Non-invasive biomarkers for detecting progression toward hypovolemic cardiovascular instability in a lower body negative pressure model.

Occult hemorrhages after trauma can be present insidiously, and if not detected early enough can result in patient death. This study evaluated a hemorrhage model on 18 human subjects, comparing the performance of traditional vital signs to multiple off-the-shelf non-invasive biomarkers. A validated lower body negative pressure (LBNP) model was used to induce progression towards hypovolemic cardiovascular instability. Traditional vital signs included mean arterial pressure (MAP), electrocardiography (ECG), plethysmography (Pleth), and the test systems utilized electrical impedance via commercial electrical impedance tomography (EIT) and multifrequency electrical impedance spectroscopy (EIS) devices. Absolute and relative metrics were used to evaluate the performance in addition to machine learning-based modeling. Relative EIT-based metrics measured on the thorax outperformed vital sign metrics (MAP, ECG, and Pleth) achieving an area-under-the-curve (AUC) of 0.99 (CI 0.95-1.00, 100% sensitivity, 87.5% specificity) at the smallest LBNP change (0-15 mmHg). The best vital sign metric (MAP) at this LBNP change yielded an AUC of 0.6 (CI 0.38-0.79, 100% sensitivity, 25% specificity). Out-of-sample predictive performance from machine learning models were strong, especially when combining signals from multiple technologies simultaneously. EIT, alone or in machine learning-based combination, appears promising as a technology for early detection of progression toward hemodynamic instability.

A Comparison of Normalization Techniques for Individual Baseline-Free Estimation of Absolute Hypovolemic Status Using a Porcine Model.

Hypovolemic shock is one of the leading causes of death in the military. The current methods of assessing hypovolemia in field settings rely on a clinician assessment of vital signs, which is an unreliable assessment of hypovolemia severity. These methods often detect hypovolemia when interventional methods are ineffective. Therefore, there is a need to develop real-time sensing methods for the early detection of hypovolemia. Previously, our group developed a random-forest model that successfully estimated absolute blood-volume status (ABVS) from noninvasive wearable sensor data for a porcine model (n = 6). However, this model required normalizing ABVS data using individual baseline data, which may not be present in crisis situations where a wearable sensor might be placed on a patient by the attending clinician. We address this barrier by examining seven individual baseline-free normalization techniques. Using a feature-specific global mean from the ABVS and an external dataset for normalization demonstrated similar performance metrics compared to no normalization (normalization: R2 = 0.82 ± 0.025|0.80 ± 0.032, AUC = 0.86 ± 5.5 × 10-3|0.86 ± 0.013, RMSE = 28.30 ± 0.63%|27.68 ± 0.80%; no normalization: R2 = 0.81 ± 0.045, AUC = 0.86 ± 8.9 × 10-3, RMSE = 28.89 ± 0.84%). This demonstrates that normalization may not be required and develops a foundation for individual baseline-free ABVS prediction.

Use of POCUS for the assessment of dehydration in pediatric patients-a narrative review.

