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1.  Tissue hemoglobin monitoring of progressive central hypovolemia in humans using broadband diffuse optical spectroscopy 
Journal of biomedical optics  2008;13(6):064027.
We demonstrate noninvasive near-infrared diffuse optical spectroscopy (DOS) measurements of tissue hemoglobin contents that can track progressive reductions in central blood volume in human volunteers. Measurements of mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (Q) are obtained in ten healthy human subjects during baseline supine rest and exposure to progressive reductions of central blood volume produced by application of lower body negative pressure (LBNP). Simultaneous quantitative noninvasive measurements of tissue oxyhemoglobin (OHb), deoxyhemoglobin (RHb), total hemoglobin concentration (THb), and tissue hemoglobin oxygen saturation (StO2) are performed throughout LBNP application using broadband DOS. As progressively increasing amounts of LBNP are applied, HR increases, and MAP, SV, and Q decrease (p<0.001). OHb, StO2, and THb decrease (p <0.001) in correlation with progressive increases in LBNP, while tissue RHb remained relatively constant (p=0.378). The average fractional changes from baseline values in DOS OHb (fOHb) correlate closely with independently measured changes in SV (r2=0.95) and Q (r2=0.98) during LBNP. Quantitative noninvasive broadband DOS measurements of tissue hemoglobin parameters of peripheral perfusion are capable of detecting progressive reductions in central blood volume, and appear to be sensitive markers of early hypoperfusion associated with hemorrhage as simulated by LBNP.
PMCID: PMC4079508  PMID: 19123673
hemorrhagic shock; lower body negative pressure; hemodynamic decompensation
2.  Early activation of the coagulation system during lower body negative pressure 
We considered that a moderate reduction of the central blood volume (CBV) may activate the coagulation system. Lower body negative pressure (LBNP) is a non-invasive means of reducing CBV and, thereby, simulates haemorrhage. We tested the hypothesis that coagulation markers would increase following moderate hypovolemia by exposing 10 healthy male volunteers to 10 min of 30 mmHg LBNP. Thoracic electrical impedance increased during LBNP (by 2·6 ± 0·7 Ω, mean ± SD; P < 0·001), signifying a reduced CBV. Heart rate was unchanged during LBNP, while mean arterial pressure decreased (84 ± 5 to 80 ± 6 mmHg; P < 0·001) along with stroke volume (114 ± 22 to 96 ± 19 ml min−1; P < 0·001) and cardiac output (6·4 ± 2·0 to 5·5 ± 1·7 l min−1; P < 0·01). Plasma thrombin–antithrombin III complexes increased (TAT, 5 ± 6 to 19 ± 20 μg l−1; P < 0·05), indicating that LBNP activated the thrombin generating part of the coagulation system, while plasma D-dimer was unchanged, signifying that the increased thrombin generation did not cause further intravascular clot formation. The plasma pancreatic polypeptide level decreased (13 ± 11 to 6 ± 8 pmol l−1; P < 0·05), reflecting reduced vagal activity. In conclusion, thrombin generation was activated by a modest decrease in CBV by LBNP in healthy humans independent of the vagal activity.
PMCID: PMC2839247  PMID: 19656165
haemorrhage; hypovolemia; pancreatic polypeptide; thrombin generation; vagal activity
3.  Non-invasive detection of hypovolemia or fluid responsiveness in spontaneously breathing subjects 
BMC Anesthesiology  2013;13:40.
In the assessment of hypovolemia the value of functional hemodynamic monitoring during spontaneous breathing is debated. The aim of our study was to investigate in spontaneously breathing subjects the changes in hemodynamic parameters during graded central hypovolemia and to test whether slow patterned breathing improved the discriminative value of stroke volume (SV), pulse pressure (PP), and their variations (SVV, PPV). In addition, we tested the alterations in labial microcirculation.
20 healthy volunteers participated in our study. Central hypovolemia was induced by lower body negative pressure (LBNP). Continuous signals of ECG, non-invasive blood pressure and central venous pressure were recorded. During baseline and each stage of LBNP the labial microcirculation was investigated by orthogonal polarization spectral imaging, 3 minute periods of patterned breathing at 6 and 15/min respiratory rate were performed, and central venous blood gas analysis was done. Data from baseline and those of different LBNP levels were compared by analysis of variance and those of different breathing rates by t-test. Finally, we performed ROC analysis to assess the discriminative values of SV, PP, SVV and PPV.
Moderate central hypovolemia induced by LBNP caused significant, clinically relevant falls in PP (p < 0.05) and SV and central venous oxygen saturation (ScvO2) (p < 0.001). The proportion of perfused vessels (p < 0.001) and microvascular flow index decreased (p < 0.05). PPV increased (p < 0.001), however the magnitude of fluctuations was greater during slow patterned breathing (p < 0.001). SVV increased only during slow patterned breathing (p < 0.001). ROC analysis confirmed the best predictive value for SV (at 56 ml cut-off AUC 0.97, sensitivity 94%, specificity 95%). Slow patterned breathing improved the discriminative value of SVV (p = 0.0023).
Functional hemodynamic monitoring with slow patterned breathing to control spontaneous respiration may be worthy for further study in different populations for the assessment of hypovolemia and the prediction of volume responsiveness.
PMCID: PMC3829671  PMID: 24188480
Hypovolemia; Functional hemodynamic monitoring; Spontaneous breathing; Microcirculation
4.  Spectral analysis of respiratory-related hemodynamic variables in simulated hypovolemia: a study in healthy volunteers with spontaneous breathing using a paced breathing activity 
Korean Journal of Anesthesiology  2010;58(6):542-549.
A dynamic preload index such as stroke volume variation (SVV) is not as reliable in spontaneous breathing (SB) patients as in mechanically ventilated patients. This study examined the hypothesis that spectral analysis of hemodynamic variables during paced breathing (PB) activity may be a feasible index of volume changes and fluid responsiveness, despite insufficient respiratory changes in the preload index during SB activity.
