Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct

Background: PROLI/NO (C5 H7 N3 O4 Na2 [center dot] CH3 OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 [degree sign] Celsius and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension.

Methods: In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F sub 2 alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 micro gram [center dot] kg sup -1 [center dot] min sup -1 of SNP or 0.75, 1.5, 3, 6, and 12 micro gram [center dot] kg sup -1 [center dot] min sup -1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized.

Results: Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 micro gram [center dot] kg sup -1 [center dot] min sup -1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 micro gram [center dot] kg sup -1 [center dot] min sup -1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled).     

吸入一氧化氮降低烟雾吸入性损伤肺动脉高压的实验研究

烟雾吸入致肺组织细胞损伤后５ｍｉｎ，行肺灌洗机械通气４ｈ，观察２４。酹明，犬随机分为三组。烟雾吸入后，对照组单纯涓氧；治疗组吸氧加０．００４５％ＮＯ，连续监测１２ｈ血循环动力学化；正常组不致伤。     

Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats.

Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with N(G)-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO. IMPLICATIONS: High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.     

吸入一氧化氮对室间隔缺损手术后肺动脉高压的疗效观察

目的　观察吸入一氧化氮(nitricoxide,NO)治疗室间隔缺损 (ventricularseptaldefect,VSD)术后肺动脉高压 (pulmonaryhypertension ,PH)的疗效。 方法　 2 0例VSD术后PH病人分别吸入 2 0×10 -6 、6× 10 -6 NO ,监测吸入前后的血流动力学、氧合指标。结果　吸入 2 0× 10 -6 NO后明显降低肺动脉压、肺循环阻力、肺内分流率、肺泡动脉血氧分压差 ,提高动脉血氧分压、氧供指数 ;以上指标停吸NO后恢复吸入NO前水平 ;再吸入 6× 10 -6 NO后恢复吸入 2 0× 10 -6 NO后水平 ,并维持至停吸NO后。吸入前后体循环压及阻力无变化。结论　吸入NO是治疗VSD手术后PH的一种有效的方法。     

Intermittent nitric oxide combined with intravenous dipyridamole in a piglet model of acute pulmonary hypertension

Continuous administration of inhaled nitric oxide is now widely used as a potent and selective pulmonary vasodilator. We have evaluated the effects of IV dipyridamole, a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, on the magnitude and duration of action of inhaled nitric oxide (NO)-mediated pulmonary vasodilation. We hypothesized that inhibition of cGMP degradation could augment and prolong the pulmonary vasodilating effects of NO and allow for intermittent NO inhalation. In eight anesthetized and mechanically ventilated piglets, IV U-46619, a thromboxane A(2) analog, was used to induce pulmonary hypertension. The effects of 2, 5, and 10 ppm of NO, delivered during 4 min for each concentration and followed by a 10-min NO-free interval after each NO concentration, were evaluated without and with dipyridamole. Pulmonary vascular resistance decreased from 825 +/- 49 dynes. s. cm(-5) (U-46619) to 533 +/- 48 dynes. s. cm(-5) (10 ppm NO) (P < 0.05 versus U-46619) and 396 +/- 42 dynes. s. cm(-5) (dipyridamole 10 microg kg-1x min-1 and 10 ppm NO) (P <0.05 versus NO), and cardiac output increased from 1.93 +/- 0.09 L/min to 2.03 +/- 0.13 L/min and 2.60 +/- 0.30 L/min (P < 0.05 versus NO). Mean arterial blood pressure decreased from 90 +/- 5 mm Hg (10 ppm NO) to 75 +/- 3 mm Hg (dipyridamole plus 10 ppm NO) (P < 0.01). The pulmonary vasodilation obtained with NO alone could be prolonged from 12 to 42 min when inhaled NO was combined with IV dipyridamole, accounting for a time-weighted reduction in NO exposure by 72%. We conclude that dipyridamole augments the effects of NO on right ventricular afterload, allows for intermittent NO inhalation, and can significantly reduce exposure to NO. IMPLICATIONS: IV dipyridamole prolongs the action of inhaled nitric oxide (NO) in a piglet model of acute pulmonary hypertension. Intermittent NO inhalation combined with IV dipyridamole decreases pulmonary artery pressure for a prolonged period of time and reduces exposure to NO.     

