Heart transplantation has become the accepted treatment for advanced heart failure, with over 4000–5000 performed in the world annually. Although the number of yearly transplants performed has been increasing over the last decade, the number of candidates in need of transplantation continues to grow at an even faster rate. To distribute these scarce and precious resources equitably, donor heart placement is based on clinical need with priority given to those who are more critically ill. As a result, donors are matched with recipient candidates over increasingly farther distances, which may subject these organs to longer ischemic times. One of the mainstays of successful heart transplantation is successful organ preservation while the donor organ is ex vivo from the time of donor procurement to recipient implantation. In order to adapt to a new era of heart transplantation where organs are shared across wider ranges, preservation strategies must evolve to accommodate longer ischemia times while mitigating the harmful sequalae of ischemia-reperfusion injury. Additionally, in order to address the ever-growing supply demand mismatch of donor organs, evolving perfusion technologies may allow for further evaluation of donor grafts outside of conventional acceptance practices, thus enlarging the effective donor pool. Herein this review, we discuss the history of organ preservation, current strategies and modalities employed in current practice, along with developing technologies in preclinical stages. Lastly, we introduce the concept of donation after circulatory death (DCD), which has been until recently a largely unexplored avenue of heart donation that relies much on current preservation techniques.  Heart transplantation is the gold standard treatment for end-stage heart failure . Each yeIn addition to careful donor/recipient selection, operative technique, and posttransplant care, a crucial yet often overlooked component of transplantation is successful preservation of the donor organ while it is transported to the recipient’s transplanting facility. Organ preservation aims to provide a means of effective organ transport while reducing the harmful sequalae of organ ischemia and hypoxia while the organ is ex vivo, as well as subsequent reperfusion injury. In light of recent allocation policy changes, organ transport distances and ischemia times have increased . AdditioIn 1967, the first human-to-human heart transplant was performed by Dr. Christiaan N. Barnard in Cape Town, South Africa . The donIn 1968, Henry Beecher and the Harvard Ad Hoc Committee began to lay the framework surrounding the legal definitions of death, most importantly by suggesting that “irreversible coma” be included as a criterion for death . By 1981The concepts of DBD donation, cold storage and inter-facility transport of donor hearts, along with the implementation of cyclosporine into heart transplantation in 1980  led to aStatic cold storage is the most commonly utilized method of heart preservation, both in the United States and the world and for both adult and pediatric hearts. This method is predicated on rapid removal of blood from the organ, complete washout of the vascular bed with a heart preservation solution, and maintenance of the organ in a state of hypothermia until it can be transported to the recipient hospital and implanted. Despite small differences in operative technique, most centers and transplanting surgeons follow a similar sequence for donor cardioectomy.After the donor heart is inspected and accepted for transplant, the cardioectomy operation commences, usually in concert with other organ procuring teams. The superior vena cava is ligated, and the inferior vena cava is incised to exsanguinate the patient. Following this, the left heart is vented, most commonly via either incision of the left atrial appendage or a pulmonary vein. The aorta is then cross-clamped, and the heart is flushed with cold heart preservation solution delivered through an aortic root cannula and cooled with topical ice. Once the heart has been cooled and flushed, it is explanted from the body . The heaHypothermia does not halt cellular metabolism entirely. However, it does slow the rate at which most human enzymes degrade compounds necessary for cell viability . FurtherUnwanted side effects of prolonged ischemia and hypothermia include cellular edema , acidosin = 38), HTK (n = 61), or Plegisol (n = 34) [n = 3107) was shown to have a statistically significant higher rate of one-year survival over Celsior (n = 1803), though the differences were clinically small  [Multiple studies have compared posttransplant outcomes with various preservation solutions. However, the results are conflicted . A study(n = 34)  one-year(n = 34) . In the  < 0.01) .Regardless of commercially available heart preservation solution used, the results of static cold storage are optimal when ischemic times are less than 4–6 h. After this timepoint, risk of posttransplant primary graft failure and death increases significantly ,42,43,44Paragonyx  has developed the SherpaPak system. This device is based on the premise that the ideal storage temperature of organs resides between 4 °C and 8 °C. This temperature range is derived from studies that demonstrate that storage of organ tissue within this range may decrease metabolic demand and hypoxic injury related to ischemia, while also preventing cellular damage and protein denaturization associated with colder temperatures ,49,50,51p = 0.02). One-year mean left ventricular ejection fraction was modestly improved in the SherpaPak group . Use of this system clinically in pediatric heart transplant is also underway [The Paragonyx SherpaPak Cardiac Transport System is a single-use, disposable and non-perfusing storage system designed to maintain donor heart temperatures between 4 °C and 8 °C for extended periods of time . In thisunderway .Early experience with normothermic, beating-heart perfusion for preservation of donor hearts during distant procurement was described in the 1980s by Hardesty and Griffith in the context of combined heart and lung transplant. After initial laboratory success with canine and bovine heart-lung blocs  they empIn current practice, the first and only current commercially available platform that offers normothermic, beating-heart perfusion is the Transmedics Organ Care System (OCS)  . This plDuring donor heart procurement, the donor heart is dissected with isolation of the main vessels. The OCS system is then primed with a nutrient-rich solution. After donor heparinization, donor blood is extracted from the patient in order to serve as perfusate for the OCS platform. This blood can be extracted from the patient via a cannula temporarily inserted into the right atrium. Following blood donation into the OCS, the cannula may be removed and the harvesting of the donor heart may proceed under standard protocol. The aorta is cross-clamped and both topical ice and antegrade cardioplegia delivered via the aortic root are applied to induce diastolic arrest. Following cardioplegia, the cardioectomy is performed in usual bicaval fashion.Following cardiectomy, the donor graft is prepared under cold ischemia prior to connection and reperfusion with the OCS system. First, an aortic cannula is secured to the donor aorta. This cannula will perfuse the aortic root, and thus, the coronary arteries with nutrient-enriched donor blood. Second, an additional cannula is inserted into the right ventricle via the pulmonary artery and secured into place. This cannula collects coronary sinus return, and allows for samples to be drawn for blood lactate measurements. Lastly, a third cannula may be inserted into the left atrium for left ventricular venting. The cannulas are then connected to the OCS system, and the heart is perfused via the aortic cannula. Once the donor graft is perfusing and reaches normothermia, the goal is to reestablish sinus rhythm. This may occur spontaneously, or require either cardioversion or placement of epicardial pacing wires. With the heart beating, the inferior and superior vena cava may be closed with either sutures or a silk tie. The OCS system can then be sealed, and the perfusion parameters adjusted via the system’s console. Additionally, a side port allows for blood gas and lactate samples to be drawn and trended during transport. Of measurable parameters, serum lactate has been shown to be the most sensitive and specific predictor of early graft failure .p = 0.20) and severe acute rejection  in those transplanted with grafts preserved with OCS. The PROCEED II trial (2010–2013) was a randomized, noninferiority trial conducted that compared 67 OCS-perfused grafts with 63 cold storage grafts [p < 0.001), however, cold ischemia times were shorter . One center that performed 38 transplants  as part of the PROCEED II trial has published 2-year outcomes [p = 0.38). Secondary outcomes at 2-years including freedom from chronic allograft vasculopathy, non-fatal major cardiac adverse events, biopsy-proven cellular rejection, and antibody-mediated rejection were similar between cohorts. Use of the OCS system has also been described for standard pediatric cardiac grafts in patients requiring complex concomitant procedures with the risk of prolonging ischemic times. Fleck and colleagues reviewed 8 children transplanted with grafts persevered using OCS compared with 13 children transplanted using static cold storage [During its early clinical applications, the OCS was first evaluated among cardiac grafts from standard donors. In a prospective, non-randomized trial performed between 2006–2008, 29 patients underwent cardiac transplantation after donor graft preservation with the OCS . Comparee grafts . Margina storage . The incIn addition to preservation of standard donor grafts, clinical interest has been focused on utilization of the OCS for marginal donors or those with anticipated long preservation times. Such efforts are aimed towards expanding the current restrictive and limiting donor pool. The EXPAND Trial was a multi-center study conducted to evaluate the efficacy of the OCS in assessing, preserving, and possibly resuscitating hearts outside the normal acceptance criteria . Ninety-p = 0.021), but with shorter cold ischemic time . Those with OCS preservation experienced improved 30-day survival . Wong and colleagues [Individual institutions have also reported experiences with utilization of the OCS for extended-criteria donors. Garcia Sáez and colleauges  reportedlleagues  reportedEarly research in machine heart perfusion was centered around hypothermic oxygenated perfusion methods . Wicomb In today’s practice, the XVIVO Heart Preservation System  (XHPS) is an additional system currently under Phase II clinical trial . This syPrior to cardiectomy, the XHPS reservoir is filled with 2.5 L of perfusion solution. Additionally, 