Continuity of care (COC) has a proven relationship with health care outcomes. However, evidence regarding an association between COC and avoidable hospitalization for elderly patients with asthma is insufficient.A retrospective cohort study was performed using Taiwanese National Health Insurance claim data from 2004 to 2013. Patients were retrospectively followed for 2 years; the COC index (COCI) for asthma was measured in the 1st year, and avoidable hospitalization for asthma and follow-up time were determined in the subsequent year. Cox proportional hazards regression was employed to examine hazard ratios (HRs) between COC and avoidable hospitalization for asthma after adjustment for confounding factors. Adjusted HR (aHR) was also calculated by stratifying each variable to investigate whether the effect of COC on hospitalization for asthma was avoidable and how this varied across levels of COCI.Of 3356 patients included in this study, 1648 patients (49%) had a COCI of 1, and the average COCI was 0.73. Compared with patients with high COC (COCI = 1), those with low COC (COCI < 0.5) had a significantly higher risk of avoidable hospitalization for asthma . In addition, after stratified analysis, we determined that COC plays a much more important role for patients who were women, had low insurance premiums, and had no comorbidities.High continuity of ambulatory asthma care is linked to a reduced risk of avoidable hospitalization for asthma in elderly asthmatic patients. In addition, asthmatic patients spent much more medical expenditures than patients without asthma. Continuity of care (COC) is a core element of primary care,,5 and it represents an ongoing therapeutic relationship between a patient and care provider that is characterized by trust and responsibility.,7 The stronger the ongoing physician–patient relationship is during the treatment of chronic diseases, the higher is the likelihood of reducing risks of unnecessary hospitalization,–12 emergency department (ED) visits,–16 and health care costs. Because of the disease characteristics of asthma, previous studies have often highlighted the effect of COC on asthmatic children or adolescents.,15,18 The findings of these studies have shown that implementing higher levels of COC would result in a lowered prevalence of hospitalization for asthma. Investigating whether these findings could be applied to older patients with asthma is warranted. To our knowledge, only 1 Korean study has been conducted involving COC in asthmatic elderly patients, and this study reported that elderly asthmatic patients aged 65 to 84 years had lower risks of hospitalization, ED visits, and care expenses if the associated COC was improved.Asthma is a common chronic respiratory disease,,21 Therefore, such conditions are also referred to as “preventable hospitalization” or “avoidable hospitalization.”,23 Also, this concept corresponds to quality, accessibility, and performance of ambulatory care in the healthcare system.,24 Although several previous studies have examined the relationship between COC and avoidable hospitalization,,10,12,25 there is currently no empirical evidence on the relationship between COC and avoidable hospitalization for asthma among older asthmatic patients. The aim of this study is to investigate the relationship between COC and the risk of subsequent hospitalization for elderly patients with asthma by using the population-based database of the Taiwanese National Health Insurance (NHI) system.Ambulatory care-sensitive conditions (ACSCs) are conditions for which satisfactory outpatient care can potentially reduce the risk of subsequent hospitalization.22.1Taiwan's NHI program was launched in March 1995. It provides universal, compulsory, and nationally administered health insurance that enhances the public's accessibility to health care services, and the program currently includes over 99% of the Taiwanese population. The database stores unique encrypted identification for each patient, in addition to the patient's sex, date of birth, medical professional consulted, and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for each medical encounter. Data accuracy and information pertaining to patient diagnosis, as retrieved from the database, were previously validated. The protocol for this study was approved by the Institutional Review Board of the National Yang-Ming University of Taiwan .To identify the study population, a retrospective cohort study was conducted using the Longitudinal Health Insurance Database 2010 (LHID2010) maintained by the National Health Research Institute in Taiwan. The database consists of 25 sets of 40,000 people randomly selected from the entire population of NHI enrollees; in 2010, the total sample comprised approximately 1 million beneficiaries. No significant differences exist in the distribution of beneficiaries’ basic characteristics, such as age and sex, between this dataset and the entire population in 2010.2.2In this study, patients aged 65 years or older diagnosed with asthma (ICD-9-CM codes 493.xx) between January 1, 2005 and December 31, 2011 were identified from the database. Patients associated with at least 2 ambulatory visits, or at least 1 asthma-related hospital admission, were eligible for inclusion.,28; or less than 4 outpatient visits during the COC period (n = 4452), because a small number of visits caused unstable COC index (COCI) estimates.,28,29The earliest date of diagnosis was defined as the index date. Exclusion criteria for the patients are outlined as follows: withdrawal from the NHI program during the study period (n = 326); having experienced inpatient asthma care prior to, or during the COC period (n = 39), because the process of continuity of ambulatory care could be impacted by the experience of hospitalization all patients (n = 3356) were followed for 2 years after the index date. The first year was denoted as the COC period and the subsequent year the outcome period . Therefore, in this study, avoidable hospitalization was defined as an event that occurred during the outcome period. The follow-up time was defined as the number of days from the date of the end of the COC period to the occurrence of the avoidable hospitalization for asthma. However, if no avoidable hospitalization for asthma occurred, the patient was censored at the end of the outcome period.The Agency for Healthcare Research and Quality provided a definition for prevention quality indicators,2.3.2 The COCI has been widely adopted in studies based on health care claim databases,,15,19,25 because it is less sensitive to the number of physician visits and is suitable for application to a large amount of outpatient visit data.The COCI score, used as the independent variable, was measured during the COC period. The score ranges from 0 to 1  and measures the dispersion of contact between patient and physician.The general formula is i is the number of visits to the ith physician, and k is the total number of physicians. In this study, the total number of physician visits (N) and the number of visits to a given physician (ni) included ambulatory claims for asthma as the major diagnosis. The patients were categorized into three groups based on the first and third quartile value of COCI as follows: low, medium, and high.,29where N is the total number of physician visits, n2.3.3,33,34 age,,33,34 and insurance premium , which was used as a proxy indicator of income status. Second, the variables measured in the year prior to the index date included chronic obstructive pulmonary disease (COPD) , pulmonary-related diseases , diabetes mellitus (DM) (ICD-9-CM code 250), the Charlson comorbidity index (CCI), and the number of asthma-related ED visits. The CCI and number of asthma-related ED visits were used as proxy indicators of health status and disease severity. The CCI score contains 17 categories of comorbid conditions defined by ICD-9-CM codes, and it is calculated according to enhanced ICD-9-CM coding algorithms. Third, because patients’ health status during the COC period also may impact the outcome, the number of asthma-related ambulatory visits was used as a proxy for patients’ health status.,19Confounding factors were identified in 3 mutually exclusive periods. First, variables measured on the index date were sex,2.3.4In this study, descriptive statistical analysis was used to present the distribution of patient characteristics. In addition, chi-squared tests and one-way analysis of variance were used to analyze associations between patient characteristics and COC. With the valid proportional hazard assumption (P = 0.7921), the Cox regression model was applied to examine the association between COC levels and the risk of avoidable hospitalization for asthma among elderly patients. Multivariate analysis was used to calculate adjusted hazard ratios (aHRs) by adjusting for sex, age, insurance premium, COPD, pulmonary-related diseases, DM, CCI, number of asthma-related ED visits, and number of asthma-related ambulatory visits. The variance inflation factor (VIF) is used to detect the presence of multicollinearity; a value greater than 10 indicates the severity of multicollinearity in the regression model. In our model, no multicollinearity was represented by a VIF of less than 5 in each variable. The aHR stratified by each variable was then calculated to investigate the effect of COC levels on the extent to which avoidable hospitalization for asthma.The Cox regression model assumes that the ratio of the hazards of two subjects is the same at all times; in this study, the scaled Schoenfeld residual was used to test whether this assumption was valid.P values of less than 0.05 were considered to be statistically significant in this study. All statistical analyses and data management were conducted using SAS software version 9.4 .Two-sided criteria with 3P < 0.05). Regarding avoidable hospitalization use during the outcome period, the percentage of patients who had avoidable hospitalization for asthma was 1.3% in the high COC group, 2.4% in the medium group, and 4.0% in the low COC group; therefore, the differences were statistically significant (P < 0.001).The average COCI of patients was 0.73 ± 0.30 (data not shown in the table). Of 3356 patients, 1648 (49.0%) were in the high COC group (COCI = 1), 851 (25.4%) in the medium COC group (COCI = 0.5–0.99), and 857 (25.7%) in the low COC group (COCI < 0.5). The characteristics of all patients and of each COC group are shown in Table The results of Cox proportional regression are presented in Table P < 0.01), patients aged 65 to 74 years , patients aged ≥75 years , patients with an insurance premium <20,000 NTD , patients with an insurance premium 20,000 to 40,000 NTD , patients with no COPD history , patients without any other pulmonary-related diseases , patients with no DM , patients with a CCI score of zero , and patients with 4 to 12 ambulatory visits .Table 4 have higher COC scores (average COCI = 0.68) than do those in the United States (average COCI = 0.39) and Canada (average COCI = 0.26).The data suggest that elderly asthmatic patients in Taiwan have a high continuity of ambulatory asthma care. The average COCI was 0.73 for elderly asthmatic patients, and half of patients received ambulatory asthma care from a single physician in the first observational year. The high COC score in Taiwan could be attributed