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The idiopathic systemic capillary leak syndrome is characterized by recurrent episodes of hypovolemia, with an unknown cause, presenting as a distributive and hypovolemic shock, due to fluid loss to the extravascular space. We describe a case of a previously healthy seven-year-old boy, who started with prodromal symptoms (abdominal pain, fatigue, nausea), followed by a fluid extravasation phase, with hemoconcentration, hypoproteinemia, and muscular edema in the abdominal wall and lower limbs, accompanied by pain - compartment syndrome. After a couple of days, spontaneous and fast recovery was noted, with clinical and analytic improvement. The inflammatory markers were always normal, and the blood cultures were negative. In this case, it is possible to distinguish the three idiopathic systemic capillary leak syndromes phases, as described in the literature. Although rare, this syndrome can be fatal, and the differential diagnosis with other causes of shock represents a challenge.
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Neonatal capillary leak syndrome (CLS) is a rare, but life-threatening condition following neonatal sepsis or inflammatory injury. The objective of this study was to describe a standardized treatment approach for CLS that improves mortality and neonatal outcomes. A retrospective cohort study of 10 infants born at 22 to 26 weeks of gestation who developed CLS following a significant inflammatory insult was performed. Time to diagnosis and treatment approaches over 2 epochs were recorded and described. In epoch 2, with increased clinical awareness of CLS and implementation of a standardized treatment approach, there was a non-statistically significant decrease in the time to treatment with a significant decrease in mortality. An early targeted treatment approach for neonatal CLS can decrease mortality rates in this highly morbid condition.
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Idiopathic capillary leak syndrome, also known as Clarkson's Disease, is a rare cause of hypovolemic shock that physicians should be aware of. It is characterized by a state of hypovolemia with features of widespread fluid third spacing and poses diagnostic and therapeutic challenges. Here, we present a challenging case of a 36-year-old woman who experienced recurrent episodes of widespread edema and hypovolemic shock symptoms suggestive of capillary leak syndrome. The resuscitative and therapeutic measures employed in managing this disease are described in this case report.
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Purpose: Capillary leak syndrome (CLS) is an intermediary phase between severe acute pancreatitis (SAP) and multiple organ failure. As a result, CLS is of clinical importance for enhancing the prognosis of SAP. Plakophilin2 (PKP2), an essential constituent of desmosomes, plays a critical role in promoting connections between epithelial cells. However, the function and mechanism of PKP2 in CLS in SAP are not clear at present. Methods: We detected the expression of PKP2 in mice pancreatic tissue by transcriptome sequencing and bioinformatics analysis. PKP2 was overexpressed and knocked down to assess its influence on cell permeability, the cytoskeleton, tight junction molecules, cell adhesion junction molecules, and associated pathways. Results: PKP2 expression was increased in the pancreatic tissues of SAP mice and human umbilical vein endothelial cells (HUVECs) after lipopolysaccharide (LPS) stimulation. PKP2 overexpression not only reduced endothelial cell permeability but also improved cytoskeleton relaxation in response to acute inflammatory stimulation. PKP2 overexpression increased levels of ZO-1, occludin, claudin1, ß-catenin, and connexin43. The overexpression of PKP2 in LPS-induced HUVECs counteracted the inhibitory effect of SB203580 (a p38/MAPK signaling pathway inhibitor) on the p38/MAPK signaling pathway, thereby restoring the levels of ZO-1, ß-catenin, and claudin1. Additionally, PKP2 suppression eliminated the enhanced levels of ZO-1, ß-catenin, occludin, and claudin1 induced by dehydrocorydaline. We predicted that the upstream transcription factor PPARγregulates PKP2 expression, and our findings demonstrate that the PPARγactivator rosiglitazone significantly upregulates PKP2, whereas its antagonist GW9662 down-regulates PKP2. Administration of rosiglitazone significantly reduced the increase in HUVECs permeability stimulated by LPS. Conversely, PKP2 overexpression counteracted the GW9662-induced reduction in ZO-1, phosphorylated p38/p38, and claudin1. Conclusion: The activation of the p38/MAPK signaling pathway by PKP2 mitigates CLS in SAP. PPARγactivator rosiglitazone can up-regulate PKP2. Overall, directing efforts toward PKP2 could prove to be a feasible treatment approach for effectively managing CLS in SAP.
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Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.