500 mL of donor/recipient compatible irradiated and leukocyte-reduced blood is added . This achieves a system hematocrit of ~15%. The donor cardiectomy is performed under standard conditions. The heart is then attached to the XHPS via an aortic cannula. Once mounted, the heart is then submerged into the reservoir of blood and perfusion solution. The XHPS contains an in-series roller pump, oxygenator, leukocyte filter, and cooler/heater. Oxygenated blood is pumped into the aortic root to maintain a pressure of 20 mmHg and coronary artery flow between 150–250 mL/min. The heater/cooler maintains a temperature of 8 °C, and the pH is maintained at 7.4 .Though less established within clinical heart transplantation, XVIVO technologies have shown much promise in the field of ex vivo lung preservation and evaluation of extended-criteria lung donors for transplantation . In an iThe median age and risk profiles of heart recipients have changed over the last few decades. Likewise, the age and comorbidity burden of donors have also evolved . NumerouAlong with utilization of extended criteria donors, renewed interest in the DCD population may offer a means of increasing the available donor pool. Largely abandoned since the development of DBD legislation, DCD for heart donation may offer an alternative donor pool, often younger and with a lower degree of comorbidity burden . HoweverAt present, two contemporary approaches to DCD harvest have been described. The first, as described by Messer and colleagues , entailsIn the second method, first described by Dhital , and latThe DCD experience utilizing NRP has been promising. Experiences from the United Kingdom, Belgium, and Spain have suggested that NRP with static cold storage, without the need for ex situ perfusion, may reduce the overall cost of organ procurement, as well as the complexity of the procurement procedure ,83,84. Ip = 1.00) and one-year  survival were equivalent between cohorts. DCD donation with OCS re-perfusion has also been described in the pediatric population in a five patient series, in which all patients had excellent graft function on follow-up [The results of direct DCD procurement with ex situ reperfusion have also been promising. In the 3-patient series of DCD donation by Dhital , utiliziollow-up . While pollow-up . The UniThese early results of DCD donation are promising and may be a possible avenue back to a largely untapped donor pool. Current estimates predict that widespread utilization of DCD donation may increase yearly adult heart transplants by 300–600 transplants/year in the United States alone ,91. As tEx vivo perfusion systems also may serve as an important vector to which therapeutic interventions can be administered to donor hearts without affecting the remainder of either donor or recipient organs. Such interventions aim to reduce the impacts of ischemia/reperfusion injury, but may also allow marginal organs that would otherwise be declined to be “re-conditioned” for acceptable usage . Though Oxygen-derived free radicals play a large role in ischemia/reperfusion injury , and myoIn addition to therapies aimed at reducing ischemia/reperfusion injury, heart perfusion systems may also a unique approach to deliver donor heart-specific gene therapy. In a model presented by Bishawi and colleagues , an adenHeart transplantation is the optimal treatment of end-stage heart failure for many patients, and the demand for donor organs is likely to continue to outgrow the available supply. Successful cardiac transplantation is dependent on the foundation of efficient organ procurement with adequate en route preservation. Heart preservation aims to reduce the harmful sequelae of myocardial ischemia to allow for safe transport and implantation. As current techniques and technologies continue to evolve, transplanting centers aim to push the boundaries on conventional practices and ischemic time restrictions. These new developments will not only allow for longer transport distances and a wider organ sharing network, but also expand the current donor pool through ex vivo evaluation of extended-criteria and DCD donor organs. Additionally, they may offer a means for donor organ-targeted therapies prior to transplantation.


A total of 197 patients  were included in this retrospective study. Clinical and angiographic characteristics of patients were obtained from hospital records. p=0.022, OR 1.151, 95% CI 1.121–1.299), low-density lipoprotein , hsCRP , and SII  were independent predictors of CSF in the multivariable analysis. The optimal cutoff value of SII in predicting CSF was >877 in ROC curve analysis . This cutoff value of SII predicted the CSF with a sensitivity of 71.5% and specificity of 92.4%. Spearman correlation analysis showed a positive correlation between the mean TFC value and PLR, NLR, hsCRP, and SII.  Patients with CSF had higher SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), and high-sensitivity C-reactive protein (hsCRP) levels compared with the control group. Body mass index ( SII may be used as a better indicator for the prediction of CSF than hsCRP. Coronary slow flow (CSF) is an angiographic finding characterized by delayed distal vessel opacification of nonobstructive epicardial coronary arteries . CSF is The definite underlying mechanism of CSF is not yet fully understood. The authors have suggested that pathophysiology of CSF may be complex and multifactorial . CSF hadn = 3045), and the remaining patients with nonobstructive epicardial coronary arteries were reassessed (n = 2493). A total of 271 patients were identified according to the diagnostic criteria of CSF. The exclusion criteria were the history of ACS, percutaneous coronary intervention (PCI) and/or surgical bypass (n = 41), hypotension during the procedure (n = 4), coronary artery spasm (n = 5), coronary ectasia or aneurysm (n = 8), chronic or acute HF (n = 21), significant valvular heart disease (n = 9), documented arrhythmias (n = 10), severe peripheral artery disease or cerebrovascular disease (n = 11), acute or chronic infection (n = 8), renal or hepatic impairment (n = 19), hematological diseases (n = 4), severe chronic obstructive pulmonary disease (n = 8), malignancies (n = 3), chronic inflammatory diseases (n = 8), chronic use of steroids or nonsteroidal anti-inflammatory drugs, and anticoagulant therapy (n = 10). After applying exclusion criteria, the remaining 102 patients with CSF and normal epicardial coronary arteries were enrolled in the study as the CSF group. Among the 2493 patients with nonobstructive coronary arteries, 95 patients with normal coronary flow who met the exclusion criteria were included as the control group. In total, 197 patients were included in the study, 102 of whom were patients with CSF without any stenosis and 95 of whom had normal coronary arteries and normal coronary flow , diabetes, hypertension, hyperlipidemia, smoking status, family history of CAD, and medical therapy were collected. Vital signs including blood pressure and heart rate were recorded.The study protocol was approved by the local ethical committees . This study was conducted in accordance with the ethical principles of the Declaration of Helsinki.Coronary angiography was performed using the standard Judkins technique with a Siemens imaging system. Angiographic views were obtained in the left and right oblique planes with caudal and cranial angulations to show the coronary arteries. The views were recorded at a film rate of 30 frames per second. Nonionic low-osmolar contrast medium  was used in all procedures. CSF was determined using the thrombolysis in myocardial infarction (TIMI) frame count which was described by Gibson and colleagues . This quAll venous blood samples for measurements were drawn after a 12 hours fasting period 24 hours before the procedure. These samples were taken into standard tubes containing EDTA for complete blood count and analyzed using an automated blood cell counter within 30 min . Biochemical analyses, including serum creatinine, lipid profile, and hsCRP levels, were performed using standard laboratory techniques . The SII was calculated using the following formula: (neutrophil count × platelet count)/lymphocyte count. NLR and PLR were calculated from the neutrophil count/lymphocyte count and platelet count/lymphocyte count, respectively. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula .t-test, and continuous variables with non-normal distributions were compared using the Mann−Whitney U test. All analyses were two-sided and accepted significant at a value of p < 0.05. Demographic, clinical, laboratory, and angiographic characteristics were compared between the patients with CSF and normal coronary flow. Variables that demonstrated significant differences (p < 0.05) were evaluated as potential predictors in the univariate analysis. To avoid a multicollinearity problem, NLR, PLR, and other indices including neutrophils, lymphocytes, and platelets were not added to the logistic regression analysis. Variables associated with CSF on univariate analysis (p < 0.05) were included in the multivariable analysis and the results were shown as odds ratios (OR) with 95% confidence intervals (CI). Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff values of the SII and hsCRP for the predicting CSF. The Spearman test was used for the correlation analysis.SPSS, version 20.0 software , was used for all analyses. The Kolmogorov−Smirnov test was used to assess the normality of the distribution of continuous variables. Continuous variables are presented as mean ± standard deviation or median and interquartile range according to the distribution pattern. Categorical variables are presented as numbers, percentages, or proportions. The chi-squared test was used to compare the proportions of the groups and categorical variables. Continuous variables with normal distributions were compared using the independent sample p=0.058). The ratio of male gender was significantly higher in patients with CSF than those with normal coronary flow . The patients with CSF were more overweight compared with controls. There was no difference between the two groups in terms of heart rate and systolic and diastolic blood pressures. The frequencies of hypertension, hyperlipidemia, and family history of CAD were similar in both groups. The patients with CSF were more diabetic and current smoker compared with normal coronary flow patients .A total of 197 patients  with CSF and normal coronary flow were included in the study. Baseline demographic and clinical characteristics of the study population are presented in p < 0.001) and RCA  and cTFC values for LAD artery  than control subjects. Baseline eGFR and hemoglobin levels were similar between the two groups. The patients with CSF had markedly elevated LDL cholesterol levels compared with normal coronary flow patients . While lymphocyte count was lower , neutrophil count , platelet count , PLR (150 (112–232) vs. 75 (59–101), p < 0.001), NLR (4.69 (3.34–7.89) vs. 1.86 (1.45–2.23), p < 0.001), hsCRP (4.4 (1.5–11.0) vs. 1.1 (0.8–2.2), p < 0.001), and SII (1313 (773–2066) vs. 539 (254–914), p < 0.001) were higher in patients with CSF.Angiographic characteristics and laboratory results of the study patients are shown in p=0.002, OR 2.535, 95% CI 1.392–4.616), diabetes , BMI , smoking , LDL cholesterol , hsCRP , and SII  showed significant differences and were associated with CSF in the univariate analysis. In the multivariable analysis, BMI , LDL cholesterol , hsCRP , and SII  were found to be independent predictors of CSF. Spearman correlation analysis showed a positive correlation between the mean TFC value and the PLR, NLR, hsCRP, and SII . This cutoff value of SII predicted the development of CIN with a sensitivity of 71.5% and specificity of 92.4%. In addition, the optimal cutoff value of hsCRP was >1.4 with a sensitivity of 77.1% and specificity of 72.8%   in the ROC curve analysis (3–0.850) .To the best of our knowledge, this is the first study to report a relationship between the SII and CSF. In the present study, BMI, LDL cholesterol, hsCRP, and SII were found to be independent predictors of CSF. Also, PLR, NLR, hsCRP, and SII showed a positive correlation with mean TFC values.T-channel blocker treatment, which may reflect the presence of a component of microvascular spasms in the pathogenesis of CSF [Near five decades ago, Tambe et al. first described the hemodynamic and clinical characteristics of a small patient group with chest pain and delayed distal vasculature opacification of nonobstructive epicardial coronary arteries on selective coronary angiography . These as of CSF . Sezgin s of CSF . The anas of CSF .E-selectin were markedly higher in patients with CSF than in controls [Chronic inflammation has a well-known pivotal role in the development of cardiovascular diseases and it is associated with all stages of atherosclerosis, from initiation through progression . In thiscontrols . Li et acontrols . Similarcontrols . In rececontrols –41. The controls . It has controls . Followicontrols . In a stcontrols . A fractcontrols . This stcontrols . Anothercontrols . Esenbogcontrols . A studycontrols . They alcontrols . Our precontrols . We founcontrols . Similarcontrols , 30, 47.There are some limitations of the present study. This was a single-center, retrospective, and observational study with a relatively small number of patients. As we do not routinely exam the albumin, uric acid levels in patients undergoing elective coronary angiography could not be investigated in our study. Although it was statistically nearly significant, previous well-known indicators of CSF such as smoking, male gender, and younger age could not be shown to be independent predictors of CSF in the multivariable analysis due to the possible relatively small number of patients in the study. Additionally, clinical outcomes of the study population could not be evaluated in the follow-up. Therefore, large scale prospective randomised-controlled studies are needed to support the relationship between SII and CSF.The SII is a relatively novel inflammation-based index derived from neutrophil, platelet, and lymphocyte counts, which has been shown to predict clinical outcomes in many malignancies and cardiovascular diseases –28, 48.


From those, all patients with complete data on donor NE support (n = 238) were included. Recipients were divided into three groups according to their donor NE support: without support (n = 26), with low support of 0.01–0.2 µg/kg/min (n = 132), and with high support of > 0.2 µg/kg/min (n = 80). Receiver operating characteristics (ROC) and Kaplan Meier analysis was used to investigate the association of donor NE support and mortality after heart transplantation. Recipient and donor variables, including peri- and postoperative characteristics, were reviewed and compared. Results: NE support in donors ranged between 0 and 2.94 µg/kg/min . No association between donor NE support and mortality after HTx was observed . Neither Kaplan-Meier analysis in survival up to 5 years after transplantation (Log Rank p = 0.284) nor group comparisons showed significant differences between the groups. With few exceptions, baseline characteristics in recipients and donors were comparable between the groups. Regarding peri- and postoperative parameters, increasing donor NE support was associated with a longer duration of mechanical ventilation (68 h and 95 h vs. 47 h), longer postoperative IMC/ICU stay (14 vs. 15 vs. 19 days), and a higher need for mechanical life support post-HTx (26% and 39% vs. 12%). Conclusion: In this retrospective analysis, NE support in donors prior to heart transplantation was unrelated to differing survival after heart transplantation. However, higher doses of donor NE were associated with prolonged ventilation, longer duration on IMC/ICU, and a higher need for extracorporeal life support in recipients post-HTx. Objective: Although the application of higher doses of norepinephrine (NE) in potential organ donors is a frequent reason for heart decline, its associations with outcomes after heart transplantation (HTx) are discussed controversially. Therefore, we aimed to explore donor NE support’s potential impact on outcomes in our single-center heart transplant cohort. Methods: All patients who had undergone HTx in our center between September 2010 and April 2022 ( Orthotopic heart transplantation is currently the preferred therapy for end-stage heart failure patients. However, prolonged waiting times due to shortages of organ procurements still lead to higher death rates on the waiting list for heart transplantation (HTx). As the quality of the donor’s heart is known to have a tremendous effect on outcome and complications after heart transplantation (HTx) , it is cTherefore, this study aims to address this by investigating a potential association of donor noradrenaline support, including those with exceptionally high dosage, with morbidity within the index stay and survival up to 5 years after heart transplantation.The study followed the principles of the Good Clinical Practice and the Declaration of Helsinki. All subjects voluntarily participated, and it was approved by the local ethics committee. n = 241) were screened for eligibility. We then included all patients where information on donor noradrenaline usage and complete data on corresponding peak dose level was given (n = 238). Recipients were divided into three groups according to their donor noradrenaline support: Group 1 without noradrenaline support (n = 26), group 2 with low peak support of 0.01–0.2 µg/kg/min (n = 132), and group 3 with high peak support of >0.2 µg/kg/min (n = 80).All patients who had undergone HTx in our center between September 2010 and April 2022  and IBM SPSS Statistics Software . Figures were generated using GraphPad Prism , Microsoft PowerPoint  and IBM SPSS Statistics Software .Receiver operating characteristics (ROC) and Kaplan Meier analysis was used to investigate the association of donor NE support and survival after heart transplantation. Qualitative (dichotomous) variables have been compared using Pearson’s chi-square test or Fisher’s exact test if its conditions of application were not met. The Yates correction was applied when any of the groups contained a null value for an event. Quantitative variables were compared by a Students’ Baseline characteristics of the recipients were similar between all groups, including parameters of size mismatch and the presence of comorbidities. Furthermore, no statistically significant difference in laboratory values could be detected, including recipients’ creatinine, sodium and potassium levels as well as bilirubin and hemoglobin see .p = 0.02). Additionally, donors with no noradrenaline support had significantly lower donor sodium levels (144 mmol/L) in comparison to those with medium  and high  donor noradrenaline support.Noradrenaline support in donors ranged between 0 and 2.94 µg/kg/min . Donors with no noradrenaline support more often died from hypoxic brain damage (31%), this being significant in comparison to medium noradrenaline levels  and longer duration of mechanical ventilation after heart transplantation, with significance in comparison of those with no (47 days) to those with medium  and high support .With respect to peri- and postoperative variables, the groups did not differ in length of postoperative hospital stay, cold or total graft ischemia time, duration of surgery, or need for transfusion of packed red blood cells see . Howeverp = 0.01).With regard to overall postoperative morbidities, patients did not vary in the occurrence of severe infection or sepsis, the likelihood of kidney failure with hemodialysis post-HTx, the incidence of acute graft rejection (>1R), postoperative neurological complications, or the need for re-thoracotomy post-HTx. However, the need for extracorporeal life support (ECLS) post-HTx was increasing with a higher need for donor noradrenaline support, significant between those with no and those with exceptionally high levels . Additionally, in a subgroup analysis between high  and exceptionally high  donor noradrenaline levels, no differences regarding survival in Kaplan-Meier survival analysis could be detected either .Using receiver operating characteristic (ROC) analysis, no clear general relationship between donor norepinephrine support and survival after HTx was detected see A: AUC foLimited information is available on the association of perioperative morbidity and survival in heart transplant recipients and the level of donor noradrenaline support prior to heart transplantation. We, therefore, aimed to enlighten possible differences between levels of donor noradrenaline support on outcome after heart transplantation, and thus retrospectively analyzed 238 HTx recipients in a 10-year study period.Here, we report two main findings: First, despite differing donor baseline characteristics, donor noradrenaline levels had no effect on short-term survival up to one year after heart transplantation. Second, however not influencing survival, increasing noradrenaline levels in donors were associated with worse short-term postoperative outcomes after heart transplantation.In the current study, we could not observe an apparent association between survival up to 5 years and donor noradrenaline levels. Compared to the literature, 30-day survival in our cohort (ranging from 89–92%) was comparable to larger HTx-cohorts (89–93% ), and eqn = 212), which is in line with published data from a cohort in Brazil (89.4%) [n = 131) had support ≥0.1 µg/kg/min, which was also in the reported range of previous studies. It is worthy of note that in our cohort, the percentage of patients