No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Inhaled Prostaglandin E1 for Treatment of Acute Lung Injury in Severe Multiple Organ Failure
Abstract
Acute lung injury is characterized by hypoxemia due to pulmonary ventilation/perfusion-mismatching. IV administered prostaglandin E1 (PGE1), a vasodilator with a high pulmonary clearance, has been studied in acute lung injury. Inhalation of the vasodilators nitric oxide and prostacyclin improved oxygenation by selective dilation of the pulmonary vasculature in ventilated lung areas. In the present study, PGE1 inhalation was used for treatment of acute lung injury. Fifteen patients with acute lung injury defined as PaO2/fraction of inspired oxygen (FIO2) <160 mm Hg were treated with PGE1 inhalation in addition to standard intensive care. The drug was continuously delivered via a pneumatic nebulizer. Acute physiology and chronic health evaluation system II and multiple organ failure scores were (mean +/- SEM) 33 +/- 2 and 10 +/- 0.3, respectively. Inhaled PGE1 was administered for 103 +/- 17 h at a dose of 41 +/- 2 [micro sign]g/h. The PaO2/FIO2 ratio increased from 105 +/- 9 to 160 +/- 17 mm Hg (P < 0.05) and to 189 +/- 25 mm Hg (P < 0.05) after 4 h and 24 h, respectively. PGE1 inhalation decreases in mean pulmonary artery pressure and central venous pressure were not statistically significant. Mean arterial pressure, pulmonary capillary wedge pressure, cardiac output, and heart rate remained unchanged. Intensive care unit mortality was 40%. The present data suggest that inhaled PGE (1) is an effective therapeutic option for improving oxygenation in patients with acute lung injury. Whether inhaled PGE1 will increase survival in acute lung injury should be investigated in a controlled prospective trial. Implications: In patients with severe acute lung injury and multiple organ failure, inhaled prostaglandin E1 improved oxygenation and decreased venous admixture without affecting systemic hemodynamic variables. Controlled clinical trials are warranted.
(Anesth Analg 1998;86:753-8)
... PGE 1 has also considered as a potential treatment option for PAH because of its high pulmonary clearance (70-90%) and pulmonary-selective vasodilating effect (Meyer et al., 1998). Intravenous PGE 1 has been used in newborns with PAH Shen et al., 2005). ...
... Intravenous PGE 1 has been used in newborns with PAH Shen et al., 2005). However, intravenous administration of PGE 1 results in side-effects, such as systemic hypotension and low cardiac output, similar to those produced by other short-acting prostacyclin analogues (Meyer et al., 1998). An attractive approach to utilize the pulmonary vasodilatory effects of PGE 1 would be to deliver the drug via the respiratory route. ...
... PGE 1 acts as a selective pulmonary vasodilator when administered as an aerosol into the lungs and thereby eliminates the complications associated with systemic vasodilation (Sood et al., 2004). In fact, intravenous PGE 1 has been reported to be used for treatment of PAH, acute respiratory distress syndrome, hypoxemic respiratory failure, and in lung transplantation (Meyer et al., 1998;, However, it has a half-life of 5-10 minutes because 70-90% of the drug metabolizes in the lungs in a single pass. ...
... This mechanism is different from cardiac striated muscles where the troponin complex is responsible for the regulation of muscle contractions. PGE1 is also considered as a potential treatment option for PAH because of its high pulmonary clearance (70%-90%) and pulmonary-selective vasodilating effect [40]. However, intravenous administration of PGE1 has side-effects such as systemic hypotension and low cardiac output, similar to those produced by other short-acting prostacyclin analogues [40]. ...
... PGE1 is also considered as a potential treatment option for PAH because of its high pulmonary clearance (70%-90%) and pulmonary-selective vasodilating effect [40]. However, intravenous administration of PGE1 has side-effects such as systemic hypotension and low cardiac output, similar to those produced by other short-acting prostacyclin analogues [40]. Recently, Della Rocca et al. [11] have documented the efficacy of inhaled PGE1 in improving pulmonary hemodynamics and oxygenation in a clinical trial enrolling 18 patients undergoing lung transplantation. ...
Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in pulmonary arterial pressure and excessive thickening and remodeling of distal small pulmonary arteries. During disease progression, PAH include increase in mean pulmonary arterial pressure, right ventricular (RV) enlargement, increased pulmonary vascular resistance, and smooth muscle hypertrophy in pulmonary arterioles. Several anti-PAH therapies targeting various pathways involved in PAH progression have been approved by the Food and Drug Adminstration. However, many of the currently available anti-PAH drugs suffer from a number of limitations, including short biological half-life, and poor pulmonary selectivity. Prostaglandin E1 (PGE1) is a potent vasodilator with selectivity toward pulmonary circulation when it is administered via the pulmonary route. However, PGE1 has a very short half-life of 5–10 minutes. Therefore, we hypothesized that long-term effect of PGE1 could reduce mal-adaptive structural remodeling of the lung and heart and prevent ventricular arrhythmias in monocrotaline-induced rat model of PAH. Our results revealed that PGE1 reduced ventricular hypertrophy, protein expressions of endothelin-1 and endothelin receptor A, and the expression of fibrosis. These results support the notion that PGE1 can improve the functional properties of RV, highlighting its potential benefits for heart and lung impairment.
... Secondary outcomes are presented in Table 2. Patients who received iVEL had shorter durations of mechanical ventilation (5 [2-7] vs 9.5 [6][7][8][9][10][11][12][13][14][15][16][17][18][19] days, P < 0.001) and ICU LOSs (7 [5][6][7][8][9][10][11][12] vs 15.5 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] days, P < 0.001) compared with patients who received iFLO. There was no difference in hospital LOS or duration of inhaled epoprostenol therapy when comparing groups. ...
... The studies evaluating these agents are small and evaluate homogeneous patient populations. [2][3][4]7,[16][17][18][19][20][21][22][23][24] We previously showed that iFLO was comparable to inhaled by guest on December 15, 2015 aop.sagepub.com Downloaded from nitric oxide in safety and efficacy in a diverse patient population. 1 No difference was seen between groups in the primary end point-namely, change in PaO 2 /FiO 2 ratio after 1 hour of inhaled pulmonary vasodilator therapy. ...
Background:
Flolan (iFLO) and Veletri (iVEL) are 2 inhaled epoprostenol formulations. There is no published literature comparing these formulations in critically ill patients with refractory hypoxemia.
Objective:
To compare efficacy, safety, and cost outcomes in patients who received either iFLO or iVEL for hypoxic respiratory failure.
Methods:
This was a retrospective, single-center analysis of adult, mechanically ventilated patients receiving iFLO or iVEL for improvement in oxygenation. The primary end point was the change in the PaO2/FiO2 ratio after 1 hour of pulmonary vasodilator therapy. Secondary end points assessed were intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of study therapy, duration of mechanical ventilation, mortality, incidence of adverse events, and cost.
Results:
A total of 104 patients were included (iFLO = 52; iVEL = 52). More iFLO patients had acute respiratory distress syndrome compared with the iVEL group (61.5 vs 34.6%; P = 0.01). There was no difference in the change in the PaO2/FiO2 ratio after 1 hour of therapy (33.04 ± 36.9 vs 31.47 ± 19.92; P = 0.54) in the iFLO and iVEL groups, respectively. Patients who received iVEL had a shorter duration of mechanical ventilation (P < 0.001) and ICU LOS (P < 0.001) but not hospital LOS (P = 0.86) and duration of therapy (P = 0.36). No adverse events were attributed to pulmonary vasodilator therapy, and there was no difference in cost.
Conclusions:
We found no difference between iFLO and iVEL when comparing the change in the PaO2/FiO2 ratio, safety, and cost in hypoxic, critically ill patients. There were differences in secondary outcomes, likely a result of differences in underlying indication for inhaled epoprostenol.
... Aerosolized prostaglandins I 2 (PGI 2 ) and E 1 (PGE 1 ) have been reported to be effective selective pulmonary vasodilators in animals, adults, and preterm and term newborns [5][6][7][8][9][10][11][12][13][14][15]. Compared to PGI 2 , PGE 1 has a shorter half-life, lower acid dissociation constant (pKa, 6.3 versus 10.5), bronchodilator action, and anti-proliferative and anti-inflammatory effects on the alveolar, interstitial, and vascular spaces of the lung [10,[16][17][18][19][20]. ...
... Aerosolized prostaglandins I 2 (PGI 2 ) and E 1 (PGE 1 ) have been reported to be effective selective pulmonary vasodilators in animals, adults, and preterm and term newborns [5][6][7][8][9][10][11][12][13][14][15]. Compared to PGI 2 , PGE 1 has a shorter half-life, lower acid dissociation constant (pKa, 6.3 versus 10.5), bronchodilator action, and anti-proliferative and anti-inflammatory effects on the alveolar, interstitial, and vascular spaces of the lung [10,[16][17][18][19][20]. In addition, PGE 1 is readily available in pharmacies of hospitals with neonatal services and has a proven safety record from its intravenous use in ductal-dependent cardiac anomalies. ...
Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.
Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of >=15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.
No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.
These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.Trial registration: ClinicalTrials.gov: Pilot one: NCT number: 00598429 https://clinicaltrials.gov/ct2/show/NCT00598429?term=PGE1&rank=5registered on 10 January 2008. Last updated: 3 February 2011.Pilot two: NCT number: 01467076 https://clinicaltrials.gov/ct2/show/NCT01467076?term=PGE1&rank=717 October 2011. Last updated: 13 February 2013.
... Administration of aerosolized prostacyclin during mechanical ventilation was originally conducted with a variety of pneumatic jet nebulizers using nebulizer flows (up to 8 L/min) with nebulizer filling by bolus dosing. [1][2][3][4][5][6][7] In the past, dose control was managed by changing the concentration of prostacyclin solution infused into the nebulizer. 7 In recent years the Aerogen Solo vibrating mesh nebulizer (VMN) (Aerogen, Dangan, Galway, Ireland ) has been marketed for use with mechanical ventilation and continuous infusion aerosol delivery by way of a "drop-by-drop (volumetric)" technique in which the drug solution concentration remains constant and inhaled delivery is adjusted by changing the infusion pump flow. ...
Background:
Continuous nebulization of prostacyclins and albuterol by infusion pump during mechanical ventilation evolved as a popular off-label treatment for severe hypoxemic respiratory failure and asthma. Most institutions use a vibrating mesh nebulizer (VMN). A new breath-enhanced jet nebulizer (BEJN) is a potential alternative. This study was designed to compare these devices to better define factors influencing continuous infusion aerosol delivery. Device function, ventilator settings and infusion pump flow were studied in vitro.
