Plasma Hepcidin Correlates Positively With Interleukin-6 in Patients Undergoing Pulmonary Endarterectomy

Hepcidin, a recently discovered antimicrobial peptide synthesized in the liver, was identified to be the key mediator of iron metabolism and distribution. Despite our knowledge of hepcidin increased in recent years, there are only limited data on hepcidin regulation during systemic inflammatory response in human subjects. In a prospective study, the time course of plasma hepcidin was analyzed in relations to six inflammatory parameters – plasma cytokines and acute-phase proteins in patients undergoing uncomplicated pulmonary endarterectomy. Twenty-four patients (males, aged 52.6±10.2 years, treated with pulmonary endarterectomy in a deep hypothermic circulatory arrest) were enrolled into study. Hepcidin, interleukin (IL)-6, IL-8, tumor necrosis factor-α, C-reactive protein, α1-antitrypsin and ceruloplasmin arterial concentrations were measured before surgery and repeatedly within 120 h post-operatively. Hemodynamic parameters, hematocrit and markers of iron metabolism were followed up. In a postoperative period, hepcidin increased from preoperative level 8.9 ng/ml (6.2-10.7) (median and interquartile range) to maximum 16.4 ng/ml (14.1-18.7) measured 72 h after the end of surgery. Maximum post-operative concentrations of hepcidin correlated positively with maximum IL-6 levels. Both hepcidin and IL-6 maximum concentrations correlated positively with extracorporeal circulation time. In conclusions, the study demonstrated that plasma hepcidin is a positive acute-phase reactant in relation to an uncomplicated large cardiac surgery. Hepcidin increase was related to IL-6 concentrations and to the duration of surgical procedure. Our clinical findings are in conformity with recent experimental studies defining hepcidin as a type II acute-phase protein.

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Plasma prohepcidin as a negative acute phase reactant after large cardiac surgery with a deep hypothermic circulatory arrest

Physiological Research ◽

10.33549/physiolres.931678 ◽

2009 ◽

pp. 827-833

Author(s):

P Maruna ◽

J Lindner ◽

J Kunštýř ◽

K Kubzová ◽

J Hubáček

Keyword(s):

Cardiac Surgery ◽

Cardiopulmonary Bypass ◽

Acute Phase ◽

Iron Metabolism ◽

Circulatory Arrest ◽

Acute Phase Reactant ◽

Deep Hypothermic Circulatory Arrest ◽

Hypothermic Circulatory Arrest ◽

Pulmonary Endarterectomy ◽

Phase Reactant

Hepcidin is a key regulator of iron metabolism and a mediator of anemia in inflammation. Recent in vitro studies recognized prohepcidin as a type II acute phase protein regulating via interleukin-6. The aim of the present study was to investigate the time course of plasma prohepcidin after a large cardiac surgery in relation to IL-6 and other inflammatory parameters. Patients with chronic thromboembolic hypertension (n=22, males/females 14/8, age 51.9±10.2 years) underwent pulmonary endarterectomy using cardiopulmonary bypass and deep hypothermic circulatory arrest were included into study. Arterial concentrations of prohepcidin, IL-1β, IL-6, IL-8, tumor necrosis factor-α, and C-reactive protein were measured before/after sternotomy, after circulatory arrest, after separation from bypass, and then 12, 18, 24, 36, 48 h and 72 h after the separation from bypass. Hemodynamic parameters, hematocrit and markers of iron metabolism were followed up. Pulmonary endarterectomy induced a 48 % fall in plasma prohepcidin; minimal concentrations were detected after separation from cardiopulmonary bypass. Prohepcidin decline correlated with an extracorporeal circulation time (p<0.01), while elevated IL-6 levels were inversely associated with duration of prohepcidin decline. Postoperative prohepcidin did not correlate with markers of iron metabolism or hemoglobin concentrations within a 72-h period after separation from CPB. Prohepcidin showed itself as a negative acute phase reactant during systemic inflammatory response syndrome associated with a cardiac surgery. Results indicate that the evolution of prohepcidin in postoperative period implies the antagonism of stimulatory effect of IL-6 and contraregulatory factors inhibiting prohepcidin synthesis or increasing prohepcidin clearance.

