Background and objectiveThe advent of robot-assisted kidney transplant (RAKT) has ushered in a new set of challenges. In this single-center retrospective observational study, we aimed to highlight the anesthetic challenges and analyze perioperative parameters to identify the risk factors for delayed graft function (DGF) in RAKT.MethodsA descriptive analysis of perioperative factors of the first 100 cases of RAKT at our center was performed. Data were retrieved from the hospital's electronic medical records (EMR) of donors and adult patients who underwent RAKT between July 2015 and December 2020. The data analyzed included demographics, preoperative optimization, intraoperative and postoperative management, and complications. DGF was defined as a requirement of dialysis within one week of transplant. The Fisher’s exact test, independent sample t-test, and the Mann-Whitney test were used to analyze data.ResultsAmong a total of 193 renal transplants performed during the study period, 100 patients underwent RAKT, which included 27 females and 73 males. Of these, 91 were live while the remaining involved deceased-donor transplants. Pneumoperitoneum and steep Trendelenburg position required various “anesthetic maneuvers” to maintain hemodynamics and respiratory parameters. Optimal fluid management, with frusemide and mannitol, ensured good urine output (UOP) (93%). Post-reperfusion, the release of pneumoperitoneum, maintenance of adequate perfusion pressures, immunosuppression, and regional hypothermia helped in ensuring adequate graft function (93%). The incidence of DGF in our series was 7% and the mortality rate was 3%. Recipient age (p=0.045), dyslipidemia (p=0.021), and diabetes mellitus (p=0.023) were identified as significant risk factors for DGF.ConclusionAdvanced recipient age, diabetes, and dyslipidemia were factors significantly associated with DGF in RAKT in our series of 100 cases. However, the duration of the steep Trendelenburg position, docking of robot/pneumoperitoneum (console time), fluid management, warm and cold ischemia times, rewarming time, and type of graft did not influence DGF. Awareness of the systemic involvement in RAKT, proper preoperative optimization, and knowledge of potential problems are essential for the efficient anesthetic management of RAKT. The emergence of surgical robotic systems has opened up new dimensions in transplant surgery . AnestheThis was a single-center retrospective cohort study of the first 100 cases of RAKT treated at our tertiary care center. The electronic medical records (EMR) in the operating room and intensive care unit (ICU) pertaining to patients who underwent RAKT from July 2015 to December 2020 at our center were evaluated after obtaining institutional approval (AM/RC/90-2019). The study was conducted in accordance with the principles of the Declaration of Helsinki. The aim of the study was to identify the anesthetic challenges and to find out the incidence and perioperative risk factors of DGF. All adult patients who underwent RAKT were included in the study. The open renal transplant patients and the pediatric recipients were excluded. The data analyzed were as follows: demographic profiles; indication for transplantation; comorbidities; duration of dialysis; preoperative hemoglobin, creatinine, and potassium levels; duration and technique of anesthesia and surgery; console time; volume and type of intravenous fluids; surgical findings; warm ischemia time (WIT); rewarming time; CIT; intraoperative urine output (UOP); immunosuppressant therapy; antibiotics; timing of extubation; perioperative complications; the need for postoperative dialysis; serum creatinine levels on postoperative days (POD) three, five, and seven, and at one month and one year; and duration of ICU and hospital stay.Kidney failure immediately after transplantation, requiring dialysis in the first week post-transplant, was defined as DGF . WIT wasAnesthesia techniqueOndansetron (4 mg), pantoprazole (40 mg), alprazolam (0.25 mg), and antihypertensive drugs were given to the patient on the night before and in the morning of surgery. Immunosuppression protocol included mycophenolate mofetil (35 mg/kg) and tacrolimus (0.1 mg/kg) initiated two days prior to surgery, and basiliximab 20 mg was added in cases of deceased-donor transplant and donors who were not first-degree relatives. All the patients received methylprednisolone (7.5 mg/kg) intraoperatively. All live-donor recipients were dialyzed 24 hours pretransplant and the deceased-donor recipients were dialyzed at the earliest before the transplant. After the dialysis, preoperative investigations, namely, hemoglobin, total count, platelet count, prothrombin time, serum electrolytes, and renal function tests, were performed.In addition to standard monitoring, an arterial line, central venous triple lumen catheter, and a bispectral index (BIS) monitor were used in all patients. General anesthesia (GA) was induced with midazolam (0.02-0.04 mg/kg), fentanyl (3-4 mcg/kg), propofol (1-2 mg//kg), and atracurium (0.5 mg/kg). Anesthesia was maintained with air, oxygen, isoflurane, atracurium (0.5 mg/kg/hour), and dexmedetomidine infusions (0.2-0.5 mcg/kg/hour). Isoflurane was titrated to maintain BIS between 40 and 60. Patients were mechanically ventilated using pressure control ventilation (PCV), peak pressures limited to less than 35 mmHg, positive end-expiratory pressures (PEEP) of 5 mmHg, and the rate adjusted to maintain normocarbia. The temperature was maintained by fluid warmers, hot-air warmers, and warming blankets. Intermittent pneumatic compression devices were used for deep vein thrombosis (DVT) prophylaxis, and a nasopharyngeal tube was inserted.A restrictive fluid management strategy (1 ml/kg/hour) of crystalloids was used in all patients till the implantation of neo kidney, followed by a more liberal fluid regimen (1.5-1.75 ml/kg/hour). This resulted in 1.5-2 liters of fluids being administered before reperfusion. Both normal saline and Ringer's lactate were used in these patients. Post-reperfusion, the fluid intake was based on the previous hour's UOP plus 200 ml. A combination of furosemide (100 mg) and 20% mannitol (0.25-0.5 mg/kg) was used before reperfusion.In addition to intravenous fluids, noradrenaline was used to maintain adequate mean arterial pressure (MAP) after reperfusion. In three (3%) cases, nitroglycerine (NTG) was used to control intraoperative hypertension.2 through the Veress needle. A 30-45-degree Trendelenburg position was executed and the robot was docked. Central venous pressure (CVP) increased by 14 ± 4 mmHg. The intra-abdominal (IAP) pressure was maintained at 15 mmHg. After reperfusion, the pneumoperitoneum was completely released for open ureteric anastomosis.A single surgeon, experienced in the Da Vinci systems  operated on all patients. Pneumoperitoneum was created by insufflating COExtubation was attempted in all except eight patients (8%). Seven patients were not extubated on the table as they were deceased-donor transplants, which were started at odd hours. One patient was a case of anticipated difficult intubation who was extubated once, fully awake in the ICU. Postoperative analgesia was provided by fentanyl infusion (0.5 mcg/kg/hour) and intravenous paracetamol 1 gram thrice daily. The patients were discharged from the hospital once their creatinine levels stabilized.Statistical analysisFor categorical variables, we presented the data as numbers and percentages. For continuous variables, we presented the mean and standard deviations (SD). In situations where the continuous data were skewed, the median and range were reported. The Fisher’s exact test was used to compare the categorical variables with postoperative complications. The independent sample t-test was used to compare the continuous variables with postoperative dialysis status. The Mann-Whitney test was used to compare the duration of dialysis and one-month postoperative creatinine with postoperative dialysis status. A p-value <0.05 was considered statistically significant. We used Bonferroni correction for presenting p-values related to multiple comparisons. Statistical analyses were performed using SPSS version 20.0 for Windows .Of the 193 renal transplants performed in total, 100 were RAKT. There were 27 females and 73 males. Ninety-one were live while the remaining involved deceased-donor transplants. All except deceased donors underwent laparoscopic nephrectomies. A custodial solution was used for perfusion. The most common indication for transplant was chronic glomerulonephritis followed by IgA nephropathy. The demographic details and comorbidities of the cohort are presented in Table Of note, 94% of patients were on a thrice-weekly dialysis regimen with a quarter of them being on dialysis for more than one year; 47% of patients were started on dialysis within six months. The intraoperative and postoperative parameters are detailed in Tables Conversion to open occurred in three (3%) cases because of the presence of an arterial thrombus, acute venous kink, and decreased perfusion in the lower renal pole. One patient required a dual kidney transplant from a deceased donor and two patients had vaginal insertion of the graft. Double renal artery implantation had to be performed in 12% of patients. Three (3%) patients had hyperkalemia before reperfusion, which was aggressively managed. Eight patients were extubated in the ICU.Gram-negative sepsis, polyuria leading to hypernatremia, impaired level of consciousness and aspiration pneumonia, and ureteric leak after stent removal were the postoperative complications we encountered. After extubation, none of the patients had airway issues although most had facial puffiness. Seven (7%) patients had DGF, necessitating two to three cycles of hemodialysis. Three patients had graft rejection, of which two were successfully managed. There were no wound infections, lymphocele, or prolonged ileus. The mean blood loss was 88 ± 51 ml.One patient was re-explored for postoperative bleeding, four hours after surgery. There were three 3%) deaths in the entire cohort. Dengue hemorrhagic fever, DGF with bacterial sepsis, and antibody-mediated rejection with sepsis were the causes of mortality. The analysis of perioperative factors revealed that there was a significant association of DGF with recipient age (p=0.045), dyslipidemia p=0.021), and diabetes mellitus (0.023) , day five (p=0.006), day seven (p=0.019), and at one month (p=0.001), but there was no difference by the end of one year. We did not get serum creatinine from seven patients at one year as they were lost to follow-up. We found that the duration of ICU stay and hospital stay were higher in the DGF group (p<0.001). We could not find an association between donor factors, namely, age, gender, comorbidities, and type of graft Table .Logistic regression model for postop dialysis with independent risk factors could not be used since the number of incidences was less corresponding to the number of risk factors associated.Anesthetizing patients for RAKT poses a great challenge because of the multisystem involvement of end-stage chronic kidney disease (CKD), the effect of pneumoperitoneum and Trendelenburg position on hemodynamics and fluid management, possible deleterious effects of pneumoperitoneum on the neo kidney, and difficulties associated with robotic surgery .LVH, coronary artery disease (CAD), arrhythmias, pulmonary hypertension, diastolic dysfunction, pericardial effusion, uremic cardiomyopathy, anemia, coagulopathy, and electrolyte and acid-base disturbances are risk factors associated with anesthesia for CKD . An earlGA in steep Trendelenburg with lithotomy position and pneumoperitoneum can lead to reduced functional residual capacity and lung compliance, promote