Methods:
Using a bench model of adult mechanical ventilation, radiolabeled saline was infused at 6 flows (1.5 - 12 mL/h) into test nebulizers; 4 examples of each were used in rotation to test device reproducibility. Four breathing patterns with duty cycles (DC, % inspiratory time) ranging from 0.13 to 0.34 were tested. Aerogen Solo VMN was installed on the "dry" side of the heated humidifier (37°C). The InspiRx i-AIRE BEJN, on the "wet" side, was powered by air at 3.5 L/min and 50 psig. Infusion time was 1 h. Inhaled Mass of aerosol (IM) was collected on a filter at the airway opening. The IM was expressed as the percentage of the initial syringe radioactivity delivered per hour (IM%/h). Radioactivity deposited in the circuit was measured by gamma camera. Data were analyzed by multiple linear regression.
Results:
Variation in IM was significantly explained by pump flow and duty cycle (R2 0.92) and not by nebulizer technology. Duty cycle effects were more apparent at higher pump flow. VMNs failed to nebulize completely in 20% of the test runs. Mass balance indicated VMN deposited 15.3% in the humidifier vs 0.2% for BEJN.
Conclusion:
Aerosol delivery was determined by infusion pump flow and ventilator settings with comparable aerosol delivery between devices. BEJN was more reliable than VMN; 10 - 12 mL/h infusion flow was the maximum for both nebulizer technologies.
... Prostaglandin (PGE1) can cause vasodilation by increasing the intracellular cyclic adenosine monophosphate (cAMP) [79]. Similar to iNO, it was thought that inhaled PGE1 may bring vasodilatory effect to the lungs and improve oxygenation [80]. PGE1 may also reduce the expression of proinflammatory mediators such as TNF-α, IL12; and promote expression of IL 10 after IRI [81]. ...
Primary graft dysfunction (PGD) is one of the most common complications in the early postoperative period and is the most common cause of death in the first postoperative month. The underlying pathophysiology is thought to be the ischaemia–reperfusion injury that occurs during the storage and reperfusion of the lung engraftment; this triggers a cascade of pathological changes, which result in pulmonary vascular dysfunction and loss of the normal alveolar architecture. There are a number of surgical and anaesthetic factors which may be related to the development of PGD. To date, although treatment options for PGD are limited, there are several promising experimental therapeutic targets. In this review, we will discuss the pathophysiology, clinical management and potential therapeutic targets of PGD.
... Cosa and Costa neonates with congenital heart defects. 34 Aerosolized PGE 1 has been used as a selective pulmonary vasodilator in adults with acute lung injury 35 and acute respiratory distress syndrome. 36 One pilot trial evaluated the use of aerosolized PGE 1 in term/near-term infants with neonatal respiratory failure. ...
Treatment for persistent pulmonary hypertension of the newborn (PPHN) aims to reduce pulmonary vascular resistance while maintaining systemic vascular resistance. Selective pulmonary vasodilation may be achieved by targeting pulmonary-specific pathways or by delivering vasodilators directly to the lungs. Abrupt withdrawal of a pulmonary vasodilator can cause rebound pulmonary hypertension. Therefore, use of consistent delivery systems that allow for careful monitoring of drug delivery is important. This manuscript reviews published studies of inhaled vasodilators used for treatment of PPHN and provides an overview of safety issues associated with drug delivery and delivery devices as they relate to the risk of rebound pulmonary hypertension. Off-label use of aerosolized prostacyclins and an aerosolized prostaglandin in neonates with PPHN has been reported; however, evidence from large randomized clinical trials is lacking. The amount of a given dose of aerosolized drug that is actually delivered to the lungs is often unknown, and the actual amount of drug deposited in the lungs can be affected by several factors, including patient size, nebulizer used, and placement of the nebulizer within the breathing circuit. Inhaled nitric oxide (iNO) is the only pulmonary vasodilator approved by the US Food and Drug Administration for the treatment of PPHN. The iNO delivery device, INOmax DSIR®IR, is designed to constantly monitor NO, NO2, and O2 deliveries and is equipped with audible and visual alarms to alert providers of abrupt discontinuation and incorrect drug concentration. Other safety features of this device include two independent backup delivery systems, a backup drug cylinder, a battery that provides up to 6 hours of uninterrupted medication delivery, and 27 alarms that monitor delivery, dosage, and system functions. The ability of the drug delivery device to provide safe, consistent dosing is important to consider when selecting a pulmonary vasodilator.
... In a study by De Wet et al [12], 26 cardiac surgery patients with pulmonary hypertension experienced improved oxygenation and few adverse events. Other studies evaluating iEPO in patients with pulmonary hypertension, after heart and lung trans- plantation, and in the setting of ARDS have produced similar results [5,[13][14][15][16]. Limitations with the available studies evaluating iEPO include small sample sizes, cross-over design, homogeneous patient populations, short study durations, and lack of survival data. ...
... When administered intravenously, PGE 1 causes both pulmonary and systemic vasodilation and, in some critically ill patients, increases cardiac output and oxygen delivery [65]. Although the effect on the pulmonary circulation is usually small, the vasodilation is more marked under hypoxic conditions, and the nebulized drug improves ventilation/perfusion matching [66]. PGE 1 also inhibits platelet aggregation [67] and neutrophil adhesion [68]. ...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of a clinical syndrome of respiratory failure due to refractory hypoxia. Acute respiratory distress syndrome is differentiated from ALI by a greater degree of hypoxemia and is associated with higher morbidity and mortality. The mortality for ARDS ranges from 22-41%, with survivors usually requiring long-term rehabilitation to regain normal physiologic function. Numerous pharmacologic therapies have been studied for prevention and treatment of ARDS; however, studies demonstrating clear clinical benefit for ARDS-related mortality and morbidity are limited. In this focused review, controversial pharmacologic therapies that have demonstrated, at minimum, a modest clinical benefit are discussed. Three pharmacologic treatment strategies are reviewed in detail: corticosteroids, fluid management, and neuromuscular blocking agents. Use of corticosteroids to attenuate inflammation remains controversial. Available evidence does not support early administration of corticosteroids. Additionally, administration after 14 days of disease onset is strongly discouraged. A liberal fluid strategy during the early phase of comorbid septic shock, balanced with a conservative fluid strategy in patients with ALI or ARDS during the postresuscitation phase, is the optimum approach for fluid management. Available evidence supports an early, short course of continuous-infusion cisatracurium in patients presenting with severe ARDS. Evidence of safe and effective pharmacologic therapies for ARDS is limited, and clinicians must be knowledgeable about the areas of controversies to determine application to patient care.
... In ARDS, intravenous prostacyclin reduces PVR and improves RV function, although it may increase intrapulmonary shunt [301]. Inhaled prostacyclin [302][303][304][305] and inhaled PGE 1 [306] improve oxygenation and reduce PVR in ARDS, with minimal effects on SVR. NO and intravenous PGI 2 have been combined in ARDS with effective reduction of PVR without adverse effects [307]. ...
Pulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.
A systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.
Clinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.
This systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.
... Neonatal hypoxemic respiratory failure (NHRF) in term/near-term infants is often associated with persistent pulmonary hypertension of the newborn (PPHN). Aerosolized prostaglandin E 1 (IPGE 1 ) has been reported to be a potential selective pulmonary vasodilator [1][2][3] . ...
Inhaled PGE(1) (IPGE(1)) is a potential pulmonary vasodilator in neonatal respiratory failure. However, its effect on the patency of the ductus arteriosus (DA) has not been described.
To investigate the effect of IPGE(1) on the DA in healthy piglets.
IPGE(1) (1200ng/kg/min) [Study] or nebulized saline [Control] was administered using a jet nebulizer. Transthoracic echocardiography (TTE) was performed prior to (T0) and after 24h of aerosol therapy (T24). The DA was also evaluated histomorphologically at autopsy.
Fifteen piglets, 1-9 days old (study=9; control=6), were evaluated for DA patency. Study piglets received IPGE(1) for 12-24h. TTE was performed on 12 piglets at T0. Nine animals showed no ductal flow and 3 (1 study, 2 control) had a small DA. TTE at T24 in 5 animals showed no change in DA. At autopsy, the ductal diameter and histologic maturity stage were comparable in study and control animals.
High dose IPGE(1) given for 12-24h does not exert significant effect on the DA of healthy term piglets as evaluated by echocardiography and histomorphology. We conclude that ductal patency in neonates is influenced not only by prostaglandins but also by factors like hypoxemia, prematurity, and heart disease.
... This small modification in a regular nebulization chamber makes the nebulization of prostaglandins readily available in any hospital. We have pub-lished results obtained with this technology in patients with acute lung injury, both with nebulization of PGI 2 [5] and with that of prostaglandin E 1 [6]. ...
... 144 A comparison of dose-response characteristics of alprostadil and epoprostenol in infants with pulmonary hypertension found that both were effec-tive pulmonary vasodilators, but epoprostenol was 6 times more potent. 145 Aerosolized alprostadil has been reported to improve gas exchange in adults patients with acute lung injury and multiple organ system failure, 146 and in infants with hypoxic respiratory failure. 147 In animals with pharmacologically induced pulmonary vasoconstriction, inhaled alprostadil appeared to be less effective than inhaled epoprostenol or INO in reducing PAH. ...
Pulmonary vasodilators are an important treatment for pulmonary arterial hypertension. They reduce pulmonary artery pressure; improve hemodynamic function; alter ventilation/perfusion matching in the lungs; and improve functional quality of life, exercise tolerance, and survival in patients with severe pulmonary arterial hypertension. This paper reviews the currently available pulmonary vasodilators and those under development, many of which can be administered via inhalation. I will also give an overview of the clinical pharmacology of, the indications for, and the evidence supporting pulmonary vasodilators, their delivery via inhalation, and potential toxic and adverse effects.
... However, lack of sustained improvement in 30 -46% of infants and the need for specialized delivery systems make the treatment expensive and limit availability. Several investigators have explored the use of aerosolized prostaglandin E 1 (PGE 1 ) as a selective pulmonary vasodilator in patients with respiratory failure to improve oxygenation because of its selective action not only on the pulmonary circulation, but also on well-ventilated lung units (2)(3)(4)(5). We have previously described the safety and feasibility of inhaled PGE 1 (IPGE 1 ) in NHRF in a phase I/II unblinded clinical trial (5). ...