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Evaluation of Rat Acute Phase Proteins as Inflammatory Biomarkers for Vaccine Nonclinical Safety Studies

Toxicologic Pathology ◽

10.1177/0192623320957281 ◽

2020 ◽

Vol 48 (7) ◽

pp. 845-856

Author(s):

William J. Reagan ◽

Ahmed M. Shoieb ◽

Shelli J. Schomaker ◽

Victoria R. Markiewicz ◽

David W. Clarke ◽

...

Keyword(s):

Injection Site ◽

Acute Phase ◽

Time Course ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Aluminum Phosphate ◽

Positive Control ◽

Meso Scale Discovery ◽

Quillaja Saponaria ◽

Time Course Study

The objectives were to characterize the kinetics of acute phase proteins (APPs) α-2 macroglobulin (A2M), α-1 acid glycoprotein (A1AGP), and fibrinogen (FIB), and injection site macroscopic and microscopic findings following intramuscular administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (TDaP; Adacel); adjuvants (aluminum phosphate [AlPO4]; aluminum hydroxide, Al[OH]3; CpG/Al[OH]3; or Quillaja saponaria 21 [QS-21]); or saline to female Wistar Han rats. Intravascular lipopolysaccharide (LPS) was a positive control. Injection sites and lymph nodes were evaluated microscopically, using hematoxylin and eosin (H&E) stained sections, 48 hours postdose (HPD) and compared with APP concentrations; A2M and A1AGP were measured using Meso Scale Discovery analyzer. Fibrinogen was measured on STA Compact analyzer. In a time-course study, APP peaked at 24 or 48 HPD. In a subsequent study at 48 HPD, injection site microscopic changes included inflammation and muscle degeneration/necrosis, which was different in severity/nature between groups. The APPs were not increased in rats administered saline, Al(OH)3, or AlPO4. Fibrinogen and A1AGP increased in rats administered CpG/Al(OH)3, QS-21, or TDaP; and A2M increased in rats administered QS-21. Fibrinogen, A2M, and A1AGP increased after LPS administration. Acute phase proteins can be used to monitor inflammatory responses to adjuvants; however, some adjuvants may induce inflammation without higher APPs.

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Perfusion strategy and mid-term results of 58 consecutive pulmonary endarterectomy

Perfusion ◽

10.1177/0267659119831518 ◽

2019 ◽

Vol 34 (6) ◽

pp. 475-481

Author(s):

Shujie Yan ◽

Song Lou ◽

Jiade Zhu ◽

Sheng Liu ◽

Yu Zhao ◽

...

Keyword(s):

Neurological Outcome ◽

Potassium Concentration ◽

Circulatory Arrest ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Deep Hypothermic Circulatory Arrest ◽

Good Recovery ◽

Pulmonary Endarterectomy ◽

Short Term ◽

Blood Potassium ◽

Thromboembolic Pulmonary Hypertension

Objective: The aim of this retrospective study was to review and report short-term and mid-term outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension at our institute in the recent 2 years and to describe perfusion strategy. Methods: A total of 58 consecutive patients with chronic thromboembolic pulmonary hypertension underwent pulmonary endarterectomy under deep hypothermia circulatory arrest with an established perfusion practice between November 2015 and December 2017. Peri-operative data and patients’ outcome were retrospectively analyzed. Results: Mean pulmonary artery pressure was decreased (49 (40-56) mmHg vs 27 (20-31) mmHg, p < 0.001), and pulmonary vascular resistance (724 (538-1108) vs 206 (141-284) dyn second cm−5, p < 0.001) improved significantly after surgery. In-hospital mortality was 1.7% and postoperative complication rate was 27.6%. Antipsychotic medication of olanzapine was prescribed for 36 patients (62.1%), which was independently related to total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit. The majority of patients recovered uneventfully with good mid-term cardiac function (New York Heart Association I-II: 98.1%) and neurological outcome (Glasgow Outcome Scale—Extended Upper Good Recovery: 74.1% and Lower Good Recovery: 20.3%). Mid-term neurological outcome was associated with post–pulmonary endarterectomy antipsychotic medication. Conclusion: Short-term and mid-term outcome after pulmonary endarterectomy was comparable to high-volume centers. Incidence of post–pulmonary endarterectomy delirium was relatively high and associated with mid-term neurological outcome. Total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit were independent risk factors of postoperative olanzapine medication. More efforts and further research are required to optimize the neuroprotection of perfusion practice.

