Analysis of effects of acute hypovolemia on arterial stiffness in rabbits monitored with cardio-ankle vascular index.

Although elasticity of the conduit arteries is known to be contribute effective peripheral circulation via Windkessel effects, the relationship between changes in intra-aortic blood volume and conduit artery elasticity remains unknown. Here we assessed the effects of change in intra-aortic blood volume induced by blood removal and subsequent blood transfusion on arterial stiffness and the involvement of autonomic nervous activity using our established rabbit model in the presence or absence of the ganglion blocker hexamethonium (100 mg/kg). Blood removal at a rate of 1 mL/min gradually decreased the blood pressure and blood flow of the common carotid artery but increased a stiffness indicator the cardio-ankle vascular index, which was equally observed in the presence of hexamethonium. These results suggest that arterial stiffness acutely responds to changes in intra-aortic blood volume independent of autonomic nervous system modification.

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

The role of tricuspite annular plane systolic excursion as a marker of hypovolemia in healthy blood donor volunteers.

AIM: The aim of this study is to compare the diameter of the inferior vena cava with tricuspid annular plane systolic excursion (TAPSE) measurement in order to determine the volume loss before and after blood donation in healthy volunteers. METHODS: This Institutional Review Board-approved single center, prospective, cross-sectional study included 60 healthy blood donors donating in a tertiary care hospital's blood bank. After obtaining written consent, systolic, diastolic, and mean arterial blood pressures along with pulse rate of the donors were measured in sitting and supine positions by the attending physician, then, inferior vena cava (IVC) and TAPSE measurements were made before and after blood donation. RESULTS: Statistically significant differences was found between standing systolic blood pressure and pulse rate, lying systolic blood pressure and pulse rate, IVC and TAPSE values before and after blood donation (p < 0.05). There was no difference between the other variables before and after blood donation. CONCLUSION: Our study revealed that, low IVC and TAPSE values correlated in determining blood loss after blood donation. TAPSE may be useful to predict blood loss in early stages of hypovolemic shock.

Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Effect of increased positive end-expiratory pressure on intracranial pressure and cerebral oxygenation: impact of respiratory mechanics and hypovolemia.

BACKGROUND: To evaluate the impact of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP) in animals with different respiratory mechanics, baseline ICP and volume status. METHODS: A total of 50 male adult Bama miniature pigs were involved in four different protocols (n = 20, 12, 12, and 6, respectively). Under the monitoring of ICP, brain tissue oxygen tension and hemodynamical parameters, PEEP was applied in increments of 5 cm H2O from 5 to 25 cm H2O. Measurements were taken in pigs with normal ICP and normovolemia (Series I), or with intracranial hypertension (via inflating intracranial balloon catheter) and normovolemia (Series II), or with intracranial hypertension and hypovolemia (via exsanguination) (Series III). Pigs randomized to the control group received only hydrochloride instillation while the intervention group received additional chest wall strapping. Common carotid arterial blood flow before and after exsanguination at each PEEP level was measured in pigs with intracranial hypertension and chest wall strapping (Series IV). RESULTS: ICP was elevated by increased PEEP in both normal ICP and intracranial hypertension conditions in animals with normal blood volume, while resulted in decreased ICP with PEEP increments in animals with hypovolemia. Increasing PEEP resulted in a decrease in brain tissue oxygen tension in both normovolemic and hypovolemic conditions. The impacts of PEEP on hemodynamical parameters, ICP and brain tissue oxygen tension became more evident with increased chest wall elastance. Compare to normovolemic condition, common carotid arterial blood flow was further lowered when PEEP was raised in the condition of hypovolemia. CONCLUSIONS: The impacts of PEEP on ICP and cerebral oxygenation are determined by both volume status and respiratory mechanics. Potential conditions that may increase chest wall elastance should also be ruled out to avoid the deleterious effects of PEEP.

Measuring the ratio of femoral vein diameter to femoral artery diameter by ultrasound to estimate volume status.

