Efficacy and safety of antifibrinolytic agents in spinal surgery: a network meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Significant blood loss is still one of the most frequent complications in spinal surgery, which often necessitates blood transfusion. Massive perioperative blood loss and blood transfusion can create additional risks. Aprotinin, tranexamic acid (TXA), and epsilon-aminocaproic acid (EACA) are antifibrinolytics currently offered as prophylactic agents to reduce surgery-associated blood loss. The aim of this study was to evaluate the efficacy and safety of aprotinin, EACA, and low/high doses of TXA in spinal surgery, and assess the use of which agent is the most optimal intervention using the network meta-analysis (NMA) method.@*METHODS@#Five electronic databases were searched, including PubMed, Cochrane Library, ScienceDirect, Embase, and Web of Science, from the inception to March 1, 2018. Trials that were randomized and compared results between TXA, EACA, and placebo were identified. The NMA was conducted with software R 3.3.2 and STATA 14.0.@*RESULTS@#Thirty randomized controlled trial (RCT) studies were analyzed. Aprotinin (standardized mean difference [SMD]=-0.65, 95% credibility intervals [CrI;-1.25, -0.06]), low-dose TXA (SMD = -0.58, 95% CrI [-0.92, -0.25]), and high-dose TXA (SMD = -0.70, 95% CrI [-1.04, -0.36]) were more effective than the respective placebos in reducing intraoperative blood loss. Low-dose TXA (SMD = -1.90, 95% CrI [-3.32, -0.48]) and high-dose TXA (SMD = -2.31, 95% CrI [-3.75, -0.87]) had less postoperative blood loss. Low-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) and high-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) significantly reduced total blood loss. However, only high-dose TXA (SMD = -2.07, 95% CrI [-3.26, -0.87]) was more effective in reducing the amount of transfusion, and was significantly superior to low-dose TXA in this regard (SMD = -1.67, 95% CrI [-3.20, -0.13]). Furthermore, aprotinin (odds ratio [OR] = 0.16, 95% CrI [0.05, 0.54]), EACA (OR = 0.46, 95% CrI [0.22, 0.97]) and high dose of TXA (OR = 0.34, 95% CrI [0.19, 0.58]) had a significant reduction in transfusion rates. Antifibrinolytics did not show a significantly increased risk of postoperative thrombosis. Results of ranking probabilities indicated that high-dose TXA had the greatest efficacy and a relatively high safety level.@*CONCLUSIONS@#The antifibrinolytic agents are able to reduce perioperative blood loss and transfusion requirement during spine surgery. And the high-dose TXA administration might be used as the optimal treatment to reduce blood loss and transfusion.

Correlation of Glypican-4 Level with Basal Active Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes Mellitus

BACKGROUND: Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. METHODS: Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level. RESULTS: The subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors. CONCLUSION: GPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels.

Evaluation of factors associated with drug-induced liver injury using electronic medical records

The causes and attributing factors of drug-induced liver injury (DILI) remain unclear as a result of exclusion-based diagnosis and low incidence. The aim of this study was to explore and evaluate potential drug-related causes and factors associated with DILI. Using electronic medical records (EMR) from the Seoul National University Bundang Hospital from 2003 to 2014, patients with DILI events were identified based on liver function test results. All patients with hepatic or biliary diseases were excluded. Patient characteristics, including demographics, clinical patterns, and severity of DILI were summarized and their associations were evaluated. Drugs frequently prescribed to patients exhibiting DILI within the month before their first DILI event compared to the total patient population were identified and the probabilities of hepatotoxicity associated with their use were assessed through examination of available reports. Among the 1,835 patients with laboratory test results, 1,023 were male and 1,053 were 65 years of age or older. Moderate DILI was dominant in older or male patients and cholestatic DILI tended to be more frequently identified in older patients of either sex. Cytarabine was the most frequently prescribed drug in DILI patients, followed by aprotinin and dopamine. Among the 30 most frequently prescribed drugs in DILI patients, 15 (50%) were identified as known hepatotoxic agents. In conclusion, this study evaluated differences in features of DILI among groups based on demographics and explored candidate drugs with possible associations with DILI, which has potential value reflecting real-world clinical practice.