In pediatric practice, POCUS (point-of-care ultrasound) has been mostly implemented to recognize lung conditions and pleural and pericardial effusions, but less to evaluate fluid depletion. The main aim of this review is to analyze the current literature on the assessment of dehydration in pediatric patients by using POCUS. The size of the inferior vena cava (IVC) and its change in diameter in response to respiration have been investigated as a tool to screen for hypovolemia. A dilated IVC with decreased collapsibility (< 50%) is a sign of increased right atrial pressure. On the contrary, a collapsed IVC may be indicative of hypovolemia. The IVC collapsibility index (cIVC) reflects the decrease in the diameter upon inspiration. Altogether the IVC diameter and collapsibility index can be easily determined, but their role in children has not been fully demonstrated, and an estimation of volume status solely by assessing the IVC should thus be interpreted with caution. The inferior vena cava/abdominal aorta (IVC/AO) ratio may be a suitable parameter to assess the volume status in pediatric patients even though there is a need to define age-based thresholds. A combination of vascular, lung, and cardiac POCUS could be a valuable supplementary tool in the assessment of dehydration in several clinical scenarios, enabling rapid identification of life-threatening primary etiologies and helping physicians avoid inappropriate therapeutic interventions.   Conclusion: POCUS can provide important information in the assessment of intravascular fluid status in emergency scenarios, but measurements may be confounded by a number of other clinical variables. The inclusion of lung and cardiac views may assist in better understanding the patient's physiology and etiology regarding volume status. What is Known: • In pediatric practice, POCUS (point-of-care ultrasound) has been mostly implemented to recognize lung conditions (like pneumonia and bronchiolitis) and pleural and pericardial effusions, but less to evaluate fluid depletion. • The size of the IVC (inferior vena cava) and its change in diameter in response to respiration have been studied as a possible screening tool to assess the volume status, predict fluid responsiveness, and assess potential intolerance to fluid loading. What is New: • The IVC diameter and collapsibility index can be easily assessed, but their role in predicting dehydration in pediatric age has not been fully demonstrated, and an estimation of volume status only by assessing the IVC should be interpreted carefully. • The IVC /AO(inferior vena cava/abdominal aorta) ratio may be a suitable parameter to assess the volume status in pediatric patients even though there is a need to define age-based thresholds. A combination of vascular, lung, and cardiac POCUS can be a valuable supplementary tool in the assessment of intravascular volume in several clinical scenarios.

Diagnostic Adjunct Techniques in the Assessment of Hypovolemia: A Prospective Pilot Project.

INTRODUCTION: Measuring the hypovolemic resuscitation end point remains a critical care challenge. Our project compared clinical hypovolemia (CH) with three diagnostic adjuncts: 1) noninvasive cardiac output monitoring (NICOM), 2) ultrasound (US) static IVC collapsibility (US-IVC), and 3) US dynamic carotid upstroke velocity (US-C). We hypothesized US measures would correlate more closely to CH than NICOM. METHODS: Adult trauma/surgical intensive care unit patients were prospectively screened for suspected hypovolemia after acute resuscitation, excluding patients with burns, known heart failure, or severe liver/kidney disease. Adjunct measurements were assessed up to twice a day until clinical improvement. Hypovolemia was defined as: 1) NICOM: ≥10% stroke volume variation with passive leg raise, 2) US-IVC: <2.1 cm and >50% collapsibility (nonventilated) or >18% collapsibility (ventilated), 3) US-C: peak systolic velocity increase 15 cm/s with passive leg raise. Previously unknown cardiac dysfunction seen on US was noted. Observation-level data were analyzed with a Cohen's kappa (κ). RESULTS: 44 patients (62% male, median age 60) yielded 65 measures. Positive agreement with CH was 47% for NICOM, 37% for US-IVC and 10% for US-C. None of the three adjuncts correlated with CH (κ -0.045 to 0.029). After adjusting for previously unknown cardiac dysfunction present in 10 patients, no adjuncts correlated with CH (κ -0.036 to 0.031). No technique correlated with any other (κ -0.118 to 0.083). CONCLUSIONS: None of the adjunct measurements correlated with CH or each other, highlighting that fluid status assessment remains challenging in critical care. US should assess for right ventricular dysfunction prior to resuscitation.

Towards a Lightweight Classifier to Detect Hypovolemic Shock.

Predicting the ability of an individual to compensate for blood loss during hemorrhage and detect the likely onset of hypovolemic shock is necessary to permit early clinical intervention. Towards this end, the compensatory reserve metric (CRM) has been demonstrated to directly correlate with an individual's ability to maintain compensatory mechanisms during loss of blood volume from onset (one-hundred percent health) to exsanguination (zero percent health). This effort describes a lightweight, three-class predictor (good, fair, poor) of an individual's compensatory reserve using a linear support-vector machine (SVM) classifier. A moving mean filter of the predictions demonstrates a feasible model for implementation of real-time hypovolemia monitoring on a wearable device, requiring only 408 bytes to store the models' coefficients and minimal processor cycles to complete the computations.

