Partial Liquid Ventilation Reduces Fluid Filtration of Isolated Rabbit Lungs with Acute Hydrochloric Acid-induced Edema

Background: Hydrochloric acid aspiration increases pulmonary microvascular permeability. The authors tested the hypothesis that partial liquid ventilation has a beneficial effect on filtration coefficients in acute acid-induced lung injury.

Methods: Isolated blood-perfused rabbit lungs were assigned randomly to one of four groups. Group 1 (n = 6) served as a control group without edema. In group 2 (n = 6), group 3 (n = 6), and group 4 (n = 6), pulmonary edema was induced by intratracheal instillation of hydrochloric acid (0.1 N, 2 ml/kg body weight). Filtration coefficients were determined 30 min after this injury (by measuring loss of perfusate after increase of left atrial pressure). Group 2 lungs were gas ventilated, and group 3 lungs received partial liquid ventilation (15 ml perfluorocarbon/kg body weight). In group 4 lungs, the authors studied the immediate effects of bronchial perfluorocarbon instillation on ongoing filtration.

Results: Intratracheal instillation of hydrochloric acid markedly increased filtration coefficients when compared with noninjured control lungs (2.3 +/- 0.7 vs. 0.31 +/- 0.08 ml [middle dot] min-1 [middle dot] mmHg-1 [middle dot] 100 g-1 wet lung weight, P < 0.01). Partial liquid ventilation reduced filtration coefficients of the injured lungs (to 0.9 +/- 0.3 ml [middle dot] min-1 [middle dot] mmHg-1 [middle dot] 100 g-1 wet lung weight, P = 0.022). Neither pulmonary artery nor capillary pressures (determined by simultaneous occlusion of inflow and outflow of the pulmonary circulation) were changed by hydrochloric acid instillation or by partial liquid ventilation. During ongoing filtration, bronchial perfluorocarbon instillation (5 ml/kg body weight) immediately reduced the amount of filtered fluid by approximately 50% (P = 0.027).     

Comparison of Adenosine and Remifentanil Infusions as Adjuvants to Desflurane Anesthesia

Background: Because adenosine has been alleged to produce both anesthetic and analgesic sparing effects, a randomized, double-blinded study was designed to compare the perioperative effects of adenosine and remifentanil when administered as intravenous adjuvants during general anesthesia for major gynecologic procedures.

Methods: Thirty-two women were assigned randomly to one of two drug treatment groups. After premedication with 0.04 mg/kg intravenous midazolam, anesthesia was induced with 2 [micro sign]g/kg intravenous fentanyl, 1.5 mg/kg intravenous propofol, and 0.6 mg/kg intravenous rocuronium, and maintained with desflurane, 2%, and nitrous oxide, 65%, in oxygen. Before skin incision, an infusion of either remifentanil (0.02 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or adenosine (25 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was started and subsequently titrated to maintain systolic blood pressure, heart rate, or both within 10-15% of the preincision values.

Results: Adenosine and remifentanil infusions were effective anesthetic adjuvants during lower abdominal surgery. Use of adenosine (mean +/- SEM, 166 +/- 17 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was associated with a significantly greater decrease in systolic blood pressure and higher heart rate values compared with remifentanil (mean +/- SEM, 0.2 +/- 0.03 [micro sign]g [middle dot] kg-1 [middle dot] min-1). Total postoperative opioid analgesic use was 45% and 27% lower in the adenosine group at 0-2 h and 2-24 h after surgery, respectively.     

Effect of Inhaled Prostacyclin in Combination with Almitrine on Ventilation-Perfusion Distributions in Experimental Lung Injury

Background: Inhaled prostacyclin and intravenous almitrine have both been shown to improve pulmonary gas exchange in acute lung injury (ALI). This study was performed to investigate a possible additive effect of prostacyclin and almitrine on pulmonary ventilation-perfusion (a/) ratio in ALI compared with inhaled prostacyclin or intravenous almitrine alone.