to several factors. The Taiwanese government implemented an asthma pay-for-performance (P4P) program in 2001, with the aim of encouraging health care agencies to provide improved disease management for patients with asthma. Previous studies have demonstrated that asthmatic children in Taiwan and aging adults. The continuity of treating asthmatic children with inhaled medicine provides safe and effective long-term disease management for asthma.,42 Previous studies have suggested that superior COC was associated with lower hospitalization and ED use among children with asthma.,15,18 Although the effect of COC may vary between different populations, our findings support that the effect of COC is also effective in reducing avoidable hospitalization for asthma for elderly populations.Asthma is the most common respiratory disease among children who investigated the effect of COC in older patients in South Korea and identified an inverse association between COC and the risk of hospitalization for asthma for older patients. Their study calculated the COCI by using medical institution units and focused on 4 different chronic diseases  among elderly patients. Their findings suggested that improved COC is associated with fewer hospital admissions for patients with asthma, and that it is more effective than in other diseases.Our findings support those of Hong et al,10,33,43 have reported that patients with superior COC had a lower risk of avoidable hospitalization. However, the effect of COC on health outcomes could be confounded when a study includes several diseases. Therefore, recent studies have focused on a single disease to clarify the association between COC and health outcomes. For example, Huang et al focused on an asthmatic children population and identified a significantly positive effect of COC in reducing asthma-related ED use. Hussey et al focused on Medicare beneficiaries with congestive heart failure, COPD, or diabetes and demonstrated that superior COC was significantly associated with lower odds of hospitalization for each of the 3 chronic conditions. Lin et al indicated that a high COC was associated with a lowered risk of COPD-related avoidable hospitalization among adults with COPD. Our study focused on elderly patients with asthma also found a significantly inverse relationship between COC levels and the risk of avoidable hospitalization for asthma. Therefore, we suggest that older asthmatic patients with low COC should endeavor to develop an ongoing relationship with a single physician to reduce the risk of avoidable hospitalization for asthma.Many previous studies calculating COC for all diseases and socioeconomic status (SES) was found to be adversely associated with avoidable hospitalization. Furthermore, the possibility of older asthma patients receiving care from other physicians was low because patients with no other comorbidities might only contact a physician when suffering an asthma attack. As a result, these patients may benefit from improving their own COC.In terms of a stratified analysis of each variable, the data suggest that COC plays a much more important role for older asthmatic patients who were women, had low insurance premiums, and had no comorbidities. In studies focused on elderly people, the rates of avoidable hospitalization for women were found to be higher, Therefore, we suggest that governments consider designing financial incentives for patients and physicians to increase motivation, thereby improving COC. A randomized clinical study proposed that offering financial incentives for both health care providers and patients could generate superior care outcomes for patients.Our study demonstrates that COC plays a major role in the reduction of avoidable hospitalization for asthma among older asthmatic patients. The findings also support the fact that improving COC is favorable for both patients and the health care system.; however, claimed data in the study did not include results of clinical pulmonary function tests such as spirometry, lung volume, and diffusing capacity to define disease severity and health status.,51 In this study, we used asthma-related ED visits as a proxy for asthma severity and used CCI and frequency of ambulatory visits for asthma as proxy indicators of patients’ health status.,19 Second, we could not collect data regarding patient educational level or household income, which may also affect the care continuity and outcome measurements.,50 Nevertheless, we adopted information concerning patient insurance premiums as an SES indicator, as obtained from the claim database. Finally, our findings are related only to patients with more than 3 asthma-related outpatient visits per year.,17This study has some limitations. First, a previous study reported that asthma severity is associated with a higher risk of hospitalization,15,18 but also the health outcomes of elderly asthmatic patients. Third, we measured COCI at a physician level, which may provide superior information about the association between COC and avoidable hospitalization among elderly asthmatic patients than that obtained from measurements at the level of health care institutions. Fourth, we focused on a specific disease and used critical criteria to identify study subjects, which is more sensitive in identifying the relationship between COC and health outcomes,,44 thereby precisely determining the association between COC and avoidable hospitalization for asthma. Fifth, more than 99% of Taiwanese are enrolled in the compulsory NHI program; thus, the findings are highly representative of the whole population. Moreover, the nationwide administrative databases provide all clinical practices and decrease the effect of recall bias, thereby delivering superior results to those from national surveys, hospital-based data sets, or small area data sets. Finally, this study applied a longitudinal study design to follow all patients for 2 years and measured the condition of care continuity prior to the health care outcome. In addition, current study not only avoids the problem of cross-sectional design,,33 but also proposes stronger evidence of the association between COC and avoidable hospitalization for asthma.This study has several advantages. First, we found that the asthma P4P program might improve patients’ COCI under a universal insurance system. Second, COCI affects not only the health care outcomes of children or adolescents with proven asthma,5Our study shows that higher continuity of ambulatory asthma care for elderly asthmatic patients could reduce the risk of avoidable hospitalization for asthma. From a policy-making perspective, we recommend that policy makers create effective policies for older patients with asthma to strengthen the ongoing physician–patient relationship and improve disease-controlling ability.


The CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5–10.0% (48–86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure.CARMELINA2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease  and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common.Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug . At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.CARMELINATrial registration ClinicalTrials.gov identifier—NCT01897532; registered July 9, 2013The online version of this article (10.1186/s12933-018-0682-3) contains supplementary material, which is available to authorized users. People with type 2 diabetes (T2D) are at increased risk for both cardiovascular (CV) disease and microvascular complications such as chronic kidney disease (CKD) and kidney failure. In 2008, concerns about adverse CV events associated with the peroxisome proliferator-activated receptor agonists rosiglitazone  and muraApproximately 50% of patients with T2D globally also have some evidence of CKD , which iDipeptidyl peptidase-4 (DPP-4) inhibitors are now established as oral glucose-lowering drugs with little intrinsic risk of causing hypoglycemia or weight gain . The DPPLinagliptin is a DPP-4 inhibitor that is excreted predominantly by non-renal pathways, unlike most other members of this drug class, and thus can be prescribed to patients with T2D at a single dose irrespective of kidney function , 26. In ®) trial. Uniquely among the outcomes studies of glucose-lowering drugs initiated to date, the CARMELINA® trial was designed to recruit patients with T2D at high risk of both CV and kidney complications who had evidence of compromised kidney function with or without CV disease. We report here the study design and methods of CARMELINA® alongside the pooled baseline clinical characteristics of the patients in this trial.The CV and kidney clinical profile of linagliptin is being comprehensively evaluated in the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin   6.5–10.0% (48–86 mmol/mol) and body-mass index (BMI) ≤ 45 kg/m2 and/or the receipt of maintenance dialysis. Premenopausal women who were pregnant, nursing, or not practicing birth control were also excluded, as were individuals with active liver disease or impaired hepatic function , and those with prior or planned bariatric surgery. The full inclusion and exclusion criteria are shown in Additional file Individuals who had had an acute coronary syndrome in the 2 months prior to screening were ineligible, as were those who had had a stroke or transient ischemic attack in the 3 months before screening, and those who were scheduled to have percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) or had had PCI and/or CABG in the 2 months before screening. Also excluded were individuals with ESKD, defined as an estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease study equation (MDRD) of < 15 mL/min/1.73 mEligible individuals were randomized 1:1 via an interactive telephone/web-based system to receive once-daily oral treatment with linagliptin 5 mg (the licensed dose) or matching placebo in a double-blind manner Fig. . TreatmeThe use of additional medication for optimizing glycemic control according to local standard of care was encouraged throughout the trial independent of study treatment assignment, and included any approved glucose-lowering drugs except DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors. Dosing was required to adhere to local labelling and be in accordance with local/international guidelines. Intensification of glycemic control was advised for participants with fasting plasma glucose > 180 mg/dL (> 10.0 mmol/L) (confirmed by at least two measurements on different days) and those with HbA1c > 7.5% (> 58 mmol/mol). Investigators were also encouraged to treat all other CV risk factors  in accordance with optimal local or regional guidelines and standards of care. Ultimately, changes in medication were at the discretion of the investigator and/or treating clinician.® steering committee based on emerging evidence from other CV outcomes studies accumulated since study start indicating that 3P-MACE is the more suitable primary outcome for studies of glucose-lowering medications ), followed by South America (n = 2310 [33.1%]), North America (n = 1180 [16.9%]) and Asia (n = 657 [9.4%]).Recruitment of participants for the CARMELINA2, respectively, with mean duration of diabetes of 14.7 years (Table 2 (62%). Mean eGFR was 54.6 mL/min/1.73 m2, and 1063 (15%) participants had severe renal impairment (eGFR < 30 and > 15 mL/min/1.73 m2). Median UACR was 162 mg/g (25th–75th percentile: 44–727 mg/g); 1390 participants (20%) were normoalbuminuric (UACR < 30 mg/g), while the majority had either microalbuminuria  or macroalbuminuria . Mean systolic and diastolic blood pressure were 141 and 78 mmHg, respectively, and 95% of participants (6637) were taking antihypertensive medication. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers were being taken by 81% of the trial population, while 53% were taking diuretics.Pooled baseline characteristics of the participants are shown in Table Mean levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides were 2.4 mmol/L (91 mg/dL), 1.2 mmol/L (45 mg/dL), and 2.1 mmol/L (188 mg/dL), respectively. A total of 5010 (72%) and 4764 (68%) participants were taking statins and platelet aggregation inhibitors (excluding heparin), respectively. Almost all participants (n = 6802 [97%]) were taking glucose-lowering medication at baseline. Over half (n = 4039 [58%]) were taking insulin, while metformin was the most frequently used oral drug   had established CV disease with elevated UACR (≥ 30 mg/g) and 2268 (32.5%) had both conditions , had prevalent kidney disease at baseline, defined as eGFR < 60 mL/min/1.73 m® participants are considered at high risk (n = 1902 [27.2%]) or very high risk (n = 3033 [43.5%]) for adverse kidney events, on the basis of their eGFR and albuminuria status at baseline according to risk stratification by Kidney Disease: Improving Global Outcomes (KDIGO) foundation standards  for ad® trial comprises 6991 patients with T2D randomized to daily oral treatment with the DPP-4 inhibitor linagliptin or placebo on top of standard care. Baseline characteristics of the treated set (n = 6980) delineate a population with long-standing T2D and a substantial burden of both CV and kidney disease. As intended, this will enable assessment of whether linagliptin is non-inferior—and, if so, superior—to placebo for CV and renal outcomes in individuals with T2D at very high vascular risk.The CARMELINAA pooled analysis of 19 randomized clinical trials of linagliptin involving 9459 individuals found no increased risk for major adverse CV events . However® study will thoroughly explore heart failure-related outcomes with linagliptin, as it includes hospitalization for heart failure as an adjudicated and pre-specified outcome and is proactively capturing information related to heart failure.In the last decade, a multitude of CV outcomes trials of glucose-lowering drugs have been initiated . The tri® will also complement the results from the ongoing CAROLINA® study of linagliptin  ) is substantially higher in CARMELINA® than in other CV outcomes studies of oral glucose-lowering drugs in T2D (9.3–29.1%) [® also includes a large number of individuals with very low eGFR (< 30 mL/min/1.73 m2) (n = 1063 [15%]) and/or elevated levels of albuminuria (n = 5587 [80%])  , 43, 44 P = 0.02) [P = 0.1954) after 24 weeks of treatment in individuals with T2D and early diabetic kidney disease who had residual albuminuria despite receiving ACE inhibitors or angiotensin-receptor blockers [® will answer an important question whether DPP-4 inhibition with linagliptin may have the potential to alter renal disease progression at more advanced stages of the renal continuum. Respective experimental evidence to support such a hypothesis has emerged from recent preclinical studies showing that linagliptin exerted anti-fibrotic, anti-inflammatory and anti-oxidant renal effects in animal models of diabetic kidney disease that—if translated to human disease—would be more likely to manifest as long-term disease-modifying renal effects than to elicit short-term changes in albuminuria [No new pharmacotherapy for diabetic kidney disease has been licensed since the early 2000s when the angiotensin-receptor blockers losartan and irbesartan demonstrated efficacy in this indication . Hypothe = 0.02) . Additio = 0.02)  and expl = 0.02) , 49 sugg = 0.02) . In MARLblockers . Since puminuria –54.® trial is designed to assess CV and kidney outcomes of the DPP-4 inhibitor linagliptin versus placebo when added to standard care in individuals with T2D and established CV and/or kidney complications. Compared with the spectrum of CV outcome trials conducted in patients with T2D to date, CARMELINA® has the highest number of individuals with prevalent kidney disease, including a large proportion of patients with severe kidney impairment and/or elevated albuminuria. These individuals are at a very high CV risk, face limited glucose-lowering treatment options, and have been largely underrepresented in previous CV outcomes trials in T2D. CARMELINA® will thus enable assessment of the inherent effects of linagliptin on CV and kidney events in a vulnerable population at high cardio-renal risk. Results are expected in 2018.The CARMELINAAdditional file 1. Full inclusion and exclusion criteria for CARMELINA®.Additional file 2. Baseline characteristics by established CV disease at baseline in CARMELINA® participants.Additional file 3. Baseline characteristics by established CV disease and prevalent kidney disease at baseline in CARMELINA® participants.Additional file 4. CARMELINA® baseline characteristics versus TECOS and SAVOR-TIMI 53.


Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson’s disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards ‘best practices’ when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members’ discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.The online version of this article (doi:10.1007/s00415-016-8375-x) contains supplementary material, which is available to authorized users. Neurogenic orthostatic hypotension (nOH) is a prevalent disorder , 2. ClinThe literature on nOH is fraught with inconsistencies in the definition and methods of diagnosis, and suffers from a lack of evidence-based guidelines to direct clinicians towards ‘best practice’. As nOH is a subset of orthostatic hypotension (OH), it should be noted that patients with nOH and OH may experience the same symptoms but for different reasons. The following consensus definition of OH was devised by the American Autonomic Society and the American Academy of Neurology, and endorsed by the European Federation of Autonomic Societies and the World Federation of Neurology: OH is “…a sustained reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of 10 mmHg, or both, within 3 min of standing or head-up tilt to at least 60° on a tilt table” . In addiTo address this issue, the American Autonomic Society and the National Parkinson Foundation jointly held an initial consensus panel meeting to formulate essential recommendations into a working guideline for the screening, diagnosis, and treatment of nOH and associated supine hypertension. Results of the discussions held during the meeting, along with continued deliberations among the panel participants are presented here along with recommendations in each of the topic areas. Whereas most patients with disorders typically associated with nOH are seen by cardiologists or neurologists, particularly movement disorder specialists, the first point of contact and potential for identification of nOH is with the primary care clinicians. Hence, the following consensus commentary is meant to provide guidance for all clinicians who might encounter and/or ultimately manage nOH.Patients suspected of, or diagnosed with any neurodegenerative disorder associated with autonomic dysfunction, including Parkinson’s Disease (PD), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), or Dementia with Lewy Bodies (DLB);Patients who have reported an unexplained fall or have had an episode of syncope;Patients with peripheral neuropathies known to be associated with autonomic dysfunction ;Patients who are elderly (≥70 years of age)  and fraiPatients with postural (orthostatic) dizziness or non-specific symptoms that only occur when standing.There is no standardized or recommended screening protocol for patients that present with symptoms of orthostatic hypotension. Presenting symptoms and signs of OH include postural lightheadedness or dizziness, the sensation of blacking out, and falls with or without syncope. Less common symptoms include orthostatic cognitive dysfunction , mental dulling, generalized weakness, neck pain or discomfort in the suboccipital and paracervical region (‘coat hanger’ configuration—a manifestation of hypotension-induced ischemia of the strap muscles of the neck), or platypnea (dyspnea while standing due to OH causing inadequate perfusion of ventilated lung apices or ventilation perfusion mismatch) –27. ThusPatients in each of these groups have a higher risk of OH/nOH when compared to the normal population .For these five categories of patients, clinicians should ask about cardinal symptoms of OH, their frequency and severity, how long they can stand, and the effect of symptoms on their activities of daily living. Questions about symptoms should also note the time of day when the symptoms occur, as symptoms of OH/nOH are most likely to occur in the morning and after meals –32. A moAfter screening to identify a patient as being at risk for OH, an accurate assessment of the underlying cause(s) is required to determine the appropriate treatment recommendation. A stepwise approach is recommended for diagnosis of nOH, specifically starting with measurement of orthostatic blood pressure and heart rate, followed by more detailed autonomic testing in select cases Fig. .Fig. 1StThe hallmark test for OH is measurement of change in blood pressure from supine, after at least 5 min of rest, to standing (or head-up tilt [HUT]) . CurrentThe recommended gold standard measurement of OH includes having patients rest in the supine position for at least 5 min and then stand for 3 min, with blood pressure measurements taken just prior to standing and at both 1 and 3 min of standing . HoweverEven this appropriate testing of blood pressure will not identify all patients with OH, since variability in meals, hydration, time of day, and medications can affect the orthostatic change in blood pressure. Additionally, there is a subgroup of patients who manifest symptoms of OH beyond the 3-min interval, defined as delayed OH , which mUpon standing from a supine or seated position, healthy, normally volume-replete individuals will typically experience a modest decline in systolic blood pressure (<10 mmHg), a very slight increase in diastolic blood pressure (approximately 2.5 mmHg) and a modest increase in heart rate (10–20 beats per minute [bpm]) . These cIn addition to in-clinic blood pressure monitoring, patients should be asked to check their blood pressure and heart rate at home and record the values in a diary. We recommend that patients or their caregivers check blood pressures at home in the supine position (at least 15 min after laying down at bedtime or prior to arising from bed in the morning) and after 3 min of standing (with assistance as necessary) after arising from bed in the morning. The following timings are our recommendations for at-home blood pressures and heart rate monitoring: (1) first thing in the morning before taking morning medications, (2) when a patient feels symptomatic, and (3) at bedtime for several days. We recommend that patients keep a blood pressure and heart rate diary for at least 7 days preceding a clinic visit, but