Intraoperative Use of Compensatory Reserve Measurement in Orthotopic Liver Transplant: Improved Sensitivity for the Prediction of Hypovolemic Events.

INTRODUCTION: The compensatory reserve measurement (CRM) is a continuous non-invasive monitoring technology that measures the summation of all physiological mechanisms involved in the compensatory response to central hypovolemia. The CRM is displayed on a 0% to 100% scale. The objective of this study is to characterize the use of CRM in the operative setting and determine its ability to predict hypovolemic events compared to standard vital signs. Orthotopic liver transplant was used as the reference procedure because of the predictable occurrence of significant hemodynamic shifts. METHODS: A prospective observational cohort study was conducted on 22 consecutive patients undergoing orthotopic liver transplant. The subjects were monitored in accordance with the standard of care. The CRM data were collected concurrently with intraoperative staff blinded to the outputs. The data were stored on secure devices on encrypted files. Based on prior literature, subgroup analysis was performed for high-tolerance (good compensators) and low-tolerance (poor compensators) groups, which was based on a shock index threshold of 0.9. Threshold events were defined as follows: CRM below 60% (CRM60), systolic blood pressure (SBP) below 90 mmHg (SBP90), and heart rate (HR) above 100 beats per minute (HR100). RESULTS: Complete data were captured in 22 subjects as a result of device malfunction or procedure cancellation. Sensitivity analysis was performed for the detection of hypovolemia at the time of the event. CRM60 was the most sensitive (62.6%) when compared to other threshold measures such as SBP90 (30.6%), HR100 (23.1%), elevated lactate (54.6%), and a drop in hemoglobin (41.7%). The number of patients meeting the CRM60 threshold at the time of the first transfusion (TFX) was higher when compared to SBP90 and HR100 in the overall group (P = .001 and P < .001, respectively) and both the high-tolerance (P = .002 and P = .001, respectively) and low-tolerance groups (P = .016 and P = .001, respectively). Similar results supporting the higher sensitivity of CRM were observed when comparing the number of patients below the threshold at the time of the first vasopressor administration. Start time was standardized so that the time-to-threshold signals for hemodynamic and laboratory parameters could be compared. The median time-to-CRM signal detection before the TFX event was -15.0 minutes (i.e., 15 minutes before TFX). There was no difference when compared to the SBP threshold (median time -5.0 minutes, P = .64) but was significantly sooner when compared to HR (P = .006), lactate (P = .002), and hemoglobin (P < .001). CONCLUSIONS: At the time of the first TFX, the CRM had a higher rate of detection of a hypovolemic event compared to SBP and HR, indicating a higher sensitivity for the detection of the first hypovolemic event. When combined with all hypovolemic events, sensitivity analysis showed that CRM60 provides the earlier predictive capability. Given that SBP is the clinical standard of care for the initiation of TFX, the finding that median time to event detection was statistically similar between CRM60 and SBP90 was not unexpected. When compared to other measures of hypovolemia, the CRM consistently showed earlier detection of hypovolemic events. Although this study had a small sample size, it produced significant results and can serve as a proof of concept for future large-scale studies.

Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status.

BACKGROUND: Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. METHODS: We measured HR, SBP, and CRM in 172 human subjects (19-55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. RESULTS: The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater ( p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94-0.97) compared with 0.91 (0.89-0.94) for SI ( p = 0.0002). CONCLUSION: Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. LEVEL OF EVIDENCE: Diagnostic Test or Criteria; Level III.

Using the ear photoplethysmographic waveform as an early indicator of central hypovolemia in healthy volunteers utilizing LBNP induced hypovolemia model.

