Myocardial ischemia induced by prostacyclin and iloprost

Vasodilators of resistive vessels may induce ischemia in patients with coronary artery disease. To evaluate this possibility during prostacyclin (PGI2; scalar doses up to 10 ng/kg/min) and prostacyclin analog (iloprost; scalar doses up to 6 ng/kg/min) infusions, we studied 33 patients with angina pectoris and proved coronary artery disease. Patients were also submitted to dipyridamole (0.15 mg/kg/min for 4 minutes) and exercise stress testing (starting at 25 W and increasing 25 W every 2 minutes). In a preliminary study the hemodynamic and side effects of iloprost were studied in seven healthy subjects. At an iloprost dose of 4 to 6 ng/kg/min, these subjects had a significant decrease in mean arterial pressure and total peripheral and pulmonary vascular resistances. Side effects were limited to facial flushing and slight headache and were readily reversible. PGI2 induced typical chest pain and significant ST segment depression in six patients with severe coronary artery disease (three with left main and three with triple vessel disease) and poor exercise tolerance (means +/- SD = 362 +/- 99 seconds). All six patients had had angina during the dipyridamole infusion. Similar findings were observed after iloprost infusion in four of these. Aminophylline (125 mg iv) completely relieved chest pain. Although the rate-pressure products occasionally rose during PGI2 and iloprost infusions, there were no significant changes between ischemic (11.3 +/- 2.3 and 10.6 +/- 1.4 X 10(-3) U) and preischemic (10.8 +/- 1.5 and 10.7 +/- 1.4 X 10(-3) U) rates of infusion. Our data indicate that PGI2 and iloprost may induce ischemia independently of changes in oxygen demand, and suggest that these drugs dilate small coronary vessels. This may result in decreased subendocardial perfusion pressure and/or "coronary steal."     

Potentiation of the antithrombotic effect of prostacyclin by simultaneous administration of aminophylline in a canine model of coronary artery thrombosis

The antithrombotic efficacy of prostacyclin (PGI2) when administered in conjunction with the phosphodiesterase inhibitor aminophylline was evaluated in a canine model in which coronary artery thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex (LCX) coronary artery. Infusions of PGI2 (25 or 50 ng/kg/min) into the left atrial appendage and aminophylline (20 micrograms/kg/min) or ethylene diamine into the left jugular vein were initiated 10 min before the start of LCX coronary artery stimulation and continued for the 6-hr stimulation period. Every animal in the control (Tris buffer plus ethylene diamine, n = 7), PGI2 (25 ng/kg/min) only (n = 6) and aminophylline only (n = 7) groups developed completely occlusive coronary artery thrombi. In contrast, none of the animals receiving PGI2 (25 ng/kg/min) plus aminophylline or PGI2 (50 ng/kg/min) plus aminophylline underwent occlusive thrombus formation. The average thrombus mass developed in response to intimal injury of the LCX coronary artery was 57 +/- 14 mg (X +/- S.E.M.) in the control group. Aminophylline administration in conjunction with PGI2 infusion at doses of 25 and 50 ng/kg/min significantly reduced thrombus mass to 11 +/- 2 and 10 +/- 1 mg, respectively (P less than .05). PGI2 (25 ng/kg/min) plus aminophylline reduced mean arterial pressure by 12% from 116 +/- 5 to 102 +/- 4 mm Hg. These data demonstrate that the combined administration of aminophylline with low-dose PGI2 provides antithrombotic efficacy while minimizing the detrimental hemodynamic effects of large-dose PGI2 administration.     

Pulmonary administration of prostacyclin (PGI2) during partial liquid ventilation in an oleic acid-induced lung injury: inhalation of aerosol or intratracheal instillation?

