Validation of non-invasive point of care blood content analysis using the TensorTip™ MTX device: a method comparison study.

OBJECTIVES: The TensorTip™ MTX is a non-invasive device designed to determine several physiological parameters with additional analysis of haemoglobin, haematocrit and blood gas analysis by interpreting blood diffusion colour of the finger skin based on spectral analysis. The aim of our study was to investigate the accuracy and precision of the TensorTip MTX in a clinical setting in comparison with routine analysis of blood samples. METHODS: Forty-six patients, scheduled for elective surgery, were enrolled in this study. Placement of an arterial catheter had to be part of the standard of care. Measurements were performed during the perioperative period. The measurements obtained with the TensorTip MTX were compared with the results of routine analysis of the blood samples as a reference using correlation, Bland-Altman analysis and mountain plots. RESULTS: No significant correlation was present in the measurements. Measurement of haemoglobin with the TensorTip MTX had a mean bias of 0.4 mmol/L, haematocrit's bias was 3.0 %. Bias of partial pressure of carbon dioxide and oxygen was 3.6 and 66.6 mmHg, respectively. Calculated percentage errors were 48.2 , 48.9, 39.9 and 109.0 %. Proportional bias was present in all Bland-Altman analyses. Less than 95 % of the differences fell within the pre-set limits of allowable error. CONCLUSIONS: Non-invasive blood content analysis with the TensorTip MTX device is not equivalent to and did not correlate sufficiently with conventional laboratory analysis. None of the parameters measured showed results within the limits of allowable error. Therefore, the use of the TensorTip MTX is not recommended for perioperative care.

Muscle Ultrasound Abnormalities in Individuals with RYR1-Related Malignant Hyperthermia Susceptibility.

BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

Perioperative Validation of the TensorTip™ MTX Device for Noninvasive Arterial Pressure Measurement: A Method Comparison Study.

Background: The noninvasive TensorTip™ MTX measures blood pressure by interpreting blood diffusion color of the finger skin. In addition to blood pressure, the device is able to measure various vital signs: heart rate, oxygen saturation, stroke volume, and cardiac output. Studies about accuracy and precision thus far available have only been conducted by the manufacturer. The aim of our study was to investigate the accuracy and precision of the TensorTip MTX in comparison to invasive radial artery blood pressure values. Methods: Forty-one patients scheduled for elective surgery were enrolled in this study. Placement of the arterial catheter had to be part of the standard of care. Once hemodynamic stable conditions were achieved, blood pressure was measured. Three measurements with the TensorTip MTX were averaged and compared with one invasive blood pressure measurement using Bland-Altman plot and error grid analysis. Results: Systolic, diastolic, and mean blood pressure had a bias of respectively 6.2, -6.9 and 4.4 mm Hg. Corresponding standard deviation were respectively 30.1, 17.0 and 22.2. Calculated percentage errors were 47.6%, 52.9% and 52.3%. Proportional bias was present in all Bland-Altman analyses. Error grid analysis showed 61.0% of systolic blood pressure measurements, and 46.3% of mean blood pressure measurements were in the clinical acceptable zone. Conclusions: The TensorTip MTX was not able to reliably measure blood pressure compared to blood pressure obtained with an arterial catheter and therefore, the measurement performance is not clinically acceptable. Moreover, a high malfunction rate makes the device unsuitable for use in perioperative period.

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis.