Objective. To study the photoplethysmographic (PPG) waveforms of different locations (ear and finger) during lower body negative pressure (LBNP) induced hypovolemia. Then, to determine whether the PPG waveform can be used to detect hypovolemia during the early stage of LBNP.Approach. 36 healthy volunteers were recruited for progressive LBNP induced hypovolemia, with an endpoint of -60 mmHg or development of hypoperfusion symptoms, whichever comes first. Subjects tolerating the entire protocol without symptoms were designated as high tolerance (HT), while symptomatic subjects were designated as low tolerance (LT). Subjects were monitored with an electrocardiogram, continuous noninvasive blood pressure monitor, and two pulse oximetry probes, one on the ear (Xhale) and one the finger (Nellcor). Stroke volume was measured non-invasively utilizing Non-Invasive Cardiac Output Monitor (NICOM, Cheetah Medical). The waveform morphology was analyzed using novel PPG waveforms indices, including phase hemodynamic index (PHI) and amplitude hemodyamaic index and were evaluated from the ear PPG and finger PPG at different LBNP stages.Main results. The PHI, particularly the phase relationship between the second harmonic and the fundamental component of the ear PPG denoted as∇φ2,during the early stage of LBNP (-15 mmHg) in the HT and LT groups is statistically significantly different (pvalue = 0.0033) with the area under curve 0.81 (CI: 0.616-0.926). The other indices are not significantly different. The 5 fold cross validation shows that∇φ2during the early stage of LBNP (-15 mmHg) as the single index could predict the tolerance of the subject with the sensitivity, specificity, accuracy andF1 as 0.771 ± 0.192, 0.71 ± 0.107, 0.7 ± 0.1 and 0.771 ± 0.192 respectively.Significance. The ear's PPG PHI which compares the phases of the fundamental and second harmonic has the potential to be used as an early predictor of central hypovolemia.

Phlebotomy resulting in controlled hypovolemia to prevent blood loss in major hepatic resections (PRICE-2): study protocol for a phase 3 randomized controlled trial.

INTRODUCTION: Blood loss and red blood cell (RBC) transfusion in liver surgery are areas of concern for surgeons, anesthesiologists, and patients alike. While various methods are employed to reduce surgical blood loss, the evidence base surrounding each intervention is limited. Hypovolemic phlebotomy, the removal of whole blood from the patient without volume replacement during liver transection, has been strongly associated with decreased bleeding and RBC transfusion in observational studies. This trial aims to investigate whether hypovolemic phlebotomy is superior to usual care in reducing RBC transfusions in liver resection. METHODS: This study is a double-blind multicenter randomized controlled trial. Adult patients undergoing major hepatic resections for any indication will be randomly allocated in a 1:1 ratio to either hypovolemic phlebotomy and usual care or usual care alone. Exclusion criteria will be minor resections, preoperative hemoglobin <100g/L, renal insufficiency, and other contraindication to hypovolemic phlebotomy. The primary outcome will be the proportion of patients receiving at least one allogeneic RBC transfusion unit within 30 days of the onset of surgery. Secondary outcomes will include transfusion of other allogeneic blood products, blood loss, morbidity, mortality, and intraoperative physiologic parameters. The surgical team will be blinded to the intervention. Randomization will occur on the morning of surgery. The sample size will comprise 440 patients. Enrolment will occur at four Canadian academic liver surgery centers over a 4-year period. Ethics approval will be obtained at participating sites before enrolment. DISCUSSION: The results of this randomized control trial will provide high-quality evidence regarding the use of hypovolemic phlebotomy in major liver resection and its effects on RBC transfusion. If proven to be effective, this intervention could become standard of care in liver operations internationally and become incorporated within perioperative patient blood management programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651154 . Registered on August 29 2018.

Assessment of Intravascular Volume Status in Children with Nephrotic Edema Using Serum and Urinary Indices and Its Correlation with Inferior Vena Cava Collapsibility Index.

Identification of volume status in nephrotic syndrome (NS) is important but clinically challenging. Urinary and serum indices can be helpful in assessing the volume status and so can be inferior vena cava collapsibility index (IVCCI). This study was done to assess the serum and urinary indices in children with nephrotic edema and to correlate them with IVCCI for intravascular volume assessment. Fifty children with nephrotic edema and 47 children in remission were analyzed for blood and urine indices. Volume status was defined as overfilling or underfilling based on the biochemical indices and also by IVCCI. Eighty-four percent individuals among cases and 23% among controls had sodium retention (FENa < 0.5%). Among cases, 54% had primary sodium retention compared to 17% among controls (p = 0.0002). Hypovolemia was observed among 36% cases based on biochemical indices and in 20% cases as per IVCCI. Hypovolemia was significantly associated with low urinary sodium and low serum albumin.

