In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm ...delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury.
Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the ...development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.
Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been ...undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.
Anatomic assessment of the medial upper arm to identify potential sites for insertion of the etonogestrel (ENG) implant.
Forty female cadaveric arms were dissected. Two rows of 1×2-cm dissection ...windows were created in the inner arm overlying the triceps approximately 2–3 and 4–5 cm posterior to the bicipital sulcus (sulcus). The primary window was 8–10 cm proximal to the medial epicondyle and approximately 2–3 cm posterior to the sulcus. Neurovascular structures within each window were identified. The entire medial upper arm was dissected to visualize underlying structures.
Mean age (± SD) of cadavers at death was 72.0±11.0 years. Arm measurements at the primary window were circumference 28.2±4.8 cm range: 21–41, skin thickness 0.6±0.2 mm 0.3–1.0 and subcutaneous tissue thickness: 12.3±4.9 mm 4.7–21. The basilic vein and the medial brachial cutaneous, ulnar and medial antebrachial cutaneous nerves were located in 40%, 58%, 40% and 18% of the primary windows, respectively. No major neurovascular structures were located 3–5 cm posterior to the sulcus. More neurovascular structures were identified overlying the biceps than triceps. Elbow flexion with the hand underneath the head displaced the ulnar nerve anteriorly towards the sulcus.
As no major neurovascular structures were identified overlying the triceps 8–10 cm proximal to the medial epicondyle and 3–5 cm posterior to the sulcus, ENG implant insertion at this location may minimize risk of injury associated with improper deep insertion. Elbow flexion deflects the ulnar nerve away from this area and may further decrease risk of injury secondary to inadvertent deep insertion.
Although a limited cadaver study, this anatomic assessment provides rationale for insertion of the ENG implant overlying the triceps 8–10 cm proximal to the medial epicondyle and 3–5 cm posterior to the sulcus. This area is theoretically safer for insertion of the ENG implant than areas of the inner arm where major neurovascular structures are commonly located.
Abstract Objective The objective was to monitor the effectiveness of the etonogestrel implant clinical training program through a voluntary active monitoring program (AMP). Study design US health ...care providers underwent mandatory training by the manufacturer on etonogestrel implant insertion, localization and removal. After training, health care providers could enroll in a voluntary AMP to provide outcome data to meet a postmarketing commitment of the manufacturer with the US Food and Drug Administration (FDA). Those who volunteered completed and faxed forms to the manufacturer after implant insertion and removal detailing the procedure and device-related outcomes, including insertion-, localization- or removal-associated events. Experts reviewed outcome data quarterly, which the Sponsor then reported to the FDA. Results Among 42,337 health care providers completing the training program, 4294 (10.1%) volunteered to participate in the AMP. The 26,198 forms submitted over 6.4 years included more insertion ( n =20,497) forms than removal forms ( n =5701). The volunteers reported 646 events on 566 (2.2%) forms related to insertion ( n =197), localization ( n =34), removal ( n =357) and “other” ( n =58). Clinically important events included noninsertion ( n =4), serum etonogestrel positive but implant not found ( n =1), and possible nerve ( n =66) or vascular ( n =5) injury. The reports did not include any insertion-, localization- or removal-associated hospitalizations. Eight (0.14%) removal reports described referral for surgical implant removal. Conclusion Events related to insertion, localization or removal of the etonogestrel implant are uncommon among US providers who received mandatory training in the use of the implant. Implications This report presents results from the first mandatory US contraceptive training program. Health care providers volunteered to report information about etonogestrel implant insertion, localization and removal. Although the data do not demonstrate whether a mandatory program improves outcomes, they elucidate the utility and real-life experience that clinical training programs can provide.
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