BACKGROUND: Currently, the accepted effective method for assessing blood volume status, such as measuring central venous pressure (CVP) and mean pulmonary artery pressure (mPAP), is invasive. The purpose of this study was to explore the feasibility and validity of the ratio of the femoral vein diameter (FVD) to the femoral artery diameter (FAD) for predicting CVP and mPAP and to calculate the cut-off value for the FVD/FAD ratio to help judge a patient's fluid volume status. METHODS: In this study, 130 patients were divided into two groups: in group A, the FVD, FAD, and CVP were measured, and in group B, the FVD, FAD, and mPAP were measured. We measured the FVD and FAD by ultrasound. We monitored CVP by a central venous catheter and mPAP by a Swan-Ganz floating catheter. Pearson correlation coefficients were calculated. The best cut-off value for the FVD/FAD ratio for predicting CVP and mPAP was obtained according to the receiver operating characteristic (ROC) curve. RESULTS: The FVD/FAD ratio was strongly correlated with CVP (R = 0.87, P < 0.0000) and mPAP (R = 0.73, P < 0.0000). According to the ROC curve, an FVD/FAD ratio ≥ 1.495 had the best test characteristics to predict a CVP ≥ 12 cmH2O, and an FVD/FAD ratio ≤ 1.467 had the best test characteristics to predict a CVP ≤ 10 cmH2O. An FVD/FAD ratio ≥ 2.03 had the best test characteristics to predict an mPAP ≥ 25 mmHg. According to the simple linear regression curve of the FVD/FAD ratio and CVP, when the predicted CVP ≤ 5 cmH2O, the FVD/FAD ratio was ≤ 0.854. CONCLUSION: In this study, the measurement of the FVD/FAD ratio obtained via ultrasound was strongly correlated with CVP and mPAP, providing a non-invasive method for quickly and reliably assessing blood volume status and providing good clinical support.

Another controller system for arterial pressure. AngII-vasopressin neural network of the parvocellular paraventricular nucleus may regulate arterial pressure during hypotension.

Angiotensin II (AngII) immunoreactive cells, fibers and receptors, were found in the parvocelluar region of paraventricular nucleus (PVNp) and AngII receptors are present on vasopressinergic neurons. However, the mechanism by which vasopressin (AVP) and AngII may interact to regulate arterial pressure is not known. Thus, we tested the cardiovascular effects of blockade of the AngII receptors on AVP neurons and blockade of vasopressin V1a receptors on AngII neurons. We also explored whether the PVNp vasopressin plays a regulatory role during hypotension in anesthetized rat or not. Hypovolemic-hypotension was induced by gradual bleeding from femoral venous catheter. Either AngII or AVP injected into the PVNp produced pressor and tachycardia responses. The responses to AngII were blocked by V1a receptor antagonist. The responses to AVP were partially attenuated by AT1 antagonist and greatly attenuated by AT2 antagonist. Hemorrhage augmented the pressor response to AVP, indicating that during hemorrhage, sensitivity of PVNp to vasopressin was increased. By hemorrhagic-hypotension and bilateral blockade of V1a receptors of the PVNp, we found that vasopressinergic neurons of the PVNp regulate arterial pressure towards normal during hypotension. Taken together these findings and our previous findings about angII (Khanmoradi and Nasimi, 2017a) for the first time, we found that a mutual cooperative system of angiotensinergic and vasopressinergic neurons in the PVNp is a major regulatory controller of the cardiovascular system during hypotension.

Novel Method of Calculating Pulse Pressure Variation to Predict Fluid Responsiveness to Transfusion in Very Low Birth Weight Infants.

A novel technique was used to calculate pulse pressure variation. The algorithm reliably predicted fluid responsiveness to transfusion, with a receiver operating characteristic area under the curve of 0.89. This technique may assist clinicians in the management of fluids and vasoactive medications for premature infants.

Comparison of non-invasive physiological assessment tools between simple and perforated appendicitis in children.

PURPOSE: The role of non-invasive measures of physiologic reserve, specifically the Compensatory reserve index (CRI) and the Shock index pediatric age-adjusted (SIPA), is unknown in the management of children with acute appendicitis. CRI is a first-in-class algorithm that uses pulse oximetry waveforms to continuously monitor central volume status loss. SIPA is a well-validated, but a discontinuous measure of shock that has been calibrated for children. METHODS: Children with suspected acute appendicitis (2-17 years old) were prospectively enrolled at a single center from 2014 to 2015 and monitored with a CipherOx CRI™ M1 pulse oximeter. CRI values range from 1 (normovolemia) to 0 (life-threatening hypovolemia). SIPA is calculated by dividing heart rate by systolic blood pressure and categorized as normal or abnormal, based on age-specific cutoffs. Univariate and multivariable regression models were developed with simple versus perforated appendicitis as the outcome. RESULTS: Almost half the patients (45/94, 48%) had perforated appendicitis. On univariate analysis, the median admission CRI value was significantly higher (0.60 versus 0.33, p < 0.001) and the ED SIPA values were significantly lower (0.90 versus 1.10, p = 0.002) in children with simple versus perforated appendicitis. In a multivariable model, only CRI significantly detected differences in the physiologic state between patients with simple and perforated appendicitis. CONCLUSIONS: CRI is a non-invasive measure of physiologic reserve that may be used to accurately guide early management of children with acute simple versus perforated appendicitis.

