[The influence of heat shock proteins on hepatic ischaemia reperfusion injury]. / A hosokkfehérjék hatása a máj ischaemiás-reperfúziós károsodására.

Hepatic ischemia-reperfusion injury as a result of inflow obstruction is a major cause of morbidity and mortality associated with liver pathologies and surgery. Heat shock proteins, a family of stress-inducible proteins involved in maintaining cell homeostasis and regulating the immune system play a major role in liver regeneration. They serve as crucial indicators of ischemia-reperfusion injury in human liver and influence liver function and recovery. The primary objectives of this article are to review the potential role of heat shock proteins as a diagnostic marker for liver diseases and therapeutic target in critical illness. The review will start by focusing on the essentials of heat shock proteins as an endogenous system as it relates to hepatic injury. It will elucidate the influence of heat shock protein-70 on hepatic diseases and ischemia-reperfusion. It will then look at their potential diagnostic role and finally highlights its activities as a possible therapeutic tool. Orv. Hetil., 2016, 157(42), 1659-1666.

Platelet aggregation in severe sepsis.

Severe sepsis and multiple organ distress syndrome remain a diagnostic and therapeutic challenge for intensive therapy. Platelet activating factor forms a bridge between inflammation and clot formation. Our study surveys the effect of severe sepsis on platelet function and focuses on spontaneous aggregation in severely ill patients. Daily arterial blood samples were collected from 45 patients (average age of 60.7 ± 13) for five consecutive days following admission and 30 healthy controls. Platelet aggregation was measured using adrenaline (ADR), adenosine diphosphate (ADP), collagen (COL) and normal saline (SAL). Clinical status was observed using Multiple Organ Dysfunction Score (MODS) and Sequential Organ Failure Assessment (SOFA) score systems. Inducible aggregation deteriorated in septic patients in all 5 days with ADR, ADP and COL (P < 0.05) while SAL aggregation was increased during intensive care. Low platelet patients showed weak inducible aggregation with ADP throughout, with ADR on the 2nd, 3rd, 4th and 5th days and with COL on the 1st, 2nd and 3rd days. SAL aggregation showed no significance. No significant difference was seen between platelet functions comparing survivors and non-survivors. In the spontaneous aggregative group, platelet count was insignificantly higher, while procalcitonin levels were lower in 1st, 3rd and 4th days and no significant difference was observed in lactate levels. We demonstrated the presence of spontaneous platelet activity while overall inducible platelet aggregation is significantly deteriorated in septic patients. There were significant differences in inducible aggregation between normal and low platelet count groups. Inducible platelet function had no predictive value in the outcome.

Comparison of oxidative stress & leukocyte activation in patients with severe sepsis & burn injury.

BACKGROUND & OBJECTIVES: We evaluated pro- and anti-oxidant disturbances in sepsis and non-sepsis burn patients with systemic inflammatory response syndrome (SIRS). Adhesion molecules and inflammation markers on leukocytes were also analyzed. We hypothesized that oxidative stress and leukocyte activation markers can lead to the severity of sepsis. METHODS: In 28 severe sepsis and 27 acute burn injury patients blood samples were collected at admission and 4 days consecutively. Oxidative stress markers: production of reactive oxygen species (ROS), myeloperoxidase, malondialdehyde and endogenous antioxidants: plasma protein sulphydryl groups, reduced glutathione, superoxide dismutase and catalase were measured. Flow cytometry was used to determine CD11a, CD14, CD18, CD49d and CD97 adhesion molecules on leukocytes. Procalcitonin, C-reactive protein, fibrinogen, platelet count and lactate were also analyzed. RESULTS: Pro-oxidant parameters were significantly elevated in sepsis patients at admission, ROS intensity increased in burn patients until the 5th day. Endogenous antioxidant levels except catalase showed increased levels after burn trauma compared to sepsis. Elevated granulocyte activation and suppressed lymphocyte function were found at admission and early activation of granulocytes caused by increasing activation/migration markers in sepsis. Leukocyte adhesion molecule expression confirmed the suppressed lymphocyte and monocyte function in sepsis. INTERPRETATION & CONCLUSIONS: Severe sepsis is accompanied by oxidative stress and pathological leukocyte endothelial cell interactions. The laboratory parameters used for the evaluation of sepsis and several markers of pro- and antioxidant status were different between sepsis and non-sepsis burn patients. The tendency of changes in these parameters may refer to major oxidative stress in sepsis and developing SIRS in burns.

[Hemodynamic effects of N-acetylcysteine and ischemic preconditioning in a liver ischemia-reperfusion model]. / Az N-acetilcisztein hemodinamikai hatása és ischaemiás prekondicionálás máj ischaemia-reperfúzió modellen.

