Design and Rationale of Cytokine Filtration in Lung Transplantation (GLUSorb): Protocol for a Multicenter Clinical Randomized Controlled Trial.

BACKGROUND: Lung transplantation (LTx) is the only treatment option for end-stage lung disease. Despite improvements, primary graft dysfunction (PGD) remains the leading cause of early mortality and precipitates chronic lung allograft dysfunction, the main factor in late mortality after LTx. PGD develops within the first 72 hours and impairs the oxygenation capacity of the lung, measured as partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2). Increasing the PaO2/FiO2 ratio is thus critical and has an impact on survival. There is a general lack of effective treatments for PGD. When a transplanted lung is not accepted by the immune system in the recipient, a systemic inflammatory response starts where cytokines play a critical role in initiating, amplifying, and maintaining the inflammation leading to PGD. Cytokine filtration can remove these cytokines from the circulation, thus reducing inflammation. In a proof-of-concept preclinical porcine model of LTx, cytokine filtration improved oxygenation and decreased PGD. In a feasibility study, we successfully treated patients undergoing LTx with cytokine filtration (ClinicalTrials.gov; NCT05242289). OBJECTIVE: The purpose of this clinical trial is to demonstrate the superiority of cytokine filtration in improving LTx outcome, based on its effects on oxygenation ratio, plasma levels of inflammatory markers, PGD incidence and severity, lung function, kidney function, survival, and quality of life compared with standard treatment with no cytokine filtration. METHODS: This study is a Swedish national interventional randomized controlled trial involving 116 patients. Its primary objective is to investigate the potential benefits of cytokine filtration when used in conjunction with LTx. Specifically, this study aims to determine whether the application of cytokine filtration, administered for a duration of 12 hours within the initial 24 hours following a LTx procedure, can lead to improved patient outcomes. This study seeks to assess various aspects of patient recovery and overall health to ascertain the potential positive impact of this intervention on the posttransplantation course. RESULTS: The process of patient recruitment for this study is scheduled to commence subsequent to a site initiation visit, which was slated to take place on August 28, 2023. The primary outcome measure that will be assessed in this research endeavor is the oxygenation ratio, a metric denoted as the highest PaO2/FiO2 ratio achieved by patients within a 72-hour timeframe following their LTx procedure. CONCLUSIONS: We propose that cytokine filtration could enhance the overall outcomes of LTx. Our hypothesis suggests potential improvements in LTx outcome and patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05526950; https://www.clinicaltrials.gov/study/NCT05526950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/52553.

Interleukin-10: A Potential Pre-Cannulation Marker for Development of Acute Kidney Injury in Patients Receiving Veno-Arterial Extracorporeal Membrane Oxygenation.

INTRODUCTION: Acute kidney injury (AKI) in patients treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is associated with high mortality. The objective of this study was to investigate whether cytokine levels before the initiation of ECMO treatment could predict AKI. We also aimed to investigate the impact of AKI on 30-day and 1-year mortality. METHODS: Serum cytokine levels were analyzed in 100 consecutive VA-ECMO-treated patients at pre-cannulation, at 48 h post-cannulation, and at 8 days. Clinical data to establish the incidence and outcome of AKI after the start of ECMO was retrieved from the local ECMO registry. SETTING: The study was conducted at tertiary care, university hospital. Participants included 100 patients treated with VA-ECMO. INTERVENTIONS: The blood samples for cytokine analysis were collected before VA-ECMO treatment, at 48 h after VA-ECMO treatment was started, and at 8 days. RESULTS: Pre-cannulation serum IL-10 levels were significantly higher in patients who developed AKI (212 [38.9, 620.7]) versus those who did not (49.0 [11.9, 102.2]; p = 0.007), and the development of AKI can be predicted by pre-cannulation IL-10 levels (p = 0.025, OR = 1.2 [1.02-1.32]). The development of AKI during ECMO treatment is associated with increased 30-day mortality (p = 0.049) compared to patients who did not develop AKI and had a pre-cannulation estimated glomerular filtration rate ≥ 45 mL/min. The 1-year survival rate for patients with AKI who survived the first 30 days of ECMO treatment is comparable to that of patients without AKI. CONCLUSION: Increased pre-cannulation IL-10 levels are associated with the development of AKI during VA-ECMO support. AKI is associated with increased 30-day mortality compared to patients with no AKI and better renal function. However, patients with AKI who survive the first 30 days have a 1-year survival rate similar to those without AKI.

