A Porcine Model of Acute Respiratory Failure with a Continuous Infusion of Oleic Acid.

This protocol outlines an acute respiratory distress model utilizing centrally administered oleic acid infusion in Yorkshire pigs. Prior to experimentation, each pig underwent general anesthesia, endotracheal intubation, and mechanical ventilation, and was equipped with bilateral jugular vein central vascular access catheters. Oleic acid was administered through a dedicated pulmonary artery catheter at a rate of 0.2 mL/kg/h. The infusion lasted for 60-120 min, inducing respiratory distress. Throughout the experiment, various parameters including heart rate, respiratory rate, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, end-tidal carbon dioxide, peak airway pressures, and plateau pressures were monitored. Around the 60 min mark, decreases in partial arterial oxygen pressure (PaO2) and fraction of oxygen-saturated hemoglobin (SpO2) were observed. Periodic hemodynamic instability, accompanied by acute increases in pulmonary artery pressures, occurred during the infusion. Post-infusion, histological analysis of the lung parenchyma revealed changes indicative of parenchymal damage and acute disease processes, confirming the effectiveness of the model in simulating acute respiratory decompensation.

The Cell Permeant Phosphopetpide mimetic of VASP Alleviates Motor Function Deficits After Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm leads to delayed vasospasm and neuroischemia, which can result in profound neurologic deficit and death. Therapeutic options after SAH are currently limited to hemodynamic optimization and nimodipine, which have limited clinical efficacy. Experimental SAH results in cerebral vasospasm have demonstrated the downregulation of nitric oxide (NO)-protein kinase G (PKG) signaling elements. VP3 is a novel cell permeant phosphopeptide mimetic of VASP, a substrate of PKG and an actin-associated protein that modulates vasorelaxation in vascular smooth muscle cells. In this study, we determined that intravenous administration of high doses of VP3 did not induce systemic hypotension in rats except at the maximal soluble dose, implying that VP3 is well-tolerated and has a wide therapeutic window. Using a single cisterna magna injection rat model of SAH, we demonstrated that intravenous administration of low-dose VP3 after SAH improved neurologic deficits for up to 14 days as determined by the rotarod test. These findings suggest that strategies aimed at targeting the cerebral vasculature with VP3 may improve neurologic deficits associated with SAH.

Adult and Pediatric Porcine Model of Acute Volume Overload.

This protocol describes an acute volume overload porcine model for adult Yorkshire pigs and piglets. Both swine ages undergo general anesthesia, endotracheal intubation, and mechanical ventilation. A central venous catheter and an arterial catheter are placed via surgical cutdown in the external jugular vein and carotid artery, respectively. A pulmonary artery catheter is placed through an introducer sheath of the central venous catheter. PlasmaLyte crystalloid solution is then administered at a rate of 100 mL/min in adult pigs and at 20 mL/kg boluses over 10 min in piglets. Hypervolemia is achieved either at 15% decrease in cardiac output or at 5 L in adult pigs and at 500 mL in piglets. Hemodynamic data, such as heart rate, respiratory rate, end-tidal carbon dioxide, fraction of oxygen-saturated hemoglobin, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, partial arterial oxygen pressure, lactate, pH, base excess, and pulmonary artery fraction of oxygen-saturated hemoglobin, are monitored during experimentation. Preliminary data observed with this model has demonstrated statistically significant changes and strong linear regressions between central hemodynamic parameters and acute volume overload in adult pigs. Only pulmonary capillary wedge pressure demonstrated both a linear regression and a statistical significance to acute volume overload in piglets. These models can aid scientists in the discovery of age-appropriate therapeutic and monitoring strategies to understand and prevent acute volume overload.

The Effect of Fluid Pre-loading on Vital Signs and Hemodynamic Parameters in a Porcine Model of Lipopolysaccharide-Induced Endotoxemia.

