Limited information is available on the clinical course of patients with severe asthma following discontinuation of biologic treatment. Therefore, a post hoc analysis was conducted in patients with severe eosinophilic asthma who participated in the COSMOS trial, where patients received mepolizumab for more than 1 year of continuous therapy. The objective of this post hoc analysis was to evaluate changes in the Asthma Control Questionnaire (ACQ-5) and blood eosinophil counts 12 weeks after the last administration of mepolizumab. Cessation of mepolizumab was associated with a rise in the blood eosinophil count and loss of asthma control after stopping therapy. These data suggest that patients with severe disease require extended and continuous treatment. Further studies evaluating longer duration of continuous treatment with mepolizumab could help understanding of whether changes in the presentation of the disease (disease modification) are possible with the use of biologics, such as mepolizumab. To the Editor:Asthma is a heterogeneous disease with diverse characteristics and biologic mechanisms. Current asthma guidelines offer a helpful framework for managing patients; however, some patients remain uncontrolled despite aggressive treatment interventions. The major goal of these guidelines is to achieve disease control and reduce the risk of future deterioration , 2. AlthCOSMOS  was a 52In the current analysis, ACQ-5 and blood eosinophil counts were chosen as their deterioration may predict subsequent asthma worsening as well as exacerbations and increases in oral corticosteroid dose. ACQ-5 and blood eosinophils were measured at weeks 4, 16, 28, 40 (ACQ-5 only), 52 , and 60 (follow-up). Values of the endpoints measured are presented as means with 95% confidence intervals (CI) to show measure of spread, in addition to presenting the proportion of subjects above and below an ACQ-5 score and blood eosinophil count of 1.5 and 150 cells/µL, respectively.Upon completion of mepolizumab treatment (week 52) in the COSMOS study, the mean ACQ-5 score was 1.31 (95% CI 1.22–1.40). ACQ-5 measured 12 weeks after the last administration of mepolizumab (week 60) showed a reduction in asthma control  with a mean ACQ-5 score of 1.66 (95% CI 1.52–1.80)  8 weeks after treatment cessation, although not considered clinically significant, suggests that patients began to experience a worsening of asthma control only a few weeks following cessation of mepolizumab treatment. In addition, at 12 weeks after the last administration of mepolizumab (week 60) the mean ACQ-5 scores were similar to the values reported at baseline, demonstrating that when treatment with mepolizumab was discontinued patients’ asthma symptoms showed signs of worsening and in parallel blood eosinophils increased. The threshold of 150 cells/µL has previously been associated with the responder phenotype to mepolizumab treatment [5 points Our findings are consistent with a previous study by Haldar et al.  in patieA limitation of the current study was the lack of a control arm, and thus between-study comparisons should be made with caution. The fact that more severe patients entered the COSMEX extension study could have introduced some selection bias in those subjects attending the follow-up visit. However, consistent results were observed following analyses of the overall study population and when restricted to only subjects completing both the exit visit and the follow-up visit (weeks 52 and 60). Furthermore, mean values of the ACQ-5 and blood eosinophil data at the end of the COSMOS study (week 52) were similar to baseline values in those patients who entered the COSMEX study with continuous treatment. In addition, we were unable to extend our observations beyond 12 weeks after the last administration of mepolizumab and therefore it is unknown if a further deterioration occurred in these patients. Another limitation is that the dose of other controller medications was not regulated throughout the study period. As such, it is difficult to establish comparisons with controlled clinical trials in which controller medication use is regulated. However, this lack of controller use regulation should be considered to reflect the real-world clinical experience of patients receiving long-term mepolizumab treatment. Overall, these data highlight the importance for continuous treatment with a biologic based on changes in key clinical outcomes after discontinuation of mepolizumab treatment.


Obstetric dfficult airway is a leading cause of maternal morbidity and mortality. The laryngeal mask airway (LMA) is often used as a rescue airway device after failed intubation, however, little is known about predictors of difficult LMA insertion, particularly in obstetrics. Since Mallampati scores of III/IV has been associated with difficult tracheal intubation, our present study aims to investigate if Mallampati score (MP) could predict airway outcomes for LMA use in obstetrics.This prospective cohort study was performed at a single-center: Quanzhou Women’s and Children’s Hospital, Fujian Province, China. Five hundred and eighty-four parturients undergoing elective cesarean section under general anesthesia were recruited. The primary outcome was time to effective ventilation, and secondary outcomes included first attempt insertion success, seal pressure, ventilation and hemodynamic parameters, occurrence of clinical aspiration, and maternal and fetal outcomes.p <  0.0001). There was no difference in maternal age, ASA status and gestational age. There was similar time to effective ventilation (mean (SD) High MP: 14.9 (4.5) vs Low MP: 15.7 (4.4) seconds, p = 0.2172), and first attempt success rate, seal pressure, and peak airway pressure. No clinical aspiration was noted. The incidence of blood on SLMA was higher in the High MP group than in Low MP (4 (6.6%) vs 4 (0.8%), p = 0.001). There was no difference in sore throat, voice hoarseness, maternal satisfaction and fetal outcomes.The parturients were classified into two groups based on MP of III/IV (High MP: 61) versus I/II (Low MP: 523). BMI was higher in the High MP group than in the Low MP group (mean (SD) 29.3 (7.0) vs 26.8 (3.1), High MP was not associated with reduced SLMA airway outcomes in cesarean section under general anesthesia, but may increase the risk of blood found on SLMA upon removal.http://www.clinicaltrials.gov, identifier: NCT02026882, retrospectively registered. Date of registration: December 31, 2013.This study was registered at  Airway complication is one of the main causes of anesthesia-related obstetric adverse events. There are several complex clinical challenges faced in managing the parturient including the risk of pulmonary aspiration, physiological changes of pregnancy, urgent nature of cesarean section, and balancing the potentially conflicting needs of the mother and fetus. Endotracheal intubation has long been considered standard of care for obstetric airway management , 2, but With the additional risk of failed intubation posed by the obstetric airway (estimated at 0.4%), the laryngeal mask airway (LMA) has emerged as a second-line airway device . AdditioNotwithstanding its utility as a rescue airway device, we should be cognizant that the incidence of first-attempt LMA failure in obstetrics is approximately 2% , 14. AddTherefore, it is vital to predict when LMA failure is likely to occur, and formulate an alternate airway plan. Additionally, to be an effective rescue airway the factors associated with LMA failure could be different from those predicting failure to intubate. This prospective cohort study aims to investigate the association between the modified Mallampati score and airway outcomes of Supreme™ LMA insertion for cesarean section under general anesthesia.This is a secondary analysis of a previously-published prospective cohort study , which w2, upper respiratory tract or neck pathology, or self-reported reflux disease. After fasting for a minimum of 4 h, the modified Mallampati score was determined by an independent assessor and the patients divided into two groups: Mallampati III/IV (High MP) and Mallampati I/II (Low MP).Parturients who were healthy or with well-controlled medical conditions (American Society of Anesthesiologists (ASA) physical status classification II) undergoing elective cesarean section under general anesthesia were recruited. We excluded patients with BMI > 35 kg/m2O via a manometer, assessment of successful SLMA placement was made by auscultation of breath sounds and the capnographic evidence of end-tidal carbon dioxide, and cricoid pressure was released. The use of additional maneuvers such as chin lift, jaw thrust, or head tilt were permitted. Rocuronium was used to maintain intraoperative muscle relaxation, and fentanyl was administered for analgesia after delivery of the fetus.The induction of anesthesia and SLMA insertion reflects the clinical practice at the study center, as well as the cohort study that forms the basis for this secondary analysis . As per 2O, positioning of the SLMA bite block between the incisors, successful orogastric tube insertion, and leak pressure > 20cmH2O. If successful SLMA insertion was not accomplished (1) after two attempts, (2) within one minute, or (3) before desaturation ensued, endotracheal intubation would be performed.We recorded (1) the number of insertion attempts required, with each attempt defined as insertion and complete removal of the SLMA; and (2) the time to effective airway placement, from when the SLMA was picked up until the first end-tidal carbon dioxide capnogram appeared. Subsequently, a pre-mounted #14 orogastric tube was inserted through the gastric drainage port, and placement confirmed by aspiration of gastric contents and auscultation of a “swoosh” over the epigastrium with air injection, followed by suctioning of the orogastric tube before surgery commenced. Finally, oropharyngeal leak pressure was measured by shutting the adjustable pressure-limiting valve and maintaining 3 L/min fresh gas flow into the closed circuit. Cesarean section was allowed to commence if the following were met: presence of square-wave capnogram, cuff pressure of 60 cmHPerioperative anesthesia management during the original cohort study  reflectsOur primary outcome was time to effective ventilation, as defined above. Secondary outcomes included the rate of successful first-attempt SLMA insertion, oropharyngeal leak pressure, ventilation parameters such as tidal volume and respiratory rate, hemodynamic parameters including heart rate and blood pressure at 2 and 5 min after induction, amount and pH of gastric aspirate, the pH of the SLMA laryngeal surface, and the presence of clinical aspiration. Obstetric and fetal outcomes included neonatal weight, Apgar scores, and umbilical venous pH.p <  0.05 and all tests were two-sided. Data analysis was generated using SAS 9.3 software .All demographic, anesthetic, and clinical categorical data were summarized as frequency with corresponding proportion, and continuous variables were expressed as mean (standard deviation (SD)) or median [interquartile range (IQR)], whichever appropriate. The difference between categorical data was tested using the Chi-Square test, while Student’s t-test and Mann-Whitney U test were used for parametric and non-parametric continuous data, respectively. Simple linear and multivariable linear regression methods were utilized to determine associated risk factors for our primary outcome of time to effective ventilation. Associations identified from linear regression were expressed as estimate (β) with 95% confidence interval (95%CI). Significance level was set at We performed a sample size calculation based on the following assumptions: a meaningful clinical difference of at least 10 s in time to effective ventilation between “High MP” and “Low MP” groups, pooled SD of 