Comparable significant associations were also found for whole-image vascular-density, for foveal vascular-density significant associations were found with pulse wave velocity and estimated glomerular filtration rate only. Our results indicate that retinal capillary rarefaction is associated with arterial stiffness and impaired kidney function. Retinal capillary rarefaction may represent a useful and simple test to assess the integrated burden of hypertension on the microvasculature irrespective of current blood pressure levels.Microvascular disease and rarefaction are key pathological hallmarks of hypertension. The retina uniquely allows direct, non-invasive investigation of the microvasculature. Recently developed optical coherence tomography angiography now allows investigation of the fine retinal capillaries, which may provide a superior marker of overall vascular damage. This was a prospective cross-sectional study to collect retinal capillary density data on 300 normal eyes from 150 hypertensive adults, and to investigate possible associations with other organ damage markers. The average age of participants was 54 years and there was a greater proportion of males  than females. Multivariate, confounder adjusted linear regression showed that retinal capillary rarefaction in the parafovea was associated with increased pulse wave velocity ( It significantly increases the risks of stroke, coronary heart disease, heart failure and kidney disease and is a major cause of premature death worldwide. Microvascular disease and rarefaction are key pathological hallmarks of hypertension2. Subtle damage to organs such as the heart, kidney, eye and the peripheral vasculature can be detected early in the disease process and may help to prevent clinical events. Diagnostic assessment of hypertension mediated organ damage (HMOD) allows better prediction of cardiovascular (CV) risk5, identifying high-risk individuals for whom a more intense treatment is needed. Successful treatment can provide significant reductions in risk of subsequent CV disease7.Hypertension has been identified as one of the most significant risk factors for global morbidity and mortality8. Hypertensive retinopathy progresses through various stages beginning with general arteriolar narrowing and subsequently focal areas of arteriolar narrowing, opacification of arteriolar walls, arteriovenous nipping, hemorrhages, hard exudates and cotton-wool spots. Signs of hypertensive retinopathy are predictive of incident stroke, congestive heart failure, and CV mortality—independent of traditional risk factors16. Even the earliest stage of hypertensive retinopathy- general arterial narrowing, is associated with stroke18, kidney disease20 and CV mortality22. Digital fundus photography can detect these retinal changes, but cannot resolve the finer retinal capillaries, which are more representative of the entire microvascular network and may provide the earliest markers of ischemia/hypoxia, before arteriolar and venular changes occur. Early detection of hypertensive damage is important to prevent further degeneration and recent evidence suggests that retinal neurodegeneration is already evident in individuals with mildly elevated blood pressure (BP) levels23.The retina uniquely allows direct, non-invasive investigation of the microvasculature, providing a valuable window into the microvascular sequelae of hypertension. Assessment of retinal damage due to hypertension (hypertensive retinopathy) is recommended in clinical guidelines for the management of patients with hypertension24 and uncontrolled hypertension25, while another study reported restoration of normal capillary density after treatment with carotid angioplasty and stenting26.Optical coherence tomographic angiography (OCT-A) is a more recent ocular imaging technology that permits fast, non-invasive assessment of the retinal capillaries and blood flow in the retina see Fig. . ImportaThis study aimed to further investigate retinal capillary changes with respect to BP and HMOD measures related to vascular stiffness and kidney function. Kidney function was assessed using urinary albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR), and arterial stiffness was assessed using carotid-femoral pulse wave velocity (PWV).The clinical characteristics of the study population are shown in Table 27, resulting in 48 participants with diabetes in the cohort, and data on diabetes unavailable for 7% of the full cohort.Of the entire cohort, 46 had T2D and 1 had type 1 diabetes. Data on HbA1c was available for 76% of the cohort and was utilised to categorise a further n = 2 participants (with missing diabetes history) as having diabetes (based on HbA1c > 6.5%)2 which placed them into the obese range. The average 24 h ambulatory BP was 135/81 mmHg.The cohort had an average BMI of 32.1 kg/mP < 0.0001 to P = 0.006) and logACR (P = 0.0001 to P = 0.02), and with reduced eGFR (P < 0.0001 to P = 0.005). These results remained statistically significant after multiple testing adjustment.Capillary density was calculated for 3 zones of interest, each centered on the fovea see Fig. . The assExamples of superficial macular OCT-A images are provided in Fig. P = 0.0003 to P = 0.007). Retinal capillary density was not directly associated with ambulatory systolic BP; however, it was associated with diastolic BP for the parafovea and whole image (P = 0.01). Retinal capillary rarefaction in the parafovea and whole image was associated with the diagnosis of T2D (P = 0.002 and P = 0.004 respectively). Retinal capillary rarefaction was associated with higher HbA1c in all 3 zones of interest (P = 0.01 to P = 0.005). The statistically significant results remained significant after multiple testing adjustment.Group comparison for eGFR < 60 (reference eGFR ≥ 60) supported the association with retinal capillary rarefaction (P = 0.08). The eGFR group comparisons were also robust to similar adjustment in the parafoveal and whole image zones, but not the foveal zone (P = 0.1). The statistically significant results remained significant after multiple testing adjustment.The linear associations between retinal capillary rarefaction and measures of HMOD were robust to adjustment for age, sex, SBP, DBP and T2D , hence we fitted an additional multivariate model adjusting for age, sex, SBP, DBP and HbA1c instead of diabetes. This did not change the outcomes considerably, as summarized in Table These findings indicate that retinal capillary rarefaction in SVP is associated with arterial stiffness as measured by PWV, and impaired kidney function as measured by eGFR and ACR, independent of age, sex, diabetes and best practice BP measures.The results from our study indicate that microvascular changes in the eye as assessed by retinal capillary density using OCT-A, are clearly associated with other well-established markers of HMOD including arterial stiffness as measured by PWV, and impaired kidney function as assessed both by eGFR and ACR. Importantly, in the context, these associations were independent of age, sex, diabetes and ambulatory BP measures. Retinal capillary rarefaction may therefore represent a useful and simple test to assess the integrated burden of hypertension on the microvasculature irrespective of current BP levels and therefore add substantially to risk stratification of hypertensive patients. Furthermore, future research will have to investigate whether longitudinal assessment and the corresponding changes in the retina may serve as an indicator of adequate/inadequate antihypertensive treatment.25. The Chua study found an association between BP and foveal density at the deep vascular plexus (DVP). It did not investigate PWV but found an association between foveal density and eGFR, similar to our result but only statistically significant for the DVP, not SVP. Findings from our study in a larger cohort of patients suggests that the association between eGFR and foveal density holds also for the SVP  and provides the first evidence that PWV is associated with retinal capillary density. There was agreement between the studies on the lack of association at the SVP layer between foveal density and 24 h ambulatory BP. However, in extending the zones of interest we found associations between retinal capillary density and DBP in the parafovea and whole image. We provide evidence therefore that hypertension may similarly affect both SVP and DVP layers, akin to other systemic disorders such as diabetes24.A recent similar small study applying OCT-A in non-diabetic hypertensive patients of Asian ethnicity was reported by Chua et al.28, along with retinal microvascular changes in pre-diabetes29. Our results provide further evidence of retinal capillary rarefaction in diabetes (in parafovea and whole image) and indicate a linear relationship between HbA1c and capillary density in all 3 zones of interest.Retinal capillary rarefaction has previously been reported in diabetes30. Current guidelines by the European Society of Hypertension state that a measured PWV larger than 10 m/s can be considered an independent marker of HMOD8. Interestingly, our study suggests that the fine retinal capillaries may also provide some information about the health of the large arteries, such as the aorta, as assessed by PVW. However, this is based on correlation analysis only and will require further substantiation. Nevertheless, the association of retinal capillary density with markers of both micro- and macro-vascular damage indicates that this measure may represent an attractive approach to better understand and quantify the overall/integrated burden of elevated BP over prolonged periods of time on susceptible vascular structures and provide superior assessment of HMOD with potential therapeutic implications.A previous study found increased PWV was associated with wider retinal venular caliber in the Atherosclerosis Risk in Communities Study23.The capillaries are more representative of the entire microvascular network and may provide the earliest markers of ischemia/hypoxia, before arteriolar and venular changes occur. Early detection of hypertensive damage is important to both CV risk stratification and to prevent further retinal degeneration. Indeed, recent evidence suggests that retinal neurodegeneration is already evident in individuals with only mildly elevated BP31, hence it is possible that retinal capillary rarefaction reflects similar changes in the kidney in hypertension. The results are consistent with previously published associations between retinal arteriolar narrowing and kidney function33 or kidney disease34. Future research will be needed to determine if retinal capillary rarefaction, compared to arteriolar narrowing, can provide an earlier or more accurate marker of hypertensive damage including kidney dysfunction.Retinal capillary rarefaction was independently associated with impaired kidney function (reduced eGFR and logACR). The retinal and renal circulations exhibit shared characteristics in terms of anatomy and physiology8, or multiple markers for a single organ in the case of the kidney (eGFR and ACR), because CV risk increases for each extra sign of HMOD35. Future longitudinal research is required to establish whether retinal OCT-A markers improve CV risk stratification over existing markers, or provide an easier method compared to less accessible or more costly tests.As OCT-A is non-invasive, accessible and relatively low cost, it could be a very useful and simple addition to the routine diagnostic workup of hypertensive patients in the future. Current guidelines recommend screening for HMOD in multiple organsAssociations between retinal capillary density and measures of HMOD were substantially stronger than those with best practice BP measures, i.e. ambulatory