OBJECTIVE: The purpose of this study was to investigate the effects of aerosolized prostacyclin (A-PGI2) and intratracheally instilled prostacyclin (I-PGI2) during partial liquid ventilation (PLV) on gas exchange and pulmonary circulation in rabbits with acute respiratory distress. DESIGN: Prospective control study. SETTING: A research laboratory at a university medical centre. SUBJECTS: Sixty-nine Japanese white rabbits. INTERVENTION: Lung injury was induced by oleic acid and the animals were divided into five groups of ten each: a mechanical gas ventilation (GV) group, an A-PGI2 group, a PLV group, an A-PGI2+PLV group and an I-PGI2+PLV group. PLV, A-PGI2+PLV and I-PGI2+PLV groups received 15 ml/ kg perflubron intratracheally while receiving mechanical GV. A-PGI2 and A-PGI2+PLV groups received aerosolized PGI2 (50 ng/kg/min) in combination with GV or PLV, respectively. The I-PGI2+PLV group was instilled 50 ng/kg/min PGI2 intratracheally in combination with PLV. RESULT: After lung injury, all animals developed hypoxia, hypercarbia and pulmonary hypertension. The improvement of partial pressure of arterial oxygen (PaO2) in the A-PGI2 and PLV groups was transient, whereas the A-PGI2+PLV and I-PGI2+PLV groups showed consistent improvement throughout the experiment. The PaO2 values of the I-PGI2+PLV group were significantly higher than those of the other groups 120 min after treatment. The mean pulmonary artery pressure (PAP) significantly decreased after treatment in the A-PGI2, APGI2+PLV and I-PGI2+PLV groups. CONCLUSIONS: The results suggest that both aerosolized and intratracheally instilled PGI2 improve oxygenation and reduce PAP during PLV in oleic acid lung injury.     

Description and evaluation of a delivery system for aerosolized prostacyclin

INTRODUCTION: Inhaled vasodilators such as nitric oxide and aerosolized prostacyclin (PGI(2)) are used to treat severe hypoxemia in acute respiratory distress syndrome. Preferential distribution of nitric oxide and PGI(2) to ventilated areas of the lung causes selective pulmonary vasodilation, improved ventilation/perfusion matching, and decreased hypoxemia. Because of the technical limitations of previously described methods, we developed a PGI(2) delivery technique that allows the aerosolized drug dose to be easily calculated, set, and adjusted. METHODS: A 50 mL solution of PGI(2) (3.0x10(4) ng/mL) and a 500 mL normal saline solution were infused by a dual-channel volumetric infusion pump into a MiniHEART jet nebulizer that has a manufacturer-specified output of 8 mL/h at a set flow of 2 L/min. By adjusting the pump infusion rate to achieve a total output of 8 mL/h, the PGI(2) concentration was altered to deliver a calculated aerosolized dose of 10-50 ng/kg/min. The effectiveness of the delivery system was retrospectively evaluated by way of the responses of 11 severely hypoxemic acute respiratory distress syndrome patients who received PGI(2) via the system we describe. The MiniHEART nebulizer output, particle size, and dose delivery were evaluated in a laboratory bench study, using a set flow of 2 L/min. RESULTS: Aerosolized PGI(2) therapy (mean dose 28 +/- 17 ng/kg/min, range 10-50 ng/kg/min) significantly increased the ratio of P(aO)(2) to fraction of inspired oxygen (P(aO)(2)/F(IO)(2)) (60 +/- 11 mm Hg vs 80 +/- 17 mm Hg, p = 0.003) and arterial oxygen saturation measured via pulse oximetry (86 +/- 8% vs 94 +/- 3%, p = 0.005) (differences evaluated with the Wilcoxon signed rank test). There was no difference in positive end-expiratory pressure, mean airway pressure, or F(IO)(2), before and after aerosolized PGI(2) (p > 0.05). Nebulizer output was 6.8 +/- 0.9 mL/h, range 6.0-7.8 mL/h. The inhaled aerosol particles had a mass median diameter of 3.1 micro m. Emitted dose was 67 +/- 13% (range 57-81%) of the calculated dose. CONCLUSION: Our system is effective in delivering aerosolized PGI(2) to the alveolar-capillary interface, as indicated by significant oxygenation improvements soon after therapy commenced. The performance of the MiniHEART nebulizer varies from the manufacturer's specifications, which may alter the delivered dose.     