Blood pressure and stroke volume (SV) were measured in 16 subjects undergoing PB (15 breaths/min), using a Finometer device and the Modelflow method. Respiratory systolic pressure variation (SPV) and SVV were measured and respiratory frequency (RF, 0.2-0.3 Hz) of power spectra of SPV (SPVRF) and SVV (SVVRF) were computed using fast Fourier transformation. Progressive hypovolemia was simulated with lower body negative pressure (LBNP). Volume challenges were produced by infusion of normal saline and subsequent release of LBNP to baseline. Fluid responsiveness, defined as a >20% increase in SV, was assessed by the area under the curve (AUC) of receiver operating characteristic curves.
Graded hypovolemia caused a significant increase in SPVRF and a decrease in SVVRF. During volume expansion, SPVRF decreased and SVVRF rose significantly. Fluid responsiveness was better predicted with SVVRF (AUC 0.75) than with SPVRF, SPV, or SVV. SVVRF before volume challenge was significantly correlated with volume expansion-induced changes in SV (r = -0.64).
These results suggest that RF spectral analysis of dynamic preload variables may enable the detection of volume change and fluid responsiveness in SB hypovolemic patients performing PB activity.
PMCID: PMC2892588  PMID: 20589179
Dynamic preload index; Fluid responsiveness; Spectral analysis; Spontaneous breathing
5.  Validation of a computational platform for the analysis of the physiologic mechanisms of a human experimental model of hemorrhage☆,☆☆ 
Resuscitation  2009;80(12):1405-1410.
Computational models of integrative physiology may serve as a framework for understanding the complex adaptive responses essential for homeostasis in critical illness and resuscitation and may provide insights for design of diagnostics and therapeutics. In this study a computer model of human physiology was compared to results obtained from experiments using Lower Body Negative Pressure (LBNP) analog model of human hemorrhage. LBNP has been demonstrated to produce physiologic changes in humans consistent with hemorrhage. The computer model contains over 4000 parameters that describe the detailed integration of physiology based upon basic physical principles and established biologic interactions. The LBNP protocol consisted of a 5 min rest period (0 mmHg) followed by 5 min of chamber decompression of the lower body to −15, −30, −45, and −60 mmHg and additional increments of −10 mmHg every 5 min until the onset of hemodynamic decompensation (n = 20). Physiologic parameters recorded include mean arterial pressure (MAP), cardiac output (CO), and venous oxygen saturation (SVO2; from peripheral venous blood), during the last 30 s at each LBNP level. The computer model analytic procedure recreates the investigational protocol for a virtual individual in an In Silico environment. After baseline normalization, the model predicted measurements for MAP, CO, and SVO2 were compared to those observed through the entire range of LBNP. Differences were evaluated using standard statistical performance error measurements (median performance error (PE) <5%). The simulation results closely tracked the average changes observed during LBNP. The predicted MAP fell outside the standard error measurement for the experimental data at only LBNP −30 mmHg while CO was more variable. The predicted SVO2 fell outside the standard error measurement for the experimental data only during the post-LBNP recovery point. However, the statistical median PE measurement was found to be within the 5% objective error measure (1.3% for MAP, −3.5% for CO, and 3.95% for SVO2). The computer model was found to accurately predict the experimental results observed using LBNP. The model should be explored as a platform for studying concepts and physiologic mechanisms of hemorrhage including its diagnosis and treatment.
PMCID: PMC3042239  PMID: 19804937
Systems analysis; Validation; Hemorrhagic shock
6.  Respiratory Variations in Pulse Pressure Reflect Central Hypovolemia during Noninvasive Positive Pressure Ventilation 
Background. Correct volume management is essential in patients with respiratory failure. We investigated the ability of respiratory variations in noninvasive pulse pressure (ΔPP), photoplethysmographic waveform amplitude (ΔPOP), and pleth variability index (PVI) to reflect hypovolemia during noninvasive positive pressure ventilation by inducing hypovolemia with progressive lower body negative pressure (LBNP). Methods. Fourteen volunteers underwent LBNP of 0, −20, −40, −60, and −80 mmHg for 4.5 min at each level or until presyncope. The procedure was repeated with noninvasive positive pressure ventilation. We measured stroke volume (suprasternal Doppler), ΔPP (Finapres), ΔPOP, and PVI and assessed their association with LBNP-level using linear mixed model regression analyses. Results. Stroke volume decreased with each pressure level (−11.2 mL, 95% CI −11.8, −9.6, P < 0.001), with an additional effect of noninvasive positive pressure ventilation (−3.0 mL, 95% CI −8.5, −1.3, P = 0.009). ΔPP increased for each LBNP-level (1.2%, 95% CI 0.5, 1.8, P < 0.001) and almost doubled during noninvasive positive pressure ventilation (additional increase 1.0%, 95% CI 0.1, 1.9, P = 0.003). Neither ΔPOP nor PVI was significantly associated with LBNP-level. Conclusions. During noninvasive positive pressure ventilation, preload changes were reflected by ΔPP but not by ΔPOP or PVI. This implies that ΔPP may be used to assess volume status during noninvasive positive pressure ventilation.
PMCID: PMC3948196  PMID: 24696781
7.  Comparison of cardiovascular response to sinusoidal and constant lower body negative pressure with reference to very mild whole-body heating 
The purpose of the present study was to compare sinusoidal versus constant lower body negative pressure (LBNP) with reference to very mild whole-body heating. Sinusoidal LBNP has a periodic load component (PLC) and a constant load component (CLC) of orthostatic stress, whereas constant LBNP has only a CLC. We tested two sinusoidal patterns (30-s and 180-s periods with 25 mmHg amplitude) of LBNP and a constant LBNP with −25 mmHg in 12 adult male subjects.