Empagliflozin in South Asians with type 2 diabetes: Real world data on effects on cardiometabolic parameters, safety and determinants of response to therapy from a diabetes practice in Sri Lanka.

AIMS: SGLT2 inhibitors provide cardiovascular and renal protection in people with type 2 diabetes (T2DM). Real-world data on their effect on improving glucose and cardiovascular risk factors, and adverse effects in South Asians are limited. METHODS: We retrospectively analyzed clinical, demographic, anthropometric and biochemical data among adults with T2DM, commenced on empagliflozin and followed up for at least one month in a diabetes clinic in Colombo. RESULTS: Among 1523 participants (men 49.6 %, age 54.9 (± 10.8) years, diabetes duration 11.5 (± 7.6) years, body mass index 28.2 (± 4.5 kg/m2), over a median follow up of 12 months (range: 1-24 months), reduction in HbA1c, weight, systolic blood pressure (SBP) and urine albumin-creatinine ratio were evident within the first month. Benefits sustained up to two-years (mean changes from baseline: HbA1c - 0.31 (± 1.49), weight - 1.14 (± 4.17), SBP - 3.44 (± 21.75), UACR - 19.84 (± 108.22) follow up. eGFR declined by the third month, returned to baseline by 12th and remained stable over 24 months. Higher baseline HbA1c, weight and SBP predicted greater decline in HbA1c, weight and SBP respectively. Weight reduction independently predicted the SBP reduction. Eighteen participants per 100 patient-years discontinued therapy due to adverse effects: genital mycotic infections and features of hypovolaemia were the commonest. We observed only two events of diabetic ketoacidosis. CONCLUSIONS: Empagliflozin effectively improves glucose, weight and SBP and retards progression of renal impairment in South Asians with T2D. Genital mycotic infections and hypovolaemia were the commonest reasons for discontinuation. Careful patient selection and advice can avoid other sinister complications.

Noninvasive Monitoring of Simulated Hemorrhage and Whole Blood Resuscitation.

Hemorrhage is the leading cause of preventable death from trauma. Accurate monitoring of hemorrhage and resuscitation can significantly reduce mortality and morbidity but remains a challenge due to the low sensitivity of traditional vital signs in detecting blood loss and possible hemorrhagic shock. Vital signs are not reliable early indicators because of physiological mechanisms that compensate for blood loss and thus do not provide an accurate assessment of volume status. As an alternative, machine learning (ML) algorithms that operate on an arterial blood pressure (ABP) waveform have been shown to provide an effective early indicator. However, these ML approaches lack physiological interpretability. In this paper, we evaluate and compare the performance of ML models trained on nine ABP-derived features that provide physiological insight, using a database of 13 human subjects from a lower-body negative pressure (LBNP) model of progressive central hypovolemia and subsequent progressive restoration to normovolemia (i.e., simulated hemorrhage and whole blood resuscitation). Data were acquired at multiple repressurization rates for each subject to simulate varying resuscitation rates, resulting in 52 total LBNP collections. This work is the first to use a single ABP-based algorithm to monitor both simulated hemorrhage and resuscitation. A gradient-boosted regression tree model trained on only the half-rise to dicrotic notch (HRDN) feature achieved a root-mean-square error (RMSE) of 13%, an R2 of 0.82, and area under the receiver operating characteristic curve of 0.97 for detecting decompensation. This single-feature model's performance compares favorably to previously reported results from more-complex black box machine learning models. This model further provides physiological insight because HRDN represents an approximate measure of the delay between the ABP ejected and reflected wave and therefore is an indication of cardiac and peripheral vascular mechanisms that contribute to the compensatory response to blood loss and replacement.