Methods: Experimental ALI was established in 24 pigs by repeated lung lavage. Animals were randomly assigned to receive either 25 ng [middle dot] kg-1 [middle dot] min-1 inhaled prostacyclin alone, 1 [mu]g [middle dot] kg-1 [middle dot] min-1 almitrine alone, 25 ng [middle dot] kg-1 [middle dot] min-1 inhaled prostacyclin in combination with 1 [mu]g [middle dot] kg-1 [middle dot] min-1 almitrine, or no specific treatment (controls) for 30 min. For each intervention, pulmonary gas exchange and hemodynamics were analyzed and a/ distributions were calculated using the multiple inert gas elimination technique. The data was analyzed within and between the groups by analysis of variance for repeated measurements, followed by the Student-Newman-Keuls test for multiple comparison when analysis of variance revealed significant differences.

Results: All values are expressed as mean +/- SD. In controls, pulmonary gas exchange, hemodynamics, and a/ distribution remained unchanged. With prostacyclin alone and almitrine alone, arterial oxygen partial pressure (Pao2) increased, whereas intrapulmonary shunt (S/T) decreased (P < 0.05). Combined prostacyclin and almitrine also increased Pao2 and decreased S/T (P < 0.05). When compared with either prostacyclin or almitrine alone, the combined application of both drugs revealed no additional effect in gas exchange or a/ distribution.     

Cerebral Blood Flow and CO2 Reactivity Is Similar during Remifentanil/N2 O and Fentanyl/N2 O Anesthesia

Background: Remifentanil, a rapidly metabolized [micro sign]-opioid agonist, may offer advantages for neurosurgical procedures in which prolonged anesthetic effects can delay assessment of the patient. This study compared the effects of remifentanil-nitrous oxide on cerebral blood flow (CBF) and carbon dioxide reactivity with those of fentanyl-nitrous oxide anesthesia during craniotomy.

Methods: After institutional approval and informed patient consent were obtained, 23 patients scheduled to undergo supratentorial tumor surgery were randomly assigned to remifentanil or fentanyl infusion groups in a double-blinded manner. Midazolam, thiopental, and pancuronium induction was followed by equipotent narcotic loading infusions of remifentanil (1 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or fentanyl (2 [micro sign]g [middle dot] kg-1 [middle dot] min-1) for 5-10 min. Patients were ventilated with 2:1 nitrous oxide-oxygen, and opioid rates were reduced and then titrated to a stable hemodynamic effect. After dural exposure, CBF was measured by the intravenous133 xenon technique at normocapnia and hypocapnia. Reactivity of CBF to carbon dioxide was calculated as the absolute increase in CBF per millimeters of mercury increase in the partial pressure of carbon dioxide (PaCO2). Data were analyzed by repeated-measures analysis of variance, unpaired Student's t tests, or contingency analysis.

Results: In the remifentanil group (n = 10), CBF decreased from 36 +/- 11 to 27 +/- 8 ml [middle dot] 100 g-1 [middle dot] min-1 as PaCO2 decreased from 33 +/- 5 to 25 +/- 2 mmHg. In the fentanyl group (n = 8), CBF decreased from 37 +/- 11 to 25 +/- 6 ml [middle dot] 100 g-1 [middle dot] min-1 as PaCO2 decreased from 34 +/- 3 to 25 +/- 3 mmHg. Absolute carbon dioxide reactivity was preserved with both agents: 1 +/- 1.2 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for remifentanil and 1.5 +/- 0.5 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for fentanyl (P = 0.318).     

Local Cerebral Blood Flow, Local Cerebral Glucose Utilization, and Flow-Metabolism Coupling during Sevoflurane versus Isoflurane Anesthesia in Rats

Background: Compared to isoflurane, knowledge of local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) during sevoflurane anesthesia is limited.

Methods: LCGU, LCBF, and their overall means were measured in Sprague-Dawley rats (8 groups, n = 6 each) during sevoflurane and isoflurane anesthesia, 1 and 2 MAC, and in conscious control animals (2 groups, n = 6 each) using the autoradiographic 2-[(14) C]deoxy-D-glucose and 4-iodo-N-methyl-[(14) C]antipyrine methods.

