of potential advantages of the use of such technology on patient outcome and resource utilization deserves further studies.
Internal Jugular Vein Occlusion Test for Rapid Diagnosis of Misplaced Subclavian Vein Catheter into the Internal Jugular Vein
Authors: Ambesh Sushil P. , Pandey Jyotish C. , Dubey Prakash K.
Published: November 2003

Background

During subclavian vein catheterization, the most common misplacement of the catheter is cephalad, into the ipsilateral internal jugular vein (IJV). This can be detected by chest radiography. However, after any repositioning of the catheter, subsequent chest radiography is required. In an effort to simplify the detection of a misplaced subclavian vein catheter, the authors assessed a previously published detection method.

Methods

One hundred adult patients scheduled for subclavian vein cannulation were included in this study. After placement of subclavian vein catheter, chest radiography was performed. While the x-ray film was being processed, the authors performed an IJV occlusion test by applying external pressure on the IJV for approximately 10 s in the supraclavicular area and observed the change in central venous pressure and its waveform pattern. The observations thus obtained were compared with the position of catheter in chest radiographs, and the sensitivity and specificity of this method were evaluated using a 2 x 2 table.

Results

In 96 patients, subclavian vein cannulation was successfully performed. In four patients, cannulation was unsuccessful; therefore, these patients were excluded from the study. There were six misplacements of venous catheters as detected by radiography. In five (5.2%) patients, the catheter tip was located in the ipsilateral IJV, and in one (1.02%), the catheter tip was located in the contralateral subclavian vein. In the patients who had a misplaced catheter into the IJV, IJV occlusion test results were positive, with an increase of 3-5 mmHg in central venous pressure, whereas the test results were negative in patients who had normally placed catheters or misplacement of a catheter other than in the IJV. There were no false-positive or false-negative test results.

Conclusion

The IJV occlusion test successfully detects the misplacement of subclavian vein catheter into the IJV. However, it does not detect any other misplacement. The test may allow avoidance of repeated exposure to x-rays after catheter insertion and repositioning.
Protamine-induced Cardiotoxicity Is Prevented by Anti-TNF-α Antibodies and Heparin
Authors: Pevni Dmitry , Frolkis Inna , Iaina Adrian , Wollman Yoram , Chernichovski Tamara , Shapira Izhak , Paz Josef , Kramer Amir , Loker Chaim , Mohr Rephael
Published: November 2003

Background

We investigated the role of tumor necrosis factor alpha (TNF-alpha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin.

Methods

Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KH). The control group was perfused with KH alone, the KH > protamine > KH group was treated from the 20th to the 40th minute with protamine, and the KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KH group but with anti-TNF-alpha antibodies added throughout perfusion. The KH + heparin > protamine + heparin > KH + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KH > protamine > KH + heparin was perfused the same as the KH> protamine > KH group but with heparin added to KH for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measured in the coronary sinus effluent. Left ventricular TNF messenger RNA was determined in the control and KH > protamine > KH groups at baseline and after the 40-min perfusion.

Results

Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the effluent in the KH > protamine > KH group (102.3 +/- 15.5 pg/min) and TNF messenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF, and KH + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression of LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin improved LV recovery and decreased protamine-induced TNF-alpha release (KH > protamine > KH + heparin group).

Conclusions

Anti-TNF-alpha antibodies and heparin prevent protamine-induced TNF-alpha release and depression of LV function. Heparin improves protamine-induced depression of cardiac function.
Rapid Endotoxin-induced Alterations in Myocardial Calcium Handling
Authors: Stamm Christof , Cowan Douglas B. , Friehs Ingeborg , Noria Sabrena , del Nido Pedro J. , McGowan Francis X.
Published: November 2003

Background

Bacterial endotoxin (lipopolysaccharide [LPS]) induces septic shock and depressed myocardial contractility. The mechanism of LPS-mediated cardiac dysfunction remains controversial. We hypothesized that LPS exerts significant effects on myocardial excitation-contraction coupling by rapid stimulation of tumor necrosis factor alpha (TNF-alpha) expression in the heart.