Although the CLC of all three LBNP conditions were configured with −25 mmHg, the mean arterial pressure (MAP) results showed a significantly large decrease from baseline in the 30-s period condition (P <0.01). In contrast, the other cardiovascular indices (heart rate (HR), stroke volume (SV), cardiac output (CO), basal thoracic impedance (Z0), total peripheral resistance (TPR), the natural logarithmic of the HF component (lnHF), and LF/HF (ln(LF/HF))) of heart rate variability (HRV) showed relatively small variations from baseline in the 30-s period condition (P <0.01). The result of the gain and phase of transfer function at the sinusoidal period of LBNP showed that the very mild whole-body heating augmented the orthostatic responses.
These results revealed that the effect of the CLC of LBNP on cardiovascular adjustability was attenuated by the addition of the PLC to LBNP. Based on the results of suppressed HRV response from baseline in the 30-s period condition, we suggest that the attenuation may be caused by the suppression of the vagal responsiveness to LBNP.
PMCID: PMC3549779  PMID: 23176638
Hemodynamics; Lower body negative pressure; Hyperthermia; Fourier analysis; Autonomic nervous system; Chronobiology phenomena
8.  Neurohumoral mechanisms associated with orthostasis: reaffirmation of the significant contribution of the heart rate response 
The inability to compensate for acute central hypovolemia underlies the clinical development of orthostatic hypotension and instability (e.g., syncope). Although neuro-humoral control of both cardiac output and peripheral vascular resistance contributes to hemodynamic stability during orthostasis, a notion has been proposed that the failure of adequate peripheral vascular constriction rather than cardiac responses represents the primary mechanism underlying the development of orthostatic intolerance. This review article provides an opportunity to present compelling evidence captured over the past 30 years in our laboratory to support the concept that neural-mediated tachycardia during orthostasis in healthy individuals represents a critical response to tolerating acute reduction in central blood volume in addition to, and independent of, peripheral vascular constriction. In this review paper, data are presented from experiments using graded lower body negative pressure (LBNP) as a method to induce orthostatic intolerance in two experimental human models: (1) comparison of heart rate and autonomic responses in individuals with relatively high and low tolerance to LBNP; and (2) vagal and sympathetic blockade of cardiac neural control. These experiments revealed that: (1) greater elevations in heart rate are associated with higher orthostatic (LBNP) tolerance; (2) higher orthostatic heart rate is associated with greater sympathetic nerve activity and withdrawal of vagally-mediated cardiac baroreflex response; and (3) non-specific sympathetic blockade causes a pronounced reduction in heart rate and LBNP tolerance. Cardiac parasympathetic withdrawal contributes to protection against development of hypotension during the initial seconds of transition to an orthostatic challenge, while the primary mechanism by which tachycardia defends orthostatic stability in healthy subjects for extended durations is mediated predominantly through sympathetic adrenergic control.
PMCID: PMC4074989  PMID: 25071585
orthostatic tolerance; blood pressure regulation; lower body negative pressure; parasympathetic activity; sympathetic activity; propranolol; atropine
9.  Use of near-infrared spectroscopy during a vascular occlusion test to assess the microcirculatory response during fluid challenge 
Critical Care  2011;15(5):R214.
Adequate volume expansion (VE) in patients with evidence of hypoperfusion should be aimed not only at achieving an increase in stroke volume (SV) and cardiac index (CI) but also at improved tissue perfusion and oxygenation. Our aim in this study was to assess the dynamic changes in muscle tissue oxygen saturation (StO2) during hypovolaemia and in response to VE.
We conducted a prospective study of 42 fluid challenges in patients undergoing major abdominal surgery with evidence of hypovolaemia, defined as pulse pressure variation (PPV) >13% and SV variation (SVV) >12%. CI, SV, SVV (FloTrac/Vigileo) and PPV were measured before and after VE. Fluid responsiveness was defined as an increase of SV >15% after a 500-mL colloid infusion over 15 minutes. In all patients, the muscle StO2 and its changes during a standardised vascular occlusion test were analysed using a near-infrared spectroscopy device after anaesthesia induction (which defined the baseline state) and before and after each VE.
No patients were preload-responsive after anaesthesia induction. Twenty-nine of forty-two fluid challenges (69%) were positive for VE, with a statistically significant (P < 0.001) difference in SV changes between positive and negative responses to VE. There was a statistically significant difference in PPV and SVV values before VE in the positive and negative fluid responses [PPV: 16% (15% to 18%) vs. 14% (13% to 15%), P = 0.001; and SVV: 14% (13% to 16%) vs. 16% (15% to 16%), P = 0.03 or positive and negative fluid responses, respectively]. Data are presented as medians and 25th and 75th percentiles Before VE there was no significant difference in StO2 values relative to baseline [86% (78% to 88%) vs. 84% (77% to 91%), P = 0.83], without a significant difference (P = 0.36) between positive and negative fluid challenges. Hypovolaemia was associated with a significant reduction (P = 0.004) in StO2 recovery slope, with a significant difference (P = 0.02) between positive and negative fluid challenges. The VE-induced increase in the StO2 recovery slope was 62 ± 49% (P < 0.001) for positive fluid challenges and 26 ± 34% (P = 0.04) for negative fluid challenges.
Hypovolaemia significantly affects the muscle StO2 recovery slope. Restoring effective intravascular volume with fluid loading significantly improves the StO2 recovery slope, despite apparently ineffective changes in systemic haemodynamics.
PMCID: PMC3334758  PMID: 21923899
10.  Passive leg raising can predict fluid responsiveness in patients placed on venovenous extracorporeal membrane oxygenation 
Critical Care  2011;15(5):R216.
In ICUs, fluid administration is frequently used to treat hypovolaemia. Because volume expansion (VE) can worsen acute respiratory distress syndrome (ARDS) and volume overload must be avoided, predictive indicators of fluid responsiveness are needed. The purpose of this study was to determine whether passive leg raising (PLR) can be used to predict fluid responsiveness in patients with ARDS treated with venovenous extracorporeal membrane oxygenation (ECMO).