Results: During anesthesia, mean cerebral glucose utilization was decreased: control, 56 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot]-1; 1 MAC isoflurane, 32 +/- 4 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-43%); 1 MAC sevoflurane, 37 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-34%); 2 MAC isoflurane, 23 +/- 3 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-58%); 2 MAC sevoflurane, 23 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-59%). Local analysis showed a reduction in LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased as follows: control, 93 +/- 8 ml [middle dot] 100 g-1 [middle dot] min-1; 1 MAC isoflurane, 119 +/- 19 ml [middle dot] 100 g-1 [middle dot] min-1 (+28%); 1 MAC sevoflurane, 104 +/- 15 ml [middle dot] 100 g-1 [middle dot] min-1 (+12%); 2 MAC isoflurane, 149 +/- 17 ml [middle dot] 100 g-1 [middle dot] min-1 (+60%); 2 MAC sevoflurane, 118 +/- 21 ml [middle dot] 100 g-1 [middle dot] min-1 (+27%). LCBF was increased in most brain structures investigated. Correlation coefficients obtained for the relationship between LCGU and LCBF were as follows: control, 0.93; 1 MAC isoflurane, 0.89; 2 MAC isoflurane, 0.71; 1 MAC sevoflurane, 0.83; 2 MAC sevoflurane, 0.59).     

Effect of Low Isoflurane Concentrations on the Ventilation-Perfusion Distribution in Injured Canine Lungs

Background: Rapid recovery and weaning from ventilatory support and cardiovascular stability are suggested advantages of isoflurane inhalation, in concentrations ranging from 0.1 to 0.6 vol%, for long-term sedation in mechanical ventilated patients. This study was designed to determine whether isoflurane in low concentrations impairs pulmonary gas exchange by increasing ventilation and perfusion ([latin capital V with dot above]A/[Latin capital letter Q with dot above]) mismatch during lung injury.

Methods: Fourteen anesthetized dogs received in random order 0, 0.25, or 0.5 vol% end-tidal isoflurane before and after induction of lung injury with oleic acid. Gas exchange was assessed by blood gas analysis and by estimating the [latin capital V with dot above]A/[Latin capital letter Q with dot above] distributions using the multiple inert gas elimination technique.

Results: Administration of oleic acid produced a lung injury with severe [latin capital V with dot above]A/[Latin capital letter Q with dot above] mismatch and 38 +/- 4% intrapulmonary shunting of blood. During lung injury, isoflurane accounted for a dose-related increase in blood flow to shunt units from 38 +/- 4 to 42 +/- 3 (0.25 vol%) and 48 +/- 4% (0.5 vol%) (P < 0.05), dispersion pulmonary blood flow distribution from 0.94 +/- 0.07 to 1.01 +/- 0.09 (0.25 vol%) and 1.11 +/- 0.11% (0.5 vol%) (P < 0.05), and a decrease in perfusion of normal [latin capital V with dot above]A/[Latin capital letter Q with dot above] units from 58 +/- 5 to 55 +/- 4 (0.25 vol%) and 50 +/- 4% (0.5 vol%) (P < 0.05) (mean +/- SE). Isoflurane decreased arterial oxygen partial pressure from 72 +/- 4 to 62 +/- 4 mmHg (0.25 vol%) and 56 +/- 4 mmHg (0.5 vol%) (P < 0.05) and oxygen delivery from 573 +/- 21 to 529 +/- 19 ml [middle dot] kg-1 [middle dot] min-1 (0.25 vol%) and 505 +/- 22 ml [middle dot] kg-1 [middle dot] min-1 (0.5 vol%) (P < 0.05). Gas exchange, perfusion of shunt and normal [latin capital V with dot above]A/[Latin capital letter Q with dot above] units, and pulmonary blood flow distribution was similar in absence of lung injury with and without isoflurane. Isoflurane 0.5 vol% lowered cardiac output during all conditions (P < 0.05).     

Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part II): Effects on the Development of Tolerance to Morphine

Background: There has been little information regarding the effects of local anesthetics on tolerance to opioids, although chronic use of combination of opioids and local anesthetics is popular for pain control. This study was designed to examine the effects of lidocaine on morphine tolerance to somatic and visceral antinociception.

Methods: Rats received a continuous intrathecal infusion of morphine (0.3-10 [micro sign]g [middle dot] kg-1 [middle dot] h-1), lidocaine (30-1000 [micro sign]g [middle dot] kg-1 [middle dot] h-1), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 [micro sign]g/10 [micro sign]l) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively.

Results: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 [micro sign]g [middle dot] kg-1 [middle dot] h-1 than in morphine 0.75 [micro sign]g [middle dot] kg-1 [middle dot] h-1 + lidocaine 150 [micro sign]g [middle dot] kg-1 [middle dot] h-1 despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 [micro sign]g [middle dot] kg-1 [middle dot] h-1) did not reduce the antinociceptive effects in the challenge test.     