Methods

Isolated rat hearts were studied with and without recirculation of cell-free perfusate. The effects of LPS, exogenous TNF-alpha, anti-TNF-alpha antibody, and ceramidase inhibition were examined. Measurements included myocardial uptake of LPS, left ventricular contractility, myocardial oxygen consumption, intracellular calcium [Ca2+] cycling, and TNF-alpha concentrations in coronary perfusate and myocardium.

Results

Lipopolysaccharide was rapidly taken up by the perfused heart. With non-recirculating perfusion, LPS had no effect on contractility, oxygen consumption, coronary vascular resistance, or intracellular free calcium concentration ([Ca2+]i). However, with recirculating perfusion contractility was significantly impaired after 30 min of LPS, associated with lower [Ca2+]i levels and attenuated systolic rise in [Ca2+]i. Significant amounts of TNF-alpha accumulated in recirculating perfusate and myocardial tissue from LPS-perfused hearts. Ceramidase inhibition or neutralizing anti-TNF-alpha antibody inhibited the effects of LPS on contractility and [Ca2+]i. Recombinant rat TNF-alpha mimicked the LPS effects with faster onset.

Conclusions

Lipopolysaccharide exerts rapid, negative inotropic effects on the isolated whole rat heart. The reduction in contractility is associated with depressed intracellular calcium cycling. In response to LPS, TNF-alpha is rapidly released from the heart and mediates the effects of LPS via the sphingomyelinase pathway. The present study for the first time directly links LPS-stimulated TNF-alpha production, abnormal calcium cycling, and decreased contractility in intact hearts.
Effects of Vaporized Perfluorocarbon on Pulmonary Blood Flow and Ventilation/Perfusion Distribution in a Model of Acute Respiratory Distress Syndrome
Authors: Hübler Matthias , Souders Jennifer E. , Shade Erin D. , Polissar Nayak L. , Schimmel Carmel , Hlastala Michael P.
Published: November 2003

Background

Perfluorocarbon (PFC) liquids are known to improve gas exchange and pulmonary function in various models of acute respiratory failure. Vaporization has been recently reported as a new method of delivering PFC to the lung. Our aim was to study the effect of PFC vapor on the ventilation/perfusion (VA/Q) matching and relative pulmonary blood flow (Qrel) distribution.

Methods

In nine sheep, lung injury was induced using oleic acid. Four sheep were treated with vaporized perfluorohexane (PFX) for 30 min, whereas the remaining sheep served as control animals. Vaporization was achieved using a modified isoflurane vaporizer. The animals were studied for 90 min after vaporization. VA/Q distributions were estimated using the multiple inert gas elimination technique. Change in Qrel distribution was assessed using fluorescent-labeled microspheres.

Results

Treatment with PFX vapor improved oxygenation significantly and led to significantly lower shunt values (P < 0.05, repeated-measures analysis of covariance). Analysis of the multiple inert gas elimination technique data showed that animals treated with PFX vapor demonstrated a higher VA/Q heterogeneity than the control animals (P < 0.05, repeated-measures analysis of covariance). Microsphere data showed a redistribution of Qrel attributable to oleic acid injury. Qrel shifted from areas that were initially high-flow to areas that were initially low-flow, with no difference in redistribution between the groups. After established injury, Qrel was redistributed to the nondependent lung areas in control animals, whereas Qrel distribution did not change in treatment animals.

Conclusion

In oleic acid lung injury, treatment with PFX vapor improves gas exchange by increasing VA/Q heterogeneity in the whole lung without a significant change in gravitational gradient.
Cervicomedullary Intrathecal Injection of Morphine Produces Antinociception in the Orofacial Formalin Test in the Rat
Authors: Grabow Theodore S. , Dougherty Patrick M.
Published: November 2003

Background

High cervical and medullary drug delivery has been advocated for the treatment of refractory head and neck pain in humans. Currently, parallel models in animals have not been developed to support this methodology. We combined an accepted animal model of pain of cranial origin with a novel technique of neuraxial drug delivery to address this issue.

Methods

Male Wistar rats were implanted with intrathecal catheters that were advanced cephalad through a lumbar guide cannula to the high cervical spinal cord. The orofacial formalin test was used to assess antinociception. Vehicle or morphine (1, 3, 6, 10, 30 microg) was injected intrathecally followed 10 minutes later by injection of formalin solution, 2.5%, into the vibrissal pad. Motor assessment and hemodynamic and respiratory blood gas measurements were evaluated in a separate group of animals.

