Krishnan Raghavendran's research while affiliated with University of California, Los Angeles and other places

Introduction Low‐ and middle‐income countries (LMICs) account for 90% of deaths due to injury, largely due to hemorrhage. The increased hemorrhage mortality burden in LMICs is exacerbated by absent or ineffective prehospital care. Hemorrhage management (HM) is an essential component of prehospital care in LMICs, yet current practices for prehospital HM and outcomes from first responder HM training have yet to be summarized. Methods This review describes the current literature on prehospital HM and the impact of first responder HM training in LMICs. Articles published between January 2000 and January 2023 were identified using PMC, MEDLINE, and Scopus databases following PRISMA‐ScR guidelines. Inclusion criteria spanned first responder training programs delivering prehospital care for HM. Relevant articles were assessed for quality using the Newcastle‐Ottawa scale. Results Of the initial 994 articles, 20 met inclusion criteria representing 16 countries. Studies included randomized control trials, cohort studies, case control studies, reviews, and epidemiological studies. Basic HM curricula were found in 15 studies and advanced HM curricula were found in six studies. Traumatic hemorrhage was indicated in 17 studies while obstetric hemorrhage was indicated in three studies. First responders indicated HM use in 55%–76% of encounters, the most frequent skill they reported using. Mean improvements in HM knowledge acquisition post‐course ranged from 23 to 58 percentage points following training for pressure and elevation, gauze application, and tourniquet application. Conclusions Our study summarizes the current literature on prehospital HM in LMICs pertaining to epidemiology, interventions, and outcomes. HM resources should be a priority for further development.

Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.

Introduction: Road traffic injuries (RTIs) are the largest individual contributor to the global burden of injury and were among the five leading causes of global disability-adjusted life years (DALYs) in 2016. In regions with limited emergency medical services, training lay first responders (LFRs) has been shown to increase availability of prehospital care for RTIs, but sustainable mechanisms to scale these programs remain unstudied. Method: Using a training of trainers (TOT) model, a six-hour LFR training program was launched in Lagos, Nigeria. The course was taught in a hybrid fashion with primary didactics over Zoom and practical in-person breakout sessions. Thirty TOTs proceeded to train 350 transportation providers as LFRs over one month. A previously validated, 23 question, pre-/post- assessment was administered digitally to assess knowledge acquisition. Participants responded to five-point Likert survey assessing instruction quality and post-course confidence. Results: TOTs scored a median of 56.5% (IQR: 43.5%, 71.7%) and 91.3% (IQR: 88.0%, 95.7%) on the pre- and post-assessments, respectively, with bleeding control scores increasing most (+69.4%). Course trainees scored a median of 34.8% (IQR: 26.0%, 43.5%) and 73.9% (IQR: 65.2%, 82.6%) on the pre- and post-assessments, respectively, with airway and breathing increasing most (+48.6%). All score increases were statistically significant with p<0.001 and did not differ by trainer. Participants rated confidence 5/5 (IQR: 5,5) in first aid skills and 5/5 (IQR: 4,5) in emergency transportation, increasing from pre-course confidences of 3/5 (IQR: 3,4) and 4/5 (IQR: 3,5), respectively (p<0.001). Participants rated the quality of education content and TOT instructors to be 5/5 (IQR:5,5). Conclusion: This is the first time the efficacy of digital instruction for first responder trainers in LMICs has been investigated and demonstrates knowledge acquisition equivalent to that of prior in-person courses. Future work will examine the cost-effectiveness of the training of LFRs and the effect of LFRs on trauma outcomes.

If not properly managed, acute lung injuries, either through direct or indirect causes, have the potential to present serious risk for many patients worldwide. One of the mechanisms for the transition from acute lung injury (ALI) to the more serious acute respiratory distress syndrome (ARDS) is the deactivation of the native lung surfactant by injury-induced infiltrates to the alveolar space. Currently, there are no surfactant replacement therapies that are used to treat ALI and subsequent ARDS. In this paper, we present an indepth efficacy study of using a novel polymer lung surfactant (PLS, composed of poly(styrene-block-ethylene glycol) (PS-PEG) block copolymer micelles), which has unique properties compared to other tested surfactant replacements, in two different mouse models of lung injury. The results demonstrate that pharyngeal administration of PLS after the instillation of either acid (HCl) or lipopolysaccharide (LPS) can decrease the severity of lung injury as measured by multiple injury markers.

Hypoxia-inducible factors (HIFs) are a family of nuclear transcription factors that serve as the master regulator of the adaptive response to hypoxia. In the lung, HIFs orchestrate multiple inflammatory pathways and signaling. They have been reported to have a major role in the initiation and progression of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, and pulmonary hypertension. Although there seems to be a clear mechanistic role for both HIF 1α and 2α in pulmonary vascular diseases including PH, a successful translation into a definitive therapeutic modality has not been accomplished to date.

Hypoxia-inducible factors (HIFs) are transcription factors critical for the adaptive response to hypoxia. There is also an essential link between hypoxia and inflammation, and HIFs have been implicated in the dysregulated immune response to various insults. Despite the prevalence of hypoxia in tissue trauma, especially involving the lungs, there remains a dearth of studies investigating the role of HIFs in clinically relevant injury models. Here, we summarize the effects of HIF-1α on the vasculature, metabolism, inflammation, and apoptosis in the lungs and review the role of HIFs in direct lung injuries, including lung contusion, acid aspiration, pneumonia, and COVID-19. We present data that implicates HIF-1α in the context of arguments both in favor and against its role as adaptive or injurious in the propagation of the acute inflammatory response in lung injuries. Finally, we discuss the potential for pharmacological modulation of HIFs as a new class of therapeutics in the modern intensive care unit.