Sub-therapeutic vasopressin but not therapeutic vasopressin improves gastrointestinal microcirculation in septic rats: A randomized, placebo-controlled, blinded trial

Introduction Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient’s mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis. Methods 40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU · kg-1 · h-1 (therapeutic)) or vehicle. Microcirculatory oxygenation (μHBO2) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm/mm2) and perfused vessel density (PVD; mm/mm2)) were measured using incident dark field-Imaging at baseline and after 60 min. Results In mild as well as in moderate septic animals with vehicle-infusion intestinal μHbO2, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU · kg-1 · h-1 elevated intestinal μHBO2 (+ 6.1 ± 5.3%; p < 0.05 vs. baseline) and TVD (+ 5.2 ± 3.0 mm/mm2; p < 0.05 vs. baseline). μHBO2, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups. Conclusion Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass

Background Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. Methods Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. Results CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10–16) to 6 (2–10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67–599) to 129 (31–292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7–15) vs. 6 (2–10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35–313) vs. 129 (31–292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. Conclusions Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

Unfractionated Heparin Improves the Intestinal Microcirculation in a Canine Septic Shock Model

Background. Alterations of microcirculation are associated with organ hypoperfusion and high mortality in septic shock. This study is aimed at investigating the effects of unfractionated heparin (UFH) on intestinal microcirculatory perfusion and systemic circulation in a septic shock model. Methods. Twenty-four beagle dogs were randomly allocated into four groups: (a) sham group: healthy controls, (b) shock group: septic shock induced by Escherichia coli, (c) basic therapy group: septic shock animals treated with antibiotics and 10 ml/kg/h saline, and (d) heparin group: septic shock animals treated with basic therapy plus UFH. Hemodynamic variables were measured within 24 h after E. coli administration. The intestinal microcirculation was simultaneously investigated with a sidestream dark-field imaging technique. Additionally, the function of vital organs was evaluated at 12 h postadministration (T12). Results. E. coli induced a progressive septic shock in which the mean arterial pressure (MAP) decreased and lactate levels sharply increased, accompanied by deteriorated microvessel perfusion. While basic therapy partially improved the microvascular flow index and the perfused microvessel density in the jejunal villi, UFH significantly restored major microcirculation variables at T12. Physiological variables, including MAP, urine output, and lactate levels, were improved by UFH, whereas some hemodynamic indices were not affected by UFH. With respect to organ function, UFH increased the platelet count and decreased the creatinine level. Conclusions. UFH improves microcirculatory perfusion of the small intestine independently of the changes in systemic hemodynamic variables in a canine model of septic shock, thereby improving coagulation and renal function.

Increased beat-to-beat variability of cerebral microcirculatory perfusion during atrial fibrillation: a near-infrared spectroscopy study

Aims Atrial fibrillation (AFib) is associated with cognitive decline/dementia, independently from clinical strokes or transient ischaemic attacks (TIA). Recent in silico data suggested that AFib may induce transient critical haemodynamic events in the cerebral microcirculation. The aim of this study is to use non-invasive spatially resolved cerebral near-infrared spectroscopy (SRS-NIRS) to investigate in vivo beat-to-beat microcirculatory perfusion during AFib and after sinus rhythm (SR) restoration. Methods and results Cerebral SRS-NIRS with high-frequency sampling (20 Hz) and non-invasive systemic haemodynamic monitoring were recorded before and after elective electrical cardioversion (ECV) for AFib or atrial flutter (AFL). To assess beat-to-beat effects of the rhythm status, the frequency distribution of inter-beat differences in tissue haemoglobin index (THI), a proxy of microcirculatory cerebral perfusion, was compared before and after SR restoration. Fifty-three AFib/AFL patients (mean age 69 ± 8 years, 79% males) were ultimately enrolled. Cardioversion was successful in restoring SR in 51 (96%) patients. In front of a non-significant decrease in arterial blood pressure extreme events between pre- and post-ECV measurements, a significant decrease of both hypoperfusive and hyperperfusive/hypertensive microcirculatory events was observed after SR restoration (P &lt; 0.001 and P = 0.041, respectively). Conclusion The present is the first in vivo demonstration that SR restoration by ECV significantly reduces the burden of extreme single-beat haemodynamic events in cerebral microcirculation. Future studies are needed to assess whether SR maintenance might slow long-term AFib-correlated cognitive decline/dementia.

Comparison of Microcirculatory Perfusion in Obese and Non-Obese Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Obesity is a frequent comorbidity among patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Cardiac surgery with CPB impairs microcirculatory perfusion, which is associated with multiple organ failure. As microvascular function is frequently compromised in obese patients, we studied whether cardiac surgery with CPB has a more detrimental effect on microcirculatory perfusion in obese patients. Sublingual microcirculatory perfusion was measured with sidestream dark field (SDF) imaging in obese patients (body mass index ≥32 kg/m2; n = 14) without type II diabetes mellitus and in lean patients (BMI 20–25 kg/m2; n = 22) undergoing cardiac surgery with CPB. CPB reduced systolic blood pressure and mean arterial pressure more profoundly in lean compared with obese patients (SBP: 38% vs. 18%; MAP: 11% vs. 8%, p < 0.05), and both restored after weaning from CPB. No differences were present in intraoperative glucose, hematocrit, hemoglobin, lactate, and blood gas values between obese and lean patients. Microcirculatory perfusion did not differ between obese and lean patients the day before surgery. CPB decreased microcirculatory perfusion with 9% in both groups, but this was only significant in lean patients (p < 0.05). Three days following surgery, microcirculatory perfusion was restored in both groups. In conclusion, microcirculatory perfusion was equally disturbed during cardiac surgery with CPB in metabolically healthy obese patients compared to lean patients.