UNLABELLED: The aim of the study was to investigate whether repeated ischemic preconditioning or N-acetylcysteine (NAC) prevents ischemic-reperfusion injury as determined by having favourable hemodynamic effects during reperfusion in canine livers. METHODS: The control group ( n = 10) underwent 60 minutes of hepatic ischemia followed by 180 minutes reperfusion. In the NAC group ( n = 5) 150 mg kg -1 of NAC was administered intravenously before inducing ischemia. In the preconditioned group ( n = 5) animals received ischemic preconditioning (10 minutes of ischemia followed by 10 minutes of reperfusion repeated three times) before clamping the portal triad. RESULTS: 18 dogs survived the study period. One dog in the NAC group died due to circulatory failure unresponsive to inotropic drugs. The cardiac index and the intrathoracic blood volume index were significantly higher in the preconditioning group compared to the controls throughout the study period. CONCLUSIONS: Repeated ischemic preconditioning might improve hemodynamic parameters, whereas we were unable to find any significant differences between the groups regarding N-acetylcysteine.

Time course of platelet aggregation during thrombolytic treatment of massive pulmonary embolism.

We studied changes in platelet aggregation and fibrinogen levels during thrombolysis with massive or submassive pulmonary embolism. Fifteen patients were randomized into ultrahigh-dose streptokinase (UH-SK n = 8) or alteplase (tPA n = 7) groups. Arterial blood samples were taken before and after thrombolysis every 4 h between 4 and 36 h, and once daily between 2 and 30 days. In-vitro platelet aggregation was examined as spontaneous (0.9% NaCl) and induced aggregation with adrenaline 10 micromol/l, collagen 2 microg/ml and ADP 10 micromol/l. D-dimer and fibrinogen were measured every 8 h on first day, and later as above. In the UH-SK group, adrenaline-induced platelet aggregation decreased at 4 and 8 h compared with baseline (P < 0.03). Adrenaline-induced platelet aggregation was significantly lower in the UH-SK group than in the tPA group at 36 h and on day 3 (P < 0.03). Platelet aggregation induced by ADP was lower at 4 h than at baseline in the UH-SK group (P < 0.05). Collagen-induced platelet aggregation was lower at 4 and 8 h than at baseline (P < 0.05) in the UH-SK group. Compared with baseline, fibrinogen levels decreased in both groups after thrombolysis. D-dimer levels were elevated in both groups at 8 h (tPA group, P < 0.0004; UH-SK group, P < 0.05). Spontaneous platelet aggregation, major bleeding or re-embolism was not documented. Platelet aggregation decreased after thrombolysis with UH-SK for 12 h, in comparison tPA caused an insignificant decrease. Fibrinogen level decreased with UH-SK treatment for 5 days but in case of tPA we could not measure significant changes. According to our findings, tPA is a more suitable drug but streptokinase is also effective because of its cost-benefit ratio.

Transesophageal Echocardiography Complications in Adult Cardiac Surgery: A Retrospective Cohort Study.

BACKGROUND: Although there have been several large reviews documenting the complications following intraoperative transesophageal echocardiography (TEE), most of these prior reports are almost 2 decades old and may not reflect current practices. The purpose of this study was to determine the incidence and types of complications following TEE in a contemporary cardiac surgical population. METHODS: We conducted a retrospective analysis of all cardiac surgical patients having undergone an intraoperative TEE between April 1, 2004, and April 30, 2012. Patients with TEE-related complications were identified from our institutional cardiac surgical database to have their medical records manually reviewed through International Classification of Diseases-10th Revision coding for: 1) a priori defined complications including dysphagia, vocal cord and laryngeal injury, dysphonia, accidental puncture and laceration during a procedure, and hemorrhage and hematoma complicating a procedure; 2) the requirement for an in-hospital esophageal or bronchial endoscopy procedure; or 3) the requirement for postoperative specialist consultation from gastrointestinal bleed or other surgery services. A multivariable model was then developed to identify risk factors for TEE complications. RESULTS: Of the 7,954 cardiac surgical cases performed during the study period, 1,074 had their records manually reviewed and 111 (1.4%) patients had possible complications. Multivariate analysis showed an increased risk of complications associated with age, body mass index, previous stroke, procedure other than isolated coronary artery bypass grafting, cardiopulmonary bypass time, and return to the operating room for any reason (model c-statistic = 0.81). CONCLUSIONS: The overall incidence of TEE complications after cardiac surgery was 1.4%. Advanced age, low body mass index, complexity of procedure, prior stroke, prolonged bypass time, and return to the operating room appear to be significant risk factors for TEE complications.

Anesthetics impact on cancer recurrence: What do we know?