after having a clinic visit patients should not need to measure blood pressure and heart rate on a continuous daily basis unless a change in therapy occurs. With any change in therapy, an additional week of blood pressure monitoring is required to determine the effectiveness of the change. (An example patient diary for blood pressure and heart rate is provided in Appendix I.)There are numerous medications that can diminish the normal compensatory postural increase in heart rate, .If blood pressure and heart rate changes indicate OH/nOH, a complete history and physical examination, as well as electrocardiogram and laboratory testing, should be focused on ruling out non-neurogenic causes of OH, including cardiogenic, vascular, or iatrogenic etiologies , 7. TablIf standard orthostatic blood pressure testing does not reveal OH in an at-risk individual with unexplained postural symptoms, falls, or syncope, then any of the following are appropriate as next steps: (1) conducting extended at-home blood pressure monitoring with results recorded by the patient or caregiver, (2) implementing 24-h ambulatory blood pressure monitoring where the patient can annotate times when supine or standing , or (3) use of autonomic function tests. Some individuals may develop delayed OH later than 3 min of standing, which can be identified with prolonged standing blood pressures, or prolonged tilt table testing (HUT) , 38.The specialized tests described below are considered by the panel to be beyond the scope of many primary care clinicians and usually require referral to a center specializing in autonomic disorders. Specialized tests for a definitive diagnosis of nOH include autonomic reflex testing . Other tests used to help diagnose nOH may include plasma fractionated catecholamine levels and/or sudomotor function testing.These specialized tests may be helpful in confirming the diagnosis of nOH by demonstrating baroreflex dysfunction based on HUT testing with beat-to-beat blood pressure measurement, and/or the beat-to-beat blood pressure and heart rate response to the Valsalva maneuver . In addiNon-neurogenic causes for OH are common and frequently include effects of medication , prolong standing time, and improve the physical capabilities of the patient to restore independence in activities of daily living. A treatment algorithm for nOH that encompasses a 4-step hierarchical process is proposed Fig. : (1) assAfter establishment of a diagnosis of symptomatic nOH, it is imperative to first consider pharmacologic simplification by reducing or discontinuing medication that exacerbate nOH. One of the keys to initial success is to complete a comprehensive medication review so that adjustments in regimens can be made as needed. Many medications  can lower blood pressure and exacerbate the symptoms of nOH Table . DiscontOnce a medication review has been conducted, it is recommended that any planned changes be discussed with the prescribing clinician such as: taking the patient off a particular drug, lowering current doses, or changing the dosing schedule. While there is limited published literature supporting this recommendation there is strong expert opinion underlying this approach. Following each adjustment to medication, changes to symptoms of nOH should be assessed, and this can be accomplished by asking the patient to respond to the screening questions listed in Table The next step in the treatment algorithm is to have the patient incorporate a number of simple non-pharmacological measures into their daily routines to address symptoms due to nOH. From a practical perspective, these measures are often incorporated into a treatment plan in parallel to the changes to pharmacology outlined in step 1 above. For patients who are experiencing syncope, near-syncope, or falls, there is some urgency to eliminating destabilizing postural changes. Hence, non-pharmacologic measures may be used individually, but are most effective when used in combination or while concomitantly titrating pharmacologic treatments.Patients with nOH require interventions which are aimed at ensuring normal or even expanded blood volume. Many patients with nOH, especially older patients, are often blood volume depleted due to inadequate oral fluid intake . This maIn addition to maintaining intravascular blood volume and to support standing blood pressure, patients with nOH who rapidly consume (within 5 min) 16 oz (approximately 500 ml) of free water can raise systolic blood pressure by 30 mmHg within 5 min . The effAnother non-pharmacologic treatment is to monitor and adjust as needed the amount of salt that the patient is ingesting. Because salt is typically seen as a negative dietary component, patients may try to remove or at least reduce salt from their diet. However, many patients who suffer orthostatic symptoms have an inadequate intake of salt. This can be verified by checking the 24-h urinary sodium . For the patient with nOH, it is recommended that they add up to 1–2 teaspoons (2.3–4.6 g) of salt per day to their normal diet –56. PatiLower body strength training and moderate, non-strenuous activities may be incorporated into standard treatment for patients with nOH , 59. DecElevation in body temperature causes peripheral vasodilation. Patients with nOH should avoid situations that could increase core body temperature, such as excessive high-intensity exercise, exercise when ambient temperature and humidity are high, utilization of hot tubs, spas, or saunas, prolonged hot showers, etc. . Simple Elevating the head of the bed  higher than the feet—stacked pillows are not adequate) will reduce supine hypertension . Supine Compression garments are another mechanism to combat blood pressure changes due to postural venous pooling , 65. ComIn patients with OH/nOH, normal sympathetic activity cannot compensate for blood pooling within the splanchnic circulation after eating. With nOH, sympathetic vasoconstrictor nerve activity is deficient and many patients become severely hypotensive within 2 h of eating , 68. It Anemia leads to decreased blood viscosity and oxygen carrying capacity and may worsen symptoms of OH/nOH . VitaminIf the implementation of non-pharmacologic measures does not adequately improve the symptoms of nOH, then it becomes necessary to initiate pharmacotherapy. For patients who are experiencing syncope, near-syncope, or falls, the potential consequences are so grave that some clinicians believe that institution of pharmacotherapy at the outset of management is appropriate. Clinicians must individualize treatment based upon the urgency of the symptoms.Until 2014, the two drugs primarily used to treat nOH were fludrocortisone and midodrine . In 2014, droxidopa received FDA approval for the treatment of nOH. The selection of one drug over the other, in many situations, was related to clinician preference and experience. Below, we present an overview of the key drugs used to treat nOH and the recommendations for usage. One of the challenges associated with treating nOH pharmacologically is the limited availability of clinical evidence and lack of comparative effectiveness studies.Midodrine is a prodrug whose metabolite, desglymidodrine, is an α 1-adrenoreceptor agonist that increases vascular resistance and blood pressure. Typical dosing is between 2.5 and 15 mg once to three times daily during waking hours  . The dosDroxidopa is an orally administered norepinephrine pro-drug that is converted into norepinephrine both in the central nervous system and in peripheral tissues, including sympathetic peripheral nerve endings. Increases in circulating plasma norepinephrine levels peak at 6 h following treatment with droxidopa and levels of norepinephrine remain elevated for at least 46 h . RepleniFludrocortisone has been used off-label for many years for the treatment of OH/nOH, and even though the level of data supporting the use of fludrocortisone in OH/nOH is low, it is included in treatment guidelines based on expert opinion . It actsPyridostigmine is an acetylcholinesterase inhibitor that has been used off-label for the treatment of OH/nOH because it potentiates neurotransmission at peripheral cholinergic synapses including those in the sympathetic ganglia. Pyridostigmine is thought to work in OH by amplifying the increased sympathetic nerve activity in response to orthostatic stress. Therefore, it is likely more useful in less severe patients with residual sympathetic function, and has the advantage of not worsening supine hypertension. Typical dosing is 30–60 mg once to three times per day. Several small studies have reported a modest improvement in OH and orthostatic symptoms , 18–21. There have been no head-to-head comparison studies to guide the initial choice of nOH treatments. An individualized treatment regimen should consider severity, co-morbid disease , and treatment goals. Midodrine has an FDA-approved indication for the treatment of symptomatic OH; FDA approval was based on studies showing an improvement in upright blood pressure as a surrogate for symptom relief. In contrast, the FDA-approved droxidopa with an orphan designation for the treatment of nOH based on studies showing improvement in symptoms of nOH. Patients receiving droxidopa reported a decrease in dizziness, lightheadedness, feeling faint, or feeling as if they might black out compared with those receiving placebo. There have been no long-term studies on the durability of the treatment effect for either midodrine or droxidopa. However, a long-term study is underway to study durability of effectiveness with droxidopa (NCT02586623) in patients with nOH for up to 36 weeks of treatment.Once initial therapy has begun, symptomatic benefit, including impact on activities of daily living, and changes in blood pressure need to be assessed frequently. If symptoms do not improve after reaching maximum labeled dose, it is recommended that the treatment be changed and symptomatic benefit be assessed once more. This process is iterative until either symptomatic benefit is achieved or maximum tolerable dose of the therapy is reached.Little data exists to determine efficacy and safety of different combinations of therapy compared to monotherapy for nOH. Based on the experience of the consensus panel, the recommendation is to appropriately titrate to maximum tolerable dose of a single agent and then, if symptomatic benefit is not obtained, consider switching to a different therapy or adding a second agent and titrate from its lowest starting dose.Assessment of treatment success needs to be a multifaceted approach involving predominantly the measurement of symptomatic improvements as well as ongoing blood pressure measurements. It is critical that patients are educated on the various symptoms and about how to keep a diary of symptoms. Similarly, it is necessary for the patient to conduct a period of home monitoring of blood pressure after implementing new or additional non-pharmacologic measures or after a change in treatment or dose. We recommend that patients check their blood pressures at home in the supine head-up position . Patients taking pressor medications such as midodrine or droxidopa should avoid the supine position during the 4–5 h after taking medication), and check blood pressure after 3 min of standing. We recommend checking blood pressures first thing in the morning prior to taking any morning