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.

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.

Assessment of Upper Extremity Venous Compliance in Patients With Abdominal Aortic Aneurysms.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is associated with morphological and functional changes in both aneurysmal and non-aneurysmal arteries. However, it remains uncertain whether similar changes also exist in the venous vasculature. The aim of this study was to evaluate global venous function in patients with AAA and controls. METHODS: This experimental study comprised 31 men with AAA (mean ± standard deviation age 70.0 ± 2.8 years) and 29 male controls (aged 70.6 ± 3.4 years). Venous occlusion plethysmography (VOP) was used to evaluate arm venous compliance at venous pressures between 10 and 60 mmHg in steps of 5 mmHg. Compensatory mobilisation of venous capacitance blood (capacitance response) was measured with a volumetric technique during experimental hypovolaemia induced by lower body negative pressure (LBNP). RESULTS: The VOP induced pressure-volume curve was significantly less steep in patients with AAA (interaction, p < .001), indicating lower venous compliance. Accordingly, the corresponding pressure-compliance curves displayed reduced venous compliance at lower venous pressures in patients with AAA vs. controls (interaction, p < .001; AAA vs. control, p = .018). After adjusting for arterial hypertension, diabetes mellitus, hyperlipidaemia, chronic obstructive pulmonary disease, and smoking, VOP detected differences in venous compliance remained significant at low venous pressures, that is, at 10 mmHg (p = .008), 15 mmHg (p = .013), and 20 mmHg (p = .026). Mean venous compliance was negatively correlated with aortic diameter (r = -.332, p = .010). Mobilisation of venous capacitance response during LBNP was reduced by approximately 25% in patients with AAA (p = .030), and the redistribution of venous blood during LBNP was negatively correlated with aortic diameter (r = -.417, p = .007). CONCLUSION: Men with AAA demonstrated reduced venous compliance and, as a result, a lesser capacity to mobilise peripheral venous blood to the central circulation during hypovolaemic stress. These findings imply that the AAA disease may be accompanied by functional changes in the venous vascular wall.

Predictors of hemodynamic decompensation in progressive hypovolemia: Compensatory reserve versus heart rate variability.

BACKGROUND: Hemorrhage remains the leading cause of death following traumatic injury in both civilian and military settings. Heart rate variability (HRV) and heart rate complexity (HRC) have been proposed as potential "new vital signs" for monitoring trauma patients; however, the added benefit of HRV or HRC for decision support remains unclear. Another new paradigm, the compensatory reserve measurement (CRM), represents the integration of all cardiopulmonary mechanisms responsible for compensation during relative blood loss and was developed to identify current physiologic status by estimating the progression toward hemodynamic decompensation. In the present study, we hypothesized that CRM would provide greater sensitivity and specificity to detect progressive reductions in central circulating blood volume and onset of decompensation as compared with measurements of HRV and HRC. METHODS: Continuous, noninvasive measurements of compensatory reserve and electrocardiogram signals were made on 101 healthy volunteers during lower-body negative pressure (LBNP) to the point of decompensation. Measures of HRV and HRC were taken from electrocardiogram signal data. RESULTS: Compensatory reserve measurement demonstrated a superior sensitivity and specificity (receiver operator characteristic area under the curve [ROC AUC] = 0.93) compared with all HRV measures (ROC AUC ≤ 0.84) and all HRC measures (ROC AUC ≤ 0.86). Sensitivity and specificity values at the ROC optimal thresholds were greater for CRM (sensitivity = 0.84; specificity = 0.84) than HRV (sensitivity, ≤0.78; specificity, ≤0.77), and HRC (sensitivity, ≤0.79; specificity, ≤0.77). With standardized values across all levels of LBNP, CRM had a steeper decline, less variability, and explained a greater proportion of the variation in the data than both HRV and HRC during progressive hypovolemia. CONCLUSION: These findings add to the growing body of literature describing the advantages of CRM for detecting reductions in central blood volume. Most importantly, these results provide further support for the potential use of CRM in the triage and monitoring of patients at highest risk for the onset of shock following blood loss.

The effect of positive-end-expiratory pressure on stroke volume variation: An experimental study in dogs.

