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 microg.kg body weight.min) 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. CONCLUSION: If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.     

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).     

Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates

PURPOSE: Selective pulmonary vasodilation is an advantageous method for testing the responsiveness of the pulmonary vasculature of heart transplant candidates. A pilot study was under-taken to test the hypothesis that inhaled aerosolized milrinone may cause selective pulmonary vasodilation. METHODS: 18 consecutive male heart transplant candidates with either dilated or ischemic cardiomyopathy were included in this open clinical study. Nine of the patients had significant pulmonary hypertension with a mean pulmonary arterial pressure > 30 mmHg. After baseline measurements, 2 mg of milrinone was administered by ultrasonic nebulization. Pulmonary and systemic hemodynamics were measured ten, 30, and 60 min after inhalation. RESULTS: After inhalation for ten minutes, milrinone induced a significant reduction of mean pulmonary arterial pressure (32.7 +/- 9.1 vs 37.7 +/- 7.5 mmHg, P = 0.01), pulmonary vascular resistance index (296 +/- 150 vs 396 +/- 151 dyn.sec(-1).cm(-5).m(2), P = 0.02) and transpulmonary gradient (10.6 +/- 5.5 vs 15 +/- 4.9, P = 0.01) only in patients with significant pulmonary hypertension. There was no significant effect on mean arterial pressure or systemic vascular resistance at any time after inhalation in either group. Furthermore, there was no influence on extravascular lung water or intrathoracic blood volume. CONCLUSIONS: We conclude that inhaled aerosolized milrinone for a short period selectively dilates the pulmonary vasculature in heart transplant candidates with elevated pulmonary arterial pressure, without producing systemic side effects. Further comparative studies are necessary to evaluate possible advantages of milrinone compared to other inhaled vasodilators.     

The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.

Selective pulmonary vasodilation is an advantageous therapeutic strategy for cardiac surgical patients with increased pulmonary vascular resistance (PVR) and right ventricular failure. We hypothesized that milrinone, an adenosine-3',5'-cyclic monophosphate (cAMP)-selective phosphodiesterase enzyme (PDE) inhibitor may, when nebulized and inhaled, cause selective pulmonary vasodilation and potentiate the vasodilation by inhaled prostacyclin (iPGI(2)). Consequently, we investigated the hemodynamic effects of inhaled milrinone or the combination iPGI(2) + inhaled milrinone in cardiac surgical patients with postoperative mean pulmonary arterial pressure (MPAP) >25 mm Hg and PVR >200 dynes. s(-1). cm(-5). During mechanical ventilation and using a conventional nebulizing system, 9 patients inhaled incremental concentrations of milrinone (0.25, 0.5 and 1 mg/mL) in subsequent 10-min periods (Study Part 1). In the same manner, 11 patients received iPGI(2) (10 microg/mL) followed by the combination of iPGI(2) (10 microg/mL) and inhaled milrinone (1 mg/mL) (Study Part 2). Inhaled milrinone reduced PVR with a maximal effect (-20%, P < 0.001) at the largest concentration. As compared with iPGI(2) alone, iPGI(2) + inhaled milrinone caused a further and prolonged reduction of PVR (-8%, P < 0.05) and increased stroke volume (+5%, P < 0.05). Systemic vascular resistance or mean arterial pressure was not affected by inhalation of either drug(s). The authors conclude that inhalation of the cAMP-selective PDE-inhibitor milrinone selectively dilates the pulmonary vasculature without systemic effects in cardiac surgical patients with pulmonary hypertension. Furthermore, inhaled milrinone appears to potentiate and prolong the pulmonary selective vasodilatory effect of iPGI(2). Inhaled milrinone alone or combined with iPGI(2) may be an important therapeutic option in the treatment of patients with pulmonary hypertension and right ventricular failure. IMPLICATIONS: Pulmonary hypertension may cause or aggravate right heart failure. IV vasodilators reduce systemic blood pressure and might thereby further impair coronary perfusion and right heart performance. In the present study of cardiac surgical patients with pulmonary hypertension, selective pulmonary vasodilation without systemic effects was induced by nebulized, inhaled vasodilators.     

