Normal Plasma Volume Research Articles

Understanding the variability in red cell and plasma volume combinations can help guide management in heart failure.

Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles across heart failure (HF) phenotypes. These profiles extend from hypovolaemia to normal BV and to variable degrees of BV hypervolaemia, frequently with similar clinical presentations. However, a comprehensive survey of BV profiles providing practical clinical guidance for the interpretation and management of quantitative plasma volume (PV) and red blood cell (RBC) mass findings has not been reported. The intent of this study is to advance this concept through a multicentre analysis. A retrospective analysis of clinical and BV data was undertaken in stable NYHA class II-III HF patients (N=546). BV was quantitated using established nuclear medicine indicator-dilution methodology. Differing combinations of PV and RBC mass were identified contributing to marked heterogeneity in overall BV profiles. A quantitatively normal BV was identified in 32% of the cohort but of these only ~1/3 demonstrated a true normal BV (i.e., normal PV+normal RBC mass). The remaining portion of normal BV profiles reflected balanced combinations of compensatory PV expansion with RBC mass deficit (anaemia) (14% of cohort) and PV contraction with RBC mass excess (erythrocythemia) (6% of cohort). Main contributors to BV hypervolaemia were PV excess with a normal RBC mass (21% of cohort; 23% female) and PV excess with erythrocythemia (24% of cohort; 26% female). Hypovolaemia was predominately defined by RBC mass deficit with a normal PV (6% of cohort; 57% female) or RBC mass deficit with PV contraction (5% of cohort; 48% female). Findings support the clinical relevance of identifying and accurately interpreting the varying combinations of PV and RBC mass in patients with chronic HF. This in turn helps guide appropriate individualized patient management strategies. A practical volume-based guideline is provided in an effort to aid clinician interpretation.

Comparison of Blood Volume Profiles in Heart Failure With Preserved and Reduced Ejection Fractions: Sex Makes a Difference.

Blood volume (BV) profiles vary markedly in patients with heart failure (HF), but how HF phenotypes and patient sex impact volume profiles remain to be explored. The aim of the study was to differentiate BV, plasma volume, and red blood cell mass profiles by phenotypes of preserved and reduced left ventricular ejection fractions and assess the impact of patient sex on profile heterogeneity. Retrospective analysis of clinical and BV data was undertaken in patients with chronic New York Heart Association II-III heart failure. BV was quantitated using the nuclear medicine indicator-dilution methodology. A total of 530 BV analyses (360 HF with reduced ejection fraction and 170 HF with preserved ejection fraction) were identified in 395 unique patients. Absolute BV was greater in HF with reduced ejection fraction (6.7±1.8 versus 5.9±1.6 liters: P<0.001); however, large variability in frequency distribution of volume profiles was observed in both phenotypes (-22% deficit to +109% excess relative to normal volumes). HF with reduced ejection fraction was characterized by a higher prevalence of BV expansion ≥+25% of normal (39% versus 26%; P=0.003), and HF with preserved ejection fraction was characterized a by more frequent normal BV (42% versus 24%; P<0.001). Male sex in both phenotypes was associated with a larger absolute BV (7.0±1.6 versus 5.1±1.3 liters; P<0.001) and higher frequency of large BV and plasma volume expansions above normal (both P<0.001), while females in both phenotypes demonstrated a higher prevalence of normal BV and plasma volume (both P<0.001). Findings support significant differences in BV, plasma volume, and red blood cell mass profile distributions between heart failure phenotypes, driven in large part by sex-specific factors. This underscores the importance of identifying and distinguishing individual patient volume profiles to help guide volume management strategies.

Patient Sex Impacts Volume Phenotypes and Hemodynamics in Chronic Heart Failure: A Multicenter Analysis

BackgroundQuantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles in patients with chronic heart failure (HF). How patient sex might impact this volume heterogeneity and relationship to cardiac hemodynamics remains to be defined. MethodsRetrospective analysis of clinical and quantitative BV, plasma volume (PV) and red blood cell (RBC) mass data was undertaken across three medical centers. BV was quantitated using nuclear medicine I-131-labelled plasma albumin indicator-dilution methodology with cardiac hemodynamics obtained within 24 hours. ResultsIn an analysis of 149 males and 106 females absolute BV was greater on average in males (6.9±1.7 vs. 5.0±1.2 liters, p<0.001) however, a wide range in BVs was demonstrated in both sexes (2.9 to 14.5 liters). Male sex was associated with higher prevalence of large (>+25% of normal) BV and PV expansions (36% vs. 15% and 51% vs. 21%, respectively, both p<0.001). In contrast, female sex was associated with higher prevalence of normal total BV (44% vs. 27%, p=0.005), PV (54% vs. 27%, p<0.001), hypovolemia (23% vs. 11%, p=0.005) and true anemia (42% vs. 26%, p<0.001). Cardiac hemodynamics differed by sex but only modest associations were demonstrated between volume profiles and cardiac filling pressures. ConclusionsFindings support unique intravascular volume profiles reflecting sex-specific differences in the prevalence and distributions of total BV, PV and RBC mass profiles in chronic HF patients. This underscores the importance of recognizing patient sex as a significant factor influencing volume homeostasis which needs to be taken into account to effectively individualize volume management strategies.

Blood volume phenotypes and patient sex in resistant hypertension.

The relationship of blood volume (BV) to systemic blood pressure (BP) is not well defined in resistant hypertension (RH). The goal of this study was to examine the extent to which systemic BP stratified by patient sex would impact BV phenotypes. A retrospective analysis of clinical and quantitative BV data was undertaken in a cohort of ambulatory patients with a history of controlled and uncontrolled RH. We analyzed 253 unique BVs with 54% of patients above goal BP of <150 mmHg. BV phenotypes were highly variable but no correlation of systolic BP to absolute BV or percentage deviation from normal volume was identified in either sex. Males demonstrated overall larger absolute BVs with higher prevalence of large plasma volume (PV) expansion; females were overall more hypovolemic by total BV but with a higher frequency of normal PV than males. Females trended towards more RBC mass deficit (true anemia) (49% vs. 38%. P = 0.084) while more males demonstrated RBC mass excess (erythrocythemia) (21% vs. 11%, P = 0.029). Importantly, a significant portion (52%) of patients with true anemia identified by BVA would go undetected by hemoglobin measurement alone. BV phenotypes are highly diverse in patients with RH. However, absolute BV or variability in BV phenotypes even when stratified by patient sex did not demonstrate an association with systemic BP. BV phenotyping provides a key to optimizing clinical management by identifying RBC mass profiles particularly distinguishing true anemia, dilutional anemia, and erythrocythemia and the contribution of PV expansion. Findings support the clinical utility of BV phenotyping in RH.

427 MUTUAL INTERDEPENDENCE OF BNP, PLASMA VOLUME, RENAL FUNCTION AND LVEF IN HEALTHY SUBJECTS

Abstract Background Natriuretic peptides play an important role in cardiovascular control, stimulating diuresis and vasodilatation and suppressing the renin-angiotensin-aldosterone system. They are also pivotal markers in diagnosis, prognosis and therapy of heart failure (HF), specially BNP and its precursor pro-hormone Nt-proBNP. .Many factors can affect BNP levels in HF patients, potentially reducing its diagnostic accuracy. The main important ones include left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR) and plasma volume (PV). Though the mutual relationship between BNP levels and these drivers is well studied in HF patients, paradoxically little is known about this relationship in physiological conditions in healthy subjects. We tried to elucidate mutual interdependence of BNP, PV, renal function and LVEF in healthy subjects. Methods A total of 200 healthy adult males underwent clinical assessment, measurement of serum levels of BNP, creatinine, uricemia, hemochrome and echocardiography for LVEF assessment. GFR was calculated according to EPI-CKD formula. PV was estimated with both the Hakim formula and the Kaplan formula. The ideal PV (iPV) i.e. the normal PV was calculated using body weight and sex: iPV (in ml) = c × body weight (in kg), where c = 39 in males and 40 in females. Results Mean levels of BP, LVEF, BNP, serum creatinine, GFR, uricemia and PV were all within the normal range. PV1 and PV2 were significantly different from each other and both differed from iPV (Friedman ANOVA; | = 28.4; df = 2; P &amp;lt;0.01 for all the comparisons). Nevertheless, the three estimates of PV were all significantly and strictly correlated to each other (Spearman correlation coefficient, Rho &amp;gt;0.82 and P&amp;lt;0.001 for all the correlations). BNP levels were positively correlated with age and inversely with both uricemia and iPV. The latter ones were positively correlated to each other. GFR was inversely correlated with both age and uricemia (but not with PV nor with BNP levels). No correlation was found between LVEF and BNP levels or PV. Conclusions In homeostatic conditions, BNP and PV are inversely correlated in healthy adult males (contrary to the positive correlation existing in HF patients due to the predominant effects of angiotensin II and aldosterone), whereas opposite correlations between uricemia and both PV (positive) and GFR (negative) exist. The positive correlation between uricemia and PV could be explained by the strict dependence of tubular reabsorption of uric acid on serum levels of sodium, which is in turn strictly related to the extracellular fluid volume. The negative correlation between uricemia and GFR can be explained by the mutual influence of these two factors, since hyperuricemia seems to be both a cause and a consequence of chronic kidney disease (CKD).