Pulmonary deposition of inhaled drugs in ventilated neonates has not been studied in vivo. The objective of this study was to evaluate pulmonary delivery of gadopentetate dimeglumine (Gd-DTPA) following nebulization in ventilated piglets using magnetic resonance imaging. Seven ventilated piglets (5 +/- 2 d old, weight 1.8 +/- 0.5 kg) were scanned in the Bruker/Siemens 4T magnetic resonance scanner using T1 weighted spin-echo sequence. Aerosols of Gd-DTPA were generated continuously using the MiniHeart jet nebulizer. Breath-hold coronal images were obtained before and every 10 min during aerosolized Gd-DTPA for 90 min. Signal intensity (SI) changes over the lungs, kidneys, liver, skeletal muscle, and heart were evaluated. A significant increase in SI was observed in the lungs, kidney, and liver at 10, 20, and 40 min respectively after start of aerosol. At the end of 90 min, the SI increased by 95%, 101%, and 426% over the right lung, left lung, and kidney, respectively. A much smaller increase in SI was observed over the liver. In conclusion, we have demonstrated effective pulmonary aerosol delivery within 10 min of contrast nebulization in ventilated piglets. Contrast visualization in the kidneys within 20 min of aerosol initiation reflects alveolar absorption, glomerular filtration and renal concentration.
Unlabelled:
Studies evaluating inhaled prostacyclins for the management of acute respiratory distress syndrome (ARDS) have produced inconsistent results regarding their effect on oxygenation. The purpose of this systematic review and meta-analysis was to evaluate the change in the Pao2/Fio2 ratio after administration of an inhaled prostacyclin in patients with ARDS.
Data sources:
We searched Ovid Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, Scopus, and Web of Science.
Study selection:
We included abstracts and trials evaluating administration of inhaled prostacyclins in patients with ARDS.
Data extraction:
Change in the Pao2/Fio2 ratio, Pao2, and mean pulmonary artery pressure (mPAP) were extracted from included studies. Evidence certainty and risk of bias were evaluated using Grading of Recommendations Assessment, Development, and Evaluation and the Cochrane Risk of Bias tool.
Data synthesis:
We included 23 studies (1,658 patients) from 6,339 abstracts identified by our search strategy. The use of inhaled prostacyclins improved oxygenation by increasing the Pao2/Fio2 ratio from baseline (mean difference [MD], 40.35; 95% CI, 26.14-54.56; p < 0.00001; I2 = 95%; very low quality evidence). Of the eight studies to evaluate change in Pao2, inhaled prostacyclins also increased Pao2 from baseline (MD, 12.68; 95% CI, 2.89-22.48 mm Hg; p = 0.01; I2 = 96%; very low quality evidence). Only three studies evaluated change in mPAP, but inhaled prostacyclins were found to improve mPAP from baseline (MD, -3.67; 95% CI, -5.04 to -2.31 mm Hg; p < 0.00001; I2 = 68%; very low quality evidence).
Conclusions:
In patients with ARDS, use of inhaled prostacyclins improves oxygenation and reduces pulmonary artery pressures. Overall data are limited and there was high risk of bias and heterogeneity among included studies. Future studies evaluating inhaled prostacyclins for ARDS should evaluate their role in ARDS subphenotypes, including cardiopulmonary ARDS.
Introduction:
Critically ill mechanically ventilated patients routinely receive aerosol delivery of the short-acting agent prostacyclin, epoprostenol, by continuous infusion via nebulizer and syringe pump. This procedure is "off-label" as no FDA approved drug presently exists. Without standardized protocols, therapy is based on prior experience with bronchodilators, limited studies of delivery systems and anecdotal clinical trials. Current protocols based upon patient body weight and drug concentration determines the infusion rate of drug dose delivered to the nebulizer by the pump, which is only distantly related to dose delivered to the lung and may be altered by many factors.
Areas covered:
This paper reviews the background of this technique as well as current methods of managing drug delivery, technical challenges, and limitations. A recent advance in aerosol laboratory bench testing, using radiolabeled aerosols, is presented to reveal important factors defining delivery.
Expert opinion:
Off-label use of continuously nebulized prostacyclin in the ICU lacks the support of large clinical trials needed for FDA clearance. However, comprehensive bench studies afford the potential for clinicians to better understand and manage therapy at a level above simple dosing of the nebulizer by body weight. New research techniques are enhancing our basic comprehension of the interaction between aerosol devices and the mechanical ventilator.
Background
There are many coronaviruses, which can cause diseases in humans and animals. The new 2019 coronavirus is highly prevalent and contagious, infecting many people in almost all countries of the world. There are many problems involved in the treatment of COVID-19 that must be discussed and examined.
Research Methods
A double-blind review was conducted on studies found on such online databases as Google Scholar, PubMed, Science Direct, Medline, Highwire, MD Consult, and Scopus by Internet-based search.
Results and Conclusions
Many deaths attributed to COVID-19 are caused by mistakes made in the prescription of medications, leading to the deterioration of the conditions of the patients, the most serious of which is the prescription of corticoids. Additionally, it has not been properly researched whether some drugs such as NSAIDs are indicated for use in COVID-19 or not. On the other hand, the application of some valuable medicinal herbs, such as peppermint and chamomile, in the treatment of this disease has not received enough attention, despite the fact that they may have valuable and remarkable effects in the treatment of this disease.
Pulmonary artery hypertension (PAH) is a progressive chronic disease with a high mortality rate. Increased pulmonary vascular resistance and over-proliferation of pulmonary artery endothelial cells lead to remodeling of pulmonary vasculature. Several anti-PAH therapies targeting various pathways involved in PAH progression have been approved by the FDA. However, many of the currently available anti-PAH drugs suffer from a number of limitations, including short biological half-life, and poor pulmonary selectivity. Prostaglandin E1 (PGE1) is a compound with vasodilatory, anti-inflammatory, anti-aggregatory, and anti-proliferative properties. Recently, PGE1 is known to accumulate in sites of inflammation or vascular lesions and thus enhance the effects of the drugs and alleviate the side effects. Therefore, we hypothesized that long-term effect of PGE1 could reduce ma adaptive structural remodeling of the lung and heart and prevent ventricular arrhythmias in monocrotaline (MCT)-induced rat model of PAH. Our results revealed that PGE1 reduced ventricular hypertrophy, protein expressions of endothelin-1 (ET-1) and endothelin receptor A (ERA), and the expression of fibrosis. These results support the notion that PGE1 can improve the functional properties of RV, highlighting its potential benefits for heart and lung impairment.
Background:
Acute respiratory distress syndrome (ARDS) is a critical condition that is associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.This review was originally published in 2010 and updated in 2017.
Objectives:
To assess the benefits and harms of aerosolized prostacyclin in adults and children with ARDS.
Search methods:
In this update, we searched CENTRAL (2017, Issue 4); MEDLINE (OvidSP), Embase (OvidSP), ISI BIOSIS Previews, ISI Web of Science, LILACS, CINAHL (EBSCOhost), and three trials registers. We handsearched the reference lists of the latest reviews, randomized and non-randomized trials, and editorials, and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception to 5 May 2017.
Selection criteria:
We included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data.
Data collection and analysis:
Three authors independently abstracted data and resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We planned to perform subgroup and sensitivity analyses to assess the effect of aerosolized prostacyclin in adults and children, and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of methodological trial components and the risk of random error through trial sequential analysis.
Main results:
We included two RCTs with 81 participants.One RCT involved 14 critically ill children with ARDS (very low quality of evidence), and one RCT involved 67 critically ill adults (very low quality evidence).Only one RCT (paediatric trial) provided data on mortality and found no difference between intervention and control. However, this trial was eligible for meta-analysis due to a cross-over design.We assessed the benefits and harms of aerosolized prostacyclin. One RCT found no difference in improvement of partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio (mean difference (MD) -25.35, 95% confidence interval (CI) -60.48 to 9.78; P = 0.16; 67 participants, very low quality evidence).There were no adverse events such as bleeding or organ dysfunction in any of the included trials. Due to the limited number of RCTs, we were unable to perform the prespecified subgroup and sensitivity analyses or trial sequential analysis.
Authors' conclusions:
We are unable to tell from our results whether the intervention has an important effect on mortality because the results were too imprecise to rule out a small or no effect. Therefore, no current evidence supports or refutes the routine use of aerosolized prostacyclin for people with ARDS. There is an urgent need for more RCTs.
Ashbaugh et al. first described the adult respiratory distress syndrome (ARDS) in 1967 (1). At that time they characterized a group of patients with a constellation of symptoms and signs that included dyspnea, tachypnea, refractory hypoxemia, poor pulmonary compliance and diffuse, bilateral, alveolar infiltration on chest radiograph. Subsequent studies reported inconsistent criteria to define the disorder, making it difficult to study the epidemiology and assess the effectiveness of new therapeutic approaches. To this end, the American-European Consensus Conference on ARDS recommended the following definitions: acute lung injury is a syndrome of acute respiratory failure with a partial pressure of oxygen/inspired oxygen concentration (PaO2/FiO2) ratio ≤300, bilateral infiltrates on chest x-ray, and no evidence of left atrial hypertension (pulmonary artery occlusion pressure ≤18); ARDS is a severe form of acute lung injury defined as a PaO2/FiO2 ratio ≤200. Neither definition estimates the severity of the disease process based on the level of continuous positive airway pressure (CPAP) necessary to establish acceptable oxygenation. More recently, the term “acute” replaced “adult” to reflect both the acuity and the occurrence in children (2).
There is no clear cut consensus on the definition of refractory hypoxemia in literature even though it is a difficult entity to treat. Some of the current treatment options have shown mortality benefits in addition to improving hypoxemia while others merely improve oxygenation only. First line therapies for management of refractory hypoxemia in acute respiratory distress syndrome [ARDS] include optimal ventilation, use of neuromuscular blocking agents, higher positive end expiratory pressure, fluid restriction, nitric oxide, recruitment maneuvers and prone ventilation. The timing of rescue therapies in oxygenation failure is not clearly defined. Rescue therapies like extracorporeal membrane oxygenation and high frequency oscillation may be useful when hypoxemia remains refractory to first line therapies. Robust studies are needed in future to elucidate the efficacy of these therapies on outcomes in patients with refractory hypoxemia. This review looks at recent evidences for various strategies that improve oxygenation and survival in hypoxemic patients in the clinical context of ARDS.