4.5, allocation ratio of 1:8, use of two-sample independent t-test, level of significance of 5% and > 95% power. The study was adequately powered (> 95%) with 584 parturients.p = 0.0001), but there was no significant difference in maternal age, fetal weight, or gestational age. The duration of surgery was similar, with mean (SD) 31.0 (11.1) minutes in the High MP group vs 29.3 (9.2) minutes in the Low MP group (p = 0.4159).We recruited 584 parturients. Of these, 61 were found to have Mallampati III/IV (High MP) and 523 with Mallampati I/II (Low MP) (Table p = 0.2172). Similarly, there was no difference in first attempt insertion success rate of 98.4% for the High MP group versus 98.3% for the Low MP group. The lowest SpO2, seal pressure and peak airway pressures were similar between the groups. No episodes of hypoxemia, laryngospasm, or bronchospasm were observed intra-operatively.Anesthetic outcomes are presented in Table p = 0.0191). The presence of blood on the SLMA was more frequently noted in the High MP group with 4 (6.6%) versus 4 (0.8%) in the Low MP group (p = 0.0010), but there were no significant differences in sore throat (p = 0.6071), voice hoarseness (p = 0.1585), or maternal satisfaction (p = 0.5131). Fetal outcomes, including Apgar scores at 1 and 5 min, and venous cord pH were similar between the groups.Maternal and fetal outcomes are summarized in Table Univariate linear regression method showed that age and baseline systolic blood pressure were significantly associated with time to effective ventilation Table ; while mThis prospective cohort study of 584 parturients undergoing cesarean section under general anesthesia compared the airway outcomes of the SLMA in patients with lower Mallampati scores (I or II) versus higher scores (III or IV). Out of 584 patients, 61 (10.4%) had Mallampati scores of III or IV. We found no association between Mallampati scores and time to effective ventilation, first attempt success rate, or SLMA seal pressure. There was no clinical aspiration detected, and the pH of the SLMA laryngeal surface was not indicative of gastric regurgitation. However, higher Mallampati scores was associated with increased risk of blood found on the SLMA, which may indicate increased risk of oropharyngeal trauma on insertion, but without corresponding change in sore throat, voice hoarseness, or maternal satisfaction.Our results suggest that LMA outcomes in obstetric general anesthesia was not significantly affected by higher Mallampati scores. The Mallampati score is postulated to be related to the size of the tongue base during difficult laryngoscopy due to occlusion of the view of pharyngeal structures . This isAlthough previous studies associated higher Mallampati scores with increased LMA failure rates , our finA common concern of LMA use in obstetrics relates to the inherently higher risk of gastric regurgitation and pulmonary aspiration, exacerbated by concomitant obesity, labor pain, or opioid analgesia. In this study, we did not detect any clinical aspiration or regurgitation, likely due to (1) the ability of second-generation LMAs to isolate the alimentary tract and facilitate gastric decompression, (2) better pharyngeal seal that prevents stomach insufflation and regurgitated gastric contents from entering the airway, (3) use of rapid-sequence induction and cricoid pressure, and (4) careful patient selection with exclusion of patients at high risk for regurgitation. However, this study was not powered to investigate the risk of pulmonary aspiration.There are several limitations in this study. First, we are cognizant that bedside tests, including the Mallampati score, are considered by some to be poor predictors of difficult intubation especially if used in isolation , 21. How2O greater than the average peak airway pressure regardless of Mallampati score, as well as gastric decompression via an orogastric tube.Second, we utilized clinical markers of SLMA airway outcomes, such as time to ventilation, first attempt insertion success rate, and seal pressure, in contrast to other studies that assessed LMA position via a fiberoptic grading scale . Several2 or higher. The retrospective study by Ramachandran et al. reported that elevated BMI of 29.3 versus 26.9 was associated with LMA Unique failure, but Mallampati scores of III to IV were not [2 in the “Low MP” group, we did not find any corresponding increased SLMA failure, although we were not specifically assessing the effects of increasing BMI on SLMA outcomes. Finally, we did not directly correlate failed intubation with LMA failure, and therefore cannot comment on the use of SLMA as a rescue airway.Third, we deliberately excluded patients at high risk of gastric regurgitation, including parturients with BMI of 35 kg/mwere not . DespiteOur prospective cohort study suggests that higher Mallampati score is not associated with longer time to effective ventilation when using the Supreme LMA in parturients undergoing elective cesarean delivery under general anesthesia, with similar time to effective ventilation, first attempt SLMA success rate, and seal pressure. More work is required to evaluate the accuracy of other bedside tests on predicting LMA airway outcomes in obstetrics.


Current medical management of pulmonary embolism (PE) is driven by risk stratification, with thrombolytic treatment reserved for patients with hemodynamic instability. We describe a case of a man with acute submassive bilateral pulmonary emboli and a right popliteal deep vein thrombosis (DVT), who had persistent shortness of breath, tachycardia, and hypoxemia but remained normotensive and was therefore not treated with thrombolytics until he suffered a fatal cardiac arrest on hospital day six. We examine the indications, risks, and potential benefits of thrombolytic treatment in patients with submassive PE who exhibit signs of instability but do not meet current indications for thrombolytic treatment with persistent hypotension or shock. The incidence of pulmonary embolism (PE) ranges from 70 to 300 cases per 100,000 persons per year, with mortality rates of approximately 40% in cases of high risk and hemodynamically unstable patients. Current guidelines recommend the use of thrombolytic treatment only for patients with hemodynamic instability defined as persistent hypotension or shock (systolic blood pressure <90 mmHg or a decrease in diastolic blood pressure ≥40 mmHg) . HoweveroC, and oxygen (O2) saturation was 93% on room air. Physical exam was notable for an obese male in no acute distress with tachycardia, regular rhythm, clear lungs, shallow breaths without accessory muscle usage, and mild epigastric tenderness. His electrocardiogram (ECG) demonstrated sinus tachycardia at 117 bpm with a deep S wave in lead I, a small Q wave and inverted T wave in lead III , his blood pressure was 120/83 mmHg, pulse 119/min, respiratory rate 22/min, temperature 36.6Initial laboratory testing was significant for serum sodium 132 mmol/L, creatinine 1.6 mg/dL, ProBNP 3188pg/mL, and initial troponin 0.12, peaking at 0.2 on hospital day two. Computed tomography (CT) chest showed bilateral submassive pulmonary emboli in multiple branches of the right and left upper and lower lobe pulmonary arteries, with no indication of a saddle embolus or main pulmonary artery thrombus Figures -2B.2 saturation. He was admitted to the medical intensive care unit (MICU) due to possible signs of acute decompensation.The patient was started on an intravenous (IV) heparin drip and thrombolytics were deferred due to perceived hemodynamic stability and timing of presentation. While in the ER, he became more tachycardic with heart rate 130-140 bpm, and developed jugular venous distention and acute hypoxemia requiring 3 liters (L) nasal cannula to maintain normal O2 saturations on 3L per nasal cannula. Transthoracic echocardiogram revealed right ventricular strain and a mobile structure in the right atrium, possibly consistent with thrombus. On hospital day four, he remained hemodynamically stable but experienced mild pleuritic chest pain and shortness of breath. On hospital day five, the patient was switched from IV heparin to enoxaparin 120 mg twice daily with a two-hour overlap; he was noted to have a transient O2 desaturation but remained normotensive. In the early hours of day six, he became diaphoretic and developed sustained tachycardia at 140/min with a blood pressure of 100/70 mmHg. He then developed chest pain and worsening dyspnea and lethargy, and was found to be in atrial flutter with 2:1 block. In the early afternoon, while speaking with the medical team and later while working with physical therapy, the patient complained of worsening shortness of breath, and was noted to be diaphoretic and persistently tachycardic at 120/min. Shortly thereafter, he lost consciousness and was found to be in cardiac arrest. He was treated per advanced cardiac life support (ACLS) protocol with temporary restoration of circulation, but became asystolic and was pronounced dead after 30 minutes.In the MICU, ultrasound revealed a right popliteal deep vein thrombosis (DVT); an inferior vena cava filter was considered, but the patient was considered hemodynamically stable and placement of a filter was deferred. Over the second and third hospital days, he remained tachycardic at 105-130/min with blood pressures in the 110/80 mmHg range and stable OPE are risk stratified into three categories: high-risk (or “massive”) defined by hemodynamic instability with sustained systolic blood pressure (SBP) <90 mmHg or a decrease in SBP by ≥ 40 mmHg from baseline, intermediate risk (or “submassive”) defined by hemodynamic stability with SBP ≥90 mmHg and features of right heart dysfunction or myocardial necrosis, and low risk . ApproxiGiven the significant mortality associated with PEs, a number of studies have retrospectively assessed various risk factors including advanced age, prolonged immobility, malignancy, polytrauma, recent major surgery, heart failure, prior venous thromboembolism, and dyslipidemia that can be utilized as diagnostic indicators . As for Systemic thrombolysis is considered standard aggressive therapy for high-risk PE. However, for intermediate-risk patients, thrombolytic use is considered controversial, and conservative therapy with anticoagulation is most commonly utilized. Early research initially found that utilization of thrombolytics had a favorable effect in the treatment of hemodynamically stable major PE and thus subsequent recent studies have analyzed the risks and benefits of thrombolytic treatment in intermediate risk patients . The PulCho et al. argue that criteria for RV dysfunction and hemodynamic instability may be considered too stringent in some cases when assessing short-term mortality and as such, some patients deemed hemodynamically stable due to their normal blood pressure may actually be high risk for clinical deterioration and subsequent instability, as was clearly the case in our patient . StewartChoi et al. contend that risk tools, notably the PESI, should be more widely used in conjunction with assessment of hemodynamic stability and echocardiographic findings in order to identify and target high-risk patients . In the Treating submassive pulmonary emboli can be very challenging. There may be subgroups of patients with submassive PE without hemodynamic instability (defined as hypotension and shock) that would benefit from thrombolytic treatment. Patients such as ours, with multiple clinical indicators of clinical instability that persist or worsen over several days despite appropriate anticoagulation, might be a particularly high-risk subgroup. Pending further clinical research, physicians should not only consider current guidelines but also take into consideration the clinical manifestations of instability over time in making treatment decisions for patients with submassive PE.


Plasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females.α-Gal A gene (GLA) for primary and secondary screens, respectively.Between 1 July 2014 and 31 December 2015, we screened 2,360 patients  referred from 169 Japanese specialty clinics , based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A  activity, and analysis of the –1) and low α-Gal A activity (≤4.0 nmol h–1 ml–1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity  and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance).Of 8 males with elevated lyso-Gb3 levels (≥2.0 ng mlPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands. Morbidity and mortality from FD—caused by renal failure, cardiac disease, and early-onset stroke—increase with age. Cardiac deaths account for most FD-related deaths in females and males.2 FD can be classified as classic or late-onset.3 Late-onset FD lacks classic early manifestations, such as acroparesthesia, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis, and exhibits exclusively renal, cardiac, and cerebral impairments. Thus, recognizing late-onset FD is difficult, and undiagnosed patients with late-onset FD may outnumber those with classic FD.4Fabry disease (FD) is an X-linked lysosomal storage disorder that results from a deficiency in the activity of α-galactosidase A .α-Gal A gene (GLA) mutation analysis was then used to confirm the diagnosis of FD.3 However, such invasive biopsies are rare, and many cases of FD may go undiagnosed. Thus, it is important to find reliable and noninvasive biomarkers for FD screening.FD targets multiple organs, and its effective treatment requires the efforts of doctors from several clinical departments. Nephrologists, cardiologists, and neurologists are important for managing both classic and late-onset FD. Previously, nephrologists and cardiologists have accidentally identified late-onset FD probands when pathological findings from kidney and cardiac biopsies were consistent with FD, and the GLA.5 Therefore, GLA analysis is not always the gold standard for diagnosis in all cases. GLA mutations can be divided into two classes: class 1 mutations, with a high probability of causing disease, and class 2 mutations representing nonpathogenic polymorphisms.6GLA analysis can definitively identify FD by class 1 mutations, or non-FD by class 2 mutations.There are many genetic variants of uncertain significance (GVUS) in GLA analysis is generally considered only when the patient presents with abnormal α-Gal A activity and clinical symptoms that suggest FD. Moreover, α-Gal A activity often remains within the normal range in female patients,7 making FD diagnosis more difficult.39 and 3% for late-onset FD in patients with male left ventricular hypertrophy (LVH).10 In a recent systematic review of high-risk populations for FD, the prevalence of a definitive diagnosis of FD was 0.12% for classic FD.5The prevalence rates of FD in Japan, as determined by α-Gal A activity screening, were 0.2% for patients with classic FD, 1.0% for late-onset FD in male patients undergoing dialysis,13 However, the usefulness of lyso-Gb3 for proband screening has not been studied. Previously, we screened for FD in male patients undergoing dialysis, using plasma α-Gal A activity as the primary biomarker and lyso-Gb3 concentration, as measured by high-performance liquid chromatography, as a secondary biomarker. This was the first study to investigate whether lyso-Gb3 could be used as a secondary biomarker to identify male probands in an FD-suspected population. We found that the plasma lyso-Gb3 screening was effective for selecting candidates for genetic counseling and testing, revealing unrecognized FD cases, and reducing the number of unnecessary gene analyses.14The deacylated form of Gb3, globotriaosylsphingosine (lyso-Gb3), was recently identified in plasma as a strong biomarker of classic FD, in studies of recognized patients with FD who had already been diagnosed.12 this is the first study to investigate whether lyso-Gb3 could be used in screening assays as the primary biomarker to identify male and female probands in patients with suspected FD. Plasma lyso-Gb3 could be used in the selection of candidates who may benefit from gene analysis, to improve the outcomes of diagnosis in multispecialty clinics.In the present study, we assessed the value of lyso-Gb3 as an FD biomarker for screening male and female patients suspected of having FD based on clinical symptoms. We screened for the concentration of lyso-Gb3, as measured by ultra-performance liquid chromatography/tandem mass spectrometry, and for the plasma α-Gal A activity in all patients. Although previous studies evaluated patients already diagnosed with FD,This was a prospective multicenter study.Lyso-Gb3 and α-Gal A screening–1: positive) and plasma α-Gal A activity (activity ≤4.0 nmol h–1 ml–1: low); (ii) patients with elevated lyso-Gb3 or low α-Gal A activity were informed that they may have FD; (iii) with the consent of the patient, the FD diagnosis was confirmed by genetic testing using GLA; and (iv) a familial diagnosis was confirmed by screening other family members based on the lyso-Gb3 concentration, α-Gal A activity, and GLA analysis when indicated.This study had four steps: (i) patients were screened for FD by measuring the concentration of plasma lyso-Gb3 ; cardiac evaluation including an electrocardiogram, echocardiogram, and cardiac magnetic resonance imaging (unexplained LVH or unexplained cardiac failure); neurological evaluation with magnetic resonance imaging (early-onset stroke or transient ischemic attack); and pediatric evaluation in children with early classic manifestations, such as acroparesthesia, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis. Acroparesthesia is defined as pain in the hands and/or feet, with the onset of pain in childhood or adolescence, and/or a course characterized by exacerbations that are provoked by fever, exercise, or heat, as well as decreased cold sensation.16 Clustered angiokeratoma should be present in the bathing trunk, periumbilical, and/or perioral regions.16 Cornea verticillata should be evaluated using a slit lamp, in the absence of amphiphilic drug use.16 Hypo-anhidrosis is defined as low or no sweating even in an environment (high temperature or humidity) that encourages sweating. Patients with known FD and their relatives were excluded.Japanese patients of unknown FD status who had been referred by specialty clinics were screened for FD between 1 July 2014 and 31 December 2015. This study is ongoing; the interim results, up to 2015, are presented here. Patients (aged 2–99 years) suspected of having FD based on clinical evaluation were recruited at 169 clinics in Japan. Clinical evaluation included: nephrological evaluation with biochemical examination, urinalysis, imaging, and kidney biopsy  and collaborating clinics. Patients were informed about the study specifics, and those who agreed to participate provided written consent. The results were reported to the patient by the attending doctor. Informed consent was also obtained from patients before Blood specimens for the primary screening were collected in Venoject II collection tubes . Plasma samples were obtained by centrifugal separation.–1 , with the highest normal value at 2.0 ng ml–1. To avoid false-positive results, we set the screening cutoff for lyso-Gb3 levels at 2.0 ng ml–1. We evaluated the suitability of this high cutoff value (2.0 ng ml–1) for both genders; the highest concentration of lyso-Gb3 among males with normal α-Gal A activity in this study was 1.8 ng ml–1.Plasma lyso-Gb3 levels were measured by ultra-performance liquid chromatography/tandem mass spectrometry at GlycoPharma , with a detection threshold of 0.1 ng ml–1  online. d-galactoside, with a detection threshold of 0.1 nmol h–1 ml–1, as described previously.14 To avoid false-negative results, the screening cutoff for the α-Gal A activity level—the percentage of the control mean or cohort mean—was recently set at high, ≥50%.14 We did not set up reference individuals for plasma α-Gal A activity. Therefore, reference values for plasma α-Gal A activity were not obtained. The cutoff for a low result for plasma α-Gal A activity was set at 4.0 nmol h–1 ml–1—54% of the mean cohort value in our previous study.14Plasma α-Gal A activity was measured at GlycoPharma using the artificial substrate 4-methylumbelliferyl-α-Patients positive for lyso-Gb3 or showing low α-Gal A values were considered candidates for genetic counseling. The results of the α-Gal A activity screening were explained to the participants or family members, as appropriate.To obtain DNA and RNA samples, blood specimens were collected in Venoject II collection tubes and PAXgene Blood RNA Tubes , respectively.Gene analysis was performed at the Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences  online.P < 0.05. Data were plotted using SigmaPlot 12.5 .The data were examined using the Shapiro–Wilk test to determine whether they showed a normal distribution. The majority of the continuous variables were non-normally distributed and therefore the medians and interquartile ranges (IQRs) are presented. Categorical data were evaluated by Fisher’s exact test and Pearson’s chi-squared test. All reported significant values were two-tailed. Data were compared between two unpaired groups by performing the Wilcoxon rank-sum test. JMP 12 software  was used for statistical analyses, and the results were considered significant at We enrolled 2,376 patients suspected of having FD based on clinical symptoms. We excluded 16 patients, including 2 patients who were known to have FD and 14 patients with relatives who were known to have FD. We obtained validated data for 2,360 patients  from 169 clinics . The med–1) or negative (<2.0 ng ml–1). The median lyso-Gb3 levels were 15.1 ng ml–1 in the 8 males in the positive group (IQR: 4.0–171.4) and 0.3 ng ml–1 in the 1,316 males in the negative group (IQR: 0.2–0.5); this difference was significant  and 0.4 ng ml–1 for the 1,021 females in the negative group (IQR: 0.2–0.6); this difference was also significant , which was significantly lower than the median of 7.6 nmol h–1 ml–1 (IQR: 6.6–8.9) in the 1,316 males in the negative group , which was significantly lower . Eight females in the positive group had normal α-Gal A activity, and six females in the negative group had low α-Gal A activity. Thus, the relationship between plasma lyso-Gb3 levels and α-Gal A activity differed between males and females.The median plasma α-Gal A activity in the 8 males in the positive group was 0.9 nmol hGLA mutation. Among the cases of FD identified in this study, we found ten previously reported GLA mutations .20 Two other mutations were identified—i.e., p.G85V and the frameshift mutation c.559_560delAT—and both probands were classified as the classic type. Thus, lyso-Gb3 screening identified both classic and late-onset FD probands in males and females  had class 1 mutations. These probands were classified as classic or late-onset FD based on the presence or absence of early classic manifestations and the type of  females .All the male FD probands were in the positive group and had low α-Gal A activity. Of the two male probands with classic FD, both were pediatric patients . Of the All male probands with classic FD were children, and those with late-onset FD were adults . The lysIn all clinical departments except pediatrics, the frequency of identification among patients who screened positive for lyso-Gb3 was higher in females than in males . Of the GLA variants associated with FD. Electron microscopy revealed lamellar bodies in kidney or endomyocardial biopsies  in the 5'-untranslated region of exon 1 that was associated with decreased α-Gal A expression;28 this is a nonpathogenic class 2 mutation  met these criteria. Of the 11 males, 7 declined gene analysis. Of the four males who underwent ordinary gene analysis, three presented the p.E66Q class 2 mutation—a nonpathogenic, functional polymorphism that was found at an unexpectedly high frequency in the mutation  online.2mutation .A subsequent intronic mutation analysis in three patients with c.