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Protocolos de Quimioterapia Combinada Antineoplásica , Síndrome de Vazamento Capilar , Linfo-Histiocitose Hemofagocítica , Linfoma Difuso de Grandes Células B , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Síndrome de Vazamento Capilar/etiologia , Síndrome de Vazamento Capilar/diagnóstico , Síndrome de Vazamento Capilar/terapia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vincristina/uso terapêutico , Masculino , Ciclofosfamida/uso terapêutico , Prednisona/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Rituximab/uso terapêutico , Pessoa de Meia-IdadeRESUMO
BACKGROUND: TAFRO syndrome is a rare disorder that causes thrombocytopenia, generalized oedema, fever, organ enlargement, and renal impairment. Few reports have suggested an association with vaccines, and few cases have undergone renal biopsy. TAFRO syndrome is often severe and fatal, and its cause is unknown. We report a case of TAFRO syndrome that occurred after vaccination with the coronavirus disease 2019 (COVID-19) vaccine. CASE PRESENTATION: An 82-year-old woman received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Two weeks later, she was admitted to the hospital with oedema, accompanied with renal failure and thrombocytopenia. After close examination, she was diagnosed with TAFRO syndrome. She was treated with steroids, cyclosporine, and thrombopoietin receptor agonists. The patient was discharged after several months in remission. CONCLUSIONS: Although an incident of TAFRO syndrome after COVID-19 vaccination has been previously reported, this is a rare case in which the patient went into remission and was discharged. A renal biopsy was also performed in this case, which was consistent with previous reports. The favorable treatment course for TAFRO syndrome provides valuable insights.
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Ciclosporina , Humanos , Feminino , Ciclosporina/uso terapêutico , Ciclosporina/efeitos adversos , Idoso de 80 Anos ou mais , Trombocitopenia/induzido quimicamente , Vacina BNT162/efeitos adversos , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , Edema/etiologia , Edema/induzido quimicamente , COVID-19/complicações , COVID-19/prevenção & controleRESUMO
Systemic capillary leak syndrome (SCLS) is a rare entity that is frequently idiopathic or, rarely, associated with infections, autoimmune diseases, drugs, surgery, and cancer. Several cancers can directly cause SCLS, although it is very uncommon as the inaugural presentation of a non-Hodgkin lymphoma. We report a case of SCLS as a paraneoplastic syndrome which revealed a large B-cell lymphoma, a non-Hodgkin lymphoma of B-cell origin.
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Immune checkpoint inhibitors (ICIs) are now being widely used for the treatment of various malignancies, but they have a distinctive set of side effects due to the overactivation of the immune system, which is important to recognize. Capillary leak syndrome (CLS) is a rare but potentially life-threatening side effect of ICIs that causes a significant increase in the permeability of capillaries, leading to the leakage of plasma-containing proteins from these small vessels. This condition results in several clinical features, including edema, hypotension, hypoalbuminemia, and hemoconcentration. Timely recognition and discontinuation of the offending immunotherapy can optimize outcomes. Treatment is focused on supportive care and prompt initiation of immunosuppressants, such as steroids.
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A 44-year-old woman was diagnosed with acute myeloid leukemia (RUNX1::RUNX1T1 translocation) and received induction chemotherapy with idarubicin hydrochloride and cytosine arabinoside. The pneumonia that had been present since admission worsened, and a drug-induced skin rash appeared. On day 17, she presented with respiratory failure and shock, complicated by hemoconcentration and hypoalbuminemia. This was considered capillary leak syndrome due to pneumonia and drug allergy, so she was started on pulse steroid therapy and IVIG, and was intubated on the same day. On day 18, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was started due to worsening blood gas parameters despite ventilatory management. Bronchoalveolar lavage fluid was serous, and both blood and sputum cultures yielded negative. The patient was weaned from VV-ECMO on day 26 as the pneumonia improved with recovery of hematopoiesis. She was disoriented, and a CT scan on day 28 revealed cerebral hemorrhage. Her strength recovered with rehabilitation. After induction chemotherapy, RUNX1::RUNX1T1 mRNA was not detected in bone marrow. The patient received consolidation chemotherapy, and has maintained complete remission. Severe respiratory failure during induction chemotherapy for acute leukemia can be fatal, but VV-ECMO may be lifesaving.
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Síndrome de Vazamento Capilar , Oxigenação por Membrana Extracorpórea , Leucemia Mieloide Aguda , Pneumonia , Insuficiência Respiratória , Humanos , Feminino , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core , Quimioterapia de Indução , Síndrome de Vazamento Capilar/complicações , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapiaRESUMO
We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.
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Síndrome de Vazamento Capilar , Síndrome de DiGeorge , Humanos , Masculino , Criança , Síndrome de Vazamento Capilar/diagnóstico , Barreira Hematoencefálica , Células Endoteliais , Permeabilidade , InflamaçãoRESUMO
Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by hypotensive shock, anasarca, hemoconcentration, and hypoalbuminemia. Despite the life-threatening course of the disease, no treatment strategy has been established. A 68-year-old man presented with hypotensive shock following a prodrome. Based on the characteristic blood test findings, ISCLS was suspected. The patient was resuscitated by administering massive amounts of fluids and inotropic and vasopressor agents. After his blood pressure had stabilized, renal replacement therapy (RRT) was promptly initiated to facilitate the removal of excess fluid, despite the presence of urine output. Typically, ISCLS has three phases: prodromal, leak, and post-leak. Diuresis should be promptly induced during the transition from the leak phase to the post-leak phase to avoid fatal complications such as pulmonary edema. We propose that in patients with ISCLS, early introduction of RRT is recommended if indicated.
