Comatose patients admitted after resuscitation from cardiac arrest have a significant risk of poor outcome due to hypoxic brain injury. While numerous studies have investigated and challenged the target temperature as the efficacious part of the guideline endorsed Targeted Temperature Management (TTM) protocols, our knowledge and how the remaining parts of the TTM are optimized remain sparse. The present randomized trial investigated two aspects of the TTM protocol: target blood pressure during the ICU stay and oxygenation during mechanical ventilation. Furthermore, the efficacy of device-based post-TTM fever management is addressed.Investigator-initiated, dual-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Patients are eligible for inclusion if unconscious, older than 18 years of age, and have return of spontaneous circulation for more than 20 min.Intervention: allocation 1:1:1:1 into a group defined by (a) blood pressure targets in double-blind intervention targeting a mean arterial blood pressure of 63 or 77 mmHg and (b) restrictive (9–10 kPa) or liberal (13–14 kPa) of arterial oxygen concentration during mechanical ventilation. As a subordinate intervention, device-based active fever management is discontinued after 36 h or 72. Patients will otherwise receive protocolized standard of care according to international guidelines, including targeted temperature management at 36 °C for 24 h, sedation with fentanyl and propofol, and multimodal neuro-prognostication. Primary endpoint: Discharge from hospital in poor neurological status  or death, whichever comes first. Secondary outcomes: Time to initiation of renal replacement therapy or death, neuron-specific enolase (NSE) level at 48 h, MOCA score at day 90, Modified Ranking Scale (mRS) and CPC at 3 months, NT-pro-BNP at 90 days, eGFR and LVEF at 90 days, daily cumulated vasopressor requirement during ICU stay, and need for a combination of vasopressors and inotropic agents or mechanical circulatory support.We hypothesize that low or high target blood pressure and restrictive and liberal oxygen administration will have an impact on mortality by reducing the risk and degree of hypoxic brain injury. This will be assessment neurological outcome and biochemical and neuropsychological testing after 90 days.ClinicalTrials.gov NCT03141099. Registered on May 2017 (retrospectively registered) The order of the items has been modified to group similar items  arrest , the in-The current study investigates two goals in the guideline-based critical care of comatose patients resuscitated from OHCA: target mean arterial blood pressure and arterial oxygen concentration.While the American and European guidelines agree that MAP below 65 mmHg should be avoided , 20, theThe important question for clinicians is how to decide on the optimal MAP after cardiac arrest. A clinical equipoise remains, and while considerable effort is put into managing comatose patients after cardiac arrest, large studies of MAP modification with noradrenaline, a cheap and easily adopted intervention, are needed, as guidelines are largely based on expert consensus .The guidelines recommend that oxygen saturations of 94–98% are targeted in the post-resuscitation period . Recentl2 is usually covering this range by targeting 9–14 kPa during TTM and when mechanical ventilation is needed. The trial will compare two strategies of targeting low-normal PaO2 of 9–10 kPa (restrictive) and high-normal PaO2 of 13–14 kPa . Measures and interventions to maintain the allocated PaO2 are left at the discretion of the attending physician, but a charter for treatment and maintenance of the allocated PaO2 targets is developed as an aid for the attending clinicians.The normal target PaOA number of predefined substudies have been included as part of the trial and will be described in detail elsewhere. The trial steering group agrees to allow the patients to be included in other interventional trials, if deemed unlike to impact on the efficacy of the blood pressure and oxygenation target interventions.Post-hypothermia fever is associated with worse clinical outcomes in comatose patients admitted after resuscitation from OHCA , 37. Cur2 interventions; analyses will not be performed until these two interventions are unblinded.As a subordinate study, the patients included in the present study will all be randomized 1:1 to be actively fever controlled for 72 h post-OHCA or to have the active fever control device withdrawn at 36 h. Randomization will occur at the time of randomization for the other main treatment allocation strata. Apart from using a mechanical fever control device, management of fever will be at the discretion of the attending physician according to local guidelines. Temperatures and administration of paracetamol and duration of active device-based fever control will be monitored. Fever above 37.5 °C should be managed in both groups for the first 72 h or until the patients are alert and responsive, and fever 38.5 °C should be avoided. Endpoints of this intervention are the same as for the BP and PaOA pulmonary artery catheter will be placed at the time of placing the central venous line. Measurement of pulmonary artery pressure, wedge pressure, central venous pressures, and mean systemic arterial pressure  will be obtained, as well as cardiac output by thermodilution technique by rapid injection of 10 ml of cold isotonic glucose. Measurements of cardiac output will be performed in triplicate and will be repeated until three measurements with a variation of less than 10% are available.The hypothesis investigated will be that the higher blood pressure group will have lower perfusion (cardiac output) than the low blood pressure target group. Further secondary outcomes are regarding the impact on systemic and pulmonary circulation, as well as the impacts of the two oxygenation targets on the pulmonary circulation in particular. Furthermore, the impact of demographic and clinical factors on central hemodynamics will be investigated.Automated pupillometry has recently been included in the American as well as in the European guidelines on prognostication after out-of-hospital cardiac arrest , 20. WhiAutomated pupillometry will be performed serially during and after TTM treatment by the Neuroptics® NPI-200 device. Measurement will be stored in the SmartGuard® device (a single-use chin guard or spacer) developed for the device. The data from the automated pupillary assessment can be requested by the clinician, but is not routinely recoded in the clinical charts, as automated pupillometry was not a guideline supported part of the prognostication when the trials were initiated. Automated pupillometry has recently been included in the European and the American guideline, still with no consensus on cutoff values for predicting poor outcome.The substudy investigates the prognostic significance of automated pupillary assessment as part of the multidisciplinary prognostic assessment of patient resuscitation from cardiac arrest. Previous studies have suggested different cutoffs for poor prognostic outcome and more data from prospective trials.A biobank containing blood drawn as several time points has been established. Neuron-specific enolase is the only predefined defined marker of outcome in the main trial, but since the initiation of the trial, several other markers have been investigated and the trial biobank will contribute to further consolidating these findings , as wellImpact of the two trial interventions on the cognitive function was estimated by the Cerebral Performance Category score , 49, theFurthermore, the quality of life of the patient and next of kin, the IQ-code CA , and twon = 60). The protocol for this intervention has been published [By means of microdialysis, via a retrograde central venous line in the jugular vein sampling blood at the jugular bulb, lactate and pyruvate concentrations are measured during the TTM phase in a subgroup  with regard to a combined endpoint of time to:Death from any cause orDischarge from hospital in a state of Cerebral Performance category 3 or 4, whichever occurs firstTo evaluate the superiority of one of the two blood pressure targets investigated: approximately 63 mmHg and approximately 77 mmHg and, separately, superiority of on the two PaOThe hospital stay includes tertiary center as well as the local hospital and or specialized hospital-based neurological rehabilitation.A stratified analysis by the following predefined design variables will also be performed: sex, age above median, pre-arrest renal failure GFR , pre-arrest hypertension, pre-arrest chronic obstructive pulmonary disease, shockable primary rhythm, and suspected STEMI on initial ECG.Initiation of renal replacement therapyDeathTime toNeuron-specific enolase (NSE) level at 48 hMOCA score at 3 months Modified Ranking Scale (mRS) and CPC at 3 monthsNT-pro-BNP at 3 months eGFR and LVEF at last available measurement within 3 months of follow-upDaily cumulated vasopressor requirement during ICU stay and need for combination of vasopressors and inotropic agents or mechanical circulatory supportAnalysis will compare the two target blood pressure groups with respect to:Blood pressure of approximately 63 mmHg or 77 mmHg does not have similar efficacy in preventing death or serious anoxic brain injury in comatose survivors of out-of-hospital cardiac arrest.Restrictive (9–10 kPa or 68–75 mmHg) vs. liberal (13–14 kPa or 98–105 mmHg) do not have similar efficacy in preventing death or serious anoxic brain injury in comatose survivors of out-of-hospital cardiac arrest.Multicenter, randomized trial in 2*2 factorial design allocating comatose OHCA patients to one of two target blood pressures (double blind) and restrictive vs. liberal oxygenation (open label) during ICU stay with blinded outcome evaluation. Both interventions allocate patients in a 1:1 ratio. The design is a superiority trial.Patients are included in the trial from the Department of Cardiology, Copenhagen University Hospital, Rigshospital, Copenhagen, Denmark, and Department of Cardiothoracic Intensive Care, Odense University Hospital, Denmark. The participating centers provide highly specialized cardiology, including out-of-hospital cardiac arrest care, invasive coronary revascularization, and advanced mechanical circulatory support for approximately 3.9 million people.Age ≥18 yearsOHCA of presumed cardiac cause#Sustained ROSCUnconsciousness (GCS < 8)  after sustained ROSC#Sustained ROSC: Sustained ROSC is when chest compressions have been not required for 20 consecutive minutes and signs of circulation persist.Conscious patients Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)In-hospital cardiac arrest (IHCA)OHCA of presumed non-cardiac cause, e.g., after trauma or