Background Animal models of distributive hypotension and resuscitation allow the assessment of hemodynamic monitoring modalities and resuscitation strategies. The fluid-first paradigm for resuscitation is currently being challenged with clinical trials. In this investigation, venous return and perfusion are assessed, and full hemodynamics are characterized, in a porcine model of endotoxemic hypotension with and without fluid pre-loading. Methods Two groups of six pigs had the induction of standardized endotoxemic hypotension ("critical hypotension"). Group 1 underwent four 10 cc/kg crystalloid boluses, and Group 2 was not fluid pre-resuscitated. Both groups underwent progressive norepinephrine (NE) up-titration to 0.25 mcg/kg/minute over 30 minutes. Vital signs, central parameters, and laboratory values were obtained at baseline, "critical hypotension," after each bolus and during NE administration. Results Endotoxemia decreased the systemic vascular resistance (SVR) in Group 1 (1031±106 dyn/s/cm-5 versus 738±258 dyn/s/cm-5; P=0.03) and Group 2 (1121±196 dyn/s/cm-5 versus 759±342 dyn/s/cm-5; P=0.003). In Group 1, the four fluid boluses decreased heart rate (HR), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) (P<0.05). No changes were observed in blood pressure, cardiac output (CO), or lactate. NE up-titration increased HR in Group 1 and decreased CVP in both groups. Higher final CVP (11 {3} versus 4 {4} mmHg; P=0.01) and PCWP (5 {1} versus 2 {2} mmHg; P=0.005) values were observed in Group 1 relative to Group 2, reflecting increased venous return. Conclusions Porcine endotoxemic hypotension and resuscitation were robustly characterized. In this model, fluid loading improved venous return with NE, though perfusion (CO) was preserved by increased NE-induced chronotropy.

Central Venous Waveform Analysis and Cardiac Output in a Porcine Model of Endotoxemic Hypotension and Resuscitation.

BACKGROUND: Cardiac output (CO) is a valuable proxy for perfusion, and governs volume responsiveness during resuscitation from distributive shock. The underappreciated venous system has nuanced physiology that confers valuable hemodynamic information. In this investigation, deconvolution of the central venous waveform by the fast Fourier transformation (FFT) algorithm is performed to assess its ability to constitute a CO surrogate in a porcine model of endotoxemia-induced distributive hypotension and resuscitation. STUDY DESIGN: Ten pigs were anesthetized, catheterized, and intubated. A lipopolysaccharides infusion protocol was used to precipitate low systemic vascular resistance hypotension. Four crystalloid boluses (10 cc/kg) were then given in succession, after which heart rate, mean arterial pressure, thermodilution-derived CO, central venous pressure (CVP), and the central venous waveform were collected, the last undergoing fast Fourier transformation analysis. The amplitude of the fundamental frequency of the central venous waveform's cardiac wave (f0-CVP) was obtained. Heart rate, mean arterial pressure, CVP, f0-CVP, and CO were plotted over the course of the boluses to determine whether f0-CVP tracked with CO better than the vital signs, or than CVP itself. RESULTS: Distributive hypotension to a 25% mean arterial pressure decrement was achieved, with decreased systemic vascular resistance (mean 918 ± 227 [SD] dyne/s/cm-5 vs 685 ± 180 dyne/s/cm-5; p = 0.038). Full hemodynamic parameters characterizing this model were reported. Slopes of linear regression lines of heart rate, mean arterial pressure, CVP, f0-CVP, and CO were -2.8, 1.7, 1.8, 0.40, and 0.35, respectively, demonstrating that f0-CVP values closely track with CO over the 4-bolus range. CONCLUSIONS: Fast Fourier transformation analysis of the central venous waveform may allow real-time assessment of CO during resuscitation from distributive hypotension, possibly offering a venous-based approach to clinical estimation of volume responsiveness.

Evaluation of common clinical and hemodynamic parameters to pulmonary capillary wedge pressures in patients undergoing right heart catheterization.