Stroke volume variation (SVV) may be affected by ventilation settings. However, it is unclear whether positive-end-expiratory pressure (PEEP) affects SVV independently of the effect of driving pressure. We aimed to investigate the effect of driving pressure and PEEP on SVV under various preload conditions using beagle dogs as the animal model. We prepared three preload model, baseline, mild and moderate haemorrhage model. Mild and moderate haemorrhage models were created in nine anaesthetized, mechanically ventilated dogs by sequentially removing 10 mL/kg, and then an additional 10 mL/kg of blood, respectively. We measured cardiac output, stroke volume (SV), SVV, heart rate, central venous pressure, pulmonary capillary wedge pressure and the mean arterial pressure under varying ventilation settings. Peak inspiratory pressure (PIP) was incrementally increased by 4 cmH2 O, from 9 cmH2 O to 21 cmH2 O, under PEEP values of 4, 8, and 12 cmH2 O. The driving pressure did not significantly decrease SV under each preload condition and PEEP; however, significantly increased SVV. In contrast, the increased PEEP decreased SV and increased SVV under each preload condition and driving pressure, but these associations were not statistically significant. According to multiple regression analysis, an increase in PEEP and decrease in preload significantly decreased SV (P < .05). In addition, an increase in the driving pressure and decrease in preload significantly increased SVV (P < .05). Driving pressure had more influence than PEEP on SVV.

Cardiovascular biomarkers and echocardiographic findings at rest and during graded hypovolemic stress in women with recurrent vasovagal syncope.

INTRODUCTION: Vasovagal reflex is the most common type of syncope but its etiology is not fully elucidated. Venous return and cardiac output are key in hemodynamic control. The aim of the study was to assess cardiovascular biomarkers and echocardiographic measures at rest and during hypovolemia in women with and without a history of vasovagal syncope. METHODS: Fourteen women (aged 18-30) suffering from recurrent vasovagal syncope and 15 age-matched healthy women were included. Graded lower body negative pressure (LBNP) was used to create central hypovolemic stress until signs of presyncope occurred. Echocardiography was applied at rest and throughout LBNP. Cardiovascular biomarkers: copeptin, mid-regional proadrenomedullin, mid-regional pro-ANP, C-terminal proendothelin-1, and plasma norepinephrine were measured both at rest and throughout graded hypovolemia to presyncope. RESULTS: Women prone to vasovagal syncope presented with a narrower right ventricle (RV) (29 ± 1 vs 32 ± 1 mm, P < .05), smaller left atrium (36 ± 2 vs 47 ± 3 cm3 , P < .01) and lower cardiac output at rest (3.1 ± 0.2 vs 3.7 ± 0.2 L/min, P < .05) and during graded hypovolemia (P < .05). Copeptin was elevated at rest (4.3 ± 0.8 vs 2.5 ± 0.2 pmol/L, P < .05) and increased more in women with vasovagal syncope during progression of LBNP (P < .01). At rest, lower C-terminal proendothelin-1 (35 ± 5 vs 46 ± 2 pmol/L, P < .05) and higher norepinephrine levels (1.1 ± 0.1 vs 0.8 ± 0.1 nmol/L, P < .01) were seen in women with vasovagal syncope. CONCLUSION: Women prone to vasovagal syncope demonstrate reduced cardiac preload, lower cardiac output, as well as increased release of vasopressin in rest and during hypovolemic challenge. The results emphasize the importance of venous return and cardiac output in the pathogenesis of vasovagal syncope.

Trigeminal Nerve Stimulation: A Novel Method of Resuscitation for Hemorrhagic Shock.