Efficacy of tranexamic acid as compared to aprotinin in open heart surgery in children.

Background: Coagulopathy is a major issue in children undergoing high‑risk pediatric cardiac surgery. Use of anti‑fibrinolytics is well documented in adults, but recently there are questions raised about safety and effectiveness of their use on routine use. Tranexamic acid is a potent anti‑fibrinolytic, but its role is not fully understood in children. This study aims to study the benefits tranexamic acid in controlling postoperative bleeding in pediatric cardiac surgical patients. Methods and Results: Fifty consecutive children who underwent cardiac surgery were randomized prospectively to receive either aprotinin (Group A; n = 24) or tranexamic acid (Group B; n = 26) from September 2009 to February 2010 were studied. Primary end points were early mortality, postoperative drainage, reoperation for bleeding and complications. Mean age and body weight was smaller in Group A (Age: 48.55 vs. 64.73 months; weight 10.75 vs. 14.80 kg) respectively. Group A had more cyanotic heart disease than Group B (87.5% vs. 76.92%). Mean cardiopulmonary bypass time (144.33 vs. 84.34 min) and aortic cross‑clamp time (78.5 vs. 41.46 min) were significantly higher in group A. While the blood and products usage was significantly higher in Group A, there was no difference in indexed postoperative drainage in first 4, 8 and 12 h and postoperative coagulation parameters. Mean C‑reactive protein was less in Group A than B and renal dysfunction was seen more in Group A (25% vs. 7.6%). Mortality in Group A was 16.66% and 7.6% in Group B. Conclusion: Anti‑fibrinolytics have a definitive role in high‑risk children who undergo open‑heart surgery. Tranexamic acid is as equally effective as aprotinin with no additional increase in morbidity or mortality. Ultramini Abstract: Coagulopathy has been a major issue in pediatric cardiac surgery, and anti‑fibrinolytics have been used fairly regularly in various settings. This study aims to evaluate the efficacy of tranexamic acid as compared against that of aprotinin in a randomized model. Tranexamic acid proves to be equally effective with less toxicity with no added mortality.

Antifibrinolytics in cardiac surgery.

Cardiac surgery exerts a significant strain on the blood bank services and is a model example in which a multi-modal blood-conservation strategy is recommended. Significant bleeding during cardiac surgery, enough to cause re-exploration and/or blood transfusion, increases morbidity and mortality. Hyper-fibrinolysis is one of the important contributors to increased bleeding. This knowledge has led to the use of anti-fibrinolytic agents especially in procedures performed under cardiopulmonary bypass. Nothing has been more controversial in recent times than the aprotinin controversy. Since the withdrawal of aprotinin from the world market, the choice of antifibrinolytic agents has been limited to lysine analogues either tranexamic acid (TA) or epsilon amino caproic acid (EACA). While proponents of aprotinin still argue against its non-availability. Health Canada has approved its use, albeit under very strict regulations. Antifibrinolytic agents are not without side effects and act like double-edged swords, the stronger the anti-fibrinolytic activity, the more serious the side effects. Aprotinin is the strongest in reducing blood loss, blood transfusion, and possibly, return to the operating room after cardiac surgery. EACA is the least effective, while TA is somewhere in between. Additionally, aprotinin has been implicated in increased mortality and maximum side effects. TA has been shown to increase seizure activity, whereas, EACA seems to have the least side effects. Apparently, these agents do not differentiate between pathological and physiological fibrinolysis and prevent all forms of fibrinolysis leading to possible thrombotic side effects. It would seem prudent to select the right agent knowing its risk-benefit profile for a given patient, under the given circumstances.

