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Lars J Bjertnaes,1,2 Anton Hauge,3 Marianne Thoresen,3,4 Lars Walløe3 1Anesthesia and Critical Care Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, N-9037, Norway; 2Department of Intensive Care Medicine, University Hospital of North Norway, Tromsø, N- 9017, Norway; 3Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, 0317, Norway; 4Translational Health Sciences, University of Bristol, Bristol, UKCorrespondence: Lars J BjertnaesAnesthesia and Critical Care Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, N-9037, NorwayTel +47 77627001Fax +47 77626042Email lars.bjertnaes@uit.noBackground: Successful cardiopulmonary resuscitation after drowning or avalanche is often attributed to hypothermia-induced decrease in metabolism, which adapts the oxygen demand to the amount supplied under cardiac compression. Four decades ago, we speculated if oxygen-sparing mechanisms like those found in marine mammals, may improve cerebral oxygenation during acute airway blockade in humans. We investigated hemodynamic changes during steady state ergometer cycling with intermittent periods of apnea and face immersion (AFI) in ice-cold water. During AFI, heart rate (HR) dropped by 58% whereas average blood velocity (ABV) determined by means of a Doppler ultrasound velocity meter (UNIDOP University of Oslo, Oslo, Norway) fell by 85% in the radial artery and rose by 67% in the vertebral artery. Similar changes occured in radial artery ABV, albeit more slowly, when the test subject only held his breath while cycling. When he breathed via a snorkel during face immersion, HR remained unchanged while radial artery ABV fell transiently and subsequently returned to its pre-immersion level. These findings later were confirmed by other investigators. Moreover, a recent study revealed that the seal even has a system for selective brain cooling during the dive.Conclusion: Our research has confirmed prioritized cerebral circulation during AFI in cold water. We hypothesize that these changes may improve brain oxygenation due both to greater blood flow and possibly also to faster brain cooling, as demonstrated in diving seals.Keywords: apnea, breath-hold, cardiopulmonary resuscitation, diving response, hypothermia

Medical records from maternity clinics in three Norwegian cities, Oslo, Bergen and Trondheim, have been used to study the relationship between lactation and post-partum amenorrhoea during the period 1860–1964. Resumption of menses after a period of post-partum amenorrhoea has been examined separately during lactation, after cessation of lactation, and in the absence of lactation, in 5250 cases. During ongoing lactation the median duration of post-partum amenorrhoea was found by survival analysis to be 12 months for women who had given birth before 1900 and 6 months for women who had given birth after 1900. In a Cox regression analysis, age of menarche and parity were found to influence the duration of post-partum amenorrhoea, in addition to the child's birth year. With a later age of menarche there was longer amenorrhoea, and primiparae resumed menses earlier than multiparae. After cessation of breast-feeding the median duration of amenorrhoea was 1 month, the only variable significantly influencing it being the age of menarche, a younger age showing a shorter duration. In the absence of lactation the survivor function started to decline after 3–4 weeks, and had a half-life of 2 months.None of the variables indicating the woman's social condition seemed to influence the duration of amenorrhoea. The decline in the duration of post-partum amenorrhoea during ongoing lactation from 1860 until today is therefore probably caused by a changed breast-feeding pattern rather than by improved nutrition for women giving birth. [ABSTRACT FROM PUBLISHER]

Various methods of assessing infant chemoreceptor responses have been reported in the literature. However, equipment dead space, trigeminal stimulation and inherent respiratory variability may have affected the results. A method is presented which attempts to reduce the effect of these factors and thereby isolate the chemoreceptor response. Inspiratory gas was delivered into a lightweight face mask with a pliable rim, minimal dead space and a connected pneumotachograph. Ventilatory data were computed breath by breath. Computer-controlled electromagnetic valves allowed instantaneous switching between air and different gas mixtures, repeated in a randomized sequence. In 18 healthy term neonates, the mask increased ventilation by 12% (95% confidence interval 6-18%), measured by calibrated strain-gauge bands. The effect on respiratory frequency and tidal volume differed significantly between sleep states. Neonates were challenged with short-lasting hyperoxia, mild hypoxia, rebreathing and mild hypercapnia. Coherent averaging of several ventilatory responses from each sleep state reduced the variability while maintaining a high time-resolution. [ABSTRACT FROM AUTHOR]