WHEN AND HOW TO USE ORTHOSTATIC VITAL SIGNS.

BACKGROUND: Much controversy surrounds the use of orthostatic vital signs (OVS), including their indications, performance, and interpretation. This can lead to conflict between nurses, physicians, and consultants. This article summarizes the evidence for OVS in selected emergency department (ED) indications and the basis for a rapid measurement protocol. OBJECTIVE: This narrative review is intended to clarify indications for OVS measurement, their performance, and interpretation. DISCUSSION: Phlebotomy studies indicate that OVS are more discriminating than supine vital signs in hypovolemia, but many findings, even some considered "positive," do not provide compelling evidence in favor of or against disease. Evaluated as a diagnostic test, they have a low yield and controversial criteria for a positive test, but as vital signs, they are useful for selected patients with frequent ED presentations-blood loss, dehydration, dizziness, weakness, and falls. Available evidence supports a rapid measurement protocol, including a 1-min interval after standing. CONCLUSION: OVS are useful in selected patients, in a variety of frequent presentations, but their indications and implications for a patient's care are subject to physician interpretation. Given their ease of measurement and effect on decision-making, physicians may consider measuring them early in the evaluation of selected patients.

Feature Importance Analysis for Compensatory Reserve to Predict Hemorrhagic Shock.

Hemorrhage is the leading cause of preventable death from trauma. Traditionally, vital signs have been used to detect blood loss and possible hemorrhagic shock. However, vital signs are not sensitive for early detection because of physiological mechanisms that compensate for blood loss. As an alternative, machine learning algorithms that operate on an arterial blood pressure (ABP) waveform acquired via photoplethysmography have been shown to provide an effective early indicator. However, these machine learning approaches lack physiological interpretability. In this paper, we evaluate the importance of nine ABP-derived features that provide physiological insight, using a database of 40 human subjects from a lower-body negative pressure model of progressive central hypovolemia. One feature was found to be considerably more important than any other. That feature, the half-rise to dicrotic notch (HRDN), measures an approximate time delay between the ABP ejected and reflected wave components. This delay is an indication of compensatory mechanisms such as reduced arterial compliance and vasoconstriction. For a scale of 0% to 100%, with 100% representing normovolemia and 0% representing decompensation, linear regression of the HRDN feature results in root-mean-squared error of 16.9%, R2 of 0.72, and an area under the receiver operating curve for detecting decompensation of 0.88. These results are comparable to previously reported results from the more complex black box machine learning models. Clinical Relevance- A single physiologically interpretable feature measured from an arterial blood pressure waveform is shown to be effective in monitoring for blood loss and impending hemorrhagic shock based on data from a human lower-body negative pressure model of progressive central hypolemia.

Demystifying hyponatremia: A clinical guide to evaluation and management.

Hyponatremia (serum sodium <135 mEq/L) is a frequent electrolyte abnormality complicating the clinical care of hospitalized patients. Hyponatremia has been associated with an increased risk of mortality. Hyponatremia can be seen in patients with euvolemia, hypovolemia, or hypervolemia. Evaluation of hyponatremia relies on clinical assessment and estimation of serum sodium, urine electrolytes, and serum and urine osmolality in addition to other case-specific laboratory parameters. In addition, point-of-care ultrasonography is an important adjunct to physical assessment in estimation of volume status. Understanding the pathophysiology of the underlying process can lead to a timely diagnosis and appropriate management of hyponatremia.

Changes in Serum Creatinine Levels Can Help Distinguish Hypovolemic from Euvolemic Hyponatremia.