with support ≥0.2 µg/kg/min  was higher than in an older multicentre study from Kutschmann et al. (approximately 13%) [The usage of donors with noradrenaline support differs regionally, and the completion of data is limited. The majority of all donors in our study had noradrenaline support  . However (89.4%) ,8. In ouely 13%) . A more n = 4, Annual Report 2019), and in the mentioned study, no heart transplantation at all was performed from donors with a circulatory determination of death. Thus, the potential confounder bias of DCD vs. DBD on outcome after HTx in our reference cohorts seems to be negligible.Additionally, D’Aragon et al. recently showed (using data of the Canadian DONATE study ) that don = 26). In addition to the previous difference, in our cohort, only donors with noradrenaline support had mildly elevated sodium levels (median 149 mmol/L and. 150 mmol/L), while those without had normonatremia (median 144 mmol/L). In general, cut-off values for hypernatremia severity range between >150 mmol/ [Regarding baseline data, the recipients’ preoperative parameters were similar between the groups. Regarding the donors, in the present study, donors with no noradrenaline support more often died from hypoxic brain damage. Recently, it could be shown that intracerebral bleeding (ICB) but not hypoxic brain damage or (ischemic) cerebrovascular events such as donor cause of death were associated with reduced recipient’ survival after heart transplantation . In our 50 mmol/  and >15650 mmol/ . There i50 mmol/ ,21. Therp = 0.01). This could be seen as a possible explanation of “coping” the worse effect of higher noradrenaline levels on recipients outcome. ECLS hereby could act as a “life saver”, balancing survival in recipients, as today ECLS therapy is more common than in past transplant eras. This observation also leads to a potential socioeconomic aspect as, although survival is not significantly reduced, the potential in-hospital costs are likely to increase dramatically through a need for ECLS therapy by accepting donors with higher noradrenaline levels.Concerning perioperative morbidity, increasing donor noradrenaline levels were associated with a trend towards longer postoperative IMC/ICU stay in our cohort. This is in line with published data from Angleitner et al. , where tMoreover, we could see in those patients a trend towards a higher need for blood transfusions, more acute allograft rejection, and a higher percentage of re-thoracotomy post-HTx. These findings suggests a higher short-term risk of cardiocirculatory failure and can be seen as an indicator of a worse disease state after heart transplantation in those recipients with higher donor noradrenaline levels.2. The neurohumoral disturbances before and closely around brain death in human donors lead to hemodynamic and neuroendocrine alterations, including a catecholamine surge, and in the end to cardiac damage on a cellular level 3. Endogenous levels of norepinephrine decrease significantly below basal levels 4 after brain death, leading to hypoperfusion and the potential need for exogenous norepinephrine administration. However, it is uncertain to what degree the additional amount of iatrogenous dosage on top of the endogenous catecholamines could affect the cardiac outcome. Also, through the administration of vasoconstrictors, the distribution of the cardioplegic solution could be potentially hindered, especially for the blood flow within the coronary arteries; however, currently no data is available to undermine this hypothesis. Additionally, one cannot exclude that noradrenaline levels are a secondary indicator of a more severe disease state of the donor, thereby causing secondary damage to the donor’s heart before heart transplantation. Therefore, most likely, the influence of donor noradrenaline levels on recipient outcomes is a combined effect of both primary and secondary damages to the donor’s heart. Some or all of those potential mechanisms could be responsible for the reduced outcome we see in recipients with high donor noradrenaline; however, we cannot technically prove this hypothesis due to the nature of this study.From a pathophysiological perspective, several potential pathways could link the amount of donor noradrenaline support to the outcome of the recipient. Older data from animal experiments in dogs showed acute myocardial necrosis when administering high noradrenaline doses (>0.4 µg/kg/min)The major and obvious limitation of the current study is that it is single-center and includes only retrospective data. Therefore, with larger cohorts, preferably from the most recent era of heart transplantation and possibly with a prospective design, future studies will need to confirm or reject the association of donor norepinephrine support with outcome and survival after heart transplantation.In this retrospective analysis, norepinephrine support in donors prior to heart transplantation was unrelated to differing survival after heart transplantation. However, higher doses of donor norepinephrine were associated with prolonged ventilation, longer duration on IMC/ICU, and a higher need for extracorporeal life support in recipients post-HTx.


Background: Immune checkpoint inhibitor (ICI)-related myositis with myocarditis is a rare but potentially fatal immune-related adverse event. However, its clinical features, response to immunosuppressive treatment, and prognosis remain poorly understood. Here, we describe the clinical course of patients with ICI-related myositis overlapping with myocarditis treated at our institution and a systematic review focusing on the response to immunosuppressive therapy.Methods: We identified patients who developed ICI-induced myositis with myocarditis and were treated at our hospital using a retrospective chart review of electronic medical records. For the systematic review, studies reporting ICI-induced myositis with myocarditis were identified using the Cochrane Library and PubMed databases.Results: Of the 625 patients treated with ICIs, four developed myositis with concurrent myocarditis. All the patients received immunosuppressive therapy. We assessed the activity of myocarditis and myositis based on temporal changes in troponin and creatine kinase (CK) levels. In all patients, peak troponin values appeared later than the peak CK values . The median time from the start of ICI therapy to the peak of troponin and CK levels was 42.5 and 28 days, respectively. In all patients, CK levels decreased rapidly and steadily after the initiation of immunosuppressants. However, troponin levels were unstable and increased. In all patients, CK levels normalized within one month , but troponin levels took several months to normalize . Fourteen cases of ICI-related myositis with myocarditis were included in the systematic review. Of the 14 cases, 12 (86%) had their CK level decreased after the initial steroid treatment, but the troponin level increased and was higher than that before the start of treatment. In addition, the peak troponin values appeared later than the peak CK values (a median of 6.5 days). Eight (89%) of 9 long-term follow-up patients had troponin levels above the normal range even after CK normalization.Conclusion: In most cases of ICI-related myositis with myocarditis, troponin levels increased after the initial steroid treatment despite decreased CK levels, and exceeded pre-steroid levels. In addition, troponin remained elevated for several months after CK normalized. Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers. These drugs are being increasingly used for a large number of solid and hematological malignancies, also at early stages, and several clinical trials are underway to expand their indications . To evadICI-related myositis is rare, accounting for less than 1% of irAEs, but has a high fatality rate of up to 22% . InteresHere, we describe the clinical course of the four cases of ICI-related myositis with myocarditis treated at our institution, focusing on changes in myositis and myocarditis in response to immunosuppressive therapy. Moreover, we performed a systematic review of the literature to evaluate the treatment response of ICI-related myositis with myocarditis.A retrospective chart review was performed to identify patients with ICI-related myositis with myocarditis who were treated at the University of Tsukuba Hospital from January 2017 to August 2021. Data extracted from medical records included demographics, clinical presentation, medical treatment for irAEs, laboratory data, discontinuation or withholding of ICIs, and clinical outcomes. This case series is in accordance with CARE guidelines . This stTo identify publications reporting treatment responsiveness in ICI-associated myositis with myocarditis, a literature search was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We condCase reports or case series were the articles considered for inclusion. In addition, letters or correspondence addressing relevant cases were included. Articles were considered to satisfy the inclusion criteria if they 1) reported on patients who received an ICI either as a single agent or in combination with other ICIs and developed concurrent ICI-induced myositis with myocarditis and 2) reported on the temporal changes in serum levels of creatine kinase (CK) and troponin, which indicate the activity of myositis and myocarditis, respectively.Two reviewers (YN and KT) independently screened the titles and abstracts of the potentially relevant articles. The full texts of eligible citations were retrieved and assessed for eligibility. All disagreements were resolved by consensus. We achieved a complete consensus before inclusion. KT extracted the following information from the articles: author, year of publication, subject age, subject sex, type of cancer, type of ICI, in-hospital outcome, treatment for irAEs, time to peak CK or troponin level from ICI initiation, and responsiveness to irAE treatment. This information was checked for accuracy by YN.To understand the treatment responsiveness of ICI-associated myositis with myocarditis overlap syndrome, we first examined our institutional database. In total, 625 patients were treated with ICIs at our hospital between January 2017 and August 2021. Among these, 583 patients were treated with a PD-1 or PD-L1 inhibitor alone and 42 were treated with a PD-1 inhibitor and CTLA-4 inhibitor combination. There were four cases of ICI-related myositis with myocarditis (incidence 0.64%), consisting of three men and one woman with a median age of 75 years  . All fouAll the patients received immunosuppressive therapy –4. Two p+ T cells, CD8+ T cells, and CD68+ histiocytes, with mild infiltration of CD20+ B lymphocytes  and troponin T  . The patphocytes . Her EMGphocytes . TherefoA 77-year-old man with metastatic renal cell carcinoma (RCC) was treated with pembrolizumab. The patient had a history of unstable angina. Twenty-one days after his first dose, he developed hoarseness and back pain with an elevated CK level , and the second dose of pembrolizumab was withheld. Twenty-seven days after the first dose, worsening hoarseness, ptosis, diplopia, diffuse body pain, and lightheadedness appeared, and he was admitted to our hospital. He did not complain of chest symptoms. Blood tests showed elevated troponin T (0.176 ng/ml) and CK  levels. ECG revealed a newly developed T-wave abnormality. Echocardiography revealed a slight decrease in LVEF to 55% and wall motion abnormality in the apex. BNP level was slightly elevated (55.8 pg/ml). The result of the edrophonium test was positive. His MRI findings were consistent with myositis. The patient was diagnosed with myocarditis concomitant with myositis and MG. He was started on plasma exchange, followed by IVIG (400 mg/kg/day for 5 days) with uptilting of the oral PSL . After t+ macrophages and CD3+ lymphocytes  in the myocardium  and troponin T (2.02 ng/ml) . His ECGreported ). His MRreported . Thereforeported ).