Background: Hypothermia is neuroprotective after neonatal hypoxic-ischaemic brain injury. However, systemic cooling to hypothermic temperatures is a stressor and may reduce neuroprotection in awake pigs. We compared two experiments of global hypoxic-ischaemic injury in newborn pigs, in which one group received propofol-remifentanil and the other remained awake during post-insult hypothermia treatment., Methods: In both studies, newborn pigs were anaesthetised using halothane during a 45-min global hypoxic-ischaemic insult induced by reducing F io 2 and graded hypotension until a low-voltage <7 μV electroencephalogram was achieved. On reoxygenation, the pigs were randomly allocated to receive 24 h of normothermia or hypothermia. In the first study ( n =18) anaesthesia was discontinued and the pigs' tracheas were extubated. In the second study ( n =14) anaesthesia was continued using propofol and remifentanil. Brain injury was assessed after 72 h by classical global histopathology, Purkinje cell count, and apoptotic cell counts in the hippocampus and cerebellum., Results: Global injury was nearly 10-fold greater in the awake group compared with the anaesthetised group ( P =0.021). Hypothermia was neuroprotective in the anaesthetised pigs but not the awake pigs. In the hippocampus, the density of cleaved caspase-3-positive cells was increased in awake compared with anaesthetised pigs in normothermia. In the cerebellum, Purkinje cell density was reduced in the awake pigs irrespective of treatment, and the number of cleaved caspase-3-positive Purkinje cells was greatly increased in hypothermic awake pigs. We detected no difference in cleaved caspase-3 in the granular cell layer or microglial reactivity across the groups., Conclusions: Our study provides novel insights into the significance of anaesthesia/sedation during hypothermia for achieving optimal neuroprotection., (© 2024 The Authors.)

We study the effect of hypothermia (HT) following hypoxic-ischaemic (HI) brain injury in postnatal day 7 (P7) rats. In 2015, new European Union animal transport regulations prompted a change in practice at the breeding facility, which henceforth crossfostered P3 litters to P8 older lactating dams prior to transportation. It is generally assumed that crossfostering does not significantly affect the experimental results. The aim of this study was to examine whether crossfostering affects our model consistency by modifying injury susceptibility and hypothermic neuroprotection. We analysed 219 pups from 11 experiments conducted between 2013 and 2015: 73 non-crossfostered and 146 crossfostered pups. At P7, all pups underwent unilateral common carotid artery ligation followed by 50 min of hypoxia (8% O2, 36°C). Immediately after this mild insult, the pups were randomized to post-insult normothermia or HT treatment. Pups were culled at P14. Injury was assessed by area loss of the ipsilateral hemisphere and histopathology scoring of the hippocampus, cortex, thalamus, and basal ganglia. Crossfostered pups had double the injury compared to non-crossfostered pups irrespective of the treatment group. Hypothermic neuroprotection was statistically significant, but with a smaller and less consistent effect in crossfostered pups (relative neuroprotection 16% vs. 31% in non-crossfostered). These results demonstrate hypothermic neuroprotection following a mild HI insult. A representative subset of 41 animals was also assessed for evidence of microglial reactivity; however, no detectable difference in microglial reactivity was observed between any of the groups. In conclusion, crossfostering alters outcomes in our established model through reduced insult tolerance and variable neuroprotection. Crossfostering as a common breeding practice is a largely unexplored variable in animal research that may result in invalid research conclusions if inadequately adjusted for by larger group sizes. As a result, crossfostering is likely to be inconsistent with the principles of replacement, reduction, and refinement., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Hypothermia-treated and intubated infants with moderate or severe hypoxic-ischemic encephalopathy (HIE) usually receive morphine for sedation and analgesia (SA) during therapeutic hypothermia (TH) and endotracheal ventilation. Altered drug pharmacokinetics in this population increases the risk of drug accumulation. Opioids are neurotoxic in preterm infants. In term infants undergoing TH, the long-term effects of morphine exposure are unknown. We examined the effect of opioid administration during TH on neurodevelopmental outcome and time to extubation after sedation ended., Methods: In this prospectively collected population-based cohort of 282 infants with HIE treated with TH (2007-2017), the cumulative opioid dose of morphine and equipotent fentanyl (10-60 µg/kg/h) administered during the first week of life was calculated. Clinical outcomes and concomitant medications were also collected. Of 258 survivors, 229 underwent Bayley-3 neurodevelopmental assessments of cognition, language and motor function at 18-24 months. Multivariate stepwise linear regression analysis was used to examine the relation between cumulative opioid dose and Bayley-3 scores. Three severity-groups (mild-moderate-severe) were stratified by early (<6 h) amplitude-integrated electroencephalography (aEEG) patterns., Findings: The cumulative dose of opioid administered as SA during TH was median (IQR) 2121 µg/kg (1343, 2741). Time to extubation was independent of SA dose ( p  > 0.2). There was no significant association between cumulative SA dose and any of the Bayley-3 domains when analysing the entire cohort or any of the aEEG severity groups., Interpretation: Higher cumulative opioid doses in TH-treated infants with HIE was not associated with worse Bayley-3 scores at 18-24 months of age., Funding: The Bristol cooling program was funded by the Children's Medical Research Charity SPARKS managing donations for our research from the UK and US, the UK Moulton Foundation, the Lærdal Foundation for Acute Medicine in Norway and the Norwegian Research Council (JKG)., Competing Interests: AF reports personal fees as a scientific consultant for Takeda Pharmaceuticals unrelated to this work. All other authors have nothing to declare., (© 2021 The Authors.)