Fibrinógeno-trombina como tratamiento puente en un caso de hemoptisis masiva / Fibrinogen-thrombin as bridge therapy in massive hemoptysis

Se presenta el caso de una paciente joven con hemoptisis masiva por tuberculosis que no pudo ser controlada de forma efectiva con la inserción de un catéter Fogarty por un fibrobroncoscopio. Ante esto y el alto riesgo de asfixia o desangramiento, se decidió infundir fibrinógeno-trombina a través de un catéter, introducido por el fibrobroncoscopio; con esto se logró controlar el sangrado, intubarla con un tubo orotraqueal de doble luz y estabilizarla para remitirla a otra institución, donde fue sometida a lobectomía y se le proporcionó tratamiento antituberculoso. La infusión de fibrinógeno-trombina podría considerarse como una opción terapéutica transitoria, de tipo puente, mientras se practica el manejo definitivo.

This article presents the case of a young woman with massive hemoptysis (1,000 mL in 6 hours) due to tuberculosis, which could not be controlled by insertion of a Fogarty catheter through a fiber-optic bronchoscope. Because of asphyxia and persistent bleeding risk we instilled fibrinogen-thrombin through a fiber-optic bronchoscope inserted catheter, achieving bleeding cessation and permitting the placing of a double-lumen oro-tracheal tube. Later on, the patient underwent lobectomy and anti-tuberculosis treatment. The fibrinogen-thrombin could be considered as a bridge, transitory measure for massive hemoptysis, while definitive treatment could be established.

Analysis and Management of Complications of Open Reduction and Medpor Insertion through Transconjunctival Incision in Blowout Fractures

PURPOSE: In accordance to an increased interest in facial appearance and the popularization of computed tomography scanning, the number of diagnosis and treatment of blowout fractures has been increased. The purpose of this article is to review pure blowout fracture surgery through transconjunctival incision focusing on complications and their management. METHODS: In this retrospective study, 583 patients, who had been treated for pure blowout fracture through transconjunctival incision from 2000 to 2009, were evaluated. Their hospital records were reviewed according to their sex, age, fracture site, preoperative presentations, time interval between trauma and surgery, and postoperative complications. RESULTS: According to postoperative follow-up results, there were early complications that included wound dehiscence and infection (0.2%), hematoma (insomuch as extraocular movement is limited) (0.7%), lacriminal duct injury (0.5%), and periorbital nerve injury (0.7%). In addition, there were late complications that lasted more than 6 months, that included persistent diplopia (1.7%), extraocular movement limitation (0.9%), enophthalmos (1.0%), periorbital sensation abnormalities (1.0%), and entropion (0.5%). CONCLUSION: We propose the following guidelines for prevention of postoperative complications: layer by layer closure; bleeding control with the epinephrine gauzes, Tachocomb, and Tisseel; conjunctival incision 2 to 3 mm away from punctum; avoidance of excessive traction; performing surgical decompression and high dose corticosteroid therapy upon confirmation of nerve injury; atraumatic dissection and insertion of Medpor Barrier implant after securing a clear view of posterior ledge; using Medpor block stacking technique and BioSorb FX screw fixation; performing a complete resection of the anterior ethmoidal nerve during medial wall dissection; and making an incision 2 to 3 mm below the tarsal plate.

Analysis and Management of Complications of Open Reduction and Medpor Insertion through Transconjunctival Incision in Blowout Fractures