Dobutamine Antagonizes Epinephrine's Biochemical and Cardiotonic Effects: Results of an In Vitro Model Using Human Lymphocytes and a Clinical Study in Patients Recovering from Cardiac Surgery

Background: Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects.

Methods: The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobutamine (10-8 to 10-4 M) or epinephrine (10-9 M to 10-5 M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or epinephrine (10, 20, or 40 ng [middle dot] kg-1 [middle dot] min-1), alone or in combination.

Results: In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration [almost equal to] 200%. However, when epinephrine (10-6 M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10-6 to 10-4 M (P = 0.001). In patients, 1.25 to 5 [micro sing]g [middle dot] kg-1 [middle dot] min-1 dobutamine increased the cardiac index (CI) 15-28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 [micro sign]g [middle dot] kg-1 [middle dot]-1 min (-1)). In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects.     

Optimal Adrenergic Support in Septic Shock Due to Peritonitis

Background: The authors evaluated optimal adrenergic support using norepinephrine, dopamine, and dobutamine in a clinically relevant model of septic shock.

Methods: Twenty-eight mature, female, anesthetized sheep (weight, 30.5 +/- 3.6 kg) underwent cecal ligation and perforation and were randomized into four groups of seven animals to be treated with norepinephrine, dopamine-norepinephrine, dobutamine-norepinephrine, or no adrenergic agent. In all groups, lactated Ringer's solution was administered to restore cardiac filling pressures to baseline. In the norepinephrine group, norepinephrine (0.5-5 [mu]g [middle dot] kg-1 [middle dot] min-1) was titrated to maintain mean arterial pressure between 75-85 mmHg. In the dopamine-norepinephrine group, dopamine was given first, and norepinephrine was added only when mean arterial pressure remained below 75 mmHg despite the infusion of 20 [mu]g [middle dot] kg-1 [middle dot] min-1 dopamine. In the dobutamine-norepinephrine group, dobutamine was started at the same time as norepinephrine and titrated up to 20 [mu]g [middle dot] kg-1 [middle dot] min-1 to get a 15% increase in cardiac output.

Results: The dobutamine-norepinephrine group had greater cardiac output; superior mesenteric blood flow, oxygen delivery (Do2), and oxygen consumption ([latin capital V with dot above]o2); and lower blood lactate concentration and partial pressure of carbon dioxide (Pco2) gap than the controls did. Cumulative urine output was significantly higher in the dobutamine-norepinephrine group than in the other groups. Survival time was significantly longer in the dobutamine-norepinephrine (24 +/- 4 h), dopamine- norepinephrine (24 +/- 6 h), and norepinephrine (20 +/- 1 h) groups than the control group (17 +/- 2 h;P < 0.05 vs. other groups), and significantly longer in the combined dopamine-norepinephrine and dobutamine-norepinephrine groups (24 +/- 5 h) than in the norepinephrine alone group (P < 0.05). Histologic examination of lung biopsies revealed less severe lesions in the dobutamine-norepinephrine group than in the control and norepinephrine alone groups. Anatomic alterations in the lung, liver, and small intestine were less severe in the dobutamine-norepinephrine group than in the other groups.     

Pancreatitis-associated Protein Protects the Lung from Leukocyte-induced Injury

Background: Severe pancreatitis is often complicated by shock and acute lung failure. Little is known about the pathophysiologic impact of the 16.6-kD lectine, named pancreatitis-associated protein (PAP), which is expressed during pancreatitis and which reduces mortality in a rat model with severe pancreatitis. Therefore, the aim of this study was to investigate the effects of PAP on the pulmonary vasculature after leukocyte activation with N-formyl-Met-Leu-Phe (fMLP).

Methods: The experiments were performed in buffer-perfused isolated rabbit lungs. Mean pulmonary artery pressure, weight gain, and thromboxane A2 synthesis of the lungs were monitored. PAP was obtained by affinity chromatography of pancreas juice from pancreatitic rats. The authors tested whether treatment with PAP (260 [mu]g/l, n = 9; or 500 [mu]g/l, n = 6) before fMLP injection (10-6 M) influences mean pulmonary artery pressure and edema formation. Lungs that were treated only with fMLP (n = 6) served as controls. Additional experiments in which PAP was applied were performed to study whether PAP (260 [mu]g/l, n = 3; 500 [mu]g/l, n = 3; 1,000 [mu]g/l, n = 3) itself effects lung vasculature.