Background: Binary prediction-models for outcome [death, cognition, presence and severity of cerebral palsy (CP)], using MRI and early clinical data applicable for individual outcome prediction have not been developed., Methods: From Dec 1 st 2006 until Dec 31 st 2013, we recruited 178 infants into a population-based cohort with moderate or severe hypoxic-ischaemic encephalopathy (HIE) including postnatal collapse (PNC, n  = 12) and additional diagnoses ( n  = 12) using CoolCap/TOBY-trial entry-criteria including depressed amplitude-integrated EEG (aEEG). Early clinical/biochemical variables and MRI scans (median day 8) were obtained in 168 infants. Injury severity was scored for cortex, basal ganglia/thalami (BGT), white matter (WM) and posterior limb of the internal capsule, summating to a total injury score (TIS, range 0-11). Outcome was categorized as adverse or favourable at 18-24 months from Bayley-III domains (cut-off 85) and neurological examination including CP classification., Findings: HIE and entry-aEEG severity were stable throughout the study. Outcome was favourable in 133/178 infants and adverse in 45/178: 17 died, 28 had low Cognition/Language scores, (including 9 with severe CP and 6 mild); seven had mild CP with favourable cognitive outcome. WMxBGT product scores and TIS were strong outcome predictors, and prediction improved when clinical/biochemical variables were added in binary logistic regression. The Positive Predictive Value for adverse outcome was 88%, increasing to 95% after excluding infants with PNC and additional diagnoses. Using WMxBGT in the regression predicted 8 of the 9 children with severe CP., Interpretation: Binary logistic regression with WMxBGT or TIS and clinical variables gave excellent outcome prediction being 12% better than single variable cross-tabulation. Our MRI scoring and regression models are readily accessible and deserve investigation in other cohorts for group and individual prediction., Funding: We thank the National Health Service (NHS) and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Lærdal Foundation for Acute Medicine and charitable donations for their support for cooling therapy., Competing Interests: M Karlsson declares patents Method of Determining Hypoxia and Testing System for Determining Hypoxia Induced Cellular Damage. All other authors have nothing to disclose., (© 2021 The Authors.)

Therapeutic hypothermia (HT) is standard care for term infants with hypoxic-ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we report a meta-analysis of data from every experiment in a single laboratory, including pilot data, examining the effect of HT in the Vannucci model. Across 21 experiments using 106 litters, median (95% CI) hemispheric area loss was 50.1% (46.0-51.9%; n = 305) in the normothermia group, and 41.3% (35.1-44.9%; n = 317) in the HT group, with a bimodal injury distribution. Median neuroprotection by HT was 17.6% (6.8-28.3%), including in severe injury, but was highly-variable across experiments. Neuroprotection was significant in females (p < 0.001), with a non-significant benefit in males (p = 0.07). Animals representing the median injury in each group within each litter (n = 277, 44.5%) were also analysed using formal neuropathology, which showed neuroprotection by HT throughout the brain, particularly in females. Our results suggest an inherent variability and sex-dependence of the neuroprotective response to HT, with the majority of studies in the Vannucci model vastly underpowered to detect true treatment effects due to the distribution of injury.

Plague has a long history on the European continent, with evidence of the disease dating back to the Stone Age. Plague epidemics in Europe during the First and Second Pandemics, including the Black Death, are infamous for their widespread mortality and lasting social and economic impact. Yet, Europe still experienced plague outbreaks during the Third Pandemic, which began in China and spread globally at the end of the nineteenth century. The digitization of international records of notifiable diseases, including plague, has enabled us to retrace the introductions of the disease to Europe from the earliest reported cases in 1899, to its disappearance in the 1940s. Using supplemental literature, we summarize the potential sources of plague in Europe and the transmission of the disease, including the role of rats. Finally, we discuss the international efforts aimed at prevention and intervention measures, namely improved hygiene and sanitation, that ultimately led to the disappearance of plague in Europe.