Inhibition of epinephrine-exacerbated coronary thrombus formation by prostacyclin in the dog

We studied the effect of intravenous prostacyclin (PGI2) infusion on epinephrine exacerbation of platelet-mediated acute coronary thrombus formation in an in vivo canine model of coronary artery stenosis. Platelet thrombi form in mechanically stenosed dog circumflex coronary arteries, producing cyclical reductions in coronary blood flow (CRF) as measured with an electromagnetic flowmeter probe. In the present study nine of 10 dogs exhibited spontaneously occurring CRF. With epinephrine (E) infusions of 10 micrograms/min CRF frequency increased 64% (p less than 0.025), CRF magnitude increased 27.1% (p less than 0.05), and the rate of flow decline increased 112.8%, indicating that the rate of thrombus formation increased with E infusion (p less than 0.005). When an identical E infusion was accompanied by simultaneous PGI2 infusion (150 ng/kg/min), CRF were abolished in nine of 10 dogs and markedly inhibited in the other. After the 10 min of simultaneous E and PGI2 infusion, E infusion alone was continued. There was a recurrence of CRF within 2.49 +/- 0.89 min after cessation of PGI2 infusion. However, CRF frequency in the subsequent 10 min was less than the frequency of CRF during the initial E infusion (p less than 0.10) and not significantly different from that of the control period (no E infusion). The rate of flow decline and magnitude during the final E infusion after cessation of PGI2 infusion were not significantly different from those of the initial E infusion. Prostacyclin infusion in the coronary care unit may be potentially beneficial in cases of acute myocardial ischemia where elevated catecholamines are a thrombogenic stimulus.     

Estimated rate of prostacyclin secretion into the circulation of normal man.

The rate of secretion of prostacyclin (PGI2) into the circulation of normal man was estimated by measurement of the 2,3-dinor-6-keto-PGF1 alpha (D) and 15-keto-13,14-dihydro-2,3-dinor-6-keto-PGF1 alpha (KDD) urinary metabolites of PGI2. Subjects received 6-h intravenous infusions of vehicle alone and PGI2 at 0.1, 0.4, and 2.0 ng/kg per min in random order. The fractional elimination of the metabolites was independent of the rate of PGI2 infusion. 6.8 +/- 0.3% of the infused PGI2 appeared as D and 4.1 +/- 0.4% as KDD. The regression of infused PGI2 upon the quantities of the two metabolites excreted in excess of control values permitted estimation of the rate of entry of endogenous PGI2 into the circulation corresponding to a given quantity of metabolite excreted. Using the quantities excreted in the 24 h from commencement of the infusions the estimated rates were 0.08 +/- 0.02 ng/kg per min from D and 0.10 +/- 0.03 from KDD. Studies with exogenous PGI2 suggest that infusion rates 2--4 ng/kg per min are required to achieve the threshold for inhibition of platelet function (ex vivo) in man. Although not precluding a role for PGI2 in local platelet-vessel wall interactions, the much lower estimates obtained in this study suggest that endogenous PGI2 is unlikely to act as a circulating antiplatelet agent in healthy man.     

Hemodynamic profiles of prostaglandin E1, isoproterenol, prostacyclin, and nifedipine in experimental porcine pulmonary hypertension

BACKGROUND AND METHODS: We compared the hemodynamic effects of four vasodilators in experimental embolic pulmonary hypertension in a randomized controlled trial, using nine pigs weighing 16 to 23 kg. After anesthesia induction and cannulation with arterial, central venous, and thermodilution output pulmonary artery catheters, animals were repetitively embolized with glass beads (60 to 160 mu) in order to establish pulmonary hypertension (pulmonary artery pressure [PAP] doubled from baseline). Prostaglandin E1 (PGE1), isoproterenol, prostacyclin (PGI2), and nifedipine were compared at doses producing equivalent reduction in systemic BP. RESULTS: Only PGE1 and PGI2 decreased both PAP and pulmonary vascular resistance (PVR). PGE1 decreased PAP from 39 +/- 1 to 33 +/- 1 mm Hg; prostacyclin decreased PAP from 38 +/- 1 to 31 +/- 1 mm Hg and produced the largest increase in cardiac output (Qt). Isoproterenol did not change PAP, markedly increased heart rate (162 +/- 8 to 216 +/- 11 beats/min), and resulted in significant arrhythmias. Nifedipine increased PVR from 1044 +/- 113 to 1125 +/- 100 dyne.sec.cm-5 and decreased Qt. CONCLUSIONS: Vasodilators demonstrate unique hemodynamic drug profiles. Isoproterenol infusion is characterized by tachycardia and arrhythmias. Both PGE1 and PGI2 effectively decrease PAP and PVR. Nifedipine depressed Qt significantly in this glass-bead embolization model of acute pulmonary hypertension.     