OBJECTIVES: To determine if trigeminal nerve stimulation can ameliorate the consequences of acute blood loss and improve survival after severe hemorrhagic shock. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Severe hemorrhagic shock was induced in rats by withdrawing blood until the mean arterial blood pressure reached 27 ± 1 mm Hg for the first 5 minutes and then maintained at 27 ± 2 mm Hg for 30 minutes. The rats were randomly assigned to either control, vehicle, or trigeminal nerve stimulation treatment groups. The effects of trigeminal nerve stimulation on survival rate, autonomic nervous system activity, hemodynamics, brain perfusion, catecholamine release, and systemic inflammation after severe hemorrhagic shock in the absence of fluid resuscitation were analyzed. MEASUREMENTS AND MAIN RESULTS: Trigeminal nerve stimulation significantly increased the short-term survival of rats following severe hemorrhagic shock in the absence of fluid resuscitation. The survival rate at 60 minutes was 90% in trigeminal nerve stimulation treatment group whereas 0% in control group (p < 0.001). Trigeminal nerve stimulation elicited strong synergistic coactivation of the sympathetic and parasympathetic nervous system as measured by heart rate variability. Without volume expansion with fluid resuscitation, trigeminal nerve stimulation significantly attenuated sympathetic hyperactivity paralleled by increase in parasympathetic tone, delayed hemodynamic decompensation, and improved brain perfusion following severe hemorrhagic shock. Furthermore, trigeminal nerve stimulation generated sympathetically mediated low-frequency oscillatory patterns of systemic blood pressure associated with an increased tolerance to central hypovolemia and increased levels of circulating norepinephrine levels. Trigeminal nerve stimulation also decreased systemic inflammation compared with the vehicle. CONCLUSIONS: Trigeminal nerve stimulation was explored as a novel resuscitation strategy in an animal model of hemorrhagic shock. The results of this study showed that the stimulation of trigeminal nerve modulates both sympathetic and parasympathetic nervous system activity to activate an endogenous pressor response, improve cerebral perfusion, and decrease inflammation, thereby improving survival.

A prospective study of the pathophysiology of carcinoid crisis.

BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.

Hypovolemic phlebotomy in liver surgery is associated with decreased red blood cell transfusion.

BACKGROUND: Perioperative red blood cell (RBC) transfusion is associated with poor outcomes in liver surgery. Hypovolemic phlebotomy (HP) is a novel intervention hypothesized to decrease transfusion requirements. The objective of this study was to examine this hypothesis. METHODS: Consecutive patients who underwent liver resection at one institution (2010-2016) were included. Factors found to be predictive of transfusion on univariate analysis and those previously published were modeled using multivariate logistic regression. RESULTS: A total of 361 patients underwent liver resection (50% major). HP was performed in 45 patients. Phlebotomized patients had a greater proportion of primary malignancy (31% vs 18%) and major resection (84% vs 45%). Blood loss was significantly lower with phlebotomy in major resections (400 vs 700 mL). Nadir central venous pressure was significantly lower with HP (2.5 vs 5 cm H2O). On multivariate logistic regression, HP (OR 0.20, 95% CI 0.068-0.57, p = 0.0029), major liver resection (OR 2.91, 95% CI 1.64-5.18, p = 0.0003), preoperative hemoglobin < 125 g/L (OR 6.02, 95% CI 3.44-10.56, p < 0.0001), and underlying liver disease (OR 2.24, 95% CI 1.27-3.95, p = 0.0051) were significantly associated with perioperative RBC transfusion. CONCLUSION: Hypovolemic phlebotomy appears to be strongly associated with a reduction in RBC transfusion requirements in liver resection, independent of other known risk factors.

Donor liver quality after hypovolemic shock and venous systemic oxygen persufflation in an experimental animal model.

BACKGROUND: The ever growing demand for liver transplantation inevitably necessitates an expansion of the donor pool. Utilization of "shock organs" is considered suboptimal to date while the associated outcome has hardly been investigated. MATERIALS AND METHODS: Male Wistar rats underwent a period of 30 min of hypovolemic shock. After 24 h livers were explanted and prior to reperfusion underwent either 18 h of cold storage (CS; N = 6) or 17 h of CS followed by 60 min venous systemic oxygen persufflation (VSOP; N = 6). The outcome of "shock organs (SHBD)" was compared to heart-beating donor (HBD; N = 12) as positive control and non-heart-beating donor (NHBD; N = 12) as negative control animal groups. Liver function was assessed by measuring enzyme release (AST, ALT, LDH), bile production, portal vein pressure and hepatic oxygen uptake during reperfusion. For reperfusion, the isolated perfused rat liver system was used. RESULTS: Liver function was severely limited in NHBD group compared to HBD organs after 18 h of CS (e.g., AST; HBD: 32.25 ± 7.25 U/l vs. NHBD: 790 ± 414.56 U/l; p < 0.005). VSOP improved liver function of NHBD organs significantly (AST; NHBD + VSOP: 333.6 ± 149.1 U/l; p < 0.005). SHBD organs showed a comparable outcome to HBD and clearly better results than NHBD organs after 18 h of CS (AST; SHBD: 76.4 ± 21.9 U/l). After 17 h of CS accompanied by 60 min VSOP, no improvement concerning liver function and integrity of SHBD organs was observed while the results were severely deteriorated by VSOP resulting in higher enzyme release (AST; SHBD + VSOP: 213 ± 61 U/l, p < 0.001), higher portal vein pressure (SHBD: 10.8 ± 1.92 mm Hg vs. SHBD + VSOP: 21.6 ± 8.8 mm Hg; p < 0.05) and lower hepatic oxygen uptake (SHBD: 321.75 ± 3.87 ml/glw/min vs. SHBD + VSOP: 395.8 ± 46.64 ml/glw/min, p < 0.05) at 24 h. CONCLUSIONS: Our data suggest that the potential of "shock organs" within liver transplantation may be underestimated. If our findings are reproducable in humans, SHBD grafts should be considered as a valuable source for expanding the thus far limited donor pool.