dissection/rupture of major artery OR cardiac arrest caused by initial hypoxia Known bleeding diathesis  does not exclude the patient)Suspected or confirmed acute intracranial bleedingSuspected or confirmed acute strokeUnwitnessed asystoleKnown limitations in therapy and Do Not Resuscitate-orderKnown disease making 180 days survival unlikelyKnown pre-arrest CPC 3 or 4> 4 h (240 min) from ROSC to screening#Systolic blood pressure < 80 mmHg despite fluid loading/vasopressor and/or inotropic medication/intra-aortic balloon pump/axial flow deviceTemperature on admission < 30 °C#If the systolic blood pressure (SBP) is recovering during the inclusion window (220 min), the patient can be included.Danish legislation permits immediate inclusion of patients in non-pharmaceutical trials and mandates that consent is obtained at first given opportunity following inclusion in the trial.Consent for inclusion of patients unable to provide informed consent  was obtained from a legal representative, usually a relative, and a medical doctor with expertise in the clinical area, but with no relation to the trial. The latter is obtained via a dedicated SMS service, approved by the ethics committee. The consent from the legal representative or relative is obtained by a medical doctor of the department at the first given opportunity. The ethics committee recommendations of time available and allowing time for considering the consent are being obeyed. Informed consent from the patient is obtained by the same staff once the patient regains consciousness.The consent covers storage, handling, and future non-genetic testing of the biobank material; data storage and access to registry and administrative health care data; and the additional intervention described in the substudies section above , and follow-up visits and questionnaires).As both main interventions  are compliant with the current guideline for post-cardiac arrest management, there is no formal hypothesis suggesting the superiority of either intervention. Two-sided tests were applied in the sample size estimation.The blood pressure target allocation is blinded to caregivers as the blood pressure module (HP/Philips M1006B Invasive Pressure module) will be used for the double-blinded intervention. In half of the modules, the calibration factor will be adjusted in order to have the blood pressure measurements being shown approximately 10 mmHg lower than the patients’ actual blood pressure at 100 mmHg, and in half of the patients, the blood pressure measurements will be shown to be approximately 10 mmHg higher at 100 mmHg. Recent validation and feasibility studies in clinical cases suggested high validity of the method . TargetiThese adjustments will be performed centrally ; the BP modules will be clearly marked and shipped to sites. At the time of randomization, and before the first invasive blood pressure is measured following the patient’s arrival to the ICU, the study BP modules are fitted in the monitor, enabling blinding of blood pressure target allocation to the patient, relatives, and care takers. Non-invasive blood pressure measurement is not allowed unless the patients’ safety is considered to be at risk.Other invasive blood pressure measurements  will be performed unblinded.After invasive blood pressure monitoring is discontinued at the ICU, the modules are shipped back to the core lab, where the calibration is re-read, before the settings are adjusted for the next batch of patients.2 is set at 60% initially in the liberal oxygenation group and 30% in the restrictive oxygenation group. FiO2 is adjusted to the allocated target but must be increased if PaSat% by peripheral pulse oximetry falls below 93%. Blood gas measurements can be performed as often as deemed necessary. Blood gas analyses are mandated every 2 h for the first 12 h and then every 6 h.Serial blood gas measurements will be performed targeting either restrictive (9–10 kPa) or liberal (13–14 kPa) oxygenation during mechanical ventilation. The FiO2) is suggested as the default goal.PEEP and other ventilatory settings are left at the discretion of the treating physician. Normocapnia , and when necessary paralyzed with neuromuscular blocking agents to reduce shivering and subsequent heat generation and energy consumption. The core body temperature will be set as quickly as possible at the predefined target temperature, according to intervention allocation, with 4 °C intravenous solutions , and comPost-trial care is provided as part of the clinical standard protocols. The intervention ends by discontinuing the arterial line for invasive blood pressure monitoring and extubation, respectively. From that time on, the only study-specific intervention will be the 3-month follow-up visit and questionnaire, for which the patients are invited at the time of hospital discharge.Death from any cause orDischarge from hospital in a state of Cerebral Performance category 3 or 4, whichever occurs firstInitiation of renal replacement therapy orDeathTime toNeuron-specific enolase (NSE) level at 48 hMOCA score at 3 months Modified Ranking Scale (mRS) and CPC at 3 monthsNT-pro-BNP at 3 months eGFR and LVEF at last available measurement within 3 months of follow-upDaily cumulated vasopressor requirement during ICU stay and need for combination of vasopressors and inotropic agents or mechanical circulatory supportAnalysis will compare the two target blood pressure groups with respect to:The OHCA population admitted to intensive care is a critically ill group of patients. Most adverse events may be of a potentially serious nature but are often common in this patient group. Cardiac arrest patients and patients being unconscious for any other reason are at great risk of developing adverse events. Adverse events will be recorded daily according to 7.1. With regard to the trial intervention, relevant SAEs are considered to be death, need for mechanical hemodynamic support, and need for renal replacement therapy in the first 3 days.Major bleeding: Uncontrolled bleeding (> 1 unit of blood/10 kg/1 h), bleeding causing fatality; symptomatic bleeding in critical organ, e.g., intracranial, intraspinal, intraocular, intraarticular, pericardial; other bleeding, e.g., retroperitoneal, muscular, solid organ, thoracic with Hb ↓ > 50 g/L  and requiring > 2 units of transfused bloodInfection: Severe sepsisRenal impairment: Need for continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)Electrolyte disorders: Hypokalemia (< 3.0 mmol/l), hypophosphatemia (< 0.7 mmol/l), hypomagnesaemia (< 0.7 mmol/l)Metabolic disorders: Sustained hyperglycemia (> 10 mmol/l > 4 h), hypoglycemia (< 3.0 mmol/l)Arrhythmia: VF, VT, tachycardia > 130/min, bradycardia < 40/min, atrial flutter, atrial fibrillation, need for pacing, circulatory collapse mandating CPRSeizures: Tonic-clonic, myoclonic, electrographic status epilepticusSafety variables and adverse events will be recorded continuously during the first 7 days, when the patient is in the intensive care unit. Adverse event occurring later than this will be evaluated at the scheduled follow-up visit at 90 days. Hereafter, no follow-up is planned.See SPIRIT Table Sample size estimation is based on blinded BP target allocation and on the assumption that no interaction with the oxygen intervention exists.The combined primary outcome is time to death or hospital discharge in a state of CPC 3 or 4. We are planning a study with 400 experimental subjects, 400 control subjects, an accrual interval of 48 months, and additional follow-up after the accrual interval of 3 months. Prior data indicate the 6-month mortality is 33% overall. Assuming a mortality of 28% in the superior group compared to 38% in the inferior groups, we will need to include 732 patients in total or 846 patients in total to achieve a power of 0.8 and 0.9, respectively. The type I error probability associated with this test of the null hypothesis that the experimental and control survival curves are equal is 0.05.Loss of final measurement is expected, but from the experience from the previous trial, the number of missing follow-up assessments is small (< 5%) and will not result in an increase of the number of patients needed.Patients are included in the trial when arriving at the tertiary center and if all inclusion criteria and no exclusion criteria are present. The formal inclusion and randomization are performed by the attending physician via a dedicated website.The allocation of treatment goals has been performed in a 1:1:1:1 manner, using varying block sizes of 4–16.The randomization to duration of device-based active temperature intervention (substudy) has been performed independently.Inclusion and randomization are performed via a dedicated website, and the allocation is kept concealed until the time of randomization (oxygenation target and duration of device-based post-TTM temperature management). The blood pressure intervention is concealed as the blood pressure module is labeled by a unique ID number, which is the patient’s study ID. The blood pressure module has been adjusted as described above before the inclusion of the patient.The attending physicians will have access to the trial inclusion webpage and assess eligibility criteria and inclusion of patients in the trial. The webpage will automatically request consent from the assigned.Staff and study personnel will remain blinded to the allocated blood pressure target, as information of the blood pressure allocation is available to the core lab, adjusting the blood pressure modules and the person able to perform unblinding if deemed necessary by the treating physician.A person will be available for unblinding if necessary. However, as unblinding should only occur for safety reasons, and the blood pressure module may be switched to a clinical non-manipulated device with minimal delay, we expect a limited need for unblinding.Individual patient data will be handled as ordinary chart records and will be kept according to the legislation  of the Danish health system. The study uses electronic data collection only, besides the consent forms that are on paper. The study database will be maintained for 15 years and anonymized if requested by the relevant authorities.Danish legislation regarding the respect for patients’ physical and mental integrity and rights will be respected. Approval for storing data relevant to the trial, including potentially sensitive information, will be sought from the relevant authorities.Staff dedicated to the ensure participant retention and promote adherence to the planned follow-up visit has been allocated to both sites involved in the trial. When participants are unable to attend an in-hospital follow-up visit, we offer a visit in the patients’ home, a telephone-based assessment of the neurological