Proteinase-activated receptor-2 (PAR2) on blood pressure and electrolyte handling in the late pregnant rat.

What is the central question of this study? Pregnancy requires marked renal sodium and potassium retention and cumulative plasma volume expansion, in the setting of reduced blood pressure. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in virgin and normal pregnant rats. What is the main finding and its importance? PAR2 expression and sensitivity to activation are increased in pregnancy. This implicates a possible role for PAR2 in supporting the renal/vascular adaptations of pregnancy required for normal maternal plasma volume expansion. A healthy pregnancy involves renal and systemic haemodynamic adaptations, which allow renal sodium and potassium retention and cumulative plasma volume expansion, accompanied by a decline in blood pressure attributable to a reduction in the total peripheral vascular resistance. When these adaptations do not occur, pregnancy is compromised. The mechanisms permitting these opposing adaptations are largely unknown. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in female virgin and normal late pregnant (LP) rats. We measured the mRNA expression of PAR2 in the renal cortex, outer medulla and inner medulla of virgin and LP rats using quantitative real-time PCR. We also measured in vivo blood pressure, natriuretic and kaliuretic responses to PAR2-activating peptide (SLIGRL-NH2 ) in anaesthetized virgin and LP rats. We found that PAR2 mRNA was increased in the inner medulla of LP rats. We also found that LP rats had larger decreases in blood pressure and increases in net sodium retention compared with virgin rats. These findings suggest that pregnancy enhances sensitivity to the blood pressure-lowering and sodium-retaining effects of PAR2.

Diuresis-Related Weight Loss Reflects Interstitial Compartment Decongestion with Minimal Impact on Intravascular Volume Expansion or Outcomes in Post-Acute Heart Failure: Metrics of Decongestion and Volume Status

BackgroundFindings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF. Methods and ResultsData were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (–6.5 ± 4.4%) and PV (–7.5 ± 11%); however, absolute decreases in the PV (–254 mL, interquartile range –11 to –583 mL) were less than 10% of interstitial volume loss (–5040 mL, interquartile range –2800 to –7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430). ConclusionsDiuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF.

Why is Diuresis-related Weight Loss Not a Consistent Predictor of Clinical Outcomes in Heart Failure? -need to Account For Variability in Volume Status