Low-dose phosphodiesterase inhibition improves responsiveness to inhaled nitric oxide in isolated lungs from endotoxemic rats

BACKGROUND: Inhalation of nitric oxide (NO) and inhibition of phosphodiesterase type 5 (PDE5) selectively dilate the pulmonary circulation in patients with acute lung injury (ALI) associated with pulmonary hypertension. PDE5 inhibitors administered at doses that decrease pulmonary artery pressures have been shown to worsen arterial oxygenation. We investigated the efficacy of doses of PDE5 inhibitors that do not reduce pulmonary artery pressure alone (subthreshold doses) to improve the response to inhaled NO in an animal model of ALI. MATERIALS AND METHODS: Adult Sprague-Dawley rats were pre-treated with 0.5 mg/kg Escherichia coli 0111:B4 endotoxin and 16 to 18 h later, their lungs were isolated perfused and ventilated. The thromboxane mimetic U46619 was used to induce pulmonary hypertension. After the determination of subthreshold doses of two different PDE5 inhibitors, either 50 microg zaprinast or 10 ng sildenafil was added to the perfusate and the decrease of pulmonary artery pressure measured in the presence and absence of inhaled NO. RESULTS: In the presence of 4 or 10 ppm NO, zaprinast (-1.6 +/- 0.4 and -2.9 +/- 0.6 mmHg, respectively) and sildenafil (-1.9 +/- 0.4 and -2.4 + 0.3 mmHg, respectively) improved responsiveness to inhaled NO compared to lungs from rats treated with LPS only (0.7 +/- 0.1 and -1.0 +/- 0.1 mmHg, respectively; P<0.05). Neither zaprinast nor sildenafil prolonged the pulmonary vasodilatory response to inhaled NO. CONCLUSIONS: Subthreshold doses of PDE5 inhibitors improved responsiveness to inhaled NO. Combining inhaled NO with subthreshold doses of PDE5 inhibitors may offer a therapeutic strategy with minimal side-effects in ALI associated with pulmonary hypertension.     

Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension.

Patients with mitral valve disease can develop pulmonary artery hypertension that persists after mitral valve replacement. In 1987, nitric oxide (NO) was reported to be an important factor accounting for the biologic activity of endothelium-derived relaxing factor. Inhaled NO was subsequently reported to be a selective pulmonary vasodilator in animals and patients. Therefore we investigated the vasodilating effect of inhaled NO in patients with mild pulmonary artery hypertension after mitral valve replacement. Six patients who underwent mitral valve replacement for mitral stenosis presented with a mean pulmonary artery pressure greater than 25 mmHg within 24 h after surgery. During mechanical ventilation at FIO2 0.5, NO (36.8-38.4 ppm) was breathed for 10 min. Hemodynamic data were recorded before NO, after 10 min of NO inhalation, and 30 min after the end of NO inhalation. Statistically significant (P < 0.05) hemodynamic response to inhaled NO included a transient decrease in systolic (-10%), diastolic (-8%), and mean (-10%) pulmonary artery pressures; a decrease in pulmonary vascular resistance (-22%); an increase in mixed venous hemoglobin O2 saturation (+6%); and a decrease in arteriovenous O2 content difference (-7%). During NO inhalation, there was no change in systemic arterial or pulmonary wedge pressures. Methemoglobin levels remained < 1%. Inhalation of this concentration of NO for 10 min causes transient pulmonary artery vasodilation and hemodynamic improvement in patients with mild chronic pulmonary artery hypertension after mitral valve replacement.     