atelectasis, and generate high airway pressures with reduced minute ventilation, hypoxia, and hypercarbia ,4. Our m2)-to-PaCO2 relationship (4-6 mmHg). Restoration of normal ETCO2-to-PaCO2 relationship after surgery may take several hours [2 by ETCO2, and the long duration of our surgeries (257 ± 50.74 minutes), we based our ventilation strategy to achieve a normal PaCO2. Therefore, an arterial line and arterial blood gas analysis were used in all. Hypercarbia and respiratory acidosis have to be avoided to prevent associated hyperkalemia, raised intracranial pressure (ICP), cardiac depression, and dysrhythmia. Hyperkalemia before reperfusion was seen in only 3% of patients, probably due to the administering of preoperative dialysis and avoidance of hypercarbia.Carbon dioxide pneumoperitoneum with a steep Trendelenburg position can alter the normal end-tidal carbon dioxide ETCO-to-PaCO2A study on laparoscopic renal transplants found that pneumoperitoneum caused a significant increase in MAP, which necessitated the initiation of NTG in 65% of patients . An incrRenal graft function and survival are directly influenced by the transplanted graft perfusion . In our In our series, even though peri-orbital and facial edema was noticed, we did not have any airway-related issues. Prolonged surgery in the steep Trendelenburg position can increase ICP and lead to post-extubation stridor, delayed awakening, visual loss, nerve injuries, and the migration of the endotracheal tube ,7. Post-Conversion to open occurred in 3% of cases. It was essential in these cases to undock the robot emergently. Our team's familiarity with the emergency undocking helped us tide over this crisis. The mortality rate (3%) and graft survival (93%) in our series were comparable to previously published data in the literature .DGF is defined as an acute renal failure of transplanted kidneys due to ischemic injury exacerbated by the reperfusion syndrome, which leads to oliguria, acute rejection, enhanced graft immunogenicity, and increased ICU and hospital stay . The incCadaveric transplants have been associated with a higher incidence of DGF due to a higher incidence of donor hemodynamic fluctuations and prolonged CIT . We did The addition of epidural to GA produced a threefold increase in DGF rates . This waOjo et al.  studied Liu et al., in their meta-analysis of six nonrandomized studies, found that although the RAKT group had significantly higher rewarming time and total ischemia time, the incidence of DGF was comparable with open transplants . AlthougThe application of intraoperative regional hypothermia has shown a clear benefit when the anastomosis takes more than 40 minutes. The use of ice slush around the graft in our cohort helped in maintaining graft temperature. The WIT (p=0.135) and rewarming time (p=0.295) did not show any statistically significant difference between the two groups. Our findings corroborated that neither surgical time nor rewarming time showed any correlation with postoperative serum creatinine levels in RAKT .A restrictive fluid regimen produced a fourfold increase in the risk of DGF. Liberal fluid therapy before reperfusion resulted in higher blood pressures, early diuresis, and early graft function ,13. A ma2) was comparable with our open transplant patients (68.37 mL/min/1.73 m2) where the fluid management was CVP-based. The total fluids used or the type of fluids did not have an influence on DGF in our cohort.Hence, we developed an institutional fluid management protocol. We did not find any association between the volume or type of crystalloids used and DGF. We also used frusemide (100 mg) to induce diuresis. Mannitol (0.25-0.5 g/kg) was used prior to reperfusion for its volume-expanding and osmotic diuretic effects. Of note, 93% of patients had immediate adequate UOP in our cohort. The estimated glomerular filtration rate (GFR) at one month in our RAKT series (64.4 mL/min/1.73 mWe found a correlation between DGF and recipient age, dyslipidemia, and diabetes mellitus. Lebranchu et al. found that the recipient age >55 years increases the risk of DGF . The aveSimilar to our findings, diabetes and dyslipidemia have been upheld as risk factors for DGF in other studies as well -25. DamoPretransplant lipoprotein disturbances have been found to influence early graft function . Poor quWe compared the duration of anesthesia, surgery, and console time between the two groups and did not find any statistically significant association. Pneumoperitoneum can reduce GFR and urine output is reduced due to renal ischemia  . HoweverDespite the challenges we described, there are a number of advantages of RAKT. It is associated with smaller incisions and lower blood loss, tissue trauma, pain, and wound infection . EarlierOur study has a few limitations. Firstly, it was retrospective in design, which could have led to some risk of detection bias and underreporting. Some unmeasured variables may have affected the accuracy of our model. Logistic regression model for postop dialysis with independent risk factors could not be used. Still, this study has important clinical implications as it was one of the first few to look into DGF in RAKT in the context of anesthesia.The incidence of DGF in our series was 7%, which is comparable with the available literature. Advanced recipient age, presence of diabetes, and dyslipidemia were factors associated with DGF in RAKT. However, CIT, rewarming time, console time, duration of surgery and Trendelenburg position, intraoperative fluid therapy, and type of graft did not have any association with DGF in our study. A thorough preoperative evaluation and optimization, knowledge and anticipation of potential problems and meticulous intraoperative fluid management, appropriate monitoring, and a multispecialty team approach are essential for the efficient anesthetic management of these complex procedures.


Persistent occult hypoperfusion after initial resuscitation is strongly associated with increased morbidity and mortality after severe trauma. The objective of this study was to analyze regional tissue oxygenation, along with other global markers, as potential detectors of occult shock in otherwise hemodynamically stable trauma patients.2) was measured non-invasively by near-infrared spectroscopy (NIRS) on the forearm. A vascular occlusion test was performed, allowing a 3-min deoxygenation period and a reoxygenation period following occlusion release. Minimal rSO2 (rSO2min), Delta-down (rSO2–rSO2min), maximal rSO2 following cuff-release (rSO2max), and Delta-up (rSO2max–rSO2min) were computed. The NIRS response to the occlusion test was also measured in a control group of healthy volunteers.Trauma patients undergoing active resuscitation were evaluated 8 h after hospital admission with the measurement of several global and local hemodynamic/metabolic parameters. Apparently hemodynamically stable (AHD) patients, defined as having SBP ≥ 90 mmHg, HR < 100 bpm and no vasopressor support, were followed for 48 h, and finally classified according to the need for further treatment for persistent bleeding , initiation of vasopressors and/or bleeding control with surgery and/or angioembolization. Patients were labeled as “Occult shock” (OS) if they required any intervention or “Truly hemodynamically stable” (THD) if they did not. Regional tissue oxygenation (rSO2min, and Delta-up.Sixty-six consecutive trauma patients were included. After 8 h, 17 patients were classified as AHD, of whom five were finally considered to have OS and 12 THD. No hemodynamic, metabolic or coagulopathic differences were observed between the two groups, while NIRS-derived parameters showed statistically significant differences in Delta-down, rSOAfter 8 h of care, NIRS evaluation with an occlusion test is helpful for identifying occult shock in apparently hemodynamically stable patients.IV, descriptive observational study.ClinicalTrials.gov Registration Number: NCT02772653. Trauma is the most frequent cause of death among people aged between 5 and 29 years old worldwide , and in 2), and it is generally used in peripheral areas such as the skeletal muscle  and ROPE Index [HR/(SBP-DBP)].Blood samples included: hemoglobin, natriuretic atrial peptide (NAP), base deficit and serum lactate concentration.® and classified in five phenotypes, according to the degree of abnormality observed: 0 = normal; 1 = fibrinogen deficiency; 2 = hypocoagulability; 3 = platelet deficiency; 4 = global deficiency; 5 = global deficiency and hyperfibrinolysis.Coagulopathy was assessed with ROTEM2) was recorded continuously using the INVOS™ 5100C Cerebral/Somatic Oximeter . The rSO2 15 mm optical surface probe was placed on intact skin on the forearm muscle. In addition to the steady-state rSO2 value, the response to a transient ischemic challenge was also computed. The ischemic challenge consisted in a standardized Vascular Occlusion Test (VOT), and was performed as previously described in the literature [2 (rSO2min) and maximum rSO2 (rSO2max) values were recorded. VOT-derived variables included Delta-down  and Delta-up (difference between rSO2min and rSO2max). Absolute rSO2 and VOT-derived variables were obtained using the INVOS Analytics Tool v1.2 .Regional oxygen saturation , mechanism of injury, causes of death, vasopressor administration, blood products, and operative and interventional radiology procedures were recorded.2 and the normal response to VOT, forearm muscle rSO2 and VOT readings were taken from healthy volunteers whose age and sex were similar to the patients analyzed for this study. Generally, these individuals were hospital and university staff and medical students. Additional parameters recorded included individual’s age, sex, blood pressure, and comorbidities. Exclusion criteria were consumption of caffeine within the previous 8 h before the test, taking medications with cardiovascular effects, and/or previous known peripheral vascular disease.To determine the normal range of forearm muscle rSOU-test or Student’s t-test for continuous variables, as appropriate. A two-tailed p value of less than 0.05 was taken to indicate statistical significance.Statistical analysis was performed by means of IBM SPSS statistics v25 software . The normal distribution of the variables studied was confirmed using the Kolmogorov–Smirnov test. Accordingly, continuous variables were expressed as means ± standard deviation (SD), and categorical variables were expressed as absolute numbers and proportions (%). A descriptive analysis was performed. Differences between groups were assessed using the Chi-squared test for categorical variables, and the Kruskal–Wallis test, Mann–Whitney’s 2 and VOT-derived variables were obtained from 48 healthy volunteers. Main characteristics of the sample population and NIRS-related results are shown in Table From December 2019 to March 2020, basal rSOFrom May 2016 to March 2019, 66 consecutive trauma patients with eligible criteria for this study were admitted to our hospital. Mean age was 42 ± 15 years old, 80% were males and median injury severity score (ISS) was 25.5 (IQR 8–68). The characteristics of AHD and HDU patients are shown in Table 2-max values in trauma patients . No differences between volunteers and THD were observed, while OS patients showed alterations in rSO2-min, Delta-down, and Delta-up as compared to healthy controls. HDU only differed from healthy subjects in terms of their rSO2-max following the VOT.Comparison between healthy volunteers and trauma patients is presented in Table The Kruskal–Wallis test showed different distributions of the NIRS-related variables among the three trauma groups. While no significant differences were detected between HDU and THD patients, OS patients differed from the rest of the groups Table .Table 2-related