BP, in this treated hypertension cohort. This was true for univariate and adjusted models. Indeed, for the fovea region there was no association between retinal capillary density and BP. Hence, we hypothesize that the correlations between retinal density and measures of HMOD reflect cumulative damage due to previous BP burden.Even ABPM, while superior in predicting CV outcomes, is only a snapshot of the BP profile at a specific point in time. It does not necessarily inform about longer term BP control and prevention of further progression or even regression of HMOD. OCT-A imaging could potentially fill this gap and provide an integrative marker for previous BP burden, similar to the use of HbA1c in assessing control of glucose metabolism over the previous ~ 3 months in patients with diabetes. An integrated measure of the BP burden on both the micro-and macro-vasculature may be most useful to improve individual management of hypertension and potentially to monitor treatment effects. This, however, will have to be addressed in appropriately designed longitudinal studies.36. A different retinal imaging modality, laser doppler flowmetry, has also been used to demonstrate reduced retinal capillary density in hypertensive patients37, along with increased retinal vascular resistance38. Hence it is possible that atherosclerotic processes that reduce blood flow are the mechanism by which retinal capillary rarefaction occurs in hypertension. Of note, foveal vascular density is anatomically influenced by the foveal avascular zone which can lead to increased variability of density estimates. Therefore, results of the para-foveal density and whole image density may be more robust.The OCT-A measures of retinal capillary density are based on optical changes due to blood flow; if blood flow drops below the detection threshold, the capillary will not be identified and the measured density will be reducedThe recent development of OCT-A technology, permitting fast, non-invasive assessment of the retinal capillaries and blood flow, is now being utilized extensively for clinical research in many disorders including ocular disease. Our results add to the evidence of retinal capillary changes due to hypertension, highlighting that clinical researchers exploring OCT-A in ocular diseases should either exclude or adjust for systemic disorders such as hypertension and diabetes.The strengths of this study include a well phenotyped cohort including ambulatory BP monitoring, PWV and kidney function (eGFR and ACR). The results from this cross-sectional study warrant further investigation with longitudinal studies. One limitation of the study was the inclusion of patients on different medications and different stages of hypertension, however this reflects a real-world hypertensive cohort. Additionally, the duration of hypertension was not exactly known, and the associations do not prove causality.39. As with other target organ damage in hypertension, recognition of the effects on the retinal capillaries could allow clinicians to better manage hypertensive patients. OCT-A is a practical, non-invasive tool for investigation of the retinal capillaries which may mirror other HMOD such as microvascular rarefaction in the kidney and stiffening of large arteries. As such, assessment of retinal capillary density may have clinically relevant advantages in that it may represent a superior marker of overall vascular damage (both micro- and macrovascular) and may serve as a stand-alone and powerful integrated measure of HMOD irrespective of the current BP level.We have demonstrated a relationship between retinal capillary density and both macro- (PWV) and micro-vascular (eGFR and ACR) parameters in adults with treated arterial hypertension. Assessment of the microcirculation is crucial to the understanding of the effects of systemic diseases such as hypertension and diabetesn = 150 participants for the current analysis. The study was approved by the East Metropolitan Health Service Ethics and Governance Committees . The research followed the tenets of the Declaration of Helsinki for research involving human subjects. Informed consent was obtained from all subjects.We conducted a prospective cross-sectional study including 155 participants with arterial hypertension from the Dobney Hypertension Centre at the Royal Perth Hospital, Perth, Australia. Patients aged 18 years or older underwent OCT-A imaging between February 2016 to October 2019. All images were evaluated by an eye specialist, participants with retinal disease  or previous retinal surgery (n = 5) were excluded, leaving 41. A thorough medical history was obtained from all patients and a routine physical examination was performed. Secondary causes of hypertension were investigated where clinically indicated. Patients with identified secondary hypertension were not included in this analysis. Office BP measurements were obtained according to unattended automated office BP principles and the average of three measurements recorded.Patients were referred to the Dobney Hypertension Centre for management of hypertension predominantly from primary care physicians. Clinical diagnosis for hypertension was based on current European guidelinesAll participants were fitted with an ambulatory BP monitor by a trained research nurse. The devices  were programmed to take 4 measurements per hour during the day (6:00 – 22:00 h) and 2 per hour during the night (22:00–6:00 h). Arm circumferences were measured and appropriate cuffs were chosen according to Spacelabs product specifications and the first reading was performed in the presence of research staff.42. The distance in between the sites where the pulse was recorded was measured by trained study nurses or doctors before the measurement. The capturing time for PWV assessment was set to 10 s with a PWV distance and subtraction method. The PWV assessments was performed twice and their average used for further analysis. For analysis purposes, an additional parameter “BP control status” was defined as poorly controlled if mean ambulatory systolic blood pressure (SBP) > 140 mmHg, or diastolic blood pressure (DBP) > 90 mmHg.Pulse wave velocity (PWV) measurements were carried out with SphygmoCor® XCEL system . Standard procedures of the manufacturer were followed to obtain the parameters. Participants were asked to attend fasted on the morning of the assessment and to abstain from smoking, caffeine and alcohol consumption 12 h before the assessment and not to take their usual BP medication. Participants were instructed to take their regular BP medication after the assessment of PWV and retinal imaging, which was usually carried out in the morning (before 12:00 h). The PWV was performed after a 5-min rest period in supine position. Parallel assessment of pulse in thigh with specialized cuffs and a mechanical sensor held against the neck of the participants allowed calculation of PWVBlood samples and mid-stream urine were obtained from participants within 4–6 weeks prior to retinal imaging. If participants had already obtained the required pathology results within 3 months prior to retinal imaging these results were used for analysis.43 in mL/min/1.73 m2) and ACR (Albumin/Creatinine ratio in mg/mmol creatinine) fasting glucose and HbA1c.Pathology tests included serum creatinine, spot urine albumin and calculation of eGFR  segmented into four retinal depths: the superficial retinal plexus (SVP), the deep retinal plexus (DVP), the outer retina and the choriocapillaris  device . Non-invasive OCT-A technology uses laser reflectance of the surface of flowing red blood cells to accurately depict vessels in the retina, including fine capillaries, without the traditional need for intravascular dyesris Fig. . The retThe OCT-A device was used to collect macular scans with a 6 mm × 6 mm field of view. AngioVue software (version 2016.1.0.26) automatically provided segmentation of the SVP and calculated the percentage image area occupied by blood vessels with flowing erythrocytes in the selected region; the superficial retinal capillary density.A trained grader blinded to the participant characteristics reviewed the quality of all OCT-A scans. Poor quality scans were excluded from the analysis if they exhibited segmentation failure or image artifacts due to optical or residual motion.For this study, capillary density at SVP was measured in macula region, in a 6 mm square region centered on the fovea. The SVP includes the vasculature between the internal limiting membrane and 10 µm above the inner plexiform layer. Capillary density was calculated for 3 regions of interest, each centered on the fovea see Fig. ; the whoBaseline demographic and clinical characteristics were reported as absolute numbers and relative proportions in percent for categorical data and mean and standard deviation (SD) for continuous data.P < 0.0001). Hence, we utilised the inter-eye variability by considering each eye as the unit of analysis, providing greater statistical power. The GLM analyses were modified according to the generalized estimating equation (GEE) approach46. The GEE provides increased precision of estimation results while accounting for the correlation between fellow eyes. Benjamini and Hochberg47 multiple testing adjustment  was applied to the retinal capillary density results .To test for associations between retinal capillary density and HMOD parameters, generalized linear modelling (GLM) was utilized, with retinal capillary density as the dependent variable. We found a moderate positive correlation between right and left eye data on retinal density  and T2D; only covariates with 2, as values above 90 mL/min/1.73 m2 are less accurate. To avoid introducing bias in the linear regressions, participants with normal eGFR were excluded from this particular analysis. Additionally, parameters of renal damage were also used as categorical, independent variables for linear regression models with main retinal vascular outcome markers as dependent variables to test for group differences. Logarithmically transformed ACR was used for linear regressions.Data for eGFR were not numerically provided above 90 mL/min/1.73 mStatistical significance was defined as p < 0.05.48.All statistical analyses were conducted in the R statistical environment


Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine.The study consisted of 100 patients with drug-refractory AF  who underwent ablation therapy  as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 μg × 5 min). The effects were observed, and the therapeutic strategy was evaluated.Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients.We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable. A large body of evidence establishes catheter ablation as an effective treatment for atrial fibrillation (AF); and thus, it is currently the first-line treatment for AF –3. HowevThe objectives of this study were to elucidate dormant conduction after PV isolation (PVI), confirm PV arrhythmia substrate, induce non-PV foci, and observe the acute efficacy of high dose isoproterenol (ISP) loading in addition to adenosine.Subjects consisted of 100 consecutive patients with drug-refractory AF  who underwent ablation therapy  as the first-time therapy at Tosei General Hospital between June 2019 and January 2020.This was a prospective single-center observational study. All patients provided written informed consent for the ablation procedure and enrollment in our ablation registry. This study was conducted after obtaining the approval of the hospital Institutional Review Board.Patients with the following risk factors for ISP administration were excluded: hypertrophic cardiomyopathy, severe aortic stenosis, severe coronary artery disease, and an ISP allergy.Bearing in mind five-times the half-life of antiarrhythmic drugs, their administration was discontinued before the ablation procedure. Cases with left atrial thrombus were detected by measuring coagulation markers, esophageal echocardiography, or contrast CT scans and were excluded. The administration of all oral anticoagulants  was continued throughout the ablation procedure.The ablation procedure was performed under sedation using propofol and dexmedetomidine. A bolus dose of heparin was administered after puncturing the inguinal and left subclavian vein to maintain the activated coagulation time (ACT) level during the ablation procedure at a minimum of 300 s. A 20-pole catheter was inserted into the coronary sinus (CS) via the left subclavian vein for cardiac defibrillation, and the superior vena cava (SVC), right atrial (RA), and CS potentials were also obtained. A trans-septal puncture was performed using an intracardiac catheter ultrasound. A 20-pole ring electrode catheter was then inserted via an SL0 sheath (Abbott) and either a THERMOCOOL SMARTTOUCH SF Catheter (Johnson & Johnson) or a TactiCath SE irrigation catheter (Abbott) was inserted via a steerable sheath  and installed in the left atrium (LA). Cardioversion was performed in patients with persistent atrial fibrillation immediately prior to ablation. Catheter ablation was performed using a 3D mapping system .The ablation therapy protocol is shown in Fig. Following PVI, adenosine was administered to reveal the sites of dormant conduction. Adenosine was not used in asthmatic patients. In patients who underwent a simultaneous separation of the PV, electrodes were attached to both sides of the PV and 30 mg of adenosine was administered, whereas, in those who underwent an individual separation or cryoablation, 30 mg of adenosine was injected into the superior and inferior PV. In cases where dormant conduction occurred continuously as a result of adenosine, additional ablation procedures were performed. The results of the additional ablation procedure were then confirmed by administering an additional 30 mg of adenosine. In cases where the administration of adenosine did not reveal the dormant conduction or in those in whom the dormant conduction was temporary, ISP was administered.A high dose of ISP was administered at a rate of 6 μg/min for 5 min. This dose was determined based on our experience in several patients at the pre-study stage that revealed no worsening of circulatory dynamics at this dose. An additional electric current was applied to patients in whom dormant conduction was revealed following the administration of ISP.In all cases, the additional ablation led to the formation of continuous ablation focal points in the region surrounding the site of re-conduction. The results obtained from our check of the PV arrhythmia substrates were categorized as no response, elevated automaticity, three consecutive firings, and continuous firing.Non-PV foci are defined as premature atrial contractions associated with AF induction. They either induce atrial tachycardia or repeat frequently. In patients in whom non-PV foci were induced, we mapped the origin and performed an additional ablation. In some cases, in addition to the above-mentioned induction by drug administration, we also conducted investigations by performing high-frequency atrial pacing and, when necessary, defibrillation, in cases of atrial fibrillation.After administering ISP, observations made during the 15 min duration of action helped to determine the following: in cases where an obvious PV arrhythmia substrate was confirmed and non-PV foci were not confirmed, the procedure was concluded after performing only PVI. However, in those with a long-lasting persistence of AF for at least 1 year and in whom neither PV arrhythmia substrate nor non-PV foci could be confirmed, left atrial linear ablation was additionally performed. The site where the line was created was determined by the operator taking into consideration the patient’s disease history.The continuous data were expressed as mean ± standard deviation for the normally distributed variables and as median [25th and 75th percentiles] for the non-normally distributed ones.The background characteristics of the 100 patients are shown in Table The details of the ablation procedures performed are shown in Table The results obtained using adenosine and ISP are shown in Tables An example of a case of dormant conduction is shown in Fig. The results of arrhythmogenic foci are shown in Table A patient with arrhythmogenicity of the pulmonary vein is shown in Fig. The additional ablation of the non-PV foci induced by ISP administration was performed in 23 patients. The details of the 24 patients with non-PV foci, including those in whom SVC firing was induced using adenosine, are shown in Table Figure AF occurs in conjunction with supraventricular extrasystoles. Many premature contractions originate in the PV, and ablation targeting the premature contractions leads to the disappearance of AF . Many caThe non-recurrence rate of paroxysmal AF in cases after PVI is around 80% –18 and tAdenosine is used to confirm the presence of post-PVI reconduction. Adenosine administration shows PV dormant conduction; and thus, it allows for the identification of PVs that are at risk of reconduction , 21. HowIn the present study, our objectives were to elucidate post-PVI dormant conduction, confirm PV arrhythmia substrates, and induce non-PV foci. This was done by administering a high dose of ISP in addition to adenosine and then observing their effects during the acute stage.The shortening of the action potential duration and the refractory period by ISP administration is considered to be the factors that cause dormant conduction . As mostSome reports have confirmed the effects of adenosine and ISP on the search for arrhythmogenic foci. It is reported that adenosine induces AF triggers especially from RA and SVC, but the clinical significance of these foci is questionable , 25. On In this study, we confirmed the acute effect of ISP in patients who underwent AF ablation. ISP acts on the beta-receptors of the sympathetic nerves, thereby increasing the heart rate and promoting conduction. As a result, the automaticity of the heart is promoted, resulting in a high degree of excitation of arrhythmia substrates and the occurrence of premature contractions. Thus, attempts have been made to utilize these effects during catheter ablation. A dose of 6 μg/min was administered for 5 min, and this was uniform across all patients in the study. Although the administration caused an elevation in heart rate and a decrease in blood pressure, none of the patients experienced any effects on their circulatory dynamics or adverse effects at the dose utilized in our study. The effects of administering ISP disappeared approximately 15 min after administration was completed, useful observations were made in many patients during this period and no major postoperative problems were observed.There are two significant results we would like to emphasize in this study. First, the temporary dormant conduction confirmed by adenosine was all sustained by the administration of ISP. Secondly, we were able to confirm the arrhythmic substrate of PVs after PVI. Based on the result of this study, we believe that ISP plays an extremely important role in cases of atrial fibrillation ablation. But it should be noted that the effects of ISP are not inclusive of all the effects of adenosine. There were cases where useful findings were observed in patients who were administered with adenosine only. Therefore, ISP should not be considered as a substitute for adenosine but as a complement to it.This study had several limitations. First, the number of patients was small because it was a prospective study conducted at a single institution. Regarding this, the accumulation of cases is required in the future. Second, the order of administration of adenosine and ISP may be a limitation. The half-life of adenosine was shorter than that of ISP, and adenosine was used first. Therefore, the order of administration may have affected the results of our study. Third, although the positions of dormant conduction observed in the multipolar catheter were the same by adenosine and ISP administration, it could not be said that they coincided with each other. Lastly, in this study, the effectiveness was confirmed in the acute stage. However, an identification of the long-term prognosis will require further study.In this study, ISP was used following a PVI in order to identify dormant conduction and arrhythmogenic foci. The results showed that ISP was effective in the acute stage. The dormant conduction that occurred as a result of ISP administration was persistent, which is useful when ablation is performed. Our results also suggest that it is useful in confirming PV arrhythmia substrates and inducing non-PV foci. However, these effects may have been a result of adjunct therapy of ISP with adenosine; and therefore, we believe that the combined use of the two drugs is a useful approach. Further studies evaluating the long-term prognosis of this intervention in AF ablation must be performed.


The receiver operating characteristic curve analysis showed an area under the curve (AUC) of 0.835 (p < 0.0001) for distinguishing CKD stage 1 from other CKD stages at 974 ppb . The AUC was 0.831 (p < 0.0001) for distinguishing between patients with/without eGFR < 60 mL/min/1.73 m2 . At 886 ppb, the sensitivity increased to 80% but the specificity decreased to 69%. This value is suitable for kidney function screening. Breath ammonia detection with V-OSC is a real time, inexpensive, and easy to administer measurement device for screening CKD with reliable diagnostic accuracy.Chronic kidney disease (CKD) is a public health problem and its prevalence has increased worldwide; patients are commonly unaware of the condition. The present study aimed to investigate whether exhaled breath ammonia via vertical-channel organic semiconductor (V-OSC) sensor measurement could be used for rapid CKD screening. We enrolled 121 CKD stage 1–5 patients, including 19 stage 1 patients, 26 stage 2 patients, 38 stage 3 patients, 21 stage 4 patients, and 17 stage 5 patients, from July 2019 to January 2020. Demographic and laboratory data were recorded. The exhaled ammonia was collected and rapidly measured by the V-OSC sensor to correlate with kidney function. Results showed no significant difference in age, sex, body weight, hemoglobin, albumin level, and comorbidities in different CKD stage patients. Correlation analysis demonstrated a good correlation between breath ammonia and blood urea nitrogen levels, serum creatinine levels, and estimated glomerular filtration rate (eGFR). Breath ammonia concentration was significantly elevated with increased CKD stage compared with the previous stage (CKD stage 1/2/3/4/5: 636 ± 94; 1020 ± 120; 1943 ± 326; 4421 ± 1042; 12781 ± 1807 ppb,  Chronic kidney disease (CKD) has become an emerging public health problem and a major economic and social burden. The prevalence is estimated to be as high as 11%–13% in the general population, and it is associated with increased cardiovascular diseases and mortality compared to non-CKD population ,3. EarlyThe glomerular filtration rate (GFR) requires collection of 24-h urine creatinine amount, and quantification of serum creatinine remains the golden standard to measure kidney function, but this method is inconvenient and time-consuming. Laboratory measurement of serum creatinine with conversion to the estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) levels are commonly used to monitor kidney function, but this requires a blood sample and it is not real-time monitoring. As a novel coronavirus, SARS-CoV-2, causes