The Effect of Acute Hypovolemia on the Eye.

INTRODUCTION: To investigate the effects of acute hypovolemia induced by blood donation on the eye. Methods or Study Design: This prospective, observational study included a single eye from each of 48 healthy men between 20 and 40 years of age who had donated 500 ml of blood and 28 eyes of 28 healthy, age- and gender-matched control subjects. The ocular parameters including ocular perfusion pressure (OPP), intraocular pressure (IOP), axial length (AL), central corneal thickness (CCT), choroidal and retinal thicknesses, and retinal nerve fiber layer (RNFL) were measured before blood donation and at 10 min and 1, 2, 3, and 4 h after blood donation. RESULTS: The mean OPP was significantly reduced following blood donation (baseline, 43.4 ± 4.9 vs. 40.8 ± 4.6 mmHg; p = 0.003). The mean subfoveal choroidal thickness (SFCT) was measured as 322.96 ± 76.23, 291.63 ± 77.85, 309.77 ± 75.72, 312.31 ± 75.98, 315.73 ± 75.43, and 317.75 ± 75.73 µm before blood donation, at baseline, 10 min, and 1, 2, 3, and 4 h following donation, respectively [F(2.462, 115.731) = 22.618, p < 0.001]. In the control group, the SFCT was measured as 302.04 ± 32.04, 301.43 ± 35.16, 298.07 ± 37.33, 298.96 ± 39.17, 302.54 ± 39.24, and 301.61 ± 40.41 µm at baseline, 10 min, and 1, 2, 3, and 4 h following donation, respectively [F(2.124, 57.340) = 0.592, p = 0.566]. There was no difference in AL, CCT, RNFL, retinal thicknesses, and IOP measurements performed before and after blood donation (p > 0.05). CONCLUSIONS: Acute hypovolemia caused a significant reduction in SFCT which persisted for 3 h. This study may pave way for better understanding of choroidal thickness changes in disease states.

Measurement of compensatory reserve predicts racial differences in tolerance to simulated hemorrhage in women.

BACKGROUND: The compensatory reserve measurement (CRM) has been established to accurately measure the body's total integrated capacity to compensate for physiologic states of reduced central blood volume and predict hemodynamic decompensation associated with inadequate tissue oxygenation. We previously demonstrated that African American (AA) women have a higher tolerance to reductions in central blood volume. Therefore, we tested the hypothesis that the CRM would identify racial differences during simulated hemorrhage, before the onset of traditional signs/symptoms. METHODS: We performed a retrospective analysis during simulated hemorrhage using lower-body negative pressure (LBNP) in 23 AA (22 ± 1 years; 24 ± 1 kg/m) and 31 white women (WW) (20 ± 1 years; 23 ± 1 kg/m). Beat-by-beat blood pressure (BP) and heart rate (HR) were recorded during progressive lower body negative pressure to presyncope. The BP waveforms were analyzed using a machine-learning algorithm to derive the CRM at each lower body negative pressure stage. RESULTS: Resting mean arterial BP (AA, 78 ± 3 mm Hg vs. WW, 74 ± 2 mm Hg) and HR (AA, 68 ± 2 bpm vs. WW, 65 ± 2 bpm) were similar between groups. The CRM progressively decreased during LBNP in both groups; however, the rate of decline in the CRM was less (p < 0.05) in AA. The CRM was 4% higher in AA at -15 mm Hg LBNP and progressively increased to 21% higher at -50 mm Hg LBNP (p < 0.05). However, changes in BP and HR were not different between groups. CONCLUSION: These data support the notion that the greater tolerance to simulated hemorrhage induced by LBNP in AA women can be explained by their greater capacity to protect the reserve to compensate for progressive central hypovolemia compared with WW, independent of standard vital signs. LEVEL OF EVIDENCE: Diagnostic test, level II.