Introduction Change in body weight is a common metric used to assess adequacy of decongestive therapy in patients hospitalized for heart failure (HF). However, the findings of clinical studies linking this metric to clinical decongestion and outcomes are mixed. We propose this reflects the failure to take into account biologic variability in intravascular volume status which would impact response to therapy. Methods Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by median diuresis-related weight loss and analyzed for 1-year outcome of HF-related mortality or 1st re-hospitalization, and the relation of change in weight to change in PV admission to discharge. Results The cohort was composed of 138 patients with median weight loss of 6 (IQR -3.2, -8.1) kg during hospitalization (5 IQR 4, 6 days). Greater than median weight loss (Figure 1) did not result in better outcomes. At the time of hospital discharge the subgroup with greater weight loss (N=61) paradoxically demonstrated greater absolute (4.8±1.0 vs. 4.2±1.0 liters, p<0.001) and relative PV expansion(+44±29% vs. +33±23% above normal, p=0.023). Also demonstrated was marked heterogeneity in PV status in both subgroups (Figure 2). Volumes for the cohort ranged from 17% with normal PV, 23% mild-moderate PV expansion, to 60% with persisting severe (≥ +25%) PV expansion at hospital discharge. In a cohort subgroup of 62 patients where PV was measured at hospital admission and discharge there was no clinically significant association between change in weight and change in PV (r=0.327, p=0.01). Conclusions Diuresis-related changes in weight reflect clinical decongestion but do not consistently reflect better HF outcomes and, importantly, do not accurately reflect changes in intravascular volume. A basis for this discordance is the significant patient-to-patient variability in volume both at admission and discharge which confounds interpretation of surrogate metrics of decongestion. Failure to account for the marked heterogeneity in volume status contributes to the observed discordance between metrics of clinical decongestion and HF outcomes. Change in body weight is a common metric used to assess adequacy of decongestive therapy in patients hospitalized for heart failure (HF). However, the findings of clinical studies linking this metric to clinical decongestion and outcomes are mixed. We propose this reflects the failure to take into account biologic variability in intravascular volume status which would impact response to therapy. Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by median diuresis-related weight loss and analyzed for 1-year outcome of HF-related mortality or 1st re-hospitalization, and the relation of change in weight to change in PV admission to discharge. The cohort was composed of 138 patients with median weight loss of 6 (IQR -3.2, -8.1) kg during hospitalization (5 IQR 4, 6 days). Greater than median weight loss (Figure 1) did not result in better outcomes. At the time of hospital discharge the subgroup with greater weight loss (N=61) paradoxically demonstrated greater absolute (4.8±1.0 vs. 4.2±1.0 liters, p<0.001) and relative PV expansion(+44±29% vs. +33±23% above normal, p=0.023). Also demonstrated was marked heterogeneity in PV status in both subgroups (Figure 2). Volumes for the cohort ranged from 17% with normal PV, 23% mild-moderate PV expansion, to 60% with persisting severe (≥ +25%) PV expansion at hospital discharge. In a cohort subgroup of 62 patients where PV was measured at hospital admission and discharge there was no clinically significant association between change in weight and change in PV (r=0.327, p=0.01). Diuresis-related changes in weight reflect clinical decongestion but do not consistently reflect better HF outcomes and, importantly, do not accurately reflect changes in intravascular volume. A basis for this discordance is the significant patient-to-patient variability in volume both at admission and discharge which confounds interpretation of surrogate metrics of decongestion. Failure to account for the marked heterogeneity in volume status contributes to the observed discordance between metrics of clinical decongestion and HF outcomes.

Plasma volume expansion across healthy pregnancy: a systematic review and meta-analysis of longitudinal studies

BackgroundPlasma volume expansion is an important physiologic change across gestation. High or low expansion has been related to adverse pregnancy outcomes, yet there is a limited understanding of normal/healthy plasma volume expansion. We aimed to evaluate the pattern of plasma volume expansion across healthy pregnancies from longitudinal studies.MethodsWe conducted a systematic review and meta-analysis to identify original studies that measured plasma volume in singleton pregnancies of healthy women. Specifically, we included studies that measured plasma volume at least two times across gestation and one time before or after pregnancy in the same women. PubMed, Web of Science, Cochrane, CINAHL, and clinicaltrials.gov databases were searched from the beginning of each database to February 2019. We combined data across studies using a random effects model.ResultsTen observational studies with a total of 347 pregnancies were eligible. Plasma volume increased by 6% (95% CI 3–9) in the first trimester compared to the nonpregnant state. In the second trimester, plasma volume was increased by 18% (95% CI 12–24) in gestational weeks 14–20 and 29% (95% CI 21–36) in weeks 21–27 above the nonpregnant state. In the third trimester, plasma volume was increased by 42% (95% CI 38–46) in weeks 28–34 and 48% (95% CI 44–51) in weeks 35–38. The highest rate of increase occurred in the first half of the second trimester. Included studies were rated from moderate to high quality; 7 out of 10 studies were conducted over 30 years ago.ConclusionsIn healthy pregnancies, plasma volume begins to expand in the first trimester, has the steepest rate of increase in the second trimester, and peaks late in the third trimester. The patterns observed from these studies may not reflect the current population, partly due to the changes in BMI over the last several decades. Additional longitudinal studies are needed to better characterize the range of normal plasma volume expansion across maternal characteristics.

Diuretic window hypothesis in cirrhosis: Changing the point of view.