a highly contagious infection and serious acute respiration disease, which requires quarantine of the public, a biomarker that well correlates with eGFR and can be easily used for CKD screening and monitoring outside the hospital would be useful.Several exhaled components have been investigated to replace blood tests for rapid monitoring of kidney function ,7. One oThe breath ammonia detection can be detected by several kinds of methods ,19,20,21Although good correlations between breath ammonia and BUN have been demonstrated in hemodialysis patients ,12,20,262 and kidney damages), stage 2 , stage 3 , stage 4  and stage 5 (<15 mL/min/1.73 m2). The demographic characteristics and comorbidities including diabetes, hypertension, congestive heart failure (CHF) and coronary artery disease (CAD) were recorded. Results of laboratory tests including hemoglobin, albumin, BUN, and serum creatinine were collected for analysis. The eGFR was calculated using the Modification of Diet in Renal Disease Study equation. Administered medicine including steroids, angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (ACEi/ARB) and proton pump inhibitor (PPI) were also recorded. All patients provided a written informed consent to participate in this study. Ethics approval was obtained from the Medial Ethics Committee of Linkou Chang Gung Memorial Hospital on 21 June 2018. (IRB number 201800857B0).We enrolled different CKD stages patients in our outpatient clinic of nephrology department from July 2019 to January 2020. One hundred and twenty-one CKD patients including 19 stage 1 patients, 26 stage 2 patients, 38 stage 3 patients, 21 stage 4 patients, and 17 stage 5 patients were enrolled in this study. We excluded patients less than 20 years old. We also excluded the patients with cirrhosis or liver dysfunction, with active gastrointestinal bleeding, with active infection, and with cancer under active treatment. Patients with admission to hospital within one month were also excluded. The CKD categories and the severity of reduced GFR were defined according to the CKD classification of Kidney Disease Outcome and Quality Initiative (K/DOQI) as stage 1  using a short straw through their mouth. The breath sample in the first bag was soon transferred into a second bag by passing through a desiccation cylinder (that was filled with sodium hydroxide [NaOH]. particles) within 3–5 s. Then, the second plastic bag was immediately connected to the inlet of the Gas Measurement System. It is noted that, when pressing the breath sample through the NaOH tube, NaOH particles also trap a small amount of ammonia. This might cause ammonia concentration deviation in low concentration regime. The gas measurement system used in our previous reports was used in this study ,27,29. At-test. For comparisons among five CKD groups, continuous variables were analyzed using a one-way analysis of variance (ANOVA), while categorical variables were compared using the chi-square test  curve analysis. The correlation analysis used Spearman’s correlation coefficient. Values of p < 0.05 were considered to be statistically significant.Continuous variables are presented as the mean ± standard errors and categorical variables are expressed as the number (%). For comparisons of breath ammonia concentrations between two CKD stages, variables were analyzed using the Student’s are test . p-value2, respectively. Demographics and laboratory measurements are summarized in p < 0.001). There was no difference in sex or body weight in the different CKD stage groups. Comorbidities including CHF, CAD, and diabetes did not differ between the groups. The proportion of hypertension, which is a common complication in CKD patients, was significantly higher in the CKD stage 2–5 group compared with the CKD stage 1 group (p = 0.010). Hemoglobin and albumin levels were not different in these CKD groups. As expected, BUN levels that were increased in all CKD patients were proportionally increased with CKD progression. The serum albumin level was not different between the groups.One hundred twenty-one patients with different CKD stages were divided into five groups according to their CKD stages (1–5). Among these patients, 19 patients (15.7%) were CKD stage 1, 26 (21.5%) were stage 2, 38 (31.4%) were stage 3, 21 (17.4%) were stage 4, and 17 (14.0%) were stage 5. The mean eGFR was 116 ± 5.7, 75 ± 1.4, 48 ± 1.3, 20 ± 1.0 and 9 ± 0.6 mL/min/1.73 mSteroids that increase protein catabolism and subsequently facilitate BUN production were used only in a few patients and the difference in steroid use was similar between the groups. The use of PPIs that suppress gastric acid secretion and reduce exhaled ammonia was not different in the groups.p = 0.442).ACEi and ARB can protect against CKD progression but may temporarily reduce kidney function and cause hyperkalemia, especially in patients with advanced CKD ,31. The R = 0.723, p < 0.0001)  A. SimilaR = 0.735, p < 0.0001; R = −0.535, p < 0.0001; We further determined the correlation between breath ammonia and kidney function. Breath ammonia concentrations were strongly correlated with serum creatinine levels . The pH value in each stage was significantly higher than that in previous stage and Our previous study demonstrated a simultaneous increase of breath ammonia and salivary pH in advanced CKD patients . To assep < 0.0001). The cutoff value of 974 ppb had a best predictive value to distinguish between CKD stage 1 and other CKD stages, with a sensitivity of 69%, a specificity of 95%, a positive predictive value (PPV) of 0.99 and a negative predictive value (NPV) of 0.36 (p < 0.001). At the cutoff value of 974 ppb, the sensitivity was 53%, specificity was 95%, PPV was 0.97, and NPV was 0.38 , the ROC curve analysis was used. The result showed that the AUC of breath ammonia was 0.835  with a sensitivity of 71%, a specificity of 78%, a PPV of 0.84, and a NPV of 0.61 at the cutoff value of 1187 ppb.Because the K/DOQI CKD classification defines CKD as GFR<60 mL/min/1.73 mOur findings showed that breath ammonia concentration was increased with the progression of CKD stages and that there was a strong correlation between breath ammonia and kidney function. Thus, we evaluated whether measurement of breath ammonia could be used as a screening tool for the occurrence of CKD. According to the definition of CKD that was established by KDIGO, the patients were divided into two groups by eGFR≥ or <60 mL/min. The sensitivity and specificity of breath ammonia concentration in predicting patients with eGFR < 60 mL/min are shown in CKD has an increasing prevalence and incidence, and it is now a worldwide public health problem and a major economic burden. Because early diagnosis is crucial for prevention and delay of adverse CKD outcomes, finding a rapid, low-cost, and non-invasive screening method to identify CKD patients is important. In this study, we used a portable, real-time biosensor to measure exhaled breath ammonia in CKD patients to determine whether breath ammonia could be used as a simple and real-time indicator of kidney function. Our previous study and Wang’s study showed a good correlation between breath ammonia concentration and BUN level in CKD stage 3–5 patients ,32. ThisOur result demonstrated that breath ammonia concentration was proportionally increased with CKD progression because the concentration at each stage was significantly higher than that at the previous stage . Although breath ammonia measurement has been reported to be well correlated with the BUN level in hemodialysis patients, studies that have assessed its use in CKD screening is rare. As per our knowledge, only two studies were performed and they used different methods including an external cavity laser (ECL)-based off-axis cavity-enhanced absorption spectroscopy and an electrochemical gas sensor analyzed breath ammonia concentrations in 27 CKD stage 3–5 and eight CKD stage 4–5 patients, respectively ,34. Both2. Compared with patients with eGFR ≥ 90 mL/min/1.73 m2 (CKD stage 1), patients with eGFR < 90 mL/min/1.73 m2 (CKD stage 2–5) had higher breath ammonia concentration. The ROC curve analysis showed that breath ammonia is a good predictor  to distinguish between individuals with and without eGFR ≥ 90 mL/min/1.73 m2. At a cutoff value of 974 ppb, the sensitivity and the specificity were 69% and 95%, respectively, and there was a high PPV of 0.99, but a low NPV of 0.36. Similarly, breath ammonia is an acceptable indicator  to differentiate between patients with eGFR ≥ 90 mL/min/1.73 m2 (CKD stage 1) and patients with a mild to moderate GFR decline (CKD stage 2 and 3) because there was a high specificity (95%) and high PPV (0.97), but there was a low sensitivity (53%) and low NPV (0.38). These results suggest that an elevated breath ammonia concentration more than 974 ppb is a reliable indicator to predict eGFR < 90 mL/min/1.73 m2 because 99% of patients with breath ammonia > 974 ppb had eGFR < 90 mL/min/1.73 m2. However, 64% of patients with a breath ammonia concentration below 974 ppb may still have eGFR < 90 mL/min/1.73 m2. Thus, breath ammonia monitoring can be used to screen asymptomatic CKD patients, but it still requires an eGFR assessment in the high-risk population.The K/DOQI working group defines decreased GFR as GFR < 90 mL/min/1.73 m2 [2 is considered to reflect abnormal kidney function in all ages, the K/DOQI CKD classification defines CKD as GFR < 60 mL/min/1.73 m2 for more than three months. Thus, we assessed whether breath ammonia could be used as a predictor to distinguish between patients with and without eGFR < 60 mL/min/1.73 m2. The AUC of the ROC curve analysis was 0.831 and at a cutoff value of 1187 ppb, the PPV was 0.84. These results suggest that a breath ammonia concentration > 1187 ppb has a good diagnostic accuracy to verify patients with eGFR < 60 mL/min/1.73 m2. However, only 71% of patients with eGFR < 60 mL/min/1.73 m2 were identified at this concentration.Normal GFR varies with age, and older individuals may have normal kidney physiological function in the range of GFR 60–89 mL/min/1.73 m2 ,38,39. B2, our results showed that a breath ammonia concentration set at 886 ppb had a sensitivity of 80% but the specificity was reduced to 69%. Because serum creatinine is commonly monitored in routine health examination and consequences of false negative and positive results for CKD detection are modest without immediate hazards, a sensitivity of 80% for CKD screening is acceptable. We believe that breath ammonia measurement at this cutoff value could be a useful tool for CKD screening.For non-fatal disease screening, a good predictor requires a good diagnostic accuracy with adequate sensitivity. To screen for patients with reduced GFR < 60 mL/min/1.73 mACEi and ARB can cause hyperkalemia and GFR reduction in some patients and no randomized controlled trials have verified the safety and efficacy in patients with advanced CKD . This maR = 0.105, p = 0.253, 2 because the AUC was 0.834, sensitivity was 83%, specificity was 56%, PPV was 0.82, and NPV was 0.57 at a cutoff value of 973 ppb (Our study also showed that salivary pH was positively correlated to BUN, and breath ammonia concentrations. Salivary pH values were significantly higher in the patients with more advanced CKD stages than earlier stages, which is compatible with our previous study . Ammonia 973 ppb .Screening for CKD is important because it is a significant public health burden with a high prevalence worldwide and early diagnosis can delay and reduce morbidity and mortality. Detection of exhaled breath ammonia that is real-time, inexpensive, and easy to administer with an acceptable diagnostic accuracy and sensitivity can be used as a good surrogate of kidney function and a reliable tool for CKD screening.