Beneficial effects of low-dose prostacyclin on cat intestinal perfusion during endotoxemia as evaluated with microdialysis and oxygen transport variables

OBJECTIVE: To evaluate the effects of low-dose prostacyclin on intestinal perfusion during endotoxemia. DESIGN: A randomized, blinded experimental study. SETTING: A university laboratory. SUBJECTS: Sixteen anesthetized cats. INTERVENTIONS: The animals received endotoxin by continuous intravenous infusion (0.5 mg/kg plus 0.5 mg x kg(-1) x hr(-1)) and a continuous volume replacement throughout the experiment. Four hours after the start of endotoxin, the animals were randomized to receive an infusion of either prostacyclin at a dose of 1 ng x kg(-1) x min(-1) (prostacyclin group) or vehicle (control group) during the next 4 hrs. MEASUREMENTS AND MAIN RESULTS: Intestinal vascular resistance was calculated from systemic arterial pressure, central venous pressure, and superior mesenteric artery blood flow, and intestinal oxygen delivery and uptake were calculated from superior mesenteric artery and vein blood samples and blood flow. Interstitial lactate, pyruvate, glucose, and glycerol in the ileal wall were measured by using microdialysis. There were no differences in baseline values between the groups. Systemic blood pressure decreased initially but recovered and remained stable in both groups. In the control group, intestinal vascular resistance increased from 10.9 +/- 1.0 to 24.7 +/- 5.3 mm Hg x mL x min(-1) x kg(-1) (p <.05) at 8 hrs, and oxygen delivery decreased from 2.6 +/- 0.2 to 1.3 +/- 0.3 mL x min(-1) x kg(-1) (p <.05). Simultaneously, microdialysis lactate increased from 1.6 +/- 0.1 to 3.6 +/- 0.5 mmol/L (p <.05) with concomitant pyruvate increase and unchanged lactate/pyruvate ratio. Blood lactate increased and pH decreased. In the prostacyclin group at 8 hrs, intestinal vascular resistance of 6.9 +/- 0.8 mm Hg x mL x min(-1) x kg(-1) was lower and intestinal oxygen delivery of 3.2 +/- 0.3 was higher (p <.05) than in the control group at 8 hrs. Intestinal oxygen uptake of 0.54 +/- 0.10 mL x min(-1) x kg(-1) was higher than in the control group, in which oxygen uptake was 0.26 +/- 0.04 mL x min(-1) x kg(-1). Lactate, pyruvate, and pH were normalized at 8 hrs in the prostacyclin group. CONCLUSION: Low-dose prostacyclin has beneficial effects on small intestinal perfusion during endotoxemia in this experimental cat model.     

Permissive role of prostaglandins in the action of bradykinin on the pancreas of anesthetized dogs

We have investigated the contribution of prostaglandins (PGs) to the effect of bradykinin on pancreatic blood flow and pancreatic exocrine secretion by examining its actions in the isolated blood-perfused pancreas of pentobarbital-anesthetized dogs. Intra-arterial injections of bradykinin (0.05-5 ng/kg) into the pancreas produced a dose-dependent vasodilation and increased pancreatic blood flow; the rate of flow, bicarbonate concentration, protein content or pH of the pancreatic juice was not altered. Administration of arachidonic acid (0.5-5 micrograms/kg) into the pancreas also produced vasodilation without altering pancreatic exocrine secretion. In animals pretreated with indomethacin or sodium meclofenamate (10 mg/kg i.v.), the vasodilator effect of bradykinin was attenuated, whereas that of arachidonic acid was abolished; the pancreatic exocrine secretion was not altered. The vasodilation produced by sodium nitroprusside (0.3 micrograms/kg i.a.) in the pancreas was not altered by indomethacin. During infusion of PGI2 or PGE2 (10 ng/kg/min i.a.), the effect of indomethacin or sodium meclofenamate to attentuate bradykinin-induced vasodilation was reduced. However, the sodium nitroprusside-induced vasodilation in animals treated with indomethacin was not altered during infusion of PGI2 or PGE2. These data indicate that PGs, presumably PGI2 and PGE2, play a permissive role in the vasodilator effect of bradykinin in the pancreas of anesthetized dogs. Moreover, these studies suggest that neither bradykinin nor PGs contribute to the regulation of pancreatic exocrine secretion.     