Since the 1970s, non-selective beta-blockers (NSBB) have been used to prevent variceal upper bleeding in advanced cirrhotic patients. However, several recent studies have raised the doubt about the benefit of NSBB in end-stage cirrhotic patients. In fact, they suggested a detrimental effect in these patients that even reduced survival. All of these studies have been assembled to compose the “window therapy hypothesis”, in which NSBB would have traditional indication to be initiated to prevent variceal upper bleeding; however, treatment should be stopped (or not be initiated) in patients with end-stage cirrhosis. NSBB would reduce the cardiac reserve of these patients, worsening systemic perfusion and prognosis. However, it should be emphasized that these studies present important bias issues, and their results also suggested that diuretic treatment may also be behind the effects observed. In this opinion review, we changed the point of view from NSBB to diuretic treatment, based on a physiopathogenic approach of circulatory parameters of cirrhotic patients studied, and based on diuretic effect in blood pressure lowering and in other hypervolemic disease, as heart failure. We suggest a “diuretic window hypothesis”, composed by an open window in hypervolemic phase, an attention window when patient present in a normal plasma volume phase, and a closed window during the plasma hypovolemic phase.

Vagal and Sympathetic Function in Neuropathic Postural Tachycardia Syndrome.

The diagnosis of neuropathic postural tachycardia syndrome (POTS) requires research techniques not available clinically. We hypothesized that these patients will have impaired vagal and sympathetic cardiovascular control that can be characterized with clinical autonomic tests. We included 12 POTS patients with possible neuropathic subtype because of normal plasma norepinephrine and no increase in upright blood pressure. We compared them to 10 healthy subjects. We assessed hemodynamics, heart rate and blood pressure variability, baroreflex sensitivity, raw and integrated muscle sympathetic nerve activity, and blood volume. To understand the vagal/sympathetic control, we dissected the phase 2 of Valsalva maneuver (VM) into early (VM2e) and late (VM2l). POTS' upright heart rate increased 43±3 bpm. Patients had normal plasma volume but reduced red blood cell volume (1.29 L versus predicted normal values 1.58 L; P=0.02). Vagal indices of heart rate variability, HFRRI (430±130 versus 1680±900; P=0.04), PNN50, and root mean squared of successive differences were lower in POTS. Patients showed a decrease in vagal baroreflex sensitivity (VM2e; P=0.04). In POTS, integrated muscle sympathetic nerve activity was lower at rest (12±1.5 versus 20±2 burst/min; P=0.004) and raw muscle sympathetic nerve activity spike analysis showed blunted responses during VM2e, despite a greater drop in systolic blood pressure (34±5 in POTS and 14±6 mm Hg in controls; P=0.01). This cohort of POTS patients enriched for possible neuropathic subtype had lower resting muscle sympathetic nerve activity, impaired vagal cardiac control, and exaggerated drop in blood pressure in response to VM and a delay in the sympathetic cardiovascular responsiveness during hypotensive challenge.

Acquired Hemophilia A in the South of Tunisia: A Single Center Study

Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by the development of autoantibodies against factor VIII. There is no previous study published in our country for AHA. The aim of this study that to describe the clinical symptoms, diagnostic criteria and treatment strategies in patients with AHA in the south of Tunisia. We retrospectively collected all patients diagnosed with AHA in the Department of Hematology of Hedi Chaker Hospital (Tunisia) from 2000 to 2017. The diagnosis was established in the presence of clinical hemorrhagic features associated with the isolated prolongation of the activated partial thromboplastin time (APTT), not corrected after two hours by incubating patient plasma with equal volumes of normal plasma, and with factor VIII less than 50%. We collected five patients with AHA in the South of Tunisia. There were 4 females and 1 male with the median age of 32 years old. The median FVIII C was 7% and the median value of FVIII inhibitor was 11 UB. The most common clinical symptoms were post-partum hematoma in 3 patients (60%), extensive cutaneous hematoma in one patient and hemorrhagic tooth extraction in one patient. All patients were treated in first-line therapy with bypassing agent FVIIa with successful response in 80% of cases. The first-line treatment of bleeding in AHA requires a bypassing agent and the optimal therapeutic strategy to eradicate the inhibitor include immunosuppression with corticosteroids alone or corticosteroids in combination with cyclophosphamide.