Background and Objectives: Differentiating between hypovolemic (HH) and euvolemic hyponatremia (EH) is crucial for correct diagnosis and therapy, but can be a challenge. We aim to ascertain whether changes in serum creatinine (SC) can be helpful in distinguishing HH from EH. Materials and Methods: Retrospective analysis of patients followed in a monographic hyponatremia outpatient clinic of a tertiary hospital during 1 January 2014−30 November 2019. SC changes during HH and EH from eunatremia were studied. The diagnostic accuracy of the SC change from eunatremia to hyponatremia (∆SC) was analyzed. Results: A total of 122 hyponatremic patients, median age 79 years (70−85), 46.7% women. In total, 70/122 patients had EH, 52/122 HH. During hyponatremia, median SC levels increased in the HH group: +0.18 mg/dL [0.09−0.39, p < 0.001], but decreased in the EH group: −0.07 mg/dL (−0.15−0.02, p < 0.001), as compared to SC in eunatremia. HH subjects presented a higher rate of a positive ∆SC than EH (90.4% vs. 25.7%, p < 0.001). EH subjects presented a higher rate of a negative/null ∆SC than HH (74.3% vs. 9.6%, p < 0.001). ROC curve analysis found an AUC of 0.908 (95%CI: 0.853 to 0.962, p < 0.001) for ∆SC%. A ∆SC% ≥ 10% had an OR of 29.0 (95%CI: 10.3 to 81.7, p < 0.001) for HH. A ∆SC% ≤ 3% had an OR of 68.3 (95%CI: 13.0 to 262.2, p < 0.001) for EH. Conclusions: The assessment of SC changes from eunatremia to hyponatremia can be useful in distinguishing between HH and EH.

Detection of a Stroke Volume Decrease by Machine-Learning Algorithms Based on Thoracic Bioimpedance in Experimental Hypovolaemia.

Compensated shock and hypovolaemia are frequent conditions that remain clinically undetected and can quickly cause deterioration of perioperative and critically ill patients. Automated, accurate and non-invasive detection methods are needed to avoid such critical situations. In this experimental study, we aimed to create a prediction model for stroke volume index (SVI) decrease based on electrical cardiometry (EC) measurements. Transthoracic echo served as reference for SVI assessment (SVI-TTE). In 30 healthy male volunteers, central hypovolaemia was simulated using a lower body negative pressure (LBNP) chamber. A machine-learning algorithm based on variables of EC was designed. During LBNP, SVI-TTE declined consecutively, whereas the vital signs (arterial pressures and heart rate) remained within normal ranges. Compared to heart rate (AUC: 0.83 (95% CI: 0.73-0.87)) and systolic arterial pressure (AUC: 0.82 (95% CI: 0.74-0.85)), a model integrating EC variables (AUC: 0.91 (0.83-0.94)) showed a superior ability to predict a decrease in SVI-TTE ≥ 20% (p = 0.013 compared to heart rate, and p = 0.002 compared to systolic blood pressure). Simulated central hypovolaemia was related to a substantial decline in SVI-TTE but only minor changes in vital signs. A model of EC variables based on machine-learning algorithms showed high predictive power to detect a relevant decrease in SVI and may provide an automated, non-invasive method to indicate hypovolaemia and compensated shock.

PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch (HES) solution versus an electrolyte solution in trauma patients: study protocol for the TETHYS study.

BACKGROUND: Trauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss to maintain or re-establish hemodynamic stability with the ultimate goal to avoid organ hypoperfusion and cardiovascular collapse. The current study compares a 6% HES 130 solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) for volume replacement therapy in adult patients with traumatic injuries, as requested by the European Medicines Agency to gain more insights into the safety and efficacy of HES in the setting of trauma care. METHODS: TETHYS is a pragmatic, prospective, randomized, controlled, double-blind, multicenter, multinational trial performed in two parallel groups. Eligible consenting adults ≥ 18 years, with an estimated blood loss of ≥ 500 ml, and in whom initial surgery is deemed necessary within 24 h after blunt or penetrating trauma, will be randomized to receive intravenous treatment at an individualized dose with either a 6% HES 130, or an electrolyte solution, for a maximum of 24 h or until reaching the maximum daily dose of 30 ml/kg body weight, whatever occurs first. Sample size is estimated as 175 patients per group, 350 patients total (α = 0.025 one-tailed, power 1-ß = 0.8). Composite primary endpoint evaluated in an exploratory manner will be 90-day mortality and 90-day renal failure, defined as AKIN stage ≥ 2, RIFLE injury/failure stage, or use of renal replacement therapy (RRT) during the first 3 months. Secondary efficacy and safety endpoints are fluid administration and balance, changes in vital signs and hemodynamic status, changes in laboratory parameters including renal function, coagulation, and inflammation biomarkers, incidence of adverse events during treatment period, hospital, and intensive care unit (ICU) length of stay, fitness for ICU or hospital discharge, and duration of mechanical ventilation and/or RRT. DISCUSSION: This pragmatic study will increase the evidence on safety and efficacy of 6% HES 130 for treatment of hypovolemia secondary to acute blood loss in trauma patients. TRIAL REGISTRATION: Registered in EudraCT, No.: 2016-002176-27 (21 April 2017) and ClinicalTrials.gov, ID: NCT03338218 (09 November 2017).