outcome, and mailing the questionnaires to the patient, in that order. Patients and relatives are not offered financial support for visiting, but expenses for transportation may be covered in selected cases.Patients who discontinue or deviate from the intervention protocols will remain in the study database, if a consent for the data handling can be obtained, in which case a full data entry will be provided.Data is stored in a RedCAP® database hosted by the Regional IT department. Data is entered by dedicated study personnel and data quality is monitored. Data quality is monitored by the primary investigator by random sampling. A GCP monitor will review and validate consent forms, eligibility criteria for the trial, and endpoint data.Confidentiality is ensured by the database system . Anonymized data for meta-analyses may be provided after the publication of the main manuscripts.The database may be supplemented by other clinical information and by novel analyses of the biobank material. The ethics committee will be consulted if there is uncertainty of the planned analyses or data catchment is covered by the informed consentThe primary outcome  for the blood pressure and oxygenation interventions will be analyzed and reported separately in a proportional hazard model (proc phreg) as a crude analysis with no co-factor adjustments. The number and fraction of the population with the endpoint will be reported.No interaction of the two interventions is expected, and the interaction of the two will be analyzed and reported with the blood pressure target intervention. A Kaplan-Meier estimate plot will be presented with a maximum of 180 days.2 respectively ±1.96SD (representing 95% of the observed cases) will be presented.Baseline and demographic data will be presented in a table, but no formal statistical testing will be performed due to the randomized design of the trial. A figure presenting the mean blood pressure or PaOt test, and logarithmic transformation will be applied if data is skewed.For the secondary outcomes, the time to renal replacement therapy and time to death will be compared in the proportional hazard model. NSE, MOCA score, Modified Rankin scale and Cerebral performance score, NT-pro-BNP, eGFR, and LVEF  and daily cumulated vasopressor requirement during the ICU stay will be reported and compared by a Safety variables: Major bleeding, infection, renal impairment , electrolyte or metabolic disorders, arrhythmia, and occurrence of seizures and or shivering will be reported and compared by the chi-square test.SAS studio, ver 3.7.For interim analyses, there will be used an alternative time point of 7 days instead of 90 days for the primary and selected secondary outcomes (death). Interim analysis after inclusion of 400 patients is planned.SexAge above the median age for the populationKnown renal failure  at time of cardiac arrestKnown hypertension at time of cardiac arrestKnown chronic obstructive pulmonary disease at time of cardiac arrestShockable primary rhythmSuspected STEMI as cause of cardiac arrestSitePredefined subgroup analyses including the following predefined variables will be performed and presented as a forest plotTrial sites will be asked to complete all CRFs and other forms if missing data is found in the electronic database. Missing data will be reported in the publication. More than 5% missing data will result in multiple imputation with the creation of 5–10 imputed datasets to be analyzed separately and the aggregated into one estimate of intervention effect on the primary and secondary outcomes , 60. AnaAccess to the protocol will be given on request. Access to participant-level data will be given only if the data regulation authorities permit.The trial steering committee consists of JK, HS, JEM, and CH. This group represents the two sites participating in the trial. Rigshospitalet is the coordinating center.The Good Clinical Practice unit at the research department of the Cardiology Research Unit oversees that the study is performed according to the principles of good clinical practice. The GCP report to the study sponsor.Department of Neuroanaesthesiology, The Neuroscience Centre and Institute for Clinical Medicine, Faculty of Health Sciences, University of Copenhagen; and Ass. Professor Jens Jacob Thune, Department of Cardiology, Bispebjerg Hospital.The data monitoring committee consists of Professor Lars Køber (Chair), Department of Cardiology, The heart Center Rigshospitalet; Professor Kirsten Møller, Adverse reporting is performed according to good clinical practice principles. However, since death is frequent, the scientific ethics committee is only informed of the number of deaths and other adverse events annually, unless the adverse are suspected to be directly related to the protocolized interventions.Planned interim analyses have been performed after 200 or 400 patients have been included in the trial and the DSMB has given their advice directly to the Steering committee. A charter for the DSMB has been published, but the DSMB will have unlimited access to data if requested.https://www.clinicaltrials.gov/ct2/show/NCT03141099 are planned, other than updating the trial status.Protocol revisions have been performed and have been communicated to the ethics committee according to their requirements. No changes in the current protocol are planned. Any deviations from the protocol will be fully documented using a breach report form. No updates to the protocol in the clinical trial registry The results of the trial will be published, regardless of being positive, negative, or inconclusive. The result of the two major interventions (blood pressure and oxygenation targets) will be published in two separate scientific papers.The trial will be analyzed by the steering group (SG) and the results interpreted by the SG with data coded as “A” and “1” and the allocation of the patients will not be revealed until the SG agrees on the statistical analysis and drafts a conclusion based on the primary outcome. A manuscript will be drafted at a closed meeting by a predefined writing group consisting of the SG members. The final manuscript will be submitted to a peer-reviewed international journal. Authorship will be granted using the Vancouver definitions and depending on personal involvement. The author list including steering group members and others who fulfilled the Vancouver criteria as well as the chair of the DSMB will be offered co-authorships. Centers recruiting ≥50 patients will be entitled to one name  per 50 patients randomized in the trial. A reference to an appendix with all sites, site investigators, and number of patients enrolled will be made.Blood pressure is an easily accessible parameter in describing and monitoring the patients’ hemodynamics and is thus a central part of the monitoring in most patients admitted to critical care. While blood pressure alone does not describe perfusion or oxygen delivery, many consider blood pressure as one of the main goals in managing patients with critical conditions, including post-cardiac arrest , 20. A cA systematic review concluded from 9 observational studies that higher blood pressure is associated with improved neurological outcome after cardiac arrest and acknowledging a significant risk of bias, not only due to the observational study designs, but also due to a significant heterogeneity between studies . Blood pPrevious studies have reported a significant higher value for MAP during TTM than what seems to be current practice. The Bernard trial of 2002 reported mean MAP values ranging from 88 to 108 during ICU admission , whereasTwo recent, relatively small clinical open-label prospective trials have investigated two different targets for blood pressure during targeted temperature management since the present trial was initiated. Ameloot et al. compared targeting a MAP of 85–100 to 65 mmHg, finding no difference in the primary outcome of the extent of neurological injury on MRI of the brain and similar fraction of patients with good neurological outcome . A seconThe current European Resuscitation Council guidelines suggest a target blood pressure sufficient for maintaining a urine output of 0.5 ml/kg/h and to avoid blood pressure < 65 mmHg , whereasThus, the current body of evidence supporting MAP targets of 65–75 mmHg is very weak, and a clinical equipoise of optimal target blood pressure in the interval of approximately 65 to 75 mmHg or higher exists.2 = 100% compared to FiO2 = 30% [Preclinical data suggest that hyperoxia increases cerebral damage and neurological dysfunction following brain ischemia. Most data originates from cardiac arrest models in which a no-flow state is induced and cerebral injury or neurological dysfunction is assessed –22. FairO2 = 30% . FurtherO2 = 30% .2 is increased to levels above 50% for simplicity.Hyperoxia during and after ischemia has been investigated in several settings, and a final consensus of its benefits and hazards has yet to be established. In the following, the term hyperoxia is used in situations where the FiO2 to be significant and various ventilation modes may have a significant impact as well [Hyperoxia may increase the risk of developing lung injury (hyperoxia-induced lung injury (HALI)), which carries a high morbidity and mortality. However, this condition seems to require several days of extremely high FiO as well . The risIschemia-reperfusion injury has been investigated in smaller studies only in relation to circulatory bypass with no significant impact on the magnitude of increase in biomarkers related to cardiac injury according to a review by . Oxygen A recent systematic review and meta-analysis suggested that the risk of surgical site infections may be reduced with hyperoxia . However2 of 9–10 kPa (target 9.5 kPa), and high normal, i.e., “liberal” PaO2 of 13–14 kPa (target 13.5 mmHg). FiO2, PEEP, and lung recruitment maneuvers for maintaining the assigned PaO2 are left at the discretion of the treating physician.In summary, hyperoxia may reduce risks associated with surgery and critical illnesses with regard to surgical site infections and possibly reperfusion injury, whereas the effects on overall benefit in terms of mortality may be detrimental. Further research is needed, and for the time being equipoise with regard to the benefits of different targets for oxygenation. Most patients will require some degree of oxygen supplement when lungs are ventilated after OHCA; hence, this study pragmatically studies low normal, i.e., “restrictive” PaOProtocol version 3.2 (07JAN2018).Recruiting; the first patient was included on March 10, 2017. The last patient was included on December 11, 2021. Completion of the 90-day follow-up before May 2022 and unblinding and statistical analysis will begin hereafter.