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats

Plasma testosterone levels are elevated in pregnant women with preeclampsia and polycystic ovaries; their offspring are at increased risk for hypertension during adult life. We tested the hypothesis that prenatal testosterone exposure induces dysregulation of the renin-angiotensin-aldosterone system, which is known to play an important role in water and electrolyte balance and blood pressure regulation. Female rats (6 mo old) prenatally exposed to testosterone were examined for adrenal expression of steroidogenic genes, telemetric blood pressure, blood volume and Na+ and K+ levels, plasma aldosterone, angiotensin II and vasopressin levels, and vascular responses to angiotensin II and arg8-vasopressin. The levels of Cyp11b2 (aldosterone synthase), but not the other adrenal steroidogenic genes, were decreased in testosterone females. Accordingly, plasma aldosterone levels were lower in testosterone females. Plasma volume and serum and urine Na+ and K+ levels were not significantly different between control and testosterone females; however, prenatal testosterone exposure significantly increased plasma vasopressin and angiotensin II levels and arterial pressure in adult females. In testosterone females, mesenteric artery contractile responses to angiotensin II were significantly greater, while contractile responses to vasopressin were unaffected. Angiotensin II type-1 receptor expression was increased, while angiotensin II type-2 receptor was decreased in testosterone arteries. These results suggest that prenatal testosterone exposure downregulates adrenal Cyp11b2 expression, leading to decreased plasma aldosterone levels. Elevated angiotensin II and vasopressin levels along with enhanced vascular responsiveness to angiotensin II may serve as an underlying mechanism to maintain plasma volume and Na+ and K+ levels and mediate hypertension in adult testosterone females.

Normal Plasma Volume Expansion and Micronutrient Status in Pregnancy

Plasma volume expansion is widely known as an important physiologic change in pregnancy, yet normal expansion in healthy pregnancies has not been well described. This expansion influences plasma micronutrient concentrations and may impact interpretation of biomarkers. Our objective was to review studies that measured plasma volume longitudinally across gestation to describe normal plasma volume expansion; secondarily, we examined the impact of plasma volume expansion on micronutrient biomarkers. We systematically searched PubMed for original articles that directly measured plasma volume in pregnant women at more than one time across gestation. We also searched reference lists from these publications for additional papers. We found 15 studies published from 1963 to 2006 that directly measured plasma volume in pregnancy more than one time. We excluded 3 studies because the measurements were not longitudinal and one study because it used an unconventional measurement technique (iron dextran) and some values appeared extreme. Of the 11 longitudinal studies included, 8 studies were conducted in the UK and one each was conducted in India, Chile, and Nigeria. All studies used the Evans blue dye (T‐1824) indicator dilution method to measure the plasma volume. The total number of women in all studies was 524; study size ranged from 11 to 95. Plasma volume was measured 3 to 7 times in women across the studies. Two studies measured plasma volume before conception and 5 studies measured postpartum values (6–8 weeks after birth) as a proxy for pre‐conception. Plasma volume increases varied across the studies. Plasma volume increased by 8% between preconception and 12 weeks, 18% by 16 weeks, 27% by 20 weeks and 36% by 25 weeks gestation. The maximum mean plasma volume increase was 52% (1267 ± 38 ml) at 33–34 weeks gestation. This peak mean expansion ranged from 48% to 59% (1218 to 1323 ml) across studies, while reports of expansion for individual women ranged from 25% to 80%. Plasma volume slightly declined from late third trimester to term. Only one plasma volume study measured micronutrient status. In that study, plasma zinc concentrations declined across gestation to 30 weeks but intravascular zinc mass (the product of zinc concentration and plasma volume) increased across pregnancy. Plasma copper concentration increased up to gestational week 35 but intravascular copper mass was not reported. Few studies have measured plasma volume longitudinally in pregnancy. Studies of healthy pregnancies similarly show plasma volume increases progressively to approximately 52% above the non‐pregnant state in the third trimester with a slight decline to term. Plasma zinc concentration changes in pregnancy did not reflect actual changes in zinc status. Future studies in pregnancy should measure plasma volume to have a valid estimation of micronutrient status and to understand underlying physiologic changes that may be related to adverse outcomes.Support or Funding InformationNIH BIRCWH 12HD055882 (Dr. Gernand)

Recurrent pre-eclampsia in women with metabolic syndrome and low plasma volume: a retrospective cohort study.