medications, when symptomatic, and at bedtime for several days. The blood pressure diary should be evaluated by the healthcare provider 2 weeks after any therapeutic change to determine the need for further adjustments. (An example patient diary for blood pressure and heart rate monitoring is provided in Appendix I). If blood pressure measurements have been stable, a reduction in monitoring frequency can be considered, but reinstituted if symptoms worsen or if medications are changed. Lastly, 24-h ambulatory blood pressure monitoring can be considered so that there is an ongoing record of the impact of treatment on blood pressure. Additional clinical assessments will be largely driven by symptom frequency and severity. However, re-assessment of the clinical condition should occur at every visit via symptom review and orthostatic blood pressure measurements.With appropriate education, the screening, diagnosis, and treatment of nOH are well within the purview of both primary and specialist clinicians. With a diagnosis of nOH, the clinician can assign an OH severity Grade based on blood pressure changes, symptoms, and impact on activities of daily living. Once diagnosis is established, the clinician can take the patient through steps 1, 2, and 3 of the treatment algorithm. However, if the patient experiences pharmacotherapy failure, it may be useful to refer the patient to a specialist who is experienced in treating patients with nOH. Additionally, if the clinician is at any time uncomfortable with treating a patient with nOH of high severity (Grades 3 to 4), they should refer the patient to a specialist with expertise in the treatment of nOH.According to the Eighth Joint National Committee (JNC8) hypertension guidelines, essential hypertension is a blood pressure consistently ≥140/90 mmHg . Supine A supine systolic blood pressure of up to 160 mmHg should be monitored but does not generally warrant treatment, especially if the symptoms of nOH have improved. The long-term risks associated with supine hypertension need to be balanced with the short-term risks of OH. Expert recommendations for the management of supine hypertension in the setting of nOH suggest that supine hypertension requires intervention if systolic blood pressure exceeds the range of 160–180 mmHg. However, it should be noted that individuals with the largest drops in blood pressure upon standing (>80 mmHg drop) will require significantly higher supine blood pressures in order to achieve a standing position, and therefore permissive supine hypertension may need to be tolerated.The first step in evaluating supine hypertension in the patient with nOH is obtaining a series of blood pressure measurements. Home supine and standing blood pressures should be obtained. The supine assessment should be in the morning (before arising) and at bedtime with the patient in their normal sleeping position and with the head of the bed raised. If necessary, 24-h blood pressure monitoring may be warranted in some patients. Blood pressure should be monitored for a week or more to establish a pattern of typical blood pressure. Once a baseline has been established and treatment initiated for nOH, regular blood pressure monitoring for a period of 2 weeks following treatment initiation is crucial to gauge the impact of treatment on supine hypertension.It is critical for clinicians to understand the physiology underlying both nOH and supine hypertension and the associated risks of each when they manage patients with nOH. Neurogenic OH is associated with loss of baroreflex function that normally buffers changes in blood pressure in both directions. Therefore, patients with autonomic nervous system dysfunction typically have nOH and supine hypertension. In addition to supine hypertension being common in patients with nOH, many of the medications used to treat nOH can cause or exacerbate supine hypertension. Because OH/nOH and supine hypertension are hemodynamic opposites, improving one can worsen the other. Thus, all patients with nOH should be evaluated for supine hypertension. There are differences in clinical practice among clinicians who treat nOH. Some clinicians may not treat nOH for fear of exacerbating supine hypertension, while others may aggressively treat nOH while accepting the resulting supine hypertension. Unlike the potential long-term consequences of hypertension in non-PD patients, the risks of nOH are immediate and represent potential major health threats. By extrapolation, similar recommendations can be made in multiple system atrophy , 4. In cIn most patients with nOH, there are strong reasons for prioritizing the treatment of nOH over supine hypertension , 86. SymAs stated above, if patients with nOH are experiencing supine hypertension (systolic blood pressure of 160–180 mmHg or diastolic blood pressure of 90–100 mmHg), the decision to treat should be individualized. However, if patients with nOH are experiencing severe supine hypertension (systolic blood pressure of >180 mmHg or diastolic blood pressure of >110 mmHg), they could be treated in the evening using short-acting anti-hypertensive agents Table . IndividThere are a number of limitations to the current publication. The recommendations listed in this document are based on expert opinion, but do not contain sufficient evidence to support official guidelines. However, the recommendations were included with the goal of providing practical information to the many physicians without specific training or experience in autonomic disorders that are most likely to manage patients with orthostatic hypotension. Additional studies are necessary to determine the utility of these recommendations.To date, little published literature is available on a “standardized approach” to the screening, diagnosis, and treatment of patients with OH/nOH and associated supine hypertension. As such, the recommendations of this panel, which were based on the discussions and experiences of the panel along with evidence in the literature, should provide clinicians with a useful working approach to dealing with this complex condition. The panel recommended that additional study in screening, diagnosis, and treatment of patients with OH/nOH and associated supine hypertension is necessary. In particular, additional studies of the treatment of nOH should be conducted to refine the diagnosis and treatment algorithms and to provide definitive evidence of efficacy and safety of medications that are currently used, but not approved, for the treatment of patients with nOH.Supplementary material 1 (PDF 478 kb)Below is the link to the electronic supplementary material.


Anti-interleukin (IL)-5 monoclonal antibodies as an eosinophil-depleting strategy is well established, with Mepolizumab being the first biologic approved as an adjunct treatment for severe eosinophilic asthma.A 62-year old woman diagnosed with severe eosinophilic asthma showed poor response to Mepolizumab therapy (100 mg subcutaneous dose/monthly) and subsequent worsening of symptoms. The treatment response to Mepolizumab was monitored using both blood and sputum eosinophil counts. The latter was superior in assessing deterioration in symptoms, suggesting that normal blood eosinophil count may not always indicate amelioration or adequate control of the ongoing eosinophil-driven disease process. This perplexing situation of persistent airway eosinophilia and increased steroid insensitivity despite an anti-eosinophil therapy can be explained if the administered dose of the mAb was inadequate in comparison to the target antigen. The resultant immune complexes could act as ‘cytokine depots’, protecting the potency of the ‘bound’ IL-5, thereby sustaining the eosinophilic inflammation within the target tissue. Molecular analysis of the sputum indicated the development of a polyclonal autoimmune response as well as an increase in group 2 innate lymphoid cells, two novel observations in severe eosinophilic asthma, which were associated with indices of disease severity and progression. This case highlights the possibility of a previously unrecognised autoimmune-mediated worsening of asthma perhaps triggered by immune complexes formed due to inadequate dosing of administered monoclonal antibodies in the target tissue.While anti-IL5 mAb therapy is an exciting novel option to treat patients with severe asthma, there is the rare possibility of worsening of asthma as observed in this case study, due to local autoimmune mechanisms precipitated by potential inadequate airway levels of the monoclonal antibody.The online version of this article (doi:10.1186/s13223-016-0174-5) contains supplementary material, which is available to authorized users. The eosinophilic nature of her asthma was confirmed by peripheral blood counts (peaked at 0.8 × 109/L in 2010) and sputum cellularity . She did not have mutations for PDGFR-FIP1L1, c-kit, JAK2, or BCR-Abl or abnormal lymphocyte population or T cell receptor rearrangements. Her routine chemistry, total serum IgE, and tryptase were normal, as were her stool microscopy, antifungal precipitins, and autoantibody profile including cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies. Computed tomography of thorax was unremarkable. She had two sinus polypectomies that did not improve her respiratory symptoms significantly. She has been prednisone-dependent since 2008. Methotrexate, hydroxyurea, and imatinib were not effective to wean her off prednisone  whose symptoms worsened at the age of 55 was seen in our clinic on February 22nd, 2010 with severe airway hyper-responsiveness (PC1 of 1.76 L (65% of predicted), blood eosinophils 0.03 × 109 cells/L, and 4% sputum eosinophils  that dropped to 0.9 L at the end of the study (Aug-13), with no demonstrable steroid-sparing effect , and prednisone requirement that now doubled from a pre-study dose of 20–40 mg daily  while on treatment with Mepolizumab, deteriorating lung function and subsequent increase in steroid-insensitivity.Our molecular studies demonstrated that sputum IL-5 levels peaked at the end of her Mepolizumab therapy Fig. . This in+ ILC2 cells by flow cytometry in both blood and sputum. There was a dramatic increase in circulating IL5+ ILC2 s after six injections of Mepolizumab , she was started on intravenous immunoglobulins  as an autoantibody mopping-up strategy. Post six monthly infusions (Nov-15) her sputum autoantibody titres reduced steadily, and FEV1 improved to 1.13 L  over the entire timeline of the case study , contributing to her daily symptoms and poor asthma control, ACQ of 1.5). She is being considered for therapy with additional IVIg and/or intravenous reslizumab  or anti-IL4Rα mAb (Dupulimab).At the last IVIg infusion, the prednisone dose was reduced to 17.5 mg to assess a steroid-sparing effect. The lowered dose was unable to suppress the local inflammatory mediators that allowed ‘lung-homing’ of lymphocytes and increased IL5+ ILC2 population provided indirect evidence of possible ICs acting as ‘cytokine depots’, supporting in situ eosinophilopoiesis. And finally, we demonstrated that Mepolizumab, at the current prescribed dose and delivery platform, may precipitate steroid-insensitivity by triggering steroid-unresponsive auto-inflammatory mechanisms, especially in patients who are predisposed to it. Further studies are necessary to understand the airway pharmacokinetics of novel mAbs, effective dosing strategies particularly whether they have to be guided by antigen-concentrations or body weight, and the appropriate therapy for patients with inadequate or worsening clinical responses with the monoclonal antibodies.To our knowledge this is the first case report of an anti-IL-5 therapy leading to worsening of clinical symptoms in eosinophilic severe asthma. In summary, we provide evidence that normal blood eosinophil counts post low-dose Mepolizumab therapy does not confirm that the eosinophil-driven disease process is adequately controlled. Indeed, sputum was demonstrated to be superior to blood in monitoring response to therapy. Although a direct evidence of in vivo IC-mediated injury could not be demonstrated, a concurrent increase in sputum IL-5 (whether in a free-form or bound) and IL5