+ T cells and CD20+ B cells with infiltration of CD68+ macrophages  and CK  were also found to be elevated. Although he did not complain of chest pain or other symptoms, he was admitted to our hospital with suspected myocarditis and myositis. ECG revealed a newly developed T-wave abnormality. Echocardiography revealed a mild decrease in LVEF (45%) with local wall motion abnormalities, but this was unchanged from the echocardiography done prior to ICI administration. His BNP level was slightly elevated (91.2 pg/ml). Endomyocardial biopsy revealed moderate to severe inflammatory cell infiltration, consisting mainly of lymphocytes, and cardiomyocyte shedding. Lymphocytes were a mixture of CD3rophages . He was rophages . TherefoAfter a review of 1,258 citations in PubMed and the Cochrane Library, 14 case reports, including 14 patients, met the selection criteria of our systematic review  Figure . The cliAll 14 patients received immunosuppressive therapy starting with steroids . After tIn this institutional case series and systematic review of ICI-related myositis overlapping with myocarditis, there were two major findings. First, in most cases, troponin levels peaked later than the CK levels. The CK levels decreased rapidly and steadily after the initiation of steroid therapy. However, the troponin levels were unstable and even increased after the initiation of steroids. Second, in the majority of cases, troponin continued to rise on immunosuppressive treatment even while CK showed a decreasing trend and remained elevated for several months after CK normalized. These results indicate that myocarditis is more resistant to immunosuppressive therapy in patients with ICI-associated myositis overlapping with myocarditis.An important finding of this study was the difference in treatment response between myositis and myocarditis, as indicated by the different behaviors of CK and troponin over time. There was no correlation between CK and troponin levels, which peaked at different times. In many cases, troponin levels remained elevated even after CK normalized. This discordance could be due to the fact that myocarditis is more resistant to immunosuppressive treatment than myositis. Considering that myocarditis may be refractory to treatment, a careful long-term follow-up with troponin is required. Few cases have reported changes in troponin levels over time in patients with ICI-related myocarditis alone . In thesFor severe cases with grade 3–4 ICI-related myositis, cancer society guidelines recommend starting with prednisone 0.5–1 mg/kg or equivalent, and consideration of intravenous mPSL 1–2 mg/kg or higher-dose bolus if severely compromised . In contAlthough steroids are the first-line treatment for ICI-related myocarditis, there is a lack of evidence regarding optimal subsequent treatment for patients who are refractory to steroid therapy. Antithymocyte globulin, infliximab, mycophenolate, IVIG, abatacept, and plasmapheresis are recommended , but theOur study had some limitations. First, this was a retrospective study in nature. The timing, interval, and duration of the CK and troponin measurements varied from case to case. Second, in some cases in the systematic review, CK and troponin values or the timing of their peaks or normalizations were inferred from figures in the articles. Further research in larger cohorts that prospectively assess changes in these markers over time is needed.In most cases of ICI-related myositis with myocarditis, troponin levels increased after the initial steroid treatment despite decreased CK levels, and exceeded pre-steroid levels. In addition, troponin remained elevated for several months after CK normalized.


To compare the effects of two hand cleaning schemes on the prevention of surgical site infection in routine orthopaedic surgery. Compared with the standard surgical seven-step washing technique and detected by ATP fluorescence method, the handwashing effects of the improved surgical eight-step washing technique and the standard surgical seven-step washing technique were compared, so as to provide a basis for eliminating the handwashing blind area of the surgical seven step washing technique and improving the surgical handwashing method. Main Outcome Measures. The infection rate of surgical site 30 days after operation was the primary end point. The qualified rate of fingertip culture was combined with ATP fluorescence in the two groups and three new culture areas in the two groups: the lateral edge of the palm, the medial edge of the palm, and the nail groove of the middle finger and the nail root were secondary end points.  A total of 800 consecutive patients who underwent clean and clean-contaminated orthopaedic surgery between January 1, 2020 and December 31, 2020. Twenty orthopaedic doctors in the operating room of our research team were randomly divided into the improved eight-step washing technique group (improved group) and the traditional seven-step washing technique group , with 10 people in each group. Each person was randomly sampled 40 times, 400 people in each group, a total of 800 people, and completed by stages in 12 months. P < 0.05). There was no significant difference in the qualified rate of fingertip culture (P > 0.05). The handwashing scheme in this study meets the recommended duration of hand disinfection and has good tolerance, and the skin dryness and skin irritation after using aqueous solution are similar.  The 2 protocols were comparable in regard to surgical site infection risk factors. The infection rate of surgical site in the traditional group was 10 cases (2.50%) in 400 cases and 0 cases (0%) in the improved group. Three culture areas were added: the qualified rate of lateral edge of palm, medial edge of palm, and nail groove and nail root of middle finger, and the nosocomial infection rate of surgical incision between the two groups was statistically significant ( The improved surgical eight-step washing technique combined with ATP fluorescence detection is helpful to eliminate the “blind area” of handwashing. It is also necessary to add three training areas. Handwashing and training are more scientific, rigorous, and effective. They are effective in reducing orthopaedic surgical infection and have application value. They can safely replace the traditional surgical seven-step washing technique, which is worthy of clinical promotion. Due to China's large population, limited medical resources, large-scale medical institutions, dense patients, and heavy workload of medical staff, medical staff often ignore hand hygiene, resulting in pollution and hospital infection; Hand is an important way to spread the sense of hospital. Surgical site infection prolongs hospital stay, is one of the main causes of incidence rate, and is also the source of high medical expenses . Hand hyIn this study, three handwashing blind areas and training blind areas existed in the standard surgical seven-step washing technique were improved. While using the standard fingertip sampling culture, the sampling culture of hand-washing blind areas was increased. The qualified rate of handwashing and the nosocomial infection rate of orthopaedic surgical incision were compared between the two groups.From January to December 2020, the handwashing environment and other conditions were the same. 20 orthopaedic doctors in the operating room environment were selected and randomly divided into the improved group and the traditional group, with 10 people in each group. Each person was randomly sampled 40 times, with 400 people in each group, a total of 800 people. They were completed in stages in 12 months. Combined with ATP fluorescence method, the qualified rates of three new culture areas in the two groups: the lateral edge of the palm, the medial edge of the palm, and the nail groove and nail root of the middle finger, were detected and compared, and the qualified rates of fingertip culture and the nosocomial infection rate of the incision after operation were compared between the two groups. The sampling work was completed by the members of this study in stages.① The traditional group used standard surgical seven-step washing to wash hands. ② The improved group used the improved surgical eight-step washing technique and washed the arm for the first time: washing hands to 5 horizontal fingers on the elbow was the objective standard. Wash your arms for the second time: wash your hands to 4 horizontal fingers on the elbow as the objective standard, and apply disinfectant to 3 horizontal fingers on the index finger, middle finger, and ring finger as the objective standard. The first seven steps are the same as above. Step 8: similar to step 6, close your fingers together and put them on the other hand. There are three blind areas: the outer edge of the palm, the inner edge of the palm, and the nail groove and the nail root, which are carried out alternately.Before and after handwashing, each subject took 4 samples from four culture areas, including conventional fingertips, and three new culture areas: the outer edge of the palm, the inner edge of the palm, and the nail groove of the middle finger and the root of the nail. Spin and smear the cotton swab of the bacterial culture tube at the above four sampling places twice and submit it for inspection; biological detection method: take the samples stored in PBS and shake them sufficiently to make the microorganisms on the cotton swab dissolve in PBS as much as possible. After the Petri dish is numbered, add 0.5 ml of the sample into the Petri dish, spread it evenly with a sterile l rod, and make 3 copies of each sample. After all smearing and culture, put it into 37°C incubator for 72 hours. Record the number of growing colonies and calculate the average value as the test result. The control adopts PBS solution control and empty Petri dish control. The positive control of Escherichia coli is added to the Petri dish. It is cultured at 37°C for 72 hours with the sample for observation and detected by ATP fluorescence method. Observe and record the results of finger improved surgical eight-step handwashing combined with ATP fluorescence detection and bacterial culture+drug sensitivity test after surgical washing manipulation.2) = plate colony × dilution multiple/sampling area (cm2). The ATP fluorescence test of the operator is negative, and the bacterial culture ≤ 5 CFU/cm2 is qualified. The infection rate of the operation site was calculated when the patient had no infection at the operation site within 30 days after the operation, which was negative and positive. 