We carried out a prospective study in a university hospital surgical ICU. All patients with ARDS treated with venovenous ECMO and exhibiting clinical and laboratory signs of hypovolaemia were enrolled. We measured PLR-induced changes in stroke volume (ΔPLRSV) and cardiac output (ΔPLRCO) using transthoracic echocardiography. We also assessed PLR-induced changes in ECMO pump flow (ΔPLRPO) and PLR-induced changes in ECMO pulse pressure (ΔPLRPP) as predictors of fluid responsiveness. Responders were defined by an increase in stroke volume (SV) > 15% after VE.
Twenty-five measurements were obtained from seventeen patients. In 52% of the measurements (n = 13), SV increased by > 15% after VE (responders). The patients' clinical characteristics appeared to be similar between responders and nonresponders. In the responder group, PLR significantly increased SV, cardiac output and pump flow (P < 0.001). ΔPLRSV values were correlated with VE-induced SV variations (r2 = 0.72, P = 0.0001). A 10% increased ΔPLRSV predicted fluid responsiveness with an area under the receiver operating characteristic curve (AUC) of 0.88 ± 0.07 (95% confidence interval (CI95): 0.69 to 0.97; P < 0.0001), 62% sensitivity and 92% specificity. On the basis of AUCs of 0.62 ± 0.11 (CI95: 0.4 to 0.8; P = 0.31) and 0.53 ± 0.12 (CI95: 0.32 to 0.73, P = 0.79), respectively, ΔPLRPP and ΔPLRPO did not predict fluid responsiveness.
In patients treated with venovenous ECMO, a > 10% ΔPLRSV may predict fluid responsiveness. ΔPLRPP and ΔPLRPO cannot predict fluid responsiveness.
PMCID: PMC3334760  PMID: 21923944
acute respiratory distress syndrome; fluid responsiveness; passive leg raising; extracorporeal membrane oxygenation; venovenous
11.  Nurses' prediction of volume status after aneurysmal subarachnoid haemorrhage: a prospective cohort study 
Critical Care  2008;12(6):R153.
Patients who have suffered aneurysmal subarachnoid haemorrhage (SAH) often have derangements in blood volume, contributing to poor outcome. To guide fluid management, regular assessments of volume status must be conducted. We studied the ability of nursing staff to predict hypovolaemia or hypervolaemia, based on their interpretation of available haemodynamic data.
In a prospective cohort study, intensive care unit and medium care unit nurses, currently treating patients with recent SAH, were asked to predict present volume status. For their assessment they could use all available haemodynamic parameters (for example, heart rate, blood pressure, fluid balance). The nurses' assessments were compared with the actual circulating blood volume (CBV), as measured daily with pulse dye densitometry during the first 10 days after SAH. Normovolaemia was defined as a CBV of 60 to 80 ml/kg body weight; hypovolaemia as CBV under 60 ml/kg; severe hypovolaemia as CBV under 50 ml/kg and hypervolaemia as CBV above 80 ml/kg.
A total of 350 combinations of volume predictions and CBV measurements were obtained in 43 patients. Prediction of hypovolaemia had a sensitivity of 0.10 (95% confidence interval [CI] = 0.06 to 0.16) and a positive predictive value of 0.37 (95% CI = 0.23 to 0.53) for actual hypovolaemia. The prediction of hypervolaemia had a sensitivity of 0.06 (95% CI = 0.01 to 0.16) and a positive predictive value of 0.06 (95% CI = 0.02 to 0.19) for actual hypervolaemia. Mean CBV was significantly lower in instances considered hypervolaemic than in instances considered normovolaemic.
Assessment of haemodynamic condition in patients with SAH by intensive care unit or medium care unit nurses does not adequately predict hypovolaemia or hypervolaemia, as measured using pulse dye densitometry. Fluid therapy after SAH may require guidance with more advanced techniques than interpretation of usual haemodynamic parameters.
PMCID: PMC2646318  PMID: 19046461
12.  WISE-2005: effect of aerobic and resistive exercises on orthostatic tolerance during 60 days bed rest in women 
Cardiovascular deconditioning after long duration spaceflight is especially challenging in women who have a lower orthostatic tolerance (OT) compared with men. We hypothesized that an exercise prescription, combining supine aerobic treadmill exercise in a Lower Body Negative Pressure (LBNP) chamber followed by 10 min of resting LBNP, 3 to 4 times a week, and flywheel resistive training every third day would maintain orthostatic tolerance (OT) in women during a 60-day head-down-tilt bed rest (HDBR). Sixteen women were assigned to two groups (exercise, control). Pre and post HDBR OT was assessed with a tilt/LBNP test until presyncope. OT time (mean ± SE) decreased from 17.5±1.0 min to 9.1±1.5 min (−50±6%) in control group (p<0.001) and from 19.3 ±1.3 min to 13.0 ± 1.9 min (−35±7%) in exercise group (p<0.001), with no significant difference in OT time between the two groups after HDBR (p=0.13). Nevertheless compared with controls post HDBR, exercisers had a lower heart rate (mean±SE) during supine rest (71±3 versus 85±4, p<0.01), a slower increase in heart rate and a slower decrease in stroke volume over the course of tilt/LBNP test (p<0.05). Blood volume (mean±SE) decreased in controls (−9±2%, p<0.01) but was maintained in exercisers (−4±3%, p=0.17).
Our results suggest that the combined exercise countermeasure fails to protect OT but improves cardiovascular response to subtolerance levels of orthostatic stress.
PMCID: PMC2881341  PMID: 19247686
Bed Rest; Dizziness; prevention & control; Exercise; physiology; Exercise Tolerance; physiology; Female; Head-Down Tilt; physiology; Heart Rate; physiology; Humans; Lower Body Negative Pressure; Stroke Volume; physiology; Tilt-Table Test; Time Factors; Weightlessness Simulation; simulated microgravity; cardiovascular deconditioning; exercise countermeasure; lower body negative pressure; WISE 2005
13.  Resetting of the cardiopulmonary baroreflex 10 years after surgical repair of coarctation of the aorta 
Heart  2001;85(3):318-325.
