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.

Safety during interhospital helicopter transfer of ventilated COVID-19 patients. No clinical relevant changes in vital signs including non-invasive cardiac output.

BACKGROUND: During the COVID-19 pandemic in The Netherlands, critically ill ventilated COVID-19 patients were transferred not only between hospitals by ambulance but also by the Helicopter Emergency Medical Service (HEMS). To date, little is known about the physiological impact of helicopter transport on critically ill patients and COVID-19 patients in particular. This study was conducted to explore the impact of inter-hospital helicopter transfer on vital signs of mechanically ventilated patients with severe COVID-19, with special focus on take-off, midflight, and landing. METHODS: All ventilated critically ill COVID-19 patients who were transported between April 2020 and June 2021 by the Dutch 'Lifeliner 5' HEMS team and who were fully monitored, including noninvasive cardiac output, were included in this study. Three 10-min timeframes (take-off, midflight and landing) were defined for analysis. Continuous data on the vital parameters heart rate, peripheral oxygen saturation, arterial blood pressure, end-tidal CO2 and noninvasive cardiac output using electrical cardiometry were collected and stored at 1-min intervals. Data were analyzed for differences over time within the timeframes using one-way analysis of variance. Significant differences were checked for clinical relevance. RESULTS: Ninety-eight patients were included in the analysis. During take-off, an increase was noticed in cardiac output (from 6.7 to 8.2 L min-1; P < 0.0001), which was determined by a decrease in systemic vascular resistance (from 1071 to 739 dyne·s·cm-5, P < 0.0001) accompanied by an increase in stroke volume (from 88.8 to 113.7 mL, P < 0.0001). Other parameters were unchanged during take-off and mid-flight. During landing, cardiac output and stroke volume slightly decreased (from 8.0 to 6.8 L min-1, P < 0.0001 and from 110.1 to 84.4 mL, P < 0.0001, respectively), and total systemic vascular resistance increased (P < 0.0001). Though statistically significant, the found changes were small and not clinically relevant to the medical status of the patients as judged by the attending physicians. CONCLUSIONS: Interhospital helicopter transfer of ventilated intensive care patients with COVID-19 can be performed safely and does not result in clinically relevant changes in vital signs.

Non-invasive electrical cardiometry cardiac output monitoring during prehospital helicopter emergency medical care: a feasibility study.

PURPOSE: Introducing advanced hemodynamic monitoring might be beneficial during Helicopter Emergency Medical Service (HEMS) care. However, it should not increase the on-scene-time, it should be easy to use and should be non-invasive. The goal of this study was to investigate the feasibility of non-invasive cardiac output measurements by electrical cardiometry (EC) and the quality of the EC signal during pre-hospital care provided by our HEMS. METHODS: A convenience sample of fifty patients who required HEMS assistance were included in this study. Problems with respect to connecting the patient, entering patient characteristics and measuring were inventoried. Quality of EC signal of the measurements was assessed during prehospital helicopter care. We recorded the number of measurements with a signal quality indicator (SQI) ≥ 80 and the number of patients having at least 1 measurement with a SQI ≥ 80. Furthermore, the SQI value distribution of the measurements within each patient was analysed. RESULTS: In the experience of the attending HEMS caregivers application of the device was easy and did not result in increased duration of on-scene time. Patch adhesion was reported as a concern due to clammy skin in 22% of all cases. 684 measurements were recorded during HEMS care. In 47 (94%) patients at least 1 measurement with an SQI ≥ 80 was registered. Of all recorded measurements 5.8% had an SQI < 40, 11.4% had an SQI 40-59, 14.9% had a SQI between 60 and 79 and 67.8% had SQI ≥ 80. CONCLUSION: Cardiac output measurements are feasible during prehospital HEMS care with good quality of the EC signal. Monitoring was easy to use and quick to install. In our view it is an promising candidate for the prehospital setting. Further research is needed to determine its clinical value during clinical decision making.

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.

Stewart analysis unmasks acidifying and alkalizing effects of ionic shifts during acute severe respiratory alkalosis.