30 days after operation, the infection rate of operation site in the two groups was the primary end point. The qualified rate of fingertip culture in the two groups and three new culture areas in the two groups: the lateral edge of the palm, the medial edge of the palm, and the nail groove of the middle finger and the nail root were detected by ATP fluorescence method. The qualified rate of culture after operation was the secondary end point. The SPSS23 0 statistical software was used for data analysis. The normal measurement data is expressed by “mean ± SD,” and the counting data is expressed by the number of cases or percentage.Calculation formula of biological monitoring quantity is as follows: total bacteria . There were significant differences in the samples of the lateral edge of the palm, the medial edge of the palm, and the nail groove of the middle finger and the nail root (P < 0.05)  .P < 0.05)  .See See In the 19th century, Semmelweis first noted the link between hospital-acquired diseases and hand hygiene . NosocomThis study focuses on orthopaedics with higher risk of implant infection, which requires higher and more rigorous surgical procedures. If it can reduce the infection of orthopaedic surgery, the improved eight-step washing technique is suitable for preoperative handwashing in orthopaedics and other surgeries with built-in objects, and it is also more suitable for preoperative handwashing in other surgeries. ATP fluorescence method and traditional bacterial culture method are effective and scientific. ATP fluorescence method is simpler than traditional bacterial culture method.P > 0.05). It shows that the disinfection of fingertips by standard seven-step washing technique is qualified. However, there were three new culture areas: the lateral edge of the palm, the medial edge of the palm, and the nail groove and nail root of the middle finger. The difference of the infection rate of the surgical incision was statistically significant. The difference was statistically significant (P < 0.05). It shows that the seven-step washing technique has a “blind area.” The improved surgical eight-step washing technique combined with ATP fluorescence detection is helpful to eliminate the “blind area” of handwashing. It is also necessary to add three training areas. Handwashing and training are more scientific, rigorous, and effective. They are effective in reducing orthopaedic surgical infection and have application value. They are worthy of preoperative handwashing with built-in devices in clinical orthopaedics and are also more suitable for preoperative handwashing in other surgeries. In addition, orthopaedic doctors wear double gloves to prevent occupational exposure caused by accidental puncture of Kirschner wire tip and broken bone end, which is also worthy of promotion. Novel coronavirus pneumonia, which is now safe, more scientific, more rigorous, and effective, is also worth promoting in the new crown pneumonia epidemic. It can reduce cross infection, protect the patients who are fighting the epidemic, and protect the people in the isolated area. The eight-step washing technique is also worth promoting in the COVID-19.Therefore, this study selected a group of orthopaedic doctors as the research object. It was found that the two handwashing methods were handwashing and sampling according to the requirements of disinfection technical specifications. There was no significant difference in the qualified rate of fingertip samples (


Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol . For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases.Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life , time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles.The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs. While the renal glomerular filtration rate (GFR) is clinically used as marker of clearance of drugs and solutes from blood , the cerSince the dual discoveries of the glymphatic system in 2012 , there hAssessment of CSF to blood clearance might as well be useful to tailor dosage of intrathecal drugs. Today, intrathecal drug administration seems promising in order to treat a wide range of diseases within the CNS, such as neuro-inflammatory, neuro-degenerative, neuro-oncologic, and neuro-vascular diseases –20. ManyOur group has used intrathecal administration of the magnetic resonance imaging (MRI) contrast agent gadobutrol (serving as a CSF tracer) to explore molecular passage from CSF to the brain , 23, menA prospective and observational study design was utilized; randomization or a priori sample size calculation was not relevant.The study included patients referred to the Department of neurosurgery, Oslo University Hospital—Rikshospitalet, Oslo, Norway, who were examined for tentative CSF disorders, and in whom intrathecal contrast enhanced MRI was considered indicated for clinical reasons. Individuals who were not eligible for inclusion included subjects with a history of hypersensitivity reactions to contrast media agents, severe allergic reactions in general, evidence of renal dysfunction, i.e. glomerular filtration rate (GFR) < 30, age < 18 or > 80 years, or pregnant or breastfeeding women.reference subjects (REF) includes individuals in whom we found no apparent evidence of CSF disturbance and no indication for surgery. The group with spontaneous intracranial hypotension (SIH) had an identified CSF leakage that required surgery to close the leakage. The present subjects in the category idiopathic intracranial hypertension (IIH) were shunted and demonstrated clinical improvement thereafter. Patients with pineal cysts (PC) or arachnoid cysts (AC) underwent surgery with cyst removal and demonstrated post-operative clinical improvement. The category idiopathic normal pressure hydrocephalus (iNPH) included patients who based on clinical workup, imaging findings and results of intracranial pressure (ICP) monitoring [Patients were categorized according to tentative diagnosis prior to MRI, and underwent work-up, including blood sampling, prior to any treatment. The category nitoring , 30, undnitoring .The MRI contrast agent gadobutrol  was administered intrathecally in volumes of 0.10, 0.25 or 0.5 mL (1.0 mmol/mL) at a speed of a few seconds. The intrathecal injection procedure was done at the lumbar level. Correct entrance to the subarachnoid space was verified by CSF backflow from the spinal needle.The first 80 patients received intrathecal gadobutrol in a dose of 0.50 mmol only, and the latter patients received intrathecal gadobutrol in alternatig doses of 0.10 mmol, 0.25 mmol or 0.5 mmol.Venous blood samples were obtained at empirically determined regular time points up to about 48 h after intrathecal administration of gadobutrol, and were stored at -80 °C. Quantification of gadolinium to estimate concentrations of gadobutrol in blood and plasma was performed as previously described . In shorIn this work, both plasma and whole-blood gadobutrol were used. Linear regression through the origin was used to determine the plasma to whole blood ratio, and whole blood concentration of gadobutrol was interpolated to plasma concentrations for the purpose of pharmacokinetic modelling.2-values of the observed versus predicted plots, Akaike’s information criteria (AIC) and the Bayesian information criteria (BIC) also guided model development to some extent. Covariates were not included, due to sole interest in individual predictions.A population pharmacokinetic model was developed in order to determine individual pharmacokinetic parameters of intrathecally administered gadobutrol. A non-parametric adaptive grid approach implemented in Pmetrics (version 1.9.7) for R (version 4.0.0) was used . Based oPosterior individual parameter values, as well as posterior individually predicted concentrations obtained from the final population pharmacokinetic model run with the complete dataset, were used for all pharmacokinetic calculations. Predictions were made in one-minute intervals from time of administration and up to 72 h. The following pharmacokinetic variables were evaluated:1/2, abs) is defined as the time for half the amount of gadobutrol in the CSF to be cleared to blood. This parameter was used as a surrogate marker for CSF to blood clearance of gadobutrol. T1/2, abs was calculated by dividing the natural logarithm of 2 over the model-estimated coefficient of absorption (Ka) from CSF to blood.The absorption half-life (Tmax) in plasma and maximum concentration (Cmax) in plasma were obtained directly from the individual predictions.Time to maximum concentration (Tlag) is the model-estimated time for the tracer to reach the site of clearance in CSF. Longer Tlag thus implies that the molecule stays longer within CSF or that it takes longer before the clearance process to blood starts.Lag-time of absorption to blood (T0-∞) was calculated with the trapezoidal approximation from individual posterior predicted concentrations using the ‘makeAUC’-function in the Pmetrics package for R. The AUC is a measure of systemic exposure of gadobutrol.Area under the concentration–time curve from zero to infinity . Patients were under clinical work-up for possible CSF disorders, with diagnosis categories as indicated in Table The study included 161 patients, with a mean ± SD age of 54 ± 19 years (range 19 to 82 years), and with a mean body mass index (BMI) of 28 ± 5 kg/mSeveral groups were statistically significantly different from the reference (REF) cohort, with respect to gender, age, height, body mass index (BMI), and kidney function. A total of 1,140 samples were analyzed for gadobutrol in plasma or whole blood; the mean number of samples was 8 ± 2 in each subject (range 1 to 11 samples).R2adjusted = 0.997; P < 0.001) with whole blood concentration of gadobutrol  and absorption lag-time, and the model described the data well Fig. A. The fi0-∞ between the dose levels of 0.1 mmol and 0.5 mmol was found . Additionally, mean predictive error of the population pharmacokinetic model was not different between dose levels.Mean pharmacokinetic