Hypertension is a global health issue and is currently increasing at rapid pace in South Asian countries including Bangladesh. Although, some studies on hypertension have been conducted in Bangladesh, there is a lack of scientific evidence in the adult student population that was missing from the previous and recent national cross-sectional studies. Moreover, the specific risk factors of hypertension in the Bangladeshi adults still need to be investigated. This study was conducted to estimate hypertension prevalence among adult students in Bangladesh and to test the hypothesis of Luke et al.  that basal metabolic rate (BMR) and blood pressure are positively associated independent of body size.The data was collected on 184 adult university students  in Dhaka, Bangladesh. Anthropometric, BMR details and an average of at least two blood pressure measurements were obtained. Hypertension was defined by a systolic blood pressure (SBP) ≥ 140 mmHg and/or, diastolic blood pressure (DBP) ≥ 90 mmHg.p < 0.001) higher prevalence in male (12.1%) than in the female (3.4%) students. Age and BMI showed positive and significant correlation with hypertension among the students. When adjusted for body mass index (BMI), as well as other potentially confounding variables such as age, sex, smoking status and degree of urbanization, BMR was positively correlated with SBP and DBP (p < 0.001). Thus, higher BMR is associated with SBP and DBP; this is opposite the well documented inverse relationship between physical activity and blood pressure. If the influence of BMR on blood pressure is confirmed, the systematically elevated BMR might be an important predictor that can explain relatively high blood pressure and hypertension in humans.Overall, 6.5% of participants had hypertension with significantly (This study reports the prevalence and associated risk factors of hypertension in the Bangladeshi adult students. The study also showed a positive association between BMR and blood pressure among the participants. A large scale longitudinal study across the country is needed to find out the underlying causes of hypertension in the Bangladeshi adults. In addition, comprehensive and integrated intervention programs focusing on modifiable risk factors are recommended to make awareness and prevent hypertension. Hypertension is a global health issue and has been recognized as a major contributor to the burden of cardiovascular diseases (CVDs), kidney failure and premature death , 15, 47.It is well known that, the consequences of high blood pressure include heart failure, coronary heart disease, peripheral arterial disease, stroke, and kidney disease , 21. A nStudies among Nigerians and African Americans have suggested a link between maintenance energy costs and blood pressure; after adjusting for the effects of age, body size, and body composition, BMR exerts a positive influence on both systolic blood pressure (SBP) and diastolic blood pressure (DBP) . AnotherIn Bangladesh, data on hypertension prevalence in the adult student population are missing from previous studies and the associated factors of hypertension still need to be investigated. Therefore, we conducted a cross-sectional study with specific aims. First, to estimate the prevalence of hypertension and find out the possible risk factors of hypertension among adult students (aged 18–25 years) in Bangladesh and secondly, to test the hypothesis of Luke et al.  that BMRThis study was carried out at the Gonoshasthaya Samaj Vittik Medical College, located of Savar region in the Dhaka district. The study population consisted of male and female students (aged between 21 and 23 years) who were studied at the first year of honours of MBBS (Bachelor of Medicine and Bachelor of Surgery).This study was cross-sectional design and data was collected between June and August 2012. A total of 184 healthy adult students  were selected from two semesters at first year of honours level. All participants gave their written consent before inclusion in the study which was approved by the Ethics Committee of the Medical College. Anthropometric data, blood pressure and BMR measurements were recorded by trained health technicians at Biochemistry and Physiology department of the Medical College. The quality of anthropometric data ensured by repeated measurements in presence of investigators. All participants provided their individual anthropometric and life style information in a structured questionnaire form.2) and BF (body fat) percentage. Percentages of body fat, basal metabolic rate (BMR) and body mass index (BMI) were measured using an Omron body fat analyzer . Fat-free mass (FFM) was calculated as body mass less fat mass. All participants rested quietly in a supine position for a minimum of 10 min before BMR measurement. Following [Anthropometric data such as height, weight, three circumferences and skinfold thickness at four sites  were obtained using the standard procedure . Individollowing  study, aollowing , BMR staollowing .The participants were allowed 10 min rest before measuring blood pressure two times at 5 min intervals on the left arm in a sitting position with the arm supported at the level of the heart using an Omron M10 digital BP machine . The mean value of the first and second measurements was considered for systolic blood pressure (SBP) and diastolic blood pressure (DBP). Blood pressure measurements taken from all participants in the morning 8:30 to 10:30 am. Pulse pressure (PP), which serves as an indicator of arterial stiffness and blood vessel wall inflammation and is a predictor of cardiovascular disease mortality , 21, wast-test (two tailed) was done to assess the differences between males and females for anthropometric, blood pressure and metabolic variables. Measured versus predicted BMR (for body mass and FFM) was compared using paired-sample t-tests (two tailed). Interrelationships between anthropometric, blood pressure and metabolic variables were assessed by Pearson’s correlation coefficient test. Linear regression analyses with blood pressure measures as the dependent variable  were used to estimate the relative contribution of BMR to blood pressure while considering sex, age, BMI, degree of urbanization  and smoking status . The values in tables were presented as mean ± standard deviation otherwise noted. A level of alpha 0.05 was assigned for statistical significance.All data were analyzed using the software IBM SPSS statistics version 23. Independent sample 2. Males (22.8 ± 3.6 kg/m2) had slightly higher BMI than females (22.1 ± 3.7 kg/m2). According to WHO [p < 0.001) higher in male students  than in the female students   are presented in Table g to WHO  categorip < 0,001). Both male and female students did not show significant elevations in BMR over that predicted by body mass . However, both male and female students showed significant elevations in BMR over predicted for FFM .Measured and predicted BMRs (± SD) relative to body mass and FFM standards were recorded for all students Table . The malp < 0.01), DBP (p < 0.05) and PP (p < 0.01). However, after independent sex analysis, age was not significantly correlated with SBP, DBP and PP in male-female subgroup (Tables p < 0.01) with SBP, DBP and PP. In subsequent analyses, BMR was significantly correlated with SBP (p < 0.001), DBP (p < 0.001) and PP (p < 0.01) in females (Table p < 0.01), DBP (p < 0.01) and PP (p < 0.05) (Table p < 0.001) of SBP and DBP in this model  than in the female (3.4%) participants  and Nigerians (n = 996) and African Americans (n = 452), respectively. When adjusted body size and composition, as well as other potentially confounding variables such as age, degree of urbanization and smoking status, BMR was positively correlated with SBP and DBP  may mediate the association between BMR and blood pressure. Clinical studies say that both hypothyroidism and hyperthyroidism can lead to elevated blood pressure, and there is plausible evidence that subclinical thyroid “dysfunction” accelerates the changes in cardiovascular function and blood pressure regulation [The mechanism responsible for the association between BMR and blood pressure is unknown at present. We agree with Snodgrass et al.  that fewgulation , 12. Morgulation . Third, gulation . This evgulation , 43. Fingulation . Studiesgulation  and thesgulation , raisinggulation .We hope that, this study finding will stimulate further research exploring the influence of BMR on blood pressure among the Bangladeshi adults. We agree with the author’s suggestions that awareness and simple health messages, increase provider visit, can reduce blood pressure and improve blood pressure control in hypertensive adults , 7.n = 118) and unequal male-female participants  that do not represent all Bangladeshi adult students. In this study, we did not record information on the anti-hypertensive medication. Other limitations included missing information of some important factors of hypertension like physical exercise, family history of hypertension, salt intake and lipid profile of the participants.The major strengths of our study were to estimate the hypertension prevalence in the adult student population (aged 18–23 years) that was missing from the national cross-sectional study in Bangladesh. The possible risk factors of hypertension have been discussed in the study. This study has also evaluated the association between BMR and blood pressure among the participants. Moreover, hypertension measurements were collected by trained and experienced health technicians using standard methods rather self-reporting. Therefore, the measurements error and bias is less in this study compared to other cross sectional studies in Bangladesh. The main limitation of our study was the small sample size (The present study reports a number of risk factors that is associated with hypertension among the Bangladeshi adult students. Statistical analysis also indicates a positive association between BMR and blood pressure among the participants. The number of young adults in Bangladesh is a significant proportion of total population in this country. Thus, hypertension prevalence in this special group is alarming. Since most of the factors associated with hypertension are preventable and modifiable. Therefore, the early diagnosis, life style changes, healthy food habits and overall awareness can reduce the rates of having hypertension in Bangladeshi population. Furthermore, a large scale longitudinal study across the country is required to find out the underlying causes of hypertension among Bangladeshi adults.