Results: Application of fMLP resulted in an increase of mean pulmonary artery pressure (+/- SD) from 8 +/- 2 mmHg up to 26 +/- 13 mmHg (P < 0.01) at a flow of 150 ml/min. Pretreatment with PAP reduced the peak pressure developed after fMLP to 15 +/- 7 mmHg (PAP 260 [mu]g/l;P < 0.05) and to 9 +/- 4 mmHg (PAP 500 [mu]g/l), respectively. In addition, the fMLP-induced lung weight gain of 9 +/- 7 g in the controls was prevented by pretreatment with PAP after 150 min in either concentration. In parallel to the attenuated pressure increase, thromboxane A2 release was significantly suppressed in the 260-[mu]g/l (200 +/- 220 pmol [middle dot] ml-1 [middle dot] min-1;P < 0.01) and 500-[mu]g/l (285 +/- 70 pmol [middle dot] ml-1 [middle dot] min-1;P < 0.05) PAP groups compared with controls (1,138 +/- 800 pmol [middle dot] ml-1 [middle dot] min-1). Treatment with PAP alone in either concentration did not induce any changes in mean pulmonary artery pressure, weight gain, or thromboxane A2 release.     

Effects of Intravenous Zaprinast and Inhaled Nitric Oxide on Pulmonary Hemodynamics and Gas Exchange in an Ovine Model of Acute Respiratory Distress Syndrome

Methods: The authors studied two groups of sheep with lung injury produced by saline lavage. In the first group, 0, 5, 10, and 20 ppm of inhaled NO were administered in a random order before and after an intravenous Zaprinast infusion (2 mg/kg bolus followed by 0.1 mg [middle dot] kg-1 [middle dot] min-1). In the second group, inhaled NO was administered at the same concentrations before and after an intravenous infusion of Zaprinast solvent (0.05 m NaOH).

Results: After lavage, inhaled NO decreased pulmonary arterial pressure and resistance with no systemic hemodynamic effects, increased arterial oxygen partial pressure, and decreased venous admixture (all P < 0.05). The intravenous administration of Zaprinast alone decreased pulmonary artery pressure but worsened gas exchange (P < 0.05). Zaprinast infusion abolished the beneficial ability of inhaled NO to improve pulmonary gas exchange and reduce pulmonary artery pressure (P < 0.05 vs. control).     

Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop

Background: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the [micro sign]-opioid receptor agonist morphine.

Methods: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 [micro sign]g/kg, followed by 30 [micro sign]g [middle dot] kg-1 [middle dot] h-1). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD.

Results: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l [middle dot] mmHg-1 (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l [middle dot] [middle dot] min-1 [middle dot] mmHg-1, not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l [middle dot] min-1 [middle dot] %-1, respectively; P < 0.05). The ventilatory response to sustained hypoxia (i.e., 15 min) did not differ between men and women.     

Prophylactic Angiotensin II Infusion during Spinal Anesthesia for Elective Cesarean Delivery

Background: Angiotensin II may prove useful in treating regional anesthesia-induced hypotension in obstetric patients, because it causes less uterine vasoconstriction than do other vasoconstrictor drugs (such as phenylephrine). This study compared (1) maternal blood pressure and heart rate and (2) fetal status at delivery in parturients given either prophylactic angiotensin II or ephedrine infusion during spinal anesthesia for elective cesarean delivery.

Methods: Fifty-four women were randomized to receive either angiotensin II or ephedrine infusion intravenously during spinal anesthesia for elective cesarean section delivery. Simultaneous with subarachnoid injection, infusion of angiotensin II (2.5 [micro sign]g/ml) or ephedrine (5 mg/ml) was initiated at 10 ng [middle dot] kg-1 [middle dot] min-1 and 50 [micro sign]g [middle dot] kg-1 [middle dot] min-1, respectively. The rate of each infusion was adjusted to maintain maternal systolic blood pressure at 90-100% of baseline.