OBJECTIVE—To characterise cardiopulmonary baroreflex responses and examine the effects of a 45 minute cycling bout late after successful repair of coarctation of the aorta.
SUBJECTS—10 young adults (mean (SEM) age 18.1 (2.6 years)) operated on for coarctation of the aorta 12.7 (3.5) years earlier, and 10 healthy controls.
DESIGN—Forearm blood flow (venous occlusion plethysmography) and vascular resistance, left ventricular internal diastolic diameter, and central venous pressure estimated from an antecubital vein were measured in the supine position at baseline and during five minute applications of lower body negative pressure (LBNP) at −15 mm Hg (LBNP−15) and −40 mm Hg (LBNP−40). Venous samples were obtained at baseline and during LBNP−40 for noradrenaline (norepinephrine), adrenaline (epinephrine), renin activity, and aldosterone. The tests were repeated after 45 minutes of moderate exercise.
RESULTS—Baseline heart rate (78 (9) v 64 (6) beats/min), echocardiographic cardiac output (6.9 (1.1) v 5.0 (0.2) l/min), shortening fraction (41.7 (1.8)% v 33.3 (1.3)%), and forearm blood flow (3.4 (0.4) v 2.3 (0.3) ml/100 g/min) were higher in the coarctation group than in the controls (p < 0.05). Changes in forearm blood flow and forearm vascular resistance from baseline to LBNP−40 were similar in both groups, but the relation between forearm vascular resistance and estimated central venous pressure or left ventricular internal diastolic diameter was shifted downward in the coarctation group. Plasma adrenaline was increased in the coarctation group (baseline: 3.2 (0.6) v 2.4 (0.3) pmol/l in controls; LBNP−40: 687 (151) v 332 (42) pmol/l) (p < 0.05). Both groups showed a similar downward displacement of forearm vascular resistance (p < 0.05) after exercise.
CONCLUSIONS—There appears to be resetting of the cardiopulmonary baroreflex to a lower forearm vascular resistance in young adults operated on for coarctation of the aorta, associated with hyperdynamic left ventricular function. Raised circulating adrenaline could contribute to the lower forearm vascular resistance.

Keywords: coarctation of aorta; cardiopulmonary baroreflex; forearm vascular resistance; circulating catecholamines
PMCID: PMC1729634  PMID: 11179275
14.  Multi-site and multi-depth near-infrared spectroscopy in a model of simulated (central) hypovolemia: lower body negative pressure 
Intensive Care Medicine  2011;37(4):671-677.
To test the hypothesis that the sensitivity of near-infrared spectroscopy (NIRS) in reflecting the degree of (compensated) hypovolemia would be affected by the application site and probing depth. We simultaneously applied multi-site (thenar and forearm) and multi-depth (15–2.5 and 25–2.5 mm probe distance) NIRS in a model of simulated hypovolemia: lower body negative pressure (LBNP).
The study group comprised 24 healthy male volunteers who were subjected to an LBNP protocol in which a baseline period of 30 min was followed by a step-wise manipulation of negative pressure in the following steps: 0, −20, −40, −60, −80 and −100 mmHg. Stroke volume and heart rate were measured using volume-clamp finger plethysmography. Two multi-depth NIRS devices were used to measure tissue oxygen saturation (StO2) and tissue hemoglobin index (THI) continuously in the thenar and the forearm. To monitor the shift of blood volume towards the lower extremities, calf THI was measured by single-depth NIRS.
The main findings were that the application of LBNP resulted in a significant reduction in stroke volume which was accompanied by a reduction in forearm StO2 and THI.
NIRS can be used to detect changes in StO2 and THI consequent upon central hypovolemia. Forearm NIRS measurements reflect hypovolemia more sensitively than thenar NIRS measurements. The sensitivity of these NIRS measurements does not depend on NIRS probing depth. The LBNP-induced shift in blood volume is reflected by a decreased THI in the forearm and an increased THI in the calf.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-2128-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3058331  PMID: 21253704
Near-infrared spectroscopy; Lower body negative pressure; Hypovolemia; Tissue oxygenation; Microcirculation; Tissue hemoglobin content
15.  The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study 
Malaria Journal  2013;12:348.
Adults with severe malaria frequently require intravenous fluid therapy to restore their circulating volume. However, fluid must be delivered judiciously as both under- and over-hydration increase the risk of complications and, potentially, death. As most patients will be cared for in a resource-poor setting, management guidelines necessarily recommend that physical examination should guide fluid resuscitation. However, the reliability of this strategy is uncertain.
To determine the ability of physical examination to identify hypovolaemia, volume responsiveness, and pulmonary oedema, clinical signs and invasive measures of volume status were collected independently during an observational study of 28 adults with severe malaria.
The physical examination defined volume status poorly. Jugular venous pressure (JVP) did not correlate with intravascular volume as determined by global end diastolic volume index (GEDVI; rs = 0.07, p = 0.19), neither did dry mucous membranes (p = 0.85), or dry axillae (p = 0.09). GEDVI was actually higher in patients with decreased tissue turgor (p < 0.001). Poor capillary return correlated with GEDVI, but was present infrequently (7% of observations) and, therefore, insensitive. Mean arterial pressure (MAP) correlated with GEDVI (rs = 0.16, p = 0.002), but even before resuscitation patients with a low GEDVI had a preserved MAP. Anuria on admission was unrelated to GEDVI and although liberal fluid resuscitation led to a median hourly urine output of 100 ml in 19 patients who were not anuric on admission, four (21%) developed clinical pulmonary oedema subsequently. MAP was unrelated to volume responsiveness (p = 0.71), while a low JVP, dry mucous membranes, dry axillae, increased tissue turgor, prolonged capillary refill, and tachycardia all had a positive predictive value for volume responsiveness of ≤50%. Extravascular lung water ≥11 ml/kg indicating pulmonary oedema was present on 99 of the 353 times that it was assessed during the study, but was identified on less than half these occasions by tachypnoea, chest auscultation, or an elevated JVP. A clear chest on auscultation and a respiratory rate <30 breaths/minute could exclude pulmonary oedema on 82% and 72% of occasions respectively.