Milrinone Modulates Endotoxemia, Systemic Inflammation, and Subsequent Acute Phase Response after Cardiopulmonary Bypass (CPB)

Background: Compromised splanchnic perfusion and the resulting intestinal mucosal injury leads to a decreased mucosal barrier function, which allows translocation of intestinal flora and endotoxemia. The authors evaluated the effects of milrinone on splanchnic oxygenation, systemic inflammation, and the subsequent acute-phase response in patients undergoing coronary artery bypass grafting.

Methods: This open, placebo-controlled randomized clinical study enrolled 22 adult patients in two groups. Before induction of anesthesia, baseline values were obtained and patients were randomized to receive milrinone (30 [micro sign]g/kg bolus administered progressively in 10 min, followed by a continuous infusion of 0.5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or saline. The following parameters were determined: hemodynamics; systemic oxygen delivery and uptake; arterial, mixed venous and hepatic venous oxygen saturation; intramucosal pH (pHi); and mixed and hepatic venous plasma concentrations of endotoxin, interleukin 6, serum amyloid A, and C-reactive protein.

Results: Milrinone did not prevent gastrointestinal acidosis as measured by pHi, but its perioperative administration resulted in significantly higher pHi levels compared with control. Venous and hepatic venous endotoxin and the interleukin 6 concentration were reduced significantly in the milrinone group. Serum amyloid A values were attenuated in the milrinone group 24 h after surgery. No significant differences could be seen in routinely measured oxygen transport-derived variables.     

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.     

Effect of Nitroglycerin Inhalation on Patients with Pulmonary Hypertension Undergoing Mitral Valve Replacement Surgery

Background: The aim of this study was to investigate the postoperative hemodynamic effects of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery.

Methods: Twenty patients who underwent mitral valve replacement surgery were included in the study. In the surgical intensive care unit, at T0 (before the inhalation of nitroglycerin), basal systemic and pulmonary hemodynamics were recorded. Then, 2.5 [mu]g [middle dot] kg-1 [middle dot] min-1 nitroglycerin liquid nebulized by a 2-l gas flow of 40% oxygen and air mixture was administered to the patients who were diagnosed as having pulmonary hypertension (mean pulmonary arterial pressures > 25 mmHg). The same parameters were measured at the first (T1), third (T2), and fifth (T3) hours after the beginning of this treatment and 1 h after the end of nitroglycerin inhalation (T4).

Results: There were no statistically significant differences at T0, T1, T2, T3, or T4 with respect to heart rate, mean arterial pressure, systemic vascular resistance, cardiac index, mixed venous oxygen saturation, arteriovenous oxygen content difference, or arterial carbon dioxide tension. However, mean pulmonary artery pressure, pulmonary vascular resistance, and intrapulmonary shunt fraction were significantly lower, and the arterial oxygen tension/fraction of inspired oxygen ratio was higher at T1, T2, and T3 when compared to that of T0 and T4.     

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).     

A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients

OBJECTIVE: To investigate the relative effects of milrinone and nitric oxide on pulmonary and systemic hemodynamic responses in cardiac surgery patients with a history of pulmonary hypertension. DESIGN: Prospective and randomized. SETTING: University hospital. PARTICIPANTS: Forty-five adult cardiac surgery patients. INTERVENTIONS: Cardiac surgery patients with pulmonary hypertension were randomly assigned to one of three study groups: Group 1 patients (n = 15) were treated with intravenous milrinone on separation from cardiopulmonary bypass, group 2 patients (n = 15) with 20 ppm of inhaled nitric oxide, and group 3 patients (n = 15) with 40 ppm of inhaled nitric oxide. Heart rate, right ventricular ejection fraction, and pulmonary vascular resistance were measured throughout the perioperative period at specific data points. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in demographics, anesthesia, surgery, or baseline hemodynamics among the groups. The group receiving 40 ppm nitric oxide had a significantly higher (p<0.05) right ventricular ejection fraction on arrival in the intensive care unit (40% v. 30% for the milrinone group and 33% for the nitric oxide 20 ppm group). The milrinone group required significantly more phenylephrine in the intensive care unit (p<0.05). CONCLUSIONS: Treatment of pulmonary hypertension in adult cardiac surgery patients with inhaled nitric oxide compared with milrinone is associated with lower heart rates, higher right ventricular ejection fraction, and a lower requirement for treatment with vasopressor agents.     