Introduction: A cornerstone of heart failure assessment is the right heart catheterization and the pulmonary capillary wedge pressure measurement it can provide. Clinical and hemodynamic parameters such as weight and jugular venous distention are less invasive measures often used to diagnose, manage, and treat these patients. To date, there is little data looking at the association of these key parameters to measured pulmonary capillary wedge pressure (PCWP). This is a large, retrospective, secondary analysis of a right heart catheterization database comparing clinical and hemodynamic parameters against measured PCWP in heart failure patients. Methods: A total of 538 subjects were included in this secondary analysis. Spearman's Rho analysis of each clinical and hemodynamic variable was used to compare their association to the documented PCWP. Variables analyzed included weight, body mass index (BMI), jugular venous distention (JVD), creatinine, edema grade, right atrial pressure (RAP), pulmonary artery systolic pressure (PASP), systemic vascular resistance, pulmonary vascular resistance, cardiac output (thermal and Fick), systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, oxygen saturation (SpO2), and pulmonary artery diastolic pressure (PADP). Results: Ten out of 17 selected parameters had a statistically significant association with measured PCWP values. PADP had the strongest association (0.73, p<0.0001), followed by RAP and PASP (0.69, p<0.0001 and 0.67, p<0.0001, respectively). Other significant parameters included weight (0.2, p<0.001), BMI (0.2, p<0.001), SpO2 (-0.17, p<0.0091), JVD (0.24, p<0.005) and edema grade (0.2, p<0.0001). Conclusion: This retrospective analysis clarifies the associations of commonly used clinical and hemodynamic parameters to the clinically used gold standard for volume assessment in heart failure patients, PCWP.

Blocking P2X7 receptor with AZ 10606120 exacerbates vascular hyperpermeability and inflammation in murine polymicrobial sepsis.

Sepsis is a devastating disease with high morbidity and mortality and no specific treatments. The pathophysiology of sepsis involves a hyperinflammatory response and release of damage-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), from activated and dying cells. Purinergic receptors activated by ATP have gained attention for their roles in sepsis, which can be pro- or anti-inflammatory depending on the context. Current data regarding the role of ATP-specific purinergic receptor P2X7 (P2X7R) in vascular function and inflammation during sepsis are conflicting, and its role on the endothelium has not been well characterized. In this study, we hypothesized that the P2X7R antagonist AZ 10606120 (AZ106) would prevent endothelial dysfunction during sepsis. As proof of concept, we first demonstrated the ability of AZ106 (10 µM) to prevent endothelial dysfunction in intact rat aorta in response to IL-1ß, an inflammatory mediator upregulated during sepsis. Likewise, blocking P2X7R with AZ106 (10 µg/g) reduced the impairment of endothelial-dependent relaxation in mice subjected to intraperitoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. However, contrary to our hypothesis, AZ106 did not improve microvascular permeability or injury, lung apoptosis, or illness severity in mice subjected to CS. Instead, AZ106 elevated spleen bacterial burden and circulating inflammatory markers. In conclusion, antagonism of P2X7R signaling during sepsis appears to disrupt the balance between its roles in inflammatory, antimicrobial, and vascular function.

Comparison of clinical symptoms and bioimpedance to pulmonary capillary wedge pressure in heart failure.