Although the inter-arm blood pressure (BP) difference has been advocated to be associated with cardiovascular events, the implication of inter-leg BP difference has not been well established. This study was conducted to investigate whether inter-arm and -leg BP differences have prognostic value in patients undergoing percutaneous coronary intervention (PCI).In this prospective study, we consecutively enrolled 667 patients who underwent PCI. Both arm and leg BPs were measured at the day after PCI. The primary outcome was a major adverse cardiovascular event (MACE) including cardiac death, acute coronary syndrome, coronary revascularization, stroke, and hospitalization for heart failure during the follow-up period.P = 0.004). The inter-arm systolic BP difference was not significantly different between patients with and without MACE (P = 0.403). In multivariable Cox regression analysis, increased ILSBPD was independently associated with the development of MACE . The inter-arm systolic BP difference was not associated with MACE in the multivariable analysis.Mean age was 64.0±11.1 years old, and males were predominant (70.5%). During a mean follow-up period of 3.0 years, MACE occurred in 209 (31.3%) patients. The inter-leg systolic BP difference (ILSBPD) was significantly higher in patients with MACE than those without (9.9±12.3 vs. 7.2±7.5 mmHg, Increased ILSBPD was independently associated with worse cardiovascular outcomes after PCI. As ILSBPD is easy to measure, it may be helpful in the risk stratification of patients undergoing PCI. The burden of cardiovascular (CV) disease continues to rise, and it has become the leading cause of death worldwide . TherefoThe cost-effectiveness differs among examinations according to patient situation, but there is an argument that BP measurement is the most inexpensive and effective way to estimate individuals’ risk . After rThe prevalence of coronary artery disease has increased, and percutaneous coronary intervention (PCI) is one of the important treatment strategies for coronary artery disease. In Korea, about 50,000 patients underwent PCI every year . As suchThis single-center, prospective study was performed at a general hospital located in a large city . From April 2012 to August 2015, we consecutively recruited patients undergoing PCI with a drug-eluting stent. All the study patients underwent bilateral arm and leg BP measurement during stabilized condition at the day after PCI. From the total of initially screened 717 patients, those who had the following conditions were excluded: 1) failed PCI, 2) previous percutaneous transluminal angioplasty for peripheral artery disease, 3) ankle-brachial index over 1.4 or less than 0.9, and 4) malignancy. After these exclusions, this cohort was made up a total of 667 patients. The study protocol was approved by the Institutional Review Board of Boramae Medical Center , and written informed consent was obtained from each study subject.2). Data on underlying medical conditions, including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, atrial fibrillation, chronic kidney disease, previous history of stroke, and smoking status, were acquired. We defined the hypertension as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or current medications. Diabetes mellitus were defined as fasting blood glucose ≥126 mg/dL, glycated hemoglobin ≥6.5%, or use of anti-diabetic medications. Coronary artery disease included a history of myocardial infarction or coronary revascularization. Atrial fibrillation was defined as a history of any atrial fibrillation which was documented by electrocardiography. Patients with chronic kidney disease were those whose estimated glomerular filtration rate (eGFR) was below 60 mL/min/1.73 m2. We obtained the history of the previous stroke from the medical records of the patients. A patient who smoked within 12 months was defined as a current smoker. After 12 hours of fasting, blood was sampled for the determination of hemoglobin, estimated glomerular filtration rate, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride. Left ventricular ejection fraction was calculated using Simpson’s biplane method in transthoracic echocardiography.We obtained the patients’ age and sex information. Body mass index was calculated by dividing body weight by squared height  ,17. WithThe study outcome was a major adverse cardiovascular event (MACE). The MACE was a composite of cardiovascular death, nonfatal acute coronary syndrome, coronary revascularization including PCI and coronary artery bypass graft surgery, non-fatal ischemic stroke, and hospitalization for cardiovascular causes. Cardiovascular death included the death caused by acute coronary syndrome, ventricular arrhythmia, heart failure, or unexplained sudden death. Nonfatal acute coronary syndrome was identified by a cardiologists using conclusive evidence, which was provided from an elevation of cardiac enzymes or ST-segment changes. A diagnosis of ischemic stroke was confirmed by a neurologist based on physical examination and brain imaging modalities. Hospitalization for the cardiovascular causes included unplanned admission for heart failure, coronary artery disease, atrial fibrillation, other arrhythmias, or transient ischemic attack. We regularly followed up the study subjects for the occurrence of MACE using hospital records; telephone interviews were used for the follow-up, if necessary.t test was used to compare continuous variables, and the Chi-square test or Fisher’s exact test was used to compare categorical variables between 2 groups. Using the Cox-proportional regression hazard method, we identified predictors for MACE among clinical and laboratory factors as well as among inter-arm and inter-leg BP differences. The confounders, which had P values of <0.1 in univariable analysis, were adjusted to investigate the association of inter-leg BP difference and MACE. The confounding factors were age, sex, hypertension, diabetes mellitus, previous coronary artery disease, atrial fibrillation, chronic kidney disease, previous stroke, current smoking, and hemoglobin. The optimal cutoff value of inter-leg systolic BP difference (ILSBPD) for MACE was estimated using maximally selected log-rank statistics [p value of <0.05 was used to verify statistical significance. All statistical analyses were conducted using R version 3.4.3 (http://www.r-projec-t.org).Continuous variables are presented as mean ± standard deviation (SD), and categorical variables as percentages. Student’s atistics . After rTable 1 shows the baseline characteristics of the patients and differences between groups with and without MACE. Patients with MACE were older  and had a higher prevalence of diabetes mellitus, coronary artery disease, atrial fibrillation, chronic kidney disease, history of the previous stroke, and the multi-vessel disease than those without. In laboratory findings, patients with MACE had lower levels of hemoglobin and eGFR than those without. The detailed information of MACE was presented in S1 Table.Among a total of 667 study patients, 209 (31.3%) had MACE, including cardiovascular death , non-fatal acute coronary syndrome , coronary revascularization , non-fatal stroke , and hospitalization for cardiovascular causes  during a mean follow-up period of 3.0 years . Table 2), right-arm systolic BP was higher in patients with MACE . The IASBPD and the inter-arm diastolic BP difference (IADBPD) were not different between the 2 groups. The ILSBPD  and inter-leg diastolic BP difference (ILDBPD)  were significantly higher in patients with MACE than those without. There were 88 patients (13.2%) whose ILSBPD was greater than 15 mmHg and 25 patients (3.7%) whose ILDBPD was greater than 15 mmHg.In 4-extremity BP measurements (Table 3). Age, diabetes mellitus, coronary artery disease, atrial fibrillation, chronic kidney disease, previous stroke, and hemoglobin level showed associations with the MACE. In extremities BP differences, both ILSBPD and ILDBPD showed a significant association, while inter-arm BP difference had no significant correlation with MACE. After adjustment for potential confounders, ILSBPD still had a significant association with MACE , but ILDBPD did not (p = 0.805). These results were consistent after adjusting IASBPD or IADBPD  and high right-arm diastolic BP (≥90 mmHg), the ILSBPD still significantly associated with MACE .To identify predictors for the occurrence of MACE, we analyzed the prognostic value of baseline clinical characteristics, and inter-arm and -leg BP differences using the Cox proportional hazard regression method (P = 0.01) . After dividing the patients into 2 groups according to the cutoff ILSBPD value of 16 mmHg, the higher ILSBPD (≥16 mmHg) group was older and had lower body mass indices, and higher prevalence rates of hypertension, diabetes mellitus and chronic kidney disease than in the lower ILSBPD (<16 mmHg) group (S3 Table). Also, the higher ILSBPD group showed lower hemoglobin and low-density lipoprotein cholesterol levels. The higher ILSBPD group showed significantly higher incidences of MACE than the lower ILSBPD group . In multivariable Cox proportional hazard regression analysis, the higher ILSBPD group showed a significantly higher risk of MACE than the lower ILSBPD group  (Table 4). Kaplan-Meier survival curves for MACE according to ILSBPD are presented in Fig 1.The optimal cutoff value of ILSBPD that maximized the log-rank statistic was 16 mmHg to predict the occurrence of MACE . Moreover, the addition of ILSBPD to age, sex, and clinical factors significantly increased prognostic value in MACE for categorical variables  and continuous variables .This study revealed that