The mortality of the acute respiratory distress syndrome (ARDS) remains high despite advances in supportive care of ARDS and in the understanding of the pathogenesis. Numerous inflammatory mediators including reactive oxygen species, arachidonic acid metabolites, and growth factors, are present in the circulation of patients with or at risk for developing this syndrome and play a key pathophysiologic role in the development of lung injury. Pharmacologic therapy is being evaluated to: 1) support the failing lung by improving gas exchange; 2) interrupt the mediator-induced mechanisms of inflammation and injury. Although none of these experimental therapies has yet been proven to improve survival in well conducted prospective, randomized, double-blind, controlled clinical trials, many have demonstrated improvement in physiologic function. These results have helped lay the groundwork for future advances in this field.
AimTo report a case of acute respiratory distress syndrome (ARDS) caused by Escherichia coli urosepsis with shock that resulted in multiple organ failure and refractory hypoxaemia successfully treated with low-dose nebulised epoprostenol.Clinical detailsA 64-year-old female with a history of hypertension and dyslipidaemia underwent elective cystoscopy for the removal of an ureteric stent and subsequently developed hypotension followed by fever. This was attributed to E. coli urosepsis with shock and resulted in multiple organ failure and refractory hypoxaemia with the development of bilateral pulmonary infiltrates, suggestive of ARDS. Hypoxia and pulmonary infiltrates progressed despite administration of non-invasive ventilation followed by intermittent positive pressure ventilation. The patient was subsequently started on continuous nebulised low doses of epoprostenol 2 to 4 ng/kg/min. The nebulised epoprostenol was continued for approximately 48 hours with significant improvement in oxygenation.Conclusion
Nebulised epoprostenol, as a rescue therapy for refractory hypoxaemia caused by ARDS may be a reasonable therapeutic strategy, although further evidence to support its impact on outcomes is required.
Akut respiratuar distres sendromu (ARDS); alveol epitel ve epitel engellerindelerinde zedelenme, akut enflamasyon ve proteinden zengin pulmoner ödemin neden olduðu akut solunum yetmezliðidir 1 . Ashbaugh 1967de ilk kez ARDS olarak takipne, oksijen tedavisine dirençli hipoksemi, yaygýn alveolar infiltratlar, pulmoner kompliyansta azalma gözlenen, pozitif basýnçlý mekanik ventilasyon ihtiyacý olan 12 hastada tanýmlamýþtýr. Pediatrik yaþ grubunda ise ilk kez 1968de bildirilmiþtir 2 . Güncel tanýmlama 1994de NAECC (North American European Consensus Conference)ýnda yapýlmýþ, eriþkin (adult) tanýmý akut tanýmý ile deðiþtirilerek ARDS ve Akut Akciðer Hasarý (AAH) için taný kriterleri kabul edilmiþtir (Tablo I) 3 . Akut respiratuar distres sendromunun gerçek insidansý bilinmemektedir. Eriþkin yaþ grubunda yýlda 1.5-13.5:100000 arasýnda deðiþen oran-lardan söz edilmektedir. Pediatrik yaþ grubu için insidans verileri olmamakla beraber pediatrik yoðun bakým ünitelerinde izlenen hastalarýn %0.6-7.2sini ARDSli hastalar oluþturmak-tadýr 4 . Patogenez Akut respiratuar distres sendromunun akciðer-lerde artmýþ abartýlý enflamatuar yanýt olduðu düþünülebilir. ARDS, pnömoni, aspirasyon, inhalasyon, emboli, sepsis, yaygýn damar içi pýhtýlaþma gibi etkenlerin akciðerde enflamatuar SUMMARY: Aslan AT, Doðru D, Özçelik U. (Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey). Acute respiratory distress syndrome. Çocuk Saðlýðý ve Hastalýklarý Dergisi 2004; 47: 209-221. The acute respiratory distress syndrome (ARDS) is a severe lung injury in patients with sepsis and other acute inflammatory insults, characterized by injury to the alveolar epithelial and endothelial barriers of the lung, acute inflammation, and protein rich pulmonary edema. Profound hypoxemia, noncardiogenic pulmonary edema, and poor lung compliance are seen. ARDS carries high morbidity and mortality rates. Considerable attention has been paid to ARDS over the last 20-30 years, not only in pathogenesis but also in many different therapy strategies. The goals of treatment of ARDS are to: (1) reverse the underlying condition leading to ARDS, (2) minimize acute lung injury, (3) maintain adequate tissue delivery of oxygen, and (4) avoid iatrogenic pulmonary complications. A substantial number of new therapies have been suggested and examined in recent years, many of which remain controversial. Physiologic, clinical, and radiologic manifestations and therapy options are outlined in this article.
Background:
Acute respiratory distress syndrome (ARDS) is a type of hypoxic respiratory failure that results from ventilation and perfusion mismatching. Inhaled epoprostenol induces relaxation of smooth muscle in pulmonary vasculature, leading to improved oxygenation.
Objective:
To determine if the use of inhaled epoprostenol produced a 10% or greater increase in the ratio of arterial partial pressure of oxygen (PaO₂) to fraction of inspired oxygen (FiO₂) in ARDS patients and to review adverse events and medication errors.
Methods:
An observational chart review was performed based on a report generated from the electronic medical record system. Patients who received at least 1 dose of inhaled epoprostenol from January 1, 2008, to December 31, 2010, at any hospital within the Florida Hospital Health System were considered for inclusion. Demographics, dose, duration of therapy, adverse effects, medication errors, and outcomes data were collected.
Results:
Sixteen patients were included in the study. Oxygenation improved by 10% or more in 62.5% (10/16) of the patients, with an initial (within the first 4 hours) median increase of 44.5% in PaO₂/FiO₂. The mean (SD) starting dose was 30 (10) ng/kg/min. Medication errors were observed in 25% (4/16) of patients. Hypotension was the most frequently observed adverse event, with a rate of 18.8% (3/16).
Conclusions:
Based on study findings, inhaled epoprostenol may improve oxygenation in patients with ARDS, with findings suggesting a 62.5% response to therapy. The significance of these effects on improving survival remains unknown. The frequency of medication errors observed in this study poses a significant concern regarding the administration of epoprostenol. Further controlled prospective studies are needed to determine the role of inhaled epoprostenol in improving survival in patients with ARDS.
This study sought to investigate the efficacy of a noninvasive and long acting polymeric particle based formulation of prostaglandin E1 (PGE1), a potent pulmonary vasodilator, in alleviating the signs of pulmonary hypertension (PH) and reversing the biochemical changes that occur in the diseased lungs. PH rats, developed by a single subcutaneous injection of monocrotaline (MCT), were treated with two types of polymeric particles of PGE1, porous and nonporous, and intratracheal or intravenous plain PGE1. For chronic studies, rats received either intratracheal porous poly (lactic-co-glycolic acid) (PLGA) particles, once- or thrice-a-day, or plain PGE1 thrice-a-day for 10 days administered intratracheally or intravenously. The influence of formulations on disease progression was studied by measuring the mean pulmonary arterial pressure (MPAP), evaluating right ventricular hypertrophy and assessing various molecular and cellular makers including the degree of muscularization, platelet aggregation, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antigen (PCNA). Both plain PGE1 and large porous particles of PGE1 reduced MPAP and right ventricular hypertrophy (RVH) in rats that received the treatments for 10 days. Polymeric porous particles of PGE1 produced the same effects at a reduced dosing frequency compared to plain PGE1 and caused minimal off-target effects on systemic hemodynamics. Microscopic and immunohistochemical studies revealed that porous particles of PGE1 also reduced the degree of muscularization, von Willebrand factor (vWF) and PCNA expression in the lungs of PH rats. Overall, our study suggests that PGE1 loaded inhalable particulate formulations improve PH symptoms and arrest the progression of disease at a reduced dosing frequency compared to plain PGE1.
Despite the extreme delicacy of the alveolar capillary membrane, the pulmonary microvascular endothelium normally functions faithfully as an effective and selective barrier, thereby protecting the lung parenchyma and the alveoli from excesses of the blood fluid, bioactive molecules, and cellular components, while allowing optimal exchange of oxygen and carbon dioxide critical to life. Advances in cellular, molecular, and biomechanical sciences have enabled the appreciation and understanding of the construction and function of the endothelial barrier, as well as the many important regulatory functions of the endothelium. Thus, as keepers of the dam, an intimate acquaintance with its composition, maintenance, and regulation is needed. There is a growing recognition that even moderate endothelial dysfunction in any anatomic site contributes to the pathological processes leading to diverse acute and chronic, vascular, and organ dysfunction. This chapter highlights integrated presentation of the advancements in endothelial biology and the development of a view toward the expansion of the comprehension of endothelial functional integrity.
Respiratory dysfunction related to sepsis is not uncommon and is associated with significant independent mortality, making
heightened awareness and vigilance for such respiratory complications more critical. Until a direct and effective therapy
appears on the horizon, the focus of care remains on supportive measures and prevention of complications.
Despite significant advances in both the knowledge of sepsis-related respiratory failure and the care of critically ill patients,
ALI/ARDS continues to be a complex problem with high mortality. The recommendations above represent the current state of knowledge
for this condition, but equally serve to highlight the vast deficiencies of knowledge that remain. To provide our patients
with the best possible outcome, a continued focus on physiologic, therapeutic, and outcomes research is necessary.
Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI.
To test the efficacy and viability of poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating an inclusion complex of prostaglandin E(1) (PGE(1)) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) for pulmonary delivery of PGE(1) for treatment of pulmonary arterial hypertension (PAH), a disease of pulmonary circulation.
PLGA-based microparticulate formulations of PGE(1)-HPβCD inclusion complex or plain PGE(1) were prepared by a double-emulsion solvent evaporation method. HPβCD was used as a complexing agent to increase the aqueous solubility of PGE(1), act as a porosigen to produce large porous particles, and promote absorption of PGE(1). Particles were characterized for micromeritic properties, in vivo absorption, metabolic degradation, and acute safety.
Incorporation of HPβCD in the microparticles resulted in development of large particles with internal pores, which, despite large mean diameters, had aerodynamic diameters in the inhalable range of 1 to 5 μm. HPβCD incorporation also resulted in a significant increase in the amount of drug released in vitro in simulated interstitial lung fluid, showing a desirable burst release profile required for immediate hemodynamic effects. Compared to plain PLGA microparticles, entrapment efficiency was decreased upon complexation with HPβCD. In vivo absorption profile indicated prolonged availability of PGE(1) in circulation following pulmonary administration of the optimized microparticulate formulations, with an extended half-life of almost 4 hours. Metabolic degradation and acute toxicity studies suggested that microparticulate formulations were stable under physiological conditions and safe for the lungs and respiratory epithelium.
This study demonstrates the feasibility of PGE(1)-HPβCD complex encapsulated in PLGA microparticles as a potential delivery system for controlled release of inhaled PGE(1).
Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200 μM) and dexamethasone (65 μM, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability-surface area product value, and tumor necrosis factor (TNF)-α levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5mg/kg, i.p.) markedly reduced lipopolysaccharide (6 mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5mg/kg, i.v., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200 μM) and dexamethasone (10 μM) pre-incubation lowered lipopolysaccharide (2 μg/mL) induced secretion of the cytokine TNF-α, and interleukins (IL)-1β, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.
To systematically assess the benefits and harms of aerosolized prostacyclin in critically ill patients with ALI and ARDS.
We identified randomized clinical trials (RCTs) from electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (to 31st January 2010). We contacted trial authors and manufacturers in the field.
We included all RCTs, irrespective of blinding or language, that compared aerosolized prostacyclin with no intervention or placebo in either children or adults with ALI or ARDS.
Two authors independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects as relative risks (RR) with 95% confidence intervals (CI) for dichotomous outcomes. Our primary outcome measure was all cause mortality. We planned to perform subgroup and sensitivity analyses to assess the effect of aerosolized prostacyclin in adults and children, and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of methodological trial components and the risk of random error through trial sequential analysis.
We included one paediatric RCT with low risk of bias and involving a total of 14 critically ill children with ALI or ARDS. Aersosolized prostacyclin over less than 24 hours did not reduce overall mortality at 28 days (RR 1.50, 95% CI 0.17 to 12.94) compared with aerosolized saline (a total of three deaths). The authors did not encounter any adverse events such as bleeding or organ dysfunction. We were unable to perform the prespecified subgroups and sensitivity analyses or trial sequential analysis due to the limited number of RCTs. We were also not able to assess the safety and efficacy of aerosolized prostacyclin for ALI and ARDS. We found two ongoing trials, one involving adults and the other paediatric participants. The adult trial has been finalized but the data are not yet available.
There is no current evidence to support or refute the routine use of aerosolized prostacyclin for patients with ALI and ARDS. There is an urgent need for more randomized clinical trials.
ARDS is characterized by hypoxemic respiratory failure, which can be refractory and life-threatening. Modifications to traditional mechanical ventilation and nontraditional modes of ventilation are discussed in Part 1 of this two-part series. In this second article, we examine nonventilatory strategies that can influence oxygenation, with particular emphasis on their role in rescue from severe hypoxemia. A literature search was conducted and a narrative review written to summarize the use of adjunctive, nonventilatory interventions intended to improve oxygenation in ARDS. Several adjunctive interventions have been demonstrated to rapidly ameliorate severe hypoxemia in many patients with severe ARDS and therefore may be suitable as rescue therapy for hypoxemia that is refractory to prior optimization of mechanical ventilation. These include neuromuscular blockade, inhaled vasoactive agents, prone positioning, and extracorporeal life support. Although these interventions have been linked to physiologic improvement, including relief from severe hypoxemia, and some are associated with outcome benefits, such as shorter duration of mechanical ventilation, demonstration of survival benefit has been rare in clinical trials. Furthermore, some of these nonventilatory interventions carry additional risks and/or high cost; thus, when used as rescue therapy for hypoxemia, it is important that they be demonstrated to yield clinically significant improvement in gas exchange, which should be periodically reassessed. Additionally, various management strategies can produce a more gradual improvement in oxygenation in ARDS, such as conservative fluid management, intravenous corticosteroids, and nutritional modification. Although improvement in oxygenation has been reported with such strategies, demonstration of additional beneficial outcomes, such as reduced duration of mechanical ventilation or ICU length of stay, or improved survival in randomized controlled trials, as well as consideration of potential adverse effects should guide decisions on their use. Various nonventilatory interventions can positively impact oxygenation as well as outcomes of ARDS. These interventions may be considered for use, particularly for cases of refractory severe hypoxemia, with proper appreciation of potential costs and adverse effects.
This study was designed to test the feasibility of polymeric microspheres as an inhalable carrier for prostaglandin E(1) (PGE(1)) for treatment of pulmonary arterial hypertension. Poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared by a double emulsion-solvent evaporation method. Six different microspheric formulations were prepared using two different blends of PLGA (50:50 and 85:15) and varying concentrations of polyvinyl alcohol (PVA) in the external aqueous phase (EAP). The particles were characterized for morphology, size, aerodynamic diameter, entrapment efficiency, release patterns, and metabolic stability. Pulmonary absorption was studied in a rat model, and safety of the formulations was evaluated by measuring cytotoxicity in Calu-3 cells and assessing injury markers in bronchoalveolar lavage (BAL) fluid. Both actual particle size and aerodynamic diameter of the formulations decreased with increasing PVA concentration. The mass median aerodynamic diameter of the particles was within the respirable range. Entrapment efficiency increased with increasing PVA concentration; PLGA 85:15 showed better entrapment due to hydrophobic interactions with the drug. Compared to intravenously administered PGE(1), microspheres prepared with PLGA 85:15 produced a 160-fold increase in the half-life of PGE(1) following pulmonary administration. Although plain PGE(1) showed rapid degradation in rat lung homogenate, PGE(1) entrapped in the particles remained intact for about 8 h. Optimized formulations were demonstrated to be safe, based on analysis of cytotoxicity and lung-injury markers in BAL fluid. Overall, the data suggest that microspheric PGE(1) formulations have the potential to be used as a noninvasive and controlled-release alternative to the current medications used for treatment of pulmonary arterial hypertension that are administered by continuous infusion or require multiple inhalations.
Non-cardiogenic pulmonary oedema, an early manifestation of the adult respiratory disease syndrome, is a serious complication following major vascular surgery. Hypovolaemia, ischaemia-reperfusion injury, massive blood transfusion, transient sepsis and transient endotoxaemia are insults responsible for initiating the process in vascular surgical patients. Free radicals, cytokines and humoral factors released secondary to the above insults activate neutrophils and facilitate their interaction with the endothelium. Activated neutrophils marginate through the endothelium where they are responsible for tissue injury by the release of free-radicals and proteases. The lungs are a large reservoir of neutrophils and bear a significant part of the injury. Conventional therapy includes treating the underlying condition and providing respiratory support. A better understanding of the pathophysiology of this process has led to new experimental treatment options. Novel therapeutic interventions have included the use of compounds to scavenge free radicals, anti-cytokine antibodies, extracorporeal lung support, nitric oxide and artificial surfactant therapy. The multifactorial nature of this process makes it unlikely that a single "magic bullet" will solve this problem. It is more likely that a combination of preventative, prophylactic and therapeutic modalities may reduce the mortality of this condition.
To systematically review clinical trials in acute respiratory distress syndrome (ARDS).
Computerized bibliographic search of published research and citation review of relevant articles.
All clinical trials of therapies for ARDS were reviewed. Therapies that have been compared in prospective, randomized trials were the focus of this analysis.
Data on population, interventions, and outcomes were obtained by review. Studies were graded for quality of scientific evidence.
Lung protective ventilator strategy is supported by improved outcome in a single large, prospective trial and a second smaller trial. Other therapies for ARDS, including noninvasive positive pressure ventilation, inverse ratio ventilation, fluid restriction, inhaled nitric oxide, almitrine, prostacyclin, liquid ventilation, surfactant, and immune-modulating therapies, cannot be recommended at this time. Results of small trials using corticosteroids in late ARDS support the need for confirmatory large clinical trials.
Lung protective ventilator strategy is the first therapy found to improve outcome in ARDS. Trials of prone ventilation and fluid restriction in ARDS and corticosteroids in late ARDS support the need for large, prospective, randomized trials.
Remarkable progress has been made in the past 10 years with regard to understanding the interplay of potent physiologic mediators in patients with acute lung injury. Because there are so many mediators and the interaction of these agents is complex, true insight into the process has been slow in coming. Clinical studies in ARDS, as well as sepsis, the leading cause of ARDS, have increased in number, size, and quality over this same period. Although none of these studies has produced an accepted new therapy for ARDS, each has laid the groundwork for more efficient and more elegant studies of the problem. The stage is now set for the real advances to be brought forward and put to rigorous, efficient clinical testing.
To date, the only therapeutic option that has convincingly been shown to decrease mortality in acute respiratory distress syndrome (ARDS) has been to use a lung-protective strategy that minimises the iatrogenic consequences of providing adequate life support through the use of mechanical ventilation. In terms of the pharmacological options for ARDS, no single drug or treatment has been shown to be the magic bullet in this disease. The search for novel therapies and pharmacological agents is active and relentless. Important pathophysiological areas of focus are preventative therapy, supportive care and treatment of the underlying inflammatory process. In this paper we will review current and experimental approaches to the management of ARDS. In addition, the pathophysiological basis for their putative modes of action, the current state of the literature and the potential for future clinical development will be discussed.
Pharmacological approaches to the treatment of ARDS are reviewed. Future treatments should be targeted at elements of the pathological process that produce specific clinical problems.
Twenty term/near term neonates with hypoxemic respiratory failure and oxygenation index >/=20 were enrolled in a Phase I/II feasibility, safety and dose escalation study of inhaled PGE(1) (IPGE(1)). Incremental doses of IPGE(1), delivered by a jet nebulizer over a 2-h period, followed by weaning over 1 h, were given to 13 patients before receiving inhaled nitric oxide (INO) (Group I), and to seven patients, who failed to respond to INO (Group II). Response was defined as an increase in P(a)O(2) of either >/= 25 (full) or 10-25 (partial) torr. Exit criteria included an acute deterioration in oxygenation status, a persistent oxygenation index above 35 in Group I, or the availability of extracorporeal membrane oxygenation (ECMO) in Group II. The mean (SD) increase in P(a)O(2) at the end of IPGE(1) administration was 63 (62.3) in Group I (p = 0.024), and 40 (62.1) in Group II (p > 0.05). In Group I, 8 of 13 neonates had a full response, but 4 deteriorated following discontinuation of IPGE(1). Of these four, two responded to INO and two were placed on ECMO. Five patients deteriorated before or during IPGE(1,) and none of them responded to INO. In Group II, three of seven patients had a full response to IPGE(1). One patient with a partial response and all patients exiting before or during IPGE(1) administration were placed on ECMO. The results of our study indicate that IPGE(1) may be a safe, selective pulmonary vasodilator in neonatal hypoxemic respiratory failure.
To measure plasma prostaglandin E1 (PGE1) levels in newborns with hypoxemic respiratory failure (NHRF) following inhaled PGE1 (IPGE1), normal term newborns, and newborns with congenital heart disease (CHD) following intravenous PGE1.