−10C>T revealed many GVUS .The results of this study are summarized in flowcharts  online. In this study, we assessed the applicability of lyso-Gb3 as an FD biomarker for screening male and female patients suspected of FD based on clinical symptoms. This method enabled us to uncover both classic and late-onset FD probands. This is the first assessment of the potential use of lyso-Gb3 as a primary screening biomarker. Our findings show that plasma lyso-Gb3 might represent a promising primary screening biomarker for identifying FD probands.29Lyso-Gb3 screening was effective for identifying male FD probands. Males who screened negative for lyso-Gb3 and displayed low α-Gal A activity presented the p.E66Q or c.−10C>T mutations. This result indicates that our current screening method—using lyso-Gb3 determined by ultra-performance liquid chromatography/tandem mass spectrometry—might exclude patients with the p.E66Q mutation. Thus, FD could be excluded in male patients with normal lyso-Gb3 levels.–1 predicts a diagnosis of classic FD in males.29 Similarly, a cutoff value around 50 nmol l–1 for the classic FD classification was reported, with lower levels found in late-onset FD except for one patient who presented a level of 74 nmol l–1.12 The integration of additional screening data will help to establish the lower levels found in classic FD and the upper levels found in late-onset FD, to determine the boundaries defining these forms of FD.Among male patients examined in this study, elevated lyso-Gb3 levels were suggestive of a diagnosis of FD. Males with classic FD exhibited higher lyso-Gb3 levels than those with late-onset FD. Therefore, it should be possible to establish a reliable lyso-Gb3 cutoff value for the classification of naive hemizygous patients with FD. A lyso-Gb3 value above 45 nmol l–1 . Lyso-Gb3 levels of female patients with FD overlap with controls.29 Therefore, setting a lower threshold for females (below 2 ng ml–1) might prove tricky. A robust analysis of lyso-Gb3 in both FD and other lysosomal storage disorders is needed to be absolutely certain regarding the specificity of setting a lower threshold for female patients. In this study, we found that setting a cutoff value to classify even naive heterozygous patients with FD may prove difficult, and lyso-Gb3 values in familial hemizygotes might help in the classification of female probands.Lyso-Gb3 screening also identified female FD probands, and has the potential to identify many unrecognized female probands. Our pedigree analyses showed that lyso-Gb3 levels in asymptomatic females of families carrying class 1 mutations did not exceed 2.0 ng ml30 For females, plasma lyso-Gb3 represents an independent risk factor for developing LVH.13 Thus, screening of females with LVH is essential. Most patients identified in previous screens for FD in patients with early stroke31 exhibited class 2 mutations rather than FD. The actual frequency of patients identified was lower than the reported frequency.31 Similarly, the identification frequencies in the recent report32 and the present study were low.Determining a top-priority target is fundamental for developing a successful screening strategy for high-risk populations. In this study, we found a high prevalence of FD in females referred from cardiology (1.3%). The incidence of LVH was particularly high in older female patients with FD, and the cumulative incidence of LVH in females over 68 years of age was 100%.5 Intronic GLA variants often remain unidentified because these regions are not evaluated by ordinary gene analyses, except for exon–intron boundaries. Surprisingly, intronic analyses in the current study identified patients with multiple GVUS. Combinations of c.−10C> and nonpathogenic intronic variants might be associated with FD.35 Although GLA analysis is our most reliable method for diagnosing FD, diagnostic clarity may remain elusive when GVUS are present. Elucidating the roles of various intronic GVUS will improve the effectiveness of lyso-Gb3 screening.Screening for FD in high-risk populations yields many individuals with GVUS.29 When patients are phenotyped according to well-defined criteria, overlap only occurs between the controls and female patients with non-classical FD.29 Hence, using lyso-Gb3 to confirm a diagnosis of FD may represent a good approach in females and patients with late-onset FD. Another issue is that subjects with an uncertain diagnosis of FD who present non-specific FD symptoms and GVUS are increasingly identified through screening.5 Both the confirmation and exclusion of FD are important for an adequate diagnosis. A diagnostic algorithm for these subjects was recently proposed.16 The gold standard for a diagnosis of FD in these subjects involves evidence of a specific storage pattern in the affected organ, as assessed by electron microscopic observation with high magnification.16Some issues arise in the diagnosis of FD. Thus, the α-Gal A activity assay is not reliable for females. Moreover, since late-onset FD lack the early classic manifestations, patients with late-onset FD may be less likely to be diagnosed than those with classic FD and may be dormant. A previous study has already shown that lyso-Gb3 levels are related to FD phenotype.In this study, we found that some female patients with high lyso-Gb3 levels and normal α-Gal A screening results presented intronic GVUS; this association was revealed exclusively through lyso-Gb3 screening. Although no clear diagnostic criteria exist for GVUS, high lyso-Gb3 levels support a likelihood of FD and might encourage subsequent histological examinations to reach a definitive diagnosis.36 and late-onset FD,37 and male patients with late-onset FD38 passed fitness checks for kidney donation, but were later diagnosed with FD based on graft biopsy findings. Obtaining a kidney biopsy from a donor candidate before transplantation is difficult. Screening for lyso-Gb3 along with a genetic analysis may offer a safeguard against transplanting an inadequate kidney from an asymptomatic female with classic FD or a donor with late-onset FD.Female patients with classic39 Namely, more than 98% of patients did not have FD and underwent gene analysis. Additionally, data on lyso-Gb3 levels were not included. We believe that reducing the number of patients without FD that undergo gene analysis is important for patients’ peace of mind. This study revealed that the frequencies of positive lyso-Gb3 screening were 0.6% in males and 1.4% in females. If all patients had undergone GLA analysis, the prevalence of FD may have exceeded 0.55%, approaching the rate obtained from genetic screening. Thus, plasma lyso-Gb3 analysis may allow the selective identification of patients who are at high risk for FD.Recently, genetic screening for FD in 2,034 probands referred from multispecialty clinics in a 10-year prospective study showed a significant increase in diagnostic yield (1.3%).29 Third, plasma lyso-Gb3 concentrations are elevated in boys with classic FD from infancy onwards, but increase gradually in girls as they get older.11 Therefore, some cases of FD in girls may have been missed. Nonetheless, lyso-Gb3 screening successfully identified several FD probands. Fourth, we did not establish a wide range for the age (2–99 years)-matched control population without class 1 mutations. Therefore, we could not compare the pathological lyso-Gb3 levels with the control population. Plasma lyso-Gb3 is a promising primary screening biomarker that effectively identified unrecognized FD probands referred from multispecialty clinics.This study has several limitations. First, not all patients were genotyped; therefore, some cases of FD may have been missed. Second, normal lyso-Gb3 concentrations do not exclude FD in females, and some cases—particularly late-onset FD—may have been missed.Supplementary File


The measurement or estimation of hemodynamic variables reflecting blood pressure, blood flow, cardiac contractility, cardiac preload, and cardiac afterload plays a pivotal role in the monitoring, diagnostic workup, and treatment of critically ill patients treated in the intensive care unit or in patients having major surgery.Besides pulmonary artery catheterization that is established as a classical method to observe, measure, and derive a variety of variables reflecting cardiovascular and oxygen dynamics , 2 a varMeidert and Saugel). The authors recommend monitoring of blood pressure with intermittent oscillometry in hemodynamically stable, low-risk patients. In surgical patients at risk for hemodynamic instability, continuous non-invasive blood pressure monitoring with innovative techniques might become an option in the near future. In critically ill and high-risk surgical patients, continuous invasive blood pressure monitoring with an arterial catheter will be the method of choice in the foreseeable future. Based on these general recommendations, an article by Stenglova and Benes describes the evidence for the use of continuous non-invasive blood pressure monitoring during surgery and its potential to improve postoperative outcome by an early recognition (or even prediction) of hypotension.As a very basic hemodynamic variable and as a main determinant of the organs' perfusion pressure, arterial blood pressure is part of routine monitoring in intensive care medicine and anesthesiology. In a narrative review article, methods for non-invasive intermittent and continuous blood pressure monitoring are summarized  enables stroke volume, cardiac output, and dynamic cardiac preload parameters to be assessed using invasive  or non-invasive (finger cuff) methods. Several articles discuss pulse wave analysis and its use in clinical practice.Grensemann comprehensively explains the basic measurement principle of commercially available invasive monitoring systems using pulse wave analysis to estimate cardiac output. He emphasizes that pulse wave analysis is limited in patients with altered vascular tone and that uncalibrated systems should be used to follow cardiac output changes (trend monitoring) rather than to guide therapy based on absolute values of cardiac out. A review article by Yamada et al. describes how minimally invasive and non-invasive hemodynmaic monitoring techniques can be used to guide perioperative hemodynamic therapy and eventually improve postoperative outcome in surgical patients. The authors conclude that “monitoring equipment that can provide precise hemodynamic information without the complications and complexity of invasive techniques can facilitate individualized hemodynamic management and lead to improved outcomes.”Saugel and Reuter focuses on the use of invasive uncalibrated pulse wave analysis for perioperative hemodynamic management . The article briefly summarizes the evidence and concludes that perioperative goal-directed therapy based on pulse wave analysis-derived blood flow and dynamic cardiac preload variables can improve patient outcome in high-risk patients. This conclusion is in line with the results of recent meta-analyses showing that perioperative goal-directed therapy seems to reduce postoperative morbidity physiology of oxygen delivery, consumption, and extraction and discuss the value of central venous oxygen saturation to individually tailor therapeutic interventions to the individual patient's needs. The authors advocate for multimodal and individualized hemodynamic treatment strategies which should integrate various physiological variables .Optimization of oxygen delivery to the end-organs is the ultimate goal of therapeutic interventions aiming at an optimization of global cardiovascular dynamics. Accordingly, In summary, this series of articles reflects that a variety of innovative less- and non-invasive methods for advanced hemodynamic monitoring in intensive care and perioperative medicine are currently available. Future research needs to confirm that goal-directed optimization of global hemodynamics based on advanced less- and non-invasive hemodynamic monitoring can eventually improve oxygen delivery and have beneficial impact on patient outcome.BS and SGS drafted the manuscript and approved the final version of the manuscript to be published.BS and SGS collaborate with Pulsion Medical Systems SE  as members of the medical advisory board and received honoraria for giving lectures and refunds of travel expenses from Pulsion Medical Systems SE. BS received research support from Edwards Lifesciences . BS received institutional research grants, unrestricted research grants, and refunds of travel expenses from Tensys Medical Inc. . BS received honoraria for giving lectures from CNSystems Medizintechnik AG . BS received refunds of travel expenses from CNSystems Medizintechnik AG .


