Cardiopulmonary Resuscitation and Rewarming from Accidental Hypothermia

This thesis springs from 3 different papers: Paper 1 A randomised controlled study in rats to investigate whether an infusion of crystalloids or colloids during rewarming from hypothermia could alleviate the alterations in cardiovascular function seen in untreated control animals. Paper 2 A randomised controlled study in pigs, examining normothermic vs hypothermic cardiopulmonary resuscitation (CPR). Our central hypothesis was that the cardiac output (CO) generated by CPR would not be affected by hypothermia, thereby replacing a larger portion of native CO at a reduced temperature. This, in turn, would provide sufficient oxygen delivery to sustain aerobic metabolism in organs during 3 hours of CPR at 27°C. Paper 3 The effects of extracorporeal membrane oxygenation (ECMO) rewarming to restore oxygen delivery and organ blood flow were explored. Pigs were cooled to 27°C, underwent 3 hours of hypothermic CPR and subsequent rewarming by ECMO. Main results and conclusions Volume substitution improved hemodynamic function during rewarming from hypothermia and mitigated post-hypothermic cardiac dysfunction. We saw a sustained hemodynamic effect in rats treated with dextran vs crystalloid solution. The treated animals displayed reduced levels of intracellular calcium (Ca2+) in cardiac tissue compared to controls. Maintaining euvolemia with intravenous fluids during rewarming from hypothermia diminished the cardiac dysfunction seen in untreated controls. CO and mean arterial pressure (MAP) generated by CPR were not affected by hypothermia. Three hours of continuous resuscitation at 27°C provided limited but sufficient oxygen delivery to allow aerobic metabolism. In contrast, the normothermic animals displayed deteriorated hemodynamic function and significantly reduced organ blood flow after 45 minutes of CPR. These findings encourage early and continuous CPR in victims of accidental hypothermia. Rewarming pigs by ECMO after 3 hours of CPR at 27°C restored CO, MAP, the oxygen extraction ratios (O2ER), and blood flow to heart, left temporal lobe, cerebellum, stomach and small intestine. After ECMO rewarming, the favourable prognostic markers of survival after cardiac arrest were present in all animals: moderately increased lactate levels, return of pH to physiologic levels, and a shockable heart rhythm. These factors may be attributed to the protective effects of hypothermia during prolonged CPR, but they also support the critical role of ECMO in rewarming victims of accidental hypothermia

Maintaining intravenous volume mitigates hypothermia-induced myocardial dysfunction and accumulation of intracellular Ca2+

Previous research exploring pathophysiological mechanisms underlying circulatory collapse after rewarming victims of severe accidental hypothermia has documented post-hypothermic cardiac dysfunction and hypothermia-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) in myocardial cells. The aim of the present study was to examine if maintaining euvolaemia during rewarming mitigates cardiac dysfunction and/or normalizes elevated myocardial [Ca2+]i. A total of 21 male Wistar rats (300 g) were surface cooled to 15◦C, then maintained at 15◦C for 4 h, and subsequently rewarmed to 37◦C. The rats were randomly assigned to one of three groups: (1) non-intervention control (n = 7), (2) dextran treated (i.v. 12 ml/kg dextran 70; n = 7), or (3) crystalloid treated (24 ml/kg 0.9% i.v. saline; n = 7). Infusions occurred during the first 30 min of rewarming. Arterial blood pressure, stroke volume (SV), cardiac output (CO), contractility (dP/dtmax) and blood gas changes were measured. Post-hypothermic changes in [Ca2+]i were measured using the method of radiolabelled Ca2+ ( 45Ca2+). Untreated controls displayed post-hypothermic cardiac dysfunction with significantly reduced CO, SV and dP/dtmax. In contrast, rats receiving crystalloid or dextran treatment showed a return to pre-hypothermic control levels of CO and SV after rewarming, with the dextran group displaying significantly better amelioration of post-hypothermic cardiac dysfunction than the crystalloid group. Compared to the post-hypothermic increase in myocardial [Ca2+]i in non-treated controls, [Ca2+]i values with crystalloid and dextran did not increase to the same extent after rewarming. Volume replacement with crystalloid or dextran during rewarming abolishes posthypothermic cardiac dysfunction, and partially mitigates the hypothermia-induced elevation of [Ca2+]i

Autoregulation of Cerebral Blood Flow During 3-h Continuous Cardiopulmonary Resuscitation at 27°C