Surgery is an important component of treatment in cancer patients. However, surgical stress, anesthesia, and perioperative analgesia interfere with the host immune defense mechanisms and may contribute to metastatic dissemination of malignant tumors and cancer progression. Little is known about the effects of anesthesia on tumor recurrence. In vivo studies and clinical data show some evidence that regional anesthesia is beneficial for cancer patients as it may decrease the risk of metastasis. This short review summarizes the clinical data on the possible association between anesthesia, perioperative analgesia, and the risk of cancer recurrence. Most of the clinical reports are based on retrospective studies, and properly designed prospective trials including a sufficient number of patients is required to reveal the interaction of various anesthetic drugs and methods and cancer progression.

A comparison of pre-operative nutritional status with post-operative morbidity and mortality in obese esophageal surgery patients.

OBJECTIVES: The nutrition state of obese patients scheduled to undergo esophageal surgery was evaluated using two nutritional score systems: the mini nutritional assessment (MNA) and the prognostic and nutritional index (PINI). A further comparison of various proteins, lymphocytes and cholesterol was performed using biochemical tests. These factors were compared with post-operative morbidity and mortality in a prospective, descriptive clinical study. MATERIAL AND METHODS: The study included 34 obese patients undergoing esophagus resection due to cancer, who were examined over four years using both scoring systems to analyze whether nutritional status influences the outcome of surgery. The patients were divided into four groups based on the severity of the outcome and their MNA and PINI scores were analyzed. RESULTS: There were no significant differences between the nutritional status of survivors and deceased patients. The European Society for Parenteral and Enteral Nutrition (ESPEN) nutritional risk score was 1.35 ± 0.47 for Group I and 1.47 ± 0.58 for Group II (p = 0.62). With respect to severe morbidity there was no significant difference between Group III and Group IV: 2.01 ± 2.28 vs. 1.02 ± 3.67 (p = 0.54). Although there were minor differences, there were no major variations seen in the MNA or PINI scores comparing the four examined groups. No significant changes were observed in the biochemical parameters. CONCLUSIONS: The study found no differences between post-operative morbidity or mortality and the pre-operative nutrition status of obese patients who underwent surgery due to esophageal cancer.

Anesthetic management for cesarean delivery in a patient with severe aortic stenosis and severe obesity.

Valvular heart disease has significant effect on the maternal and fetal outcome of pregnancy. The severity and extent of aortic stenosis is of great value for risk assessment and for the design of a therapeutic plan. The therapeutic plan for such patients is further complicated by severe obesity. We report a case describing the anesthetic management of an extremely obese patient for cesarean delivery with severe aortic valve stenosis and regurgitation. The case was made complex due to the patient's deteriorating condition and not offering consent to emergency surgical procedures. The 34-year-old parturient underwent cesarean delivery at 32 weeks gestation under general anesthesia in the presence of a cardiothoracic surgical team. This case report demonstrates the importance of multidisciplinary preoperative assessment in such patients and careful anesthetic planning to avoid the deterioration of perioperative cardiac performance in parturients with complex valvular disease.

Kinetics of inflammatory markers following cancer-related bowel and liver resection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) was originally described as a cytokine that inhibits migration of macrophages at the site of inflammation. Subsequently it was also identified as a stress-induced hormone released from the anterior pituitary lobe in response to some pro-inflammatory stimuli like endotoxins and tumour necrosis factor (TNF-α). AIM: To compare postoperative changes in serum MIF levels of patients undergoing bowel and liver resections. It has clinical relevance to describe the kinetics of this crucial mediator of systemic inflammation in surgery. METHODS: A total of 58 patients were studied over 4 years. Group A (28 patients) underwent only hepatic resection without enterotomy. Group B (30 patients) had bowel resection with enterotomy. MIF, IL-1ß, IL-8, prealbumin, albumin, α1-glycoprotein, fibrinogen, and C-reactive protein levels were measured preoperatively, immediately following surgery, and postoperatively for three consecutive days. To evaluate organ functions, multiple organ dysfunction score was used. RESULTS: A significantly higher level of MIF (4,505 pg/mL) was found in group A when compared to that of group B immediately following surgery. Other parameters monitored in this study were not statistically different between the two groups. CONCLUSION: Higher elevations in MIF levels with liver resections, compared to bowel resections, might be attributable to MIF release from damaged liver cells. The presumably minimal endotoxin exposure during bowel surgery was either insufficient or inefficient to induce relevant MIF elevations in our patients. To fully delineate implications of this finding further studies are needed.

Carbon monoxide: endogenous mediator, potential diagnostic and therapeutic target.

The primary objectives of this article are to review the potential role of carbon monoxide (CO) as an endogenous mediator, diagnostic marker for pulmonary disorders, and therapeutic target in critical illness. The review will start by focusing on the importance of the heme oxygenase (HO)-CO axis as an endogenous system as it relates to the cardiovascular and pulmonary systems. It will elucidate the influence of HO gene expression on critical events like shock, sepsis, ischemia-reperfusion and others. Our focus will then shift and look at the potential diagnostic role of exhaled CO in major inflammatory states of the lung, and finally we will highlight the activities on inhaled CO being considered as a possible therapeutic tool and the controversies surrounding it.