Alterations in Canine Left Ventricular-arterial Coupling and Mechanical Efficiency Produced by Propofol

Background: Propofol reduces blood pressure by decreasing left ventricular (LV) afterload and myocardial contractility. This investigation tested the hypothesis that propofol preserves LV-arterial coupling and mechanical efficiency because of these simultaneous hemodynamic actions.

Methods: Experiments were conducted in open-chest dogs (n = 8) instrumented for measurement of aortic and LV pressure, dP/dtmax, and LV volume. Myocardial contractility was assessed with the slope (E sub es) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea; the ratio of end systolic arterial pressure to stroke volume), stroke work (SW), and pressure-volume area (PVA) were determined from the LV pressure-volume relationships. Dogs were studied 30 min after instrumentation and after 15-min intravenous infusions of propofol at 5, 10, 20, and 40 mg [center dot] kg sup -1 [center dot] h sup -1.

Results: Propofol caused dose-dependent decreases in Ees (4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dosage) and dP/dtmax, indicating a direct negative inotropic effect. Ea increased at the 10 mg [center dot] kg sup -1 [center dot] h sup -1 dose of propofol but decreased at higher dosages. Propofol decreased the ratio of Ees to Ea (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dosage), consistent with impairment of LV-arterial coupling. Propofol also reduced the ratio SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg [center dot] kg sup -1 [center dot] h sup -1), suggesting a decline in LV mechanical efficiency. SW and PVA recovered toward baseline values at the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose.     

Nitrogen Dioxide Production during Mechanical Ventilation with Nitric Oxide in Adults: Effects of Ventilator Internal Volume, Air Versus Nitrogen Dilution, Minute Ventilation, and Inspired Oxygen Fraction

Background: Inhaled nitric oxide (NO) may be useful in the treatment of adult respiratory distress syndrome and other diseases characterized by pulmonary hypertension and hypoxemia. NO is rapidly converted to nitrogen dioxide (NO2) in oxygen (Oxygen2) environments. We hypothesized that in patients whose lungs are mechanically ventilated and in those with a long residence time for NO in the lungs, a clinically important [NO2] may be present. We therefore determined the rate constants for NO conversion in adult mechanical ventilators and in a test lung simulating prolonged intrapulmonary residence of NO.

Methods: NO (800 ppm) was blended with nitrogen (Nitrogen2), delivered to the high-pressure air inlet of a Puritan-Bennett 7200ae or Siemens Servo 900C ventilator, and used to ventilate a test lung. The ventilator settings were varied: minute ventilation (VE) from 5 to 25 l/min, inspired Oxygen2 fraction (FIO2) from 0.24 to 0.87, and [NO] from 10 to 80 ppm. The experiment was then repeated with air instead of Nitrogen2 as the dilution gas. The effect of pulmonary residence time on NO2 production was examined at test lung volumes of 0.5-4.0 l, V with dotE of 5-25 l/min, FIO2 of 0.24-0.87, and [NO] of 10-80 ppm. The inspiratory gas mixture was sampled 20 cm from the Y-piece and from within the test lung. NO and NO sub 2 were measured by chemiluminescence. The rate constant (k) for the conversion of NO to NO2 was determined from the relation 1/[NO]1 1/[NO]0 k x [Oxygen2] x t, where t = residence time.

Results: No NO2 was detected during any trial with V with dot sub E 20 or 25 l/min. With Nitrogen2 dilution and the Puritan- Bennett 7200ae, NO2 (less or equal to 1 ppm) was detected only at a V with dotE of 5 l/min with an FIO2 of 0.87 and [NO] greater or equal to 70 ppm. In contrast, [NO2] values were greater with the Servo 900C ventilator than with the Puritan-Bennett 7200ae at similar settings. When NO was diluted with air, clinically important [NO sub 2] values were measured with both ventilators at high [NO] and FI sub O2. Rate constants were 1.46 x 109 ppm2 *symbol* min sup -1 when NO was mixed with Nitrogen2, 1.17 x 108 ppm sup - 2 *symbol* min sup -1 when NO was blended with air, and 1.44 x 109 ppm sup -2 *symbol* min sup -1 in the test lung.     

Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro-receptor agonist morphine.

Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup -1 [center dot] h sup -1) in 12 men and 12 women.

Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l [center dot] min sup -1 [center dot] mmHg sup -1 (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l [center dot] min sup -1 [center dot] mmHg sup -1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 to 0.5 +/- 0.4 l [center dot] min sup -1 [center dot] % sup -1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 vs. morphine = 0.9 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes.     

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).     

Inhalation of the Phosphodiesterase-3 Inhibitor Milrinone Attenuates Pulmonary Hypertension in a Rat Model of Congestive Heart Failure

Background: Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF.

Methods: In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 [mu]g [middle dot] kg body weight-1 [middle dot] min-1) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.

Results: In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation.     

Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy.

BACKGROUND: The inhalation of nitric oxide (NO) in patients with heart failure decreases pulmonary vascular resistance (PVR) and is associated with an increase in pulmonary artery wedge pressure (PAWP). The mechanism for this effect remains unclear. METHODS: In dogs rapid-paced for 8 weeks to induce cardiac dysfunction, we performed left ventricular pressure-volume analysis of unpaced hearts in situ to determine whether during NO inhalation (80 ppm), the mechanism for the rise in PAWP is due to: 1) primary pulmonary vasodilation; 2) a direct negative inotropic effect; or 3) impairment of ventricular relaxation. RESULTS: Inhalation of NO decreased PVR by 51%+/-3.8% (257+/-25 vs 127+/-18 dynes x sec x cm(-5) [NO 80 ppm]; p < 0.001) and increased PAWP (15.4+/-2.4 vs 18.1+/-2.6 mm Hg [NO 80 ppm]; p < 0.001). Calculated systemic vascular resistance remained unchanged. Left ventricular (LV) end-diastolic pressure rose (16.4+/-1.9 vs 19.1+/-1.8 mm Hg [NO 80 ppm]; p < 0.001), as did LV end-diastolic volume (83.5+/-4.0 vs 77.0+/-3.4 mL [NO 80 ppm]; p = 0.006). LV peak +dP/dt was unchanged by NO (1,082+/-105 vs 1,142+/-111 mm Hg/sec [NO 80 ppm]; p = NS). There was a trend toward a stroke volume increase (17.4+/-1.2 vs 18.8+/-1.3 mL; p = NS), but the relaxation time constant and end-diastolic pressure-volume relation were both unchanged. CONCLUSIONS: In this canine model of cardiomyopathy, inhaled NO decreases pulmonary vascular resistance. The associated increase in left ventricular filling pressure appears to be secondary to a primary pulmonary vasodilator effect of NO without primary effects on the contractile or relaxation properties of the left ventricle.     

Effects of a Dobutamine-induced Increase in Splanchnic Blood Flow on Hepatic Metabolic Activity in Patients with Septic Shock

Background: Septic shock leads to increased splanchnic blood flow (Qspl) and oxygen consumption (VO2 spl). The increased Qspl, however, may not match the splanchnic oxygen demand, resulting in hepatic dysfunction. This concept of ongoing tissue hypoxia that can be relieved by increasing splanchnic oxygen delivery (DO2 spl), however, was challenged because most of the elevated VO2 spl was attributed to increased hepatic glucose production (HGP) resulting from increased substrate delivery. Therefore the authors tested the hypothesis that a dobutamine-induced increase in Qspl and DO2 spl leads to increased VO sub 2 spl associated with accelerated HGP in patients with septic shock.

Methods: Twelve patients with hyperdynamic septic shock in whom blood pressure had been stabilized (mean arterial pressure greater or equal to 70 mmHg) with volume resuscitation and norepinephrine received dobutamine to obtain a 20% increase in cardiac index (CI). Qspl, DO2 spl, and VO sub 2 spl were assessed using the steady-state indocyanine green clearance technique with correction for hepatic dye extraction, and HGP was determined from the plasma appearance rate of stable, non-radioactive-labeled glucose using a primed-constant infusion approach.