parameters may help to detect apparently hemodynamically stable patients who are still under-resuscitated. These findings are relevant, since alterations in NIRS parameters can provide clinicians with important information regarding the evaluation of otherwise clinically stable patients.Our data suggest that, after 8 h of active treatment, alterations in rSOOccult shock, defined as persistent hypoperfusion with normal vital signs, remains a controversial entity , and its2 desaturation rates can only be attributed to two underlying mechanisms, or a combination of them: (a) diminished local blood flow, and (b) increased local metabolic rate. In situations of hypovolemia, blood flow is diverted from the periphery to the central compartment, causing a “stealing effect” of blood from these peripheral or non-vital areas. This compensatory mechanism is mainly driven by the activation of the sympathetic system, which also increases the metabolic rate, as a result of the effect of the release of catecholamines [Our findings are consistent with previous data on NIRS monitoring, and are based on a strong pathophysiological rationale. We observed that, in apparently stable patients, higher rates of desaturation following a VOT were associated with the need for further resuscitation interventions to control bleeding in the following 48 h. These higher rSOolamines . Regrettolamines , 20. Int2 and performed a VOT in 150 trauma patients, and concluded that, even though rSO2 had prognostic value for mortality and multiple organ failure, it did not identify occult shock states. This was considered an inherent limitation of the technology, insofar as peripheral vasoconstriction associated with compensated shock states may be accompanied by a reduction in regional tissue oxygen demand and compromised supply. However, stressing the system by producing a vascular occlusion yielded parameters such as the rSO2 de-saturation and re-saturation slopes, which distinguished between patients requiring bleeding control maneuvers and those that did not. Additionally, the analysis of lactate and SBP found no statistical relationship for these variables, and the authors concluded that VOT-derived variables were capable of detecting occult shock when vital signs and lactate were normal. NIRS technology has also been recommended in AHD patients before starting resuscitation maneuvers [2 and severe shock, and not with mild or moderate shock. It should be stressed that no VOT was performed; therefore, in situations of severe shock absolute rSO2 is altered, but in states of moderate or occult shock it remains normal while VOT-derived variables are altered. In general, we can infer that absolute rSO2 values may be capable of detecting overt shock, and that VOT-derived parameters are useful in situations where the hemodynamic status is apparently compensated and provide additional help in the detection of tissue hypoperfusion. When analyzing the HDU group, one would expect HDU patients to show lower regional oxygenation parameters. However, the lack of differences might derive from our definition of HDU, including those patients who were hypotensive, tachycardic, and/or requiring vasopressors. In fact, 27 patients were classified as HDU because they were on vasopressors. Therefore, although we considered those patients to be HDU, they were probably resuscitated, with normalized tissue perfusion/oxygenation, despite requiring vasopressors to achieve that normalization. Our study adds to the current evidence and underlines the value of regional tissue oxygenation as part of the monitoring tool kit for the hemodynamic resuscitation of trauma patients.Previous studies have already described NIRS technology as a useful tool for detecting tissue hypoperfusion in trauma patients , 21, 22.aneuvers , 21. Theaneuvers  found a The predictive power of non-NIRS-related variables was very limited except for lactate and BD, two parameters that have classically been related to occult shock detection –6, 23–26Blow et al.  defined In contrast, our study did not detect a statistically significant relationship between lactate or BD and occult shock. This absence of a statistical relation might be attributable, on the one hand, to the small sample size, as we compared 12 THD patients with five OS patients. On the other hand, most authors associate lactate and BD with mortality , 25, 28 A previous study by our group considered the Shock Index (SI) as a marker of occult shock when it was ≥ 0.8  because In contrast, our study did not find a statistically significant relationship between the SI and occult shock. This may have been due to the moment in time when the SI was evaluated. Generally, the studies that associate the SI with bleeding control maneuvers use it during prehospital care , 32 or aThe main limitation of our study is the small sample of trauma patients analyzed. However, and though the number of patients is small, VOT-derived variables presented statistically significant relationships with occult shock, while the other variables did not.After 8 h of hospital care, NIRS evaluation with an occlusion test might be helpful for identifying occult shock in otherwise apparently hemodynamically stable trauma patients. In this study, no other resuscitation marker analyzed showed a statistically significant association with occult shock detection. Therefore, VOT-derived parameters may be a relevant screening tool for detecting patients at risk of hemodynamic deterioration. Further and larger prospective study would be needed to confirm our findings.


During the 0.10 Hz maneuver (N = 6 CKD and N = 12 CON), Coherence: CKD = 0.61 ± 0.10, CON = 0.67 ± 0.11, Phase (radians): CKD = 1.43 ± 0.26, CON = 1.30 ± 0.23, Gain (cm/s/mmHg): CKD = 0.75 ± 0.15, CON = 0.84 ± 0.26, nGain (%/mmHg): CKD = 1.50 ± 0.28, CON = 1.29 ± 0.24, p ≥ 0.12. Contrary to our hypothesis, dynamic cerebral autoregulation remains intact in CKD stages III‐IV. These findings suggest that other mechanisms likely contribute to the increased cerebrovascular disease burden experienced by this population. Future work should determine if other cerebrovascular regulatory mechanisms are impaired and related to cerebrovascular disease risk in CKD.Chronic Kidney Disease (CKD) patients experience an elevated risk for cerebrovascular disease. One factor that may contribute to this heightened risk is an impairment in dynamic cerebral autoregulation, the mechanism by which cerebral vessels modulate cerebral blood flow during fluctuations in arterial pressure. We hypothesized that dynamic cerebral autoregulation would be impaired in CKD. To test this hypothesis, we compared dynamic cerebral autoregulation between CKD patients stages III‐IV and matched controls (CON) without CKD. Fifteen patients with CKD and 20 CON participants performed 2, 5‐minute bouts of repeated sit‐to‐stand maneuvers at 0.05 Hz and 0.10 Hz while mean arterial pressure  and middle cerebral artery blood velocity  were measured continuously. Cerebral autoregulation was characterized by performing a transfer function analysis (TFA) on the MAP‐MCAv relationship to derive coherence, phase, gain, and normalized gain (nGain). We observed no group differences in any of the TFA metrics during the repeated sit‐to‐stand maneuvers. During the 0.05 Hz maneuver, Coherence: CKD = 0.83 ± 0.13, CON = 0.85 ± 0.12, Phase (radians): CKD = 1.39 ± 0.41, CON = 1.25 ± 0.30, Gain (cm/s/mmHg): CKD = 0.69 ± 0.20, CON = 0.71 ± 0.22, nGain (%/mmHg): CKD = 1.26 ± 0.35, CON = 1.20 ± 0.28,  Chronic Kidney Disease (CKD) patients experience an elevated risk for cerebrovascular disease, which may be mediated in part by an impairment in dynamic cerebral autoregulation. We compared dynamic cerebral autoregulation between CKD patients stages III‐IV vs matched controls (CON) without CKD and hypothesized that dynamic cerebral autoregulation would be impaired in CKD. Contrary to our hypothesis, dynamic cerebral autoregulation remains intact in CKD, which suggests that other mechanisms likely contribute to the increased cerebrovascular disease burden experienced by this population. Written informed consent was obtained for all study participants and all study procedures conformed to the standards set forth by the Declaration of Helsinki. This study is registered at clinicaltrials.gov (NCT 02947750).2.22), as defined by the CKD‐EPI equation  in the seated position after 5 minutes of quiet rest with the arm supported at the heart level in accordance with the American College of Cardiology/American Heart Association Guidelines  were measured on a breath‐by‐breath basis through an oral‐nasal cannula via capnography . Middle cerebral artery blood velocity (MCAv) was measured via transcranial Doppler (TCD) ultrasound . Specifically, 2 MHz probes were secured over the temporal window of the participants head via adjustable headgear  while MCAv was acquired using a standardized approach as outlined in the literature  via a standard three lead ECG (AD Instruments), and beat to‐beat arterial pressure via finger photoplethysmography  applied to the dominant hand. This arm was placed in a sling at heart level for stability to ensure accurate detection of the blood pressure waveform throughout the repeated sit‐to‐stand maneuvers. Respiration rate and end tidal CO2.4Cerebral autoregulation was assessed during repeated bouts of sit‐to‐stand, performed at 0.05 Hz and 0.10 Hz  were collected at 1000 Hz  and analyzed offline via specialized software (Elucimed). The timing of each cardiac cycle was determined from the R‐wave of the ECG signal and beat‐to‐beat arterial pressures and MCAv were then detected. Mean arterial pressure (MAP) and mean MCAv were automatically calculated as the area under the arterial pressure and cerebral blood velocity waveform. Cerebral autoregulation was assessed in accordance with standardized guidelines set forth by the Cerebrovascular Research Network (CARnet) . All continuous waveform data  and low frequency (0.07–0.20 Hz) ranges were compared between groups via unpaired, two‐tailed, T‐tests for continuous variables, or chi‐square analysis for categorical variables. During each of the two repeated sit‐to‐stand maneuvers, MAP and MCAv spectral power and MAP‐MCAv transfer function coherence, phase, gain, and nGain were compared at the point estimates of the driven frequencies (0.05 Hz and 0.10 Hz) via unpaired, two‐tailed 33.1N = 9 CKD, N = 4 CON) so these participants did not complete the experimental protocol and were thus excluded from analyses. As such, we obtained data from N = 15 CKD  and N = 20 CON for all measurements unless otherwise indicated. Demographic data for both groups are reported in Table p ≥ 0.08).Twenty‐four patients with CKD stages III‐V and 24 controls free from renal disease were recruited to participate in this study. We were unable to acquire useable ultrasound signals for the MCA in 13 participants .Resting hemodynamic and cerebrovascular parameters are provided in Table 3.3p ≥ 0.52). EtCO2 remained stable throughout both maneuvers with no differences between groups .The repeated sit‐to‐stand maneuvers induced robust oscillations in blood pressure and MCAv at their respective frequencies. Figure p = 0.67), phase , gain , or nGain  between groups during the 0.05 Hz maneuver . Of the participants that did complete the 0.10 Hz maneuver, coherence remained <0.5 for N = 4 CKD and N = 6 CON, precluding our ability to analyze phase and gain metrics, so these participants were also excluded from the final analysis. As such, N = 6 CKD and N = 12 CON during 0.10 Hz repeated sit‐to‐stand. There were no group differences in MAP‐MCAv coherence , phase , gain , or nGain  between groups during the 0.10 Hz maneuver  and the National Institutes of Health Grants (R01HL135183 and R61AT010457 PI: J.P.).