The utility of bioelectrical impedance analysis (BIA) derived adiposity measures as compared to anthropometric measures for the assessment of adiposity-related health risk is not clear. We aimed to clarify the relationships of BIA and anthropometric derived adipose measures with blood pressure and hypertension, and to compare the discriminative ability of the respective measures for hypertension.N = 5990; age 30–69 years). We examined and compared the associations and discriminative ability between anthropometric  and BIA (whole body and trunk fat percentage) derived adiposity measures with blood pressure components  and hypertension.We used baseline data collected between 2015 and 2016 from the Indian Study on Health of Adults (ISHA), an ongoing population based cohort study in India (Regardless of whether the adiposity measure was derived from BIA or anthropometry, all were strongly and positively associated with blood pressure and hypertension. For both men and women, the magnitude of association of BIA measures with blood pressure and hypertension were comparable to those of anthropometric measures. Further, the ability of BIA derived adiposity measures to distinguish between those with and without hypertension was similar to the discriminative ability of anthropometric measures.As compared to simple anthropometric measures, BIA derived estimates of adiposity provide no apparent advantage in the assessment of blood pressure and hypertension. The observed similarities between adiposity measures suggest that simple anthropometrics may be sufficient to assess adiposity and adiposity-related risks. In India, demographic, socioeconomic and health transitions have contributed to an increasing burden of adiposity-related diseases, such as cardiovascular disease (CVD) , 2. A weCriterion methods such as magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) are available to assess body composition and determine relative amounts of adipose tissue, but these methods are costly, invasive and time consuming. Moreover, they are not readily available for large scale use in low and middle-income countries (LMIC), such as India. In comparison, bioelectrical impedance analysis (BIA) represents a relatively low-cost and simple method to obtain estimates of body fat and identify those at increased health risk . FurtherAs more sophisticated measures of body fat (i.e. those derived from BIA) become readily available, reliable studies evaluating whether they provide any value over simple anthropometric measures are necessary. We therefore examine and compare the associations of anthropometric and BIA derived adiposity measures with blood pressure and hypertension in a large population-based cohort of men and women from India.N = 5996). Of these participants, 6 were excluded because of pregnancy.We conducted a cross-sectional analysis comparing the associations between anthropometric and BIA derived adiposity measures with blood pressure and hypertension in India. The Indian Study on Health of Adults (ISHA) is an ongoing population-based cohort study of men and women age 30–69 years from the general population of the town of Barshi . We used baseline data collected between 2015 and 2016 for our analyses , household health survey (days 3–4) and a health checkup camp (days 5–7). First, field teams enumerated the households in the village, collecting information on household size and the usual residing members. Second, trained surveyors  visited the households and interviewed eligible members (30–69 years of age) to obtain detailed information on demographic, socioeconomic, and lifestyle characteristics, along with blood pressure measurements and antihypertensive medication use. After completion of the interview participants were invited to attend a health checkup camp, and were given an invitation card detailing the time and place of their health checkup. Each health checkup camp was set up in the village with direct input from the Sarpanch or any other administrative head to ensure ease of access for participants. Lastly, participants attended the health checkup camp where their blood pressure was measured, along with physical and body composition measurements.After 5 min of rest, three blood pressure measurements were taken at heart level in a seated position using the Omron BP-742CAN  digital automatic monitor. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated as the average of the three readings. We calculated pulse pressure, mean arterial pressure, and mid-blood pressure using previously reported formulas . HyperteA measuring tape was used to measure height to the nearest 0.1 cm . Weight The anthropometric measures of adiposity were BMI, WC, HC, WHR, and WHtR. BMI was calculated as weight in kilograms divided by the square of height in meters. WHR was calculated as WC in centimeters divided by HC in centimeters, and WHtR as WC in centimeters divided by height in centimeters. The BIA derived measures of adiposity were whole body fat percentage and trunk fat percentage, as estimated with proprietary algorithms by the Tanita body composition analyzer.We performed all analyses separately for men and women. We calculated Pearson’s partial correlation coefficients for the intercorrelations of the different adiposity measures  and blood pressure components , adjusted for age. In order to compare the associations between anthropometric and BIA derived adiposity measures with blood pressure and hypertension, we evaluated the relationships using several methods. First, we used multiple linear regression models to quantify the associations between adiposity measures with blood pressure components. Second, we used Poisson regression models to examine the relationships between adiposity measures and hypertension. We estimated the means of each blood pressure component, and calculated the prevalence ratios (PR) for hypertension per sex-specific standard deviation (SD) change in an adiposity measure. We used two models for these analyses. In the first model, adjustments were made for age and level of education . In the second model, further adjustments were made variously for either an anthropometric or BIA derived measure of general  or central  adiposity. 198 individuals  who reported current use of antihypertensive medication were excluded from the continuous blood pressure analyses.Lastly, we used receiver operating characteristic (ROC) curves and the area under the curve (AUC), estimated by logistic regression models with adjustments for age and education, to compare the discriminative ability of each adiposity measure for hypertension. The AUC is a measure of the overall discriminative ability of each adiposity measure for hypertension, with values falling between 0.5 and 1.0, representing no discriminative and perfect discriminative ability, respectively. The AUC for all measures of adiposity were compared using a nonparametric approach for the comparison of multiple AUC from ROC curves .In addition to age and education adjustments, further adjustment for tobacco use  and alcohol consumption  did not substantially affect any of the estimates (results not presented). We performed all statistical analyses using SAS version 9.3 , and provide estimates with their respective 95% confidence intervals (CI).The means (SD) of anthropometric and BIA derived adiposity measures, blood pressure components, and hypertension prevalence are presented in Table Overall, the sex-specific correlation coefficients of adiposity measures with blood pressure components were comparable, except for pulse pressure, whereby the correlations were relatively weaker Table . The intThe differences in mean blood pressure components [mmHg per SD (95% CI)] for each anthropometric and BIA derived adiposity measure are presented in Table On average, the associations between anthropometric derived measures and blood pressure were slightly weaker than BIA derived measures among men. For instance, each SD difference in an anthropometric measure was associated with a 3.23 mmHg to 4.56 mmHg change in SBP, whereas changes in SBP for each SD difference in a BIA measure ranged from 4.62 to 4.69 mmHg. In comparison, the relationship of anthropometric measures with SBP were moderately stronger than BIA measures among women, and ranged from 2.86 to 4.26 mmHg, and 3.73 mmHg to 3.86 mmHg for anthropometric and BIA derived measures, respectively. Apart from pulse pressure, which had much weaker associations with all measures of adiposity, similar  relationships were observed between each measure and the remaining blood pressure components.p < 0.05).The further adjustment of an anthropometric measure for a BIA measure, and vice versa, diminished the relation between each  adiposity measure and all blood pressure components regardless of measurement method. Although attenuated, the association between both an anthropometric and BIA derived measure with blood pressure were, for the most part, independent of each other and remained significant (The PRs (95% CI) for hypertension per SD difference in each measure of adiposity are shown for men and women in Figs. p < 0.05) associated with hypertension regardless of whether or not additional adjustments were made for the other measurement method.The further adjustment of an anthropometric measure for a BIA measure, and vice versa, resulted in an attenuation of their relationships with hypertension. Among men, there appears to be a more marked attenuation of the association of BMI and WC with hypertension after adjusting for body and trunk fat percentage, respectively Fig. , Model 2p < 0.05) less for both sexes. Nevertheless, the relative sex-specific difference for the AUC between either an anthropometric or BIA derived measure of adiposity was negligible, and not statistically significant between the majority of measures irrespective of their derivation method.Summarized in Table In our study of adults from India, the strength of association of anthropometric  and BIA (whole body and trunk fat percentage) derived adiposity measures with blood pressure and hypertension were similar. Moreover, the discriminative ability of BIA measures for hypertension was comparable to anthropometric measures. Our findings suggest that BIA derived measures of adiposity have no apparent benefit over simple anthropometrics in the assessment of blood pressure and hypertension.Although there is potential for the utilization of BIA to assess body composition and health risks, there is a paucity of studies from India reporting its use. Further, very limited information is available on the association between BIA derived body fat and health risks related to CVD. One study among 850 men in India indicates that high body fat percentage, as determined by BIA, is associated with hypertension and high coronary artery disease prevalence . SimilarAn often cited limitation of BMI and anthropometric measures in general, is their inability to discern differences in body composition . Hence, The capability of segmental analysis by BIA may be a useful addition to whole body analysis as it is able to provide information on the distribution of body tissues. However, given our findings, no further value of BIA was obtained from the use of segmental analysis for investigating the association of adiposity with blood pressure and hypertension. Both whole body and trunk fat estimates were highly correlated with each other (i.e. correlation coefficient of 0.97), which may explain, to some extent, the similarities in their observed relationships. Indeed, the use of segmental analysis may be limited by its ability to accurately assess different body components as compared to the body as a whole. For example, using DXA as the reference, it has been shown that estimates of segments  may be more prone to error than estimation of whole body composition by BIA . Taking Apart from HC and WHR, we found no significant differences for the discriminative ability between anthropometric and BIA derived measures of adiposity for hypertension. In comparison to BIA estimated whole body and trunk fat, HC and WHR had significantly lower discriminative power for hypertension. This may be due, in part, to the limited ability of HC alone to distinguish those with greater adiposity, and the potential for decreased precision of WHR as a measure of adiposity. For instance, WHR does not differentiate those with either a small WC and HC or a large WC and HC, both would have a similar WHR. The inability to distinguish these differences may diminish the relationship that WHR has with blood pressure and hypertension, and indeed, among all the adiposity measures, the weakest associations were most consistently observed for WHR. Hence, our results suggest that HC and WHR may have lesser value than the other anthropometric measures considered in our study for assessing hypertension risk. Nonetheless, comparable to the similarities found for the strength of association between anthropometric and BIA measures with blood pressure and hypertension, the overall differences in discriminative ability between all measures were slight.The limitations of our study warrant mention. First, the generalizability of our findings may be limited by the population-based study. Second, due to the cross-sectional analysis, causal inferences cannot be made for the association of adiposity with blood pressure and hypertension. However, the largely causal relationship between adiposity and blood pressure is well-established , and theWe provide additional evidence to support the adequacy of simple anthropometric measures in evaluating adiposity-related risk. Our findings suggest no material differences between BIA and anthropometric measures of adiposity in relation with blood pressure and hypertension. The observed similarities between adiposity measures may have important implications for facilitating research and risk stratification of populations in remote resource-limited settings where more intricate health measures are not feasible. Nevertheless, as more sophisticated body composition methods become readily available, further studies in India and other LMIC are required to identify the best and most suitable measure of adiposity and its associated risks.