Results: Although the increase in CI resulted in a similar increase in Qspl (from 0.91 +/- 0.21 to 1.21 +/- 0.34 l [center dot] min sup -1 [center dot] m2; P < 0.001) producing a parallel increase of DO2 spl (from 141 +/- 33 to 182 +/- 44 ml [center dot] min sup -1 [center dot] m2; P < 0.001), there was no effect on VO2 spl (73 +/- 16 and 82 +/- 21 ml [center dot] min sup -1 [center dot] m2, respectively). Hepatic glucose production decreased from 5.1 +/- 1.6 to 3.6 +/- 0.9 mg [center dot] kg sup -1 [center dot] min sup -1 (P < 0.001).     

Inhaled nitric oxide reduces pulmonary artery pressures in portopulmonary hypertension.

Pulmonary artery hypertension in association with liver failure (portopulmonary hypertension [PPHTN]) is a significant barrier to liver transplantation because patients with this condition have a very high mortality when transplantation is undertaken. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, reduces pulmonary artery pressure (PAP) in some patients with primary pulmonary hypertension, but its effect in patients with PPHTN is controversial. We investigated the hemodynamic effects of inhaled NO in 6 patients with PPHTN. Five of 6 patients responded to NO inhalation with decreases in PAP and pulmonary vascular resistance of greater than 10%; these decreases were statistically significant at NO concentrations of 10 and 30 ppm. Cardiac output did not significantly change. We conclude that inhalation of NO reduces PAPs in some patients with PPHTN.     

Clearance of Mucus from Endotracheal Tubes during Intratracheal Pulmonary Ventilation

Background: Intratracheal pulmonary ventilation (ITPV) is a form of tracheal gas insufflation in which all gas emerges in a cephalad direction from the tip of a reverse-thrust catheter positioned within an endotracheal tube. In vitro experiments have shown that this rapid gas flow, with 5 ml/h of normal saline added to the gas flow, continuously removes tracheal secretions from within the endotracheal tube. The authors evaluated its effectiveness to remove mucus in long-term studies in sheep.

Methods: Fourteen healthy sheep were tracheally intubated and ventilated for 3 days with ITPV or with volume-controlled ventilation. Measurements were made of the total amount of secretions within the endotracheal tubes (weight gain), the protein content within the endotracheal tubes, and the increase in resistance to constant air flow. The structure of the airways was examined grossly and histologically. Three additional sheep were ventilated for 24 h with ITPV, and Evans Blue dye was added to the saline to assess the distribution of the infused saline.

Results: There was significantly less mucus in endotracheal tubes of sheep ventilated with ITPV than with conventional ventilation, as shown by minimal weight gain (0.70 +/- 0.14 g vs. 2.44 +/- 0.81 g; P < 0.001), lower protein content (14.09 +/- 10.79 mg vs. 294.99 +/- 153.06 mg; P <0.001), and lower resistance to constant air flow (6.15 +/- 0.54 cm H2 O [center dot] l sup -1 [center dot] s sup -1 vs. 15.34 +/- 5.28 cm H2 O [center dot] l sup -1 [center dot] s sup -1; P < 0.001). Results of gross and histological examinations of the tracheas of animals in both groups were similar, and the tracheas were well preserved. More than 95% of the instilled saline was recovered during ITPV. Only traces of Evans Blue dye were found near the tip of the endotracheal tubes.     

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

Background: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.

Methods: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micro gram [center dot] kg [center dot] sup -1 min sup -1) or remifentanil (n = 31; 1 micro [center dot] kg sup -1 [center dot] min sup -1). After tracheal intubation, infusion rates were reduced to 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (fentanyl) or 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil ([nearly equal] 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7.

Results: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar.     