End-tidal carbon dioxide (EtCO2) monitoring is a noninvasive tool used to estimate Paco2 values.Alterations in the partial pressure of carbon dioxide, arterial  higher than EtCO2. Overall, 187 of all Paco2-EtCO2 pairs (42.0%) agreed. There was larger variation in the Paco2-EtCO2 difference during the first 8 hours compared with 9 to 24 hours after admission to the pediatric intensive care unit. Development of pediatric acute respiratory distress syndrome within 24 hours of admission was associated with a lower likelihood of Paco2-EtCO2 agreement  compared with no development of pediatric acute respiratory distress syndrome. A diagnosis of pediatric acute respiratory distress syndrome 1 to 7 days after admission was associated with a larger first-day Paco2-EtCO2 difference compared with those who never developed pediatric acute respiratory distress syndrome .The analysis included 137 patients  and 445 paired Paco2-EtCO2 agreement was low, especially among patients with pediatric acute respiratory distress syndrome. Low Paco2-EtCO2 agreement early in hospitalization may be associated with future development of pediatric acute respiratory distress syndrome. Data on EtCO2 should not be substituted for data on Paco2 during the first 24 hours.In this study of pediatric traumatic brain injury, Pa co2) and end-tidal carbon dioxide (EtCO2) and associated factors in children with traumatic brain injury (TBI).This secondary analysis of a cohort study examines agreement between partial pressure of carbon dioxide, arterial (Pa However, arterial sampling can be challenging in children, and complications are not uncommon.4 Capnography allows for noninvasive, continuous measurement of end-tidal carbon dioxide (EtCO2) with lower cost and fewer complications compared with arterial cannulation, and it is widely used in clinical pediatric practice as a substitute for arterial cannulation.5 End-tidal CO2 reasonably estimates Paco2 in healthy adults.6 A mean difference of 0 to 5 mm Hg between Paco2 and EtCO2 is generally accepted as good agreement, and good agreement has been demonstrated in patients during general anesthesia who are undergoing prolonged neurosurgical procedures, in clinically stable patients in the pediatric intensive care unit (PICU), and in adult patients with TBI without hypotension, metabolic acidosis, or severe lung injury.10 However, the utility of EtCO2 as a substitute for Paco2 in critically injured children with TBI has not been examined, to our knowledge.Globally, traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality.co2 less than 30 mm Hg in the initial 48 hours after admission.11 A recent study showed that adhering to this recommendation improved discharge outcomes.12 The Brain Trauma Foundation does not, however, include a recommendation either for or against the use of EtCO2 measurements because of the lack of data comparing Paco2 with EtCO2 to prevent unwanted hypocarbia and hypercarbia. To evaluate the validity of using EtCO2 as an indicator of Paco2 in children and adolescents hospitalized with TBI, we performed a secondary analysis of a prospective cohort study to describe the agreement between Paco2 and EtCO2 early after TBI and determine the factors associated with Paco2-EtCO2 agreement.Recently, the Brain Trauma Foundation published the third edition of medical management guidelines for severe pediatric TBI, recommending avoidance of prophylactic hyperventilation and Pa12 Waiver of consent was granted by the University of Washington Institutional Review Board for the parent project because this research was a secondary data analysis that was deemed to involve no more than minimal risk to participants and waiver would not adversely affect the rights and welfare of the participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.After approval by the University of Washington Human Subjects Division, from December 17, 2018, to January 10, 2019, we conducted a secondary analysis of data from the recently published Pediatric Guideline Adherence and Outcomes program study.Harborview Medical Center is a 450-bed mixed level I adult and pediatric trauma hospital that serves the 5-state  Pacific Northwest region. The 18-bed PICU admits approximately 120 pediatric trauma patients with TBI annually.2 values recorded within 30 minutes of a Paco2 measurement during the first 24 hours after admission and (2) had 1 or more Paco2-EtCO2 pairs with a systolic blood pressure (SBP) measured at any point within the 60 minutes prior to the Paco2 value  had 1 or more EtCOco2, EtCO2, SBP, oxygenation index, oxygenation saturation index, and Glasgow Coma Scale score were abstracted from the electronic health record. Race and ethnicity were self-reported.Data on demographic characteristics, mechanisms of injury, and injury severity measures were obtained from the Harborview Trauma Registry. Ascertainment of diagnosis of TBI via computed tomography, surgical procedures performed, Paco2 measured via arterial blood gas was entered into the electronic health record by laboratory personnel. End-tidal CO2 was measured via Medtronic capnography and manually entered by PICU nurses or respiratory therapists into the electronic health record at a minimum of every hour. Data on SBP associated with EtCO2 and Paco2 levels were recorded with a digital sphygmomanometer or by invasive arterial monitoring and were automatically entered from SpaceLabs monitoring system at least every hour, or more frequently as dictated by clinical care. All paired data points were collected while the patients were intubated and mechanically ventilated.Clinical data collected during the first 24 hours of clinical care after admission to the PICU were examined. Pa13 Patients with at least 3 qualifying values of the oxygenation index or the oxygenation saturation index during a minimum of 6 hours were determined to meet oxygenation criteria for PARDS. Medical record abstraction was performed for all patients meeting oxygenation criteria to evaluate for the presence of a new parenchymal infiltrate detected on a chest radiograph (based on review by the attending radiologist and secondary review by a pediatric intensivist [E.Y.K.]) and for the origin of edema (based on documentation by the attending physician).Patients were determined to have pediatric acute respiratory distress syndrome (PARDS) if they met Pediatric Acute Lung Injury Consensus Conference PARDS criteria within 7 days of their injury.2 value recorded within 30 minutes was used to create 1 Paco2-EtCO2 data pair. The nearest SBP value within 60 minutes prior to the Paco2 value being measured was then added to create a Paco2-EtCO2-SBP trio. Values measured during apnea trials for brain death were excluded because the patients were no longer receiving routine TBI care.For every arterial blood gas measurement obtained during routine medical care, the nearest EtCO2 measured by capnography is a mixture of relatively CO2-rich alveolar gas diffused from capillaries with CO2-poor gas in ventilated lung regions with poor perfusion . Dead space includes the components of the respiratory system that are ventilated but do not participate in gas exchange and alveoli that receive ventilation but are not perfused because of physiologic or pathologic factors, as well as the airways and breathing apparatus. The Paco2 value is typically 2 to 5 mm Hg higher than the EtCO2 value under physiologically stable conditions.14 Therefore, Paco2-EtCO2 pairs were categorized as either in agreement, if the Paco2 value was between 0 and 5 mm Hg greater than its paired EtCO2 value, or not in agreement.End-tidal COco2 measurement and when EtCO2 was recorded.Potential explanatory variables were determined a priori based on literature review and research team discussion, and they included severity of chest injury, severity of nonhead-nonchest injury, presence of PARDS (within 24 hours or 1-7 days after admission), hypotension, patient age, time since admission, and the time difference between PaThe presence of severe chest injury or nonhead-nonchest injury with a region-specific Abbreviated Injury Score greater than 2 was coded as a binary variable. Hypotension was defined as SBP less than 70 mm Hg +2 × (patient age in years) coded as a binary variable. The PARDS status for each patient was categorized as follows: did not develop within the first week of PICU admission, developed within 24 hours of PICU admission, or developed after 24 hours but within 1 week of PICU admission. Time after admission was dichotomized into 0 to 8 hours and 9 to 24 hours, and age was categorized into younger than 1, 1 to 4, 5 to 9, 10 to 14, and 15 to 17 years.co2 and EtCO2 was assessed for the overall study population and stratified by PARDS status at 24 hours using Bland-Altman plots with limits of agreement adjusted for repeated measures.15 We also assessed the proportion of Paco2-EtCO2 pairs with Paco2 values 0 to 5 mm Hg greater than their paired EtCO2 value.We used descriptive statistics to examine clinical injury characteristics. Agreement between Paco2-EtCO2 pairs in agreement with pairs that did not agree. Stratified Bland-Altman plots were created to visually compare trends in agreement across levels of age and whether patients developed PARDS within the first 24 hours and within 1 to 7 days of PICU admission. We assessed constant and proportional differences between Paco2 and EtCO2 within each Paco2-EtCO2 pair, and we estimated Pearson correlation coefficients using Passing and Bablok regression and Deming regression.17The characteristics that may have affected the likelihood of agreement between measures were initially assessed descriptively, comparing Paco2 and EtCO2, we used univariate logistic regression models clustered by patient; to minimize confounding, we used multivariable logistic regression models clustered by patient adjusted for age, PARDS within the first 24 hours of PICU admission, severe TBI, severe chest injury, severe nonhead-nonchest injury, and shock. Anatomic dead space in the pediatric population could have considerable variation and may affect Paco2-EtCO2 agreement. Although we were not able to measure dead space individually, we chose to adjust for age and cluster by patient to address this issue. To account for the nonindependence of data points within patients, we used a fixed-effects model to assess the association between hypotension (the only time-varying a priori selected explanatory variable) and Paco2-EtCO2 agreement within individual patients.To determine the characteristics associated with agreement between Paco2 and EtCO2 difference graphically to assess the association between time after PICU admission and Paco2-EtCO2 agreement. To explore how the median first-day Paco2-EtCO2 difference after PICU admission differed by the timing of PARDS diagnosis, we also constructed side-by-side boxplots of patients who had no PARDS, received a diagnosis within 24 hours of PICU admission, or received a diagnosis 1 to 7 days after PICU admission. Two-sample t tests were used to determine if there were statistically significant differences in the mean Paco2-EtCO2 difference between these groups. The 2 analyses were repeated among patients who survived the first 24 hours of PICU admission to examine the association of early death with our findings.We described the temporal trends of Paco2-EtCO2 differences with subsequent PARDS among patients who had not developed PARDS within the first 24 hours, we