Prostacyclin effects on renal hemodynamic and excretory functions in the rat.

Blood pressure, renal blood flow, glomerular filtration rate and urine composition and flow rate were measured, and renal vascular resistance was calculated, before and during infusion of prostacyclin (PGI2) i.v. or i.a. just proximal to the origins of 250 ng/min, PGI2 caused a significant but slight (13%) reduction in renal vascular resistance, but did not consistently increase renal blood flow. Given at the highest infusion rate which could be sustained without reducing blood pressure, PGI2 did not alter glomerular filtration rate or urine composition or flow rate. Intravenous PGI2 infusion caused reductions in systemic blood pressure and renal blood flow at a dose of 50 ng/min; infusion into the abdominal aorta produced equal reductions in pressure and flow at a dose of 500 ng/min. Although PGI2 is the only prostaglandin shown to reduce renal vascular resistance in the rat, it does not appear to be sufficiently specific for the renal vasculature or potent enough to justify suggesting a physiological role in regulation of renal function in the rat.     

The hemodynamic effects of dobutamine infusion in the chronically instrumented newborn piglet

OBJECTIVE: To determine the systemic, pulmonary, mesenteric, and renal hemodynamic effects of short and prolonged infusions of dobutamine. DESIGN: Prospective randomized unblinded study. SETTING: University research laboratory. SUBJECTS: Thirteen newborn (1-3 days old) piglets. INTERVENTIONS: Piglets were instrumented and studied 48 hrs later. Fifteen-minute infusions of dobutamine at 5, 10, 20 and 50 microg/ kg x min were randomly given with 15-min rests between the doses. After a 1-hr hiatus, a dose of 10 microg/kg x min was continuously administered for 2 hrs. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary arterial pressures, cardiac index (thermodilution), and superior mesenteric and renal artery flows were measured. Vascular resistance values were calculated. MAIN RESULTS: Fifteen-minute infusions: Dobutamine dose-dependently increased cardiac index with tachycardia but not stroke volume (from 187 +/- 43 to 238 +/- 51 mL/kg x min at baseline and 50 microg/ kg x min, respectively, p < .05; values expressed as mean +/- SD). Systemic, but not pulmonary, vascular resistance decreased, resulting in a significant decrease in systemic to pulmonary arterial pressure ratio (from 3.8 +/- 0.8 at baseline to 3.2 +/- 1.0 at 50 microg/ kg x min). Superior mesenteric and renal flows were not affected. Two-hour infusion at 10 microg/kg x min: Cardiac index progressively increased from 173 +/- 34 to 240 +/- 58 mL/kg x min at baseline and 120 mins, respectively, (p < .05). The initial tachycardia was transient, and stroke volume was significantly increased at 60 mins and thereafter. Although systemic and pulmonary vascular resistance values fell simultaneously, systemic to pulmonary arterial pressure ratio decreased significantly to 3.4 +/- 0.9 at 120 mins from 3.9 +/- 0.7 at baseline. Superior mesenteric and renal artery flows increased significantly with vasodilation after 60 mins. CONCLUSIONS: Short infusions of dobutamine dose-dependently increase cardiac output due to tachycardia, without significant effect on mesenteric and renal blood flows. Prolonged infusion of dobutamine at 10 microg/kg x min progressively increases cardiac output and stroke volume with transient tachycardia, and increases mesenteric and renal blood flows. Caution is required in the treatment of critically ill neonates with dobutamine, which could also reduce systemic to pulmonary arterial pressure ratio.     

Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension

OBJECTIVE: To determine whether inhaled nitric oxide (IN0) and intravenous milrinone have additive pulmonary vasodilator effects in a rat model of pulmonary hypertension. DESIGN: Prospective, experimental study. SETTING: Animal laboratory of a university medical center. SUBJECTS: Male New Zealand White rabbits. INTERVENTIONS: Anesthetized rabbits were mechanically ventilated and instrumented for measurement of systemic mean arterial pressure (MAP), pulmonary artery pressure (PAP), left atrial pressure, and cardiac output (CO). After baseline measurements, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (30 mg/kg iv) was administered. Pulmonary hypertension was produced by the continuous infusion of U46619, a thromboxane A2 mimetic. INO (40 ppm) was added to the inspired gas, and hemodynamic measurements were obtained before and after INO. Milrinone was administered sequentially as a 30-mg/kg bolus followed by a 3-microg/kg/min infusion, a 100-mg/kg bolus followed by a 10-microg/kg/min infusion, and a 300-mg/kg bolus followed by a 30-microg/kg/min infusion (M3). Hemodynamic measurements were obtained with and without INO at each dose of milrinone. MEASUREMENTS AND MAIN RESULTS: During U46619-induced pulmonary hypertension, INO decreased PAP and pulmonary vascular resistance (PVR) but did not affect MAP, systemic vascular resistance (SVR), or CO. Milrinone dose dependently decreased PAP, PVR, MAP, and SVR and increased CO. At each dose of milrinone, INO further decreased PVR but not SVR. M3 decreased PVR 49%, and the addition of INO decreased PVR an additional 19% so that PAP and PVR decreased to baseline values. CONCLUSIONS: Milrinone and INO both decrease pulmonary hypertension individually, and the combination produces additive effects. Combination therapy may produce potent and selective pulmonary vasodilation during the treatment of pulmonary hypertension.     

Prostacyclin is neither sufficient alone nor necessary to cause pulmonary dysfunction: results from infusions of prostacyclin and antiprostacyclin antibody in porcine septic shock.

OBJECTIVE: This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock. DESIGN: Experimental. SETTING: Laboratory. SUBJECTS: Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion. MEASUREMENTS AND MAIN RESULTS: Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups. CONCLUSIONS: Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.     

Prostacyclin (epoprostenol) induces headache in healthy subjects

The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I(2), (PGI(2))) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI(2) might induce headache and vasodilatation of cranial vessels. A stable analog of PGI(2) epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V(mean MCA)) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI(2) day and no subjects reported headache on the placebo day (p=0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p=0.005). PGI(2) caused headache associated with the dilatation of STA (AUC, p<0.001), but no significant dilatation of the MCA (AUC, p=0.508). These data indicate that PGI(2) induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.     

Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response

OBJECTIVES: To examine the hypothesis that the response to inhaled prostacyclin (PGI2 on oxygenation and pulmonary hemodynamics may be related to different morphologic features that are supposed to be present in acute respiratory distress syndrome (ARDS) originating from pulmonary (primary ARDS [ARDS(PR)]) and from extrapulmonary disease (secondary ARDS [ARDS(SEC)]). DESIGN: Prospective, nonrandomized interventional study. SETTING: Multidisciplinary intensive care unit, secondary care center. PATIENTS: Fifteen consecutive, mechanically ventilated patients with ARDS and severe hypoxemia, defined as PaO2/FIO2 of <150 torr at the time of admission. INTERVENTIONS: After an initial stable period of at least 60 mins, patients received nebulized PGI2 in 15-min steps; the drug was titrated to find the dose with the best improvement of PaO2, starting with 2 ng/kg/min up to an allowed maximum dose of 40 ng/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood gas, gas exchange, and hemodynamic measurements were performed at the following time points: a) baseline; b) during the optimal or maximum dose of PGI2; and c) 1 hr after withdrawal of the drug. Patients underwent a computed tomographic (CT) scan using a basal CT section to compute the mean CT numbers and the density histogram. Patients were considered responders to PGI2 if an increase in PaO2 of > or =7.5 torr or an increase in PaO2/FIO2 ratio of > or =10% occurred. For the group as a whole, mean pulmonary artery pressure decreased from 32 +/- 1 to 29 +/- 1 mm Hg during PGI2 nebulization, whereas pulmonary vascular resistance decreased 1 hr after withdrawal of nebulization from 177 +/- 18 to 153 +/- 16 dyne x sec/cm5; oxygenation did not change significantly. Eight patients responded to PGI2 nebulization on oxygenation (all were in the ARDS(SEC) subgroup), whereas seven did not (all but one were in the ARDS(PR) subgroup). Among the physiologic variables examined to assess any difference between the two ARDS groups at time of PGI2 nebulization, there was a significant difference concerning the mean CT density number, which was -445 +/- 22 Hounsfield Units in the ARDS(SEC) group and -258 +/- 16 Hounsfield Units in the ARDS(PR) group. In patients presenting with an ARDS(PR), PGI2 induced a reduction in PaO2/FIO2 and a reduction in PaO2 from 87 +/- 2 to 79 +/- 2 torr, whereas in patients with an ARDS(SEC) there was an increase in PaO2/FIO2 and in PaO2 from 76 +/- 4 to 84 +/- torr with a decrease in mean pulmonary artery pressure. CONCLUSIONS: Based on the data from this study, the clinical recognition of the two types of the syndrome together with the CT number frequency distribution analysis may be associated with a prediction of the PGI2 nebulization response on oxygenation.     