Noninvasive monitoring of physiologic compromise in acute appendicitis: New insight into an old disease.

INTRODUCTION: Physiologic compromise in children with acute appendicitis has heretofore been difficult to measure. We hypothesized that the Compensatory Reserve Index (CRI), a novel adjunctive cardiovascular status indicator, would be low for children presenting with acute appendicitis in proportion to their physiological compromise, and that CRI would rise with fluid resuscitation and surgical management of their disease. METHODS: Ninety-four children diagnosed with acute appendicitis were monitored with a CipherOx CRI™ M1 pulse oximeter (Flashback Technologies Inc., Boulder, CO). For clarity, CRI=1 indicates supine normovolemia, CRI=0 indicates hemodynamic decompensation (systolic blood pressure<80mmHg), and CRI values between 1 and 0 indicate the proportion of volume reserve remaining before collapse. Results are presented as counts with proportion (%), or mean with 95% confidence interval (CI). RESULTS: Mean age was 11years old (95% CI: 10-12), and 49 (52%) of the children were male. Fifty-four (57%) had nonperforated appendicitis and 40 (43%) had perforated appendicitis. Mean initial CRI was significantly higher in those with nonperforated appendicitis compared to those with perforated appendicitis (0.57, 95% CI: 0.52-0.63 vs. 0.36, 95% CI: 0.29-0.43; P<0.001). The significant differences in mean CRI values between the two groups remained throughout the course of treatment, but lost its significance at 2h after surgery (0.63, 95% CI: 0.57-0.70 vs. 0.53, 95% CI: 0.46-0.61; P=0.05). CONCLUSION: Low CRI values in children with perforated appendicitis are indicative of their lower reserve capacity owing to peritonitis and hypovolemia. CRI offers a real-time, noninvasive adjunctive tool to monitor tolerance to volume loss in children. LEVEL OF EVIDENCE: Study of diagnostic test; Level of evidence: Level III.

A Systematic Review of Neuroprotective Strategies during Hypovolemia and Hemorrhagic Shock.

Severe trauma constitutes a major cause of death and disability, especially in younger patients. The cerebral autoregulatory capacity only protects the brain to a certain extent in states of hypovolemia; thereafter, neurological deficits and apoptosis occurs. We therefore set out to investigate neuroprotective strategies during haemorrhagic shock. This review was performed in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Before the start of the search, a review protocol was entered into the PROSPERO database. A systematic literature search of Pubmed, Web of Science and CENTRAL was performed in August 2017. Results were screened and evaluated by two researchers based on a previously prepared inclusion protocol. Risk of bias was determined by use of SYRCLE's risk of bias tool. The retrieved results were qualitatively analysed. Of 9093 results, 119 were assessed in full-text form, 16 of them ultimately adhered to the inclusion criteria and were qualitatively analyzed. We identified three subsets of results: (1) hypothermia; (2) fluid therapy and/or vasopressors; and (3) other neuroprotective strategies (piracetam, NHE1-inhibition, aprotinin, human mesenchymal stem cells, remote ischemic preconditioning and sevoflurane). Overall, risk of bias according to SYRCLE's tool was medium; generally, animal experimental models require more rigorous adherence to the reporting of bias-free study design (randomization, etc.). While the individual study results are promising, the retrieved neuroprotective strategies have to be evaluated within the current scientific context-by doing so, it becomes clear that specific promising neuroprotective strategies during states of haemorrhagic shock remain sparse. This important topic therefore requires more in-depth research.

Urine flow rate monitoring in hypovolemic multiple trauma patients.

