New Findings What is the topic of this review?Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non‐modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight?Cardiovascular stress tests performed in preterm‐born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. Abstract Preterm‐born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro‐ and micro‐physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later‐life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex‐matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N2O (ISO+ N2O: 0.8% +70%), in this randomized cross‐over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO2), and thermal (Tre and Tsk) measures were recorded continuously throughout anesthesia. Blood gas measures pre‐ and post‐ anesthesia were performed. Incorporation of 70% N2O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N2O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia‐induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N2O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia.

Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period.Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% β-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR.Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term.Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.

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Key points Traumatic haemorrhagic shock carries significant morbidity and mortality related to the severity and duration of tissue hypoperfusion, much of which occurs in the pre‐hospital environment where therapy must be easy to use and would augment, not replace, local haemorrhage control measures. Vasopressor therapy use in haemorrhagic shock remains controversial. Potential benefits from improved blood pressure and tissue perfusion need to be weighed against possible harm from increased blood loss if haemorrhage is uncontrolled. We demonstrate that 20 IU I.M. vasopressin produces a progressive, sustained and clinically significant increase in blood pressure and carotid blood flow compared to 1 mg I.M. adrenaline or placebo in an animal model of controlled haemorrhagic shock. I.M. vasopressin may play a role in the early management of haemorrhagic shock by improving cerebral perfusion and haemodynamic stability; however, further studies are required to establish the potential benefit against the risk of exacerbating haemorrhage, if it is uncontrolled. Abstract Haemorrhagic shock causes significant morbidity and mortality. Novel pre‐hospital therapy to improve haemodynamic stability and cerebral perfusion may improve outcomes but remains controversial. In an ovine model of controlled haemorrhagic shock, the effects of early intramuscular arginine vasopressin (AVP), adrenaline or placebo on haemodynamic stability and cerebral perfusion were compared. Carotid pressure and flow catheters were placed in healthy, anaesthetized adult ewes. Frontal cortex cerebral oxygenation was measured using near infrared spectroscopy. Controlled, rapid, haemorrhage (∼30% estimated blood volume) was induced. Five minutes post‐bleed a 1 ml intramuscular dose of 0.9% saline, adrenaline 1 mg or AVP 20 IU was administered. Carotid blood pressure and flow improved significantly in the AVP group over the first 30 min post‐intervention. To emulate standard trauma care, 1 L of 0.9% saline was infused 30 min post‐bleed followed by re‐transfusion of the sheep's own blood at 60 min post‐bleed. Carotid blood pressure and flow in the AVP group remained significantly higher post‐crystalloid infusion, but this difference was lost post‐blood transfusion. Data were analysed by two‐way ANOVA with time, group as the main factors. When compared to saline or adrenaline, a single dose of intramuscular AVP resulted in a progressive and sustained increase in carotid artery blood pressure and flow with commensurate increase in cerebral oxygenation. Intramuscular AVP has potential as an emergency pre‐hospital therapy following exsanguinating haemorrhage; however, further studies are required to investigate whether the benefit of improved perfusion pressure outweighs the risks of exacerbating ongoing bleeding.