ILSBPD was independently associated with MACE in patients who underwent PCI. Patients with ILSBPD ≥16 mmHg had a 1.5-fold higher risk of MACE than those with ILSBPD <16 mmHg ILSBPD even after adjustment for many risk factors. Moreover, adding information on ILSBPD to clinical risk factors significantly increased prediction power for the future development of MACE. To the best of our knowledge, this is the first report to investigate the prognostic value of ILSBPD in patients with coronary artery disease undergoing PCI, suggesting that ILSBPD measurement could be a reliable and convenient method for predicting MACE in high-risk patients.et al. [Many studies have reported that higher IASBPD is associated with PAD, cerebrovascular diseases, cardiovascular diseases, and mortality –11. Howeet al.  investiget al. . And theet al. . The resAnother interesting finding of our study is that only ILSBPD had a significant association with MACE, while IASBPD did not. Previous studies showing the evidence of the prognostic value of IASBPD included patients with hypertension , outpatiPatients with higher ILSBPD ≥16 mmHg) were older and had higher proportions of hypertension, diabetes mellitus, and chronic kidney disease. The higher risk in patients with higher ILSBPD may improve the prognostic value of ILSBPD in predicting future cardiovascular events. In addition, PAD, a strong prognostic marker of cardiovascular diseases, is usually defined as the vascular disease of the lower extremity arteries; therefore, it is acceptable that ILSBPD has a stronger association with PAD compared to IASBPD  mmHg wer,21. IndeThe measurement of ILSBPD is simple. Therefore, ILSBPD is very useful as a primary screening test for selecting high-risk patients. If patients undergoing PCI have high ILSBPD, they will need more attention, and intensive treatment and monitoring.This study has several limitations. First, our study population was limited to patients who underwent PCI and without significant PAD which may make it difficult to generalize our findings to other populations. Secondly, our study design was observational and not fully controlled; therefore, there could be uncontrolled confounding factors even with the effort of adjustment. Third, there could be a concern for including the patients with atrial fibrillation. We repeated the measurements at least three times and used an average of these multiple measurements for advancing the accuracy. Furthermore, an independent association between ILSBPD and MACE still exist in multivariable analysis even after excluding the patients with atrial fibrillation. Finally, we included soft prognostic endpoints to MACE, such as hospitalization for cardiovascular causes, because hard endpoint events were rare in our cohort.In conclusion, ILSBPD was independently associated with worse cardiovascular outcomes after PCI. As a simple measurement of atherosclerosis, ILSBPD may be useful for the risk stratification of patients undergoing PCI. Further investigations will be needed to validate the prognostic value of ILSBPD in higher risk patients and/or more general population for acceptance in clinics.S1 Figp = 0.01).The optimal cutoff value of ILSBPD, for predicting the major adverse cardiovascular events, that maximized the log-rank statistic was 16 mmHg ((DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function.In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system  and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis.In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic  and diastolic  ABP and less reduction of central systolic BP  and central pulse pressure . No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17).In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters.Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528). Sodium glucose cotransporter (SGLT)2 inhibitors introduced as antidiabetic agents have been found to decrease incidence of cardiovascular mortality, heart failure hospitalisations and renal events of progressive renal disease . Their oBlood levels of ketones have been described to be increased in patients with type 1 and 2 diabetes after treatment with SGLT2 inhibitors , 6. A reThe aim of the current analysis is to assess the influence of the SGLT2 inhibitor empagliflozin on blood levels of ketone bodies in patients with CHF and to analyse their relation to blood pressure (BP) and to vascular function.http://www.clinicaltrials.gov: NCT03128528). Between July 2017 and March 2020, subjects with stable CHF were recruited from the investigator’s outpatient clinics, referring physicians, and advertisement in local newspapers, and social media. After being off any SGLT-2 inhibitors for at least 10 weeks, subjects entered a run-in phase of 2 weeks and primary and secondary evaluation criteria were assessed. Patients were then consecutively randomised to either empagliflozin 10 mg orally once daily or placebo (2:1) for 12 weeks. The study was approved by the local Ethics Committee (University of Erlangen-Nuremberg) and performed in accordance with the Declaration of Helsinki and the principles of good clinical practice guidelines.This was a secondary analysis of an investigator initiated, prospective, double blind, placebo controlled, parallel-group phase II single centre study in order to analyse changes in blood β-OHB levels in patients with CHF following SGLT2 inhibition with empagliflozin. Furthermore, the relationship between β-OHB and parameters of vascular stiffness were analysed. All participants were treated in our Clinical Research Unit of the Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany  in stable conditions or heart failure with reduced ejection fraction (HFrEF) in stable conditions, according to the ESC guidelines for the diagnosis and treatment of acute and chronic heart failure were included in the study , 13. PatDemographic data were recorded at the first visit (screening). At randomisation (baseline), fasting blood samples were withdrawn in order to evaluate HbA1c, fasting plasma glucose, lipid levels, β-OHB levels  and other bio-chemical safety parameters . Blood levels of β-OHB, were measured by an automated clinical chemistry analyser (Beckman Coulter DxC 700 AU), with a lower detection border for β-OHB of 0.05 mmol/l and a variation coefficient 1.68% for normal controls and—2.29% for pathological controls. Squared average of the errors of measurement was 0.00802 with an error margin of 0.02271.Office brachial BP was assessed according to the European Society of Hypertension guideline recommendations by an oscillometric device  and averages of the last three measurements were taken .Central (aortic) BP represents the BP acting directly on internal organs like heart and kidney and have been found to independently predict cardiovascular outcome . A validTwenty four-hour ambulatory BP (ABP) monitoring was assessed by a repeatedly validated device  . BP measBefore further analysis, abnormal or normal distribution of variables was evaluated using Kolmogorov–Smirnov test. Normally distributed data are expressed as mean ± standard deviation and not normally distributed data presented as median and interquartile range (IQR). A two-sided P-value < 0.05 was considered statistically significant. The comparison between baseline and the end of the 12 week treatment phase within each treatment group was performed using the non-parametric Wilcoxon test . Statistical significance of differences between the empagliflozin and the placebo treatment arm was determined applying the non-parametric Mann–Whitney-test , accordingly. Correlations were calculated by using the Spearman analysis. All analyses were performed using SPSS software, version 24.0.0.2 .A total of 87 patients with CHF were screened and 72 of them completed the study. In 19 patients at the time of both measurements (at baseline and 12 weeks after randomisation) levels of β-OHB were beneath the lower detection border of our assay (< 0.05 mmol/l) at baseline and 12 weeks after randomisation, therefore being excluded from the subsequent analysis   compared to baseline. There was no significant change in β-OHB after 12 weeks of treatment with placebo compared to baseline . Change of β-OHB between baseline and 12 weeks of treatment with empagliflozin was not significantly different compared to change between baseline and 12 weeks of treatment with placebo p = 0.321) , as well as in systolic (p = 0.005) and diastolic brachial (p = 0.269) BP compared to baseline (Table Subjects treated with empagliflozin for 12 weeks showed the following changes in laboratory parameters compared to baseline: haematocrit: 40.2 ± 3.9% to 42.4 ± 3.8% (p = 0.197), HbA1c: 5.9 ± 0.6% to 5.8 ± 0.4% (p = 0.135), fasted plasma glucose: 105.9 ± 19.4 mg/dl to 95.6 ± 13.1 mg/dl (p < 0.001) and serum uric acid 6.9 ± 1.7 mg/dl to 5.7 ± 1.4 mg/dl (p < 0.001). No significant changes were found in the same clinical parameters after 12 weeks placebo therapy compared to baseline (data not shown).Significant correlations were observed between the change of β-OHB and the changes in BP parameters in subjects treated with empagliflozin for 12 weeks. Greater increases of β-OHB blood levels were related to smaller decreases in diastolic ABP , brachial systolic  and diastolic  BP and tended to be related to smaller decreases in 24-h systolic ABP.Regarding vascular parameters an increase of β-OHB correlated with the decrease of cSBP , cPP  and forward pulse pressure height . There were no significant correlations between changes of β-OHB and changes of BP and vascular parameters in the placebo group.No significant correlations between changes in β-OHB and changes in the