PURPOSE: In accordance to an increased interest in facial appearance and the popularization of computed tomography scanning, the number of diagnosis and treatment of blowout fractures has been increased. The purpose of this article is to review pure blowout fracture surgery through transconjunctival incision focusing on complications and their management. METHODS: In this retrospective study, 583 patients, who had been treated for pure blowout fracture through transconjunctival incision from 2000 to 2009, were evaluated. Their hospital records were reviewed according to their sex, age, fracture site, preoperative presentations, time interval between trauma and surgery, and postoperative complications. RESULTS: According to postoperative follow-up results, there were early complications that included wound dehiscence and infection (0.2%), hematoma (insomuch as extraocular movement is limited) (0.7%), lacriminal duct injury (0.5%), and periorbital nerve injury (0.7%). In addition, there were late complications that lasted more than 6 months, that included persistent diplopia (1.7%), extraocular movement limitation (0.9%), enophthalmos (1.0%), periorbital sensation abnormalities (1.0%), and entropion (0.5%). CONCLUSION: We propose the following guidelines for prevention of postoperative complications: layer by layer closure; bleeding control with the epinephrine gauzes, Tachocomb, and Tisseel; conjunctival incision 2 to 3 mm away from punctum; avoidance of excessive traction; performing surgical decompression and high dose corticosteroid therapy upon confirmation of nerve injury; atraumatic dissection and insertion of Medpor Barrier implant after securing a clear view of posterior ledge; using Medpor block stacking technique and BioSorb FX screw fixation; performing a complete resection of the anterior ethmoidal nerve during medial wall dissection; and making an incision 2 to 3 mm below the tarsal plate.

Rol del sistema kallicreína kinina y su interrelación con sistemas vasoactivos durante la preñez / Role of the kallikrein kinin system and its interrelationship with vasoactive systems in pregnancy

La hiperfiltración glomerular y el aumento de la reabsorción de sodio son factores fundamentales para el desarrollo de la unidad feto placentaria. Dichos factores resultan de adaptaciones hemodinámicas y renales en las que participan sistemas vasoactivos. Se pudo demostrar en ratas que la activación del sistema kallicreína kinina (SKK) precede a la instalación de la hiperfiltración glomerular, dado que su inhibición por aprotinina previene el aumento del filtrado glomerular. Además, la inhibición individual o asociada de los efectores específicos del SKK, las prostaglandinas (PGs) y el óxido nítrico (ON), confirman la dependencia del filtrado glomerular del SKK durante la preñez. Encontramos también que el sistema renina angiotensina (SRA) participa en la generación de la hiperfiltración glomerular dado que ésta es afectada por la administración de bloqueantes del SRA. La inhibición máxima sobre el pico de hiperfiltración se obtuvo con el bloqueo de ambos sistemas (SKK y SRA). Además, estrategias para alterar la hiperfiltración glomerular y la reabsorción de sodio de la preñez evidenciaron alteraciones en el desarrollo de la unidad feto placentaria, menor número de crías, mayor cantidad de reabsorciones intrauterinas y retardo en el crecimiento. El tratamiento combinado de inhibidores del SKK asociados a bloqueantes del SRA o de óxido nítrico mostraron los mayores efectos. En consecuencia, demostramos que el SKK juega un rol central en los fenómenos de adaptación que acompañan la preñez normal. La interrelación del SKK con varios sistemas vasoactivos parecería formar una red que participa en las adaptaciones hemodinámicas para un adecuado desarrollo de la gestación y de la unidad feto-placentaria.

Glomerular hyperfiltration and increased sodium reabsorption are key factors for the development of the fetus and placenta in pregnancy. These adjustments result from hemodynamic and renal factors involving vasoactive systems. It was demonstrated in rats that activation of KKS precedes the installation of glomerular hyperfiltration as aprotinin prevents the increase in glomerular filtration. In addition, individual or associated inhibition of specific kallikrein kinin system effectors, prostaglandins (PGs) and nitric oxide (NO), confirm the glomerular filtration rate dependence of KKS during pregnancy. It was also found that the renin-angiotensin system (RAS) contributes to glomerular hyperfiltration as this is affected by the administration of RAS blockers. The peak of hyperfiltration maximum inhibition was obtained by the blockade of both systems (KKS and RAS). In addition, strategies used to alter the glomerular hyperfiltration and increased sodium reabsorption during pregnancy, showed abnormalities in the development of the fetus and placenta, fewer offspring, more fetus resorptions and intrauterine growth retardation. KKS inhibitors associated with RAS or nitric oxide blockers showed the greatest impact. As a consequence, it was demonstrated that KKS plays a central role in the adaptation phenomenom that accompanies normal pregnancy. The interplay of KKS with several vasoactive systems, seem to arrange a network involved in the hemodynamic adaptations to allow the proper development of pregnancy and the fetus and placenta.