performed a receiver operating characteristic curve analysis and examined the sensitivity and specificity of various cutoff values. All statistical analyses were performed using R, version 3.5.1 , and Stata, version 14.2 package (StataCorp),19 and analyses were approved by the study epidemiologist (B.M.).To explore the association of Paco2-EtCO2 pairs were excluded owing to a lack of data within the predefined measurement time window  .Of the 199 potentially eligible patients, 137 (103 boys and 34 girls) met the inclusion criteria; 62 patients and 6 Paa points . The medco2-EtCO2 pairs (15.1%) were recorded for patients who experienced PARDS within 24 hours of PICU admission (co2-EtCO2 pairs (20.7%) were recorded for patients who developed PARDS between 1 and 7 days after PICU admission. Compared with data pairs in agreement, pairs not in agreement were more commonly from patients with PARDS diagnosed within 24 hours of admission (56 of 258 [21.7%] vs 11 of 187 [5.9%]).A total of 67 of the 445 Padmission , and 92 co2-EtCO2 pairs, Paco2 was on average 2.7 mm Hg  higher than its paired EtCO2 value . A total of 43 patients (31.4%) had at least 1 paired data point with disagreement. Among the 378 Paco2-EtCO2 pairs obtained from patients who did not experience PARDS within the first 24 hours of admission, Paco2 was on average 1.4 mm Hg  higher than EtCO2 . Among the 67 Paco2-EtCO2 pairs obtained from patients who developed PARDS within first 24 hours of admission, Paco2 was on average 9.9 mm Hg  higher than its paired EtCO2 value .Among all 445 PaO2 value A. Paco2 an EtCO2 B. Paco2 O2 value C. Paco2 co2 and EtCO2 are most similar are shown by Passing and Bablok regression ; there was no meaningful change in association after multivariable model adjustment.co2-EtCO2 difference during the first 24 hours of admission among those who developed PARDS within 24 hours was 9.41 mm Hg greater than those who never developed PARDS . The mean Paco2-EtCO2 difference during the first 24 hours of admission among patients who developed PARDS 1 to 7 days after admission was 4.02 mm Hg greater than those who never developed PARDS  ; restricting the sample to 24-hour survivors resulted in no meaningful change in findings. In the receiver operating characteristic curve analysis, the Paco2-EtCO2 difference among those who did not develop PARDS within 24 hours was associated with subsequent PARDS development between 1 and 7 days after admission . In addition, a Paco2-EtCO2 difference of 3 mm Hg or greater had a sensitivity and specificity of 0.72 for the onset of PARDS between 1 and 7 days after PICU admission, given that PARDS had not developed within the first 24 hours .The mean Pa1 mm Hg) . The meaco2-EtCO2 pairs were in agreement, and correlation was only moderate; (2) the presence of PARDS in the first 24 hours of PICU admission was associated with a lower likelihood of Paco2-EtCO2 agreement; and (3) even if PARDS was not diagnosed in the first 24 hours, the median Paco2-EtCO2 differences were higher among a subset of patients who developed PARDS later in the first week after injury than among those who never developed PARDS. Together, these findings suggest that, despite the appeal of EtCO2 monitoring, EtCO2 data should not be substituted for Paco2 data early after pediatric TBI.The main findings of this study of hospitalized pediatric patients with TBI are that (1) overall, fewer than half of all Pa2 as a Paco2 surrogate. First, we used Bland-Altman analysis, which revealed less than 50% agreement of EtCO2 with Paco2. Second, we used Passing and Bablok regression, which demonstrated that Paco2 and EtCO2 had positive constant and proportional differences between measurements. Finally, we used the Pearson correlation coefficient and demonstrated that Paco2 and EtCO2 were only moderately correlated. Collectively, these indicators demonstrated a moderate level of agreement and correlation between Paco2 and EtCO2. To our knowledge, this study is the first to use multiple measures of accuracy to address Paco2-EtCO2 agreement, and the results suggest a need to further define the role of capnography and the need to incorporate Paco2 measurements early after pediatric TBI.We used 3 complementary statistical approaches to understand the accuracy of EtCO10 reported that among adults with TBI, 77.3% of Paco2 and EtCO2 values were within 5 mm Hg of each other. In contrast, our pediatric study demonstrated lower agreement and did not identify hypotension or severe chest injury as contributing factors to Paco2-EtCO2 agreement. Differences in the definition of Paco2-EtCO2 agreement and in the study design  may contribute to these differences in results. However, to reflect clinical practice, we defined agreement using a narrower range (Paco2-EtCO2 <5 mm Hg) and paired the data within clinically reasonable intervals, which likely decreased measured levels of agreement. Although the number of infants and young children in our study is too small to make definitive conclusions, the relatively larger amount of dead space in infants and children might further increase the Paco2-EtCO2 difference and lower Paco2-EtCO2 agreement.Lee et alco2 values that are higher than EtCO2 values obtained simultaneously.14 Although there is generally no physiologic basis for why Paco2 would be lower than EtCO2, a negative Paco2-EtCO2 difference was observed among many of our Paco2-EtCO2 pairs. It is possible that this negative difference resulted from the accumulation of exhaled CO2 in ventilation circuitry prior to EtCO2 measurement or poor equipment calibration, but most likely it was due to our method of aligning Paco2-EtCO2 pairs during a period of up to 30 minutes, thus allowing the potential for intervening changes in patients’ clinical conditions to result in recorded peaks in EtCO2 values being paired with recorded dips in Paco2 values.Anatomic and physiologic dead space results in Pa22 It is thus reasonable to expect that many critically injured children with TBI, especially those with PARDS or other pulmonary pathologic characteristics, may have an elevated alveolar dead space fraction and thus lower Paco2-EtCO2 agreement. This study identified PARDS as an independent factor associated with a lower likelihood of Paco2-EtCO2 agreement, which provides new information on the utility of capnography among children with TBI with concurrent lung disease. These data also demonstrated that, for patients who had not received a diagnosis of PARDS during the first 24 hours of PICU admission, Paco2-EtCO2 differences were still greater among those who developed PARDS after the first 24 hours of admission compared with those who never developed PARDS, suggesting that patients may have had a ventilation-perfusion mismatch and worsening dead space fraction before meeting the full criteria for PARDS. Future work is needed to further evaluate Paco2-EtCO2 agreement as a potential early indicator of PARDS development in pediatric TBI.We specifically examined PARDS because children hospitalized with TBI are at risk for PARDS owing to a variety of factors, including intracranial hypertension, severe systemic inflammation, direct traumatic lung injury, and secondary lung injury from aspiration or pneumonia.2 measurements in TBI, this study provides new evidence to fill this knowledge and practice gap. Our data show that, despite the relatively constant mean Paco2-EtCO2 difference and despite the moderate agreement correlation during the first 24 hours of PICU admission, there was even larger variability in the Paco2-EtCO2 difference in the first 8 hours of PICU admission compared with the subsequent 16 hours. Therefore, in addition to the overall observation that Paco2-EtCO2 agreement was low in the first 24 hours after TBI and in the presence of PARDS with large and variable alveolar dead space, EtCO2 may be even more unreliable as a surrogate for Paco2 during the first 8 hours after TBI. Therefore, serial Paco2 measurements during the first 24 hours of admission should still be considered the optimal modality to monitor CO2 levels, especially when ongoing resuscitation may be needed and optimizing cerebral perfusion is critical. Given the focus on prevention of prophylactic hypocarbia in severe pediatric TBI, these findings suggest a need for the Brain Trauma Foundation guidelines to address arterial measurements for Paco2.Because neither the Trauma Quality Improvement Program nor the Brain Trauma Foundation guidelines address the utility of EtCOco2-EtCO2 agreement and hypotension with temporal vicinity, inclusion of PARDS diagnosis as an explanatory variable based on laboratory and clinical information, and a comprehensive description of age subgroups. These methodical strengths enabled us to examine in greater detail the association of Paco2-EtCO2 agreement with hypotension and PARDS. In addition, compared with using severe chest trauma to investigate the association of respiratory disorders with Paco2-EtCO2 agreement, the use of the PARDS diagnosis provided more specific information regarding oxygenation dysfunction and resultant ventilation-perfusion mismatch. To our knowledge, this is the first analysis to effectively obtain timely data on blood pressure and PARDS diagnosis and to use them to examine Paco2-EtCO2 agreement.This study has several strengths, such as a relatively large sample size, a priori analytic framework, use of age-specific definitions of hypotension, examination of the association between Pa2 data points were recorded within 10 minutes of Paco2 measurement, some paired data points had a time gap of up to 30 minutes, which may have reduced the precision of our findings. We did not examine data beyond 24 hours. Despite using fixed-effects multivariable regression models and an a priori analytic framework, we cannot exclude residual confounding that could not be captured by measurable variables.We acknowledge the study limitations. Our findings might not be fully generalizable because the data are from a single level I trauma center and the excluded patients who did not have paired data points differed in several clinical characteristics. Although more than 40% of EtCOco2-EtCO2 agreement is below 50%, especially in the presence of PARDS. Agreement is worst in the first 8 hours after PICU admission, and poor Paco2-EtCO2 agreement early in hospitalization may be associated with future development of PARDS. End-tidal CO2 data should not be a substitute for Paco2 data during the first 24 hours.In children hospitalized with TBI, Pa