Findings on physical examination correlate poorly with true volume status in adults with severe malaria and must be used with caution to guide fluid therapy.
Trial registration identifier: NCT00692627
PMCID: PMC3851438  PMID: 24079262
Severe malaria; Physical examination; Fluid resuscitation
16.  The role of pre-hospital blood gas analysis in trauma resuscitation 
To assess, whether arterial blood gas measurements during trauma patient's pre-hospital shock resuscitation yield useful information on haemodynamic response to fluid resuscitation by comparing haemodynamic and blood gas variables in patients undergoing two different fluid resuscitation regimens.
In a prospective randomised study of 37 trauma patients at risk for severe hypovolaemia, arterial blood gas values were analyzed at the accident site and on admission to hospital. Patients were randomised to receive either conventional fluid therapy or 300 ml of hypertonic saline. The groups were compared for demographic, injury severity, physiological and outcome variables.
37 patients were included. Mean (SD) Revised Trauma Score (RTS) was 7.3427 (0.98) and Injury Severity Score (ISS) 15.1 (11.7). Seventeen (46%) patients received hypertonic fluid resuscitation and 20 (54%) received conventional fluid therapy, with no significant differences between the groups concerning demographic data or outcome. Base excess (BE) values decreased significantly more within the hypertonic saline (HS) group compared to the conventional fluid therapy group (mean BE difference -2.1 mmol/l vs. -0.5 mmol/l, p = 0.003). The pH values on admission were significantly lower within the HS group (mean 7.31 vs. 7.40, p = 0.000). Haemoglobin levels were in both groups lower on admission compared with accident site. Lactate levels on admission did not differ significantly between the groups.
Pre-hospital use of small-volume resuscitation led to significantly greater decrease of BE and pH values. A portable blood gas analyzer was found to be a useful tool in pre-hospital monitoring for trauma resuscitation.
PMCID: PMC2873276  PMID: 20412593
17.  Platelet Activation after Presyncope by Lower Body Negative Pressure in Humans 
PLoS ONE  2014;9(12):e116174.
Central hypovolemia elevates hemostatic activity which is essential for preventing exsanguination after trauma, but platelet activation to central hypovolemia has not been described. We hypothesized that central hypovolemia induced by lower body negative pressure (LBNP) activates platelets. Eight healthy subjects were exposed to progressive central hypovolemia by LBNP until presyncope. At baseline and 5 min after presyncope, hemostatic activity of venous blood was evaluated by flow cytometry, thrombelastography, and plasma markers of coagulation and fibrinolysis. Cell counts were also determined. Flow cytometry revealed that LBNP increased mean fluorescence intensity of PAC-1 by 1959±455 units (P<0.001) and percent of fluorescence-positive platelets by 27±18%-points (P = 0.013). Thrombelastography demonstrated that coagulation was accelerated (R-time decreased by 0.8±0.4 min (P = 0.001)) and that clot lysis increased (LY60 by 6.0±5.8%-points (P = 0.034)). Plasma coagulation factor VIII and von Willebrand factor ristocetin cofactor activity increased (P = 0.011 and P = 0.024, respectively), demonstrating increased coagulation activity, while von Willebrand factor antigen was unchanged. Plasma protein C activity and tissue-type plasminogen activator increased (P = 0.007 and P = 0.017, respectively), and D-dimer increased by 0.03±0.02 mg l−1 (P = 0.031), demonstrating increased fibrinolytic activity. Plasma prothrombin time and activated partial thromboplastin time were unchanged. Platelet count increased by 15±13% (P = 0.014) and red blood cells by 9±4% (P = 0.002). In humans, LBNP-induced presyncope activates platelets, as evidenced by increased exposure of active glycoprotein IIb/IIIa, accelerates coagulation. LBNP activates fibrinolysis, similar to hemorrhage, but does not alter coagulation screening tests, such as prothrombin time and activated partial thromboplastin time. LBNP results in increased platelet counts, but also in hemoconcentration.
PMCID: PMC4278859  PMID: 25546432
18.  Heat stress reduces cerebral blood velocity and markedly impairs orthostatic tolerance in humans 
Orthostatic tolerance is reduced in the heat-stressed human. This study tested the following hypotheses: 1) whole body heat stress reduces cerebral blood velocity (CBV) and increases cerebral vascular resistance (CVR); and 2) reductions in CBV and increases in CVR in response to an orthostatic challenge will be greater while subjects are heat stressed. Fifteen subjects were instrumented for measurements of CBV (transcranial ultrasonography), mean arterial blood pressure (MAP), heart rate, and internal temperature. Whole body heating increased both internal temperature (36.4 ± 0.1 to 37.3 ± 0.1° C) and heart rate (59 ± 3 to 90 ± 3 beats/min); P < 0.001. Whole body heating also reduced CBV (62 ± 3 to 53 ± 2 cm/s) primarily via an elevation in CVR (1.35 ± 0.06 to 1.63 ± 0.07 mmHg · cm-1 · s); P < 0.001. A subset of subjects (n = 8) were exposed to lower-body negative pressure (LBNP 10, 20, 30, 40 mmHg) in both normothermic and heat-stressed conditions. During normothermia, LBNP of 30 mmHg (highest level of LBNP achieved by the majority of subjects in both thermal conditions) did not significantly alter CBV, CVR, or MAP. During whole body heating, this LBNP decreased MAP (81 ± 2 to 75 ± 3 mmHg), decreased CBV (50 ± 4 to 39 ± 1 cm/s), and increased CVR (1.67 ± 0.17 to 1.92 ± 0.12 mmHg · cm-1 · s); P < 0.05. These data indicate that heat stress decreases CBV, and the reduction in CBV for a given orthostatic challenge is greater during heat stress. These outcomes reduce the reserve to buffer further decreases in cerebral perfusion before presyncope. Increases in CVR during whole body heating, coupled with even greater increases in CVR during orthostasis and heat stress, likely contribute to orthostatic intolerance.