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OBJECTIVE: Capillary leak syndrome (CLS) is characterized by severe systemic edema without specific treatment, resulting in a high mortality rate. This study investigated whether there is organ edema in neonatal CLS patients and specific treatment strategies to improve patient prognosis. METHODS: Thirty-seven newborns diagnosed with CLS were included in this study. (1) Routine point-of-care ultrasound (POCUS) was used to identify whether the patients had visceral edema or fluid collection. (2) All patients were treated with 3% NaCl intravenously, and the clinical manifestations, laboratory indices and outcomes were compared before and after treatment. RESULTS: (1) Diffuse severe edema was found in 92.0% of the patients. (2) The POCUS examination revealed that CLS patients exhibited significant visceral edema in addition to diffuse severe edema, which included pulmonary edema in 67.6%, cerebral edema in 37.8%, severe intestinal edema in 24.3%, severe myocardial edema in 8.1%, pericardial effusion in 5.4%, pleural effusion in 29.7% and peritoneal effusion in 18.9%. Two patients (5.45%) had only myocardial edema without other manifestations. (3) Before and after the intravenous injection of 3% NaCl, there were no significant differences in the serum sodium or potassium levels of CLS patients, while the hemoglobin and hematocrit levels were significantly lower after treatment (p < 0.01). Her plasma ALB concentration and arterial pressure returned to normal levels after the treatment was completed. (4) All the patients survived, and no side effects or complications were observed during or after treatment with 3% NaCl. CONCLUSIONS: (1) In addition to diffuse severe edema, visceral edema and effusion are common and important clinical manifestations of neonatal CLS and need to be detected by routine POCUS. (2) The intravenous injection of 3% NaCl is a safe, effective and specific treatment strategy for neonatal CLS, with a survival rate of 100% and no adverse effects.
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Síndrome de Vazamento Capilar , Humanos , Recém-Nascido , Feminino , Síndrome de Vazamento Capilar/diagnóstico por imagem , Síndrome de Vazamento Capilar/terapia , Cloreto de Sódio/uso terapêutico , Estudos Prospectivos , Edema , Volume SanguíneoRESUMO
BACKGROUND: Clarkson's disease is a very rare entity characterised by acute episodes of systemic oedema and severe hypotension associated with paraproteinaemia. Its classical treatment relies on methylxanthine combined with terbutaline. Although this prophylactic therapy reduces the mortality rate, relapses are frequent. Eighty percent of patients with Clarkson's disease present with monoclonal gammopathy of unknown significance (MGUS). The risk of progression to multiple myeloma is 1% per year. CASE DESCRIPTION: Here, we present a 49-year-old woman who suffered multiple such episodes requiring treatment in the intensive care unit. Treatment with terbutaline and theophylline was ineffective. She was diagnosed with multiple myeloma (MM) 8 years after the first of these acute episodes. Antimyeloma treatment with bortezomib and dexamethasone was started, followed by autologous haemopoietic transplantation, with no further acute episodes since then. CONCLUSION: Our case is, to our knowledge, unique because eradication of MM was followed by complete disappearance of acute episodes of capillary leakage. Our case report is also the first to support the use of bortezomib and dexamethasone in this setting. Furthermore, autologous peripheral blood progenitor cell transplantation consolidated the MM stringent complete remission achieving a very long progression-free survival (> 11 years) of both MM and Clarkson's disease.
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Increased vascular permeability is a prevalent feature in a wide spectrum of clinical conditions, but no effective treatments to restore the endothelial barrier are available. Idiopathic systemic capillary leak syndrome (ISCLS) is a life-threatening Paroxysmal Permeability Disorder characterized by abrupt, massive plasma extravasation. This condition serves as a robust model for investigating therapeutic approaches targeting interendothelial junctions. We conducted a single-center, interventional in vitro study at the Referral Center for ISCLS in Italy, involving four diagnosed ISCLS patients, aiming at investigating the effects of FX06, a Bß15-42 fibrin-derived peptide binding to VE-Cadherin, on endothelial barrier exposed to intercritical and acute ISCLS sera. The Transwell Permeability Assay was used to assess the permeability of human umbilical vein endothelial cells (HUVECs) exposed to ISCLS sera with or without FX06 (50 µg/ml). Acute ISCLS serum was also tested in a three-dimensional microfluidic device. Nitric oxide (NO), VE-Cadherin localization, and cytoskeletal organization were also assessed. In two and three-dimensional systems, ISCLS sera increased endothelial permeability, with a more pronounced effect for acute sera. Furthermore, acute sera altered VE-Cadherin localization and cytoskeletal organization. NO levels remained unchanged. FX06 restored the endothelial barrier function by influencing cellular localization rather than VE-Cadherin levels. In conclusion, FX06 prevents and reverts the hyperpermeability induced by ISCLS sera. These preliminary yet promising results provide initial evidence of the in vitro efficacy of a drug targeting the underlying pathophysiological mechanisms of ISCLS. Moreover, this approach may hold potential for addressing hyperpermeability in a spectrum of clinical conditions beyond ISCLS.
