Toxicity of prolonged high dose inhaled PGE1 in ventilated neonatal pigs

Sood, Beena G.; Dawe, Elizabeth J.; Maddipati, Krishna Rao; Malian, Monica; Chen, Xinguang; Galli, Robert; Rabah, Raja

doi:10.1016/j.pupt.2008.01.011

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Sections were analyzed by an observer blinded to the treatment and the strain of the animals. The extent and the severity of parenchyma infiltration with inflammatory cells and fibrosis were analyzed using a scoring system adapted from the literature (20). Scores were assigned to edema (perivascular, peribronchial, alveolar), infiltration of inflammatory cells (perivascular, peribronchial, parenchymal) and fibrosis, following the classification: none (score 0), slight (score 1), moderate (score 2), marked (score 3), and severe (score 4).…”

Section: Methodsmentioning

confidence: 99%

Bleomycin‐induced lung injury in mice investigated by MRI: Model assessment for target analysis

Babin

Cannet

Gérard

et al. 2011

Magnetic Resonance in Med

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Magnetic resonance imaging (MRI) has been used to follow the course of bleomycin-induced lung injury in mice and to investigate two knockout mouse lines with the aim of providing potential therapeutic targets. Bleomycin (0.25 mg/kg) was administered intranasally six times, once a day. MRI was carried out on spontaneously breathing animals up to day 70 after bleomycin. Neither cardiac nor respiratory gating was applied during image acquisition. A long lasting response following bleomycin has been detected by MRI in the lungs of male C57BL/6 mice. Histology showed that, from day 14-70 after bleomycin, fibrosis was the predominant component of the injury. Female C57BL/6 mice displayed a smaller response than males. Bleomycin-induced injury was significantly more pronounced in C57BL/6 than in Balb/C mice. MRI and histology demonstrated a protection against bleomycin insult in female heterozygous and male homozygous cancer Osaka thyroid kinase knockout animals. In contrast, no protection was seen in cadherin-11 knockout animals. In summary, MRI can quantify, in spontaneously breathing mice, bleomycin-induced lung injury. With the ability for repetitive measurements in the same animal, the technique is attractive for in vivo target analysis and compound profiling in this murine model. Magn Reson Med 67:499-509,

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Section: Methodsmentioning

confidence: 99%

Bleomycin‐induced lung injury in mice investigated by MRI: Model assessment for target analysis

Babin

Cannet

Gérard

et al. 2011

Magnetic Resonance in Med

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“…The study protocol was complex and difficult to master for investigative teams. At the time of inception of this study, the MiniHeart low flow jet nebulizers were the only FDA approved nebulizers available for use in neonates; preliminary data were obtained using the MiniHeart nebulizer [ 26 , 12 , 34 – 38 ] and consequently the protocol allowed the use of MiniHeart nebulizers only in this study. Since then, ultrasonic and vibrating mesh nebulizers have been developed and are increasingly being used clinically [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

Sood

Keszler

Garg

et al. 2014

Trials

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BackgroundInhaled 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.MethodsTwo 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.ResultsNo 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.ConclusionsThese 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.govPilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011.Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.

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“…However, although they survive hyperoxic environments, altricial neonates show abnormal alveolarisation and pulmonary vascular development (Frank 1991). These factors may be important in prolonged administration of high O 2 concentrations to companion animals in the intensive care setting; laboratory animal studies of lung structure or function; prolonged surgical or experimental procedures involving anaesthesia, where O 2 -induced lung damage may increase morbidity, and extended pharmacological studies involving aerosolised medications (Sood and others 2008). Protective strategies for hyperoxic situations at least in rats include pre-exposure to high FiO 2 , treatment with bacterial endotoxin or antioxidant enzymes or rest periods in lower oxygen environments (Frank 1991).…”

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confidence: 99%

Reducing the oxygen concentration of gases delivered from anaesthetic machines unadapted for medical air

et al. 2011

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High fractional concentrations of inspired oxygen (FiO 2 ) delivered over prolonged periods produce characteristic histological changes in the lungs and airway of exposed animals. Modern medical anaesthetic machines are adapted to deliver medical air (FiO 2 =0.21) for the purpose of reducing FiO 2 ; anaesthetic machines designed for the veterinary market have not been so adapted. Two inexpensive modifications that allow medical air to be added to the gas flow from veterinary anaesthetic machines are described. The advantages and disadvantages of each modification are discussed.HIGH oxygen (O 2 ) concentrations are toxic to dogs (Cimons and others 1966, Clarke and others 1973), cats (Lambertsen and others 1953) and laboratory animal species (Frank and others 1978), including pigs (Yam and Roberts 1980), when delivered over prolonged periods (Smith 1899) or under hyperbaric conditions. They also increase the risk of combustion or explosion during surgery involving high-energy devices (Wolf and others 2004). Oxygen toxicity, which may be fatal, is characterised by adverse neurological signs, for example, seizures and pulmonary signs (atalectasis, pulmonary capillary congestion, interstitial oedema, haemorrhage) that appears to be dependent on age and species. Younger animals have a variable response to high inspired fractional O 2 concentrations (FiO 2 ): precocial neonates such as guinea pigs respond in a similar fashion to adults, but rat, mouse and rabbit neonates appear to be resistant (Frank and others 1978); the same is true for piglets (Yam and Roberts 1980). However, although they survive hyperoxic environments, altricial neonates show abnormal alveolarisation and pulmonary vascular development (Frank 1991). These factors may be important in prolonged administration of high O 2 concentrations to companion animals in the intensive care setting; laboratory animal studies of lung structure or function; prolonged surgical or experimental procedures involving anaesthesia, where O 2 -induced lung damage may increase morbidity, and extendedCorrespondence: e.clutton@ed.ac.uk. Provenance not commissioned; externally peer reviewed Europe PMC Funders Group

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Toxicity of prolonged high dose inhaled PGE1 in ventilated neonatal pigs

Cited by 7 publications

References 45 publications

Bleomycin‐induced lung injury in mice investigated by MRI: Model assessment for target analysis

Bleomycin‐induced lung injury in mice investigated by MRI: Model assessment for target analysis

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

Reducing the oxygen concentration of gases delivered from anaesthetic machines unadapted for medical air

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