雾化吸入与静脉输注米力农治疗先天性心脏病患儿术后肺动脉高压效果的比较

目的 比较雾化吸入与静脉输注米力农治疗先天性心脏病患儿术后肺动脉压的效果.方法 先天性心脏病患儿40名,年龄5～14岁,体重15～38 kg,肺动脉压(PAP)30～90mm Hg,随机分为2组(n=20):雾化吸入组和静脉输注组.体外循环结束即刻,雾化吸入组每隔30 min吸入米力农1 mg/ml 10 min,共吸入12 h;静脉输注组先静脉注射米力农负荷剂量10μg/kg,然后以0.5μg·kg-1·min-1的速率静脉辅注12 h.于给药12 h时行血气分析,记录混合静脉血氧饱和度(S(-v)O2);于术前(基础状态)、给药12 h内每隔2 h记录MAP、PAP、肺血管阻力指数(PVRI)和体血管阻力指数(SVRI);记录带管时间和给药12 h内肺动脉高压、肺部感染以及术后低氧血症的发生情况.结果 与静脉输注组比较,雾化吸入组PAP和PVRI降低,S(-v)O2、MAP和SVRI升高,肺动脉高压和肺部感染发生率降低(P＜0.05),低氧血症发生率和带管时间差异无统计学意义(P＞0.05).结论 雾化吸入米力农治疗先天性心脏病患儿术后肺动脉高压的效果优于静脉输注,提示先天性心脏病患儿更宜选择雾化吸入的方法给予米力农.     

Remifentanil Induces Systemic Arterial Vasodilation in Humans with a Total Artificial Heart

Background: To assess intrinsic vascular effects of remifentanil, increased concentrations were infused in critically ill patients with a total artificial heart.

Methods: In the early postoperative period after implantation of a total artificial heart, nine ventilated patients requiring short general anesthesia were included in this study. After anesthesia was induced with 0.3 mg/kg intravenous etomidate, the artificial heart settings were modified to render cardiac output "preload-independent." While maintenance of anesthesia was ensured by a continuous infusion of etomidate, increased concentrations of remifentanil (from 0.1 to 1 [mu]g [middle dot] kg-1 [middle dot] min-1) were infused in steps of 5 min under hemodynamic monitoring, including left and right atrial pressures, systemic and pulmonary arterial pressures, and left and right cardiac indices. The invasive procedure was started under the highest concentration of remifentanil tolerated by the patient. Infusion of remifentanil was stopped at the end of the invasive procedure, while etomidate infusion was maintained. New hemodynamic measurements were performed at the end of the 12-min recovery period.

Results: Remifentanil produced a dose-dependent and significant decrease in systemic arterial pressure and vascular resistances (n = 9) from a concentration of 0.25 [mu]g [middle dot] kg-1 [middle dot] min-1. No significant changes were observed on pulmonary vascular resistances (n = 6). Neither right (n = 9) nor left (n = 6) atrial pressures were affected by remifentanil infusion. Hemodynamic variables returned to baseline value over the 12-min recovery period.     

Inhaled milrinone: a new alternative in cardiac surgery?

The administration of milrinone through inhalation has been studied in only a few animal and human studies. Compared to the intravenous administration, inhaled milrinone has been shown to reduce pulmonary artery pressure without systemic hypotension. Therefore, this approach could represent an alternative to nitric oxide. This current state of knowledge of intravenous and inhaled milrinone is presented and summarized.     

Milrinone Combined with Vasopressin Improves Cardiac Index after Cardiopulmonary Resuscitation in a Pig Model of Myocardial Infarction

Background: Milrinone used for acute cardiac insufficiency could be of interest during cardiopulmonary resuscitation because of its positive inotropic effects. In this study, the combination of milrinone-vasopressin was compared with epinephrine and vasopressin, as well as with the combination of epinephrine-vasopressin, in reference to hemodynamics.

Methods: Thirty-two pigs underwent ligation of the circumflex coronary artery and induction of ventricular fibrillation lasting for 4 min. Cardiopulmonary resuscitation was performed after randomization to one of four groups: epinephrine (30-[mu]g/kg bolus), vasopressin (0.4-U/kg bolus), epinephrine-vasopressin (15-[mu]g/kg epinephrine bolus, 0.2-U/kg vasopressin bolus), or milrinone-vasopressin (0.4-U/kg vasopressin bolus, 50-[mu]g/kg milrinone bolus over 5 min and a continuous infusion of 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1). The hemodynamic variables were measured before cardiopulmonary resuscitation as well as 4, 8, 15, and 30 min after return of spontaneous circulation.