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Anticoagulation management during pulmonary endarterectomy with cardiopulmonary bypass and deep hypothermic circulatory arrest

Perfusion ◽

10.1177/0267659120928682 ◽

2020 ◽

Vol 36 (1) ◽

pp. 87-96

Author(s):

Dennis Veerhoek ◽

Laurentius JM van Barneveld ◽

Renard G Haumann ◽

Suzanne K Kamminga ◽

Alexander BA Vonk ◽

...

Keyword(s):

Cardiopulmonary Bypass ◽

Confidence Interval ◽

Circulatory Arrest ◽

Deep Hypothermic Circulatory Arrest ◽

Hypothermic Circulatory Arrest ◽

Clotting Time ◽

Pulmonary Endarterectomy ◽

Anticoagulation Management ◽

Activated Clotting Time ◽

Protamine Administration

Introduction: Pulmonary endarterectomy requires cardiopulmonary bypass and deep hypothermic circulatory arrest, which may prolong the activated clotting time. We investigated whether activated clotting time–guided anticoagulation under these circumstances suppresses hemostatic activation. Methods: Individual heparin sensitivity was determined by the heparin dose–response test, and anticoagulation was monitored by the activated clotting time and heparin concentration. Perioperative hemostasis was evaluated by thromboelastometry, platelet aggregation, and several plasma coagulation markers. Results: Eighteen patients were included in this study. During cooling, tube-based activated clotting time increased from 719 (95% confidence interval = 566-872 seconds) to 1,273 (95% confidence interval = 1,136-1,410 seconds; p < 0.01) and the cartridge-based activated clotting time increased from 693 (95% confidence interval = 590-796 seconds) to 883 (95% confidence interval = 806-960 seconds; p < 0.01), while thrombin–antithrombin showed an eightfold increase. The heparin concentration showed a slightly declining trend during cardiopulmonary bypass. After protamine administration (protamine-to-heparin bolus ratio of 0.82 (0.71-0.90)), more than half of the patients showed an intrinsically activated coagulation test and intrinsically activated coagulation test without heparin effect clotting time >240 seconds. Platelet aggregation through activation of the P2Y12 (adenosine diphosphate test) and thrombin receptor (thrombin receptor activating peptide-6 test) decreased (both −33%) and PF4 levels almost doubled (from 48 (95% confidence interval = 42-53 ng/mL) to 77 (95% confidence interval = 71-82 ng/mL); p < 0.01) between weaning from cardiopulmonary bypass and 3 minutes after protamine administration. Conclusion: This study shows a wide variation in individual heparin sensitivity in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest. Although activated clotting time–guided anticoagulation management may underestimate the level of anticoagulation and consequently result in a less profound inhibition of hemostatic activation, this study lacked power to detect adverse outcomes.

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Cognitive function and surgical success following pulmonary endarterectomy. A randomised controlled trial to compare deep hypothermic circulatory arrest with selective anterograde cerebral perfusion

http://isrctn.org/> ◽

10.1186/isrctn84972261 ◽

2013 ◽

Author(s):

David Jenkins

Keyword(s):

Cognitive Function ◽

Randomised Controlled Trial ◽

Cerebral Perfusion ◽

Controlled Trial ◽

Circulatory Arrest ◽

Deep Hypothermic Circulatory Arrest ◽

Hypothermic Circulatory Arrest ◽

Pulmonary Endarterectomy ◽

Surgical Success ◽

Randomised Controlled

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Long-term assessment of NFκB expression in the brain and neurologic outcome following deep hypothermic circulatory arrest in rats

Perfusion ◽

10.1177/0267659109358655 ◽

2009 ◽

Vol 24 (6) ◽

pp. 429-436 ◽

Cited By ~ 2

Author(s):

Kristine Kellermann ◽

M. Lucia Gordan ◽

Georg Nollert ◽

Manfred Blobner ◽

Eberhard F. Kochs ◽

...