above mentioned laboratory parameters were observed.To the best of our knowledge, the current study is the first to evaluate the effect of SGLT2 inhibitors on blood ketone body concentration, as assessed by β-OHB, in patients with CHF, and to analyse the relationship between changes in serum β-OHB levels and changes in vascular stiffness and BP.The main finding of this study is that 12 weeks treatment with empagliflozin leads to an increase of fasting serum β-OHB in our patients with stable CHF compared to the placebo group. Consistently, in rodent models employing empagliflozin, ketone levels were significantly increased in both lean control and obese ZSF1 groups , as wellHowever, the increase of serum ketone bodies under SGLT2 inhibition has also been described to be linked to diabetic ketoacidosis. A recent review of literature found a small risk of diabetic ketoacidosis in patients with type 2 diabetes under the therapy of SGLT2 inhibitors. The study collective included 39 randomised controlled studies and 60,580 patients . In our Analysing the effects of 12 weeks treatment with empagliflozin, we observed significant improvement in BP and vascular function. Brachial systolic BP and systolic 24 h ABP decreased significantly after 12 weeks of treatment with empagliflozin. Yet, we did not observe any significant improvement in brachial diastolic BP and 24 h ABP. Accordingly, DBP compared with SBP has been described to decrease slower in patients treated with empagliflozin [In the current study we found that the improvement in vascular stiffness and BP is inversely related to the increase in serum β-OHB, indicating that a greater increase of β-OHB is associated with less improvement of central BP and 24 h ABP. Central BP and 24 h ABP are both being considered as strong independent predictors of cardiovascular events and overall mortality , 26.Interestingly, our findings propose rather negative effects of the β-OHB increase after treatment with empagliflozin questioning the concept whether ketone bodies are responsible for the improved cardiovascular outcomes under the treatment with empagliflozin. Our study suggests exactly the opposite of the “fuel hypothesis”: β-OHB attenuates the beneficial effects of empagliflozin on vascular function and BP.Coppola et al. reported increased arterial stiffness and early functional endothelial damage in children with drug resistant epilepsy that were treated with a ketogenic diet. Vascular parameters like the β-index and augmentation index, indicative for early functional endothelial damage and vascular stiffness, increased after treatment with ketogenic diet in this specific study . ConcordThe strength of our study is that the effects of SGLT2 inhibitors on ketone bodies and their subsequent interaction with vascular parameters were observed in a double blind randomised controlled trial in patients with CHF. This is the first time that ketone bodies and their subsequent interaction with vascular parameters are evaluated in patients with stable CHF after SGLT2 inhibitor therapy and timely in face of the new guidelines for CHF.Nevertheless we have to acknowledge certain limitations: our study population is relatively small which clearly diminishes the statistical power of our findings. This is also due to the fact that several subjects had to be excluded from our analysis as their serum levels of β-OHB were below the measurement range of our assay at both time points when blood was collected. However, no differences in the clinical characteristics of the subgroup with measurable β-OHB concentrations and with the total study group were found (data not shown). The lower limit of quantification for the enzymatic assay used is 0.05 mmol/l. However, we want to stress, that this assay is a validated method of β-OHB measurement used by our university laboratory in the clinical daily routine . It woulData on the relationship between ketone bodies, SGLT2 inhibitors and cardiovascular effects are very limited. We therefore related our data to various studies in different experimental settings, including empagliflozin-induced ketonemia, ketogenic diet and infusion with ketone bodies. It is difficult to compare and standardise blood levels of ketone bodies from different studies as they are very fluctuating and depend on various factors like length of fasting, type of diet, medications, concomitant diseases and amount of physical activity. Ketogenic diet leads to a larger increment in serum ketone body levels than SGLT2 inhibition. Accordingly, Johnson et al. observed an increase in serum β-OHB concentration of 0.24 mmol/l after 6 weeks of ketogenic diet as compared to 0.04 mmol/l in our analysis . HoweverIn conclusion, treatment with empagliflozin lead to a small but significant increase of serum ketones in patients with HFmEF or HFrEF. The observed improvement of BP and vascular function after treatment with empagliflozin was attenuated by the increase of serum ketone bodies.


In 78 patients (65%), peak VO2 was normal or mildly reduced (>14 mL/kg/min) (group 1) while it was markedly reduced (≤14 mL/kg/min) in 41 (group 2). In univariate analysis, systolic fraction (S Fract), a predictor of elevated pre-a LV diastolic FP, appeared to be the best diastolic parameter predicting a significantly reduced peak VO2. Logistic regression analysis identified five parameters yielding a unique, statistically significant contribution in predicting reduced ExC: creatinine clearance < 52 mL/min (odds ratio (OR) = 7.4, p = 0.007); female gender ; BMI > 28 , age > 62 years , S Fract < 59% . Conclusion: KI was the strongest predictor of reduced ExC. The other modifiable factors were obesity and severe LV diastolic dysfunction expressed by blunted systolic venous flow. Contrarily, LV ejection fraction was not predictive, confirming other previous studies. This has important clinical implications.The aim of this study was to clarify the relative contribution of elevated left ventricle (LV) filling pressure (FP) estimated by pulmonary venous (PV) and mitral flow, transesophageal Doppler recording (TEE), and other extracardiac factors like obesity and renal insufficiency (KI) to exercise capacity (ExC) evaluated by cardiopulmonary exercise testing (CPX) in patients with dilated cardiomyopathy (DCM). During the CPX test, 119 patients (pts) with DCM underwent both peak VO Dilated cardiomyopathies (DCM) are an escalating problem in the modern medicine, aggravated by the still poor knowledge of the underlying etiology and associated with poor prognosis and disabling symptoms like dyspnea and reduced functional capacity . GeneralTransesophageal Doppler echocardiography (TEE) is the best approach to predict LV diastolic filling pressure in patients with dilated cardiomyopathy (DCM) by optimally recording blood flow velocity in pulmonary veins . A systo2 [In addition, the atrial reversal duration, if longer than the transmitral A-wave, can reliably predict an increased LV telediastolic pressure; in the absence of an S Fract abnormality, this may predict an increase in LV pressure confined to the telediastole . While a2 .Moreover, in patients with DCM, the relative role of renal insufficiency (KI) and obesity in reducing functional capacity is not properly known; KI impact on functional capacity has been mainly assessed in hemodialysis patients ,16 and nThe study was an observational prospective cohort analysis. Overall, 122 consecutive patients with newly diagnosed DCM in sinus rhythm and clinical stability were enrolled; their clinical and demographic characteristics are summarized in We included dilated cardiomyopathies of all etiologies in this study. DCM was diagnosed on the basis of the following criteria: LV end-diastolic dimension > 60 mm, left fractional shortening < 25%, and an increased E-point septal separation obtained in the M-mode with cross-sectional echocardiographic guidance . IschemiAll the patients were on the best-known therapy at that time.The exclusion criteria were the presence of an acute cardiac or extracardiac illness, atrial fibrillation or any cardiac arrhythmia, severe valvulopathy, and, in particular, severe mitral valve regurgitation because this affects LV diastolic filling causing increased E-wave velocity.All the patients were fully informed about the nature of the study and gave informed consent to take part.Fasting blood samples were taken to evaluate the routine hematological parameters and in particular kidney function and hemoglobin levels. Regarding renal function, glomerular filtration was assessed with the Cockcroft–Gault formula .All the patients were subdivided by New York Heart Association (NYHA) Functional Classification .2 defined as oxygen consumption (mL/kg/min) at peak exercise calculated as the average VO2 value over the last 30 s of exercise. Measured peak VO2 was obtained with breath-by-breath analyses of expired gas . A 12-lead electrocardiogram was continuously recorded and blood pressure was measured at every step of the exercise. The patients were encouraged to exercise until they reached at least the anaerobic threshold (AT), that is, the point when carbon dioxide production increases disproportionately in relation to oxygen consumption and the respiratory ratio is >1.0 [Cardiopulmonary exercise testing (CPX). All the patients who could undergo an effort test underwent an ergospirometric examination with a treadmill test using a modified Naughton protocol . We assessed the peak VO is >1.0 .All the patients underwent a transthoracic echocardiographic examination with an HP Sonos 2500 ultrasound device .Standard two-dimensional echocardiography was performed to obtain the following parameters: left