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ABSTRACT: Myocardial dysfunction in sepsis may be associated with changes in left ventricular (LV) size. The goal of this study was to evaluate the impact of myocardial dysfunction and changes in LV diameter on hemodynamics and survival in a murine model of sepsis.
C57Bl/6 mice (N = 30) were used. Septic mice (n = 24) had cecal ligation and puncture (CLP) followed by fluid and antibiotic resuscitation and control mice (n = 6) received sham ligation. Echocardiography with a 30-mHz probe was performed at baseline and at frequent predefined time points after CLP. Stroke volume (SV), cardiac output (CO), LV internal diameter in diastole (LVIDd), and fractional shortening (FS) were measured. LV dilation was prospectively defined as an increase in LVIDd ≥ 5% from baseline values. Septic animals were classified as dilators or nondilators.
Among septic animals, 37% were dilators and 63% were nondilators. After CLP, SV and CO decreased early in both groups. With resuscitation, SV and CO improved to a greater extent in dilators than nondilators (for SV, 46.0 ± 8.2 vs 36.1 ± 12.7 μL at 24 h, P = .05; for CO, 20.4 ± 4.8 vs 14.8 ± 6.7 mL/min, P = .04). Survival at 72 h was significantly improved in dilators compared with nondilators (88% vs 40%, P = .01).
In a clinically relevant murine model of sepsis, animals with LV dilation had better cardiovascular performance and increased survival. Our results suggest that LV dilation is associated with improved SV and CO, a pattern resulting in greatly improved survival. These studies highlight the importance of diastolic function in septic shock.
Chest 10/2010; 138(4):848-55. · 5.25 Impact Factor
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ABSTRACT: Current murine models of sepsis do not account for the effects of aggressive fluid resuscitation on hemodynamics and mortality.
Evaluate the impact of fluid resuscitation regimens on cardiovascular performance and survival in a murine model of sepsis.
Mice (n = 90) were made septic by cecal ligation and puncture (CLP), and received antibiotics plus Low, Intermediate, or High fluid resuscitation regimens. Stroke volume (SV), cardiac output (CO), and fractional shortening (FS) were measured by echocardiography at predefined time points.
Baseline echocardiographic measurements were similar in all groups. After CLP, SV and CO decreased early in all groups; High: 57.2 +/- 9.2 to 23.9 +/- 7.2 microL, and 26.8 +/- 4.9 to 13.1 +/- 5.8 ml/min; Intermediate: 52.1 +/- 7.0 to 21.5 +/- 6.6 microL, and 24.9 +/- 4.1 to 11.9 +/- 3.9 ml/min; Low: 54.0 +/- 7.0 to 20.3 +/- 5.6 microL, and 25.8 +/- 4.0 to 11.3 +/- 3.9 ml/min (P < 0.05 for all vs. baseline). With resuscitation there was a dose-dependent improvement in SV and CO (P < 0.05). At 24 h SV and CO were 44.0 +/- 13.8 microL and 20.7 +/- 8.5 ml/min in the High group, 39.8 +/- 12.3 microL and 16.7 +/- 6.5 ml/min in the Intermediate group, and 30.1 +/- 12.4 microL and 14.0 +/- 7.2 ml/min in the Low group. Survival was improved in the High fluid group (75%) compared to the Intermediate (58%) and the Low (35%) resuscitation groups (P < 0.05).
In this model, as in human sepsis, the intensity of fluid resuscitation modulates hemodynamic response and mortality. Incorporation of early and aggressive fluid resuscitation can significantly enhances the clinical relevance of murine models of sepsis.
European Journal of Intensive Care Medicine 01/2009; 35(4):748-54. · 5.17 Impact Factor
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ABSTRACT: Abbott developed the first experimental accessory heart transplant rat model in 1964. This intra-abdominal model required a labor-intensive aortic anastomosis. In 1971, Heron modified the operation by using sutureless cervical vessel anastomoses. Rao and Lisitza developed a femoral heart accessory transplant model in 1985. Our goal was to improve this femoral model for the study of cardiac transplantation between both syngeneic and allogeneic rats.
ACI and Lewis rats weighing 150 to 350 g were used as donors and recipients (n = 12). The left common carotid and left pulmonary arteries were anastomosed to the femoral artery and vein in an end-to-end fashion, respectively. Improved modifications included the use of hemostatic vessel clips, heparinization of both donor and recipient, a ventricular prolene stay-suture for secure graft placement, and transfemoral echocardiography (TFE). Total operative time averaged 61 +/- 12 minutes.
Femoral accessory transplanted hearts (FATHs) allowed easier pulse palpation and access for TFE versus previously described cervical and intra-abdominal models. This modification allows precise detection of acute graft rejection (AGR) and is defined as absent ventricular contraction in the presence of anastomostic patency.