Introduction: Victims of accidental hypothermia in hypothermic cardiac arrest (HCA) may survive with favorable neurologic outcome if early and continuous prehospital cardiopulmonary resuscitation (CPR) is started and continued during evacuation and transport. The efficacy of cerebral autoregulation during hypothermic CPR is largely unknown and is aim of the present experiment. Methods: Anesthetized pigs (n = 8) were surface cooled to HCA at 27°C before 3 h continuous CPR. Central hemodynamics, cerebral O2 delivery (DO2) and uptake (VO2), cerebral blood flow (CBF), and cerebral perfusion pressure (CPP) were determined before cooling, at 32°C and at 27°C, then at 15 min after the start of CPR, and hourly thereafter. To estimate cerebral autoregulation, the static autoregulatory index (sARI), and the CBF/VO2 ratio were determined. Results: After the initial 15-min period of CPR at 27°C, cardiac output (CO) and mean arterial pressure (MAP) were reduced significantly when compared to corresponding values during spontaneous circulation at 27°C (−66.7% and −44.4%, respectively), and remained reduced during the subsequent 3-h period of CPR. During the first 2-h period of CPR at 27°C, blood flow in five different brain areas remained unchanged when compared to the level during spontaneous circulation at 27°C, but after 3 h of CPR blood flow in 2 of the 5 areas was significantly reduced. Cooling to 27°C reduced cerebral DO2 by 67.3% and VO2 by 84.4%. Cerebral VO2 was significantly reduced first after 3 h of CPR. Cerebral DO2 remained unaltered compared to corresponding levels measured during spontaneous circulation at 27°C. Cerebral autoregulation was preserved (sARI > 0.4), at least during the first 2 h of CPR. Interestingly, the CBF/VO2 ratio during spontaneous circulation at 27°C indicated the presence of an affluent cerebral DO2, whereas after CPR, the CBF/VO2 ratio returned to the level of spontaneous circulation at 38°C. Conclusion: Despite a reduced CO, continuous CPR for 3 h at 27°C provided sufficient cerebral DO2 to maintain aerobic metabolism and to preserve cerebral autoregulation during the first 2-h period of CPR. This new information supports early start and continued CPR in accidental hypothermia patients during rescue and transportation for in hospital rewarming

Rewarming With Closed Thoracic Lavage Following 3-h CPR at 27°C Failed to Reestablish a Perfusing Rhythm

Introduction: Previously, we showed that the cardiopulmonary resuscitation (CPR) for hypothermic cardiac arrest (HCA) maintained cardiac output (CO) and mean arterial pressure (MAP) to the same reduced level during normothermia (38°C) vs. hypothermia (27°C). In addition, at 27°C, the CPR for 3-h provided global O2 delivery (DO2) to support aerobic metabolism. The present study investigated if rewarming with closed thoracic lavage induces a perfusing rhythm after 3-h continuous CPR at 27°C. Materials and Methods: Eight male pigs were anesthetized, and immersion-cooled. At 27°C, HCA was electrically induced, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed by combining closed thoracic lavage and continued CPR. Organ blood flow was measured using microspheres. Results: After cooling with spontaneous circulation to 27°C, MAP and CO were initially reduced by 37 and 58% from baseline, respectively. By 15 min after the onset of CPR, MAP, and CO were further reduced by 58 and 77% from baseline, respectively, which remained unchanged throughout the rest of the 3-h period of CPR. During CPR at 27°C, DO2 and O2 extraction rate (VO2) fell to critically low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. During rewarming with closed thoracic lavage, all animals displayed ventricular fibrillation, but only one animal could be electro-converted to restore a short-lived perfusing rhythm. Rewarming ended in circulatory collapse in all the animals at 38°C. Conclusion: The CPR for 3-h at 27°C managed to sustain lower levels of CO and MAP sufficient to support global DO2. Rewarming accidental hypothermia patients following prolonged CPR for HCA with closed thoracic lavage is not an alternative to rewarming by extra-corporeal life support as these patients are often in need of massive cardio-pulmonary support during as well as after rewarming

CLET: Computation of Latencies in Event-related potential Triggers using photodiode on virtual reality apparatuses

To investigate event-related activity in human brain dynamics as measured with EEG, triggers must be incorporated to indicate the onset of events in the experimental protocol. Such triggers allow for the extraction of ERP, i.e., systematic electrophysiological responses to internal or external stimuli that must be extracted from the ongoing oscillatory activity by averaging several trials containing similar events. Due to the technical setup with separate hardware sending and recording triggers, the recorded data commonly involves latency differences between the transmitted and received triggers. The computation of these latencies is critical for shifting the epochs with respect to the triggers sent. Otherwise, timing differences can lead to a misinterpretation of the resulting ERPs. This study presents a methodical approach for the CLET using a photodiode on a non-immersive VR (i.e., LED screen) and an immersive VR (i.e., HMD). Two sets of algorithms are proposed to analyze the photodiode data. The experiment designed for this study involved the synchronization of EEG, EMG, PPG, photodiode sensors, and ten 3D MoCap cameras with a VR presentation platform (Unity). The average latency computed for LED screen data for a set of white and black stimuli was 121.98 ± 8.71 ms and 121.66 ± 8.80 ms, respectively. In contrast, the average latency computed for HMD data for the white and black stimuli sets was 82.80 ± 7.63 ms and 69.82 ± 5.52 ms. The codes for CLET and analysis, along with datasets, tables, and a tutorial video for using the codes, have been made publicly available

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362