ventricular end-diastolic and systolic diameters  and volumes  with a modified Simpson rule, the inferior vena cava diameter in inspiration and expiration. Then, the left ventricular ejection fraction was calculated using volumes and the percentage of the inferior vena cava inspiratory collapse (diameter in expiration–diameter in inspiration/diameter in expiration).The presence and magnitude of mitral valve regurgitation was quantitatively assessed by means of color Doppler, calculating the ratio of the mitral jet area to the left atrium area as visualized in the four-chamber view (patients with severe regurgitation were excluded from the study).Transesophageal Doppler echocardiography. To evaluate LV filling pressure, pulmonary venous and mitral flow was recorded. To optimize PVF recording, a transesophageal approach was adopted ,13. TherDuring the TEE examination, first, the transmitral flow was recorded: under color guidance, the sample volume was placed first between the tips of the mitral leaflets, where the E/A ratio and E-wave deceleration time are determined best, and then at the annulus level, where the A duration is measured best . Then, pAll these measures were performed taking care to ensure the correct alignment of the ultrasound beam and the color Doppler diastolic signal flow, place the sample volume in the area of the laminar flow, and reduce the spectral broadening in order to avoid under- or overestimation of the velocities and time intervals .The velocity curves were analyzed using the supplied commercial analysis system. The peak flow velocity and time–velocity integral during the forward systolic and diastolic flow, the deceleration time of the early diastolic flow, and the maximal velocity, velocity integral, and duration of flow reversal during atrial systole were measured as schematically illustrated in The peak systolic and diastolic PVF wave ratio (S/D), mitral E- and A-wave ratio (E/A), mitral E deceleration time, and the time difference between the PVF atrial reversal Ar and the mitral A-wave duration (Ar-A) were calculated. In cases of double systolic waves, S2 was considered for the ratio. When the onset of the pulmonary Ar wave was difficult to determine (very rarely), we used the onset of the mitral A-wave because they are temporally coincident, as suggested by Appleton , or the All the examinations were recorded on videotapes, and the calculations were performed offline using the ultrasound equipment’s (HP Sonos 2500) built-in calculation software. We recorded Doppler signals during apnea at the end of expiration at a sweep speed of 50–100 mm/s and considered for calculations the mean of three beats.t-test or Mann–Whitney U test were used as appropriate to compare continuous variables between group 1 (peak VO2 > 14 mg/kg/min) and group 2 (peak VO2 ≤ 14 mg/kg/min) patients. The effect size for the independent samples t-test was assessed by means of Cohen’s d effect size statistics: 0.2 = small effect, 0.5 = medium effect, and 0.8 = large effect. Comparisons between groups of discrete variables were performed by means of the χ2 or Fisher’s exact test if the expected cells count was <5. The S Fract best cutoff point was empirically estimated using the receiver operating characteristic (ROC). One-way ANOVA was performed to assess the effect of three different grades of diastolic dysfunction on peak VO2. Two-way ANOVA was performed to assess the interaction and the main effect of the LVEF and the inferior vena cava diastolic collapse (best dichotomized on the basis of the ROC) on creatinine clearance. The most clinically relevant variables with p < 0.05 in univariate analysis were then included as predictors (enter mode) in a logistic regression model. All the predictors were categorical in order to predict or explain our categorical dependent variable (peak VO2 categorized as > or ≤14 mL/kg/min). Statistical calculations were performed using IBM SPSS version 23 .Continuous variables were expressed as the means ± SD, discrete variables—as absolute numbers and percentages. Independent samples The study was initially carried out on 122 patients with dilated cardiomyopathy, all in sinus rhythm. The prediction of the left ventricular filling pressure best attained with the combination of transmitral and pulmonary venous flow Doppler recording identified 62 (51%) patients with normal left ventricular filling pressure, 20 (16%) with isolated increase in LV filling pressure after atrial contraction with presumably normal mean atrial pressure, and 40 (33%) with elevation of the left ventricular pressure before atrial contraction (Pre-a increase of pressure) .2 consumption assessment (2 > 14 mL/kg/min), including 19 patients who were unable to exercise but with a NYHA class ≥ II, and 41 patients (34%) (second subgroup with peak VO2 ≤ 14 mL/kg/min), including five patients unable to exercise but with a NYHA class III or IV  that was not predictive  were significantly predictive of the peak VOedictive .2 impairment, we found that S Fract, that indicates a more severe LV diastolic abnormality since it predicts an increased filling pressure in the passive filling phase before atrial contraction, had the largest effect size , the sensitivity and specificity of predicting a reduced peak VO2 consumption were 61% and 72%, respectively  in the group with the measured peak VO2 (88 patients), one way between-groups analysis of variance was performed. There was a statistically significant difference, with a medium–large effect size (η2 = 0.11) in the peak VO2 in three categories . Post hoc comparison showed that only a pre-A increase in pressure by S Fract identified a significantly lower peak VO2 than that predicted by just a telediastolic restriction and no restriction categories ; there was a statistically significant main effect for the LVEF , with a considerable effect size . Contrarily, the main effect for the IVC-IC did not reach statistical significance .We found that only a depressed forward systolic flow expressed by a severely impaired LV EF (<25%) and not-backward heart failure quantified by a severe reduction (<30%) of the vena cava inspiratory collapse (IVC-IC) explained a reduction in creatinine clearance. In fact, based on the two-way analysis of variance, the interaction effect between the LVEF and the IVC-IC was not statistically significant  = 76.40, p < 0.001), indicating that the model was able to distinguish between the patients with the peak VO2 > or ≤14 mL/kg/min. The model taken overall explained between 44% (Cox and Snell R-squared) and 61% (Nagelkerke R-squared) of the total variance in the peak VO2 consumption. As shown in 2 was not a cardiac but a renal parameter, namely creatinine clearance, recording an odds ratio of 7.4. This indicated that the patients with an estimated creatinine clearance (Cockcroft-Gault equation) < 52.2  were 7.4 times more likely to have a peak VO2 ≤ 14 mL/kg/min than those with clearance > 52.2. Only the more severe diastolic dysfunction category resulted in a valid predictor of impaired peak VO2, identifying patients 4.9 times more likely than the reference category (no diastolic dysfunction) to have a reduced functional capacity, whereas an isolated telediastolic restriction did not. BMI in the higher category only (>28) was the third best predictor of impaired functional capacity. As expected, greater age and female gender were predictive of a reduced functional capacity. LV systolic function expressed by EF was not predictive of functional capacity in multivariate analysis.The model contained six independent variables ; two continuous variables (age and BMI) were collapsed in three categories with an approximately equal number of patients, while two other continuous variables  were dichotomized on the basis of the best cutoff attained with the ROC curves; lastly, the patients were subdivided into three groups for diastolic dysfunction on the basis of a progressive increase in the LV diastolic pressure estimate: group 1 (reference category), no sign of increase in the diastolic pressure; group 2, isolated telediastolic restriction; group 3, a pre-a pressure increase as estimated via the systolic fraction of PVF. The full model containing all the predictors was statistically significant  of PVF. Regarding the second point, we believe that S Fract works better than the simplified S/D ratio since it takes into account all the complexities of the pulmonary venous flow, being based on measurements of flow velocity integrals both in the systole and in the diastole . Systolic flow, in fact, is very complex. A reduction of systolic flow can be related either to the reduction of the first wave (S1) owing to impaired atrial relaxation or to the second wave reduction  that is basically related to both poor LV ventricular contraction with a consequently minimal descent of the mitral annulus and/or also to inadequate right ventricular contraction that has insufficient strength to push the pulmonary venous flow forward from the back. So PVF, better delineated by S Fract, also takes into account the contractile performance of the right ventricle that has been shown to independently predict the functional capacity . RemarkaMore studies are needed to analyze the deceleration time of mitral E- and pulmonary D-waves.Creatinine clearance < 52.2 mL/min was the best predictor of impaired functional capacity. We believe that the kidney-mediated major mechanism affecting functional capacity is volume expansion that finally brings about more filling pressure, limiting cardiac efficiency. Low cardiac output causes renal vasoconstriction, particularly of the efferent arterioles, via hormonal  and catecholamine