Results

Intrathecal morphine produced a dose-dependent decrease in the first and second phases of the behavioral response (P < 0.05). The ED50 (95% confidence limits) values for the first and second phases were 6.65 microg (3.52-14.9 microg) and 3.40 microg (2.37-4.61 microg), respectively. Ten micrograms intrathecal naloxone antagonized the morphine effect (P < 0.05). Significant cardiovascular and respiratory depression was observed. No significant motor dysfunction was observed.

Conclusions

Cervicomedullary injection of morphine produced antinociception in the orofacial formalin test in the rat. This animal model may be useful to assess analgesics designed for parallel clinical application in humans.
Preferential Block of Small Myelinated Sensory and Motor Fibers by Lidocaine
Authors: Gokin Alexander P. , Philip Benjamin , Strichartz Gary R.
Published: November 2003

Background

Controversy still surrounds the differential susceptibility of nerve fibers to local anesthetics and its relation to selective functional deficits. In the current study we report features of conduction blockade in different classes of rat sciatic nerve fibers after injection of lidocaine by a percutaneous procedure that closely resembles clinical applications.

Methods

In 30 adult male Sprague-Dawley rats (weight, 300-400 g) during general anesthesia, impulses were recorded in different classes of sensory axons (large, Aalpha and beta fibers; small, Adelta myelinated fibers and unmyelinated C fibers) and motor axons (large, Aalpha fibers; small, Agamma myelinated fibers) classified by conduction velocity. The sciatic nerve was stimulated distally, and impulses were recorded from small filaments teased from L4-L5 dorsal (sensory) and ventral (motor) roots sectioned acutely from the spinal cord. Lidocaine at concentration of 0.05-1% was injected percutaneously in 0.1-ml solutions at the sciatic notch. Both tonic (stimulated at 0.5 Hz) and use-dependent (stimulated at 40 Hz for Adelta and Agamma fibers and at 5 Hz for C fibers) impulse inhibitions by lidocaine were assayed.

Results

Minimal effective (threshold) lidocaine concentrations (i.e., to block conduction in 10% of fibers) were, for sensory, 0.03% for Adelta, 0.07% for Aalphabeta, and 0.09-0.1% for C fibers, and for motor, 0.03% for Agamma and 0.05% for Aalpha fibers. The order of fiber susceptibility, ranked by concentrations that gave peak tonic fiber blockade of 50% (IC50s), was Agamma > Adelta = Aalpha > Aalphabeta > C. Faster-conducting C fibers (conduction velocity > 1 m/s) were more susceptible (IC50 = 0.13%) than slower ones (conduction velocity < 1 m/s; IC50 = 0.30%). At 1% lidocaine, all fibers were tonically blocked. Use-dependent effects accounted for only a modest potentiation of block (at a lidocaine concentration of 0.25%) in Adelta and Agamma fibers, and in C fibers phasic stimulation had even smaller effects and sometimes relieved tonic block.

Conclusions

Susceptibility to lidocaine does not strictly follow the "size principle" that smaller (slower) axons are always blocked first. This order of fiber blockade is qualitatively consistent with previous reports of the order of functional deficits in the rat after percutaneous lidocaine, that is, motor = proprioception > nociception, if we assume that motor deficits first arise from conduction failure in Agamma fibers and that nociception relies on C fiber conduction.
Stereospecific Effect of Pregabalin on Ectopic Afferent Discharges and Neuropathic Pain Induced by Sciatic Nerve Ligation in Rats
Authors: Chen Shao-Rui , Xu Zemin , Pan Hui-Lin
Published: November 2003

Background

The new anticonvulsants, gabapentin and pregabalin, are effective in the treatment of neuropathic pain. The sites and mechanisms of their analgesic action are not fully known. The authors have previously demonstrated that systemic gabapentin suppresses ectopic afferent discharges recorded from injured sciatic nerves in rats. In the current study, they further examined the stereospecific effect of pregabalin on neuropathic pain and afferent ectopic discharges in a rodent model of neuropathic pain.