Our new modified technique for heterotopic femoral heart transplantation in rats is a relatively easily learned and reproduced procedure that allows superior allograft access for palpation and improved echocardiographic assessment. Femoral heterotopic heart transplantation remains an effective model for allograft transplantation study.
Journal of Surgical Research 06/2007; 139(2):157-63. · 2.25 Impact Factor
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ABSTRACT: Noninvasive assessment of heterotopic heart transplants using Doppler echocardiography was first described in two patients by Allen at Stanford in 1981. Since then, numerous experiments studying heterotopic heart transplantation in humans and large animals have confirmed its utility by employing either an intra-abdominal or cervical model. In rats, however, prior research investigating intra-abdominal heterotopic hearts has showed echocardiography to be ineffective. We have recently developed a new technique for heterotopic femoral heart transplantation in rats, which employs the novel use of trans-femoral echocardiography. Therefore, our goal was to re-examine the efficacy of echocardiography for detection of graft rejection.
Microsurgery 02/2007; 27(4):240-4. · 1.61 Impact Factor
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ABSTRACT: To study early microcirculatory perfusion indices in patients with severe sepsis/septic shock, compare early microcirculatory indices in sepsis survivors versus nonsurvivors, and identify systemic hemodynamic/oxygen transport variables that correlate with early microcirculatory perfusion indices.
This prospective observational study used orthogonal polarization spectral imaging to directly visualize the sublingual microcirculation in patients with severe sepsis/septic shock treated with early goal-directed therapy. We performed initial imaging within 6 hours of early goal-directed therapy initiation and late follow-up studies at 24-hour intervals until death or resolution of organ dysfunction. We imaged 5 sublingual sites and analyzed the data offline in a blinded fashion. We calculated 3 microcirculatory perfusion indices: flow velocity score, flow heterogeneity index, and capillary density. We analyzed early data to compare survivors versus nonsurvivors and examine correlations with systemic hemodynamic measurements. We used a linear mixed-effects model for longitudinal analyses.
We performed 66 orthogonal polarization spectral studies in 26 sepsis patients. Early microcirculatory indices were more markedly impaired (lower flow velocity and more heterogeneous perfusion) in nonsurvivors compared with survivors. These same early indices, flow velocity and heterogeneity, were also more markedly impaired with increasing severity of systemic cardiovascular dysfunction (lower arterial pressure or increasing vasopressor requirement).
Early microcirculatory perfusion indices in severe sepsis and septic shock are more markedly impaired in nonsurvivors compared with survivors and with increasing severity of global cardiovascular dysfunction.
Annals of emergency medicine 02/2007; 49(1):88-98, 98.e1-2. · 4.23 Impact Factor
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ABSTRACT: Microvascular dysfunction causing intravascular leakage of fluid and protein contributes to hypotension and shock in sepsis. We tested the hypothesis that abrogation of inducible nitric oxide synthase (iNOS) activation would decrease leukocyte rolling, leukocyte adhesion, and microvascular leakage in sepsis. We compared wild-type mice made septic by cecal ligation and puncture with mice deficient in iNOS.
Leukocyte dynamics and microvascular permeability were assessed simultaneously by fluorescence intravital microscopy in the cremaster muscle 15 to 20 hours after induction of sepsis by cecal ligation and puncture in C57Bl/6 mice. Rolling and adhesion of leukocytes labeled with rhodamine and leakage of fluorescein isothiocyanate-conjugated albumin was measured in single nonbranching venules (25 to 40 microm) and compared among septic wild-type, septic iNOS-deficient transgenic, and sham-operated control mice.
Leukocyte rolling and adhesion were increased in septic animals (61.6 +/- 14.4 cells/minute and 4.1 +/- 0.6 cells/100 microm per minute, respectively) as compared with control animals (8.5 +/- 2.3 cells/minute and 1.1 +/- 0.2 cells/100 microm per minute, respectively; P < 0.001 for both). Rolling increased in iNOS-deficient septic mice (to 105.5 +/- 30.0 cells/minute, P = 0.048, versus wild-type septic); adhesion was unchanged (5.1 +/- 0.5 cells/100 microm per minute, P = 0.30). Sepsis produced an increase in leakage ratio in wild-type septic mice compared with controls (0.36 +/- 0.05 versus 0.08 +/- 0.01, P < 0.001). Leakage was attenuated in iNOS-deficient septic mice (0.12 +/- 0.02, P < 0.001, versus wild-type septic mice).
Leukocyte adhesion and vascular leakage were discordant in this setting. The finding that septic iNOS-deficient mice exhibited less microvascular leakage than wild-type septic mice despite equivalent increases in leukocyte adhesion suggests an important role for nitric oxide in modulating vascular permeability during sepsis.
Critical care (London, England) 01/2007; 11(6):R125. · 4.61 Impact Factor