Sepsis is a severe illness which results in alterations in the end organ microvascular haemodynamics and is associated with a high risk of mortality. There is currently no real-time method of monitoring microcirculatory perfusion during sepsis. Retinal microcirculation is closely linked to cerebral perfusion and may reflect systemic vascular alterations. Retinal perfusion can be assessed using the non-invasive imaging technique of optical coherence tomography angiography (OCTA). This narrative review aims to discuss the utility of using retinal imaging and OCTA in systemic illness and sepsis. OCTA can be used as a functional, non-invasive and real-time biomarker along with other haemodynamic parameters for assessing and managing patients with sepsis. Sepsis is a dysregulated response to infection causing widespread inflammation, leading to life-threatening organ dysfunction . EstimatNo single diagnostic test can definitively establish the diagnosis of sepsis or septic shock. Diagnosis is clinical and relies on early recognition of hypotension, high cardiac output, and end-organ damage. The quick Sequential Organ Failure Assessment (qSOFA) score is a fast scoring method to identify patients with suspected infection who are likely to die in hospital, and which takes into consideration respiratory rate, altered mentation, and systolic blood pressure (BP) . The SOFAltered microvascular blood flow is a core feature of sepsis –7, involFluid resuscitation is a standard intervention to treat septic patients and prevent end-organ dysfunction, such as renal failure, which is a significant cause of sepsis-induced morbidity and mortality . HoweverThere is currently no real-time method to monitor microcirculatory reperfusion in septic patients, which would be beneficial for monitoring sepsis progression and response to therapeutic intervention. This review discusses the potential for retinal blood flow as a surrogate marker for end-organ (brain) perfusion in sepsis.The retinal vasculature arises directly from the cerebral blood vessels, as the internal carotid artery supplies the ophthalmic artery, which supplies the central retinal artery: the sole blood supply to the retina . Both reOptical coherence tomography (OCT) and OCT angiography (OCTA) are non-invasive imaging techniques that allow high-resolution cross-sectional retinal imaging of its structure and blood flow respectively , 20, witSepsis is a time sensitive critical illness, with early recognition and regular monitoring of progression proving pivotal to survival, especially when there may be haemodynamic instability . It is tMonitoring mean arterial pressure (MAP) is a standard assessment in sepsis as it approximates organ perfusion pressure, with a MAP of <70 mmHg deemed a criteria point for sepsis . CardiacRetinal blood flow has been investigated in many disease states which affect different organ systems, suggesting its potential for use as a biomarker across numerous diseases. The following study results are detailed in p = 0.039) (p = 0.004 and 0.002 respectively) (p = 0.000 and 0.005 respectively) before pulmonary vein isolation treatment. After treatment, only flow density in the optic nerve head significantly improved (p = 0.007), showing that retinal perfusion was reduced in patients with AF, with OCTA offering novel information on global perfusion in AF patients  had a significantly lower retinal capillary density in the deep vascular plexus than patients with well-controlled BP (125 ± 9 mmHg) (= 0.039) . Similarctively) . Patientpatients .p = 0.004), showing retinal vascular thinning in proportion to CKD severity, suggesting retinal vessel calibre may serve as a biomarker of CKD progression (p = 0.03), and a higher VD of the superficial and deep capillary plexus (p = 0.002–0.04), indicating higher retinal blood flow in these patients, compared with those who did not have hypotensive episodes (Patients with chronic kidney disease (CKD) have differing retinal microvascular calibres depending on the disease stage . Using dgression . Patientepisodes . This suAfter transcatheter aortic valve implantation, OCTA scans found new retinal capillary dropout in 28.6% of participants in both the superficial and deep capillary plexi , while vp < 0.05) compared with healthy controls, although as they only included 12 patients, a larger sample would be required to quantify vascular changes with disease progression  (p = 0.002) (2) and superficial/deep vascular density (r = 0.559/0.800 respectively), and a highly negative correlation between pO2 and FAZ size (r = −0.876) (p < 0.05) (Patients with chronic obstructive pulmonary disorder (COPD) had reduced retinal vascular density compared with healthy controls in the superficial and deep capillary plexi on OCTA (= 0.002) . COPD pa= 0.002) , and the −0.876) , suggest −0.876) . Retinal < 0.05) .These studies highlight the increasing use of retinal vasculature to investigate disease states, progression, and treatment response.As cerebral and retinal perfusion are closely related, and sepsis primarily affects that microcirculation, the retina is expected to reflect disease progression during a septic episode. The following study results are detailed in p = 0.029); lower cardiac index (CI) (p = 0.039); and lower levels of C-reactive protein (p = 0.011) than patients with a short RAFT (<8.3 s), although there were no differences when considering vasopressor dose, MAPs, or serum lactate levels (Fluorescein angiography (FA) is a retinal imaging technique in which fluorescein dye is injected intravenously to visualise the superficial retinal vasculature . Thirty-e levels . Septic e levels . Althougp = 0.002 and p < 0.001 respectively), yet CRVE did not differ between the two groups (p = 0.396) (p = 0.005), arterial tortuosity and diastolic BP (p = 0.036), vascular length density and lactate (p = 0.047), and vascular length density and CI (p = 0.014). This use of fundus imaging—a non-invasive technique—showing retinal vascular changes in septic patients demonstrates the potential to use similar retinal imaging techniques in this cohort of patients. A strength of this technique is its ability to quantify the microvascular dysfunction reproducibly.Using a handheld fundus photography device, large retinal vessel calibres and density were calculated by CRAE and CRVE respectively, and in septic patients, the median CRAE was higher and vascular length density lower compared with healthy controls (ps p = 0.6 (39). Hp < 0.001) in all IDF conjunctival microcirculation measures in septic patients compared with healthy controls. There was also significantly lower perfused VD in non-survivors compared with survivors at 24 h (p < 0.05). Non-survivors also had significantly lower retinal vascular length density (large vessels) by fundus photography at 6 and 24 h compared with baseline (p < 0.05) (Incident dark field (IDF) imaging—a non-invasive technique using a green light source absorbed by haemoglobin to detect red blood cells—has been used to assess conjunctival microvascular blood flow . When co < 0.05) . This cop = 0.000) compared to healthy controls. VD was also reduced in the foveal area of the choriocapillaris (p = 0.046). However there was no difference between groups in either the superficial or deep plexus VD percentage  from retinal and choroidal OCTA scans at 6 and 24 h after induction  which shp = 0.001) after indution and then increased close to baseline levels following resuscitation (p = 0.164). CI also decreased during shock (p = 0.051) and increased after resuscitation (p = 0.001), and central venous oxygen decreased during shock (p = 0.003) and increased to baseline levels after resuscitation (p = 0.027) (p = 0.027) and returned to baseline levels following resuscitation (p = 0.027). Conjunctival flow also showed similar changes, with the proportion of perfused vessels reducing significantly during shock compared with baseline (p = 0.013), increasing following resuscitation to near baseline (p = 0.173). Microvascular flow index also decreased (p = 0.034) and then increased following resuscitation (p = 0.081). Further, the authors showed that flow density in the superficial retinal OCTA significantly correlated with changes to conjunctival microcirculation and haemodynamic measures (p = 0.002–0.014)  . In the 2–0.014) . The chaSepsis is a life-threatening condition with high mortality risk without prompt recognition and treatment. Currently, there is no validated, reproducible method to measure the microcirculation in sepsis. OCTA can potentially monitor haemodynamic resuscitation by targeting good capillary perfusion. In an ideal world of precision medicine, such targeted therapy has the potential to improve outcomes in sepsis and other low-flow states. Several studies have demonstrated retinal blood flow changes in systemic illnesses, including sepsis, demonstrating the potential for OCTA to provide microcirculatory monitoring. When considering this with the studies that demonstrate retinal blood flow returns to baseline in septic models after resuscitation , 42, retIn addition to reporting retinal blood flow alterations in systemic disease , 33–35, There are gaps in this area of research, with the main limitation of small sample sizes in human studies. Different retinal blood flow metrics were used in each study, which makes comparison difficult, as well as different imaging techniques used and different OCTA manufacturers between studies. It would also be beneficial to measure OCT and OCTA sequentially in systemically ill and septic patients to investigate the extent of perfusion dysfunction and its correlation with neurocognitive dysfunction. Future studies would benefit from larger cohorts of patients, and it would be of value to include patients in different severities of sepsis to investigate how retinal perfusion may be different.Using OCTA to visualise retinal blood flow is a promising method of monitoring microcirculation during sepsis and response to resuscitation. Further human studies are warranted to determine how this could be implemented in a cohort of septic patients.EC was a major contributor in writing the manuscript. All authors read, edited and approved the final manuscript.