Effect of Cyclosporine on Cytokine Production in Elective Coronary Artery Bypass Grafting: A Sub-Analysis of the CiPRICS (Cyclosporine to Protect Renal Function in Cardiac Surgery) Study.

OBJECTIVES: The augmented inflammatory response to cardiac surgery is a recognized cause of postoperative acute kidney injury. The present study aimed to investigate the effects of preoperative cyclosporine treatment on cytokine production and delineate factors associated with postoperative kidney impairment. DESIGN: A randomized, double-blind, placebo-controlled, single-center study. SETTING: At a tertiary care, university hospital. PARTICIPANTS: Patients eligible for elective coronary artery bypass grafting surgery; 67 patients were enrolled. INTERVENTIONS: Patients were randomized to receive 2.5 mg/kg cyclosporine or placebo before surgery. Cytokine levels were measured after the induction of anesthesia and 4 hours after the end of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Tissue-aggressive (interleukin [IL]-1ß, macrophage inflammatory protein [MIP]-1ß, granulocyte colony-stimulating factor [G-CSF], IL-6, IL-8, IL-17, MCP-1), as well tissue-lenient (IL-4) cytokines, were significantly elevated in response to surgery. Changes in cytokine levels were not affected by cyclosporine pretreatment. CONCLUSIONS: Elective coronary artery bypass grafting surgery with cardiopulmonary bypass triggers cytokine activation. This activation was not impacted by preoperative cyclosporine treatment.

Monitoring lung injury with particle flow rate in LPS- and COVID-19-induced ARDS.

In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.

Cyclosporine before Coronary Artery Bypass Grafting Does Not Prevent Postoperative Decreases in Renal Function: A Randomized Clinical Trial.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery, leading to increased morbidity and mortality. One suggested cause for acute kidney injury is extracorporeal circulation-induced ischemia-reperfusion injury. In animal studies, cyclosporine has been shown to reduce ischemia-reperfusion injury in the kidneys. We hypothesized that administering cyclosporine before extracorporeal circulation could protect the kidneys in patients undergoing cardiac surgery. METHODS: The Cyclosporine to Protect Renal Function in Cardiac Surgery (CiPRICS) study was an investigator-initiated, double-blind, randomized, placebo-controlled, single-center study. The primary objective was to assess if cyclosporine could reduce acute kidney injury in patients undergoing coronary artery bypass grafting surgery with extracorporeal circulation. In the study, 154 patients with an estimated glomerular filtration rate of 15 to 90 ml · min · 1.73 m were enrolled. Study patients were randomized to receive 2.5 mg/kg cyclosporine or placebo intravenously before surgery. The primary endpoint was relative plasma cystatin C changes from the preoperative day to postoperative day 3. Secondary endpoints included biomarkers of kidney, heart, and brain injury. RESULTS: All enrolled patients were analyzed. The cyclosporine group (136.4 ± 35.6%) showed a more pronounced increase from baseline plasma cystatin C to day 3 compared to placebo (115.9 ± 30.8%), difference, 20.6% (95% CI, 10.2 to 31.2%, P < 0.001). The same pattern was observed for the other renal markers. The cyclosporine group had more patients in Risk Injury Failure Loss End-stage (RIFLE) groups R (risk), I (injury), or F (failure; 31% vs. 8%, P < 0.001). There were no differences in safety parameter distribution between groups. CONCLUSIONS: Administration of cyclosporine did not protect coronary artery bypass grafting patients from acute kidney injury. Instead, cyclosporine caused a decrease in renal function compared to placebo that resolved after 1 month.

Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

INTRODUCTION: Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia-reperfusion injury. We hypothesised that ciclosporin given before the start of ECC in cardiac surgery can decrease the degree of AKI. METHODS AND ANALYSIS: Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) study is an investigator-initiated double-blind, randomised, placebo-controlled, parallel design, single-centre study performed at a tertiary university hospital. The primary objective is to assess the safety and efficacy of ciclosporin to limit the degree of AKI in patients undergoing coronary artery bypass grafting surgery. We aim to evaluate 150 patients with a preoperative estimated glomerular filtration rate of 15-90 mL/min/1.73 m2. Study patients are randomised in a 1:1 ratio to receive study drug 2.5 mg/kg ciclosporin or placebo as an intravenous injection after anaesthesia induction but before start of surgery. The primary end point consists of relative P-cystatin C changes from the preoperative day to postoperative day 3. The primary variable will be tested using an analysis of covariance method. Secondary end points include evaluation of P-creatinine and biomarkers of kidney, heart and brain injury. ETHICS AND DISSEMINATION: The trial is conducted in compliance with the current version of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Good Clinical Practice guidelines E6 (R1) and was approved by the Regional Ethical Review Board, Lund and the Swedish Medical Products Agency (MPA). Written and oral informed consent is obtained before enrolment into the study. TRIAL REGISTRATION NUMBER: NCT02397213; Pre-results.

Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial).

BACKGROUND: To date, there are no known methods for preventing acute kidney injury after cardiac surgery. Increasing evidence suggests that erythropoietin has renal antiapoptotic and tissue protective effects. However, recent human studies have shown conflicting results. The authors aimed to study the effect of a single high-dose erythropoietin preoperatively on renal function after coronary artery bypass grafting in patients with preoperative impaired renal function. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 75 patients scheduled for coronary artery bypass grafting with preexisting renal impairment estimated glomerular filtration rate based on p-cystatin C (<60 and >15 ml/min). The patients either received a single high-dose erythropoietin (400 IU/kg) or placebo preoperatively. The primary endpoint was renal protection evaluated by p-cystatin C at the third postoperative day compared to the preoperative values. Incidence of acute kidney injury and other renal biomarker changes were among secondary endpoints. RESULTS: There was no statistically significant difference on the third postoperative day for relative p-cystatin C level changes from baseline between the groups, 131 ± 31% (mean ± SD) for the study group and 125 ± 24% for the control group (P = 0.31; 95% CI, -0.6 to 20% for the difference). There were no statistically significant differences in other renal biomarkers or measures between the groups (p-neutrophil gelatinase-associated lipocalin, p-creatinine, p-urea, and estimated glomerular filtration rate). There were no other differences in outcome variables between the groups. CONCLUSION: Intravenous administration of a single high-dose (400 IU/kg) erythropoietin did not have a renal protective effect on patients with reduced kidney function undergoing coronary artery bypass surgery.

Inotropic support during experimental endotoxemic shock: part I. The effects of levosimendan on splanchnic perfusion.

BACKGROUND: Septic shock may cause splanchnic hypoperfusion. We hypothesized that levosimendan would improve systemic and hepatosplanchnic perfusion during endotoxemic shock. METHODS: In 16 anesthetized pigs (31.4 +/- 3.4 kg), a jugular vein, a carotid artery, the pulmonary artery (thermodilution), the portal vein, and a hepatic vein were cannulated for hemodynamic monitoring and blood sampling. Ultrasonic flowprobes were placed around the portal vein, the hepatic artery, and the superior mesenteric artery (SMA). In addition to 30 mL/kg of dextran 70 given before baseline, all animals received 10 mL x kg(-1) x h(-1) of IV fluids throughout the experiment. An endotoxin infusion (2 microg x kg(-1) x h(-1)) was given for 300 min; 100 min after the start of endotoxin, the pigs were randomized to receive levosimendan (50 microg x kg(-1) x h(-1), n = 8) or placebo (n = 8). To evaluate the isolated effects of endotoxemia, all data before randomization were pooled into one group. Data were analyzed by analysis of variance and presented as mean +/- sem. RESULTS: Endotoxemia (t = 90 min, pooled data) decreased systemic vascular resistance (SVR, 2526 +/- 203 to 1946 +/- 122 dyn x s x cm(-5), P = 0.003) and mean arterial blood pressure (MAP, 109 +/- 6 to 84 +/- 3 mm Hg, P < 0.05), whereas heart rate (66 +/- 4 to 98 +/- 8 bpm), and mean pulmonary arterial pressure (MPAP, 20 +/- 1 to 38 +/- 2 mm Hg) increased (P < 0.001). Cardiac output (CO, 3.4 +/- 0.2 L/min) and systemic oxygen delivery (414 +/- 33 mL/min) were unchanged, but blood flows in the SMA (575 +/- 34 to 392 +/- 38 mL/min) and the portal vein (881 +/- 62 to 568 +/- 39 mL/min) decreased (P < 0.001). Although hepatic arterial blood flows increased (36 +/- 8 to 219 +/- 38 mL/min), gut (114 +/- 11 to 84 +/- 7 mL/min) and hepatic (94 +/- 11 to 67 +/- 8 mL/min) oxygen deliveries decreased (P < 0.05). At t = 300 min, the levosimendan group showed lower MPAP (39 +/- 3 vs 49 +/- 2 mm Hg, P = 0.025), lower SVR (2158 +/- 186 vs 3069 +/- 370 dyn x s x cm(-5), P = 0.052), and lower MAP (55 +/- 9 vs 87 +/- 9 mm Hg, P < 0.001) than the control group. In both groups, CO, portal vein, and hepatic arterial blood flows decreased (P < 0.001); the mean values for the levosimendan group at t = 300 min were 2.0 +/- 0.4 L/min, 390 +/- 83 mL/min, and 36 +/- 12 mL/min, respectively. SMA blood flow decreased only in the levosimendan group (432 +/- 40 to 320 +/- 78 mL/min, P < 0.001), whereas gut oxygen delivery decreased in the levosimendan (85 +/- 12 to 63 +/- 12 mL/min, P < 0.001) and in the control (83 +/- 6 to 59 +/- 3 mL/min, P = 0.03) groups. CONCLUSION: Levosimendan administered after the establishment of endotoxemic shock to pigs receiving moderate fluid resuscitation prevented further increases in MPAP and maintained a low SVR. There were, however, no improvements in CO, MAP decreased, and levosimendan neither prevented the development of circulatory shock nor improved hepatosplanchnic perfusion.