Results: Cumulative vasopressor doses (mean +/- SD) through 10, 20, and 30 min were 150 +/- 100, 310 +/- 180, and 500 +/- 320 ng/kg in the angiotensin group and 480 +/- 210, 660 +/- 390, and 790 +/- 640 [micro sign]g/kg in the ephedrine group. Maternal heart rate was significantly higher (P < 0.001) during vasopressor infusion in the ephedrine group than in the angiotensin group. Umbilical arterial and venous blood pH and base excess were all significantly higher (P < 0.05) in the angiotensin group than in the ephedrine group.     

High-dose Remifentanil Does Not Impair Cerebrovascular Carbon Dioxide Reactivity in Healthy Male Volunteers

Background: Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv).

Methods: Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics.

Results: Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for 2 and 4 [mu]g[middle dot]kg-1[middle dot]min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm [middle dot] s-1 [middle dot] mmHg-1 for 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ.     

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Alfentanil

Background: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study.

Methods: After institutional approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO(2)] = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 [micro sign]g/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PECO(2)) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred. During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO(2)). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO(2) data were described by an indirect response model. The model accounted for the respiratory stimulation resulting from increasing PaCO(2). The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations.

Results: The indirect response model adequately described the time course of the PaCO(2). The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 [micro sign]g/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min-1 (44%); and the gain in the carbon dioxide response, 4 (28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO(2) in maintaining alveolar ventilation in the presence of opioid.     

Effects of Short-term Fenoldopam Infusion on Gastric Mucosal Blood Flow in Septic Shock

Background: Inadequate splanchnic perfusion in septic shock is associated with increased morbidity and mortality. As result of splanchnic ischemia, mucosal permeability increases. Considering the implication of improved mucosal perfusion in terms of maintenance of mucosal barrier integrity, dopamine-1 receptor stimulation could be helpful in septic shock. The goal of the current study was to determine the effects of fenoldopam on systemic hemodynamic parameters and gastric mucosal perfusion in patients with septic shock. Furthermore, the authors tested the hypothesis that the addition of fenoldopam (0.1 [mu]g [middle dot] kg-1 [middle dot] min-1) to a combination of norepinephrine and dobutamine (5 [mu]g [middle dot] kg-1 [middle dot] min-1) may improve gastric mucosal perfusion in septic shock.

Methods: Patients with septic shock were randomized to a double-blind 2-h infusion of fenoldopam (n = 20) or placebo (n = 20). Each group received dobutamine (5 [mu]g [middle dot] kg-1 [middle dot] min-1), and the dosage of norepinephrine was adjusted to achieve a mean arterial pressure between 70 and 80 mmHg. A laser-Doppler probe and tonometer were introduced into the gastric lumen.

Results: A significant increase in gastric mucosal perfusion, detected by laser-Doppler flowmetry, was observed in the group treated with fenoldopam (P < 0.05). In addition, this increase in microcirculatory flow occurred despite the fact that systemic flow remained unchanged. Differences in gastroarterial partial pressure of carbon dioxide values were not statistically significant in the fenoldopam and placebo groups.     

Effects of Perfluorohexan Vapor on Gas Exchange, Respiratory Mechanics, and Lung Histology in Pigs with Lung Injury after Endotoxin Infusion

Background: Inhaled perfluorohexan vapor has been shown to improve gas exchange and pulmonary mechanics in oleic acid- and ventilator-induced lung injury. However, in the clinical setting, lung injury frequently occurs in the context of systemic inflammation and consecutive lung injury, which may be induced experimentally by intravenous administration of endotoxin. The authors studied whether vaporized perfluorohexan is efficacious during endotoxin-induced lung injury in domestic pigs.

Methods: Twenty-two pigs (29 [23, 31] kg body weight [first, third interquartile]; tracheostomy) were anesthetized and mechanically ventilated. In the endotoxin (n = 8) and perfluorohexan groups (n = 7), we administered endotoxin of Escherichia coli 111:B4, 1 mg [middle dot] kg-1 [middle dot] h-1 for 1 h and 10 [mu]g [middle dot] kg-1 [middle dot] h-1 for 5 h in consecutive order. In the perfluorohexan group, inhalation of the test drug was started 2 h 30 min after the start of the intravenous endotoxin and terminated after 30 min. In a control group (n = 7), animals were instrumented and observed over time without further intervention. Oxygenation function was assessed from oxygen partial pressures (Po2, blood gases) and calculated shunt fraction. Respiratory compliance was calculated from airway pressure and tidal volume. Measurements were performed before and every hour during endotoxin infusion.