Introduction: Clinical symptoms of heart failure commonly include fatigue, edema, and shortness of breath. Unfortunately, clinical monitoring has proven unreliable in predicting congestion and the need for hospitalization. Biosensing wearables have been developed as a potential adjunct to clinical signs and symptoms to detect congestion before it becomes severe thus preventing a heart failure hospitalization. Hypothesis: Clinical signs and symptoms of heart failure will correlate with thoracic bioimpedance measurements (ZOE®) and pulmonary capillary wedge pressure (PCWP). Methods: One hundred and fifty-five subjects undergoing right heart catheterization (RHC) were prospectively enrolled. A Zo value (ohms) was obtained, jugular venous pressure (JVP) was estimated, edema graded, and shortness of breath (SOB) assessed in all subjects. RHC was performed by a scheduled cardiologist per routine. One-way ANOVA was performed to assess the relationship between variables. A Pearson correlation coefficient was used to compare the Zo value and PCWP. Results: Neither estimated JVP (cmH2O) (p = 0.65, n = 110) nor edema scores (p = 0.12, n = 110) demonstrated a significant relationship to PCWP. The presence of subjective SOB also did not demonstrate a significant association with PCWP (p = 0.99, n = 110). There was no correlation between ZOE® and PCWP (r = -0.08, p = 0.56, n = 56). Conclusions: These findings support the idea that traditional measures for monitoring heart failure patients are limited.

Noninvasive Venous Waveform Analysis Correlates With Pulmonary Capillary Wedge Pressure and Predicts 30-Day Admission in Patients With Heart Failure Undergoing Right Heart Catheterization.

BACKGROUND: Heart failure is the leading cause of hospitalization in the elderly and readmission is common. Clinical indicators of congestion may not precede acute congestion with enough time to prevent hospital admission for heart failure. Thus, there is a large and unmet need for accurate, noninvasive assessment of congestion. Noninvasive venous waveform analysis in heart failure (NIVAHF) is a novel, noninvasive technology that monitors intravascular volume status and hemodynamic congestion. The objective of this study was to determine the correlation of NIVAHF with pulmonary capillary wedge pressure (PCWP) and the ability of NIVAHF to predict 30-day admission after right heart catheterization. METHODS AND RESULTS: The prototype NIVAHF device was compared with the PCWP in 106 patients undergoing right heart catheterization. The NIVAHF algorithm was developed and trained to estimate the PCWP. NIVA scores and central hemodynamic parameters (PCWP, pulmonary artery diastolic pressure, and cardiac output) were evaluated in 84 patients undergoing outpatient right heart catheterization. Receiver operating characteristic curves were used to determine whether a NIVA score predicted 30-day hospital admission. The NIVA score demonstrated a positive correlation with PCWP (r = 0.92, n = 106, P < .0001). The NIVA score at the time of hospital discharge predicted 30-day admission with an AUC of 0.84, a NIVA score of more than 18 predicted admission with a sensitivity of 91% and specificity of 56%. Residual analysis suggested that no single patient demographic confounded the predictive accuracy of the NIVA score. CONCLUSIONS: The NIVAHF score is a noninvasive monitoring technology that is designed to provide an estimate of PCWP. A NIVA score of more than 18 indicated an increased risk for 30-day hospital admission. This noninvasive measurement has the potential for guiding decongestive therapy and the prevention of hospital admission in patients with heart failure.

Respiratory Non-Invasive Venous Waveform Analysis for Assessment of Respiratory Distress in Coronavirus Disease 2019 Patients: An Observational Study.