Malignant hyperthermia and exertional rhabdomyolysis have conventionally been considered episodic phenotypes that occur in otherwise healthy individuals in response to an external trigger. However, recent studies have demonstrated a clinical and histopathological continuum between patients with a history of malignant hyperthermia susceptibility and/or exertional rhabdomyolysis and RYR1-related congenital myopathies. We hypothesize that patients with a history of RYR1-related exertional rhabdomyolysis or malignant hyperthermia susceptibility do have permanent neuromuscular symptoms between malignant hyperthermia or exertional rhabdomyolysis episodes. We performed a prospective cross-sectional observational clinical study of neuromuscular features in patients with a history of RYR1-related exertional rhabdomyolysis and/or malignant hyperthermia susceptibility (n = 40) compared with healthy controls (n = 80). Patients with an RYR1-related congenital myopathy, manifesting as muscle weakness preceding other symptoms as well as other (neuromuscular) diseases resulting in muscle weakness were excluded. Study procedures included a standardized history of neuromuscular symptoms, a review of all relevant ancillary diagnostic tests performed up to the point of inclusion and a comprehensive, standardized neuromuscular assessment. Results of the standardized neuromuscular history were compared with healthy controls. Results of the neuromuscular assessment were compared with validated reference values. The proportion of patients suffering from cramps (P < 0.001), myalgia (P < 0.001) and exertional myalgia (P < 0.001) was higher compared with healthy controls. Healthcare professionals were consulted because of apparent neuromuscular symptoms by 17/40 (42.5%) patients and 7/80 (8.8%) healthy controls (P < 0.001). Apart from elevated creatine kinase levels in 19/40 (47.5%) patients and mild abnormalities on muscle biopsies identified in 13/16 (81.3%), ancillary investigations were normal in most patients. The Medical Research Council sum score, spirometry and results of functional measurements were also mostly normal. Three of 40 patients (7.5%) suffered from late-onset muscle weakness, most prominent in the proximal lower extremity muscles. Patients with RYR1 variants resulting in malignant hyperthermia susceptibility and/or exertional rhabdomyolysis frequently report additional neuromuscular symptoms such as myalgia and muscle cramps compared with healthy controls. These symptoms result in frequent consultation of healthcare professionals and sometimes in unnecessary invasive diagnostic procedures. Most patients do have normal strength at a younger age but may develop muscle weakness later in life.

Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study.

OBJECTIVES: To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies. DESIGN: Double-blinded, placebo-controlled, randomized study. SETTING: Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands. PATIENTS: One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery. INTERVENTIONS: Ninety mg/kg/hr EA-230 or placebo administered during surgery. MEASUREMENTS AND MAIN RESULTS: During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL × hr [1,968-3,760] vs 2,680 pg/mL × hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean ± sem increase in the EA-230 vs placebo groups: glomerular filtration rateiohexol measured using iohexol plasma clearance: 19 ± 2 vs 16 ± 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 ± 1 vs 2 ± 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 ± 108 vs 605 ± 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11] vs 10 d [8-12]; p = 0.001). Efficacy results were more pronounced in patients that had longer duration of surgery and thus longer duration of study drug infusion. CONCLUSIONS: EA-230 was safe in patients undergoing on-pump cardiac surgery. It did not modulate interleukin-6 plasma concentrations but appeared to exert beneficial renal and cardiovascular effects and shortened in-hospital length of stay.

Endotoxemia-Induced Release of Pro-inflammatory Mediators Are Associated With Increased Glomerular Filtration Rate in Humans in vivo.