Increases in circulating matrix metalloproteinase-9 levels following fibrinolysis for acute pulmonary embolism.

INTRODUCTION: Fibrinolyis is one of the first line therapies in high risk pulmonary embolism (PE) according to current guidelines. Previous studies showed that fibrinolytic therapy with tPA (tissue plasminogen activator, or alteplase) upregulates the concentrations of matrix metalloproteinases (MMPs) and contributes to hemorrhagic transformation after cardioembolic stroke. However, no previous study has described the circulating MMPs levels following fibrinolysis for acute PE. MATERIALS AND METHODS: We serially measured the circulating levels of MMPs (MMP-9 and MMP-2) and their endogenous inhibitors, the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in alteplase and in streptokinase-treated patients with acute PE by gelatin zymography and by enzyme-linked immunosorbent assays, respectively. RESULTS: We found that therapy of PE streptokinase or with alteplase is associated increased pro-MMP-9, but not MMP-2, concentrations for up to 24hours, whereas no significant changes were found in TIMP-1 or TIMP-2 concentrations. This alteration returned to normal 3 to 5days after thrombolysis. This is the first study reporting on MMPs alterations following fibrinolysis for acute PE. CONCLUSIONS: We found transient increases in circulating pro-MMP-9 levels following fibrinolysis for acute PE. Our findings support the hypothesis that increased MMP-9 levels may underlie the risk of intracerebral hemorrhage or other bleeding complication of thrombolysis for acute PE, and the use of MMP inhibitors may decrease such risk.

Evaluation of oxidative stress in the thrombolysis of pulmonary embolism.

BACKGROUND: To analyse leukocyte function parameters and oxidative stress (OS) in patients with acute pulmonary embolism (PE) treated with thrombolytics. METHODS: Fifteen patients undergoing thrombolysis (TL) with ultra-high dose streptokinase (n = 8), or alteplase (tPA) (n = 7) treatment were studied. Blood samples were collected prior to TL, and then 8 h, 1, 3, 5 and 30 days after treatment. Malondialdehyde (MDA), reduced glutathione (GSH), plasma protein sulfhydryl groups (PSH) levels, superoxide dismutase (SOD) and myeloperoxidase enzyme (MPO) activities were measured in plasma or whole blood for monitoring of the OS markers. Production of reactive oxygen species (ROS) in whole blood was measured by luminol dependent chemiluminescence. Flow cytometry was used to determine CD11a, CD18, and CD97 surface antigen expression on leukocytes. RESULTS: The elevated MDA, ROS and MPO, decreased GSH and PSH levels indicated the presence of OS in patients with PE. MDA significantly (P < 0.05) increased, GSH significantly (P < 0.05) decreased following thrombolysis. ROS production peaked on the 3rd and 5th days. TL was accompanied by significant decrease in granulocyte and monocyte CD11a and CD18 as well as in granulocyte CD97 expression (P < 0.05). CONCLUSION: PE led to OS that was augmented following TL. Decreased adhesion molecule expression of circulating leukocytes in the early phase of TL reflects the pathological leukocyte endothelial cell interactions.

Effects of inhaled carbon monoxide on acute lung injury in mice.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality in the intensive care unit, but despite continuing research few effective therapies have been identified. In recent years, inhaled carbon monoxide (CO) has been reported to have cytoprotective effects in several animal models of tissue injury. We therefore evaluated the effects of inhaled CO in three different in vivo mouse models of ALI. Anesthetized C57BL/6 mice were ventilated with oxygen in the presence or absence of CO (500 parts per million) for 1 h before lung injury was induced by lipopolysaccharide (LPS) or oleic acid (OA) administration. Ventilation was then continued with the same gases for a further 2-3 h, with hemodynamic and respiratory parameters monitored throughout. Intratracheal LPS administration induced lung injury with alveolar inflammation (increased lavage fluid neutrophils, total protein, and cytokines). In contrast, intravenous LPS induced a predominantly vascular lung injury, with increased plasma TNF and increased neutrophil activation (surface Mac-1 upregulation and L-selectin shedding) and sequestration within the pulmonary vasculature. Intravenous OA produced deteriorations in lung function, reflected by changes in respiratory mechanics and blood gases and lavage fluid neutrophil accumulation. However, addition of CO to the inspired gas did not produce significant changes in the measured physiological or immunological parameters in the mouse models used in this study. Thus the results do not support the hypothesis that use of inhaled CO is beneficial in the treatment of ALI and ARDS.