Temporal Analysis of Sequential Changes in Heart Rate Variability During Non-hypotensive Hypovolemia.

INTRODUCTION: Haemorrhage is associated with changes in the cardiac autonomic drive which begins during early stages of mild haemorrhage. The knowledge of chronology of the autonomic changes at smaller timescale during the period of haemorrhage can help identify the primary autonomic parameter which signals the institution of cardiovascular reflex mechanisms. AIM: To evaluate the heart rate variability in 2-min sequential segments with one minute overlap during and after the period of mild haemorrhage (450 ml) using blood donation as a model of acute blood loss. METHODS: 47 male blood donors who had volunteered for blood donation were recruited for the study. Continuous lead II ECG was recorded before the start of the blood donation (5 min), during the period of the blood donation (~ 5-7 min) and after blood donation (5 min). The parasympathetic and sympathetic drive to heart was estimated by measures of heart rate variability in time and frequency domain. RESULTS: A significant decrease in the parameters assessing parasympathetic drive i.e., normalised High frequency (HFn) and NN50 (Number of pairs of adjacent NN intervals differing by more than 50 ms) and pNN50 (NN50 divided by the total number of all NN Intervals) was observed during blood donation at 3-5 min, as compared to baseline. An increase in parameters associated with sympathetic drive i.e., normalised low frequency (LFn) was observed only in the post donation period at 2-3 min. A significant rise in LF/HF ratio which is a marker of sympatho vagal balance was observed at 4-5 min during blood donation when compared to baseline. CONCLUSION: The initial cardiac autonomic change during mild haemorrhage is withdrawal of parasympathetic drive, followed by an increase in sympathetic tone which occurs much later.

Effects of experimental hypovolemia and pain on pre-ejection period and pulse transit time in healthy volunteers.

Trauma patients may suffer significant blood loss, and noninvasive methods to diagnose hypovolemia in these patients are needed. Physiologic effects of hypovolemia, aiming to maintain blood pressure, are largely mediated by increased sympathetic nervous activity. Trauma patients may however experience pain, which also increases sympathetic nervous activity, potentially confounding measures of hypovolemia. Elucidating the common and separate effects of the two stimuli on diagnostic methods is therefore important. Lower body negative pressure (LBNP) and cold pressor test (CPT) are experimental models of central hypovolemia and pain, respectively. In the present analysis, we explored the effects of LBNP and CPT on pre-ejection period and pulse transit time, aiming to further elucidate the potential use of these variables in diagnosing hypovolemia in trauma patients. We exposed healthy volunteers to four experimental sequences with hypovolemia (LBNP 60 mmHg) or normovolemia (LBNP 0 mmHg) and pain (CPT) or no pain (sham) in a 2 × 2 fashion. We calculated pre-ejection period and pulse transit time from ECG and ascending aortic blood velocity (suprasternal Doppler) and continuous noninvasive arterial pressure waveform (volume-clamp method). Fourteen subjects were available for the current analyses. This experimental study found that pre-ejection period increased with hypovolemia and remained unaltered with pain. Pulse transit time was reduced by pain and increased with hypovolemia. Thus, the direction of change in pulse transit time has the potential to distinguish hypovolemia and pain.