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Síndrome de Vazamento Capilar , Humanos , Síndrome de Vazamento Capilar/metabolismo , Células Endoteliais , Permeabilidade Capilar , Endotélio Vascular , Caderinas/metabolismo , ItáliaRESUMO
Capillary leak syndrome (CLS) represents a phenotype of increased fluid extravasation, resulting in intravascular hypovolemia, extravascular edema formation and ultimately hypoperfusion. While endothelial permeability is an evolutionary preserved physiological process needed to sustain life, excessive fluid leak-often caused by systemic inflammation-can have detrimental effects on patients' outcomes. This article delves into the current understanding of CLS pathophysiology, diagnosis and potential treatments. Systemic inflammation leading to a compromise of endothelial cell interactions through various signaling cues (e.g., the angiopoietin-Tie2 pathway), and shedding of the glycocalyx collectively contribute to the manifestation of CLS. Capillary permeability subsequently leads to the seepage of protein-rich fluid into the interstitial space. Recent insights into the importance of the sub-glycocalyx space and preserving lymphatic flow are highlighted for an in-depth understanding. While no established diagnostic criteria exist and CLS is frequently diagnosed by clinical characteristics only, we highlight more objective serological and (non)-invasive measurements that hint towards a CLS phenotype. While currently available treatment options are limited, we further review understanding of fluid resuscitation and experimental approaches to target endothelial permeability. Despite the improved understanding of CLS pathophysiology, efforts are needed to develop uniform diagnostic criteria, associate clinical consequences to these criteria, and delineate treatment options.
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Idiopathic systemic capillary leak syndrome (ISCLS) is a rare condition caused by the extravasation of intravascular fluids and proteins into the interstitial space due to increased vascular endothelium permeability. It is characterized by episodes of hypotension, hypoalbuminemia, and hemoconcentration with generalized edema. Its etiopathogenesis is unknown. However, it is associated with monoclonal gammopathy in more than 80% of cases. There is currently no targeted treatment, and the approach during a crisis is supportive, mainly to control blood pressure, maintain perfusion of vital organs, and prevent complications, such as acute pulmonary edema and organ failure due to ischemia, which are the primary causes of death. We present the case of a 72-year-old man with generalized edema and pleural, pericardial, and peritoneal effusions whose laboratory results showed hypoalbuminemia, hypoproteinemia, and immunoglobulin G kappa monoclonal gammopathy. Other etiologies for severe hypoalbuminemia with anasarca were excluded after an exhaustive complementary study, leading to the diagnosis of ISCLS associated with monoclonal gammopathy. The patient showed progressive clinical improvement with albumin and diuretic therapy. However, they were readmitted to the hospital due to hypotension with multiorgan dysfunction and died a few hours later.
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Desde 1991, há 8 casos relatados de síndrome da fragilidade capilar pulmonar associada à psoríase pustulosa ou eritrodérmica, induzida ou não pelo uso de acitretina ou sirolimus - um dos casos, fatal. Reportamos um caso de psoríase pustulosa de von Zumbusch em paciente feminina com antecedente de várias internações por quadro semelhante, evoluindo nesta ocasião com acometimento pulmonar e resolução com corticosteroide. A paciente não estava em uso de quaisquer medicações previamente descritas como capazes de precipitar o quadro pulmonar (metotrexate e acitretina). Esta é uma complicação rara associada à psoríase, não descrita em pacientes brasileiros até o momento.
Since 1991, eight cases of pulmonary leak capilary syndrome have been described associated with pustular or erythrodermic psoriasis induced or not by the use of acitretin or sirolimus - being one of the cases, fatal. We report the case of a female patient with diagnosed GPP or von Zumbusch and multiple hospitalizations due to such condition. At that time, the condition was evolving with pulmonary onset and resolution with corticosteroids. The patient was not using any previously described medication that could precipitate pulmonary condition (methotrexate and acitretin). This is a rare complication associated with psoriasis which has not been described in Brazilian patients so far.
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Adulto , Feminino , Humanos , Psoríase/complicações , Síndrome do Desconforto Respiratório/etiologia , Tomografia Computadorizada por Raios XRESUMO
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.