profiles across intrathecally-administered doses of gadobutrol are shown in Fig. max) and dose-normalized maximum concentration (Cmax) were 8.60 ± 4.58 h (CV 53%) and 0.69 ± 0.42 μM (CV 61%) respectively. The large inter-individual variability of pharmacokinetic parameters irrespective of diagnosis is shown in Fig. Irrespective of diagnosis category, a large degree of inter-individual variability was observed with respect to the pharmacokinetic parameters of intrathecally administered gadobutrol. For the complete dataset, mean absorption half-life was 3.83 ± 2.50 h, with a coefficient of variation (CV) of 65%, which did not vary with dose. Time to maximum concentration  to urine. It also has been demonstrated reduced clearance of a PET ligand from cerebral ventricles to the nasal turbinate in Alzheimer patients [18F-THK5351 and 11C-PiB) from ventricular CSF in 99mTc-DPTA), and the diagnostic process is both expensive and time-consuming.Up to now, the literature on CSF to blood clearance has been scarce. The presently described model is derived from 1,140 blood samples in 161 patients, referring to plasma levels of gadobutrol measured subsequently to intrathecal injections of predefined quantities. Utilizing positron emission tomography (PET), others  previouspatients . Furtherpatients  showed rThe most significant observation of the present study is the large inter-individual variation in CSF to blood clearance, as well as the differences between CSF disease. Compared to the reference cohort, patients diagnosed with pineal or arachnoid cysts, and to some degree patients with spontaneous intracranial hypotension, did not present any differences in pharmacokinetics of intrathecally administered gadobutrol. On the other hand, a statistically significant longer lag-time was found in Patients with idiopathic intracranial hypertension, on the other hand, demonstrated a significantly reduced absorption-half life, possibly indicating faster egress of molecules from CSF to blood due to increased ICP. Furthermore, in lag) might be related to passage capacity within the thecal sac, but we have previously not found differences between groups for time between lumbar injection and first appearance at the cranio-cervical junction, i.e. spinal transit time [We may not from the present data decipher which transport routes gadobutrol follow from the CSF to blood. Emerging evidence points at the role of meningeal lymphatic vessels for molecular egress from CSF to blood, which is supported by findings of reduced clearance of neurotoxic metabolites from CSF when meningeal lymphatic clearance routes are impaired . In humasit time . We suggsit time , 51, andsit time  and Alzhsit time  diseasessit time . In compsit time .While plasma levels of gadobutrol primarily reflect clearance from CSF along extra-vascular pathways, a minor leakage of tracer through the BBB may to a limited extent contribute to the clearance as ageing as well as neurodegenerative disease may be accompanied with impaired BBB integrity , 56. Evi99mTc-DPTA nuclear imaging [The present observations may have several clinical implications; we would like to highlight three areas. First, the present observations suggest that assessing CSF to blood clearance adds to characterization of CSF diseases on the individual level. One example is the identification of CSF leakage in individuals with spontaneous intracranial hypotension; it is well established that it may be very difficult to identify the site of CSF leakage . Current imaging , though max), longer lag time (Tlag) and higher AUC, as compared with reference subjects. However, the difference in AUC may be attributed to the difference in age and renal function compared to the reference cohort.Second, direct measurements of CSF to blood clearance might prove useful in preclinical stages of neurodegenerative and dementia disease. Measurements of circulating substances such as amyloid-β and tau may be used for screening purposes, providing an indicative risk of disease . HoweverThird, estimation of CSF to blood clearance may be useful preceding intrathecal drug administration for treatment of neurological disease. Even though it was traditionally thought that a substance within the CSF only passed a few millimeters into the cortical substance , intrathSome limitations should be noted. Gadobutrol is administered off-label as it is not approved for intrathecal use. However, here we used gadobutrol in intrathecal doses of 0.10, 0.25 and 0.50 mmol, which have all been proven safe . Toxic eIn this work, the less tangible absorption half-life was used as a surrogate marker for CSF to blood clearance, instead of actual clearance, due to the lack of accurate determinations of individual CSF volume. However, this does not affect the interpretation or accuracy of the results. With regard to the possible normal CSF to blood clearance in healthy people, it may as well be considered a limitation that we included a range of patients spanning multiple defined CSF disturbances. It was, however, beyond the scope of this work to discuss in detail the underlying diagnoses and the clinical significance of each disease category. Additional work on the subject would benefit from the inclusion of individuals without evident neurological disorders, in order to establish a reference value and level of variability in a healthy population. Furthermore, it remains to be determined whether gadobutrol is a valid marker for clearance of other intrathecally administered drugs and endogenous metabolites of interest in disease such as amyloid-β, tau, and α-synuclein.In conclusion, this work provides a population pharmacokinetic model of CSF to blood clearance based on 1,140 blood samples from 161 subjects. Our data demonstrates a large degree of inter-individual variability in CSF to blood clearance as well as different clearance profiles across disease categories. CSF clearance function might both be a secondary feature of various neurological diseases, and a primary driver behind disease. As such, extensive clearance may characterize CSF leakage and spontaneous intracranial hypotension, while protracted clearance may be a contributing factor in neurodegenerative diseases. In the therapeutic setting, CSF to blood clearance may prove useful for tailoring dosage of intrathecal drugs, an administration route with prospects of increased utility in the near future.


During hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations.This observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels.p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol . Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels.Groups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (Hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities. Under normal physiological conditions, the glycolytic hexokinase pathway metabolises cerebral glucose via brain-specific hexokinase isoforms . HoweverPolyols are cyto- and neurotoxic , 4, and Previous research has demonstrated low CSF polyol concentrations in normoglycaemic healthy individuals  and pregGiven the likelihood of saturation of the hexokinase pathway under supraphysiological glucose concentrations, we hypothesised that hyperglycaemia causes a proportional increase in CSF glucose, sorbitol and fructose concentrations, and in ratios of CSF fructose and sorbitol to CSF glucose. However, polyol concentrations and CSF polyol/glucose ratios under varying glycaemic conditions in patients without evident neurological abnormalities have not been investigated to date. Therefore, we aimed to study CSF fructose and sorbitol concentrations and ratios of CSF fructose and sorbitol to CSF glucose in patient groups with either normal or elevated CSF glucose concentrations., we used biomaterial and data from patients enrolled in a prospective cohort study, the Anaesthetic Biobank of Cerebrospinal Fluid (ABC) study. Plasma, CSF and clinical data were obtained from a subset of participants of the ABC repository, which was designed to collect and store CSF from patients without major neurological disease for future neuroscientific research. Patients aged 18 years or older, scheduled for elective surgery under spinal anaesthesia, were eligible for inclusion. More extensive details of the study design, patient inclusion, and data and biomaterial collection are described elsewhere  and groups 1 and 3 [p=0.002]), and sex differed significantly between groups 1 and 3 (p=0.015). BMI ranged from 19 to 40 kg/m2, with a median of 30 for the total sample. There was a significant difference in the American Society of Anesthesiology (ASA) physical status [n = 23). Only group 1 had a median MoCA score in the normal range , groups 2 (n = 6) and 3 (n = 7) had a significantly lower MoCA score . Median Qalb values differed significantly between groups 1 and 3 (p<0.001), but were within the normal range in all groups , and 90% were using at least one medication. Twenty-six of the patients had not suffered from an active central nervous system disorder in the 12 months preceding the collection of biomaterials. The four patients who did have a central nervous system disorder in the 12 months before biomaterial collection included one patient from group 1 (depression), two patients from group 2 , and one patient from group 3 . One patient from group 1, three patients from group 2, and no patients from group 3 used corticosteroids. All patients in group 3 used glucose-lowering medication. Five patients were on insulin therapy, of whom three used a combination of rapid-acting and long-acting insulin, one patient used rapid-acting and intermediate-acting insulin, and one patient used rapid-acting insulin together with ultra-long-acting insulin. Four patients were on oral glucose-lowering drugs, including biguanides, sulfonylurea derivatives and dipeptidyl peptidase 4 inhibitors. One patient used a combination of rapid-acting and long-acting insulin and a biguanide.p<0.001). Pairwise comparisons between groups showed significant differences for plasma glucose levels between groups 1 and 2 (p=0.030) and groups 1 and 3 (p<0.001). CSF glucose concentrations differed significantly between groups 1 and 2 (p=0.009) and groups 1 and 3 (p<0.001). Group 3 showed a significant difference compared with group 1 for both CSF sorbitol (p<0.001) and fructose levels (p<0.001), and also showed a significant difference for CSF sorbitol compared with group 2 (p=0.036) .Plasma glucose and CSF glucose, sorbitol and fructose values are shown in Table Our test samples showed that the detection limit of sorbitol and fructose in plasma and CSF was 6 μmol/l when processing 500 μl of material. Sorbitol was not detectable in plasma, and plasma fructose showed an abnormal peak pattern compared with what would be expected for CSF fructose (data not shown). Therefore, it was decided not to determine