Cardiovascular effects of levosimendan in the early stages of endotoxemia.

Sepsis-associated myocardial depression is associated with calcium desensitization and adrenergic uncoupling. We conducted a prospective randomized investigation on the effects of the calcium sensitizer, levosimendan, on hemodynamics, myocardial blood flow, and myocardial lactate metabolism during porcine endotoxemia. Twelve pigs were studied. Oxygen consumption was measured by indirect calorimetry, and myocardial blood flow was measured by retrograde thermodilution. Pulmonary, arterial, and venous indwelling catheters allowed measurements of cardiac output, vascular pressures, and blood sampling. Fluids were given at an average of 15 mL . kg . h. After baseline measurements (0 min), an infusion of Escherichia coli LPS (2 microg . kg . min) was started in all animals. Beginning at 100 min, six animals received levosimendan (50 microg . kg . h), whereas six control animals received placebo. The study lasted for 300 min. All animals responded to endotoxin with pulmonary hypertension, a transient decrease in cardiac output, tachycardia, and systemic hypotension. Levosimendan infusion decreased systemic vascular resistance (P = 0.001), coronary vascular resistance (P = 0.004), and mean arterial (P < 0.001) and coronary perfusion pressures (P < 0.001), whereas pulmonary hypertension was unaffected. Heart rate progressively increased in both groups and was significantly higher in the levosimendan group (P = 0.048). Myocardial blood flow remained unchanged in both groups; however, 80 min after the start of levosimendan infusion, left ventricular myocardial hypoxia ensued, as evidenced by a negative myocardial lactate gradient (P = 0.01). Two control and five levosimendan animals died before the end of the study. Early administration of levosimendan during porcine endotoxemia increased heart rate, caused arterial vasodilation, and decreased coronary perfusion pressure, resulting in myocardial hypoxia.

Can pulsed ultrasound increase tissue damage during ischemia? A study of the effects of ultrasound on infarcted and non-infarcted myocardium in anesthetized pigs.

BACKGROUND: The same mechanisms by which ultrasound enhances thrombolysis are described in connection with non-beneficial effects of ultrasound. The present safety study was therefore designed to explore effects of beneficial ultrasound characteristics on the infarcted and non-infarcted myocardium. METHODS: In an open chest porcine model (n = 17), myocardial infarction was induced by ligating a coronary diagonal branch. Pulsed ultrasound of frequency 1 MHz and intensity 0.1 W/cm2 (ISATA) was applied during one hour to both infarcted and non-infarcted myocardial tissue. These ultrasound characteristics are similar to those used in studies of ultrasound enhanced thrombolysis. Using blinded assessment technique, myocardial damage was rated according to histopathological criteria. RESULTS: Infarcted myocardium exhibited a significant increase in damage score compared to non-infarcted myocardium: 6.2 +/- 2.0 vs. 4.3 +/- 1.5 (mean +/- standard deviation), (p = 0.004). In the infarcted myocardium, ultrasound exposure yielded a further significant increase of damage scores: 8.1 +/- 1.7 vs. 6.2 +/- 2.0 (p = 0.027). CONCLUSION: Our results suggest an instantaneous additive effect on the ischemic damage in myocardial tissue when exposed to ultrasound of stated characteristics. The ultimate damage degree remains to be clarified.

Global repolarization sequence of the right atrium: monphasic action potential mapping in health pigs.