Comparison of three dose regimens of aprotinin in infants undergoing the arterial switch operation.

To determine the most effective dose regimen of aprotinin for infants undergoing arterial switch operation for transposition of the great arteries in reducing blood loss and postoperative packed red blood cell (PRBC) requirements. A total of 24 infants scheduled for arterial switch operation for transposition of the great arteries were included in the study. The infants were randomly assigned to one of the three groups. Group I (n = 8) patients received aprotinin in a dose of 20,000 kallikrein inhibiting units (KIU)/kg after induction of anesthesia, 20,000 KIU/kg was added to the pump prime, and 20,000 KIU/kg/hour infusion for three hours after weaning from bypass; group II (n = 8) patients received aprotinin 30,000 KIU/kg after induction of anesthesia, 30,000 KIU/kg was added to the pump prime and 30,000 KIU/Kg/hour infusion for three hours after weaning from bypass; group III patients (n = 8) received aprotinin 40,000 KIU/kg after induction of anesthesia, 40,000 KIU/kg was added to the pump prime and 40,000 KIU/kg/hour infusion for three hours after weaning from bypass. Postoperatively, the cumulative hourly blood loss and PRBC requirements were noted up to 24 hours from the time of admission in the intensive care unit (ICU). Use of blood and blood products were noted. Coagulation parameters such as hematocrit, activated clotting time (ACT), fibrinogen, prothrombin time (PT), international normalized ratio (INR), platelet count, and fibrin degradation products (FDP) were investigated before cardiopulmonary bypass (CPB), after protamine administration, and at four hours postoperatively in the ICU. The number of infants reexplored for increased mediastinal drainage was recorded. Renal functions were monitored by measuring urine output (hourly) and serum urea (mg%) and serum creatinine (mg%) at 24 hours. The sternal closure time was comparable in all the three groups. Cumulative blood loss (ml/kg/24 hours) was greatest in group I (17.30 ± 7.7), least in group III (8.14 ± 3.17), whereas in group II, it was 16.45 ± 6.33 (P = 0.019 group I versus group III; (P = 0.036 group II versus group III). Postoperative PRBC requirements were significantly less in high dose group III (P = 0.008, group I versus III; p = 0.116, group II versus group III) . Tests for coagulation performed at four hours postoperatively, viz. ACT, PT, INR, FDP, and platelets were comparable in the three groups. Urine output on CPB was comparable in all the groups. Serum urea and creatinine showed no significant difference between the three groups twenty four hours postoperatively. Aprotinin dosage regimen of 40,000 KIU/kg at induction, in CPB prime and postoperatively for three hours was most effective in reducing postoperative blood loss and PRBC transfusion requirements. Aprotinin does not have any adverse effect on renal function.

Avaliação da aprotinina na redução da resposta inflamatória sistêmica em crianças operadas com circulação extracorpórea / Assessment of aprotinin in the reduction of inflammatory systemic response in children undergoing surgery with cardiopulmonary bypass