OBJECTIVES: Due to the rapid rate of severe acute respiratory syndrome coronavirus 2 transmission and the heterogeneity of symptoms of coronavirus disease 2019, expeditious and effective triage is critical for early treatment and effective allocation of hospital resources. DESIGN: A post hoc analysis of respiratory data from non-invasive venous waveform analysis among patients enrolled in an observational study was performed. SETTING: Vanderbilt University Medical Center. PATIENTS: Peripheral venous waveforms were recorded from admission to discharge in enrolled coronavirus disease 2019-positive patients and healthy age-matched controls. INTERVENTIONS: Data were analyzed in LabChart 8 to transform venous waveforms to the frequency domain using fast Fourier transforms. The peak respiratory frequency was normalized to the peak cardiac frequency to generate a respiratory non-invasive venous waveform analysis respiratory index. Paired Fisher exact tests were used to compare each patient's respiratory non-invasive venous waveform analysis respiratory index at admission and discharge. A nonparametric one-way analysis of variance was used for multiple comparisons between patients with coronavirus disease 2019 and healthy controls for respiratory non-invasive venous waveform analysis respiratory index. MEASUREMENTS AND MAIN RESULTS: Fifty coronavirus disease 2019-positive patients were enrolled between April 2020, and September 2020, and 45 were analyzed; 34 required supplemental oxygen and 11 did not. The respiratory non-invasive venous waveform analysis respiratory index was significantly higher for the 34 patients with coronavirus disease 2019 who received supplemental oxygen (median, 0.27; interquartile range, 0.11-1.28) compared with the 34 healthy controls (median, 0.06; interquartile range, 0.03-0.14) (p < 0.01). For patients with coronavirus disease 2019 who received supplemental oxygen, respiratory non-invasive venous waveform analysis respiratory index was significantly lower at hospital discharge (p = 0.02; 95% CI, 0.10-1.9) compared with hospital admission (median = 0.12; interquartile range, 0.05-0.56). For patients with coronavirus disease 2019, a respiratory non-invasive venous waveform analysis respiratory index of 0.64 demonstrated sensitivity of 92%, specificity of 47%, and positive predictive value of 93% for predicting requirement of supplemental oxygen during the hospitalization. CONCLUSIONS: Respiratory non-invasive venous waveform analysis respiratory index represents a novel physiologic respiratory measurement with a promising ability to triage early care and predict the need for oxygen support therapy in coronavirus disease 2019 patients.

Therapeutic MK2 inhibition blocks pathological vascular smooth muscle cell phenotype switch.

Vascular procedures, such as stenting, angioplasty, and bypass grafting, often fail due to intimal hyperplasia (IH), wherein contractile vascular smooth muscle cells (VSMCs) dedifferentiate to synthetic VSMCs, which are highly proliferative, migratory, and fibrotic. Previous studies suggest MAPK-activated protein kinase 2 (MK2) inhibition may limit VSMC proliferation and IH, although the molecular mechanism underlying the observation remains unclear. We demonstrated here that MK2 inhibition blocked the molecular program of contractile to synthetic dedifferentiation and mitigated IH development. Molecular markers of the VSMC contractile phenotype were sustained over time in culture in rat primary VSMCs treated with potent, long-lasting MK2 inhibitory peptide nanopolyplexes (MK2i-NPs), a result supported in human saphenous vein specimens cultured ex vivo. RNA-Seq of MK2i-NP-treated primary human VSMCs revealed programmatic switching toward a contractile VSMC gene expression profile, increasing expression of antiinflammatory and contractile-associated genes while lowering expression of proinflammatory, promigratory, and synthetic phenotype-associated genes. Finally, these results were confirmed using an in vivo rabbit vein graft model where brief, intraoperative treatment with MK2i-NPs decreased IH and synthetic phenotype markers while preserving contractile proteins. These results support further development of MK2i-NPs as a therapy for blocking VSMC phenotype switch and IH associated with cardiovascular procedures.

Vasorelaxing cell permeant phosphopeptide mimetics for subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to vasospasm resulting in delayed cerebral ischemia. Therapeutic options are currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy. Nitric oxide (NO) modulates cerebral blood flow through activation of the cGMP-Protein Kinase G (PKG) pathway. Our hypothesis is that SAH results in downregulation of signaling components in the NO-PKG pathway which could explain why treatments for vasospasm targeting this pathway lack efficacy and that treatment with a cell permeant phosphopeptide mimetic of downstream effector prevents delayed vasospasm after SAH. Using a rat endovascular perforation model, reduced levels of NO-PKG pathway molecules were confirmed. Additionally, it was determined that expression and phosphorylation of a PKG substrate: Vasodilator-stimulated phosphoprotein (VASP) was downregulated. A family of cell permeant phosphomimetic of VASP (VP) was wasdesigned and shown to have vasorelaxing property that is synergistic with nimodipine in intact vascular tissuesex vivo. Hence, treatment targeting the downstream effector of the NO signaling pathway, VASP, may bypass receptors and signaling elements leading to vasorelaxation and that treatment with VP can be explored as a therapeutic strategy for SAH induced vasospasm and ameliorate neurological deficits.