Diltiazem increases renal prostacyclin.

We sought to determine whether the specific renal vasodilator effect of low dose diltiazem (D) was mediated by increased renal prostacyclin (PGI2) synthesis. Groups of 7-9 Sprague-Dawley rats were fitted with an indwelling transabdominal bladder cannula. Cannulae were placed in the jugular and femoral veins and the carotid artery and the rats allowed to recover for 24 h. Angiotensin II (AII) was infused intravenously at a rate (10 ng/kg/min) which increased mean arterial pressure (MAP) by 5-10%. After 30 min D(1 mg/kg and 2 micrograms/kg/min), D plus indomethacin (IND) (2 mg/kg and 33 micrograms/kg/min), IND plus vehicle or vehicle alone were added to AII. AII increased urinary 6-keto-prostaglandinF1 alpha (6-ketoPGF1 alpha) excretion from 1.36 +/- 0.12 to 1.86 +/- 0.20 ng/30 min (p less than 0.05) and D increased it further to 3.19 +/- 0.39 (p less than 0.05). Renal plasma flow (RPF) was estimated by 14C-PAH clearance (CPAH). Urinary excretion of 6-ketoPGF1 alpha was increased with AII indicating increased renal PGI2 synthesis. This increase in PGI2 was unable to prevent a reduction in RPF. D administration further increased the excretion of 6-ketoPGF1 alpha and reversed AII-induced renal vasoconstriction. IND augmented the AII response and prevented the effect of D, suggesting the renal vasodilator effect of D is, at least in part, PGI2-mediated. This mechanism may help maintain renal blood flow under conditions of vasoconstrictor stress.     

Comparison of continuous versus intermittent furosemide administration in postoperative pediatric cardiac patients.

OBJECTIVE: To compare the effects of furosemide administered by intermittent iv infusion vs. continuous iv infusion on urine output, hemodynamic variables, and serum electrolyte concentrations. DESIGN: Prospective, randomized trial. SETTING: Pediatric ICU. PATIENTS: Postoperative pediatric cardiac patients. INTERVENTIONS: Patients were assigned to either the continuous iv infusion or the intermittent infusion groups. The intermittent group received 1 mg/kg iv of furosemide every 4 hrs to be increased by 0.25 mg/kg iv every 4 hrs to a maximum of 1.5 mg/kg iv if the urine output was less than 1 mL/kg.hr. The continuous infusion group received an initial furosemide dose of 0.1 mg/kg iv (minimum 1 mg) followed by an iv infusion rate of 0.1 mg/kg.hr of furosemide to be doubled every 2 hrs to a maximum of 0.4 mg/kg.hr if the urine output was less than 1 mL/kg.hr. MEASUREMENTS AND MAIN RESULTS: Demographic variables, fluids, electrolyte and inotropic requirements were the same in both groups. A significantly (p = .045) lower daily dose of furosemide (4.90 +/- 1.78 vs. 6.23 +/- 0.62 mg/kg.day) in the continuous iv infusion group produced the same 24-hr urine volume as that of the intermittent group. There was more variability in urine output in the intermittent group as well as more urinary losses of sodium (0.29 +/- 0.15 vs. 0.20 +/- 0.06 mmol/kg.day, p = .0007) and chloride (0.40 +/- 0.20 vs. 0.30 +/- 0.12 mmol/kg.day, p = .045). CONCLUSION: Furosemide administered by continuous iv infusion is advantageous in the post-operative pediatric patient because of a more controlled and predictable urine output with less drug requirement and less urinary loss in sodium and chloride.     