Although cardiovascular diseases in particular Pulmonary Arterial Hypertension (PAH) is associated with, high morbid-mortality in chronic hemodialysis, but its magnitude remains paradoxically unknown in sub-Saharan Africa. The aim of this study was to evaluate the prevalence of PAH and associated factors in chronic hemodialysis in Sub-Saharan African population.In a cross-sectional study, patients treated with HD for at least 6 months in 4 hemodialysis centers were examined. PAH was defined as estimated systolic pulmonary arterial pressure (sPAP) ≥ 35 mmHg using transthoracic Doppler echocardiography performed 24 h after the HD session.p = 0.010). In multivariate analysis, unsecured healthcare funding , arrhythmia , vascular access change  and diastolic dysfunction  were male. Mean duration of HD was 13.3 ± 11 months. With reference to vascular access, 12 (14.1%), 29 (34.1%) and 44 (51.8%) patients had AVF, tunneled cuff and temporary catheter, respectively. The underlying cause of ESRD was diabetes in 30 patients (35.3%). The prevalence of PAH was 29.4%. Patients with PAH had more hyponatremia (11 (44%) vs 10 (16.7%), One third of hemodialysis patients exhibit PAH, which is independently associated with low socioeconomic status  and cardiovascular complications . Excessive cardiovascular mortality in patients with end-stage renal disease (ESRD) has been described in epidemiological and clinical studies. It accounts for about 50% of deaths in dialysis  with a rTo date, there has been no study assess the burden of PAH on maintenance HD from Sub-Saharan Africa (SSA). Yet, early intervention to reduce pressure in the pulmonary artery can prevent the worsening of heart failure and death –16. TherA cross-sectional study was conducted, between Mars 2016 and June 2019, in 4 hemodialysis centers .All consecutive ESRD patients aged > 18 years old on maintenance HD for more than 6 months were eligible to participate in this study  at each session. Most patients were treated with synthetic dialyzer membranes (high flux) and bicarbonate-based on dialysis solution upon a bicarbonate concentration of 32 mEq/L. Blood flow and dialysate flow rate varied between 200 and 400 mL/min and 500–800 mL/min, respectively using 4008 and 5008 s generators of Fresenius.Transthoracic Doppler echocardiograms were performed by a single cardiologist using an ultrasound system with a 3.5 Hz cardiac lead  as a non-invasive method, in post dialysis, 24 h after when patients were on optimal dry weight, PHT was defined as Systolic PAP equal to or greater than 35 mmHg. Systolic right ventricular (or pulmonary artery) pressure was calculated using the modified Bernoulli equation: PAP = tricuspid systolic jet (TR) + 10–15 mmHg  .Laboratory investigations encompassed: blood urea nitrogen (BUN), serum creatinine, natremia, kaliemia, uric acid, hemoglobin, hematocrit, iron, ferritin, ProBNP, Troponin, calcium, phosphorus, and parathyroid hormone level. The results of the predialysis blood samples at the time of echocardiographic study and the mean of the preceding 3 months values were evaluated.Others parameters of interest included the following: age, sex, comorbidities, medications, etiology of kidney disease, age at time of ESRD, source of funding, duration of hemodialysis therapy, and blood access location.✓ Diastolic dysfunction: was defined as E/A < 1 or > 2 and between1–2, additionally with E/E’>15 .✓ Systolic dysfunction: LVEF < 55%.✓ Hypervolemia: water retention with tissue infiltration or clinical signs of hyperhydration✓ Hyponatremia is an electrolyte disorder defined by a sodium concentration in the blood plasma of less than 136 mmol /l .✓ Hypocalcemia: electrolyte disorder characterized by an adjusted total serum calcium level of < 8.4 mg/dl✓ Arrhythmia: any rhythm disturbance objectified by the cardiologist during the echocardiography✓ ESRD was defined as irreversible and advanced loss of kidney function due to any etiology requiring long term RRT with HD.✓ Funding was considered secured when health insurance, social security, company or government provided financial support in HD, whereas unsecured healthcare funding as patient without secure financing.All statistical analyses were performed with using SPSS  software for Windows version 24.p < 0.05.Data are presented as crude counts (n) and relative (%) frequencies for categorical variables, as an average (± standard deviation) for quantitative variables normally distributed, whereas non-normally distributed are presented as a median (Interquartile range: EIQ). Proportions were compared by the Pearson square Chi-square test or Fischer’s exact test as appropriate, whereas means or medians by the Student’s t test or the Man Whitney U test, respectively. Univariate logistic regression analysis was used to identify factors associated with PAH. In order to control the effect of potential confounding, we further performed multivariable logistic regression analysis (using ascending step-by-step approach) to search factors independently associated with PAH. The adjusted ORs and their 95% CI were calculated finally to determine the degree of association between the PAH and the independent variables. To search for risk factors, two multivariate mathematical models were used to limit the cumulative effect of independent variables. The significance level retained was then The research followed the tenets of the Declaration of Helsinki and informed consent was obtained. The Clinical Research Ethics Committee of Kinshasa School of Public Health (number ESP/CE/013/2016) approved the study protocol.Eighty-five patients were enrolled in the study; 57 patients (67.1%) were male. Mean duration of HD was 13.3 ± 11 months. With reference to vascular access, 12 (14.1%), 29 (34.1%) and 44 (51.8%) patients had AVF, tunneled cuff and temporary catheter, respectively. The underlying cause of ESRD was diabetes in 30 patients (35.3%). Twenty-five (29.4%) patients (mean age 54.6 ± 14.3 years) had PAH with a mean value for SPAP of 28.0 ± 10 mmHg.p = 0.010), arrhythmia  and had lower β blockers  and Aspirin junior  than to those without PAH. They also did not have a secure funding  and experimented a vascular access change  (Table p = 0.014)], pulse pressure [(67.3 ± 16.7) vs (82.2 ± 16.8) (p < 0.001)] (Table p = 0.004), filling pressures E / E ‘(p = 0.001) and proportion of diastolic dysfunction (p = 0.007) (Table PAH was present in 25 (29.4%) patients. Patients with PAH had more hyponatremia (11 (44%) vs 10 (16.7%), ckers [8 2% vs 9  had died compared to 18 out of 60 (30%) without PAH and there was no statistically significant difference between the two groups with a The main findings of the present study are as follows. First, roughly 3 out of 10 patients on maintenance hemodialysis had PAH. Second, arrhythmia, vascular access change, diastolic dysfunction and no secure healthcare funding emerged as the main factors independently associated with PAH.The prevalence of PAH in this study is 29.4%. This value is within the range of 27–57% reported by most studies , 21 and Possible explanations of PAH in long term hemodialysis patients can be grouped into 3 categories: 1) a volumetric overload caused by increased cardiac output following an arteriovenous fistula, anemia or hypervolemia , 25; 2) including pulmonary disease chronic obstructive or connective tissue disease, and 3) an increase in pulmonary capillary pressure caused by systolic and diastole in heart failure . Some auThe independent determinants of pulmonary arterial hypertension in our study were unsecured funding for dialysis, arrhythmia, vascular access first change, and diastolic dysfunction. The positive association of unsecured funding (due to low socioeconomic status) with PAH reflects irregular dialysis sessions with subsequent significant interdialytic weight gain through renal sodium and water retention . Sodium In the present study patients with PAH had elevated E/E ratio and ProBNP level suggesting a chronic volume overload and subsequent diastolic dysfunction . This chThe interpretation of the results of the present study should take into account of some limitations. First, the cross-sectional design of the study precludes the establishment of temporal relationship between the issues of interest. Second, the small sample size did not allow sufficient power to statistical tests to identify potential associations between variables of interest. Third, the unique measurement of parameters of interest could have over- or underestimated their true values. Fourth, computerized tomography was not performed to exclude other potential causes of PAH.PAH, was a common clinical finding in the present case series and affects more than one in four patients on maintenance hemodialysis in sub-Saharan African.