Results: All animals were resuscitated successfully. The animals of the milrinone-vasopressin group displayed significantly (P < 0.05) higher cardiac index values (30 min after return of spontaneous circulation: epinephrine, 65.8 +/- 13.2; vasopressin, 70.7 +/- 18.3; epinephrine-vasopressin, 69.1 +/- 36.2; milrinone-vasopressin, 120.7 +/- 34.8 ml [middle dot] min-1 [middle dot] kg-1) without a decrease in mean arterial pressure or coronary perfusion pressure.     

The effects of intravenous milrinone for the patient undergoing CABG

The hemodynamic effects of intravenous infusion of milrinone were evaluated in 25 patients undergoing CABG using an internal mammary artery graft. Milrinone was administered to 9 patients at the time of weaning from cardiopulmonary bypass, at a dosage of 3 to 5 micrograms/kg/min. Postoperative cardiac function was compared in this group versus the other 17 patients who were treated without milrinone. We determined such parameters as cardiac index, wedge pressure and mean pulmonary pressure. Our findings did not show any significant difference between the 2 groups. We also studied a subject of low-output patients (EF < 0.5). In the patients with low-cardiac output, the use of milrinone in addition to standard postoperative administration of low-dose dopamine reduced mean pulmonary pressure and wedge pressure. Thus, milrinone not only improved the left ventricular function, but also expanded the pulmonary vascular bed.     

Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass

OBJECTIVE: Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. Milrinone is a type III phosphodiesterase inhibitor. The objective of this study was to compare the effects of inhaled and intravenous milrinone on the pulmonary endothelium-dependent relaxations and hemodynamic and oxygenation parameters after cardiopulmonary bypass in a porcine model. METHODS: Five groups of Landrace swine were compared: (1) control group, no cardiopulmonary bypass; (2) bypass group, 90 minutes of normothermic bypass and 60 minutes of reperfusion; (3) inhaled milrinone group, bypass preceded by a 1.8-mg bolus of inhaled milrinone followed by a continuous milrinone nebulization; (4) intravenous milrinone group, bypass preceded by 2 mg of intravenous milrinone; and (5) inhaled NaCl group, bypass preceded by inhaled saline solution. After sacrifice, pulmonary arterial endothelium-dependent relaxations to acetylcholine and bradykinin were studied in organ chambers. RESULTS: Inhaled milrinone caused less hypotension ( P < .05), a lesser decrease in peripheral vascular resistances ( P < .01), and a lower heart rate ( P < .05) than intravenous milrinone. Inhaled milrinone prevented the alterations in relaxations of pulmonary arteries to acetylcholine caused by cardiopulmonary bypass, and relaxations to bradykinin were improved in the inhaled milrinone group ( P < .05) compared with the cardiopulmonary bypass and control groups. CONCLUSIONS: Inhaled milrinone prevents the occurrence of the pulmonary endothelial dysfunction seen after cardiopulmonary bypass. The hemodynamic and oxygenation profiles obtained with inhaled milrinone are safer than with intravenous milrinone. These strategies might be useful in preventing pulmonary hypertension after cardiac surgery.     

Inhaled aerosolized iloprost in the evaluation of heart transplant candidates--experiences with 45 cases

PURPOSE: Pulmonary hypertension represents a significant predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. As the use of intravenous vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost in heart transplant candidates with elevated pulmonary vascular resistance. METHODS: Forty-five male heart transplant candidates with dilated or ischemic cardiomyopathy were included in the study. After assessing baseline hemodynamics, 20 microg of aerosolized iloprost was administered by ultrasonic inhalation. All patients were breathing spontaneously. RESULTS: Inhalation of iloprost reduced pulmonary vascular resistance index (395 +/- 205 vs 327 +/- 222 dyne.s.cm(-5).m(-2); P < 0.05) and mean pulmonary arterial pressure (28.7 +/- 10 vs 24.3 +/- 10 mm Hg; P < 0.05). An additional improvement of ventricular performance with an increase of cardiac index (2.7 +/- 0.7 vs 3.0 +/- 0.8 L.min(-1).m(-2); P < 0.05) and a decrease of pulmonary capillary wedge pressure (16.6 +/- 7.7 vs 13.4 +/- 7.3 mm Hg; P < 0.05) was accompanied by a slight decrease of systemic vascular resistance (1280 +/- 396 vs 1172 +/- 380 dyne.s.cm(-5); P < 0.05). However, the mean arterial pressure remained uninfluenced. CONCLUSIONS: Inhaled aerosolized iloprost effectively reduces mean pulmonary arterial pressure and also induces an increase in cardiac index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost represents a useful drug to screen for vascular reactivity in cardiac transplantation patients.     