We hypothesized that the cardiovascular responses to Surviving Sepsis Guidelines (SSG)-defined resuscitation are predictable based on the cardiovascular state.dyn), arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees), Ees/Ea (VAC), LV ejection efficiency (LVeff), mean systemic pressure analogue (Pmsa), venous return pressure gradient (Pvr), and cardiac performance (Eh), using standard formulae.Fifty-five septic patients treated by SSG were studied before and after volume expansion (VE), and if needed norepinephrine (NE) and dobutamine. We measured mean arterial pressure (MAP), cardiac index (CI), and right atrial pressure (Pra) and calculated pulse pressure and stroke volume variation (PPV and SVV), dynamic arterial elastance (Ea−1), with increased lactate levels (lactate = 5.0 ± 4.2 mmol L−1) with a worsened VAC. CI was variable but > 2 L min−1 M−2 in 74%. Twenty-eight-day mortality was 48% and associated with admission lactate, blood urea nitrogen (BUN), and creatinine levels but not cardiovascular state. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Fluid administration improved Pra, Pmsa, and Pvr in all patients, whereas both HR and Ea decreased after VE, thus normalizing VAC. CI increases were proportional to baseline PPV and SVV. CI increases proportionally decreased PPV and SVV. VE increased MAP > 65 mmHg in 35/55 patients. MAP responders had higher PPV, SVV, and Eadyn than non-responders. NE was given to 20/55 patients in septic shock, but increased MAP > 65 mmHg in only 12. NE increased Ea, Eadyn, Pra, Pmsa, and VAC while decreasing HR, PPV, SVV, and LVeff. MAP responders had higher pre-NE Ees and lower VAC. Dobutamine was given to 6/8 patients who remained hypotensive following NE. It increased Ees, MAP, CI, and LVeff, while decreasing HR, Pra, and VAC. At all times and all steps of the protocol, CI changes were proportional to Pvr changes independent of treatment.All patients were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beat minThe cardiovascular response to SSG-based resuscitation is highly heterogeneous but predictable from pre-treatment measures of cardiovascular state.The online version of this article (10.1186/s13054-019-2414-9) contains supplementary material, which is available to authorized users. Human sepsis is the result of a complex pathological process characterized by an infection-induced generalized intravascular inflammatory state causing marked dysregulation of cardiovascular adaptive responses , 2. Initdyn), predicts the blood pressure response to changing cardiac output [We and others have documented the ability to estimate at the bedside of patients in septic shock mean systemic pressure (Pms) , left vec output  or decrec output . Thus, bAlthough these powerful methods have been used separately to assess selected cardiovascular aspects of septic shock resuscitation, their combined analysis during protocolized resuscitation steps in septic patients is lacking. Thus, we analyzed the cardiovascular effects of standardized SSG resuscitation protocol  in septi−1). All patients who became stable signed informed consent, whereas those who never regained consciousness did not sign the consent but, as allowed by EEC rules, were still included in the analysis. We excluded patients < 18 years of age and those patients with known significant mitral valve regurgitation and aortic valve or aortic pathologies because the arterial pressure signal was to be used to estimate CO.After ethical committee for human experimentation approval of both institutions, we enrolled 55 septic patients treated according to SSG . Entry c−1 min−1, and then inotropic support with dobutamine was titrated between 5 and 15 μg kg−1 min−1, if evidence of hypotension and organ hypoperfusion persisted following NE, with all treatments given within < 5 h after enrollment. We limit norepinephrine to 1 μg kg−1 min−1 to minimize the deleterious effects of high-dose vasopressors. All resuscitation decisions were made by the attending physicians. All patients had blood samples, appropriate body fluid, and other appropriate source cultures taken and received broad-spectrum antibiotics within 2 h of presentation and required mechanical ventilation. Prior to the initiation of the initial 30 mL kg−1 fluid bolus, we estimate that patients received between 250 and 500 mL 0.9 N NaCl during the initial instrumentation.Initial cardiovascular management included sequential VE with 30 mL/kg 0.9 N NaCl within < 3 h of enrollment, followed by norepinephrine infusion (NE), if needed to achieve an initial MAP > 65 mmHg following VE, titrated between 0.01 and 1 μg kg−1 ideal body weight with a positive end-expiratory pressure/FiO2 ratio as defined by ARDSnet guidelines [2 between 32 and 35 mmHg.Patients were instrumented with a central venous catheter, to infuse fluids and drugs and to measure Pra, a radial artery catheter to monitor MAP, to measure systolic arterial pressure, and by uncalibrated pulse contour analyses  to continuously estimate CI, LV stroke volume, SVV, and PPV. Transthoracic echocardiography (TTE) was performed upon admission and then after each therapeutic intervention, if needed. Transesophageal echocardiography was used when TTE did not give sufficient images to assess cardiac function. Echocardiographic estimates of CO were used to assess the accuracy of the Mostcare® CO measures across treatments. Electrocardiograph (lead 2) RR intervals defined heart rate (HR) and peripheral pulse oximetry pulse oxygen saturation. Controlled mechanical ventilation was at a tidal volume of 6–8 mg kgidelines . RespiraDerived hemodynamic parameters were calculated using standard formulae as illustrated in Fig. t test and Wilcoxon ranked sign test were carried out to assess differences induced by interventions. Independent sample t test for normally distributed data and Mann-Whitney U test for nonparametric measurements were used to test differences between variables grouped by MAP restored (> 65 mmHg), MAP increased, and CI increased at ≥ 15%. Pearson’s correlation analysis was used to find correlation between normally distributed data, Spearman’s correlation was used for nonparametric data, and chi-square test was used to find correlation between categorical data. Receiver operating characteristic analysis was used to test sensitivity and specificity of hemodynamic variables in predicting changes in categorical endpoints. Statistical studies were two-tailed, and p value of less than 0.05 was considered significant. Analyses were performed using SPSS . Unless otherwise stated, data are presented as mean ± SD.To obtain a statistical power of 0.8 with alpha 0.5 and 95% confidence intervals for the first enrollment were calculated a priori that we would need 42 patients . Thus, w−1), with elevated lactate levels (lactate 5.0 ± 4.2) and had an increase in Ea relative to Ees consistent with ventriculo-arterial uncoupling. CI was variable, but in 74%, CI was > 2 L min−1 M−2. The mean admission SOFA score was 16.1, and the 30-day mortality rate was 47%. Thirty-day mortality was associated with higher admission lactate, BUN, and creatinine levels, but not with any other measured or derived hemodynamic variables. Specifically, 35 patients resolved their hypotension with VE alone but retained a 44% 30-day mortality rate, whereas those in septic shock had a 52% 30-day mortality rate of which was not significantly different. Additional file Patient features on admission are described in Table Table dyn values . CI responders > 15%  had higher pre-NE Ees and Ea values and lower HR than the MAP non-responders . Four of the 6 patients increased CO > 15%, and in those patients, Ees improved more than in the other 2 CO non-responders  that reported only two thirds of patients being volume responders [dyn predicted the associated change in MAP in response to changing CO. [dyn, suggesting that fluid resuscitation based on these dynamic measures may result in more efficient fluid resuscitation by giving less fluid to non-responders. Several patients did not increase the CO in response to VE. Non-responders may become volume overloaded, with its associated increase morbidity [First, that in most patients, VE restores MAP to > 65 mmHg while simultaneously increasing CO, Ees, and Pmsa, resulting in an improved VAC, LVeff, and Eh. Presumably, the increasing MAP improved coronary perfusion increasing Ees. Although Ees is a load-independent parameter of LV contractility, LV contractility is also improved by restoring coronary perfusion pressure, which occurred in these patients Figs.  and 4b. sponders . We enrosponders  and thatging CO.  We foundorbidity . These dorbidity .Second, NE increased Ea and MAP in most patients but did not achieve a MAP > 65 mmHg in a majority, consistent with prior studies of a variable response to norepinephrine in septic shock . The preThird, when dobutamine was added, VAC normalized while CO increased in all subjects. MAP simultaneously increased by a small but clinically significant amount Fig. a, d. TheFourth, at all times , changes in CO were proportional to changes in Pvr, independent of Pmsa changes Fig. . These dThe study has several limitations. First, we did not personalize resuscitation therapy but used a defined SSG resuscitation protocol. Still, our findings agree with previous studies on VE responders  and suppFrom the clinical perspective, several points become clear. First, it is impossible to know a priori if a septic patient who presents with hypotension fits the Sepsis-3 criteria for septic shock  without dyn) is useful to both predict the responses to therapy and understand the differences in hemodynamic response among septic shock patients during resuscitation.Initial fluid resuscitation based on SSG restores MAP and CI in most patients, while simultaneously restoring VAC and LVeff. However, individual patient responses vary widely. Similarly, the responses to NE in those persistently hypotensive or to subsequent dobutamine were also variable, but predictable based on their pre-treatment physiologic state. Finally, NE induced ventriculo-arterial decoupling which potentially may cause myocardial damage, if persistent. The bedside determination of Ea, Ees, and VAC plus dynamic parameters of volume responsiveness  and arterial tone Additional file 2:Table S1. Individual patient characteristics. (DOCX 13 kb)Additional file 3:Figure S1. Relation between individual values of cardiac output (CO) over steps in the protocol: baseline, volume expansion (VE), plus norepinephrine (+NE), and plus dobutamine. Figure S2. Relation between individual values of mean arterial pressure (MAP) over steps in the protocol: baseline, volume expansion (VE), plus norepinephrine (+NE), and plus dobutamine. Figure S3. Relation between individual values of left ventricular end-systolic elastance (Ees) over steps in the protocol: baseline, volume expansion (VE), plus norepinephrine (+NE), and plus dobutamine. Figure S4. Relation between individual values of arterial elastance (Ea) over steps in the protocol: baseline, volume expansion (VE), plus norepinephrine (+NE), and plus dobutamine. Figure S5. Relation between individual values of mean systemic pressure analogue (Pmsa) over steps in the protocol: baseline, volume expansion (VE), plus norepinephrine (+NE), and plus dobutamine. Figure S6. Relation between individual values of ventriculo-arterial coupling (VAC) from baseline to volume expansion (VE) to plus norepinephrine (+NE) with mean ± SD for each step shown in blue. Values above 1.35 reflect uncoupling and values below 1.35 reflect normal VAC. Figure S7. Baseline to Volume Expansion relation between change in CO (DCO) and either pre-volume expansion pulse pressure variation (PPV) or dynamic arterial elastance (Eadyn). These data relate to the receiver operating characteristic results in Fig. Figure S8. Baseline to volume expansion relation between change in mean arterial pressure (DMAP) and either pre-volume expansion pulse pressure variation (PPV) or dynamic arterial elastance (Eadyn). These data relate to the receiver operating characteristic results in Fig. Figure S9. Volume Expansion to Norepinephrine relation between change in mean arterial pressure (DMAP) and either pre-norepinephrine arterial elastance (Ea) or dynamic arterial elastance (Eadyn). These data relate to the receiver operating characteristic results in Fig.