Methods

Tactile allodynia and thermal hyperalgesia were induced by partial ligation of the left sciatic nerve in rats. Single-unit activity of afferent ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation.

Results

Intravenous injection of 10-30 mg/kg pregabalin dose-dependently attenuated tactile allodynia (n = 10) and thermal hyperalgesia (n = 8). The stereoisomer of pregabalin, R-3-isobutylgaba, had no analgesic effect in this dose range. Furthermore, intravenous injection of pregabalin, but not R-3-isobutylgaba, significantly inhibited the ectopic discharges from injured afferents in a dose-dependent manner (from 20.8 +/- 2.4 impulses/s during control to 2.3 +/- 0.7 impulses/s after treatment with 30 mg/kg pregabalin, n = 15). Pregabalin did not affect the conduction velocity of afferent fibers and the response of normal afferent nerves to mechanical stimulation.

Conclusions

These data strongly suggest that the analgesic effect of pregabalin on neuropathic pain is likely mediated, at least in part, by its peripheral inhibitory action on the impulse generation of ectopic discharges caused by nerve injury.
Postoperative Titration of Intravenous Morphine in the Elderly Patient
Authors: Aubrun Frédéric , Monsel Stéphanie , Langeron Olivier , Coriat Pierre , Riou Bruno
Published: November 2003

Background

Intravenous morphine titration is used to obtain rapid and complete postoperative pain relief. Whether this titration can be safely administered in the elderly patients remains a matter for debate.

Methods

Intravenous morphine titration was administered as a bolus of 2 (body weight < or = 60 kg) or 3 (body weight > 60 kg) mg. The interval between each bolus was 5 min. There was no limitation in the number of boluses given until pain relief or severe adverse effect occurred. The visual analog scale threshold required to administer morphine was 30 mm, and pain relief was defined as a visual analog scale score of 30 mm or less. Patients were divided into two groups: young and elderly (age > or = 70 yr) patients. Data were expressed as mean +/- SD.

Results

Eight hundred seventy-five patients (83%) were young and 175 patients (17%) were elderly. At the end of morphine titration, the visual analog scale score and the number of patients with pain relief were not significantly different between groups. The total dose of morphine per kilograms of body weight administered was not significantly different between groups (0.15 +/- 0.10 vs. 0.14 +/- 0.09 mg/kg, not significant). No significant differences were observed in the incidence of morphine-related adverse effects (13 vs. 14%, not significant), the number of sedated patients (60 vs. 60%, not significant), and the number of patients whose titration had to be stopped (2 vs. 2%, not significant).

Conclusion

Intravenous morphine titration can be safely administered to elderly patients. Because titration is adapted to individual pain, the same protocol can be applied to young and elderly patients.
Early Decay of Pain-related Cerebral Activation in Functional Magnetic Resonance Imaging
Authors: Kurata Jiro , Thulborn Keith R. , Gyulai Ferenc E. , Firestone Leonard L.
Published: November 2003

Background

Although pain-related activation was localized in multiple brain areas by functional imaging, the temporal profile of its signal has been poorly understood. The authors characterized the temporal evolution of such activation in comparison to that by conventional visual and motor tasks using functional magnetic resonance imaging.

Methods

Five right-handed volunteers underwent whole brain echo-planar imaging on a 3 T magnetic resonance imaging scanner while they received pain stimulus on the right and left forearm and performed visually guided saccade and finger tapping tasks. Pain stimulus on the right and left forearm consisted of four cycles of 15-s stimulus at 47.2-49.0 degrees C, interleaved with 30-s control at 32 degrees C, delivered by a Peltier-type thermode, and visually guided saccade and finger tapping of three cycles of 30-s active and 30-s rest conditions. Voxel-wise t statistical maps were standardized and averaged across subjects. Blood oxygenation level-dependent signal time courses were analyzed at local maxima of representative activation clusters (t > 3.5).

Results

Pain stimulus on the right forearm activated the secondary somatosensory (S2), superior temporal, anterior cingulate, insular, prefrontal cortices, premotor area, and lenticular nucleus. Pain stimulus on the left forearm activated similar but fewer areas at less signal intensity. The S2 activation was dominant on the contralateral hemisphere. Pain-related activation was statistically weaker and showed less consistent signal time courses than visually guided saccade- and finger tapping-related activation. Pain-related signals decayed earlier before the end of stimulus, in contrast to well-sustained signal plateaus induced by visually guided saccade and finger tapping.