Supine Parasympathetic Withdrawal and Upright Sympathetic Activation Underly Abnormalities of the Baroreflex in Postural Tachycardia Syndrome: Effects of Pyridostigmine and Digoxin.

[Figure: see text].

The effect of hypercapnia on regional cerebral blood flow regulation during progressive lower-body negative pressure.

PURPOSE: Previous work indicates that dynamic cerebral blood flow (CBF) regulation is impaired during hypercapnia; however, less is known about the impact of resting hypercapnia on regional CBF regulation during hypovolemia. Furthermore, there is disparity within the literature on whether differences between anterior and posterior CBF regulation exist during physiological stressors. We hypothesized: (a) lower-body negative pressure (LBNP)-induced reductions in cerebral blood velocity (surrogate for CBF) would be more pronounced during hypercapnia, indicating impaired CBF regulation; and (b) the anterior and posterior cerebral circulations will exhibit similar responses to LBNP. METHODS: In 12 healthy participants (6 females), heart rate (electrocardiogram), mean arterial pressure (MAP; finger photoplethosmography), partial pressure of end-tidal carbon dioxide (PETCO2), middle cerebral artery blood velocity (MCAv) and posterior cerebral artery blood velocity (PCAv; transcranial Doppler ultrasound) were measured. Cerebrovascular conductance (CVC) was calculated as MCAv or PCAv indexed to MAP. Two randomized incremental LBNP protocols were conducted (- 20, - 40, - 60 and - 80 mmHg; three-minute stages), during coached normocapnia (i.e., room air), and inspired 5% hypercapnia (~ + 7 mmHg PETCO2 in normoxia). RESULTS: The main findings were: (a) static CBF regulation in the MCA and PCA was similar during normocapnic and hypercapnic LBNP trials, (b) MCA and PCA CBV and CVC responded similarly to LBNP during normocapnia, but (c) PCAv and PCA CVC were reduced to a greater extent at - 60 mmHg LBNP (P = 0.029; P < 0.001) during hypercapnia. CONCLUSION: CBF regulation during hypovolemia was preserved in hypercapnia, and regional differences in cerebrovascular control may exist during superimposed hypovolemia and hypercapnia.

'Diagnosing food protein-induced enterocolitis syndrome'.

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES.

Venous Waveform Analysis Correlates With Echocardiography in Detecting Hypovolemia in a Rat Hemorrhage Model.

BACKGROUND: Assessing intravascular hypovolemia due to hemorrhage remains a clinical challenge. Central venous pressure (CVP) remains a commonly used monitor in surgical and intensive care settings for evaluating blood loss, despite well-described pitfalls of static pressure measurements. The authors investigated an alternative to CVP, intravenous waveform analysis (IVA) as a method for detecting blood loss and examined its correlation with echocardiography. METHODS: Seven anesthetized, spontaneously breathing male Sprague Dawley rats with right internal jugular central venous and femoral arterial catheters underwent hemorrhage. Mean arterial pressure (MAP), heart rate, CVP, and IVA were assessed and recorded. Hemorrhage was performed until each rat had 25% estimated blood volume removed. IVA was obtained using fast Fourier transform and the amplitude of the fundamental frequency (f1) was measured. Transthoracic echocardiography was performed utilizing a parasternal short axis image of the left ventricle during hemorrhage. MAP, CVP, and IVA were compared with blood removed and correlated with left ventricular end diastolic area (LVEDA). RESULTS: All 7 rats underwent successful hemorrhage. MAP and f1 peak amplitude obtained by IVA showed significant changes with hemorrhage. MAP and f1 peak amplitude also significantly correlated with LVEDA during hemorrhage (R = 0.82 and 0.77, respectively). CVP did not significantly change with hemorrhage, and there was no significant correlation between CVP and LVEDA. CONCLUSIONS: In this study, f1 peak amplitude obtained by IVA was superior to CVP for detecting acute, massive hemorrhage. In addition, f1 peak amplitude correlated well with LVEDA on echocardiography. Translated clinically, IVA might provide a viable alternative to CVP for detecting hemorrhage.

Mechanisms and management of gastrointestinal symptoms in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance associated with many GI manifestations that can be broadly classified into two different categories: those present all the time (non-positional) and those that occur with orthostatic position change. There are also many conditions that can co-exist with POTS such as mast cell activation syndrome and the hypermobile form of Ehlers-Danlos syndrome (hEDS) that are also oftentimes associated with GI symptoms. In the current issue of Neurogastroenterology and Motility, Tai et al. explored the relationship between functional GI disorders among hEDS patients with and without concomitant POTS and showed that the hEDS-POTS cohort was more likely to have more than one GI organ involved compared to the cohort with hEDS alone, and certain GI symptoms were also more common in the hEDS-POTS cohort. In this review article, we will briefly review the literature surrounding putative mechanisms responsible for GI symptoms in POTS with an emphasis on the contributory role of concomitant hEDS and then discuss management strategies for GI symptoms in POTS.