BACKGROUND: The urine output is an important clinical parameter of renal function and blood volume status, especially in critically ill multiple trauma patients. In the present study, the minute-to-minute urine flow rate and its variability were analyzed in hypotensive multiple trauma patients during the first 6 h of their ICU (intensive care unit) stay. These parameters have not been previously reported. METHODS: The study was retrospective and observational. Demographic and clinical data were extracted from the computerized Register Information Systems. A total of 59 patients were included in the study. The patients were divided into two study groups. Group 1 consisted of 29 multiple trauma patients whose systolic blood pressure was greater than 90 mmHg on admission to the ICU and who were consequently deemed to be hemodynamically compromised. Group 2 consisted of 30 patients whose systolic blood pressure was less than 90 mmHg on admission to the ICU and who were therefore regarded as hemodynamically uncompromised. RESULTS: The urine output and urine flow rate variability during the first 6 h of the patients' ICU stay was significantly lower in group 2 than in group 1 (p < 0.001 and 0.006 respectively). Statistical analysis by the Pearson method demonstrated a strong direct correlation between decreased urine flow rate variability and decreased urine output per hour (R = 0.17; P = 0.009), decreased mean arterial blood pressure (R = 0.24; p = 0.001), and increased heart rate (R = 0.205; p = 0.001). CONCLUSION: These findings suggest that minute-to-minute urine flow rate variability is a reliable incipient marker of hypovolemia and that it should therefore take its place among the parameters used to monitor the hemodynamic status of critically ill multiple trauma patients.

A machine-learning based analysis for the recognition of progressive central hypovolemia.

OBJECTIVE: Traditional patient monitoring during surgery includes heart rate (HR), blood pressure (BP) and peripheral oxygen saturation. However, their use as predictors for central hypovolemia is limited, which may lead to cerebral hypoperfusion. The aim of this study was to develop a monitoring model that can indicate a decrease in central blood volume (CBV) at an early stage. APPROACH: Twenty-eight healthy subjects (aged 18-50 years) were included. Lower body negative pressure (-50 mmHg) was applied to induce central hypovolemia until the onset of pre-syncope. Ten beat-to-beat and four discrete parameters were measured, normalized, and filtered with a 30 s moving window. Time to pre-syncope was scaled from 100%-0%. A total of 100 neural networks with 5, 10, 15, 20, or 25 neurons in their respective hidden layer were trained by 10, 20, 40, 80, 160, or 320 iterations to predict time to pre-syncope for each subject. The network with the lowest average slope of a fitted line over all subjects was chosen as optimal. MAIN RESULTS: The optimal generalized model consisted of 10 hidden neurons, trained using 80 iterations. The slope of the fitted line on the average prediction was -0.64 (SD 0.35). The model recognizes in 75% of the subjects the need for intervention at >200 s before pre-syncope. SIGNIFICANCE: We developed a neural network based on a set of physiological variables, which indicates a decrease in CBV even in the absence of HR and BP changes. This should allow timely intervention and prevent the development of symptomatic cerebral hypoperfusion.

Validation of a noninvasive monitor to continuously trend individual responses to hypovolemia.

BACKGROUND: Humans are able to compensate for significant blood loss with little change in traditional vital signs, limiting early detection and intervention. We hypothesized that the Compensatory Reserve Index (CRI), a new hemodynamic parameter that trends changes in intravascular volume relative to the individual patient's response to hypovolemia, would accurately trend each subject's progression from normovolemia to decompensation (systolic blood pressure < 80) and back to normovolemia in humans. METHODS: Men and women, ages 19 years to 36 years, underwent stepwise (~333 mL aliquot) removal and replacement of 20% blood volume (men, 15 mL/kg; women, 13 mL/kg) via a large bore intravenous (i.v.) line. During each experiment, subjects were monitored with four CipherOx CRI Tablets. Withdrawn blood was reinfused at the end of each experiment. RESULTS: Forty-two subjects (24 men; 18 women) were enrolled in the study, of which 32 completed the protocol. Seven subjects became symptomatic and collapsed (systolic blood pressure < 80), six never achieving maximum blood loss; each was rescued with a saline infusion followed by reinfusion of their stored blood. The mean CRI at baseline for all 42 subjects was 0.9 ± 0.04. The mean CRI for the 32 subjects while asymptomatic at maximum blood loss was 0.611 ± 0.028. For the asymptomatic subjects, the average blood loss volume was 1018 mL ± 286 mL. In comparison, the mean CRI at maximum blood loss for the seven subjects who collapsed was 0.15 ± 0.007 and their average blood loss volume was 860 ± 183 mL. Mean CRI after reinfusion of blood was 0.89 ± 0.02. In addition symptomatic subjects demonstrated three times larger average decrease in CRI per liter of blood removed, 0.85 versus 0.28 for asymptomatic subjects. CONCLUSION: CRI trends change in intravascular volume relative to an individual's response to hypovolemia and is sensitive to the differing risks associated with individuals' differing tolerance to volume loss. LEVEL OF EVIDENCE: Prognostic study, level II.