To determine the prevalence of recurrent pre-eclampsia in women with a history of pre-eclampsia with both metabolic syndrome and low plasma volume postpartum, as compared with women without either entity. Retrospective cohort study. Three tertiary referral hospitals in the Netherlands. Women with a history of pre-eclampsia. In 196 women with a history of pre-eclampsia we determined the presence or absence of metabolic syndrome using the World Health Organization criteria and measured plasma volume with the (125) I-human serum albumin indicator dilution technique. We compared the prevalence of recurrent pre-eclampsia in four groups, classified according to presence or absence of metabolic syndrome and low or normal plasma volume, calculating odds ratios (OR), adjusted for confounders. Recurrence of pre-eclampsia in the subsequent pregnancy. The prevalence of recurrent pre-eclampsia was 12% (12/99) in women without metabolic syndrome with normal plasma volume, versus 47% (8/17) in women with both metabolic syndrome and low plasma volume: OR 6.44 (95% CI 2.09-19.90), adjusted OR 7.90 (95% CI 2.30-27.16). Recurrent pre-eclampsia was present in 44% (10/23) and 25% (14/57) of women with isolated metabolic syndrome and low plasma volume, respectively. In the concomitant presence of metabolic syndrome and low plasma volume, the prevalence of recurrent pre-eclampsia was nearly 50%, which is four times as high as the prevalence in women without either entity. Metabolic syndrome and low plasma volume raise the risk of recurrent pre-eclampsia to nearly 50%.

Low Plasma Volume in Normotensive Formerly Preeclamptic Women Predisposes to Hypertension.

Formerly preeclamptic women are at risk for cardiovascular disease. Low plasma volume may reflect latent hypertension and potentially links preeclampsia with chronic cardiovascular disease. We hypothesized that low plasma volume in normotensive formerly preeclamptic women predisposes to hypertension. We longitudinally studied n=104 formerly preeclamptic women in whom plasma volume was measured 3 to 30 months after the preeclamptic pregnancy. Cardiovascular variables were assessed at 2 points in time (3-30 months postpartum and 2-5 years thereafter). Study population was divided into low plasma volume (≤1373 mL/m(2)) and normal plasma volume (>1373 mL/m(2)). Primary end point was hypertension at the second visit: defined as ≥140 mm Hg systolic or ≥90 mm Hg diastolic. Secondary outcome of this study was change in traditional cardiovascular risk profile between visits. Variables correlating univariately with change in blood pressure between visits were introduced in regression analysis. Eighteen of 104 (17%) formerly preeclamptic women who were normotensive at first visit had hypertension at second evaluation 2 to 5 years later. Hypertension developed more often in women with low plasma volume (10/35 [29%]) than in women with normal plasma volume (8/69 [12%]; odds ratio, 3.2; 95% confidence interval, 1.4-8.6). After adjustments, relationship between plasma volume status and subsequent hypertension persisted (adjusted odds ratio, 3.0; 95% confidence interval, 1.1-8.5). Mean arterial pressure at second visit correlated inverse linearly with plasma volume (r=-0.49; P<0.01). Initially normotensive formerly preeclamptic women have 17% chance to develop hypertension within 5 years. Women with low plasma volume have higher chance to develop hypertension than women with normal plasma volume. Clinically, follow-up of blood pressure seems warranted in women with history of preeclampsia, even when initially normotensive.

Extracellular hydration, cardiovascular risk, and the interstitium: a three-dimensional view

Volume expansion is a major contributor to poor cardiovascular outcomes in kidney disease. The relationship of extracellular volume (ECV) overload to cardiovascular changes in chronic kidney disease (CKD) remains speculative. Recent studies are challenging traditional concepts and providing new insight into mechanisms and the relationship of ECV to cardiovascular health. A dynamic role of the extracellular interstitium in inducing cardiovascular risk is emerging in CKD.

Optimisation of lupus anticoagulant tests: should test samples always be mixed with normal plasma?