Hemodynamic Parameters in the Assessment of Fluid Status in a Porcine Hemorrhage and Resuscitation Model.

BACKGROUND: Measuring fluid status during intraoperative hemorrhage is challenging, but detection and quantification of fluid overload is far more difficult. Using a porcine model of hemorrhage and over-resuscitation, it is hypothesized that centrally obtained hemodynamic parameters will predict volume status more accurately than peripherally obtained vital signs. METHODS: Eight anesthetized female pigs were hemorrhaged at 30 ml/min to a blood loss of 400 ml. After each 100 ml of hemorrhage, vital signs (heart rate, systolic blood pressure, mean arterial pressure, diastolic blood pressure, pulse pressure, pulse pressure variation) and centrally obtained hemodynamic parameters (mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac output) were obtained. Blood volume was restored, and the pigs were over-resuscitated with 2,500 ml of crystalloid, collecting parameters after each 500-ml bolus. Hemorrhage and resuscitation phases were analyzed separately to determine differences among parameters over the range of volume. Conformity of parameters during hemorrhage or over-resuscitation was assessed. RESULTS: During the course of hemorrhage, changes from baseline euvolemia were observed in vital signs (systolic blood pressure, diastolic blood pressure, and mean arterial pressure) after 100 ml of blood loss. Central hemodynamic parameters (mean pulmonary artery pressure and pulmonary capillary wedge pressure) were changed after 200 ml of blood loss, and central venous pressure after 300 ml of blood loss. During the course of resuscitative volume overload, changes were observed from baseline euvolemia in mean pulmonary artery pressure and central venous pressure after 500-ml resuscitation, in pulmonary capillary wedge pressure after 1,000-ml resuscitation, and cardiac output after 2,500-ml resuscitation. In contrast to hemorrhage, vital sign parameters did not change during over-resuscitation. The strongest linear correlation was observed with pulmonary capillary wedge pressure in both hemorrhage (r2 = 0.99) and volume overload (r2 = 0.98). CONCLUSIONS: Pulmonary capillary wedge pressure is the most accurate parameter to track both hemorrhage and over-resuscitation, demonstrating the unmet clinical need for a less invasive pulmonary capillary wedge pressure equivalent.

Physiology and clinical utility of the peripheral venous waveform.

The peripheral venous system serves as a volume reservoir due to its high compliance and can yield information on intravascular volume status. Peripheral venous waveforms can be captured by direct transduction through a peripheral catheter, non-invasive piezoelectric transduction, or gleaned from other waveforms such as the plethysmograph. Older analysis techniques relied upon pressure waveforms such as peripheral venous pressure and central venous pressure as a means of evaluating fluid responsiveness. Newer peripheral venous waveform analysis techniques exist in both the time and frequency domains, and have been applied to various clinical scenarios including hypovolemia (i.e. hemorrhage, dehydration) and volume overload.

A brief report on the effects of vasoactive agents on peripheral venous waveforms in a porcine model.