A total of 120 patients recovering from COVID-19 at three to six months after confirmed diagnosis were included. The clinical examinations, laboratory test results, echocardiography, non-invasive body mass analysis, and spiroergometry were evaluated. The subjects were divided into the following groups: study patients’ group with worsen oxygen uptake  and control group presenting%VO2pred ≥ 80% (n = 73). ClinicalTrials.gov Identifier: NCT04828629. The male gender and the percent of total body water content (TBW%) were significantly higher in the study group compared to the control group  vs. 49.89 (±4.59), p = 0.02; respectively). Patients with %VO2pred < 80% presented significantly lower global peak systolic strain (GLPS), tricuspid annular plane systolic excursion (TAPSE), and late diastolic filling (A) velocity (19.34 (±1.72)% vs. 20.10 (±1.35)%, p = 0.03; 21.86 (±4.53) vs. 24.08 (±3.20) mm, p = 0.002 and median 59.5 (IQR: 50.0–71.0) vs. 70.5 (IQR: 62.0–80.0) cm/s, p = 0.004; respectively) compared to the controls. The results of the multiple logistic regression model show that (A) velocity  and male gender  were independently associated with %VO2pred. Conclusions: Men have over twice the risk of persistent limited exercise tolerance in Long-COVID than women. The decreased (A) velocity, TAPSE, GLPS, and hydration status are connected with limited exercise tolerance after COVID-19 in patients with normal LVEF. Exercise intolerance de novo is one of the most common reported symptoms in patients recovering from the Coronavirus Disease 2019 (COVID-19). The present study determines etiological and pathophysiological factors influencing the mechanism of impaired exercise tolerance in patients during Long-COVID. Consequently, the factors affecting the percentage predicted oxygen uptake at peak exercise (%VO CPET is considered the gold standard for the assessment of physical fitness and evaluating the interaction of cardiovascular, respiratory, and metabolic systems. Cardiopulmonary evaluation can be conducted safely among non-hospitalized people affected by COVID-19 symptoms. Thus, we sought to quantify and describe the extent and the main mechanisms of exercise limitation in these patients.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The pandemic has spread all over the world since its first appearance in Wuhan (China) in December 2019 . This enThe aim of the study was to identify the etiological and pathophysiological factors influencing the mechanism of exercise intolerance assessed in CPET, as well as biochemical and echocardiographic parameters in the COVID-19 survivors.2pred is a percentage predicted oxygen uptake at peak exercise VO2. The patients were divided into a group that demonstrated worse oxygen uptake  at the median age of 49 years old (median VO2max 17 mL/kg/min) and a control group at the median age of 55 years old who presented VO2pred ≥ 80% .We recruited 120 consecutive patients from the Department of Cardiology recovering from COVID-19 at three to six months after confirmed diagnosis in this study. The subjects were hospitalized in the Department of Cardiology and Congenital Heart Diseases of Adults between December 2020 and December 2021. There were no differences in medical treatment between the groups. All patients enrolled in this study performed CPET on the ergometer. The definition of %VOThe exclusion criteria were as following: diagnosis of cardiomyopathy; diagnosis of heart failure—left ventricular ejection fraction (LVEF) < 50% and signs and symptoms of heart failure or LVEF ≥ 50% with signs and symptoms and raised natriuretic peptides; unstable angina; unstable heart rhythm disorders; advanced atrioventricular block; acute pulmonary embolism; past myocardial infarction; uncontrollable arterial hypertension—systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 100 mmHg; acute pericarditis or myocarditis; active endocarditis; intracerebral hemorrhage, transient ischemic attack and stroke in past medical history; chronic kidney disease ; severe hypo- and hyperthyroidism; active autoimmune disorder; recorded neoplastic process; taking cytostatic drugs, antiretroviral drugs, glucocorticosteroids, and immunosuppressants; blood transfusion within the last 6 months; documented bone marrow or other transplanted organs; active systemic infection; human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) carrier or positive for hepatitis B surface antigen (HBsAg) or antibodies to HCV; alcohol and drug abuse; pregnancy and lactation; severe injury or surgery in the last month; inability of the patient to collaborate and/or provide informed consent to participate in the study; physical disability preventing the performance of a cardiopulmonary exercise testing; and subjects who did not express their informed consent to participate in a research study.The research was accepted by the Polish Mother’s Memorial Hospital Research Institute (PMMHRI-BCO.75/2020), and it is in compliance with the Declaration of Helsinki.Blood samples were collected into polyethylene-terephthalate tubes from each patient. Laboratory tests were obtained following a minimum of 12 h after the last meal in the hospital laboratory. We measured renal function  was estimated by Modification of Diet in Renal Disease (MDRD)) parameters and liver function (aspartate transaminase (ASP) and alanine aminotransferase (ALT)) parameters; lipoprotein profile: low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC); glucose levels; inflammatory cytokine (C-reactive protein (CRP)); and hematology. Additionally, the measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) was performed.Echocardiograms were performed using the Vivid E95 system . Quantitative measures were achieved in accordance with current guidelines . The mod2) is calculated from the difference between the volume of O2 in the inhaled and exhaled air during exercise per unit of time and when the steady state is equal to the metabolic O2 consumption. The definition of the VO2 peak is the highest attainable VO2 for a subject. Other measured CPET parameters include oxygen uptake at anaerobic threshold (VO2AT), the minute ventilation/carbon dioxide production slope (VE/VCO2 slope), and the respiratory exchange ratio (RER)  in comparison to the control group. Statistically significant differences were not observed regarding other biochemical parameters. The results are shown in Subjects with %VOp = 0.004; 19.34 (±1.72)%vs. 20.10 (±1.35)%, p = 0.03; 21.86 (±4.53) vs. 24.08 (±3.2) mm, p = 0.002; respectively) in patients who presented with peak VO2 < 80% compared to controls. In the study group, E/A was higher (median 1.23 (IQR: 0.98–1.70) vs. 1.01 (IQR: 0.80–1.22), p = 0.006) than in the control group. There were no statistically significant differences regarding EF, LA volume, LAVi, E, and TDE S’ . Data are presented in The (A) velocity, GLPS, and TAPSE were significantly lower (median 59.5 (IQR: 50.0–71.0) vs. 70.5 (IQR: 62.0–80.0) cm/s, 2AT (132.87 (±33.61) vs. 146.63 (±20.46), p = 0.006; median 150 (IQR: 130–170) vs. 180 (IQR: 150–200) mmHg, p < 0.0001; 99.61 (±14.74) vs. 111.71 (±16.95) %, p < 0.0001; median 12 (IQR: 10–15) vs. 15 (IQR: 13–16) mL/min/kg, p = 0.001; respectively). In the study group, the FEF 25–75 was higher in comparison to the controls (3.25 (±1.23) vs. 2.66 (±1.13) L/s, p = 0.01). There were no significant differences concerning exercise time, peripheral DBP max, FEV1, FVC (L), FEV1/FVC, FEV1/FVC%, RER, or VE/VCO2 slope . The results are presented in Patients with worse oxygen consumption presented with significantly decreased HR max, peripheral SBP max, FVC%, and VO2 ≥ 80% VO2 predicted (52.67 (±6.41)% vs. 49.89 (±4.59)%, p = 0.02) compared to controls. Statistically significant differences in the remaining parameters (Fat (kg and %), FFM, TBW (kg), ECW, ICW, ECW/TBW) were not detected . The data are shown in Considering body mass compartments, only the TBW level (%) was significantly larger in patients with peak VOp value < 0.05 in the univariate analysis were entered into the multivariate analysis using the logistic regression analysis. In a multiple logistic regression model, the two factors were found to be significantly associated with %VO2pred were as follows: (A) velocity  and gender .Parameters with a 2pred < 80% presented with significantly lower GLPS, TAPSE, and (A) velocity in comparison to controls. A indicates late diastolic mitral flow due to atrial contraction. Peak (A) velocity is often considered a measure of LA function with normal values of 0.8 ± 0.2 m/s in young healthy individuals. Multiple studies have used this parameter as an index of LA function assessment [2pred ≥ 80%. The results of multiple logistic regression models independently associated with %VO2pred were (A) velocity and male gender.As far as we are aware, the present study is the first analysis of any connection between echocardiographic parameters, hydration status, and worse oxygen uptake in CPET in COVID-19 survivors during Long-COVID. Patients with %VOsessment . The per2), in addition to physical fitness levels measurement, is an indicator of disease severity in patients with heart failure, chronic obstructive pulmonary disease (COPD), restrictive pulmonary disease, and pulmonary hypertension [2. Viral toxicity, systemic inflammatory response, changes in the immune system, microvascular injury, fibroblast proliferation due to diffuse alveolar damage, medications, prolonged hospitalization, and stress are considered to be main hypotheses of reduced exercise capacity [2 values. The median peak VO2 was 17.9 [Oxygen consumption  at rest, and a lower arteriovenous O2 difference compared to healthy controls. Additionally, in the study group, a lower muscle O2 extraction in the absence of increased pulmonary artery pressure and pulmonary vascular resistance, justifying the reduced peak VO2 during exercise, was observed [p = 0.001) for hydration and 2.528  for ECW/TBW [The study of Baratto et al. revealed that COVID-19 patients at the time of hospital discharge presented with decreased arterial Oobserved . Some probserved . In one observed . Echocarobserved . All parobserved . The metobserved . Sex difobserved . In anotobserved . However ECW/TBW .The strength of our study is that this is the first study to assess the etiological and pathophysiological factors influencing the mechanism of exercise intolerance assessed with spiroergometry, as well as the biochemical and echocardiographic parameters in the COVID-19 survivors. We are the first to demonstrate that the patients during Long-COVID without heart failure diagnosis, but with impaired exercise tolerance had worse function of the right ventricle, lower GLPS, LA function, and higher TBW. These findings, however, must be also seen in light of some limitations, including a relatively small study population (120 participants). It needs to be emphasized that it is an ongoing project, and these results need to be considered as preliminary. The study design was limited with regard to the evaluation of the possible effect of used medications. Furthermore, the study included only subjects who could perform CPET. In addition, transthoracic echocardiogram was assessed only at rest. Some echocardiographic parameters, such as left atrial strain, were not evaluated.In conclusion, men have over twice the risk of persistent limited exercise tolerance after COVID-19 infection than women. Decreased (A) velocity, TAPSE, and worse GLPS and hydration status are associated with exercise intolerance after COVID-19 in patients with normal LVEF. Further studies are necessary to confirm our results.