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).     

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.     

Inhaled Nitric Oxide, Almitrine Infusion, or Their Coadministration as a Treatment of Severe Hypoxemic Focal Lung Lesions

Background: The partition of pulmonary blood flow between normal and shunting zones is an important determinant of oxygen tension in arterial blood (PaO(2)). The authors hypothesized that the combination of inhaled nitric oxide (iNO) and almitrine infusion might have additional effects related to their pharmacologic properties to improve PaO(2). Such a combination was tested in patients with hypoxia caused by focal lung lesions, distinct from the acute respiratory distress syndrome.

Methods: Fifteen patients with hypoxic focal lung lesions despite optimal therapy were included and successively treated with (1) 5 ppm iNO, (2) low-dose almitrine infusion (5.5 +/- 1.7 [micro sign]g [middle dot] kg (-1) [middle dot] min-1) during iNO, and (3) almitrine infusion alone (with NO turned off). Then iNO was reintroduced and we studied the effect of the coadministration in reducing the fractional concentration of oxygen in inspired gas (FIO(2)) and positive end-expiratory pressure (PEEP) levels. Changes in blood gases and pulmonary and systemic hemodynamics were measured.

Results: Systemic hemodynamic variables remained stable in all protocol conditions. Use of iNO improved arterial oxygenation and decreased intrapulmonary shunt. Almitrine similarly improved PaO(2) but increased pulmonary artery pressure and right atrial pressure. Coadministration of iNO and almitrine improved PaO(2) compared with each drug alone and with control. All patients responded (that is, they had at least a +30% increase in PaO(2)) to this coadministration. When the drug combination was continued, FIO(2) and PEEP could be reduced over 8 h. The hospital mortality rate was 33% and unrelated to hypoxia.     

Inhaled Albuterol, but Not Intravenous Lidocaine, Protects Against Intubation-induced Bronchoconstriction in Asthma

Background: The ability of intravenous lidocaine to prevent intubation-induced bronchospasm is unclear. The authors performed a prospective, randomized, double-blind, placebo-controlled trial to test the ability of intravenous lidocaine and inhaled albuterol to attenuate airway reactivity after tracheal intubation in asthmatic patients undergoing general anesthesia.

Methods: Sixty patients were randomized to receive either 1.5 mg/kg intravenous lidocaine or saline, 3 min before tracheal intubation. An additional 50 patients were randomized to receive 4 puffs of inhaled albuterol or placebo 15-20 min before tracheal intubation. Anesthesia was induced with propofol. Immediately after intubation and at 5-min intervals, transpulmonary pressure and airflow were recorded, and lower pulmonary resistance (RL) was calculated. Isoflurane was administered after the initial two measurements to assess reversibility of bronchoconstriction. A bronchoconstrictor response to intubation was defined as RL greater than or equal to 5 cm H2O [middle dot] l-1 [middle dot] s-1 in the first two measurements after intubation and RL subsequently decreasing by 50% or more after isoflurane.

Results: The lidocaine and placebo groups were not different in the peak RL before administration of isoflurane (8.2 cm H2O [middle dot] l-1 [middle dot] s-1vs. 7.6 cm H2O [middle dot] l-1 [middle dot] s-1) or frequency of airway response to intubation (lidocaine 6 of 30 vs. placebo 5 of 27). In contrast, the albuterol group had lower peak RL (5.3 cm H2O [middle dot] l-1 [middle dot] s-1vs. 8.9 cm H2O [middle dot] l-1 [middle dot] s-1;P < 0.05) and a lower frequency of airway response (1 of 25 vs. 8 of 23;P < 0.05) than the placebo group.