Positron Emission Tomography Study of Regional Cerebral Metabolism in Humans during Isoflurane Anesthesia

Background: Although the anesthetic effects of the intravenous anesthetic agent propofol have been studied in the living human brain using brain imaging technology, the nature of the anesthetic state evident in the human brain during inhalational anesthesia remains unknown. To examine this issue, the authors studied the effects of isoflurane anesthesia on human cerebral glucose metabolism using positron emission tomography (PET).

Methods: Five volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism and the other scan assessed metabolism during isoflurane anesthesia titrated to the point of unresponsiveness (means +/- SD; expired = 0.5 +/- 0.1%). Scans were obtained with a GE2048 scanner (4.5-mm resolution-FWHM) using the18 fluorodeoxyglucose technique.

Results: Awake whole-brain glucose metabolism averaged 6.9 +/- 1.5 mg [center dot] 100 g sup -1 [center dot] min sup -1 (means +/- SD). Isoflurane reduced whole-brain metabolism 46 +/- 11% to 3.6 +/- 0.3 mg [center dot] 100 g sup -1 [center dot] min sup -1 (P less or equal to 0.005). Regional metabolism decreased fairly uniformly throughout the brain, and no evidence of any regional metabolic increases were found in any brain region for any participant. A region-of-interest analysis showed that the pattern of regional metabolism evident during isoflurane anesthesia was not significantly different from that seen when participants were awake.     

Inhaled iloprost in eight heart transplant recipients presenting with post-bypass acute right ventricular dysfunction

BACKGROUND: During heart transplantation, weaning from cardiopulmonary bypass may be particularly laborious as a result of superimposed acute right ventricular dysfunction in the setting of pre-existing pulmonary hypertension. Research in recent years has focused on inhaled vasodilatory treatment modalities which selectively target the pulmonary circulation. METHODS: We present a series of eight patients in whom inhaled iloprost, a synthetic prostacyclin analog, was used to treat pulmonary hypertension and right ventricular dysfunction detected by transesophageal echocardiography during a heart transplant procedure. In addition to conventional inotropic support, 20 mug of inhaled iloprost was administered via nebulized aerosol for a 20-min period. Complete sets of hemodynamic measurements were obtained before inhalation and during and after cessation of the inhalation period. RESULTS: Inhaled iloprost decreased the transpulmonary gradient at the end of the inhalation period relative to baseline (8.2 +/- 1.6 mmHg vs. 11.2 +/- 0.9 mmHg, P < 0.05). The mean pulmonary artery pressure to systemic artery pressure ratio decreased over this period (0.24 +/- 0.07 vs. 0.44 +/- 0.09, P < 0.05). A statistically significant decrease in the pulmonary vascular resistance to systemic vascular resistance ratio was also observed (0.10 +/- 0.02 vs. 0.19 +/- 0.02, P < 0.05). Improved indices of right ventricular function were observed in echocardiographic monitoring. CONCLUSION: During heart transplantation procedures, episodes of pulmonary hypertension can be successfully treated with inhaled iloprost administration, without untoward side-effects or significant systemic impact.     

Remifentanil versus Remifentanil/midazolam for Ambulatory Surgery during Monitored Anesthesia Care

Background: This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting.

Methods: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter, double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 micro gram/kg, given over 30 s followed by a continuous infusion of 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil); remifentanil, 0.5 micro gram/kg, given over 30 s followed by a continuous infusion of 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Five minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or midazolam, 1 mg, (remifentanil + midazolam). If patients were not oversedated, a second dose of placebo or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin closure.

Results: At the time of the local anesthetic, most patients in the remifentanil and remifentanil + midazolam groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively). The final mean (+/- SD) remifentanil infusion rates were 0.12 +/- 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and 0.07 +/- 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Fewer patients in the remifentanil + midazolam group experienced nausea compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four patients (5%) in the remifentanil group and two patients (2%) in the remifentanil + midazolam group experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/min).