Twenty newborns with NHRF received IPGE1 by jet nebulizer in doses of 25, 50, 150, and 300 ng/kg/min followed by weaning. Blood for PGE1 assay using enzyme immunoassay was available in eight neonates with NHRF, 10 normal newborns, and three neonates with CHD.
There were no differences in PGE1 levels between cord arterial blood in normal newborns and baseline samples from newborns with NHRF. Oxygenation improved significantly following IPGE1 (p=0.024) in newborns with NHRF. No adverse events were identified. Although a reversible increase in PGE1 levels was detected following a dose of 50 ng/kg/min (p<0.05), there was no association between PGE1 levels and IPGE1 duration, PaO2, temperature, heart rate, and blood pressure.
A reversible increase in mean PGE1 levels was demonstrable at low doses of IPGE1 in babies with NHRF using a sensitive assay, suggesting effective drug delivery. Levels did not increase further with increasing dose or duration of administration, suggesting local action in the lungs and a lack of systemic spillover due to extensive pulmonary metabolism offering pulmonary selectivity.
The aim of this article is to discuss the various factors that influence aerosol delivery in mechanically ventilated patients and clarify optimal techniques for aerosol administration in this patient population. Clinical use of various inhaled therapies in patients receiving invasive and noninvasive mechanical ventilation is also discussed.
With optimal techniques for using pressurized metered-dose inhalers and nebulizers in ventilator circuits, the efficiency of inhaled drug delivery in mechanically ventilated patients is comparable to that in ambulatory patients. Techniques for enhancing inhaled drug delivery during noninvasive positive pressure ventilation are also being investigated.
Pressurized metered-dose inhalers of bronchodilator and corticosteroid aerosols are more efficient and convenient to use than nebulizers for routine therapy in ventilated patients. Nebulizers are, however, more versatile and are employed to generate aerosols of bronchodilators, corticosteroids, antibiotics, prostaglandins, surfactant, and mucolytic agents. Factors influencing drug delivery during noninvasive positive pressure ventilation are not fully understood as yet, and further work is needed to enhance drug delivery in this setting. Improvements in drug formulations and the design and efficiency of aerosol generating devices have led to increasing application of inhaled therapies in mechanically ventilated patients.
Acute respiratory distress syndrome was first described in 1967. Acute respiratory distress syndrome and acute lung injury are diseases the busy intensivist treats almost daily. The etiologies of acute respiratory distress syndrome are many. A significant distinction is based on whether the insult to the lung was direct, such as in pneumonia, or indirect, such as trauma or sepsis. Strategies for managing patients with acute respiratory distress syndrome/acute lung injury can be subdivided into 2 large groups, those based in manipulation of mechanical ventilation and those based in nonventilatory modalities. This review focuses on the nonventlilatory strategies and includes fluid restriction, exogenous surfactant, inhaled nitric oxide, manipulation of production, or administration of eicosanoids, neuromuscular blocking agents, prone position ventilation, glucocorticoids, extracorporeal membrane oxygenation, and administration of beta-agonists. Most of these therapies either have not been studied in large trials or have failed to show a benefit in terms of long-term patient mortality. Many of these therapies have shown promise in terms of improved oxygenation and may therefore be beneficial as rescue therapy for severely hypoxic patients. Recommendations regarding the use of each of these strategies are made, and an algorithm for implementing these strategies is suggested.
To study the toxicity of inhaled PGE1 (IPGE1) in healthy ventilated piglets.
Mechanically ventilated anesthetized piglets received either high dose IPGE1 (IPGE1 group) or nebulized saline (control group) continuously for 24h. Cardio-respiratory parameters, complete blood counts and serum electrolytes were monitored. Lung histology was evaluated by a masked pathologist for the severity (minimal, moderate, and severe) and extent (focal, multifocal, and diffuse) of histologic injury.
Ten neonatal pigs were instrumented. Four received nebulized saline and six received high dose IPGE1. There was no evidence of adverse cardio-respiratory effects, bronchial irritation or hypernatremia related to IPGE1. Diffuse/multifocal alveolar edema and focal polymorphonuclear infiltration was observed in both the control and IPGE1 groups suggesting that alveolar alterations may be secondary to effects of mechanical ventilation. The most distinct histomorphological abnormalities observed in the IPGE1 animals were focal ulceration, flattening of the bronchial epithelium and loss of cilia of moderate to severe degree in the trachea and bronchi.
In healthy piglets, inhalation of high dose IPGE1 was not associated with adverse cardiorespiratory effects, bronchial irritation, or hypernatremia and produced minimal signs of pulmonary toxicity even after 24h. Prolonged inhalation of high dose PGE1 therefore appears safe in newborn piglets.
The adult respiratory distress syndrome is characterized by pulmonary hypertension and right-to-left shunting of venous blood. We investigated whether inhaling nitric oxide gas would cause selective vasodilation of ventilated lung regions, thereby reducing pulmonary hypertension and improving gas exchange.
Nine of 10 consecutive patients with severe adult respiratory distress syndrome inhaled nitric oxide in two concentrations for 40 minutes each. Hemodynamic variables, gas exchange, and ventilation-perfusion distributions were measured by means of multiple inert-gas-elimination techniques during nitric oxide inhalation; the results were compared with those obtained during intravenous infusion of prostacyclin. Seven patients were treated with continuous inhalation of nitric oxide in a concentration of 5 to 20 parts per million (ppm) for 3 to 53 days.
Inhalation of nitric oxide in a concentration of 18 ppm reduced the mean (+/- SE) pulmonary-artery pressure from 37 +/- 3 mm Hg to 30 +/- 2 mm Hg (P = 0.008) and decreased intrapulmonary shunting from 36 +/- 5 percent to 31 +/- 5 percent (P = 0.028). The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2), an index of the efficiency of arterial oxygenation, increased during nitric oxide administration from 152 +/- 15 mm Hg to 199 +/- 23 mm Hg (P = 0.008), although the mean arterial pressure and cardiac output were unchanged. Infusion of prostacyclin reduced pulmonary-artery pressure but increased intrapulmonary shunting and reduced the PaO2/FiO2 and systemic arterial pressure. Continuous nitric oxide inhalation consistently lowered the pulmonary-artery pressure and augmented the PaO2/FiO2 for 3 to 53 days.
Inhalation of nitric oxide by patients with severe adult respiratory distress syndrome reduces the pulmonary-artery pressure and increases arterial oxygenation by improving the matching of ventilation with perfusion, without producing systemic vasodilation. Randomized, blinded trials will be required to determine whether inhaled nitric oxide will improve outcome.
Inhalation of nitric oxide (NO), an endogenous vasodilator, was recently described to reduce pulmonary vascular resistance, and to improve arterial oxygenation by selective vasodilation of ventilated areas in patients with adult respiratory distress syndrome (ARDS). We describe the time-course and dose-response of initial short-term NO inhalation in 12 patients with ARDS. Enhanced oxygenation was achieved within 1-2 min after starting NO inhalation; after inhalation, baseline conditions were re-achieved within 5-8 min. Effective doses for improvement of oxygenation [baseline: PaO2 = 10.2 +/- 2.5 KPa (76.4 +/- 18.7 mmHg)] were low: ED50 was about 100 ppb--a concentration similar to the atmosphere. NO doses of more than 10 ppm [10 ppm NO: PaO2 = 17.3 +/- 3.3 KPa (129.4 +/- 25.1 mmHg)] re-worsen the arterial oxygenation. The ED50 for reduction of mean pulmonary artery pressure was 2-3 ppm. This indicates that inhalation of NO for improvement of oxygenation in severe ARDS should be performed using lower doses, with lower risk of toxic side effects.
Pulmonary hypertension and reduced arterial oxygenation are the clinically most relevant symptoms of acute respiratory failure. Inhaled nitric oxide (NO) proved to be effective in reducing pulmonary hypertension and improving arterial oxygenation. We hypothesized that the inhalation of vasodilatory agents such as prostacyclin or prostaglandin E1 would have similar effects than inhaled NO. We tested this hypothesis in an established model of ovine smoke inhalation injury. Sheep (N = 6) were prepared for chronic study. Three days later, the sheep were insufflated with cotton wool smoke under halothane anesthesia. After 24 h, first NO, then PGI2, and thereafter PGE1 were added to the inspired air. Smoke inhalation injury caused a serious deterioration of pulmonary hemodynamics and arterial oxygenation. All three compounds selectively reduced pulmonary hypertension, but none of them improved oxygenation. Inhaled NO caused a slight but significant increase in methemoglobin, which could not been obtained during PGI2 or PGE1 nebulization.
Prostaglandin E1 (PGE1) was compared to placebo in a 100-patient (50 PGE1, 50 placebo) randomized, double-blind, clinical trial to determine whether PGE1 therapy enhances survival of patients with adult respiratory distress syndrome (ARDS) when infused through a central line at 30 ng/kg/min continuously for seven days. At 30 days postinfusion, 30 PGE1 and 24 placebo patients had died. Total deaths judged to be related to the syndrome were 32 and 28 in the PGE1 and placebo groups respectively at six months. We conclude that PGE1 did not enhance survival in patients with established ARDS. PGE1 augmented the hyperdynamic circulation of these patients by reducing systemic and pulmonary vascular resistance, which resulted in a reduction of blood pressures and increased stroke volume, cardiac output, and heart rate. An improvement in oxygen availability and oxygen consumption was observed with PGE1 therapy. PGE1 was associated with an increased incidence of diarrhea (six patients in the PGE1 group vs one in the placebo group, p less than 0.05). Other adverse effects included hypotension (ten patients in the PGE1 group vs seven in the placebo group), fever (six patients in the PGE1 group vs three in the placebo group), and non-fatal dysrhythmias (ten in the PGE1 group vs five in the placebo group).
Pulmonary cells are both critical sources and targets of toxic reactive species, with the mechanisms of free radical formation and tissue target reactions poorly understood .NO can contribute to novel pathophysiologic reactions that can occur in lungs. The toxicology of inhaled .NO is poorly and incompletely described, and there is a limited mechanistic understanding of the significant contribution of .NO and O2. to pulmonary pathologic conditions. Finally, antioxidant defense supplementation will be the most effective when the location and nature of toxic species contributing to tissue injury are revealed, and the antioxidants are site-directed.