Coagulation factor deficiencies are thought to interfere with the detection of the phospholipid-dependent coagulation inhibitor known as lupus anticoagulant (LA). Treatment with vitamin K antagonists (VKA) in particular, is thought to preclude accurate LA assessment. For this reason, the procedure to detect LA includes a mixing test, in which coagulation factor deficiencies are corrected by mixing samples with an equal volume of normal plasma. Despite these mixing tests, interpretation of LA test results is considered difficult in patients receiving high intensity VKA treatment. As a result, VKA treatment is often temporarily discontinued to allow LA assessment. However, whether coagulation factor deficiencies influence LA test results is unclear. We found that neither deficiency of a single coagulation factor, nor a functional coagulation factor deficiency due to high intensity VKA treatment, resulted in false positive dRVVT- or APTT-based (silica clotting time; SCT) LA test results. LA was readily detected in unmixed samples from VKA-treated LA-positive patients with both dRVVT and SCT reagents. VKA treatment caused an underestimation of the strength of the LA with SCT reagents, but did not lead to misclassification of LA status. Although mixing with normal plasma during both screen and confirm tests allowed more accurate assessment of the strength of the LA with SCT reagents in samples with an international normalised >2.5, the mixing procedure itself lead to misclassification of LA in weakly positive samples from patients not treated with VKA. Based on these findings, we conclude that mixing studies are not necessary during LA-assessment.

432

Introduction: Cerebral salt wasting (CSW) and the syndrome of inappropriate antidiuretic hormone release (SIADH) are two causes of hyponatremia in neurocritical care patients. CSW presents with decreased plasma volume (PV); SIADH presents with normal or increased PV. Clinical exam and CVP are unreliable for assessing circulating volume. Bedside isotopic blood volume analysis (BVA) can accurately measure PV and total blood volume (TBV). CSW and SIADH are the result of alterations in the hormonal regulation of plasma volume. Therefore plasma volume levels can be used to distinguish between CSW and SIADH. Methods: The records of patients admitted between 2007 and 2013 who underwent a BVA were reviewed. Patients with a neurointensive care diagnosis were grouped by BVA and Na+ levels. Data collected included: Age, Ht, Wt, Sex; Serum Na+, K+, BUN, Crt, Hct; Urine SG, Na+, Osmo. Additionally, BVA results & outcome were recorded. The incidence of CSW and SIADH based on BVA was determined. A normalized Hct was calculated based on the actual red cell volume and predicted normal plasma volume based on the BVA results. Results: The records of 95 patients with a neurointensive care diagnosis were reviewed. There were a total of 106 BVA performed on these 95 patients. The group consisted of 50 females and 45 males. The mean age was 59.8 + 18.5 years. Overall mortality was 22.1% (21/95). 53.7% (51/95) of patients experienced hyponatremic episodes (Serum Na+< 136 mEq/dl). The most common neurological diagnoses were intraparenchymal hemorrhage (IPH) (26.5%), subarachnoid hemorrhage (SAH) (26.5%), or subdural hematoma (SDH) (24.5%). BVA results in the hyponatremic group demonstrated that plasma volume (PV) was Decreased in 7.8% (4/51), Normal in 43.1% (22/51) and Increased in 49.0% (25/51). Regardless of volume status, all patients had normocytic anemia. Peripheral Hct was 33.0 (+ 4.6), 29.8 (+ 4.5), and 29.0 (+ 4.5) in the Decreased, Normal and Increased plasma volume patients, which was not significant. However, after correcting for plasma volume, the normalized Hct was 24.8 (+ 4.7), 25.5 (+ 5.5), and 30.4 (+ 6.6) in the Decreased, Normal and Increased plasma volume patients (p<0.05). No patient had increased Red Cell Volume (RCV), 3 had a normal RCV (5.9%). There was no significant difference in Hct based on the reason for neurocritical care. Total blood volume (TBV) was decreased in 45.1% (23/51), normal in 39.2% (20/51), and increased in 15.7% (8/51) of the patients. Serum Na+, K+, BUN, Crt, Hct and Urine SG, Na+, Osmolality were not associated with plasma or blood volume status. Among hyponatremic patients, mortality was 18.4%. Conclusions: Evaluation and treatment of hyponatremia in neurointensive care patients remains a challenge. Anemia is common in hyponatremic patients with neurocritical illness. Paradoxically, the normalized Hct is lowest in patients with decreased volume status. Peripheral Hct does not correlate with volume status and may be misleading in this group of patients. The mechanism for this anemia requires additional research. Based on plasma volume levels, CSW was present in only 7.8% of hyponatremic pts. SIADH appears to be more common than CSW in hyponatremic patients. Traditional markers of volume status are not useful in these pts. Measurement of TBV alone may incorrectly identify CSW in 45.1% of hyponatremic pts. Management of hyponatremia can be improved with BVA data and contraindicated interventions avoided. A prospective evaluation of BVA in neurointensive care patients is warranted.