OBJETIVO: Avaliar se a aprotinina em altas doses hemostáticas pode reduzir o processo inflamatório após circulação extracorpórea (CEC) em crianças. MÉTODOS: Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, o fármaco foi administrado antes e durante a CEC. A resposta inflamatória sistêmica e disfunções hemostática e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com P<0,05. RESULTADOS: Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no CTIP e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24 h pós-operatório, no Grupo Controle. As perdas sanguíneas foram semelhantes nos dois grupos. No grupo Aprotinina surgiu leucopenia significativa, em CEC, seguida de leucocitose. Fator de necrose tumoral alfa (TNF-α), Interleucinas (IL)-6, IL-8, IL-10, proporção IL-6/IL-10 não apresentaram diferenças marcantes intergrupos. A proporção IL-6/IL-10 PO aumentou no grupo Controle. Não houve complicações com o uso da aprotinina. CONCLUSÃO: Nesta casuística, a Aprotinina em altas doses hemostáticas não minimizou as manifestações clínicas e os marcadores séricos de resposta inflamatória sistêmica.

OBJECTIVE: To evaluate if the hemostatic high-dose aprotinin seems to reduce the inflammatory process after extracorporeal circulation (ECC) in children. METHODS: A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered before and during ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. RESULTS: The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of CONCLUSION: In this series, hemostatic high-dose aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory systemic response.

Long-term prognostic value of analysis of sympathetic drive by myocardial 123I-metaiodobenzylganidine scintigraphy in chronic heart failure / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The over increase of sympathetic drive in chronic heart failure (CHF) is with main responsibility for the deterioration and mortality of the disease. Myocardial (123)I-metaiodobenzylganidine (MIBG) scintigraphy is a non-invasive convenient method to assess sympathetic dysfunction in patients with CHF. The aim of the study was to detect if sympathetic antidrive analysed through myocardial MIBG scintigraphy plays a crucial role in long-term prognosis in CHF.</p><p><b>METHODS</b>Sixty-four enrolled patients underwent myocardial MIBG scintigraphy, and their plasma concentration of brain natriuretic peptide (BNP), myocardial contractile reserve (MCR), rest left ventricular ejection fraction (rest LVEF) and New York Heart Association (NYHA) function class were assessed. They were separated into groups according to median of above parameters. Endpoint was cardiac death and it was recorded in each group during average 54 months' follow-up.</p><p><b>RESULTS</b>At the end of follow-up, group with lower ratio of heart/mediastinum (H/M) had more death events (P = 0.001), and its BNP level was higher and MCR level was lower (P = 0.003 and 0.001, respectively); but its rest LVEF and NYHA function class were not significantly different. H/M, MCR and BNP correlated closely with death (P = 0.000, 0.000 and 0.001, respectively). Among the three indicators the death risk ratio (RR) of H/M was 4.66, more than MCR and BNP (1.88 and 2.56, respectively). However, rest LVEF and NYHA function class did not correlate with death (P = 0.652 and 0.384, respectively). The group with lower H/M and MCR, higher BNP had much more death than that with higher H/M and MCR, lower BNP, the RR being 12.8.</p><p><b>CONCLUSIONS</b>Myocardial MIBG scintigraphy is a long-term prognostic marker in CHF. BNP, MCR are also excellent predictors of long-term prognosis in CHF, but not stronger than myocardial MIBG scintigraphy. If the three indicators were joined together, the prediction would become most powerful. Rest LVEF and NYHA have no significance in long-term prediction of CHF.</p>

Blood hibernation: a novel strategy to inhibit systemic inflammation and coagulation induced by cardiopulmonary bypass / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass (CPB), these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 (PGE1), and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB.</p><p><b>METHODS</b>Thirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB (32 degrees C). Each group received respectively the following treatments: (1) inhalation of 40 ppm nitric oxide; (2) intravenous infusion of 20 ng x kg(-1) x min(-1) of PGE1; (3) 80,000 kallikrein inhibitor units (KIU)/kg of aprotinin; (4) the combination of all three agents (blood hibernation group); and (5) no treatment (control group) during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB.</p><p><b>RESULTS</b>As compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group (P < 0.05 versus other four groups after CPB). Plasma prothrombin fragment (PTF)1+2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group (P < 0.05 versus other four groups at 6 and 12 hours after CPB). Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact.</p><p><b>CONCLUSION</b>Blood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.</p>