The aim of the study was to explore the global sequence of atrial repolarization and its correlation to that of activation. Endocardial monophasic action potentials (MAPs) were sequentially recorded from 51 +/- 14 sites in the right atrium of ten healthy pigs using the CARTO electroanatomic mapping system. Local activation time (AT), MAP duration, and 90% repolarization time (RT) were obtained, and from these data, color coded three-dimensional maps of AT and RT sequences and spatial distribution of MAP duration were reconstructed. The results of the study were: (1) An activation sequence was recognizable in all maps, starting from the posterosuperior wall and ending in the posteroinferior wall near the tricuspid annulus. (2) The repolarization sequence was also recognizable in all maps, and mainly followed the sequence of activation. (3) A significant positive correlation between the RT and AT was observed in all maps with an average r value being 0.571 +/- 0.159 (P < 0.01 - 0.0001), suggesting that progressively later AT associates with progressively longer RT. (4) No consistent correlation between the MAP duration and AT was found. In conclusion, repolarization gradients exist over the atrial endocardium in healthy pigs. The repolarization sequence follows the same sequence as the activation, suggesting that the spatiotemporal pattern of activation is an important determinant of the characteristics of the repolarization sequence.

Monophasic action potential mapping in swine and humans using modified-tip ablation catheter and electroanatomic mapping system.

OBJECTIVE: To evaluate the feasibility of monophasic action potential (MAP) mapping using a modified-tip NaviStar catheter in swine and humans. METHODS: MAP mapping was performed using the modified-tip catheter at 71 +/- 21 atrial and 60 +/- 16 ventricular sites in 10 healthy pigs and at 56 ventricular sites in one patient, and using an ordinary Navi-Star catheter at 30 atrial sites in one patient and 50 +/- 14 ventricular sites in four patients. In an additional 20 patients, MAPs were also recorded at 9 +/- 2 atrial sites using the modified-tip catheter or at 12 +/- 9 atrial sites using the ordinary catheter. RESULTS: In pigs, the plateau amplitudes of the MAPs recorded using the modified-tip catheter were 4.1 +/- 3.2 mV for the atrial and 9.5 +/- 4.3 mV for the ventricular MAPs. In patients, both the ventricular and atrial MAPs recorded using the modified-tip catheter were significantly higher than using the ordinary catheters, 15.7 +/- 8 and 3.0 +/- 0.9 mV vs 9.5 +/- 3.9 and 2.0 +/- 0.6 mV for the ventricular and atrial MAPs, respectively (p < 0.0001). The baseline disturbances were <10% of the MAP amplitude in 95% of the pig and 96% of the patient MAPs. CONCLUSION: A modified-tip Navi-Star catheter could be used in swine and in humans for prompt recording of MAPs with acceptable amplitudes and baselines. MAP mapping using the modified-tip catheter is safe and feasible for clinical use.

Global and local dispersion of ventricular repolarization: endocardial monophasic action potential mapping in swine and humans by using an electro-anatomical mapping system.

This article evaluates whether the global dispersion of ventricular repolarization (DVR) can be estimated from measurements between a few adjacent or remote sites. Monophasic action potentials (MAP) were recorded from 61 +/- 18 left (LV) or right ventricular (RV) sites in 10 pigs and 44 +/- 16 LV, or RV sites in 8 patients by using the CARTO mapping system. MAP duration (MAPd) and end-of-repolarization time were calculated at each site and 13 repolarization maps from pigs and 10 from patients were reconstructed. Global dispersions in MAPd and EOR over the LV or RV were compared with the adjacent DVR among 3 - 7 MAPs in areas > or = 0.7 and < or = 1 cm(2) and with the remote DVRs between 2 MAPs with the greatest activation time difference (remote DVR1) and between the apical and laterobasal LV or RV (remote DVR2). The adjacent dispersions in end-of-repolarization and MAPd were significantly smaller than the global ones, 13 +/- 3 and 12 +/- 3 ms vs. 44 +/- 9 and 42 +/- 12 ms in pigs and 13 +/- 7 and 14 +/- 8 ms vs. 72 +/- 24 and 66 +/- 22 ms in patients. The remote DVR1 (30 +/- 8 and 17 +/- 10 ms in pigs and 40 +/- 28 and 28 +/- 17 ms in patients) and remote DVR2 (16 +/- 7 and 11 +/- 10 ms in pigs and 35 +/- 24 and 21 +/- 21 ms in patients) were also significantly smaller than the global DVRs. In conclusion, global DVR is poorly estimated from MAP recordings from a few adjacent or remote sites, suggesting the importance of obtaining global information in evaluating DVR.