OBJECTIVES: Non-invasive venous waveform analysis (NIVA) is a recently described, novel technique to assess intravascular volume status. Waveforms are captured with a piezoelectric sensor; analysis in the frequency domain allows for calculation of a "NIVA value" that represents volume status. The aim of this report was to determine the effects of vasoactive agents on the venous waveform and calculated NIVA values. DESIGN: Porcine experimental model. SETTING: Operating theatre. PARTICIPANTS: A piezoelectric sensor was secured over the surgically exposed saphenous vein in eight anesthetized pigs. MAIN OUTCOME MEASURES: NIVA value, pulmonary capillary wedge pressure (PCWP), and mean arterial pressure prior to and post intravenous administration of 150-180 µg of phenylephrine or 100 µg of sodium nitroprusside. RESULTS: Phenylephrine led to a decrease in NIVA value (mean 9.2 vs. 4.6, p < 0.05), while sodium nitroprusside led to an increase in NIVA value (mean 9.5 vs. 11.9, p < 0.05). Mean arterial pressure increased after phenylephrine (p < 0.05) and decreased after sodium nitroprusside (p < 0.05). PCWP did not change significantly after phenylephrine (p = 0.25) or sodium nitroprusside (p = 0.06). CONCLUSIONS: Vasoactive agents lead to changes in non-invasively obtained venous waveforms in euvolemic pigs, highlighting a potential limitation in the ability to NIVA to estimate static volume in this setting. Further studies are indicated to understand the effects of vasoactive agents in the setting of hypovolemia and hypervolemia.

Non-Invasive Venous waveform Analysis (NIVA) for volume assessment during complex cranial vault reconstruction: A proof-of-concept study in children.

BACKGROUND: Non-Invasive Venous waveform Analysis (NIVA) is novel technology that captures and analyzes changes in venous waveforms from a piezoelectric sensor on the wrist for hemodynamic volume assessment. Complex cranial vault reconstruction is performed in children with craniosynostosis and is associated with extensive blood loss, potential life-threatening risks, and significant morbidity. In this preliminary study, we hypothesized that NIVA will provide a reliable, non-invasive, quantitative assessment of intravascular volume changes in children undergoing complex cranial vault reconstruction. OBJECTIVE: To present proof-of-concept results of a novel technology in the pediatric population. METHODS: The NIVA prototype was placed on each subject's wrist, and venous waveforms were collected intraoperatively. Estimated blood loss and fluid/blood product administration were recorded in real time. Venous waveforms were analyzed into a NIVA value and then correlated, along with mean arterial pressure (MAP), to volume changes. Concordance was quantified to determine if the direction of change in volume was similar to the direction of change in MAP or change in NIVA. RESULTS: Of 18 patients enrolled, 14 had usable venous waveforms, and there was a significant correlation between change in NIVA value and change in volume. Change in MAP did not correlate with change in volume. The concordance between change in MAP and change in volume was less than the concordance between change in NIVA and change in volume. CONCLUSION: NIVA values correlate more closely to intravascular volume changes in pediatric craniofacial patients than MAP. This initial study suggests that NIVA is a potential safe, reliable, non-invasive quantitative method of measuring intravascular volume changes for children undergoing surgery.

Non-invasive venous waveform analysis (NIVA) for volume assessment in patients undergoing hemodialysis: an observational study.

BACKGROUND: Accurate assessment of volume status to direct dialysis remains a clinical challenge. Despite current attempts at volume-directed dialysis, inadequate dialysis and intradialytic hypotension (IDH) are common occurrences. Peripheral venous waveform analysis has recently been developed as a method to accurately determine intravascular volume status through algorithmic quantification of changes in the waveform that occur at different volume states. A noninvasive method to capture peripheral venous signals is described (Non-Invasive Venous waveform Analysis, NIVA). The objective of this proof-of-concept study was to characterize changes in NIVA signal with dialysis. We hypothesized that there would be a change in signal after dialysis and that the rate of intradialytic change in signal would be predictive of IDH. METHODS: Fifty subjects undergoing inpatient hemodialysis were enrolled. A 10-mm piezoelectric sensor was secured to the middle volar aspect of the wrist on the extremity opposite to the access site. Signals were obtained fifteen minutes before, throughout, and up to fifteen minutes after hemodialysis. Waveforms were analyzed after a fast Fourier transformation and identification of the frequencies corresponding to the cardiac rate, with a NIVA value generated based on the weighted powers of these frequencies. RESULTS: Adequate quality (signal to noise ratio > 20) signals pre- and post- dialysis were obtained in 38 patients (76%). NIVA values were significantly lower at the end of dialysis compared to pre-dialysis levels (1.203 vs 0.868, p < 0.05, n = 38). Only 16 patients had adequate signals for analysis throughout dialysis, but in this small cohort the rate of change in NIVA value was predictive of IDH with a sensitivity of 80% and specificity of 100%. CONCLUSIONS: This observational, proof-of-concept study using a NIVA prototype device suggests that NIVA represents a novel and non-invasive technique that with further development and improvements in signal quality may provide static and continuous measures of volume status to assist with volume directed dialysis and prevent intradialytic hypotension.