Aprotinina não influencia troponina I, NTproBNP e função renal em crianças operadas com circulação extracorpórea / High-dose aprotinin does not affect troponin I, N-Terminal pro-B-type natriuretic peptid and renal function in children submitted to surgical correction with extracorporeal circulation

Objetivo: Avaliar se o uso de aprotinina em altas doses hemostáticas pode influenciar as funções miocárdicas, renais e metabólicas em crianças operadas com circulação extracorpórea (CEC). Métodos: Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada antes e durante a CEC. As disfunções miocárdicas e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com P<0,05. Resultados: Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no Centro de Terapia Intensiva Pediátrica (CTIP) e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24h PO, no Grupo Controle. As perdas sanguíneas foram semelhantes nos dois grupos. Os marcadores troponina I cardíaca (cTnI), fração MB da creatinofosfoquinase (CKMB), transaminase glutâmico-oxalacética (TGO) e fração amino-terminal do peptídio natriurético tipo B (NT-proBNP) não apresentaram diferenças marcantes inter-grupos. A lactatemia e acidose metabólica pós-CEC foi maior no Grupo Aprotinina. Não houve complicações tromboembólicas, neurológicas ou de hipersensibilidade com o uso da aprotinina. Conclusão: A aprotinina em altas doses não influenciou significativamente nos marcadores séricos troponina I e NTproBNP e de função renal, porém foi associado com maior hemodiluição, lactatemia e acidose metabólica.

Objective: To evaluate if the use of hemostatic high-dose aprotinin seems influence to myocardial, renal and metabolic functions in children submitted to surgical correction with extracorporeal circulation (ECC). Material and Methods A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered before and during ECC and the myocardial and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. Results: The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the pediatric postoperative intensive care unit (ICU) and length of hospitalization, or regarding the use of inotropic drugs and renal function. The partial arterial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) was significantly reduced 24h after surgery in the Control Group. Blood loss was similar for both groups. Cardiac troponin I (cTnI), creatine kinase MB fraction (CKMB), serum glutamic-oxaloacetic transaminase (SGOT) and the aminoterminal fraction of natriuretic peptide type B (NT-proBNP) did not differ significantly between groups. Post-ECC blood lactate concentration and metabolic acidosis was more intense in the Aprotinin Group. There were no complications with the use of aprotinin. Conclusion: High-dose aprotinin did not significant influence in serum markers troponin I, NT-proBNP and renal function, but did associated with hemodilution, blood lactate concentration and metabolic acidosis more intense.

Aprotinina preserva plaquetas em crianças com cardiopatia congênita acianogênica operadas com circulação extracorpórea? / Does aprotinin preserve platelets in children with acyanogenic congenital heart disease undergone surgery with cardiopulmonary bypass?

OBJETIVO: Avaliação dos efeitos hemostáticos e plaquetários em crianças submetidas a correção de cardiopatias congênitas acianogênicas com circulação extracorpórea que receberam aprotinina. MÉTODOS: Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas a correção de cardiopatia congênita acianogênica, com circulação extracorpórea (CEC) e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada antes e durante a CEC. A disfunção hemostática foi analisada por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com P<0,05. RESULTADOS: Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no centro de terapia intensiva pediátrica e hospitalar, nem quanto ao uso de inotrópicos e função renal. Ocorreu preservação da concentração plaquetária com a Aprotinina, enquanto no grupo Controle houve plaquetopenia desde o início da CEC. As perdas sanguíneas foram semelhantes nos dois grupos. Não houve complicações com o uso da Aprotinina. CONCLUSÃO: A Aprotinina preservou quantitativamente as plaquetas em crianças com cardiopatia congênita acianogênica