Keyword(s):

Motor Cortex ◽

Time Course ◽

Circulatory Arrest ◽

Deep Hypothermic Circulatory Arrest ◽

Hypothermic Circulatory Arrest ◽

Cerebral Injury ◽

Neurologic Outcome ◽

Neurologic Deficits ◽

Institutional Review ◽

Cox 2

Objectives: Inflammatory response is discussed as a contributor to neurologic deficits following cardiac surgery using deep hypothermic circulatory arrest (DHCA). Nuclear Factor Kappa B (NFκB) presents a central transcription factor whose expression pattern and subsequent role very much depend on the type and manner of cerebral injury. This study was designed to assess the time course of cerebral NFκB expression in relation to neurologic performance over 28 days following 45min of DHCA in rats. Methods: With Institutional Review Board approval, 30 rats were subjected to cardiopulmonary bypass (CPB) with 45min of DHCA (rectal temperature 15-18°C) and randomly assigned to 1, 3, 7, 14 and 28 days of postoperative survival. Untreated animals served as control (n=6). Cerebral NFκB expression was analyzed immunohistochemically, cyclooxygenase-2 (COX-2) and inhibitor of kappa B-alpha (IκBα) using Western Blot and the number of eosinophilic neurons with hematoxylin and eosin (HE) staining. Neurologic outcome was assessed pre- and postoperatively. Results: Neuronal expression of NFκB in the hippocampus peaked at day one, remaining elevated in the motor cortex until day 28. Rats showed neurologic deficits on postoperative day one. Cerebral COX-2 was increased during the first postoperative week and IκBα peaked on day 14. Histologic damage in the motor cortex and hippocampus persisted until day 28. No systemic inflammation was detectable postoperatively. Conclusions: Postoperative day one presents with the highest NFκB-expression in the ischemia-sensitive hippocampus, accompanied by neurologic dysfunction and histologic damage following 45min of DHCA in rats.

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Preoperative platelet count, preoperative hemoglobin concentration and deep hypothermic circulatory arrest duration are risk factors for acute kidney injury after pulmonary endarterectomy: a retrospective cohort study

Journal of Cardiothoracic Surgery ◽

10.1186/s13019-019-1026-4 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 2

Author(s):

Congya Zhang ◽

Guyan Wang ◽

Hui Zhou ◽

Guiyu Lei ◽

Lijing Yang ◽

...

Keyword(s):

Risk Factors ◽

Platelet Count ◽

Circulatory Arrest ◽

Kidney Injury ◽

Hemoglobin Concentration ◽

Deep Hypothermic Circulatory Arrest ◽

Pulmonary Endarterectomy ◽

Short Term ◽

Preoperative Hemoglobin ◽

Postoperative Aki

Abstract Background Acute kidney injury (AKI) is a major postoperative morbidity of patients undergoing cardiac surgery and has a negative effect on prognosis. The kidney outcomes after pulmonary endarterectomy (PEA) have not yet been reported; However, several perioperative characteristics of PEA may induce postoperative AKI. The objective of our study was to identify the incidence and risk factors for postoperative AKI and its association with short-term outcomes. Methods This was a single-center, retrospective, observational, cohort study. Assessments of AKI diagnosis was executed based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Results A total of 123 consecutive patients who underwent PEA between 2014 and 2018 were included. The incidence of postoperative AKI was 45% in the study population. Stage 3 AKI was associated with worse short-term outcomes and 90-day mortality (p < 0.001, p = 0.002, respectively). The independent predictors of postoperative AKI were the preoperative platelet count (OR 0.992; 95%CI 0.984–0.999; P = 0.022), preoperative hemoglobin concentration (OR 0.969; 95%CI 0.946–0.993; P = 0.01) and deep hypothermic circulatory arrest (DHCA) time (OR 1.197; 95%CI 1.052–1.362; P = 0.006) in the multivariate analysis. Conclusion The incidence of postoperative AKI was relatively high after PEA compared with other types of cardiothoracic surgeries. The preoperative platelet count, preoperative hemoglobin concentration and DHCA duration were modifiable predictors of AKI, and patients may benefit from some low-risk, low-cost perioperative measures.