Results: After 6 h of endotoxin, gas exchange and pulmonary compliance were deteriorated in the endotoxin group (Pao2: 184 [114, 289] vs. 638 [615, 658] mmHg, pulmonary shunt fraction: 30 [23, 38] vs. 4 [3, 6]%, respiratory compliance: 12 [11, 14] vs. 22 [19, 23] ml/mbar; P < 0.05, endotoxin vs. control). Inhalation of vaporized perfluorohexan did not improve Pao 2 (107 [60, 221] mmHg), pulmonary shunt fraction (32 [26, 58]%), or respiratory compliance (14 [10, 17] ml/mbar) when compared with intravenous endotoxin (not significant, perfluorohexan vs. endotoxin).     

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.

Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.

Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.     

Assessment of Depth of Anesthesia and Postoperative Respiratory Recovery after Remifentanil-versus Alfentanil-based Total Intravenous Anesthesia in Patients Undergoing Ear-Nose-Throat Surgery

Background: The authors investigated whether total intravenous anesthesia (TIVA) with precalculated equipotent infusion schemes for remifentanil and alfentanil would ensure appropriate analgesia and that remifentanil would result in better recovery characteristics.

Methods: Forty consenting patients (classified as American Society of Anesthesiologists physical status I-III) scheduled for microlaryngoscopy were randomized to receive, in a double-blind manner, either remifentanil (loading dose 1 [mu]g/kg; maintenance infusion, 0.25 [mu]g [middle dot] kg-1 [middle dot] min-1) or alfentanil (loading dose, 50 [mu]g/kg; maintenance infusion, 1 [mu]g [middle dot] kg-1 [middle dot] min-1) as the analgesic component of TIVA. They were combined with propofol (loading dose, 2 mg/kg; maintenance infusion, 100 [mu]g [middle dot] kg-1 [middle dot] min-1). To insure an equal state of anesthesia, the opioids were titrated to maintain heart rate and mean arterial pressure within 20% of baseline, and propofol was titrated to keep the bispectral index (BIS) less than 60. Neuromuscular blockade was achieved with succinylcholine. Drug dosages and the times from cessation of anesthesia to extubation, verbal response, recovery of ventilation, and neuropsychological testing, orientation, and discharge readiness were recorded.

Results: Demographics, duration of surgery, and anesthesia were similar between the two groups. Both groups received similar propofol doses. There were no difference in BIS values preoperatively (mean, 96), intraoperatively (mean, 55), and postoperatively (mean, 96). Recovery of BIS and times for verbal response did not differ. At 20, 30, and 40 min after terminating the opioid infusion, the peripheral oxygen saturation and respiratory rate were significantly higher in the remifentanil group compared with the alfentanil group.     

Short-term Cardiorespiratory Effects of Proportional Assist and Pressure-support Ventilation in Patients with Acute Lung Injury/Acute Respiratory Distress Syndrome

Background: Recent data indicate that assisted modes of mechanical ventilation improve pulmonary gas exchange in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proportional assist ventilation (PAV) is a new mode of support that amplifies the ventilatory output of the patient effort and improves patient-ventilator synchrony. It is not known whether this mode may be used in patients with ALI/ARDS. The aim of this study was to compare the effects of PAV and pressure-support ventilation on breathing pattern, hemodynamics, and gas exchange in a homogenous group of patients with ALI/ARDS due to sepsis.

Methods: Twelve mechanically ventilated patients with ALI/ARDS (mean ratio of partial pressure of arterial oxygen to fractional concentration of oxygen 190 +/- 49 mmHg) were prospectively studied. Patients received pressure-support ventilation and PAV in random order for 30 min while maintaining mean airway pressure constant. With both modes, the level of applied positive end-expiratory pressure (7.1 +/- 2.1 cm H2O) was kept unchanged throughout. At the end of each study period, cardiorespiratory data were obtained, and dead space to tidal volume ratio was measured.

Results: With both modes, none of the patients exhibited clinical signs of distress. With PAV, breathing frequency and cardiac index were slightly but significantly higher than the corresponding values with pressure-support ventilation (24.5 +/- 6.9 vs. 21.4 +/- 6.9 breaths/min and 4.4 +/- 1.6 vs. 4.1 +/- 1.3 l [middle dot] min-1 [middle dot] m-2, respectively). None of the other parameters differ significantly between modes.