In this study, we aimed to highlight the common early‐stage clinical and laboratory variables independently related to the acute phase duration in patients with uncomplicated coronavirus disease (COVID‐19) pneumonia.In hospitalized patients, the acute phase disease duration was followed using the Brescia‐COVID respiratory severity scale. Noninvasive ventilation was administered based on clinical judgment. Patients requiring oropharyngeal intubation were excluded from the study. For parameters to be measured at the hospital entrance, age, clinical history, National Early Warning Score 2 (a multiparametric score system), partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F ratio), C‐reactive protein, and blood cell count were selected.P < .001).In 64 patients, age (direct relationship), P/F, and platelet number (inverse relationship) independently accounted for 43% of the acute phase duration of the disease (For the first time, the present results revealed that the acute phase duration of noncomplicated pneumonia, resulting from severe acute respiratory syndrome coronavirus 2, is independently predicted from a patient's age, as well as based on the hospital entrance values of P/F ratio and peripheral blood platelet count. COVID‐19 has rapidly spread worldwide, straining the national health systems of several countries.It is needed to identify simple predictors of hospitalization duration to properly allocate medical resources.Age, P/F ratio, and platelet values predict acute phase duration of non‐complicated CoViD pneumonia. All these parameters were altered in coronavirus disease (COVID‐19) pneumonia. Furthermore, D‐dimer and procalcitonin could be allocated to later stage thrombotic and septic complications, respectively.Apart from common disease signs and symptoms, organized in multiparametric score systems, optimal laboratory variables should be considered indices for systemic inflammation, including C‐reactive protein (CRP), white blood cell (WBC) count, and platelet count, known to be related to the hematologic impact of the disease, with PaOMoreover, owing to the short time of disease outbreak, prediction models for COVID‐19 are poorly reported and present a high risk of bias, necessitating urgent collaborative efforts to develop more rigorous models.Predicting disease duration, particularly the acute phase, is crucial for superior clinical resource allocation. To date, a single, nonpeer‐reviewed chest computed tomography‐based model, has been reported as a predictor of short‐ and long‐term hospital stay (more than 10 days) in patients with pneumonia associated with SARS‐CoV‐2.Therefore, it is important to comprehensively identify predictors of disease duration, which could allow clinicians to perform appropriate patient risk stratification and resource allocation.In the present study, we aimed to identify early‐stage, commonly available clinical and laboratory variables related to the duration of the acute phase in uncomplicated COVID‐19 pneumonia.22.1This study was performed using clinical data collected from patients with COVID‐19 pneumonia, discharged to go home by the Internal Medicine plus Infectious Disease Units of Santa Chiara Hospital in Trento , and by the High‐Intensity Internal Medicine Unit of Santa Maria del Carmine Hospital in Rovereto , between 1 March and 18 April 2020. Data for the parameters used for predictive analyses were obtained on the first day of hospital admission. Given the exclusion of patients with complications during in‐hospital stay, and the rigorous protocol for admission and discharge, the length of stay was assimilated to the acute phase duration of this disease.2.2https://www.apss.tn.it/documents/10180//179124//Informativa+fascicolo+sanitario+elettronico+FSE.pdf). The identity of all subjects was deleted, and random identification numbers were used to analyze the data.In the present investigation, data were collected and examined anonymously (nonsensitive data) and extracted as aggregated from the electronic health record. Patients had previously provided informed consent for treatment . Obesity was defined as a BMI of greater than or equal to 30 kg/m2. Diabetes was defined as fasting blood glucose greater than or equal to 126 mg/dL on two occasions, and/or the use of antidiabetic agents. Hyperlipidemia was defined as total cholesterol and/or triglycerides greater than or equal to 200 mg/dL, and/or the use of lipid‐lowering drugs. Hypertension was defined as systolic blood pressure/diastolic blood pressure greater than or equal to 140/90 mm Hg, and/or the use of antihypertensive agents. Subjects who smoked regularly during the previous 12 months were classified as smokers.Body mass index (BMI) was computed as weight (in kg) divided by height (in m2). The fraction of inspired oxygen (FiO2) was annotated. Then, the PaO2/FiO2 ratio (P/F ratio) was calculated.Laboratory examinations included serum CRP, complete blood count, and partial pressure of oxygen in arterial blood (PaO2) was measured by pulse oximetry. The National Early Warning Score 2 (NEWS2), a multiparametric score system, was calculated from respiratory rate, oxygen saturation with ambient air conditions, temperature, blood pressure, pulse/heart rate, hypercapnic respiratory failure, room air or supplemental O2, level of consciousness, or new confusion.Arterial blood saturation with oxygen  was administered depending on the Brescia‐COVID respiratory severity scale (BCRSS) using continuous positive airway pressure.Tocilizumab therapy was administered as 324 mg subcutaneously, repeated after 16 hours, based on clinical judgment .All patients underwent anticoagulant treatment, defined as receiving enoxaparin from 4000 to 8000 UI/d as low molecular weight heparin; the dose range was based on clinical judgment.2.61.Patient wheezing OR unable to speak in full sentences while resting/with minimal effort;2.Respiratory rate greater than 22 breaths/min;3.2 less than 65 mm Hg or SpO2 less than 90%;PaO4.Significantly worsening repeated chest rays.Patients with confirmed COVID‐19 pneumonia were evaluated before admission to BCRSS.If the patient presented no or one criterion, he returned home for active remote surveillance.If the patient presented two criteria, he was admitted to internal medicine facilities and received medical treatment, becoming eligible for this study.If the patient presented three or more criteria, he was admitted to the High‐Intensity Internal Medicine for additional NIV, becoming eligible for this study. If recovered, he was transferred for medical treatment to the internal medicine facilities; otherwise, he was moved to an intensive care unit for oropharyngeal intubation, exiting the present study protocol.Hospital discharge was performed when the patient presented no BCRSS criteria (zero score), returning home for treatment through eventual on‐call remote facilities. RNA detection of SARS‐CoV‐2 from nasal and/or pharyngeal swab specimens was repeated the day before and at discharge. If one or both were positive, the patient was instructed for out‐of‐hospital isolation until two tests were negative over a 2‐day span.2.7P < .05.Statistical analyses were performed using PASW 18.0 for Windows. The normality of distribution was assessed using the Shapiro‐Wilk test. All continuous variables presented normal distribution except for CRP, WBC count, lymphocytes, and neutrophil count, and platelet number. Non‐normally distributed variables were log‐transformed before analyses. Pearson or Spearman's correlation coefficients were used as appropriate, to test the correlation between continuous variables in simple and multiple approaches. Multiple regression analyses were performed to test the independent association between disease duration and clinical and biochemical variables. In detail, variables were entered into two blocks, one for preexistent clinical conditions and one for both clinical and biochemical disease presentations. In the first block, age, sex, obesity, diabetes mellitus, hypertension, hyperlipidemia, smoking, and previous cardiovascular disease were included; in the second block, the P/F ratio, NEWS2 index, CRP, platelet count, lymphocyte count, and neutrophil counts were included. Statistical significance was set at 3Overall, 64 patients were recruited for the present analysis. Table r = .29, P = .018), NEWS2 score , P/F ratio , CRP , and lymphocyte count .Following simple regression analyses, disease duration was found to be significantly associated with age (P < .001).To further investigate the association between disease duration and clinical and biochemical variables, a multiple regression analysis was performed. Disease duration was used as the dependent variable, while independent variables were entered into two blocks: age, sex, and clinical history variables in the first block; hospital entrance clinical parameters in the second block. As displayed in Table 4Since its first appearance in China, COVID‐19 has rapidly spread worldwide, straining the national health systems of several countries. Hence, it is crucial to identify simple clinical or laboratory predictors of hospitalization duration at the first contact of patients with hospital facilities, to appropriately allocate medical resources. Our investigation demonstrated that patient age, P/F ratio at admission, and platelet count predicted the acute phase duration of noncomplicated SARS‐CoV‐2 pneumonia.symptoms of mild‐to‐moderate COVID‐19 , with symptoms disappearing after 11.5 ± 5.7 days. This difference is attributed to patient being discharged after the acute phase of pneumonia, only when alarm symptoms and signs such as dyspnea and oxygen desaturation disappeared, while still presenting symptoms such as cough or asthenia.The mean disease duration was approximately 1 week. Other studies have utilized different admission and discharge protocols. However, data from a large cohort of 1420 patients from 18 European hospitals are availablevirus shedding; in one such study, virus shedding was found to be significantly longer in men than in women and in older age groups, partly explaining the high rate of severe illness in men over 60 years of age.Several other reports investigated the duration of disease aggravation, one study has highlighted risk factors such as male sex, older age, diabetes, cardiovascular diseases, chills, dyspnea, and SatO2 value of less than or equal to 93%, WBC counts greater than 10 × 109/L, and large consolidated opacities on computed tomography images.n = 168, 80.8%) and progressive group : comorbidity, older age, lower lymphocyte count, and higher lactate dehydrogenase at presentation were reported as independent high risk factors for COVID‐19 progression.In terms of literature regarding The results of our investigation recorded age, P/F ratio, and platelet count as predictors of hospital stay. The coefficients of simple regression analyses were poor. We speculate that the low number of subjects and the presence of several confounding factors might account for these results. To the best of our knowledge, only a few studies have analyzed this issue.Liu et alOur results appear consistent with those of Qu et al.In our investigation, age was associated with prolonged hospitalization. Typically, older individuals present a diminished immune response, reduced mucociliary clearance, and have multiple comorbidities than younger individuals. Moreover, several studies have considered age; in a multivariate logistic analysis, age (odds ratio = 1.06) and CD4 T cell count (odds ratio = 0.55/100 cells/μL increase) were independently associated with oropharyngeal intubation.Finally, in our research, the P/F ratio on admission demonstrated a stronger relationship with hospitalization when compared with other variables.Moreover, P/F was considered in mortality studies; its mean value was reportedly 290 mm Hg in 67 patients who died during COVID‐19 pneumonia and 400mm Hg in 1032 survivors.5The present data, for the first time, demonstrated that age, and easily available measurements of P/F ratio and peripheral blood platelets, can predict almost half the variabilities observed in the acute disease phase duration of uncomplicated pneumonia induced by SARS‐CoV‐2. These variables might be considered an easy‐to‐obtain information package that could guide medical resource allocation, presenting novel candidates for new prediction models.The authors declare that there are no conflict of interests.Study concept and design: CC, FP, and CT. Study collection: FP, LL, and CO. Acquisition and analysis of data: FP, GF, and GMG. Drafting and writing of the manuscript: CC and CT. Revision of the manuscript: WS and SC.