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Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension

European Respiratory Review ◽

10.1183/16000617.00000815 ◽

2015 ◽

Vol 24 (136) ◽

pp. 263-271 ◽

Cited By ~ 80

Author(s):

David Jenkins

Keyword(s):

Pulmonary Hypertension ◽

Vascular Resistance ◽

Circulatory Arrest ◽

Pulmonary Arteries ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Right Ventricular Dysfunction ◽

Operative Management ◽

Deep Hypothermic Circulatory Arrest ◽

Pulmonary Endarterectomy ◽

Thromboembolic Pulmonary Hypertension

Pulmonary endarterectomy (PEA) is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It is a complex surgical procedure with a simple principle: removal of obstructive thromboembolic material from the pulmonary arteries in order to reduce pulmonary vascular resistance, relieve pulmonary hypertension (PH) and alleviate right ventricular dysfunction. In the majority of patients there is symptomatic and prognostic benefit. However, not all patients with CTEPH are suitable for treatment with PEA. Operability assessment is not always easy, being largely subjective and based on experience. It is therefore important that all patients are referred to an experienced CTEPH centre for careful evaluation of suitability for surgery. The most common reason for inoperability is distal vasculopathy accounting for a high proportion of the vascular resistance. Surgery requires cardiopulmonary bypass and periods of deep hypothermic circulatory arrest. Complications include reperfusion lung injury and persistent PH. However, with careful patient selection, surgical technique and post-operative management, PEA is a highly effective treatment with mortality rates <5% at experienced centres. Patients who are unsuitable for surgery may be candidates for medical therapy.

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Major plasma proteins in pig serum during postnatal development

Reproduction Fertility and Development ◽

10.1071/rd04064 ◽

2005 ◽

Vol 17 (4) ◽

pp. 439 ◽

Cited By ~ 31

Author(s):

M. Martin ◽

M. A. Tesouro ◽

N. González-Ramón ◽

A. Piñeiro ◽

F. Lampreave

Keyword(s):

Acute Phase ◽

Plasma Proteins ◽

Time Course ◽

Serum Proteins ◽

Acute Phase Proteins ◽

Acute Phase Protein ◽

Serum Levels ◽

Acid Glycoprotein ◽

Newborn Pigs ◽

Low Levels

The time-course of changes in the levels of albumin, α-fetoprotein (AFP), α1-protease inhibitor (α1-antitrypsin), α1-acid glycoprotein, fetuin, haptoglobin, transferrin, IgG and the major acute-phase protein (Pig-MAP) in the blood sera of pigs during the first days and weeks of life was investigated by quantitative radial immunodiffusion. The serum of newborn pigs before suckling was characterised by a very low concentration of total proteins (approximately 25 mg mL–1), low levels of albumin and transferrin and the lack of immunoglobulins. In contrast, α1-acid glycoprotein and fetuin are present at high levels (approximately 12 and 5 mg mL–1 respectively). The results of the present study show that the piglets undergo a very rapid metabolic maturation with regard to serum proteins, evolving from a characteristic ‘fetal’ pattern to an ‘adult’ one. We have paid special attention to the evolution of haptoglobin and Pig-MAP, which are two important acute-phase proteins in pigs. The evolution of serum levels of these proteins suggests that piglets must overcome a moderate acute-phase situation during the first week of life.

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