Ac Nogueira

Potential role of poly(adenosine 5'-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock.

Objective:Sepsis is associated with increased production of superoxide and nitric oxide, with consequent peroxynitrite generation. Cardiodepression is induced in the heart during oxidative stress associated with septic shock. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) polymerase (PARP), with subsequent loss of myocardial contractile function. The aim of the study was to investigate whether cardiodepression found in septic patients is associated with plasma markers of myocardial necrosis and with myocardial PARP activation. Design:Prospective and observational study. Setting:University hospital intensive care unit for clinical and surgical patients. Patients:Twenty-five patients older than 18 yrs presenting with severe sepsis or septic shock. Patients with history of chronic heart failure, cancer, coronary artery disease, diabetes, or acquired immune deficiency syndrome were excluded. Interventions:Patients were followed for 28 days, and biochemical and hemodynamic data were collected on days 1, 3, and 6 of sepsis. The groups were survivors and nonsurvivors, defined only after the end of clinical patient evolution. Heart sections from patients who died were analyzed with hematoxylin-eosin and Picro Sirius-Red immunostaining and with electron microscopy. Measurements and Main Results:The study population included 25 individuals, of whom 12 (48%) died during the 6 days of follow-up. The initial data of the inflammation marker C-reactive protein and Acute Physiologic and Chronic Health. Evaluation severity were similar in both groups (nonsurvivors, 26 ± 2; survivors, 24 ± 5; NS). Overall, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histologic analysis of heart sections showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial cristae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP, was demonstrated in septic hearts. There was a positive correlation between PAR staining densitometry and troponin I (r2 = 0.73; p < .05), and the correlation of PAR staining densitometry and left ventricular systolic stroke work index was r2 = 0.33 (p = .0509). Conclusion:There is significant PARP activation in the hearts of septic patients with impaired cardiac function. We hypothesize that PARP activation may be partly responsible for the cardiac depression seen in humans with severe sepsis.

Endotoxemic myocardial dysfunction: subendocardial collagen deposition related to coronary driving pressure.

ABSTRACT Sepsis impairs the autoregulation of myocardial microcirculatory blood flow, but whether this impairment is correlated with myocardial remodeling is unknown. This study investigated the role of coronary driving pressure (CDP) as a determinant of microcirculatory blood flow and myocardial fibrosis in endotoxemia and sepsis. The study is composed of two parts: a prospective experimental study and an observational clinical study. The experimental study was performed on male Wistar rats weighing 300 to 320 g. Endotoxemia was induced in rats by lipopolysaccharide (LPS) injection (10 mg·kg−1 intraperitoneally). Hemodynamic evaluation was performed 1.5 to 24 h after LPS injection by measuring the mean arterial pressure, CDP, left ventricular end-diastolic pressure, dP/dtmax, and dP/dtmin. Microspheres were also infused into the left ventricle to measure myocardial blood flow, and myocardial tissue was histologically assessed to analyze collagen deposition. The CDP, mean arterial pressure, and myocardial blood flow were reduced by 55%, 30%, and 70%, respectively, in rats 1.5 h after LPS injection compared with phosphate buffer saline injection (P < 0.05). The CDP was significantly correlated with subendocardial blood flow (r = 0.73) and fibrosis (r = 0.8). Left ventricular function was significantly impaired in the LPS-treated rats, as demonstrated by dP/dtmax (6,155 ± 455 vs. 3,746 ± 406 mmHg·s−1, baseline vs. LPS; P < 0.05) and dP/dtmin (−5,858 ± 236 vs. -3,516 ± 436 mmHg·s−1, baseline vs. LPS; P < 0.05). The clinical study was performed on 28 patients with septic shock analyzed for CDP. The CDP data and histological slices were collected from septic patients. In addition, the clinical data demonstrated fibrosis and 45% CDP reduction in nonsurvivors compared with survivors. In conclusion, the left ventricular subendocardial blood flow was positively correlated with CDP, and higher CDP was negatively correlated with myocardial collagen deposition. Thus, early reductions in myocardial blood flow and CDP facilitate late myocardial fibrosis in rats and likely in humans.

Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability

Free fatty acids (FFAs) have been shown to produce alteration of heart rate variability (HRV) in healthy and diabetic individuals. Changes in HRV have been described in septic patients and in those with hyperglycemia and elevated plasma FFA levels. We studied whether sepsis-induced heart damage and HRV alteration are associated with plasma FFA levels in patients. Thirty-one patients with sepsis were included. The patients were divided into two groups: survivors (n = 12) and nonsurvivors (n = 19). The following associations were investigated: (a) troponin I elevation and HRV reduction; and (b) clinical evolution and HRV index, plasma troponin, and plasma FFA levels. Initial measurements of C-reactive protein and gravity Acute Physiology and Chronic Health Evaluation scores were similar in both groups. Overall, an increase in plasma troponin level was related to increased mortality risk. From the first day of study, the nonsurvivor group presented a reduced left ventricular stroke work systolic index and a reduced low frequency (LF) that is one of the HRV indexes. The correlation coefficient for LF values and troponin was r2 = 0.75 (P < 0.05). All patients presented elevated plasma FFA levels on the first day of the study (5.11 ± 0.53 mg/ml), and this elevation was even greater in the nonsurvivor group compared with the survivors (6.88 ± 0.13 vs 3.85 ± 0.48 mg/ml, respectively; P < 0.05). Cardiac damage was confirmed by measurement of plasma troponin I and histological analysis. Heart dysfunction was determined by the left ventricular stroke work systolic index and the HRV index in nonsurvivor patients. A relationship was found between plasma FFA levels, Lfnu index, troponin levels, and histological changes. Plasma FFA levels emerged as a possible cause of heart damage in sepsis.

Diabetes e gravidez: aspectos clínicos e perinatais

Durante a gestacao, as pacientes que nao se ajustam as alteracoes metabolicas proprias da gravidez e aquelas com alteracoes previas no metabolismo dos carboidratos apresentam um aumento significativo da morbimortalidade perinatal. Visando contribuir para o aperfeicoamento da conduta pre-natal na gestante diabetica, os autores estudaram retrospectivamente 60 casos de gravidez associada ao diabetes, atendidos no Departamento de Ginecologia e Obstetricia da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo. A amostra estudada foi dividida em dois grupos: com controle pre-natal segundo o protocolo para a gestante diabetica e encaminhadas ao Servico para resolucao da gravidez. No grupo com pre-natal adequado nao ocorreram obitos fetais ou neonatais e as complicacoes neonatais observadas estiveram associadas principalmente com a prematuridade. No grupo encaminhado para resolucao e sem seguimento pre-natal adequado foram diagnosticados 3 casos de malformacao fetal multipla, 1 caso de hipoglicemia neonatal grave, 3 casos de prematuridade, 1 caso de retardo de crescimento intra-uterino, 1 caso de macrossomia fetal e ainda um caso de obito neonatal. A comparacao entre os grupos estudados demonstra claramente os beneficios do controle pre-natal adequado para a gestante diabetica e expoe tambem a necessidade de uma maior integracao entre a rede periferica regional e os centros de atencao terciaria, permitindo o diagnostico e o encaminhamento precoce de todos os casos de gestacao complicada pelo diabetes.

Is the widening of the QTc associated with mortality in sepsis

The widening of the QTc is a mortality predictor in acute coronary syndromes and cerebral vascular accident.

Acute effect of low-dose corticosteroids on muscle function in patients with severe sepsis and septic shock

The rationale for the use of glucocorticoids in severe sepsis and septic shock can be attributed to well-defined anti-inflammatory and hemodynamic effects recognized for decades. However, with the introduction of corticosteroid therapy for a variety of conditions, it was reported that this treatment could induce a myopathy. Animal studies have confirmed that the administration of high doses of corticosteroid can produce myopathy affecting both ventilatory and peripheral skeletal muscles. Actually, it remains uncertain whether doses of corticosteroid, typically used to manage patients with severe sepsis and septic shock, do in fact cause peripheral and respiratory muscle weakness.