Conclusions

The authors speculate that pain-related blood oxygenation level-dependent signals were attenuated by the pain-induced global cerebral blood flow decrease or activation of the descending pain inhibitory systems.
Artifact Robustness, Inter- and Intraindividual Baseline Stability, and Rational EEG Parameter Selection
Authors: Bruhn Jörgen , Bouillon Thomas W. , Hoeft Andreas , Shafer Steven L.
Published: November 2003

Background

Artifact robustness (i.e., size of deviation of an electroencephalographic parameter value from baseline caused by artifacts) and baseline stability (i.e., consistency of median baseline values) of electroencephalographic parameters profoundly influence electroencephalography-based pharmacodynamic parameter estimation and the usefulness of the processed electroencephalogram as measure of the arousal state of the central nervous system (depth of anesthesia). In this study, the authors compared the artifact robustness and the interindividual and intraindividual baseline stability of several univariate descriptors of the electroencephalogram (Shannon entropy, approximate entropy, spectral edge frequency 95, delta ratio, and canonical univariate parameter).

Methods

Electroencephalographic data of 16 healthy volunteers before and after administration of an intravenous bolus of propofol (2 mg/kg body weight) were analyzed. Each volunteer was studied twice. The baseline electroencephalogram was recorded for a median of 18 min before drug administration. For each electroencephalographic descriptor, the authors calculated the following: (1) baseline variability (= (median baseline - median effect) [i.e., signal]/SD baseline [i.e., noise]) without artifact rejection; (2) baseline variability with artifact rejection; and (3) baseline stability within and between individuals (= (median baseline - median effect) averaged over all volunteers/SD of all median baselines).

Results

Without artifact rejection, Shannon entropy and canonical univariate parameter displayed the highest signal-to-noise ratio. After artifact rejection, approximate entropy, Shannon entropy, and the canonical univariate parameter displayed the highest signal-to-noise ratio. Baseline stability within and between individuals was highest for approximate entropy.

Conclusions

With regard to robustness against artifacts, the electroencephalographic entropy parameters and the canonical univariate parameter were superior to spectral edge frequency 95 and delta ratio. Electroencephalographic approximate entropy displayed the best interindividual and intraindividual baseline stability.
Intrathecal Adenosine following Spinal Nerve Ligation in Rat
Authors: Bantel Carsten , Tobin Joseph R. , Li Xinhui , Childers Steven R. , Chen Shao Rui , Eisenach James C.
Published: November 2003

Background

Intrathecal adenosine produces a remarkably prolonged effect to relieve mechanical hypersensitivity after peripheral nerve injury in animals. The purpose of the current study was to investigate whether this reflected an alteration in kinetics of adenosine in cerebrospinal fluid or in the number of spinal A1 adenosine receptors after nerve injury.

Methods

Male rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Two weeks later, a lumbar intrathecal catheter and intrathecal space microdialysis catheter were inserted. Adenosine, 20 microg, was injected intrathecally in these and in normal rats, and microdialysates of the intrathecal space were obtained. Radioligand binding studies of adenosine A1 receptors were determined in spinal cord tissue from other normal and spinal nerve-ligated rats.

Results

Adenosine disappeared from rat cerebrospinal fluid within 30 min after intrathecal injection, with no difference between normal and spinal nerve-ligated animals. A1 adenosine receptor binding sites in the spinal cord were increased after spinal nerve ligation. This increase disappeared when adenosine deaminase was added to the membrane homogenates, suggestive of decreased endogenous adenosine in the membranes of nerve-ligated animals.

Conclusion

These data show that prolonged alleviation of hypersensitivity observed with intrathecal adenosine in this animal model of neuropathic pain is not due to prolonged residence in cerebrospinal fluid, although pharmacokinetics in tissues are unknown. Similarly, there is no evidence for up-regulation in spinal A1 adenosine receptors after spinal nerve ligation, and the adenosine deaminase experiment is consistent with a depletion of adenosine in spinal cord tissue after spinal nerve ligation.