Background: Some children with chronic kidney disease (CKD) develop hypertension faster than others. This may be attributable to endothelial dysfunction, among other reasons. Short-chain fatty acids (SCFAs), that is, acetate, butyrate, and propionate, are known for reducing cardiovascular risks via preserving endothelial function. This study aimed to investigate the association between changes in plasma SCFA concentrations and in cardiovascular and endothelial parameters in children with CKD.Methods: In total, 105 children and adolescents who met the CKD criteria were enrolled in this study, and 65 patients aged >6 years were divided into two groups based on the ambulatory BP measurements. The parameters of plasma SCFAs, endothelial function and morphology, and echocardiography were examined at the index visit and followed up after 1 year.Results: We observed that 27.69% of 65 patients developed hypertension during the study period. Plasma acetate increased by 22.75 μM in the stable group (P < 0.001), whereas there was no change in the worsened BP group. The index higher plasma butyrate was positively correlated with worsened BP . At the follow-up, plasma butyrate decreased by 2.12 and 4.41 μM in the stable and worsened BP groups, respectively (P < 0.001). In 105 subjects, higher index plasma propionate was positively correlated with decreasing ejection fraction .Conclusions: Plasma acetate seemed to play a role in preventing hypertension in children with CKD. However, the index plasma propionate and butyrate concentrations seemed to imply the development of cardiovascular problems in our 1-year study. Children with chronic kidney disease (CKD) are at high risk for the accelerating development of cardiovascular disease (CVD). They may not have any perceptible symptoms during childhood, but certain parameters regarding endothelial dysfunction, that is, increased carotid artery intima-media thickness (IMT) and increased pulse wave velocity (PWV), are frequently observed in these children , 2. Howevia high-fiber diet or SCFA supplementation can slow the progression of hypertension in children and adolescent with CKD.Hypertension is a complex phenomenon associated with endothelial dysfunction. Recent studies have reported that short-chain fatty acids (SCFAs) have inflammatory effects and preserve endothelial function . SCFAs aHowever, higher SCFA concentrations were also observed in some unexpected situations. Our previous study found that children with CKD and an abnormal ambulatory BP monitoring (ABPM) profile had higher plasma concentrations of propionate and butyrate . CertainThe retrospective cohort study was in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all patients before participating in this study. Children and adolescents aged 3 to 18 years with CKD from the pediatric nephrology outpatient clinics in Kaohsiung Chang Gung Memorial Hospital, Taiwan, were recruited between December 2016 and October 2018. CKD was defined and staged according to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) . Using t−1 1.73 m−2, (b) was undergoing dialysis, (c) was a kidney transplant patient, (d) was currently pregnant, (e) had a history of congenital heart disease, (f) lost to follow-up, or (g) was unable to cooperate during the examinations.A patient was excluded from this study if she/he (a) had eGFR <15 ml min−1 1.73 m−2. The measurements of renal and cardiovascular parameters are described in the following sections.The analysis was limited to children and adolescents with baseline eGFR >15 ml minThe following examinations were performed on a subject at a clinic visit: (a) history taking, office BP measurements, and physical examination; (b) blood and urine investigations; (c) echocardiography; (d) ABPM; and (e) carotid sonography. The etiologies of kidney diseases were divided to two categories: (a) congenital anomalies of kidney and urinary tract (CAKUT) and (b) non-congenital anomalies of kidney and urinary tract (non-CAKUT). CAKUT includes renal hypoplasia, renal dysplasia, unilateral renal agenesis, reflux nephropathy, polycystic kidney disease, horseshoe kidney, duplex kidney, posterior urethral valve, and ureter abnormalities.Body mass index (BMI) z-score was based on data from the Health Promotion Administration, Ministry of Health and Welfare in Taiwan .According to the 2017 American Academy of Pediatrics (AAP) guidelines , hyperteData from 24-h ABPM were collected from subjects aged 6–18 years within 1 week after clinic visits, using the Oscar 2 ABP Monitor . BP and heart rate (HR) were recorded by ABPM every 20 min for 24 h, while these subjects were normally active. BP load was defined as the percentage of hypertensive BP readings. The second timing of ABPM, as well as other exams, was approximately 1 year later.The criteria of hypertension diagnosed by 24-h ABPM included (a) mean daytime SBP/DBP exceeding the 95th percentile or 130/80 mmHg and (b) mean night-time SBP/DBP dropping <10% below 95th percentile or 130/80 mmHg.Based on two-time ABPM data in the index and the following visits, the category of worsened BP group included both patients with persistent and worse BP, and stable BP includes both no hypertension and improved BP on follow-up.−2.7 . Based on the 2017 AAP guideline, left ventricular mass index (LVMI) was calculated as left ventricular (LV) mass (g) divided by height (m) to the 2.7th power . The rep−2.7 . Low eje−2.7 .Carotid sonography was performed by I-Chun Lin, Mao-Hung Lo, and Pei-Chen Lu as previously reported . A 5–12-−1, respectively. An aliquot of 2 μl sample was injected into the column. The temperatures of inlet and FID were set to 200°C and 240°C, respectively. The total running time was 17.5 min. Analytical standard grades as internal standards for acetate and propionate were acquired from Sigma-Aldrich , and internal standards for butyrate from Chem Service .As previously reported , circulat test was used to examine differences in variables between subjects between index and following visits. Multivariate logistic analysis was performed to investigate the associations between plasma concentrations of SCFAs and worsening renal and cardiovascular parameters . SPSS version 22.0  was used for all analyses.Continuous variables were expressed as median , whereas categorical variables were reported as number (%). Non-parametric statistics or Chi-square test was used to compare the index variables between subjects with or without worsened BP. Paired The design of study is presented in −1 1.73 m−2 ; 73.3% had CKD stage G1, 18.1% were G2, 5.7% were G3, and 2.9% were G4.Data are presented in P < 0.001). These worsened BP group were older  and more male predominant  and had higher BMI z-score . Obesity was more prevalent in this group, accounting for closely 40%, whereas only 10.63% were obese in the stable BP group. Only 22.22% of the worsened BP group were CKD stage G1, which is 26.72% lower than the stable BP group (P = 0.050). Nearly 40% of the worsened BP group took immunosuppressants for treating their renal diseases and <7% of the stable BP .Baseline characteristics by presence or absence of worsened BP are presented in Comparison of the index data of the ABPM profile, echocardiography, carotid echography, and plasma SCFAs by the presence of future hypertension was presented P < 0.05). Furthermore, in the BP loads, worsened BP group revealed significantly higher values than the stable BP group .Overall, median BPs were higher in the worsened BP group than the stable BP group . Eight subjects (44.44%) in the worsened BP group had LVH, whereas five subjects (10.64%) in the stable BP group had LVH (P < 0.001).Indicators for cardiovascular deterioration, such as heavier LV mass, higher LVMI, thicker IMT, and higher PWV, were noted in the worsened BP group compared with stable BP group . Interestingly, plasma butyrate was 5.65 μM in the worsened BP group, which was 3.45 μM higher than that in the stable BP group (P = 0.005).No statistical difference was found in the plasma acetate and propionate concentrations between the stable and worsened BP groups (−1 (P = 0.016). In 105 subjects, LV mass increased in 59.05%, LVMI increased in 35.24%, EF decreased in 55.24%, and eGFR decreased in 63.81%. Their eGFR decreased by 5.14 ml min−1 1.73 m−2 (P = 0.001).SCFA concentrations, cardiovascular, and renal changes between index and following visits are presented in P = 0.015). Plasma butyrate concentrations decreased by 2.27 μM from 2.15 μM (P < 0.001). Plasma propionate did not have significant changes between the index and the following years.With regard to SCFAs, plasma acetate concentrations increased by 15.99 μM from 33.65 μM . Compared with the index data, eGFR declined by 6.15 ml min−1 1.73 m−2 in the stable BP group (P = 0.017). However, we observed that eGFR dropped by 11.42% in the worsened BP group, whereas no statistical change in eGFR was observed in stable BP in percentage .Comparison of the difference between the index and the following visit data is presented P < 0.05). Although ABPM profile revealed no BP change in the stable BP group, BP loads increased by 2.70 and 6.72% in DBP overall, and DBP asleep, respectively (both P < 0.05).In the worsened BP group, increase in almost every ABPM parameter was observed, such as mean SBP overall and awake, mean DBP overall and awake, and all BP load parameters . Plasma acetate increased by 22.75 μM in stable BP groups, whereas no significant change was observed in worsened BP groups . Plasma butyrate decreased by 2.12 μM in stable BP group (P < 0.001), whereas plasma butyrate decreased by 4.41 μM in worsened BP group (P < 0.001).In echographic parameters, PWV increased by 0.2 m sP = 0.013). Additionally, the probability of getting vs. not getting decreasing EF was 1.281 times for each 1 μM increase in index plasma propionate (P = 0.046). These index plasma SCFAs remained significant after multivariable adjustment controlling for index data such as age, gender, BMI z-score, eGFR, and UPCR.The correlation between index plasma SCFAs and future cardiovascular changes and renal function outcome is presented in Firmicutes/Bacteroidetes ratio and increasing the prevalence of Bacteroides acidifaciens, has been shown to reduce BP in mineralocorticoid excess-treated mice . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.C-NH, P-CL, and Y-LT conceived and designed the experiments. Y-LT contributed reagents and materials. I-CL, M-HL, and P-CL performed carotid echography and echocardiography. C-NH and P-CL analyzed the data. P-CL wrote the manuscript. M-YY was the thesis advisor. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cardiopulmonary arrest (CPA), the acute cessation of blood flow and ventilation, is fatal if left untreated. Cardiopulmonary resuscitation (CPR) is targeted at restoring oxygen delivery to tissues to mitigate ischemic injury and to provide energy substrate to the tissues in order to achieve return of spontaneous circulation (ROSC). In addition to basic life support (BLS), targeted at replacing the mechanical aspects of circulation and ventilation, adjunctive advanced life support (ALS) interventions, such as intravenous fluid therapy, can improve the likelihood of ROSC depending on the specific characteristics of the patient. In hypovolemic patients with CPA, intravenous fluid boluses to improve preload and cardiac output are likely beneficial, and the use of hypertonic saline may confer additional neuroprotective effects. However, in euvolemic patients, isotonic or hypertonic crystalloid boluses may be detrimental due to decreased tissue blood flow caused by compromised tissue perfusion pressures. Synthetic colloids have not been shown to be beneficial in patients in CPA, and given their documented potential for harm, they are not recommended. Patients with documented electrolyte abnormalities such as hypokalemia or hyperkalemia benefit from therapy targeted at those disturbances, and patients with CPA induced by lipid soluble toxins may benefit from intravenous lipid emulsion therapy. Patients with prolonged CPA that have developed significant acidemia may benefit from intravenous buffer therapy, but patients with acute CPA may be harmed by buffers. In general, ALS fluid therapies should be used only if specific indications are present in the individual patient. Untreated cardiopulmonary arrest (CPA), the acute cessation of blood flow and ventilation, is uniformly fatal, and the only known treatment to reverse it is cardiopulmonary resuscitation (CPR). CPR is delivered in two phases. The first and most important phase, basic life support (BLS), consists of chest compressions to re-establish blood flow and oxygen delivery to the tissues, and ventilation, to oxygenate the arterial blood and excrete carbon dioxide. The second phase of CPR, advanced life support (ALS), consists of adjunctive therapies that are targeted at improving the efficacy of the BLS interventions to maximize oxygen delivery to the tissues through drug therapy and defibrillation.Intravenous fluid bolus therapy has been commonly used to increase preload during CPR in an attempt to increase cardiac output. In addition, specific fluid therapies to address acid-base and electrolyte disturbances that occur commonly in patients with CPA have been proposed. Finally, the use of intravenous lipid emulsions for the treatment of CPA secondary to specific toxicities has been studied. In 2012, the Reassessment Campaign on Veterinary Resuscitation (RECOVER) Initiative published the first evidence-based veterinary CPR guidelines after an extensive review of the primary literature  is unlikely. The coronary arteries arise from the base of the aorta just as it leaves the left ventricle and supply oxygen to the myocardium. Large epicardial vessels branch into smaller intramuscular vessels and ultimately to the myocardium before entering the capillary beds where oxygen delivery occurs. Venous drainage from the capillary beds feed into myocardial and then epicardial coronary veins. The latter ultimately coalesce into the coronary sinus, which drains into the right atrium. During systole, the myocardium contracts and compresses the myocardial coronary arteries, dramatically increasing resistance. Therefore, in the spontaneously beating heart, the bulk of myocardial perfusion occurs during ventricular diastole when the myocardium relaxes and myocardial coronary arterial resistance decreases. The driving pressure for blood flow into the myocardium during diastole is the aortic diastolic pressure (ADP). However, this driving pressure is resisted by the pressure within the left ventricle at the end of diastole (LVEDP) since the myocardial coronary arteries serving the left ventricle are exposed to left ventricular pressures as they course into the endocardium. During CPR, left ventricular end-diastolic pressures  are very low, commonly less than the right atrial pressure (RAP), and coronary arterioles are maximally vasodilated . TherefoSimilarly, the pressure gradient leading to cerebral blood flow is cerebral perfusion pressure (CePP). The primary driving pressure for cerebral blood flow is mean arterial pressure (MAP), and the counteracting outflow pressure is either central venous pressure (CVP) or intracranial pressure (ICP), whichever is greater (CePP = MAP-CVP or MAP-ICP).The dependence of tissue blood flow on perfusion pressures has a substantial impact on fluid therapy during CPR. Intravenous fluid loading has the potential to increase tissue driving pressures by increasing ADP and MAP during CPR. However, such fluid loading may also increase the counteracting outflow pressures, both RADP and CVP, which will decrease CoPP and CePP, respectively, and worsen oxygen delivery to myocardial and cerebral tissue beds. Ultimately, intravenous fluid loading should only be administered during CPR if it is likely that an increase in driving pressure (ADP or MAP) rather than in outflow pressure (RADP and CVP) will occur. By definition, this is more likely in patients that are effectively hypovolemic, either due to intravascular volume losses or inappropriate vasodilation . However, patients that are already fully fluid loaded or euvolemic will not likely experience significant increases in driving pressure. Rather, a further rise in intravascular volume in these patients will predominantly increase the outflow pressure (RADP and CVP), which will decrease perfusion pressures and result in decreased blood flow to the tissues.These theoretical concerns have been documented in experimental studies. In a study of 18 euvolemic dogs with induced CPA, infusion of 11 ml/kg of either lactated Ringer's solution or whole blood resulted in a 34% increase in cardiac output, but a concurrent 26% decrease in left ventricular blood flow and a 35% decrease in cerebral blood flow. This was explained by a 22% reduction in CoPP that resulted from a disproportional increase in RADP compared to ADP . SimilarIn patients with acute CPA, assessment of intravascular volume status can be challenging. Typical physical examination parameters that may be helpful, such as capillary refill time, mucous membrane color, heart rate and pulse quality, cannot be assessed in patients with CPA. Therefore, review of pre-arrest physical exam findings, an understanding of the precipitating causes of the arrest , or evidence of acute blood loss  are required to make the best intravenous fluid therapy plan during CPR. The RECOVER ALS guidelines recommend a conservative approach to fluid administration during CPR, reserving fluid boluses only for patients with known or suspected hypovolemia or distributive shock .As described previously, for hypovolemic patients in CPA, fluid boluses are recommended because they are likely to increase tissue driving pressures more than outflow pressures and improve CoPP and CePP. Generally, isotonic crystalloid fluid boluses of 1/4–1/3 of the total blood volume over 15–20 min  are recommended to treat hypovolemia.There is experimental evidence that hypertonic saline (HS) may have beneficial effects beyond volume expansion during CPR. It is posited that HS may have neuroprotective effects by reducing cerebral edema, neuronal excitotoxicity, inflammation, and neuronal apoptosis. A recent experimental study in rats showed improved neurologic outcome post-CPR and reduced hippocampal apoptosis in rats receiving hypertonic saline during CPR compared to rats receiving isotonic crystalloids or synthetic colloids . ImportaThere is limited clinical data available to inform a decision about the use of HS during CPR. A prospective, randomized controlled clinical trial (RCT) of 200 human patients with out-of-hospital cardiac arrest (OHCA) in which 100 patients received 2 ml/kg of HHS and 100 patients received 2 ml/kg of HES over 10 min showed no difference in short or long-term outcomes between the groups . A retroTaken together, this evidence suggests that HS may have a benefit over isotonic crystalloid fluids during CPR in patients with hypovolemia or vasodilatory shock. Given the consistent finding that intravenous fluid boluses of any kind lead to decreases in CoPP and CePP, and in the absence of any long-term outcome studies demonstrating a survival or neurologic function benefit to the use of HS during CPR in euvolemic patients, it is difficult to recommend volume expansion of any kind in patients known or suspected to be euvolemic during CPR. Taken in context with recent evidence of harm associated with the administration of HES  and the Where CPA is caused or compounded by hypovolemia, fluid resuscitation is recommended as outlined above, and where hypovolemia is the consequence of severe hemorrhage, those fluids should include blood products . While tSuccessful resuscitation from traumatic CPA is resource intensive. In addition to massive transfusion therapy, effective management of severe traumatic hemorrhage requires a comprehensive strategy potentially including damage control surgery, minimization of crystalloid administration, treatment of hyperfibrinolysis , permissive hypotension and other interventions , 28. In Hypothermia protects all tissues, but in particular the brain, from the consequences of ischemia and reperfusion by a multitude of mechanisms . The posExperimental studies using intra-arrest cooling by ice-cold fluid bolus infusion are limited to swine , 38. In A single randomized controlled trial in humans including 245 subjects with OHCA of any rhythm studied the effect of intra-arrest cooling with intravenous cold saline compared to no such cooling . Up to 2Animal research suggests that early induction of hypothermia after ROSC is superior to delayed cooling . IntraveIn summary, available evidence from animal studies suggest that mild hypothermia itself, either applied intra-arrest or early after ROSC mitigates ischemia-reperfusion injury. However, the harm associated with administration of large intravenous boluses of cold isotonic crystalloids during or after CPR suggests that other avenues for cooling should be considered in most cases. As dogs and cats are generally of lower thermal mass than humans, hypothermia  often occurs spontaneously during treatment of CPA and rapid administration of cold fluids is likely not necessary.Under special circumstances, the intra-arrest administration of calcium, magnesium, potassium and dextrose can be considered, but evidence of broad benefit is lacking.Hyperkalemia can occur for a multitude of reasons and can lead to life-threatening cardiotoxicity and cardiopulmonary arrest once serum potassium concentrations are severely increased  . IntraveAs for calcium, there is no conclusive evidence for an overall benefit of routine administration of magnesium during cardiac arrest, despite several RCTs in people examining the utility of magnesium in OHCA and IHCA . NeverthExperimentally induced hypokalemia in dogs below 3.0 mEq/L was found to increase vulnerability to ventricular tachycardia and fibrillation through a variety of arrhythmia mechanisms –57. WhilThe use of intravenous lipid emulsions (ILE) has been extensively reported in veterinary medicine to treat a wide range of poisonings and has recently been reviewed . In the The general recommendation for the clinical use of ILE in dogs and cats is (a) to administer 20% formulations, as 10% solutions are less effective; (b) to use inline filters (1.2 micron) as lipid aggregates are common; (c) to administer the solution as a bolus (1.5 mL/kg IV over 1 min) followed by an infusion (0.25 mL/kg/min IV CRI) for 30–60 min; (d) to limit the daily dose to 10 mL/kg . To faciPoisoning with other drugs than local anesthetics may also warrant the administration of ILE during CPR. Treatment with ILE is recommended in humans, and in extension animals, with CCB overdose alongside calcium gluconate, ALS measures as per standard guidelines and possibly other measures such as insulin/dextrose , 47. TwoAdverse effects of ILE therapy, while infrequent, deserve mention . In a ra2 rose above 350 mm Hg   or THAM  were tested as alternatives to bicarbonate, but studies in dogs and swine did not show any benefit over NaBic  , 87, 89. in vivo . Non-CO2er NaBic , 87, 88.er NaBic . In facter NaBic , 93. MorIn people, 2 RCTs and one systematic review that incorporates the findings of observational studies with a total of more than 18,000 patients showed no overall benefit of intra-arrest buffer therapy, with some studies reporting worse outcomes with buffer therapy –96. One The last evidence evaluation by the International Liaison Committee on Resuscitation examining intra-arrest buffer therapy was conducted in 2010 and did not recommend routine administration of NaBic or any other buffer . HoweverDF and MB co-wrote and critically revised the manuscript. Both authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SD declared a past co-authorship with one of the authors (DF) to the handling Editor.