Introduction: Sepsis is the most prevalent cause of Acute Kidney Injury (AKI). Conversely, in some septic patients the glomerular filtration rate (GFR) is augmented. The role of the inflammatory response and blood pressure to induce this increased GFR is unknown. Herein, we relate inflammatory mediators and blood pressure to the iohexol clearance-derived "true" GFR and kidney injury markers during systemic inflammation in healthy volunteers. Methods: Twelve healthy subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli-derived lipopolysaccharide, LPS). As a gold-standard to determine the GFR, iohexol plasma clearance (GFRiohexol) was calculated during a 6-h period on the day before (baseline) as well as 2 and 24 h after LPS administration. Intra-arterial blood pressure was recorded continuously using a radial artery catheter. Circulating inflammatory mediators and urinary excretion of kidney injury markers were serially measured. Results: Experimental endotoxemia profoundly increased plasma concentrations of inflammatory mediators, including [mean ± SD or median [IQR] peak values (pg/mL) of tumor necrosis factor (TNF)-α: 92 ± 40, interleukin (IL)-6: 1,246 ± 605, IL-8: 374 ± 120, IL-10: 222 ± 119, IL-1 receptor antagonist (RA): 8,955 ± 2,429, macrophage chemoattractant protein (MCP)-1: 2,885 [2,706 - 3,765], vascular adhesion molecule (VCAM)-1: 296,105 ± 34,822, intercellular adhesion molecule (ICAM)-1: 25,0170 ± 41,764]. Mean arterial pressure decreased with 13 ± 11 mmHg (p < 0.0001). No significant increase in the urinary excretion of tubular injury markers was observed following LPS administration. GFRiohexol increased from 97 ± 6 at baseline to 118 ± 10 mL/min/1.73m2 (p < 0.0001) post-LPS administration and returned to baseline levels at 24 h post-LPS (99 ± 9 mL/min/1.73m2). Peak plasma concentrations of IL-6 (R 2 = 0.66, p = 0.001) and IL-8 (R 2 = 0.51, p = 0.009), MCP-1 (R 2 = 0.38, p = 0.03) and VCAM-1 levels (R 2 = 0.37, p = 0.04) correlated with the increase in GFRiohexol, whereas a trend was observed for TNF-α (R 2 = 0.33, p = 0.0509) and IL-1RA (R 2 = 0.28, p = 0.08). None of the kidney injury markers or changes in blood pressure were associated with GFRiohexol. In multiple linear regression analysis, both peak IL-6 (p = 0.002) and IL-8 (p = 0.01) concentrations remained significantly correlated with GFRiohexol, without collinearity. Discussion: Concentrations of pro-inflammatory cytokines, but not blood pressure, are correlated with the endotoxemia-induced increase in GFR in healthy volunteers. These findings may indicate that inflammatory mediators orchestrate the augmented GFR observed in a subgroup of sepsis patients.

The Human Chorionic Gonadotropin Derivate EA-230 Modulates the Immune Response and Exerts Renal Protective Properties: Therapeutic Potential in Humans.

The extent of the systemic inflammatory response following infectious or noninfectious insults is related to impaired patient outcome. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230 is a newly developed synthetic linear tetrapeptide derived from the "pregnancy hormone" human chorionic gonadotropin. In this review, we describe the immunomodulatory and renoprotective properties of EA-230 in preclinical animal models, phase 1 studies in humans and phase 2a studies performed during human experimental endotoxemia. In addition, details pertaining to the design of a recently completed phase 2b study in 180 patients who underwent cardiac surgery to investigate the safety and immunomodulatory and renoprotective properties of EA-230 are discussed.

The Safety, Tolerability, and Effects on the Systemic Inflammatory Response and Renal Function of the Human Chorionic Gonadotropin Hormone-Derivative EA-230 Following On-Pump Cardiac Surgery (The EASI Study): Protocol for a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study.