This review analyzes the available clinical evidence on 3 budesonide/formoterol DPI devices, SpiromaxThe effectiveness of dry powder inhalers (DPI) depends largely on the device and the patient’s inhaler technique. Equally important are the patient’s perception of the inhaler and adherence. Given the high burden of these diseases, it is important that efforts be made to select the best DPI for each patient and to analyze the impact of these variables to help improve the health and quality of life of our patients.®, Turbuhaler®, and Easyhaler®.This review provides a comprehensive overview of the present knowledge about PROs, inhaler handling errors, and asthma and COPD control achieved by Spiromax Asthma and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality worldwide . Both di®, Turbuhaler®, and Easyhaler® dry powder inhalers (DPIs) in the management of asthma and COPD.Treatment is based on the delivery of drugs via an inhaler, with the aim of controlling symptoms, reducing exacerbations, improving exercise tolerance and health status, and reducing mortality . The theAlthough many pharmacological treatments are recommended in clinical practice guidelines, both diseases remain uncontrolled in a considerable number of patients , 6. This®, Turbuhaler®, and Easyhaler® on asthma and COPD control, in order to guide the selection of the best DPI for each patient.The analysis of patient-reported outcomes (PROs) is being used increasingly in clinical research. The parameters consist of a patient’s evaluation of a drug based on their own perception of their disease and treatment(s). Since the device itself and its suitability for the patient are important elements to consider , strategThe dose delivered by an DPI and the particle size distribution are determined by the formulation, the inhaler, and the patient’s inhaler technique . This te®, Turbuhaler®, and Easyhaler®. A review by Haidl et al. ), but differences were not significant. An exploratory analysis by independent experts indicated that the probability of maintaining device mastery after 12 weeks was significantly higher for BF Spiromax® versus BF Turbuhaler® (OR 2.11 [95% CI 1.25–3.54]). Median Patient Satisfaction and Preference Questionnaire (PSAPQ) scores were higher for BF Spiromax® versus BF Turbuhaler® . According to the ACQ, disease control improved with both DPIs, although changes were non-significant (OR 0.11 [95% CI − 0.09 to 0.30])  1.6). Nearly all (98.8%) of the BF Spiromax® users were at least satisfied with their inhaler, while 85.4% were very satisfied. Mean ease-of-use score for BF Spiromax® was 9.1 (SD 1.3). In conclusion, asthma and COPD patients using BF Spiromax® showed moderate-to-high therapeutic adherence, were very satisfied with their inhaler, and found it easy to use , p < 0.001. In the COPD cohort, disease control was measured with the COPD Assessment Test (CAT), which showed an absolute mean effect at 3 months of 4.34 [95% CI − 0.4 to 2.8], p < 0.001. Similarly, BF Spiromax® was superior in terms of satisfaction  . BF Spiromax® also showed non-inferiority to BF Turbuhaler® in clinical efficacy according to forced expiratory volume in 1 s (FEV1) [A national multicenter observational study (the INHALA ZS study) that evaluated clinical efficacy, disease control, and satisfaction with BF Spiromaxs (FEV1) , 44.® after switching from another inhaler compared with continuing the original inhaler, according to a risk management algorithm. In the 385 subjects who switched to BF Spiromax® (253 with asthma and 132 with COPD), non-inferiority was observed compared to the 1091 subjects who did not switch (743 with asthma and 348 with COPD) . Asthma patients who switched to BF Spiromax® compared with those who continued BF Turbuhaler® reported fewer exacerbations , were less likely to use high daily doses of short-acting β2 agonists (SABA) , used fewer SABA inhalers , and were more likely to achieve treatment stability . There were no significant differences in these variables in COPD patients. The authors concluded that the use of BF Spiromax® in routine clinical practice by patients with asthma and COPD was not inferior to BF Turbuhaler® in terms of disease control. Asthma patients who switched to BF Spiromax® showed reduced exacerbations, lower SABA use, and greater treatment stability compared with those who continued BF Turbuhaler® [Another retrospective cohort study in routine clinical practice conducted in the UK collected data from adults with asthma and COPD treated with inhaled ICS/LABA. The researchers assessed the non-inferiority of BF Spiromaxbuhaler® , 46.®. Overall, 3943 patients were included, 2707 (68.7%) of which had asthma and 1236 (31.3%) COPD. At the start of the study, according to the Satisfaction with Inhalers and Preference questionnaire, 60.1% of the patients were satisfied-to-very satisfied with their previous inhaler, and this increased to 88.8% after using BF Spiromax®. Overall, 62.1% of pre-treated patients preferred BF Spiromax® over their old inhaler. According to the modified Easy Low Instruction Over Time checklist, the rate of handling errors observed with BF Spiromax® at week 12 was lower than at baseline . After 12 weeks, 77.4% showed improved  overall health status compared to baseline. The severity of the disease assessed by both clinicians and patients improved during the study in both patients with asthma and COPD. BF Spiromax® was well tolerated. In conclusion, BF Spiromax® was associated with high satisfaction, a low handling error rate, and an improvement in clinical outcomes in patients in routine clinical practice [A 12-week prospective observational study conducted in Germany also assessed satisfaction, handling errors, disease control, and safety in adults with asthma and COPD treated with BF Spiromaxpractice .® or Seretide® Diskus® , to BF Spiromax®. After 12 weeks of use, inhaler techniques and the relationship between critical errors and disease control were assessed, and factors related to handling errors were identified. At the end of the study, 67% of patients were using BF Spiromax® without handling errors and 88% without critical handling errors. In general, the presence of comorbidities was associated with handling errors, while concurrent illness that could affect device management and prior training was associated with critical handling errors. Most patients (85.4%) preferred BF Spiromax® over their previous device. Inadequately controlled or uncontrolled asthma levels were reduced from baseline in patients using BF Spiromax® (8.6% vs. 64.6%), and were higher in individuals with critical handling errors. In conclusion, effective patient training, correct inhaler technique, adherence, and devices associated with high patient satisfaction are interrelated factors key to the successful delivery of inhaled therapy in this disease. In addition, inhaler technique and patient satisfaction with the device should be routinely assessed in patients treated with uncontrolled asthma [®, Turbuhaler®, and Easyhaler® devices.Finally, a prospective, multicenter, observational study was conducted in France in 1435 adults with asthma who switched from their previous inhaler, BF Turbuhalerd asthma . Table 2® and found it easier to use than its competitors. In asthma patients, favorable PROs were accompanied by increased disease control associated with the use of BF Spiromax®.In the clinical trials under review, most individuals preferred Spiromax®/BF Spiromax® demonstrated lower handling error rates, greater preference for use, and greater adherence compared to other inhalers in patients with asthma and COPD. In terms of disease control, BF Spiromax® proved to be superior or non-inferior to its competitors.According to the observational studies analyzed, SpiromaxSince patient preferences may vary among DPIs, patient choices should be considered when selecting a device, in order to optimize adherence and control of asthma and COPD. Only a good patient-inhaler combination will improve the effectiveness of treatments and medical care in this population.


Early detection followed by clinical management is among the best approaches for the affected individuals. However, a sensitive screening tool is not yet available. (2) Methods: We retrospectively reviewed 600 patients aged >20 years with a full range of estimated glomerular filtration rate (eGFR) for clinical assessment of kidney function between 1 January 2020, to 30 April 2021, at the Taichung Veterans General Hospital, Taichung, Taiwan. With stratified sampling based on the level of eGFR, participants were evenly grouped into training and validation sets for predictive modeling. Concurrent records of laboratory data from urine samples were used as inputs to the model. (3) Results: The predictive model proposed two formulae based on urine conductivity for detecting suspected early-stage CKD. One formula, P_male45, was for used male subjects aged ≥45 years, and it had a prediction accuracy of 76.3% and a sensitivity of 97.3%. The other formula, P_female55, was used for female subjects aged ≥55 years. It had a prediction accuracy of 81.9% and a sensitivity of 98.4%. Urine conductivity, however, had low associations with urine glucose and urine protein levels. (4) Conclusion: The two predictive models were low-cost and provided rapid detection. Compared to urine protein, these models had a better screening performance for suspected early-stage CKD. It may also be applied for monitoring CKD in patients with progressing diabetes mellitus. Kidneys are responsible for maintaining the homeostasis of body fluids by regulating the balance of water, electrolytes, and acid-base ,2. It is2) of ≥90; stage 2 (G2): with mildly decreased eGFR of 60–89; stage 3 (G3): with moderated decreased eGFR of 30–59; stage 4 (G4): with severely decreased eGFR of 15–29, and stage 5 (G5): with eGFR < 15 and kidney failure. CKD affects >10% of the general population, or >800 million global population [Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function for over three months according to the guidelines of KDIGO  2021 . Based oCKD poses a significant risk for cardiovascular morbidity and mortality . It is a2) [The conductivity of an electrolyte solution, like urine, is a simple, cheap, and fast parameter to assess its electrical impedance . A previ2) . Based oWe retrospectively reviewed patients aged > 20 years with a full range of eGFR for clinical assessment of kidney function between 1 January 2020, to 30 April 2021, received at the Taichung Veterans General Hospital, Taichung, Taiwan. In total, 704 patients fulfilled the inclusion criteria and enrolled initially. In total, 104 patients were excluded since they were without eGFR, urine protein, or complete urine electrolytes . A totalThe Institutional Review Board and Ethics Committee of Taichung Veterans General Hospital approved our study . Informed consent was waived due to its retrospective and electronic medical chart review nature.Scr (mg/dL) is the concentration of serum creatinine, it was determined with the enzymatic method provided by LABOSPECT 008 AS . The suspected early-stage CKD (stage 1 and stage 2) was defined as those participants with an eGFR ≥ 60 (mL/min/1.73 m2).The estimated glomerular filtration rate (eGFR) was reported by the guidelines of KDIGO  with theUrine protein (UP), urine glucose (UG), and urine creatinine (UC) levels were determined, respectively, based on the Turbidimetric, Hexokinase method, and enzymatic methods, using the LABOSPECT 008 AS . The normal range was set at <15 mg/dL, while the positive range was set at ≥15 mg/dL.+, urine K+, urine Cl−, and urine Ca++ were routine measurements of urine electrolytes. They can be determined with the ION SELECTIVE ELECTRODE method by LABOSPECT 008 AS .Urine Na2. Urine osmolality measures the number of dissolved particles per unit of water in the urine. Both urine conductivity and osmolality were measured with Sysmex UF-5000 .Urine conductivity represents the ability of urine to conduct electric current. It is the reciprocal of the resistance measured when the current passes through a liquid column with a length of 1 cm and a cross-sectional area of 1 cmSpecific gravity  is the density ratio of urine with respect to water. It was measured with Sysmex UF-5000 .With stratified sampling data based on their level of eGFR, participants were evenly grouped into training and validation datasets for later predictive modeling. Predictive formulae based on urine conductivity (UCond) were developed in the training set. The predicted values were tested using the unseen validation dataset. r ≥ 0.3) with eGFR in the training set. To identify other potential variables that may interfere with UCond, their correlations between laboratory data with a urine sample were analyzed.Since eGFR was estimated with age, sex, and serum creatinine, age is a potential variable of the predictive models. Therefore, age was merged with UCond to create a stepwise regression model once it had shown a moderate correlation  > 0.7 of UCond against age was set as the threshold of fitness for the prediction model.2). The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) were performed [p < 0.05.Predicted errors were assessed with a Bland–Altman plot on the validation set . Since Uerformed . The con2). The number (and percentage) of patients in the five groups of eGFR values were 39 (6.5%) ≥ 90, 136 (22.7%) for 60–89, 268 (44.7%) for 35–59, 84 (14.0%) for 15–29, and 73 (12.2%) for < 15. Their UCond was 10.8 ± 4.6 (mEq/L), and urine protein (UP) was 81.3 ± 192.3 (mg/dL). For those who tested negative for UP (<15 mg/dL), UP was 7.5 ± 3.2 (mg/dL). Other laboratory data are shown in A total of 600 patients, 61.9 ± 15.0 years old, with 332 males (55.3%) and 268 females (44.7%), were enrolled in the final analysis . Their eSerum creatinine for males was 2.24 ± 1.78 (mg/dL). It was higher than females at 2.01 ± 2.11 (mg/dL). However, there was no significant difference between males and females . Neither++ to Cl−, respectively. Moreover, we found a correlation coefficient of 0.628 between UCond and urine S.G. and 1.000 between UCond and urine osmolality. We also noted the very low correlation coefficients for UCond between urine protein, urine glucose, and age.The value of eGFR with which the analysis of Pearson correlation coefficients between UCond and eGFR in the training set was performed . Results2); while AUC was 0.712 for males aged ≥50 and 0.710 for males aged ≥45 with eGFR of 60.0 (mL/min/1.73 m2) (2). By the age-applicable standard, a total of four predictive models, including UCond and/or age for eGFR, were proposed  . Howeverproposed . For malFor males aged ≥50, the predicted eGFR wasFor females aged ≥50, the predicted eGFR wasFor females aged ≥55, the predicted eGFR wasThe four predictive models gave prediction errors of −1.3 ± 21.6, −1.7 ± 21.8, 3.1 ± 24.7, and 2.2 ± 24.3, respectively, using the above formulae from (2) to (5) with the validation set . In addiWe have proposed four predictive models to detect patients with early-stage chronic kidney disease (CKD). Among these models, P_male45 combined with urine conductivity (UCond) for male patients aged ≥45 gave an accuracy of 76.3%, while P_female55 with UCond and age gave an accuracy of 81.9% for females aged ≥55. These results were all better than those based on urine protein . Our results also showed that urine protein and urine glucose were poorly correlated with UCond. The UCond-based predictive models for eGFR may be less influenced by proteins present in the urine of patients with an injured kidney or glucose present in the urine of patients with progressive diabetes mellitus. This result is consistent with those previously reported ,27.The kidney plays a critical role in the control of electrolyte balance. In response to dietary intake and endogenous production or drug intake, the excretion of electrolytes into urine is regulated by the kidney . Accordi+), potassium (K+), chloride (Cl−), and calcium (Ca++) are used for routine assessments in urine analysis. Through co-transportation with glucose, amino acids, and phosphate, sodium is reabsorbed and exchanged with chloride in the tubular region [Levels of sodium  , urine cThe level of urine protein (UP) is widely recognized as a marker of CKD severity. It is also a predictor of future decline in glomerular filtration rate and an indicator of CKD risks ,16. The For quantitative analysis, either the albumin-to-creatinine ratio (ACR) or the protein-to-creatinine ratio (PCR) was recommended for initial albuminuria testing ,21. Once2) were regarded as having early-stage CKD for screening conditions. Based on the proposed formulae of P_male45 and P_female55, the Sn for males aged ≥ 45 and females aged ≥ 55 was 97.3% and 98.45, respectively, indicating a very high positive screening rate for suspected early-stage CKD. These highly sensitive screening tools mean that there are few false negative results, and thus fewer cases of early-stage CKD are missed. This may provide long time monitor for suspected early-stage CKD. Once the predicted value of eGFR is less than 60, it is recommended to go to the nephrology department for follow-up. In contrast, UP showed a low sensitivity of 67.5% and 75.0% for the same participants in the validation set. However, the proposed formulae presented Sp of only 17.5% and 30.0%. That meant a large proportion of false positives for the participants with eGFR < 60 (mL/min/1.73 m2) screening as early-stage CKD. Nevertheless, patients will experience some symptoms, such as high blood pressure, swelling in the legs, anemia, loss of appetite, or nausea [Sn, Sp, PPV, and NPV are four standard measures to reflect the accuracy of a test . In the +, K+, Cl−, and Ca++ alone. Patients often take diuretics , angiotensin-converting enzyme inhibitors , or those with hyperkalemia could affect UCond [We used UCond in a spot urine sample to develop predictive formulae for eGFR. They may use to monitor the rate of change in renal function over time in future work. However, UCond and other laboratory data in the sample could vary due to underlying diseases, drugs, or diet. For example, high blood pressure or sleep apnea could elevate UP levels ,39 but nct UCond . ConsequTwo predictive formulae have been developed for screening suspected early-stage CKD. Among the two, P_male45 was for males aged ≥45 with 76.3% accuracy and 97.3% sensitivity. The other P_female55 was for females aged ≥55 with 81.9% accuracy and 98.4% sensitivity. Since urine conductivity was poorly correlated with urine glucose and urine protein, our UCond-based predictive models for eGFR are likely less prone to interference by proteins present in the urine of patients with kidney injury or by glucose in diabetic patients. Our models have the desirable features of low cost and rapid detection. It may be put into practice for monitoring CKD in patients with progressive diabetes mellitus.