Zusammenfassung
Die Therapie des pulmonalen Hypertonus ist von großer Bedeutung für die Intensivmedizin. Durch intravenöse Applikation von
Vasodilatatoren wie Prostazyklin können zwar die Drücke im pulmonalen Gefäßbett effektiv gesenkt werden, allerdings kommt
es zeitgleich zu einer Reduktion der hypoxischen pulmonalen Vasokonstriktion mit konsekutiver Einschränkung des Gasaustauschs
sowie zur systemischen Vasodilatation. Die Inhalation von Vasodilatatoren wie Stickstoffmonoxyd (NO) oder Prostazyklin (PGI
2
) dagegen führt zu einer selektiven Vasodilatation in ventilierten Alveolen mit konsekutiver Verbesserung des Gasaustauschs,
ohne daß es bei therapeutischer Dosierung zur systemischen Hypotension kommt. Dies Konzept ist daher auch in der Behandlung
der schweren pulmonalen Gasaustauschstörung von Interesse. Doch sind diesen Therapieverfahren Grenzen gesetzt: NO betreffend
sind es vor allem toxische Nebenwirkungen (MetHb, Stickoxide), während beim PGI
2
Dosierungs- bzw. Applikationsprobleme im Vordergrund stehen. Sowohl tierexperimentell als auch in der klinischen Anwendung
bei Patienten wurden Non-Responder beobachtet, die auf inhaliertes NO oder PGI
2
entweder nur mit einer Reduktion des pulmonalarteriellen Drucks, aber nicht mit einer Veränderung des Gasaustauschs reagieren,
oder aber gar keinen Effekt zeigen. Die genauen pathophysiologischen Grundlagen bleiben dabei noch unklar.
The concept of directly administering potent vasodilatory agents into the lungs via inhalation has been shown, in practice, to be effective in treating patients with pulmonary hypertension or hypoxaemia, or both. Inhaled nitric oxide and, to a lesser extent, aerosolized prostacyclin have been used successfully for this purpose. Their pharmacological profile, cardiopulmonary effects, clinical applications and potential side effects are discussed.
(C) Lippincott-Raven Publishers.
Prostaglandin E1 (PGE1) has been reported to attenuate COPD-related pulmonary hypertension and to slightly lower the arterial oxygen tension (PaO2). In order to infer the involved mechanisms, the effects of intravenous infusion of PGE1 on pulmonary haemodynamics, diffusing lung capacity for CO (DLCO), membrane diffusing capacity (Dm), pulmonary capillary blood volume (Vc), physiological shunt (Qps/Qt), arterial blood gases and other lung functional indices were evaluated in 20 COPD patients with pulmonary hypertension and, excluding right catheterization, in 14 control subjects. The examines were studied at baseline and during infusion of 20–30 ng kg-1min PGE1 or placebo. In control subjects PGE1 only caused systemic arterial pressure decrease (-17.8%). In COPD patients, as expected, PGE1 increased cardiac index (16-2%), but decreased systemic arterial pressure (-21.2%), pulmonary arterial pressure (-27.9%), pulmonary vascular resistance (-45.4%) and PaO2 (-10.4%), worsening their hypoxaemia. However, the effect of PGE1 on DLCO was an increase (11.9%), due to an increase in Vc (15.2%) and less markedly in Dm (4.9%). Physiological and anatomical shunts were increased with PGE1 (20.2% and 14.8%) and the overall ventilation/perfusion ratio decreased from 0.89 to 0.79. Decrements in PaO2 correlated with increments in Qps/Qt (r= 0.86). In conclusion, in COPD patients studied, PGE1 increased DLCO, which compensated for the deleterious effect of increased cardiac output on alveolar-capillary gas equilibration. Therefore, worsening of hypoxaemia during PGE1 infusion was related with increased right-to-left shunt and deterioration of ventilation-perfusion relationship.,
Five scoring systems for predicting the severity and outcome of acute haemorrhagic necrotizing pancreatitis were retrospectively evaluated in 39 patients. The respective scores were Ranson, Imrie, APACHE II, multiple organ failure (MOF) and Sepsis Sensitivity Score (SSS). Twenty-two (56%) of the patients died. The survivors were significantly younger than the non-survivors, 68% of whom died within 3 weeks of admission to the intensive care unit. Stay in the unit was significantly longer in the former group. Sensitivity in prediction of death was best with APACHE II score greater than 9 (96%) and Ranson score greater than or equal to 3 (95%). Of the five scores, MOF greater than or equal to 4 gave the best equilibration between sensitivity (73%) and specificity (76%) and the strongest prediction of lethal outcome (80%). Although the independent factor age had low sensitivity (55%), it showed the highest values for specificity (88%) and prediction of death (86%). APACHE II scoring is concluded to be best for grading the severity of disease on admission to intensive care, while the MOF score is best for monitoring the degree of organ dysfunction and the intensity of supportive treatment.
Nine patients who had developed pulmonary artery hypertension during the adult respiratory distress syndrome (ARDS) were treated with an infusion of prostacyclin (PGI2) (12.5-35.0 ng.kg-1.min-1). Whether PGI2 might decrease the pulmonary capillary pressure (PCP) obtained by analysis of the pulmonary artery occlusion pressure decay curve and improve systemic oxygen delivery was examined. Gas exchange alterations induced by PGI2 were analyzed by using the multiple inert gas elimination technique. PGI2 reduced the pulmonary artery pressure from 35.6 to 28.8 mmHg (P less than 0.001) and the PCP from 22.9 to 19.7 mmHg (P less than 0.01) without changing the contribution of the pulmonary venous resistance to the total pulmonary vascular resistance. The cardiac index increased from 4.2 to 5.7 1.min-1.m-2 (P less than 0.001) due to both increased stroke volume and heart rate. Despite a marked deterioration of ventilation-perfusion (VA/Q) matching with increased true intrapulmonary shunt flow from 28.6% to 38.6% (P less than 0.01) of the cardiac output, the PaO2 was unchanged due to increased mixed venous oxygen content indicated by an augmented mixed venous PO2 (from 37.0 to 41.9 mmHg, P less than 0.01). This caused a 35% (P less than 0.001) increase of the systemic oxygen delivery rate. Thus, short-term infusions of PGI2 reduced PAP and PCP without deleterious effects on arterial oxygenation in patients with ARDS. Hence, PGI2 may be useful to lower pulmonary vascular pressures in patients with ARDS.
Prostaglandin E1 (PGE1) is currently being evaluated in clinical trials to determine its usefulness in the treatment of adult respiratory distress syndrome (ARDS). The drug is administered to ARDS patients by continuous intravenous infusion at dosage rates of up to 30 ng/kg/min for 7 days. The present study was conducted to determine the pulmonary extraction efficiency and pharmacokinetics of PGE1 under these conditions. Plasma levels of PGE1 were determined by high performance liquid chromatography in 14 patients who either had ARDS or were considered to be at risk of developing ARDS following trauma or sepsis. Predose plasma levels of PGE1 were below the detection limit of the assay (50 pg/ml). At a dosage rate of 30 ng/kg/min, pulmonary arterial and systemic arterial plasma levels ranged from 265 to 1,009 pg/ml and 50 to 796 pg/ml, respectively. The pulmonary extraction ratio (Ep) of PGE1 varied from 0.11 to 0.90 and was independent of dose but dependent on cardiac output. The data were adequately described by first-order pharmacokinetic equations which assumed that the lung was the only site of PGE1 clearance. Nine of 10 patients with AaPO2/FlO2 below 510 mm Hg had Ep greater than 0.7 and high pulmonary intrinsic clearance for PGE1 (ca. 250 L/min), but all 4 patients with AaPO2/FlO2 above 510 mm Hg had Ep less than 0.6 and low intrinsic clearance (ca. 37 L/min or less). The intrinsic clearance of the lung for PGE1 in ARDS patients therefore appears to decrease abruptly once a threshold of severe respiratory failure is achieved.
A 7-day infusion of prostaglandin E1 (PGE1), an immunomodulator, was evaluated in a prospective, randomized, placebo-controlled, double-blinded trial in surgical patients with the adult respiratory distress syndrome (ARDS). The drug seemed to improve pulmonary function--only two PGE1 patients died with severe pulmonary failure compared with nine placebo patients (p = 0.01). Survival at 30 days after the end of the infusion--the predetermined end point of the study--was significantly better in the patients given PGE1 (p = 0.03), with 15 of 21 PGE1 patients (71%) alive at this time compared with seven of 20 placebo patients (35%). Improvement in overall survival in the PGE1 patients did not reach statistical significance (p = 0.08). Overall survival in patients initially free of severe organ failure, however, was significantly better in the PGE1 patients (p = 0.03). Of the six PGE1 patients free of severe organ failure at time of entry, all survived to leave the hospital; of the 10 placebo patients initially free of severe organ failure, four survived. The drug had no serious side effects and did not potentiate susceptibility to infection. PGE1 is a promising agent for the treatment of ARDS.
Because experimental lung injury is associated with decreased removal of 3H-prostaglandin E1 (3H-PGE1) and 14C-5-hydroxytryptamine (14C-5-HT), we questioned whether a similar reduction would be evident in patients with the adult respiratory distress syndrome (ARDS). Accordingly, we measured, by indicator dilution techniques, pulmonary removal of 3H-PGE1 and 14C-5-HT in 11 patients undergoing cardiopulmonary bypass surgery in whom respiratory function was essentially normal, and compared them with similar measurements in 9 patients who had ARDS. In addition, we made 5 successive measurements of lung removal functions in the bypass group of patients during the 48-h period after the first measurement. These measurements were made before and 4 times (within 48 h) after the first measurement. Before bypass, removal of 3H-PGE1 and 14C-5-HT was 78 +/- 2 SEM and 89 +/- 2%, respectively; these did not change during the subsequent 48 h. Therefore, we compared prebypass values in this group with measurements made in patients with ARDS. The latter group had significantly decreased removal of 3H-PGE1 and 14C-5-HT (values were 66 +/- 3 and 72 +/- 5%, respectively). We suggest that these changes reflect a diffuse functional injury to the endothelium similar to that seen after acute lung injury in laboratory animals.
To investigate the initial and long-term effect of nitric oxide (NO) inhalation in patients with severe acute respiratory distress syndrome (ARDS).
Retrospective, clinical study.
University surgical ICU.
Eighty-seven patients with severe ARDS.
Thirty of 87 patients with ARDS inhaled low concentrations of NO for more than 48 h in addition to the standard treatment. Initial and long-term effects of NO inhalation on hemodynamics, gas exchange, and methemoglobin formation were determined. Survival of patients treated with inhaled NO was compared with survival in similar patients without NO inhalation.
