Emiel Hendrik Post

Renal perfusion in sepsis: from macro- to microcirculation.

The pathogenesis of sepsis-associated acute kidney injury is complex and likely involves perfusion alterations, a dysregulated inflammatory response, and bioenergetic derangements. Although global renal hypoperfusion has been the main target of therapeutic interventions, its role in the development of renal dysfunction in sepsis is controversial. The implications of renal hypoperfusion during sepsis probably extend beyond a simple decrease in glomerular filtration pressure, and targeting microvascular perfusion deficits to maintain tubular epithelial integrity and function may be equally important. In this review, we provide an overview of macro- and microcirculatory dysfunction in experimental and clinical sepsis and discuss relationships with kidney oxygenation, metabolism, inflammation, and function.

The harmful effects of hypertonic sodium lactate administration in hyperdynamic septic shock

ABSTRACT Hypertonic sodium lactate (HTL) expands intravascular volume and may provide an alternative substrate for cellular metabolism in sepsis. We compared the effects of HTL, hypertonic saline (HTS), 0.9% (“normal”) saline (NS) and Ringers lactate (RL) on hemodynamics, sublingual and renal microcirculation, renal, mesenteric and brain perfusion, renal and cerebral metabolism, and survival in anesthetized, mechanically ventilated, adult female sheep. Animals (7 in each group) were randomized to receive a bolus (over 15-min) of 3 mL/kg 0.5 M HTL, 3 mL/kg 3% HTS, 10.8 mL/kg NS, or 10.8 mL/kg RL at 2, 6, and 10 h after induction of fecal peritonitis, followed by 2-h infusions of 1 mL/kg/h (HTL/HTS groups) or 3.6 mL/kg/h (NS/RL groups). Animals also received RL and hydroxyethyl starch (ratio 1:1) titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. Animals were observed until their spontaneous death. Fluid balance was lower in the HTL and HTS groups than in the other groups from 4 h. Hemodynamic variables were similar among groups during the first 12 h, but thereafter the HTL group had more pronounced decreases in blood pressure and cardiac function. Sublingual and renal microcirculatory abnormalities occurred earlier in the HTL group. Kidney and brain perfusion decreased more rapidly in the HTL group. Median survival times were significantly shorter in the HTL (17 h) and NS (16 h) groups than in the HTS (22 h) or RL (20 h) groups (P = 0.0029). In conclusion, in an ovine model of septic shock, administration of HTL was associated with earlier onset impaired tissue perfusion and shorter survival time. These observations raise concerns about use of HTL in septic shock.

THE EFFECTS OF FENOLDOPAM ON RENAL FUNCTION AND METABOLISM IN AN OVINE MODEL OF SEPTIC SHOCK.

Introduction: The importance of renal perfusion and metabolism in septic acute kidney injury (AKI) remains unclear. Prophylactic administration of the dopaminergic agent, fenoldopam, has been suggested to reduce the occurrence of AKI, but its effects in septic shock are poorly defined. Methods: Sepsis was induced in 15 adult female sheep by injecting autologous feces into the abdominal cavity. Two hours later, the animals were randomized to one of three groups: low-dose fenoldopam (1.0 &mgr;g/kg/min, n = 5), high-dose fenoldopam (5.0 &mgr;g/kg/min, n = 5), or placebo (control, n = 5). A perivascular flow probe was placed around the renal artery and a catheter in the renal vein for measurement of renal blood flow index (RBFI) and oxygen consumption (VO2renI). Metabolism in the renal cortex was evaluated using microdialysis. Serum creatinine was measured 6-hourly and the sublingual microcirculation assessed using sidestream dark-field videomicroscopy. Results: High-dose fenoldopam was associated with a lower RBFI at 18 h (P = 0.032) than in the control group, but VO2renI was maintained by a higher oxygen extraction (P < 0.05 vs. baseline). Sublingual microcirculatory alterations at 18 h were more severe in the high-dose than in the control and low-dose groups (P = 0.021 and P = 0.032). Renal cortex lactate and pyruvate levels increased earlier in the high-dose group than in the other two groups (P < 0.001 vs. baseline). Fenoldopam did not affect creatinine clearance or urine output. Conclusions: In this model of septic shock, fenoldopam did not improve renal blood flow, worsened microcirculatory alterations, and induced metabolic changes that were indicative of increased glycolysis.

Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis.

BACKGROUND: Excessive adrenergic signaling may be harmful in sepsis. Using &bgr;-blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting &bgr;-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome. METHODS: After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables. RESULTS: Esmolol was infused for 11 (9–14) hours; the target heart rate (80–100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8–12] vs 14 [11–20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups. CONCLUSIONS: In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival.