PMCID: PMC2442822  PMID: 16763078
hyperthermia; syncope; transcranial Doppler; cerebral vascular resistance
19.  Heart Rate Variability during Simulated Hemorrhage with Lower Body Negative Pressure in High and Low Tolerant Subjects 
Heart rate variability (HRV) decreases during hemorrhage, and has been proposed as a new vital sign to assess cardiovascular stability in trauma patients. The purpose of this study was to determine if any of the HRV metrics could accurately distinguish between individuals with different tolerance to simulated hemorrhage. Specifically, we hypothesized that (1) HRV would be similar in low tolerant (LT) and high tolerant (HT) subjects at presyncope when both groups are on the verge of hemodynamic collapse; and (2) HRV could distinguish LT subjects at presyncope from hemodynamically stable HT subjects (i.e., at a submaximal level of hypovolemia). Lower body negative pressure (LBNP) was used as a model of hemorrhage in healthy human subjects, eliciting central hypovolemia to the point of presyncopal symptoms (onset of hemodynamic collapse). Subjects were classified as LT if presyncopal symptoms occurred during the −15 to −60 mmHg levels of LBNP, and HT if symptoms occurred after LBNP of −60 mmHg. A total of 20 HRV metrics were derived from R–R interval measurements at the time of presyncope, and at one level prior to presyncope (submax) in LT and HT groups. Only four HRV metrics (Long-range Detrended Fluctuation Analysis, Forbidden Words, Poincaré Plot Descriptor Ratio, and Fractal Dimensions by Curve Length) supported both hypotheses. These four HRV metrics were evaluated further for their ability to identify individual LT subjects at presyncope when compared to HT subjects at submax. Variability in individual LT and HT responses was so high that LT responses overlapped with HT responses by 85–97%. The sensitivity of these HRV metrics to distinguish between individual LT from HT subjects was 6–33%, and positive predictive values were 40–73%. These results indicate that while a small number of HRV metrics can accurately distinguish between LT and HT subjects using group mean data, individual HRV values are poor indicators of tolerance to hypovolemia.
PMCID: PMC3221414  PMID: 22125539
lower body negative pressure; hypovolemia; hemorrhage; heart rate variability; heart period variability
20.  Autonomic Heart Rate Control at Rest and During Unloading of the Right Ventricle in Repaired Tetralogy of Fallot in Adolescents 
The American journal of cardiology  2008;102(8):1085-1089.
Arrhythmias in patients with repaired tetralogy of Fallot (ToF) might be due in part to altered autonomic heart rate (HR) control caused by altered right ventricle hemodynamics. This study investigated autonomic HR control in ToF adolescents at rest and during unloading of the right ventricle. A total of 17 ToF patients and 56 healthy controls aged 12 to 18 years underwent orthostatic stress with lower body negative pressure (LBNP) of −20 mm Hg. HR, blood pressure and stroke volume were recorded non-invasively. Indices of HR variability were computed in time and frequency domains. All ToF patients also underwent cardiac magnetic resonance imaging, demonstrating pulmonary regurgitation and right ventricular dilation. At rest, HR variability indices of vagal heart rate control were non-significantly lower in the ToF patients compared to controls. During LBNP, HR increased more in controls than ToF patients (p ≤ 0.001). Further, most HR variability indices decreased among controls, but increased among ToF patients (p ≤ 0.01 or p ≤ 0.001 for all variables), suggesting vagal activation in the ToF patients. In conclusion, adolescents after ToF repair have fairly normal HR control at rest despite altered right ventricular hemodynamics. During unloading of the right ventricle, however, vagal HR control increases in the ToF patients and decreases in the controls.
PMCID: PMC2645862  PMID: 18929714
Tetralogy of Fallot; autonomic nervous system; heart rate variability; adolescence
21.  Sympathetic Responses to Central Hypovolemia: New Insights from Microneurographic Recordings 
Hemorrhage remains a major cause of mortality following traumatic injury in both military and civilian settings. Lower body negative pressure (LBNP) has been used as an experimental model to study the compensatory phase of hemorrhage in conscious humans, as it elicits central hypovolemia like that induced by hemorrhage. One physiological compensatory mechanism that changes during the course of central hypovolemia induced by both LBNP and hemorrhage is a baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA), as assessed with microneurography. The purpose of this review is to describe recent results obtained using microneurography in our laboratory as well as those of others that have revealed new insights into mechanisms underlying compensatory increases in MSNA during progressive reductions in central blood volume and how MSNA is altered at the point of hemodynamic decompensation. We will also review recent work that has compared direct MSNA recordings with non-invasive surrogates of MSNA to determine the appropriateness of using such surrogates in assessing the clinical status of hemorrhaging patients.
PMCID: PMC3337468  PMID: 22557974
hemorrhage; sympathetic activity; MSNA; baroreflex function; central hypovolemia; LBNP
22.  Greater cardiac response of colloid than saline fluid loading in septic and non-septic critically ill patients with clinical hypovolaemia 
Intensive Care Medicine  2010;36(4):697-701.
Background and objective
The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis.
Design and setting
A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI).
Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preload-recruitable stroke work was also greater with colloids and did not differ among conditions.
Fluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-1776-x) contains supplementary material, which is available to authorized users.