Ultimately, monitoring the microcirculation may help not only to identify alterations in tissue perfusion but also to identify the type of alterations: diffuse decrease in microvascular perfusion versus heterogeneity in the alterations, as in sepsis, with well perfused areas in close vicinity to poorly perfused areas. Regarding supportive therapy, a step-by-step approach is suggested, with fluid optimization followed by vasoactive support to preserve perfusion pressure and global and regional blood flows. The different variables should be integrated into decision and management pathways, and therapies adapted accordingly.Evaluation of the cardiovascular profile of critically ill patients is one of the most important actions performed in critically ill patients. It allows recognition that the patient is in shock and characterization of the type of circulatory failure. This step is crucial to initiate supportive interventions and to cure the cause responsible for the development of shock. Evaluation of tissue perfusion allows identification of the patient insufficiently resuscitated and also to trigger therapeutic interventions. Monitoring tissue perfusion can be achieved by lactate, venoarterial gradients in PCO Evaluation of the cardiovascular profile of critically ill patients is one of the most common explorations performed in the ICU. Several tools can be used to evaluate the hemodynamic state of a patient but the interest of a given technique goes well beyond its invasiveness. Even though ideally less invasive methods should be preferred over more invasive methods, the reliability of cardiac output measurements with some of the noninvasive techniques is sometimes questioned in patients in shock states . More imIn patients with shock, the decision to use a given hemodynamic technique should be based on what the physician expects from the measured variables. The following four important questions should be addressed: Is the patient in shock? What is the type of shock? Is tissue perfusion adequate, and if not how to improve it? Is cardiovascular function adequate?2 by the tissues becomes limited by DO2. In the past, VO2/DO2 relationships were evaluated at the bedside, but this was quite cumbersome and subject to errors in measurements. Accordingly, surrogate markers are often used to identify shock, among which are measurements of blood lactate levels as lactate levels rise sharply when DO2 reaches the point at which VO2 becomes dependent on DO2. Shock is also associated with signs of impairment of tissue perfusion , but these may already be present before the onset of VO2/DO2 dependency.In a recent consensus, shock was defined as “a life-threatening, generalized form of acute circulatory failure associated with inadequate oxygen utilization by the cells”. Shock is thus a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysoxia. Hence, VOImportantly, even though hypotension is often encountered in shock states, shock may sometimes develop without hypotension . Accordingly, a patient who presents signs of impaired tissue perfusion and increased plasma lactate levels should be considered a patient in shock.The next important point would be to evaluate the type of shock that the patient presents, as it would orient not only supportive therapies but also causal management. There are four types of shock: hypovolemic, cardiogenic, obstructive, and distributive. Several hemodynamic tools can be used to determine the type of shock. However, echocardiography is the most convenient tool as it can rapidly lead to the diagnosis of the type of shock. In a study including 108 patients in shock, echocardiography diagnosed the type of shock within 4.9 ± 1.3 min . There wThe advantage of the pulmonary artery catheter and transpulmonary thermodilution over other less invasive techniques is that these provide not only reliable cardiac output measurements even in extreme conditions, but also additional variables that help to understand the cardiovascular profile. The pulmonary artery catheter allows the measurement of intravascular pressures while transpulmonary thermodilution estimates intravascular volumes. With the measurements of intravascular pressures and volumes it is feasible to identify the type of shock Fig. .Fig. 2DiMeasurements of blood lactate levels can be useful to detect occult tissue hypoxia and also to monitor the effects of therapy.2O, and CO2, but can also be transformed into lactate if oxygen is lacking or in some cells that do not contain mitochondria. In normal conditions, most pyruvate enters the mitochondria, so that the normal lactate/pyruvate ratio is around 10. In anaerobic conditions, pyruvate cannot enter the mitochondria and massive amounts of lactate will be produced and the lactate/pyruvate ratio increases well above 20.Lactate is a byproduct of glycolysis. In the first phase, which is anaerobic and occurs in the cytoplasm, glucose is transformed into pyruvate. If oxygen is present, the pyruvate enters the mitochondria to participate in the second phase of reactions, generating ATP, HIt is commonly accepted that hyperlactatemia is mostly of hypoxic origin in critically ill patients with circulatory failure. However, tissue hypoxia cannot be sustained for long periods of time without inducing cell death, as the energy produced by anaerobic metabolism is quite low compared to aerobic metabolism. Mild hyperlactatemia in hemodynamically stable septic patients is often not related to tissue hypoxia. Sepsis-induced inflammatory mediators accelerate aerobic glycolysis, increasing pyruvate availability. This increase in pyruvate availability can lead to increased lactate production, even in the presence of large amounts of oxygen. In addition to the increased lactate production, a decrease in lactate clearance can participate in hyperlactatemia. In patients with shock, hyperlactatemia is often of hypoxic origin shortly after admission, while hyperlactatemia persisting for more than 1 day is often of nonhypoxic origin .2 is inversely related to flow, provided CO2 production remains constant. The normal PvaCO2 gradient is lower than or equal to 6 mmHg. When ScvO2 is abnormal, the increase in PvaCO2 mostly reflects the decrease in cardiac output. When ScvO2 is normal, an increase in PvaCO2 reflects microcirculatory dysfunction [According to the Fick equation, the difference between venous and arterial PCOfunction , 6.2 can also reflect occurrence of anaerobic metabolism. In anaerobic conditions, aerobic CO2 production decreases but CO2 is also generated by buffering the protons generated by ATP hydrolysis so that CO2 production becomes higher than VO2. Accordingly, the respiratory quotient becomes higher than 1. The respiratory quotient can be approximated by dividing PvaCO2 by arteriovenous O2 difference, and a ratio above 1.3 suggests anaerobic metabolism. In order to eliminate potential interference with the Haldane effect, the ratio between venoarterial CO2 content/arteriovenous O2 difference is computed, with a ratio above 1 reflecting anaerobic metabolism.Interestingly, the increase in PvaCO2 content/arteriovenous O2 difference ratio above 1 was associated with a poor outcome.In patients with septic shock, Ospina-Tascon et al.  demonstr2 differences, and ScvO2 can help to discriminate between normal and abnormal patterns, and to identify which part of the system is mostly contributing to these alterations. Of course, combination of several processes may occur  but one often prevails over the other. The decision algorithm is shown in Fig. Combining lactate, COIn patients with circulatory failure, organ perfusion is often decreased as a result of a low cardiac output or perfusion pressure. However, tissue perfusion can remain altered even after achievement of within-target cardiac output and arterial pressure. The microcirculation is the part of the circulation responsible for fine tuning the distribution of flow at the organ level. Alterations in microvascular perfusion occur in sepsis and septic shock , as wellMicrovascular perfusion can be monitored by several techniques, but direct videomicroscopy is probably the most appropriate method as it allows one to detect heterogeneity of perfusion, which is the hallmark of these alterations . In normThe therapeutic approach should be guided by the hemodynamic monitoring variables. An important question is whether therapy should be protocolized or individualized. Protocolized hemodynamic resuscitation is based on the concept that similar target values should be achieved in all patients, and these targets are determined on the basis that the majority of the patients reaching these goals would have a better outcome. However, some patients may be exposed to the side effects of the therapies applied to reach these goals when reaching lower goals was sufficient.Fluid management is the cornerstone for the resuscitation of the septic patient, aiming at improved tissue perfusion through an increase in cardiac output. While most patients are usually fluid responsive in the initial stages, fluid resuscitation becomes more challenging at a later stage as many patients may no longer be fluid responsive. In addition, a positive fluid balance, especially at later stages, is associated with poor outcome. Hence, several approaches can be used to predict the response to fluids. Static measurements of preload such as CVP are only useful at their extreme values . TargetiAn alternative is the so-called mini fluid challenge. It has been proposed that administration of a limited amount of fluids (~100 ml) in a short period of time may predict the administration of further fluids . This coBlood pressure is a resuscitative target that has been investigated broadly. Guidelines recommend reaching a mean arterial pressure of 65 mmHg while recognizing that some patients may require higher values , 16. Thi2) based on measurements of ScvO2 and administration of fluids, red blood cell transfusions, and inotropes. The concept of EGDT was initially tested by Rivers et al. [Early goal directed therapy (EGDT) is the second target that has been studied extensively in septic shock patients. Of note, the term EGDT has become evasive as it was interpreted in many directions, so its initial meaning is sometimes lost. For some, EGDT represents aggressive fluid resuscitation, sometimes based on CVP, for others it represents optimal early hemodynamic resuscitation, for others the prompt use of broad-spectrum antibiotics, and so forth. EGDT consists of the optimization of oxygen transport  still be implemented in the most severe, especially if presenting with low ScvO2 at baseline. It should nevertheless be noted that high ScvO2, together with signs of tissue hypoperfusion and organ dysfunction, is not reassuring. High ScvO2 is associated also with a poor outcome and may represent microvascular alterations as well as mitochondrial dysfunction.Several large-scale randomized trials failed to reproduce these results . Does thThe second aspect of the bundle that was criticized was the use of CVP to guide fluid resuscitation. Indeed, initial bundles recommended maintaining CVP between 8 and 12 mmHg. While this may be relatively satisfactory on a statistical basis, as many (2/3) of the patients with CVP values below 8 mmHg would respond to fluids and as most of the patients with CVP > 12 mmHg will not respond to fluids , the useHow to manipulate the microcirculation? Increasing flow without recruiting the microcirculation is ineffective. Fluids, at the early stages, improve the microcirculation but this effect is blunted at later stages , 27. Int2 or SvO2, in addition to signs of tissue perfusion.Cardiac output measurements provide only one part of the information. However, it is very important to evaluate whether or not cardiac output is adequate. Adequacy of cardiac output can be evaluated by ScvOIn addition, measurements of filling pressures or volumes of cardiac chambers can be helpful to evaluate the cardiovascular performance .When deciding to treat or not an alteration in myocardial contractility, it is important to evaluate the consequences of the impaired contractility: is cardiac output inadequate and is it associated with impaired tissue perfusion? Indeed, the relationship between contractility and cardiac output is relatively loose . Some paA recent trial illustrated the need for individualizing therapy in this domain. In the trial administering levosimendan to patients with septic shock, the addition of levosimendan to standard treatment was not associated with a lower incidence of sepsis-induced organ dysfunction or lower mortality . HoweverHemodynamic assessment remains an important aspect of the care of the critically ill patient. Several tools are available, and the selection of the different tools should be based on the potential interest in a given patient of the measured variables. More than the tools, the use of the measured variables is of critical relevance. The different variables should be integrated into decision and management pathways, and therapies adapted accordingly.