Sepsis: Vasopressin: a first-line agent for septic shock?

Noradrenaline is the currently recommended first-line vasopressor agent for patients with refractory septic shock. Although vasopressin adjunct therapy might be beneficial, new data from the VANISH trial do not support use of vasopressin as a first-line agent in these patients.

Feature selection for the accurate prediction of septic and cardiogenic shock ICU mortality in the acute phase

Circulatory shock is a life-threatening disease that accounts for around one-third of all admissions to intensive care units (ICU). It requires immediate treatment, which is why the development of tools for planning therapeutic interventions is required to deal with shock in the critical care environment. In this study, the ShockOmics European project original database is used to extract attributes capable of predicting mortality due to shock at the ICU. Missing data imputation techniques and machine learning models were used, followed by feature selection from different data subsets. Selected features were later used to build Bayesian Networks, revealing causal relationships between features and ICU outcome. The main result is a subset of predictive features that includes well-known indicators such as SOFA and APACHE II, but also less commonly considered ones related to cardiovascular function such as Left Atrial Dilation, Inferior Vena Cava Distensibility Index, or shock treatment (Norepinephrine). Importantly, certain selected features are shown to be most predictive at certain time-steps. This means that, as shock progresses, different attributes could be prioritized. Clinical traits obtained at 24h. from ICU admission are shown to accurately predict cardiogenic and septic shock mortality, suggesting that relevant life-saving decisions could be made shortly after ICU admission.

Renal autoregulation in experimental septic shock and its response to vasopressin and norepinephrine administration

Evidence suggests that septic shock patients with chronic arterial hypertension may benefit from resuscitation targeted to achieve higher blood pressure values than other patients, possibly as a result of altered renal autoregulation. The effects of different vasopressor agents on renal autoregulation may be important in this context. We investigated the effects of arginine vasopressin (AVP) and norepinephrine (NE) on renal autoregulation in ovine septic shock. Sepsis was induced by fecal peritonitis. When shock developed (decrease in mean arterial pressure to <65 mmHg and no fluid-responsiveness), animals were randomized to receive NE or AVP in a crossover design. Before the switch to the second vasopressor, the first vasopressor was discontinued for 30 minutes to ensure complete washout of the first vasopressor. Renal autoregulation was evaluated by recording the change in renal blood flow (RBF) in response to manual, stepwise reductions in renal inflow pressure. In this model, the lower limit of renal autoregulation was not significantly altered 6 hours after sepsis induction (59±9 vs. 64±7 mmHg at baseline, p=0.096). After development of shock, the autoregulatory threshold was lower with AVP than with NE (59±5 vs. 65±7 mmHg, p=0.010). However, RBF was higher with NE both at the start of autoregulatory measurements (206±58 vs. 170±52 mL/min; p=0.050) and at the autoregulatory threshold (191±53 vs. 150±47 mL/min; p=0.008). As vasopressors may have different effects on renal autoregulation, blood pressure management in patients with septic shock should be individualized and take into account drug-specific effects.

Renal autoregulation and blood pressure management in circulatory shock

The importance of personalized blood pressure management is well recognized. Because renal pressure–flow relationships may vary among patients, understanding how renal autoregulation may influence blood pressure control is essential. However, much remains uncertain regarding the determinants of renal autoregulation in circulatory shock, including the influence of comorbidities and the effects of vasopressor treatment. We review published studies on renal autoregulation relevant to the management of acutely ill patients with shock. We delineate the main signaling pathways of renal autoregulation, discuss how it can be assessed, and describe the renal autoregulatory alterations associated with chronic disease and with shock.

Acute renal denervation does not ameliorate renal function in an ovine model of septic shock

Effects of low tidal volume ventilation in a murine model of ventilator-induced diaphragmatic dysfunction Hwa jin Cho, Seongwoo Kang, Sukhan Jeong, Hyunwoo Kim, Do hyeon Yu, In seok Jeong Chonnam National University Hospital, Republic of Korea Chonnam National University, College of Veterinary Medicine, Republic

Hemodynamic and metabolic alterations associated with septic acute kidney injury in experimental sepsis.

The role of renal perfusion in the development of septic acute kidney injury (AKI) remains elusive. When septic AKI develops in the presence of hypotension, renal dysfunction is considered to be caused by reduced renal blood flow and tissue hypoxia. However, an integrated view of the effects of sepsis on renal blood flow, oxygenation and local metabolism is currently lacking.