OBJECTIVE: Evaluation of the hemostatic and platelets effects in children with acyanogenic congenital heart disease undergone on-pump surgery who received aprotinin. METHODS: A prospective randomized study was performed on children aged 30 days to 4 years who had undergone correction of acyanogenic congenital heart disease using cardiopulmonary bypass (CPB) and were divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered before and during CPB and the hemostatic dysfunction was analyzed by clinical and biochemical markers. Differences were considered to be significant when P<0.05. RESULTS: The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug presented no benefit regarding time of mechanical pulmonary ventilation, stay in the postoperative intensive care unit and hospital, or regarding the use of inotropic drugs and renal function. Platelet concentration was preserved with the use of Aprotinin, whereas thrombocytopenia occurred in the Control Group since the initiation of CPB. Blood loss was similar for both groups. There were no complications with the use of Aprotinin. CONCLUSION: Aprotinin quantitatively preserved the blood platelets in children with acyanogenic congenital heart disease

Aprotinin Inhibits Vascular Smooth Muscle Cell Inflammation and Proliferation via Induction of HO-1

Aprotinin is used clinically in cardiopulmonary bypass surgery to reduce transfusion requirements and the inflammatory response. The mechanism of action for the anti-inflammatory effects of aprotinin is still unclear. We examined our hypothesis whether inhibitory effects of aprotinin on cytokine-induced inducible nitric oxide synthase (iNOS) expression (IL-1beta plus TNF-alpha), reactive oxygen species (ROS) generation, and vascular smooth muscle cell (VSMC) proliferation were due to HO-1 induction in rat VSMCs. Aprotinin induced HO-1 protein expression in a dose-dependent manner, which was potentiated during inflammatory condition. Aprotinin reduced cytokine mixture (CM)-induced iNOS expression in a dose dependent manner. Furthermore, aprotinin reduced CM-induced ROS generation, cell proliferation, and phosphorylation of JNK but not of P38 and ERK1/2 kinases. Aprotinin effects were reversed by pre-treatment with the HO-1 inhibitor, tin protoporphyrin IX (SnPPIX). HO-1 is therefore closely involved in inflammatory-stimulated VSMC proliferation through the regulation of ROS generation and JNK phosphorylation. Our results suggest a new molecular basis for aprotinin anti-inflammatory properties.

Heme Oxygenase-1 Induced by Aprotinin Inhibits Vascular Smooth Muscle Cell Proliferation Through Cell Cycle Arrest in Hypertensive Rats

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.

The Comparison of Parathyroid Hormone Degradation Effect by Various Protease Inhibitors in Blood Specimen / 대한진단검사의학회지

BACKGROUND: The objective of this study was to evaluate the role of proteases on the degradation of parathyroid hormone (PTH) in blood samples. METHODS: Protease inhibitors with specificity against serine proteases (aprotinin), cysteine proteases (E-64), serine and cysteine proteases (leupeptin), metalloproteases (EDTA), or a protease inhibitor cocktail with a broad spectrum of inhibitory activity were added to blood samples. After storage at room temperature (0-48 hr), PTH levels were measured. RESULTS: PTH levels in samples with the protease inhibitor cocktail did not change significantly after 48 hr of storage at room temperature, but the average PTH levels decreased by 40.7% and 20.1%, in samples stored at room temperature and stored at 4degrees C without protease inhibitors, respectively. PTH levels in samples with leupeptin were stable for up to 24 hr. After 48 hr, the mean PTH levels decreased by 17.1%, 16.0%, 26.2%, and 32.1%, with 500 KIU/mL aprotinin, 100 micro mol/L leupeptin, 10 micro mol/L E-64, and 10 micro mol/L EDTA, respectively, in the samples stored at room temperature. CONCLUSIONS: The decrease in PTH levels in blood samples seemed to be due to the degradation of PTH by proteases. Various proteases, including especially serine proteases, would act together to degrade PTH in blood specimen. The PTH degradation may be inhibited in blood specimen with protease inhibitor cocktail.