Intravenous administration of prostacyclin in rabbits: elimination kinetics and blood pressure response

Prostacyclin (PGI2) has been used extensively in human clinical trials and animal studies, but because of its instability, knowledge of its pharmacokinetics has progressed slowly. We assayed plasma PGI2 concentrations with a quantitative chromatographic method following bolus intravenous injection and during continuous infusion in rabbits. Blood pressure response was correlated with plasma PGI2 concentrations and compared with the concentrations necessary to inhibit platelet aggregation in vitro. A two-compartment model was used to analyze the elimination kinetics for PGI2 after a single injection. The half-life of the terminal elimination phase was 2.7 minutes. The calculated systemic clearance and whole body volume of distribution were 93 ml/kg/min and 357 ml/kg, respectively. During continuous infusion, steady-state plasma concentrations were reached within 15 minutes and increased linearly with increasing infusion rate from 4.2 to 604 ng/kg/min, which resulted in PGI2 concentrations of 0.06 +/- 0.01 to 7.6 +/- 2.1 ng/ml, respectively. At steady-state plasma concentrations of PGI2 greater than 0.1 ng/ml, the mean arterial blood pressure decreased in a concentration-dependent manner, reaching a decrease of 45 mm Hg when the plasma concentration was 7.6 ng/ml. Prostacyclin caused a concentration-dependent inhibition of adenosine diphosphate-induced platelet aggregation in vitro with 10% inhibition at 0.4 ng/ml. These results indicate that in the rabbit the level of PGI2 at which the onset of hypotension occurs coincides with the inhibition of platelet aggregation.     

Hemodynamic effects of terlipressin (a synthetic analog of vasopressin) in healthy and endotoxemic sheep

OBJECTIVE: Hypotension, vasodilation, and vasoplegia are characteristic signs of septic shock. The vasoconstrictive response to catecholamines typically is reduced. A decreased vasopressive effect of catecholamines can be observed in the late phase of hemorrhagic shock. Interestingly, an unaltered vasopressive response to vasopressin can be demonstrated in hemorrhagic shock. In this study, we investigated the vasoconstrictive response to an agonist of the vasopressin receptor, terlipressin, in healthy sheep as well as in ovine hyperdynamic endotoxemia. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six female adult sheep. INTERVENTIONS: Healthy sheep, instrumented for chronic study, received terlipressin (15 microg/kg) as a bolus; 30 mins later, norepinephrine was continuously given for 30 mins. Three hours later, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng x kg(-1) x min(-1)) was started in the same sheep and given for the next 23 hrs. After 20 hrs of endotoxemia, terlipressin and norepinephrine were given as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were measured before and 30 mins after application of terlipressin and after 30 mins of continuous infusion of norepinephrine. Terlipressin significantly increased systemic vascular resistance index in healthy and endotoxemic sheep (p <.05). The increase was higher in endotoxemic compared with healthy animals (p <.05). Only during endotoxemia, terlipressin increased pulmonary vascular resistance index. This was accompanied by a significant decrease in cardiac index, whereas mean pulmonary arterial pressure did not change after application of terlipressin. Additional treatment with norepinephrine did not further increase systemic vascular resistance index or pulmonary vascular resistance index. CONCLUSIONS: Terlipressin reversed the hemodynamic changes in ovine endotoxemia. However, its pulmonary vasopressive effect might limit its therapeutic use in septic shock.