PURPOSE: Although both the Henderson-Hasselbalch method and the Stewart approach can be used to analyze acid-base disturbances and metabolic and respiratory compensation mechanisms, the latter may be superior in detecting subtle metabolic changes. MATERIALS AND METHODS: We analyzed acid-base disturbances using both approaches in six healthy male volunteers practicing extreme voluntary hyperventilation. Arterial blood gas parameters were obtained during a breathing exercise consisting of approximately 30 cycles of powerful hyperventilation followed by breath retention for approximately 2 min. RESULTS: Hyperventilation increased pH from 7.39 ± 0.01 at baseline to 7.74 ± 0.06, PaCO2 decreased from 34.1 ± 1.1 to 12.6 ± 0.7 mmHg, PaO2 increased from 116 ± 4.6 to 156 ± 4.3 mmHg. Baseline apparent strong ion difference was 42.3 ± 0.5 mEq/L, which decreased to 37.1 ± 0.7 mEq/L following hyperventilation. The strong ion gap significantly decreased following hyperventilation, with baseline levels of 10.0 ± 0.9 dropping to 6.4 ± 1.1 mEq/L. CONCLUSIONS: Henderson-Hasselbalch analysis indicated a profound and purely respiratory alkalosis with no metabolic compensation following extreme hyperventilation. The Stewart approach revealed metabolic compensation occurring within minutes. These results challenge the long-held axiom that metabolic compensation of acute respiratory acid-base changes is a slow process.

The neuromuscular and multisystem features of RYR1-related malignant hyperthermia and rhabdomyolysis: A study protocol.

INTRODUCTION: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM. METHODS: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM. DISCUSSION: This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM and will establish a well-characterized baseline cohort for future studies on RYR1-related disorders. The results of this study are expected to improve recognition of RYR1-related symptoms, counselling and a more personalized approach to patients affected by these conditions. Furthermore, results will create new insights in the role of the immune system in the pathophysiology of MH and ERM. TRIAL REGISTRATION: This study was pre-registered at ClinicalTrials.gov (ID: NCT04610619).

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.

Pharmacokinetics, safety and tolerability of the novel ß-hCG derived immunomodulatory compound, EA-230.

AIMS: EA-230 is a newly developed synthetic linear tetrapeptide (AQGV) derived from the chorionic gonadotropin hormone (ß-hCG). We investigated the pharmacokinetics, safety and tolerability of EA-230 in healthy subjects using different administration strategies. METHODS: Double-blind, randomized, placebo-controlled, dose-escalating phase I studies in healthy subjects using intravenous administration were conducted. In the single dosage study, 32 subjects were assigned to four single dosage groups (1, 3, 10 or 30 mg/kg). In the multiple dosage study, 24 subjects were assigned to three dosage groups (10, 20 or 30 mg/kg, thrice daily for 3 days). In the continuous dosage study, 24 subjects were assigned to three dosage groups (15, 30, or 90 mg/kg/hour for 2 hours). Pharmacokinetics, safety and tolerability assessments were performed up to 14 days. RESULTS: The highest dosage of EA-230 (continuous infusion of 90 mg/kg/hour for 2 hours) showed more than proportional increases in exposure (Cmax 136%; AUC0-last 137%), a large volume of distribution (geometric mean and 95% CI: 13 [3-58] L/kg), a high clearance rate (26 [15-43] L/h/kg), and a short half-life (0.35 [0.13-1.0] minutes). EA-230 was well tolerated and no safety concerns were observed. CONCLUSION: These dose-escalating phase I studies with different administration strategies reveal a pharmacokinetic profile of EA-230 with a large volume of distribution and a short half-life. Furthermore, EA-230 was well tolerated and no safety issues emerged. These results have enabled further clinical development in a phase IIa trial assessing the pharmacodynamics of this compound during systemic inflammation described elsewhere in this issue.

A randomized double-blind, placebo-controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA-230 during experimental human endotoxaemia.

AIMS: EA-230 is a human chorionic gonadotropin hormone-derived linear tetrapeptide, developed for the treatment of systemic inflammation-related disorders. EA-230 has shown promising immunomodulatory and tissue-protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows-up on these results by investigating the safety, efficacy and pharmacokinetics of EA-230 under systemic inflammatory conditions induced by experimental human endotoxaemia. METHODS: In this randomized, double blind, placebo-controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli-derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2-hour continuous infusion of EA-230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12). RESULTS: EA-230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA-230 resulted in a significant attenuation of the LPS-induced increase in plasma levels of inflammatory mediators interleukin (IL)-6, IL-8, IL-1 receptor antagonist, monocyte chemoattractant protein-1, macrophage inflammatory proteins-1α and -1ß, and vascular cell adhesion protein-1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 ± 0.1°C to 1.3 ± 0.2°C, P < .05) and symptom scores (peak decrease from 7.4 ± 1.0 to 4.0 ± 1.2 points, P < .05). EA-230 exhibited a very short elimination half-life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12-0.24] hours and 2.2 [1.3-3.8] L/kg, respectively). CONCLUSION: Administration of EA-230 is safe and results in attenuation of the systemic inflammatory response in humans.

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.