The aim of this study is to assess maternal cardiac function in the postpartum period, after 2 and 6 months in the parturient with preeclampsia and eclampsia. Prospective study: 90 postpartum women after preeclampsia and eclampsia and 55 patients after an uncomplicated pregnancy. The parameters of maternal hemodynamics were recorded on days 1, 3, 5, 9, and 14 of postpartum period, after 2 and 6 months. The cardiac parameters were assessed. PE is accompanied by increased peripheral vascular resistance. The indicator of vascular resistance, SVR, is elevated for both mild and severe PE. With mild PE, a significant increase in SVR is observed up to 5 days of postpartum period, with severe PE/E up to 9 days. We found that in case of severe PE, SVR remains elevated to 6 months after delivery. The parameters of the contractile function of the heart  were significantly decreased: with mild PE up to 5-9 days, with severe up to 9-14 days of puerperia. ESV, SV, SI, CO, and CI remain low with severe PE up to 6 months. The revealed decreasing of contractile function of the heart is a sign of asymptomatic heart failure. The hemodynamics of the puerperas after PE and E is characterized by impaired contractility of the myocardium and an increase in the indices of peripheral resistance. The degree of deviation in the parameters of cardiac hemodynamics and vascular resistance depended on the severity of hypertensive complications of pregnancy. Understanding the main features of maternal hemodynamics in normal pregnancy as well as in various obstetric pathologies is the basis for prediction of pregnancy complications, perinatal outcomes and choosing the right treatment of pregnancy disorders.Hypertensive disorders during pregnancy are present in about 10% of pregnant women, with preeclampsia being seen in 2-8% of all pregnancies [Every year more than 50,000 women worldwide die during pregnancy due to complications associated with hypertension. In developed countries, arterial hypertension and preeclampsia are the second direct cause of ante- and postnatal mortality due to preterm delivery .Hypertensive disorders take the 4th place in the list of causes of maternal mortality in the last decade . MoreoveHowever, with proper management majority of adverse outcomes are preventable. Severe hypertensive disorders during pregnancy can also reduce postpartum quality of life for women often leading to increased frequency of chronic hypertension, diabetes mellitus, myocardial infarction, and stroke, as well as increase frequency of impaired physical and psychosomatic development of premature infants which in turn can lead to significant social and health issues –19.The evidence is now clear that preeclampsia is associated with higher risk of developing cardiovascular disease later in life , 18, 19.The objective of this study is to assess maternal cardiac function immediately in the postpartum period, and also after 2 and 6 months, in the parturients who were diagnosed with preeclampsia and eclampsia.The part of the study was presented as a poster at 25th World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI) Vienna, Austria, November 30–December 2nd, 2017.This is a prospective observational case-control study done between 2012 and 2015. The study included only women with singleton pregnancies.Preeclampsia was defined as the new onset of hypertension and proteinuria in human pregnancy after the 20th week of gestation [Diagnostic Criteria for Preeclampsia. Preeclampsia is diagnosed when systolic blood pressure is greater than or equal to 140 mm Hg or diastolic blood pressure is greater than or equal to 90 mm Hg on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure and proteinuria with excretion of 300 mg or more of protein per 24-hour urine collection (or this amount extrapolated from a timed collection) or protein/creatinine ratio greater than or equal to 0.3 (each measured as mg/dl) (Dipstick reading of 1+ can be used only if other quantitative methods are not available). We consider all patients meeting criteria of preeclampsia have mild preeclampsia (without severe features). If any features of severe preeclampsia are registered at any gestational age, we consider these patients to have severe preeclampsia.Severe Features of Preeclampsia (Any of These Findings)Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher on two occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive therapy is initiated before this time)Thrombocytopenia Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes , severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or bothProgressive renal insufficiency Pulmonary edemaNew-onset cerebral or visual disturbancesAll patients with mild and severe preeclampsia in the postpartum period were under intensive care for 2-4 days, where they were treated with a complex therapy based on current international guidelines for the treatment of preeclampsia and eclampsia.The survey was conducted on days 1, 3, 5, 9, and 14 of postpartum period, as well as after 2 and 6 months after delivery. We included only those cases that could be traced throughout the entire study period after delivery.We measured cardiovascular parameters noninvasively by echocardiography.Exclusion criteria included chronic diseases of the cardiovascular system and kidneys. Women with medical comorbidities, smokers, on medication, or with fetal abnormalities were excluded from recruitment in the study.The study was conducted using an ultrasound diagnostic system Accuvix-A30 Samsung Medison company. Phased probe 2-4 MHz was used to perform echocardiography.The following indicators were assessed by echocardiography: end-systolic volume (ESV), end-diastolic (EDV), stroke volume (SV), cardiac output (CO), stroke index (SI), cardiac index (CI), mean velocity of circumferential fiber shortening (MVCF), heart rate (HR), mean blood pressure (MBP), and systemic vascular resistance (SVR).Echocardiography was performed by one investigator. All conventional echocardiographic indices were adjusted for body surface area.Data sets were analyzed and are presented as means ± SD. For comparison of data, sets were tested for normal distribution (Shapiro-Wilk test). To compare outcome parameters between groups of healthy and pathologic pregnancies, an analysis of variance was performed. The Pearson correlation coefficient was calculated to analyze relationships. Time points were compared pair-wise with a Sidak correction for the significance level due to the multiple comparisons applied herein.P values (two-sided) lower than 0.05 were considered statistically significant. Statistical analysis was performed with SPSS 21 .All women provided informed consent and the study was approved by the local review committee (Reference number 5-12).After providing written informed concerns, a total of 145 women were included in this study.In order to study the maternal cardiac function after labor, we examined 55 patients after an uncomplicated pregnancy (control group) and 90 postpartum women with mild and severe preeclampsia and eclampsia (main group) at any gestational age.Demographic and pregnancy characteristics in the cohorts of patients are presented in The maternal age of healthy women of control group was 24,8 ±3,08 year. Pregnancy in all patients was uneventful and ended with term delivery at 38-40 weeks. The average gestation period at the time of birth was 39,4± 0,75 weeks.Cesarean section deliveries were performed for indications not related to hypertensive disorders for all patients in the control group.Blood loss after caesarean section was 610 ± 75.8 ml. All infants had Apgar scores of 8-9 points.The average weight of children at birth was 3445 ± 405,8 with individual variations from 2800 g to 4400 g; newborn height was 51,43±2,75 cm, with individual variations from 49 cm to 56 cm.The average age of patients in the main group was 26,7 ± 1,6 years. Nulliparous women represented 61 (67.8%), multiparous 29 (32.2%). It should be noted that 20 (68.9%) of the 29 multiparous women had previous pregnancy complicated by preeclampsia.In the analysis of somatic anamnesis of women in the main group, it was found that 22 (24.5%)of patients had extragenital pathology. Diseases of the digestive system were observed in 17 (18.9%) postpartum women with preeclampsia, infections of the upper respiratory tract in 31 (34.4%), overweight in 7 (7.8%), and eye diseases 13 (14.4%).There were no significant differences in somatic anamnesis among control, the main group.43.3% (39) of the women were found to have mild preeclampsia, 52.2% (47) severe preeclampsia, and 4.4% (4) eclampsia. It should be noted that during pregnancy eclampsia occurred in 3 (3.3%) of women, and during the first 48 hours of postpartum period in 1 patient.In the main group, gestational age at the time of delivery ranges from 26 to 39 weeks . Early oAll patients had to be delivered by caesarean section due to severe preeclampsia, or combination of mild preeclampsia and progressive fetal distress.Blood loss after caesarean section in main group was 622 ± 63.3 ml.In the main group a total of 88 children were born with 2 fetus dead prenatally and 3 infants who died in the early neonatal period. Thus, the overall perinatal loss was 5 -5.6%.It should be noted that all cases of perinatal death were seen with severe preeclampsia and eclampsia and accompanied by severe fetal growth retardation (below the 10th percentile) and very preterm cesarean labor. The average weight of the newborn, including stillbirths, was in the group with a mild preeclampsia 2747,6± 320,6 g, with a severe - 1912,2 ±236,2 g .Parameters of cardiac hemodynamics in women after an uncomplicated pregnancy as well as patients with mild and severe preeclampsia are presented in Comparing the volume of central hemodynamic parameters showed a significant  increase in EDV on the 3rd day after the birth of 11.9% with no significant change  of ESV. At the same time, there is an increase in the SV and CO by 21.3% and 24.7%, respectively.Due to dependence of indicators of cardiac hemodynamics on constitutional features of the subjects, as well as decrease in woman's weight after labor, we calculated CI  and SI.2, CI 3,72± 0,19 l/min/m2.Conversion of SV and CO per unit body surface area also confirmed that on the 3rd day of postpartum period occurs a significant  increase in SI and CI by 18.9% and 21.6%, respectively. In this case the maximum values of SI are 46,34 ±2,01 ml/mSubsequently, the average values of ESV, EDV, SI, and CI gradually declined. We did not observe any changes in the cardiac parameters after 2 and 6 months postpartum. The average values of SVR declined on 3rd day after delivery by 11.6% and then increased by the end of the second week postpartum period by 26.1%.Thus, after turning off the uteroplacental blood flow and reducing blood volume in the circulatory system, puerperal patients develop compensatory-adaptive reactions, which are characterized by an increase of cardiac indicators of maternal hemodynamics and reducing systemic vascular resistance.In order to identify the typical changes in cardiac hemodynamics after mild and severe preeclampsia we examined 90 patients on days 1, 3, 5, 9, and 14, 2 and 6 months after delivery.At 43.3% (39) of the women were diagnosed mild PE, 52.2% (47) severe PE, 4.4% (4) eclampsia.Our studies have shown that women with mild and severe of preeclampsia have disorders of the cardiac function, manifested in significantly lower values of volume indicators and the contractility of the myocardium with increase in mean blood pressure and systemic vascular resistance.PE is accompanied by increased peripheral vascular resistance. According to our data, the indicator of vascular resistance, SVR, is elevated for both mild and severe PE.With mild PE, a significant increase in SVR is observed up to 5 days of postpartum period, with severe PE/E up to 9 days. The absolute values of SVR with mild PE were 1422.31 ± 117, 08 dyn • s • cm-5, with severe PE 1702.31 ± 127.08 dyn • s • cm-5 .We found that in case of severe PE, SVR remains elevated to 6 months after delivery (p> 0.05).The parameters of the contractile function of the heart  were significantly decreased in the postpartum period in the patients of the main group (p <0.05): with mild PE up to 5-9 days and with severe up to 9-14 days of puerperia .ESV, SV, SI, CO, and CI remain low with severe PE up to 6 months (p> 0.05).The revealed decreasing of contractile function of the heart is a sign of asymptomatic heart failure.Our data shows that maternal hemodynamics in the puerperium in healthy women and patients with preeclampsia are significantly different.The results of our echocardiographic study of healthy postpartum women that were delivered by cesarean section according to indications not related to hypertensive disorders reveal a significant increasing of EDV, SV, and SI on day 3 after delivery by 18.9%, 9%, and 21.6% respectively and decreasing of SVR, compared with the same indicators in the first day postpartum.In addition, there is an increase in the rate of MVCF, indicating an adequate cardiac pumping function in the setting of increased EDV.Further, due to the decrease in the volume of circulating blood and the total vascular volume, we demonstrated gradual decrease in the main cardiac indices and an increase in the SVR.This is consistent with earlier studies , where aIn the study of hemodynamic profiles in patients with mild and severe forms of preeclampsia, we demonstrate significantly (P <0.05) lower values of EDV, SV, and SI and elevated SVR values in the first 24 hours after delivery.We demonstrated that a decrease in volume indices of cardiac function correlates with the severity of preeclampsia. In addition, after severe preeclampsia, increased ESV values and reduced MVCF parameters indicate decrease in the contractility of the myocardium.This does not conflict with the data of several authors , 13, 17 The important study was conducted by T. Ghi et al. : echocarGhossein-Doha C. et al.  found thWe demonstrated that disorders of hemodynamics in the puerperium are observed in almost all patients with mild to severe preeclampsia and manifested by dissociation between the SV and SVR, indicating reduced compensation of circulatory system.According to our data, recovery of hemodynamic parameters in the postpartum period directly depends on the severity of preeclampsia.Orabona R. et al.  also demMurphy MS. et al.  found thTihtonen K. et al.  also revBellamy L. et al.  demonstrThese data are consistent with our findings that patients with preeclampsia are at high risk of the development of cardiovascular complications in the long term.Hemodynamics of women whose pregnancies were complicated by PE/E has significant differences from hemodynamics of postpartum women that were delivered by cesarean section due to indications not related to hypertensive disorders. The major issue is impaired contractility of the myocardium and increased values of peripheral vascular resistance. The degree of deviation in the parameters of cardiac hemodynamics and vascular resistance depends on the severity of hypertensive disorder of pregnancy.Thus, patients after PE/E are at high risk of long-term cardiovascular disease, requiring cardiologic follow-up and tight control of blood pressure.When planning a subsequent pregnancy, we recommend assessing cardiac function, tight blood pressure control, and administration of antihypertensive therapy to achieve it.