plasma polyols for the entire study population.Qalb and age are shown in Table rs = 0.813, p<0.001), sorbitol  and fructose  when all patients were grouped together , as well as in group 1 , group 2  and group 3  individually.The correlations between plasma and CSF glucose, sorbitol and fructose, MoCA scores, er Table . Moreovep<0.01), CSF glucose (p<0.01), CSF sorbitol (p<0.05) and CSF fructose (p<0.01) .Preoperative MoCA scores were moderately inversely correlated with plasma glucose (1) Table . There wrs = 0.516, p=0.004)  and CSF fructose . The CSF sorbitol/glucose ratio differed significantly across the groups (p=0.009), and there was a significant difference in the ratio between groups 1 and 3 (p=0.017) and between groups 2 and 3 (p=0.031)   Fig. , but not31) Fig. . The CSF24) Fig. .p≤0.001) (Table p=0.015), but not with the CSF fructose/glucose ratio (p=0.188). Finally, there was a significant difference between men and women for plasma glucose, CSF glucose and CSF sorbitol/glucose ratio , and for CSF sorbitol and CSF fructose (p<0.01), but not for the CSF fructose/glucose ratio (p=0.146).Age was positively correlated with plasma glucose and CSF glucose, sorbitol and fructose  Table , and theIn this study, patients with elevated CSF glucose levels also had significantly higher CSF sorbitol and fructose levels. Even when CSF glucose values were similar, patients with diabetes had a significantly higher CSF fructose, CSF sorbitol and CSF sorbitol/glucose ratio compared with patients without diabetes. Furthermore, CSF glucose, sorbitol and fructose concentrations increased linearly with an increase in systemic glucose levels. These findings are in line with our primary hypothesis that hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without brain disorders.This proof-of-concept study is relevant because we demonstrate an activation of the polyol pathway across a broad spectrum of plasma and CSF glucose levels in patients both with and without diabetes. Activation of the polyol pathway is associated with possible cyto- and neurotoxic properties, and is thought to play a role in brain abnormalities and cognitive impairment through the formation of AGEs, non-enzymatic glycation of myelin or oxidative damage/stress –10. For Our findings are consistent with the principle of Michaelis–Menten kinetics , which sQalb. Thus, the differences between the two groups could not be attributed to these factors. The steep increase may be due to a statistical dispersion; however, no such correlation was demonstrated between CSF sorbitol/systemic glucose ratios and between CSF fructose/systemic glucose ratios. Possibly it is due to upregulation of the cerebral polyol pathway in diabetes patients because of chronic hyperglycaemia, combined with a saturation of the hexokinase pathway, leaving more glucose in the CSF for the polyol pathway. It has previously been shown that a state of chronic hyperglycaemia leads to an upregulation of the polyol pathway [Interestingly, the CSF polyol/glucose ratios were exponentially increased when patients had diabetes, despite the fact that the CSF glucose levels of groups 2 and 3 were similar and there were no between-group differences in age, sex, MoCA scores or  pathway , 29, and pathway , there i pathway .Plasma glucose correlated significantly with the CSF sorbitol/glucose ratio, but not with the CSF fructose/glucose ratio. Possibly this difference may be related to fructose catabolism by redirection of fructose to the pentose phosphate pathway via hexokinase or ketohexokinase . AlternaThe measurement of polyols in CSF is a derivative measure of cerebral metabolism. As polyols can also be transported across the blood–CSF barrier, one may question the validity of CSF polyol values as a marker of cerebral glucose metabolism . However1c levels); it would be preferable to include these diagnostic measurements in future studies of diabetes patients.A limitation of the present study is that the data do not provide information about changes in glucose, sorbitol and fructose concentrations in the CSF over time, as these could not be determined given our current study design. Proof of activation of the cerebral polyol pathway over time could be provided by infusion of stable isotope-labelled glucose and subsequent recovery of these isotope labels in the sorbitol and fructose. In addition, a relatively small sample size was used, which did not allow statistical correction for patient characteristics such as age, sex, ASA physical status classification or MoCA scores. This may be remedied in the future by using a larger sample size. Finally, it is possible that some patients in group 2 may have had undiagnosed type 2 diabetes, and not all data important for diabetes patients were known (e.g. lipid status and HbAIt is important to study whether these harmful metabolites are related to patient-relevant postoperative complications, and our results show that future studies can explore the potential of systemic glucose-lowering therapies such as insulin or incretin-based therapies to optimise cerebral glucose and polyol metabolism . SuppresIn conclusion, this study has demonstrated that, even in patients without evident neurological abnormalities, glucose is converted to polyols in the polyol pathway. We have shown increased levels of cerebral polyols in patients with diabetes, which is a first indication of an upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities. Future studies could further investigate how this increase in polyols in the CSF evolves over time, and whether they are indeed associated with clinically relevant patient outcomes, and if so, whether reducing glucose conversion in the polyol pathway results in a reduction in the incidence of such outcomes.


Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with an unpredictable clinical behavior. Pleural EHEs have been associated with poor response to treatment and reduced survival. To date, no standard treatment for EHE is available. Here we report the case of a 53-year-old man who underwent radical surgery for a symptomatic primary pleural EHE. Clinical presentation was characterized by chronic pain in the left hemithorax with transitory flare, anemia, weight loss and progressive worsening of clinical conditions. After surgery, he resumed active life and normal daily activities and, at 8 months, 18F-FDG PET and computed tomography scan showed no radiological evidence of recurrent disease. Clinical signs of this rare disease, histological features, imaging findings and functional imaging are discussed. We also report a summary of other cases with resected pleural EHE and we briefly review the role of chemotherapeutic, immunomodulatory and antiangiogenic drugs for advanced disease. Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma, affecting approximately less than one in a million people worldwide. The clinical courses of patients with EHE are characterized by initial misdiagnoses and unpredictable behavior ,2.Although different primary tumor locations have been described so far, more frequently EHE arises in liver, soft tissue or lung, with a typical multifocal and/or multicentric onset. Pleura is an uncommon site for primary tumor and ,4 pleuraGiven the rarity of the disease and the lack of large prospective trials, no established standard treatment for EHE is available. The management of advanced and symptomatic disease is often very challenging since chemotherapeutic agents approved for soft tissue sarcomas have limited activity in EHE .WWTR1-CAMTA1 gene fusion in about 90% of cases, and YAP1-TFE3 gene fusion in about 10% of cases, seemingly associated with different clinical course [Two translocations are the most common gene alterations of EHE: l course .Here we report a patient who had successfully treated with macroscopically radical surgery for symptomatic primary pleural EHE.In April 2020, a 53-year-old Caucasian man came to our hospital, presenting chronic pain in the left hemithorax with transitory flare, particularly in the evening. A diagnosis of pleurisy was initially suspected and the patient received antibiotics, corticosteroids and no steroidal anti-inflammatory drugs with low improvement. The patient was then hospitalized due to a quick pain worsening. A computed tomography (CT) scan showed a very slight left pleural effusion, multiple bilateral ground glass pulmonary nodules with ‘tree-in-bud’ pattern and an inflammatory thickening in the left lower lobe. Thus, bronchoscopy with transbronchial needle aspiration was performed with negative results. In May 2020, an 18F-FDG PET showed a mild diffuse tracer uptake in the left pleura Fig. . On surgSurgery consisted in a left extrapleural pneumonectomy Fig. . A firstn = 32) treated at The Royal Marsden Hospital, 20% of whom underwent surgical resection, surgery and liver only disease were the two main factors associated with long-term survival outcomes [Diagnosis and treatment of EHE remain a challenge. A watchful-waiting approach until disease progression could be a reasonable option mostly in patients with multifocal and/or multicentric presentation without symptoms and/or serosal effusions. Some authors indeed reported long-lasting stable disease (SD) with observation only or even a spontaneous regression of metastatic lesions ,8,20. Aloutcomes . Unfortuoutcomes ,21–24. Aoutcomes ,25,26.P < 0.0001) and OS of 10.6 months (P < 0.0001) [Immunomodulatory and antiangiogenic drugs seem to be the most promising treatment options, but evidence derives primarily from retrospective case series and case reports. Interferon and thalidomide were initially used with conflicting results ,24,27,28 0.0001) .et al. Although no responses were observed in pretreated patients, disease stabilization and symptom control were reported [Given the vascular origin of EHE, the antiangiogenic strategy was considered a rational approach and the activity of several drugs has been studied in the past. The French Sarcoma Group conducted a phase II trial with sorafenib in 15 patients with EHE, of whom 10 in first-line treatment and 5 in subsequent lines. Only one patient in this group had a primary pleural EHE. Sorafenib showed a modest clinical activity with 9-month PFS rate of 30.7% and 2-year OS rate of 26%. Two PR were reported [reported . Prolongreported ,32, withreported . A retroreported  conversereported . Bevacizreported .Although our patient had several negative prognostic factors as pleuro-pulmonary disease, pleural effusion and systemic symptoms, he greatly benefited from palliative surgery. Nevertheless, the management of patients with pleural EHE remains challenging and extended palliative surgery, as in our case, cannot be routinely proposed. Only a few cases of patients treated with palliative surgery for pleural EHE have been reported Table . OverallThere are no conflicts of interest.