drive. On one hand, this tends to normalize the Bowman intracapsular pressure, but on the other, it causes a drop of hydrostatic pressure in the peritubular capillaries. Moreover, since the glomerular filtration rate declines, albeit less than the renal blood flow, the filtration fraction increases due to elevation of the oncotic pressure in the peritubular capillaries. These last two events cause a drop of transcapillary hydraulic pressure of the vasa recta that mediates more sodium reabsorption in the proximal tubule  with a consequent blood volume expansion. In addition, the antidiuretic hormone level is constantly elevated since the reduced effective blood volume serves as a potent non-osmotic stimulus to enhance the release of the antidiuretic hormone (ADH) . FinallyThe increased venous systemic pressure, or “back” pressure, can also reduce the glomerular filtration rate; congested veins can compress the tubules and increase the capsular pressure, thereby opposing filtration and finally reducing the glomerular filtration rate and sodium and water excretion . HoweverApart from volume expansion, renal insufficiency can impair cardiac performance and functional capacity by means of a variety of other mechanisms: first of all, hypertension with an increased ventricular afterload, but also anemia that implies increased cardiac work and ionic alterations  with potentially negative inotropic effects .However, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. In DCM patients, renal deterioration can progress independently of HF. In fact, the deterioration can be due to drugs and environmental toxicants ,37 that Considerable evidence demonstrates the adverse effects of obesity on central and peripheral hemodynamics, as well as on cardiac structure and function. In particular, with exercise in class III obese patients, central blood volume increases by 20%, LV end-diastolic pressure increases by 50% , and LV dP/dt increases by 57% . Fat-freThe major limitations of the previous reports are, firstly, that diastolic function has not been properly studied ,42,43,44Major practical suggestions arise from these data on how to improve symptoms and possibly even prognosis. First of all, LV diastolic function must be primarily addressed with echocardiography. In cases where LV diastolic restriction is present and functional capacity is impaired, therapeutic intervention to ameliorate the LV diastolic function is warranted. The former can reverse the consequences of diastolic dysfunction , and the second can eliminate or reduce the factors responsible for diastolic dysfunction  . While tSeveral limitations are present in this study.Even though the systolic fraction of PVF velocity is a very robust parameter in predicting LV restriction and now in predicting functional capacity, the diastolic deceleration time of the pulmonary D-wave, shown to have a very high prediction power for the pulmonary wedge pressure, was not assessed . AlthougWe did not measure systematically the E/e’ ratio. This is a pretty robust parameter , but it TEE is a semi-invasive approach that cannot be routinely used in DCM patients; therefore, this study should be considered a benchmark study for assessing the potential of the pulmonary venous flow in predicting functional capacity in DCM. Fortunately, a transthoracic approach has now shown feasibility of almost 100% in terms of recording the S- and D-waves and slightly less 90%) of the reversal wave, with a very tight correspondence with TEE recording . The use0% of theThis study did not specifically address the prognostic impact of these parameters. However, S Fract and creatinine clearance have also been shown to have a major independent prognostic implication in a 13-year follow-up, as previously reported . Further2 consumption. Therefore, other predictors are possibly missing. We believe that a reduced alveolar–capillary membrane diffusing capacity [The study explained at most 61% (Nagelkerke R-squared) of the total variance in the peak VOcapacity ,63,64 ancapacity  should aThe model needs to be prospectively applied to demonstrate model validation .A blunted systolic PVF, indicating a high pre-a LV filling pressure rather than a depressed LV EF has an independent role in predicting impaired functional capacity in patients with DCM. Cardiorenal syndrome and obesity in patients with DCM have a major impact on reducing functional capacity. This assessment has important clinical implications.


Cardiovascular events are seen more frequently after the age of 60 and they are a significant cause of morbidity and mortality. Arterial stiffness is a property that can be expressed by pulse wave velocity and this value is assumed to be a predictor of cardiovascular events. Patients with chronic kidney disease and dysregulated blood sugar have increased atherosclerosis and arterial stiffness, but the relationship between physiological levels of Hba1c and arterial stiffness is less clear in chronic kidney disease patients without diabetes mellitus.Here, we aimed to investigate the degree of arterial stiffness among non-diabetic, non-dialysis dependent chronic kidney disease patients with physiological HbA1c levels.We enrolled 51 patients who were followed up at Ege University Hospital Nephrology Department between February and June 2015. Non-diabetic, non-dialysis dependent chronic kidney disease patients were included in the study. Blood pressure and pulse wave velocity were measured with an applanation tonometry device . Correlations between pulse wave velocity and the aforementioned parameters were investigated (see below).We detected a significant correlation between pulse wave velocity and systolic blood pressure (p=0.0001) and Hba1c (p=0.044) separately. There was an inverse correlation with creatinine clearance (p=0.04). We also detected a significant correlation with serum phosphorus level (p=0.0077) and furosemide use (p=0.014). No correlations were found among the other parameters.Arterial stiffness is an important predictor of cardiovascular events and measuring it is an inexpensive method for estimating morbidity and mortality. Our study supports the importance of measuring arterial stiffness and of controlling blood glucose levels, even at physiological Hba1c values, especially for chronic kidney disease patients. Being over the age of 18 years and having stage 2-5 CKD were defined as the inclusion criteria; whereas the exclusion criteria were defined as having DM or stage 1 CKD, using anti-diabetic or immunosuppressive drugs, receiving renal replacement therapy, having active infection, malignity, or an immunosuppressive condition, and being pregnant or breastfeeding. Patients who were previously enrolled on any other clinical trial or unwilling to participate into the study were also excluded. Sample size analysis determined that 23 patients were required to achieve a power of 80% (standardized effect size: 0.82 with a 5% type I error margin).The stage of CKD is determined by glomerular filtration rate (GFR).8All procedures were conducted in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical committee approval was obtained for the study (14-9.1/11). Informed consent forms were obtained from all patients for participation and publication.Statistical assessment was performed using the SPSS 15.0  software program. Conformity of numerical variables to normal distribution was measured with the Shapiro Wilks test. Descriptive statistics for numerical variables were expressed as mean ± standard deviation (SD) and median (minimum-maximum), whereas counts and percentages were used for categorical data. Linear relationships between two numerical variables were examined by Pearson correlation analysis if parametric test assumptions were met or by Spearman correlation analysis if they were not. The results were evaluated within a 95% confidence interval and a p value below 0.05 was considered significant.Our study was performed with 51 patients , with non-diabetic, stage 2-5 non-dialysis dependent chronic kidney disease. The mean age of the patients was 57.4 ± 16.3 and the mean BMI value was 27. The mean systolic (SBP) and diastolic blood pressure (DBP) of the patients were 138 ± 17 mm Hg and 80 ± 15 mm Hg respectively. The mean HbA1c value of the cases was calculated as 5.3%. Seventeen percent of 51 patients had previously-known coronary arterial disease and 3% had peripheral arterial disease. When they were classified according to the causes of CKD; it was determined that 19.6% of the cases had glomerulonephritis, 15.6% had tubulointerstitial nephritis and drug-related causes, 17.6% had hypertension (HT), 13.7% had urolithiasis (and other obstructive causes), and 5.8% had polycystic kidney disease. The causative pathology could not be determined in 27.4% of the cases. Regarding drug use, 23% were taking aspirin, 5% were on antihyperlipidemic drugs, 33% were taking calcium channel blockers, 35% were on beta blockers, 33% were taking angiotensin-converting-enzyme (ACE) inhibitors, and 27% were receiving furosemide. Seventeen percent of the cases used to have a smoking habit at the time of enrollment on the study. The descriptive data and laboratory parameters of the cases are shown in ,1,15-20-Arterial stiffness is a property that is measured as the PWV between the carotid and femoral arteries, with the unit m/sec. Different causes contribute to AS, of which HT, DM, smoking, hypercholesterolemia, and aging are the most prominent.10,It is a well-known fact that AS, which is accepted as a predictor of CVE with morbidity and mortality, is expected to be increased in individuals with CKD ± insulin resistance or uncontrolled blood sugar regulation.6