BACKGROUND: The cardiac surgery-induced systemic inflammatory response may induce postoperative hemodynamic instability and impairment of renal function. EA-230, a linear tetrapeptide (A-Q-G-V), is derived from the beta chain of the human chorionic gonadotropin pregnancy hormone. It has shown immunomodulatory and renoprotective effects in several animal models of systemic inflammation. In phase 1 and phase 2a studies, these immunomodulatory effects were confirmed during human experimental endotoxemia, and EA-230 was found to have an excellent safety profile. OBJECTIVE: The objective of this first in-patient study is to test the safety and tolerability as well as the immunomodulatory and renoprotective effects of EA-230 in a proof-of-principle design in patients with systemic inflammation following on-pump cardiac surgery. METHODS: We describe a prospective, randomized, double-blind, placebo-controlled study in which 180 elective patients undergoing on-pump coronary artery bypass grafting, with or without concomitant valve surgery, are enrolled. Patients will be randomized in a 1:1 ratio and will receive either EA-230 (90 mg/kg/hour) or a placebo. These will be infused at the start of the surgical procedure until the end of the use of the cardiopulmonary bypass. The primary focus of this first-in-patient study will be on safety and tolerability of EA-230. The primary efficacy end point is the modulation of the inflammatory response by EA-230 quantified as the change in interleukin-6 plasma concentrations after surgery. The key secondary end point is the effect of EA-230 on renal function. The study will be conducted in 2 parts to enable an interim safety analysis by an independent data monitoring committee at a sample size of 60. An adaptive design is used to reassess statistical power halfway through the study. RESULTS: This study has been approved by the independent competent authority and ethics committee and will be conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, and European Directive 2001/20/CE regarding the conduct of clinical trials. Results of this study will be submitted for publication in a peer-reviewed scientific journal. Enrollment of this study commenced in July 2016, and results are expected at the end of 2018. CONCLUSIONS: This adaptive phase 2 clinical study is designed to test the safety and tolerability of EA-230 in patients undergoing cardiac surgery. In addition, efficacy end points focused on the effect of the systemic inflammatory response and renal function are investigated. TRIAL REGISTRATION: ClinicalTrials.gov NCT03145220; https://clinicaltrials.gov/ct2/show/NCT03145220 (Archived by WebCite at http://www.webcitation.org/74JPh8GNN). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11441.

Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation.

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients.

Immunomodulatory and Kidney-Protective Effects of the Human Chorionic Gonadotropin Derivate EA-230.

The systemic inflammatory response following infectious or non-infectious insults is related to morbidity (including acute kidney injury) and mortality. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230, a linear tetrapeptide (Alanine-Glutamine-Glycine-Valine), derived from the ß-chain of the human chorionic gonadotropin hormone, has shown immunomodulatory and renoprotective properties in several pre-clinical animal models of systemic inflammation. Furthermore, an excellent safety profile of EA-230 was observed in phase 1 studies in humans, and the immunomodulatory effects of EA-230 were recently demonstrated in a phase IIa study during human experimental endotoxemia. A prospective double-blind placebo-controlled randomized trial in 180 patients undergoing elective CABG-surgery with or without valve surgery is currently conducted to investigate the immunomodulatory and renoprotective properties of EA-230.

Inflammation-associated changes in lipid composition and the organization of the erythrocyte membrane.

BACKGROUND: Reduced erythrocyte survival and deformability may contribute to the so-called anemia of inflammation observed in septic patients. Erythrocyte structure and function are affected by both the membrane lipid composition and the organization. We therefore aimed to determine whether these parameters are affected during systemic inflammation. METHODS: A sensitive matrix-assisted laser desorption and ionization time-of-flight mass spectrometric method was used to investigate the effect of plasma components of 10 patients with septic shock and of 10 healthy volunteers subjected to experimental endotoxemia on erythrocyte membrane lipid composition. RESULTS: Incubation of erythrocytes from healthy control donors with plasma from patients with septic shock resulted in membrane phosphatidylcholine hydrolysis into lysophosphatidylcholine (LPC). Plasma from volunteers undergoing experimental human endotoxemia did not induce LPC formation. The secretory phospholipase A2 IIA concentration was enhanced up to 200-fold in plasma of septic patients and plasma from endotoxin-treated subjects, but did not correlate with the ability of these plasmas to generate LPC. Erythrocyte phosphatidylserine exposure increased up to two-fold during experimental endotoxemia. CONCLUSIONS: Erythrocyte membrane lipid remodeling as reflected by LPC formation and/or PS exposure occurs during systemic inflammation in a secretory phospholipase A2 IIA-independent manner. GENERAL SIGNIFICANCE: Sepsis-associated inflammation induces a lipid remodeling of the erythrocyte membrane that is likely to affect erythrocyte function and survival, and that is not fully mimicked by experimental endotoxemia.

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study.

INTRODUCTION: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. METHODS: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. RESULTS: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. CONCLUSIONS: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT01944228. Registered 12 September 2013.