A cell permeant phosphopeptide mimetic of Niban inhibits p38 MAPK and restores endothelial function after injury.

Vascular injury leads to membrane disruption, ATP release, and endothelial dysfunction. Increases in the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and decreases in the phosphorylation of Niban, a protein implicated in ER stress and apoptosis, are associated with vascular injury. A cell permeant phosphopeptide mimetic of Niban (NiPp) was generated. The effects of NiPp in restoring endothelial function were determined ex vivo using intact rat aortic tissue (RA) after pharmacological activation of p38 MAPK and also in multiple clinically relevant injury models. Anisomycin (Aniso) increased p38 MAPK phosphorylation and reduced endothelial-dependent relaxation in RA. Treatment with NiPp prevented Ansio-induced reduction in endothelial function and increases in p38 MAPK phosphorylation. NiPp treatment also restored endothelial function after stretch injury (subfailure stretch), treatment with acidic Normal Saline (NS), and P2X7R activation with 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate (BzATP). Aged, diseased, human saphenous vein (HSV) remnants obtained from patients undergoing coronary bypass surgical procedures have impaired endothelial function. Treatment of these HSV segments with NiPp improved endothelial-dependent relaxation. Kinome screening experiments indicated that NiPp inhibits p38 MAPK. These data demonstrate that p38 MAPK and Niban signaling have a role in endothelial function, particularly in response to injury. Niban may represent an endogenous regulator of p38 MAPK activation. The NiPp peptide may serve as an experimental tool to further elucidate p38 MAPK regulation and as a potential therapeutic for endothelial dysfunction.

Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis.

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.

Observational Study of Noninvasive Venous Waveform Analysis to Assess Intracardiac Filling Pressures During Right Heart Catheterization.

BACKGROUND: Outpatient monitoring and management of patients with heart failure (HF) reduces hospitalizations and health care costs. However, the availability of noninvasive approaches to assess congestion is limited. Noninvasive venous waveform analysis (NIVA) uses a unique physiologic signal, the morphology of the venous waveform, to assess intracardiac filling pressures. This study is a proof of concept analysis of the correlation between NIVA value and pulmonary capillary wedge pressure (PCWP) and the ability of the NIVA value to predict PCWP > 18 mmHg in subjects undergoing elective right heart catheterization (RHC). PCWP was also compared across common clinical correlates of congestion. METHODS AND RESULTS: A prototype NIVA device, which consists of a piezoelectric sensor placed over the skin on the volar aspect of the wrist, connected to a data-capture control box, was used to collect venous waveforms in 96 patients during RHC. PCWP was collected at end-expiration by an experienced cardiologist. The venous waveform signal was transformed to the frequency domain (Fourier transform), where a ratiometric algorithm of the frequencies of the pulse rate and its harmonics was used to derive a NIVA value. NIVA values were successfully captured in 83 of 96 enrolled patients. PCWP ranged from 4-40 mmHg with a median of 13 mmHg. NIVA values demonstrated a linear correlation with PCWP (r = 0.69, P < 0.05). CONCLUSIONS: This observational proof-of-concept study using a prototype NIVA device demonstrates a moderate correlation between NIVA value and PCWP in patients undergoing RHC. NIVA, thus, represents a promising developing technology for noninvasive assessment of congestion in spontaneously breathing patients.