Background: A decade ago, it became possible to derive mean systemic filling pressure (MSFP) at the bedside using the inspiratory hold maneuver. MSFP has the potential to help guide hemodynamic care, but the estimation is not yet implemented in common clinical practice. In this study, we assessed the ability of MSFP, vascular compliance (Csys), and stressed volume (Vs) to track fluid boluses. Second, we assessed the feasibility of implementation of MSFP in the intensive care unit (ICU). Exploratory, a potential difference in MSFP response between colloids and crystalloids was assessed.Methods: This was a prospective cohort study in adult patients admitted to the ICU after cardiac surgery. The MSFP was determined using 3–4 inspiratory holds with incremental pressures (maximum 35 cm H2O) to construct a venous return curve. Two fluid boluses were administered: 100 and 500 ml, enabling to calculate Vs and Csys. Patients were randomized to crystalloid or colloid fluid administration. Trained ICU consultants acted as study supervisors, and protocol deviations were recorded.Results: A total of 20 patients completed the trial. MSFP was able to track the 500 ml bolus (p < 0.001). In 16 patients (80%), Vs and Csys could be determined. Vs had a median of 2029 ml (IQR 1605–3164), and Csys had a median of 73 ml mmHg−1 (IQR 56–133). A difference in response between crystalloids and colloids was present for the 100 ml fluid bolus (p = 0.019) and in a post hoc analysis, also for the 500 ml bolus (p = 0.010).Conclusion: MSFP can be measured at the bedside and provides insights into the hemodynamic status of a patient that are currently missing. The clinical feasibility of Vs and Csys was judged ambiguously based on the lack of required hemodynamic stability. Future studies should address the clinical obstacles found in this study, and less-invasive alternatives to determine MSFP should be further explored.Clinical Trial Registration:ClinicalTrials.gov Identifier NCT03139929. At present, a decade after it became possible to estimate mean systemic filling pressure (MSFP) at the bedside, the parameter has not yet been implemented in (routine) clinical care. MSFP is considered the combined upstream pressure that drives blood flow into the right atrium, and MSFP allows the calculation of additional hemodynamic parameters such as the driving pressure for venous return (VRdp), stressed volume (Vs), and total systemic vascular compliance (Csys) . Vs provMSFP can be determined in sedated and ventilated patients by extrapolating central venous pressure (CVP) versus cardiac output (CO) at different ventilatory plateau pressures during inspiratory holds . PreviouIn this study, our first aim was to assess the ability of MSFP, Csys, and Vs to track two fluid boluses. Our second aim was to assess the feasibility of the clinical implementation of MSFP in the ICU. In exploratory, as a third aim, a potential difference in response between colloids and crystalloids was assessed. As the intravascular half-life for crystalloids is around 20–40 min and for colloids 2–3 h, we hypothesized a difference in the delta MSFP after a fluid bolus . If presThis was a prospective cohort study in post-surgical patients after coronary artery bypass grafting (CABG). The study is written according to the Strobe guidelines for cohort studies and was conducted in accordance with the Declaration of Helsinki . The stu2 or patients in which the MAP remained highly fluctuating (delta 40 mmHg in 10 min) after optimizing initial treatment. A maximum of 1 hour was allowed for patients to fulfil the hemodynamic stability criteria after arrival in the ICU. During study measurements, no alterations in the respiratory rate, positive end expiratory pressure (PEEP), fraction of inspired oxygen (FiO2), and position of the patient were allowed. Also, the rates of anesthetic, analgesic, and vasoactive drugs were set before the start of the study and could not be altered during study measurements.During surgery, anesthesia was provided as per routine care. At the end of surgery, noradrenalin, propofol, and/or sufentanil were continued for transport to the ICU. The exclusion criteria at the ICU were a contraindication for fluid loading and persistent hemodynamic instability. Hemodynamic instability was defined as a persistent mean arterial pressure (MAP) below 55 mmHg, a cardiac index below 1.5 L/min/mStudy measurements were performed by a dedicated study team consisting of one member to control the ventilator (inspiratory holds), one member for circulation (administering fluid bolus), one member as the annotator, and one as the supervising ICU consultant.via a catheter in the radial artery, and CVP was monitored via a catheter inserted into the right internal jugular vein. Both were connected to a pressure transducer, and both pressure transducers were referenced to the intersection of the anterior axillary line and the fifth intercostal space. Beat-to-beat CO was obtained by Modelflow pulse contour analysis  was monitored analysis . Measure2O above PEEP. The CVP and CO data at those inspiratory holds were fitted by linear regression. A previous animal study demonstrated three holds sufficient to reliably assess MSFP (2O above PEEP) could be omitted as decided by the supervising ICU consultant.MSFP was measured employing successive inspiratory holds as previously published . In shoress MSFP . TherefoFor this study, MSFP was measured at three timepoints: at baseline (T = 0), after 100 ml of fluid loading (T = 1), and after a second bolus of 500 ml (T = 2), To assess the effects of the type of fluid on MSFP, 50% of the patients who fulfilled hemodynamic stability criteria prior to start of the study were randomized between crystalloid  or colloid infusion  MSFP was determined as explained previously, by extrapolating CO versus CVP at different inspiratory plateau pressures to CVP is zero. CVP was used as a surrogate for right atrial pressure. The driving pressure for venous return (VRdp) was defined as MSFP-CVP. Venous return (VR) was defined as VRdp divided by resistance to venous return (RVR). RVR is the reciprocal of the slope of the VR curve, or RVR = (MSFP-CVP)/CO. The total systemic vascular resistance (Rsys) was calculated as the ratio between the pressure difference of MAP and CVP with CO .With MSFP measured before and after fluid administration, a pressure-volume relationship could be constructed. Csys is the slope of this relation, or delta volume/delta MSFP . Csys = Since Vs and Csys may vary widely if sympathetic tone or blood flow distribution varies, hemodynamic stability was required during the two volume challenges. Hemodynamic instability during the study was defined as a change in heart rate exceeding 10 beats per minute between two time points , a decrease in MAP despite fluid administration, or a change in the respiratory rate.Protocol deviations, to assess feasibility, were defined as any deviation from the study protocol. The supervising ICU consultant was asked to clarify the rationale for the protocol deviation.U test were used for differences between colloid and crystalloid groups. A post hoc analysis was performed to correct for patients who did not receive the total amount of 500 ml during the second fluid bolus. The post hoc analysis was performed by dividing the planned fluid administration (=500 ml) by the actual administered fluids (in ml) and multiplying with the delta MSFP.Continuous data are presented as means with standard deviations when normally distributed or as medians with interquartile ranges (IQR 25–75th) when the data were not normally distributed. The distribution was assessed visually based on Q–Q plots and histograms. Categorical data are presented as frequencies with percentages. The paired t-tests or the non-parametric Wilcoxon signed-rank test were used for comparison of hemodynamic variables on T = 0, T = 1, and T = 2. The independent t-test or the non-parametric Mann–Whitney p value of <0.05 was considered to indicate significance. All analyses were performed using MATLAB version 14 and SPSS version 28.A t-test with a 0.05 two-sided significance level.To detect the 500 ml bolus, a sample size of seven patients was calculated to have 90% power to detect a difference in Vs means of 500 ml, assuming a standard deviation of 400 ml, using a paired t-test with a 0.05 two-sided significance level.To detect the 100 ml bolus, a sample size of 38 patients was calculated to have 90% power to detect a difference in Vs means of 100 ml, assuming a standard deviation of 210 ml, using a paired Assuming a drop-out rate of 10%, a sample size of 42 patients was calculated based on the first 100cc-fluid bolus, between T = 0 and T = 1. As this was the smallest fluid bolus, it required the largest number of patients.Sample sizes were calculated using nQuery Advanced, version 8.5.1.n = 18) or because of logistic reasons (n = 6), e.g., night-time or incomplete study team, For this prospective cohort study, 121 patients were assessed for eligibility, of these 44 patients had undergone solely CABG surgery and were enrolled in the ICU. A total of 20 patients completed the trial. The exclusion of 24 patients before the start of study measurements at ICU was because of hemodynamic instability  fit the inclusion criteria for hemodynamic stability  and were used for Vs and Csys calculations, −1 (IQR 55.77–132.58). Corrected for body weight, this translates to a median Vs of 24.17 ml kg−1 (IQR 15.68–38.48) and a median Csys of 0.87 ml mmHg−1 kg−1 (IQR 0.54–1.49).Since Vs after 100 ml of crystalloid did not consistently result in an increase in MSFP, it was judged not reliable to present mean/median Vs and Csys at T = 1, 2O above PEEP). The reason for not performing a fourth hold was a significant temporary decrease in MAP  after the third hold.In 5 out of 20 patients, the second fluid bolus (500 cc) was terminated before the total volume was infused because of a considerable increase in the systolic blood pressure (mean highest systolic blood pressure of 169 mmHg ±11.97).In the dissecting type of fluids, the choice to cease the infusion of fluids between T = 1 and T = 2 was 3 out of 15 (20%) in the crystalloid group and 2 out of 5 (40%) in the colloid group.p = 0.019), p = 0.038), whereas the first crystalloid bolus infusion did not (p = 0.110). For the second fluid bolus, no significant difference in delta MSFP between the types of fluids was found (p = 0.122), p = 0.01, The independent t-test demonstrated a significant difference in the response on the first fluid bolus (100 ml) between crystalloids and colloids  after the total 600 ml fluid loading.In 1990, Vs was calculated to represent 30% ± 17% of total predicted blood in patients on the cardiac bypass for major vascular sugery . During −1 ±1.0 . This isechnique , where V−1  and it assumes the administered fluid is added