PMCID: PMC2837190  PMID: 20165941
Colloids; Crystalloids; Sepsis; Preload-recruitable stroke work; Hypovolaemia; Global end-diastolic volume; Fluid challenge
23.  The role of low pressure baroreceptors in reflex vasoconstrictor responses in man 
Journal of Clinical Investigation  1972;51(11):2967-2972.
Studies were performed on 11 healthy men to evaluate the role of low pressure baroreceptors in the reflex forearm vasoconstrictor responses (plethysmography) to venous pooling produced by lower body negative pressure. Lower body negative pressure (LBNP) at - 5, - 10, - 20, and - 40 mm Hg lowered central venous pressure by 42, 59, 74, and 93%, respectively, and decreased forearm vascular conductance by 24, 29, 34, and 40%, respectively. The decreases in forearm blood flow and conductance during the low levels of venous pooling (LBNP - 5 and - 10 mm Hg) occurred without significant changes in arterial pressure, arterial dP/dt. and heart rate. These results with the low levels indicate that maneuvers which decrease venous return and central venous pressure in man can influence forearm vascular tone without significant changes in the determinants of carotid and aortic baroreceptor activity. During high levels of venous pooling (LBNP - 20 and - 40 mm Hg), significant decreases in arterial pressure and dP/dt and significant increases in heart rate accompanied the further reductions in central venous pressure, forearm blood flow, and forearm vascular conductance. About 73% of the decrease in conductance during venous pooling at LBNP - 40 mm Hg, which was sufficient to decrease arterial pressure and activate high pressure baroreceptor reflexes, occurred during low levels of venous pooling at LBNP - 10 mm Hg without changes in arterial pressure. This suggests that much of the forearm vasoconstriction with the high levels of venous pooling, which were sufficient to decrease arterial pressure, may be accounted for by reflexes originating in areas other than high pressure baroreceptors. The results of these studies suggest that low pressure baroreceptors exert an important influence on forearm vascular tone during decreases in venous return and central venous pressure in man.
PMCID: PMC292447  PMID: 5080421
24.  Resting sympathetic baroreflex sensitivity in subjects with low and high tolerance to central hypovolemia induced by lower body negative pressure 
Central hypovolemia elicited by orthostasis or hemorrhage triggers sympathetically-mediated baroreflex responses to maintain organ perfusion; these reflexes are less sensitive in patients with orthostatic intolerance, and during conditions of severe blood loss, may result in cardiovascular collapse (decompensatory or circulatory shock). The ability to tolerate central hypovolemia is variable and physiological factors contributing to tolerance are emerging. We tested the hypothesis that resting muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (BRS) are attenuated in male and female subjects who have low tolerance (LT) to central hypovolemia induced by lower body negative pressure (LBNP). MSNA and diastolic arterial pressure (DAP) were recorded in 47 human subjects who subsequently underwent LBNP to tolerance (onset of presyncopal symptoms). LT subjects experienced presyncopal symptoms prior to completing LBNP of −60 mm Hg, and subjects with high tolerance (HT) experienced presyncopal symptoms after completing LBNP of −60 mm Hg. Contrary to our hypothesis, resting MSNA burst incidence was not different between LT and HT subjects, and was not related to time to presyncope. BRS was assessed as the slope of the relationship between spontaneous fluctuations in DAP and MSNA during 5 min of supine rest. MSNA burst incidence/DAP correlations were greater than or equal to 0.5 in 37 subjects (LT: n = 9; HT: n = 28), and BRS was not different between LT and HT (−1.8 ± 0.3 vs. −2.2 ± 0.2 bursts·(100 beats)−1 ·mm Hg−1, p = 0.29). We conclude that tolerance to central hypovolemia is not related to either resting MSNA or sympathetic BRS.
PMCID: PMC4074874  PMID: 25071587
hemorrhage; orthostatic intolerance; autonomic reflex
25.  Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention. 
British Heart Journal  1994;72(6):534-539.
BACKGROUND--Hypovolaemia stimulates the sympathoadrenal and renin systems and water retention. It has been proposed that in congestive heart failure reduction of cardiac output and any associated decrease in blood pressure cause underfilling of the arterial compartment, which promotes and perpetuates neurohumoral activation and the retention of fluid. This study examined whether an intravascular volume deficit accounts for patterns that largely exceed the limits of a homoeostatic response, which are sometimes seen in advanced congestive heart failure. METHODS AND RESULTS--In 22 patients with congestive heart failure and water retention the body fluid mass was reduced by ultrafiltration and the neurohumoral reaction was monitored. A Diafilter, which was part of an external venous circuit was regulated to produce 500 ml/hour of ultrafiltrate (mean (SD) 3122 (1199) ml) until right atrial pressure was reduced to 50% of baseline. Haemodynamic variables, plasma renin activity, noradrenaline, and aldosterone were measured before and within 48 hours of ultrafiltration. After ultrafiltration, which produced a 20% reduction of plasma volume and a moderate decrease in cardiac output and blood pressure (consistent with a diminished degree of filling of the arterial compartment), there was an obvious decrease in noradrenaline, plasma renin activity, and aldosterone. In the next 48 hours plasma volume, cardiac output, and blood pressure recovered; the neurohumoral axis was depressed; and there was a striking enhancement of water and sodium excretion with resolution of the peripheral oedema and organ congestion. The neurohumoral changes and haemodynamic changes were not related. There were significant correlations between the neurohumoral changes and increase in urinary output and sodium excretion. CONCLUSIONS--In advanced congestive heart failure arterial underfilling was not the main mechanism for activating the neurohumoral axis and retaining fluid. Because a decrease in circulating hormones was associated with reabsorption of extravascular fluid it is likely that hypoperfusion and/or congestion of organs, such as the kidney and lung, reduce the clearance of circulating noradrenaline and help to keep plasma concentrations of renin and aldosterone raised. A positive feedback loop between fluid retention and plasma hormone concentrations may be responsible for progression of congestive heart failure.
PMCID: PMC1025638  PMID: 7857735

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