Severe acute pancreatitis: capillary permeability model linking systemic inflammation to multiorgan failure.

Severe acute pancreatitis (SAP) includes persistent systemic inflammation (SIRS) and multiorgan failure (MOF). The mechanism of transition from SIRS to MOF is unclear. We developed a fluid compartment model and used clinical data to test predictions. The model includes vascular, interstitial and "third-space" compartments with variable permeability of plasma proteins at the capillaries. Consented patients from University of Pittsburgh Medical Center Presbyterian Hospital were studied. Preadmission and daily hematocrit (HCT), blood urea nitrogen (BUN), creatine (Cr), albumin (Alb), and total protein (TP) were collected, and nonalbumin plasma protein (NAPP = TP minus the Alb) was calculated. Subjects served as their own controls for trajectory analysis. Of 57 SAP subjects, 18 developed MOF (5 died), and 39 were non-MOF (0 died). Compared with preadmission levels, admission HCT increased in MOF +5.00 [25%-75% interquartile range, IQR] versus non-MOF -0.10 [-1.55, 1.40] (P < 0.002) with HCT > +3 distinguishing MOF from non-MOF (odds ratio 17.7, P = 0.014). Preadmission Alb fell faster in MOF than non-MOF (P < 0.01). By day 2, TP and NAPP dropped in MOF but not non-MOF (P < 0.001). BUN and Cr levels increased in MOF (P = 0.001), but BUN-to-Cr ratios remained constant. Pancreatic necrosis was more common in MOF (56%) than non-MOF (23%). Changing capillary permeability to allow loss of NAPP in this model predicts loss of plasma oncotic pressure and reduced vascular volume, hypotension with prerenal azotemia and acute kidney dysfunction, pancreas necrosis, and pulmonary edema from capillary leak in the lung with acute respiratory distress syndrome. Sequential biomarker analysis in humans with or without MOF is consistent with this model. This study is registered on https://clinicaltrials.gov at NCT03075605.NEW & NOTEWORTHY Acute pancreatitis is a sudden inflammatory response to pancreatic injury that may spread to systemic inflammation, multiorgan failure, and death in some patients. With the use of the predictions of a new mechanistic model, we compared patients with severe acute pancreatitis with or without multiorgan failure. All biomarkers of capillary leak and clinical features of multiorgan failure were accurately predicted. This provides a new paradigm for understanding and developing new treatments for patients with severe acute pancreatitis.

Oxytocin-monomeric red fluorescent protein 1 synthesis in the hypothalamus under osmotic challenge and acute hypovolemia in a transgenic rat line.

We generated a transgenic rat line that expresses oxytocin (OXT)-monomeric red fluorescent protein 1 (mRFP1) fusion gene to visualize the dynamics of OXT. In this transgenic rat line, hypothalamic OXT can be assessed under diverse physiological and pathophysiological conditions by semiquantitative fluorometry of mRFP1 fluorescence intensity as a surrogate marker for endogenous OXT. Using this transgenic rat line, we identified the changes in hypothalamic OXT synthesis under various physiological conditions. However, few reports have directly examined hypothalamic OXT synthesis under hyperosmolality or hypovolemia. In this study, hypothalamic OXT synthesis was investigated using the transgenic rat line after acute osmotic challenge and acute hypovolemia induced by intraperitoneal (i.p.) administration of 3% hypertonic saline (HTN) and polyethylene glycol (PEG), respectively. The mRFP1 fluorescence intensity in the paraventricular (PVN) and supraoptic nuclei (SON) was significantly increased after i.p. administration of HTN and PEG, along with robust Fos-like immunoreactivity (co-expression). Fos expression showed neuronal activation in the brain regions that are associated with the hypothalamus and/or are involved in maintaining water and electrolyte homeostasis in HTN- and PEG-treated rats. OXT and mRFP1 gene expressions were dramatically increased after HTN and PEG administration. The plasma OXT level was extremely increased after HTN and PEG administration. Acute osmotic challenge and acute hypovolemia induced upregulation of hypothalamic OXT in the PVN and SON. These results suggest that not only endogenous arginine vasopressin (AVP) but also endogenous OXT has a key role in maintaining body fluid homeostasis to cope with hyperosmolality and hypovolemia.