to the stressed volume compartment  Hahn et. Interes2O) compared to previous studies because of (transient) hypotension  to detect a difference in Vs means of 500 ml, but a post hoc sample size analysis demonstrated this to reduce the power for detection of the 100 ml bolus to 56%. The majority of patients were excluded because they did not meet the hemodynamic stability criteria to start the study in the ICU. Our criteria could be too strict, or our cardiac surgery population more severely ill. Comparison with previous studies was not possible, as these numbers were not reported.The colloid versus crystalloid analysis should be regarded as exploratory, but it could be used as a stepping stone for new trials. The post hoc analysis requires MSFP to increase linearly with infused fluids, as suggested by previous data . Still, The high number of protocol deviations in the study protocol might not solely describe clinical feasibility but can also illustrate that the supervising ICU consultants in the study hospital were more conservative.In this study, we used Modelflow pulse contour to calculate CO. For MSFP, Vs and Csys absolute CO values are not necessary; trends are sufficient, An unintended but important finding is that all the patients studied were men. All the initially included women were deemed hemodynamically unstable in the ICU. Aiming to include women in order to obtain a study population that is reflective of the clinical population and in order to translate findings across genders remains important .MSFP determined with inspiratory holds is of great interest for research purposes, but based on this study, not yet ready for clinical use. Yet, less invasive alternatives for determining MSFP do exist . The MSFIf MSFP determined with inspiratory holds is to become more commonly used, studies need to define the minimum number of inspiratory holds for accurate MSFP determination and should assess whether holds with lower plateau pressures also result in accurate MSFP values . FurtherMean systemic filling pressure, estimated with inspiratory holds, behaves predictably conform known physiological principles. Clinical feasibility for Csys and Vs calculations was judged ambiguously based on the lack of required hemodynamic stability and on the assumption of administered fluids to stay intravascular. Future studies should address the clinical obstacles found in this study, and less-invasive alternatives to determine MSFP should be further explored.


The international sepsis guidelines emphasize the importance of early identification along with the combined administration of fluids, antibiotics and vasopressors as essential steps in the treatment of septic shock in childhood. However, despite these recommendations, septic shock mortality continues to be very high, especially in countries with limited resources. Cardiovascular involvement is common and, in most cases, determines the outcomes. Early recognition of hemodynamic dysfunction, both in the macro and microcirculation, can help improve outcomes. Capillary refill time (CRT) is a useful, available and easily accessible tool at all levels of care. It is a clinical sign of capillary vasoconstriction due to an excessive sympathetic response which seeks to improve blood redistribution from the micro- to the macrocirculation. An important reason for functionally evaluating the microcirculation is that, in septic shock, the correction of macrocirculation variables is assumed to result in improved tissue perfusion. This has been termed “hemodynamic coherence.” However, this coherence often does not occur in advanced stages of the disease. Capillary refill time is useful in guiding fluid resuscitation and identifying more seriously affected sepsis patients. Several factors can affect its measurement, which should preferably be standardized and performed on the upper extremities. In this review, we seek to clarify a few common questions regarding CRT and guide its correct use in patients with sepsis. Sepsis and septic shock continue to be the main causes of death in children. The global incidence of sepsis for the general population in 2017 was estimated to be 48.9 million cases, with 11 million deaths  .Early recognition of hemodynamic abnormalities with bedside measurement in the different areas of the hospital is fundamental for improving outcomes. Capillary refill time is one of these tools for evaluating tissue perfusion which is easily available, easy to perform, and has no additional cost for patients with sepsis. Capillary refill time refers to the time it takes the nail bed of a distal phalange to return to its normal color after pressure has been applied with the extremity at heart level –6. It waToday, the sepsis guidelines, American Academy of Pediatrics, World Health Organization (WHO) and American Heart Association recommend CRT measurement as part of a systematic assessment –5. It isdynamic incoherence” . At the same time, there are other associated metabolic factors in sepsis which alter capillary blood flow, such as arteriolar tone and capillary permeability . The firα1 adrenergic receptors are stimulated, activating Gαq protein and, subsequently, the phospholipase-C-dependent signaling pathways, which allow calcium to enter the cell. All of this leads to vascular smooth muscle cell contraction α1 adrenetraction . The oppAn evaluation of perfusion and of microcirculation disorders is essential in the clinical approach to critically ill patients. Recent studies suggest that microcirculatory and endothelial abnormalities are the common basis of organ failure in sepsis . In septIn the skin, poor peripheral perfusion represents a high adrenergic tone and low blood flow in the microcirculation. Recently, Valenzuela et al. evaluated the microvascular response to hyperoxia in healthy patients and those with sepsis . They siCapillary refill time, as defined previously, can be measured in different ways. There are no studies comparing the various measuring techniques nor the ideal site for measuring it. Capillary refill time measurement requires visual inspection of blood returning to the distal capillaries after having been emptied by applying pressure . The sitHernández et al. standardized CRT measurement in their ANDROMEDA-SHOCK study . In this©) which uses a sensor on the patient's distal phalange to evaluate perfusion. After applying pressure and using algorithms, the exponential drop in the photodiode signal from the light source is calculated. The change in capillary flow timed with the pressure sensor can calculate the duration of capillary filling. After applying it in various critical care settings with septic patients, it was found to correlate well (r = 0.69) with the traditional method. The advantage of this system is that it would allow CRT measurement to be standardized through the use of technology and decrease variability and measurement errors , the upper limit of normal may be 5–7 s , which iCapillary refill time is susceptible to factors that can profoundly affect the results, such as room temperature, the temperature of the skin, the patient's age, the room lighting, the quality of the technique and the pressure site . Some ofRegarding the influence of temperature on CRT, it has been reported that, in healthy children in a warm environment, the normal CRT should be less than two seconds. The amount of light also affects the measurements. Under good conditions, 94.2% of the participants were reported as normal, compared with only 31.7% of the same participants in dim lighting .Anderson et al. evaluated the environmental factors affecting CRT in adults. They found that the temperature of both the patient and the room modified CRT. For every 1°C decrease in the patient's temperature, the CRT increased 5%, regardless of the room temperature . The useInterobserver variability in measuring CRT should be taken into account, which has been reported to be up to 1.94 s, depending on the measuring environment . This grPeripheral perfusion is an expression of the microcirculatory dysfunction in advanced stages of septic shock. It tends to be correlated with elevated lactate and multiple organ failure. In fact, microcirculation and endothelial abnormalities are considered to be the common denominator in multiple organ dysfunction syndrome in sepsis, as mentioned previously , 12, 15.p = 0.02), and that this was the first hemodynamic parameter to return to normal   and fewer vasopressors (p = 0.001) and had a lower risk of death than those whose treatment was guided by lactate   . However= 0.003) . It is ip < 0.01] and inpatient mortality  than those with a normal CRT after fluid resuscitation with crystalloids. In fact, patients with a normal CRT after fluid administration had a greater probability of normalizing or decreasing their lactate levels than those with an abnormal CRT  ;  = 0.01) .Capillary refill time, like other clinical parameters such as mottled skin, is an indicator of regional blood flow and has been described as an ultrasound substitute for vascular tone in visceral organs during early shock , 27. In Possibly one of the greatest benefits of CRT is that it may be very useful for predicting patients with unsatisfactory outcomes, especially the groups with the greatest risk of death. Both in adults as well as in children, a CRT greater than three seconds is associated with worse outcomes , 28. SomIn this regard, Bakker et al. found that an abnormal CRT after the initial fluid resuscitation was associated with an almost six times greater mortality compared with patients with a normal CRT after the initial fluid resuscitation . FlemingCapillary refill time is a reliable measure of mortality, regardless of the patient's disease stage and vasopressor support. Ait-Oufella et al. found that, in septic patients who received norepinephrine [0.3 mcg/kg/min (IQR 0.1–0.6)] and epinephrine [0.2 mcg/kg/min (IQR 0.02–0.2)] support, CRT was a good predictor of 14-day mortality, regardless of the type and intensity of vasopressor support they received. They also found that it was correlated with lactate and the SOFA score . The claIn patients with septic shock, tissue hypoperfusion can be evaluated at the bedside using simple, easily accessible and universally applied clinical indicators such as CRT. For initial fluid resuscitation as well as follow up, this clinical tool provides a rapid and real-time guide to the hemodynamic support needs of patients in septic shock. Due to its characteristics, CRT may be affected by many environmental, age and support intensity factors, and therefore should be measured in a standardized manner and preferably in the upper extremities. The use of new technologies like digital videography or oxygen saturation probes will help decrease this test's rate of false negatives and will allow for an automated and standardized CRT measurement.