In 83% of the patients, NO increased the ratio of arterial PO2 to the fraction of inspired O2 (PaO2/FIO2) by > or = 10 mm Hg; in 87%, NO reduced venous admixture (QVA/QT) by > or = 10%, and in 63%, NO decreased mean pulmonary artery pressure (PAP) by > or = 3 mm Hg. Daily short interruption of continuous inhalation of NO for a duration of 17 +/- 2.4 days was consistently associated with a decrease in PaO2/FIO2 by 81 +/- 4 mm Hg (p < 0.001). QVA/QT increased by 8.3 +/- 0.4% (p < 0.001) and PAP by 5.3 +/- 0.3 mm Hg (p < 0.001). Over time, we observed neither tachyphylaxis nor a more pronounced effect of inhaled NO. Methemoglobin increased from 0.74 +/- 0.56% to 0.98 +/- 0.02% (p < 0.001). Survival rates in patients treated with NO did not differ from survival rates in patients not treated with NO.
Beneficial effects of NO inhalation can be observed in most patients with severe ARDS; in some cases, however, it may fail to improve pulmonary gas exchange or to reduce pulmonary hypertension without obvious explanation. To demonstrate a possible increase in survival associated with NO inhalation, large randomized prospective trials are required.
Neutrophils accumulated in the lung are thought to play a pivotal role in the pathogenesis of host auto-injury such as adult respiratory distress syndrome (ARDS). We investigated the effect of prostaglandin E1 (PGE1) on several aspects of human neutrophil function. PGE1 significantly decreased reactive oxygen species (ROS), (O2-, H2O2, OH.) generation by neutrophils as well as neutrophil phagocytosis and chemotaxis. In contrast, the drug did not affect the levels of ROS generated by a cell-free ROS generating system. In addition, intracellular calcium concentrations ([Ca2+]i) in neutrophils stimulated by f-Met-Leu-Phe were decreased in the presence of PGE1. These data suggest that the reduction in ROS production and neutrophil phagocytosis and chemotaxis by PGE1 may contribute to the effectiveness of the drug in host auto-injury including ARDS. The suppression of the increase in [Ca2+]i may at least be responsible for inhibition of these neutrophil functions by PGE1.
We studied the effects of aerosolised prostacyclin (PGI2) in three patients with acute severe adult respiratory distress syndrome. 17-50 ng/kg per min, nebulised into the afferent limb of the ventilator circuit, decreased mean pulmonary artery pressure (SEM) from 40.3 (13.5) to 32.0 (3.8) mm Hg (pulmonary vascular resistance fell by 30%); systemic arterial pressure decreased slightly from 76.8 (2.2) to 74.5 (6.1) mm Hg. Concomitantly, the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen increased from 120 (19) to 173 (18), mainly due to redistribution of blood flow from shunt areas to regions of normal ventilation-perfusion. All effects were reversed on drug withdrawal.
We found that treatment with liposome-entrapped prostaglandin E1 (Lip-PGE1), but not with empty liposomes and/or free PGE1, decreased the leak of intravascularly administered 125I-labeled albumin into lungs of rats given interleukin-1 alpha (IL-1 alpha) intratracheally. Lip-PGE1 treatment also decreased lung myeloperoxidase activity, lung lavage neutrophil increases, and lung histological abnormalities found in rats given IL-1 alpha intratracheally. Interestingly, decreased lung leak and lung neutrophil accumulation occurred when Lip-PGE1 was given intravenously 2.5 h after, but not immediately before, intratracheal IL-1 alpha administration. When Lip-PGE1 treatment was given both before and 2.5 h after IL-1 alpha administration, lung leak was decreased to baseline levels. Lip-PGE1 treatment given 2.5 h after IL-1 alpha administration also decreased lung oxidized glutathione levels, which increased in rats given IL-1 alpha intratracheally. We conclude that postinsult treatment with Lip-PGE1 decreases lung leak, neutrophil recruitment, and oxidative responses in lungs of rats given IL-1 alpha intratracheally.
To evaluate the lowest dose of inhaled nitric oxide (NO) in patients with adult respiratory distress syndrome (ARDS), which is able to improve arterial oxygenation more than 30% compared to baseline data.
Prospective, clinical study.
Anesthesiological ICU in a university hospital.
3 consecutive patients with severe ARDS according to clinical and radiological signs.
Pressure-controlled ventilation with positive end-expiratory pressure of 8-12 cm H2O. Inhalation of NO was performed with a blender system and a Servo 300 ventilator. The lowest effective NO dose was defined by titrating the inspiratory NO dose until reaching a 30% improvement of PaO2/FiO2. This dose was used for the following continuous long-term NO inhalation; controls of efficacy by investigation of hemodynamics and blood gas exchange were performed initially and 2 times per patient after intervals of 3-5 days.
Initial NO concentrations were found to be effective at 60, 100, and 230 parts per billion (ppb). In all measurements, arterial oxygenation was found to be elevated by NO inhalation with the initially evaluated dose compared to baseline data; in parallel, the venous admixture (Qva/Qt) was reduced. The O2 delivery increased, although O2 consumption and hemodynamics did not change. In 1 patient, interruption of NO inhalation caused remarkable increase of pulmonary resistance.
The improvement of oxygenation by NO inhalation in ARDS does not require reduction of pulmonary resistance and can be performed using low doses in the ppb range, which has to be considered as probably non-toxic.
To evaluate the safety and efficacy of liposomal prostaglandin E1 (TLC C-53) in the treatment of patients with the acute respiratory distress syndrome (ARDS).
Randomized, prospective, multicenter, double-blind, placebo-controlled, phase II clinical trial.
Eight community and university-affiliated hospitals in the United States.
Twenty-five patients with ARDS.
Patients were prospectively randomized in an unbalanced ratio within each site to receive either TLC C-53 (n = 17) or placebo (n = 8). Study drug was infused intravenously over 60 mins every 6 hrs for a 7-day period, starting at a dose of 0.15 micrograms/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 micrograms/kg/hr) was attained, intolerance to further increases developed, or invasive monitoring was discontinued. Patients received standard, aggressive, medical/surgical care throughout the trial.
Outcome measurements were Pao2/FI0(2), dynamic pulmonary compliance, ventilator dependence on day 8, and 28-day all-cause mortality rate. At baseline, the distribution of variables describing Lung Injury Scores, Acute Physiology and Chronic Health Evaluation II scores, Pao2/FI0(2), pulmonary compliance, and time from onset of ARDS to first dose of study drug was similar between patients in the TLC C-53 and placebo treatment groups. On day 8, all eight patients given placebo required mechanical ventilation, while eight of 17 patients given TLC C-53 were healthy enough to be removed from the ventilator (p = .03). Improvement in PaO2/FIO2 during the initial 8-day study period was greater in patients receiving TLC C-53. This trend achieved statistical significance on day 3, when the increase in PaO2/FIO2 from baseline was 82.5 +/- 14.6 in the TLC C-53 group compared with 28.3 +/- 22.1 in the placebo group (p = .05). By day 8, lung compliance also increased from baseline significantly more in TLC C-53 patients than in placebo patients (5.7 +/- 1.7 vs -1.5 +/- 1.8 mL/cm H2O; p = .01). The 28-day mortality rate was 6% (1/17 patients) in the TLC C-53 group and 25% (2/8 patients) in the placebo group (p = .23). Drug-related adverse events were reported in 82% of the patients receiving TLC C-53 compared with 38% of the placebo group, with half of the adverse events in the TLC C-53 group being localized infusion site irritation. TLC C-53 was hemodynamically well tolerated, with transient hypotension occurring in three patients.
In patients with ARDS, TLC C-53 was associated with improved oxygenation, increased lung compliance, and decreased ventilator dependency.
Inhaled E-type prostaglandins (PGE) have been shown to modulate responses to both allergic and nonallergic provocation. Misoprostol, a PGE1 analog, was developed as an antiulcer agent because it prevents gastrointestinal ulceration. Little is known about the effect inhaled misoprostol has on the airway and whether its potential antiasthmatic activity would be similar to other PGEs. Nebulizied solutions of misoprostol and PGE2 effectively blocked the acute bronchospasm caused by a subsequent inhaled antigen challenge in actively sensitized guinea pigs. The minimal concentration to result in a significant reduction in specific airway resistance was 3 and 30 micrograms/ml for misoprostol and PGE2, respectively. Exposure to a 300 micrograms/ml nebulized misoprostol solution provided significant protection for 2 h. Eosinophil recovery in bronchoalveolar lavage performed 24 h after antigen challenge was significantly reduced by 72%. In a chronic model of antigen-induced airway inflammation in which guinea pigs are given multiple antigen exposures over a 3-wk period, both misoprostol and its free acid-active metabolite 5C-30695 significantly reduced bronchoalveolar lavage eosinophils by 50 to 55%. Treatment with TRFK5, a monoclonal antibody to interleukin-5, resulted in a 76% decrease in eosinophil recovery. The combination of antibronchoconstrictive and anti-inflammatory effects suggests that inhaled misoprostol may be an effective treatment for the acute and chronic symptoms of asthma.
Inhalation of nitric oxide (NO) and prostacyclin (PGI2) may induce selective pulmonary vasodilation and-by improving ventilation-perfusion ratio in ventilated areas of the lung-increase Pao2 in patients with acute lung injury. To assess the therapeutic efficacy of both compounds, dose-response curves were established in patients with adult respiratory distress syndrome (ARDS). Patients received both PGI2 (doses of 1, 10, and 25 ng/kg/min) and NO (concentrations of 1, 4, and 8 ppm). Cardiorespiratory parameters were assessed at control, at each drug concentration, and after withdrawal of NO and PGI2. PGI2 resulted in a significant, dose-dependent and selective reduction of pulmonary artery pressure (PAP) from 35.1 +/- 6.3 mm Hg at control to 33.1 +/- 4.8 (1 ng/kg/min), 31.3 +/- 4.8 mm Hg (10 ng/kg/min) and 29.6 +/- 4.5 mm Hg (25 ng/kg/min), respectively. Inhaled NO reduced PAP from 34.5 +/- 5.6 to 32.1 +/- 5.9 mm Hg at 4 ppm, and to 31.8 +/- 6.1 mm Hg at 8 ppm, respectively, with no effect at 1 ppm. Pao2/Flo2 ratio increased from 105 +/- 37 to 125 +/- 56 mm Hg (range of increase: 0 to 57 mm Hg) at PGI2 10 ng/kg/min and to 131 +/- 63 mm Hg (range: -5 to 89 mm Hg) at 25 ng/kg/min with no effect at 1 ng/kg/min. NO improved Pao2 (e.g., from 116 +/- 47 to 167 +/- 86 mm Hg at 8 ppm) and reduced intrapulmonary shunt at all doses tested. We conclude that both inhaled PGI2 and NO may induce selective pulmonary vasodilation and increase Pao2 in severe ARDS.