Microvascular Flow Index Research Articles

Ocular microvascular changes in patients with sepsis: a prospective observational study

BackgroundThe aim of the study was to detect differences in the conjunctival microcirculation between septic patients and healthy subjects and to evaluate the course of conjunctival and retinal microvasculature in survivors and non-survivors over a 24-h period of time.MethodsThis single-center prospective observational study was performed in mixed ICU in a tertiary teaching hospital. We included patients with sepsis or septic shock within the first 24 h after ICU admission. Conjunctival imaging, using an IDF video microscope, and retinal imaging, using portable digital fundus camera, as well as systemic hemodynamic measurements, were performed at three time points: at baseline, 6 h and 24 h. Baseline conjunctival microcirculatory parameters were compared with healthy controls.ResultsA total of 48 patients were included in the final assessment and analysis. Median APACHE II and SOFA scores were 16[12–21] and 10[7–12], respectively. Forty-four (92%) patients were in septic shock, 48 (100%) required mechanical ventilation. 19 (40%) patients were discharged alive from the intensive care unit. We found significant reductions in all microcirculatory parameters in the conjunctiva when comparing septic and healthy subjects. In addition, we observed a significant lower microvascular flow index (MFI) of small conjunctival vessels during all three time points in non-survivors compared with survivors. However, retinal arteriolar vessels were not different between survivors and non-survivors.ConclusionsConjunctival microvascular blood flow was altered in septic patients. In the 24-h observation period conjunctival small vessels had a significantly higher MFI, but no difference in retinal arteriolar diameter in survivors in comparison with non-survivors.Trial registration NCT04214743, https://www.clinicaltrials.gov. Date of registration: 31 December 2019 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04214743

Sublingual microcirculation does not reflect red blood cell transfusion thresholds in the intensive care unit\u2014a prospective observational study in the intensive care unit

PurposeHemoglobin (Hb) transfusion thresholds are established in intensive care units. A restrictive transfusion threshold (Hb 70–75 g/l) is recommended in septic patients, and a liberal transfusion threshold (Hb 90 g/l) for cardiogenic shock. It is unclear whether these historically adopted transfusion thresholds meet the challenges of individual patients.MethodsWe evaluated microvascular flow index (MFI) and proportion of perfused vessels (PPV) in the sublingual microcirculation with CytoCam-IDF microscopy and near-infrared spectroscopy (NIRS). A study team-independent, treating intensivist assigned a total of 64 patients to 1 of 2 two transfusion thresholds, 43 patients to the Hb 75 g/l threshold and 21 patients to the Hb 90 g/l threshold, at a surgical intensive care unit. We performed microcirculatory measurements 1 h before and 1 h after transfusion of 1 unit of red blood cells.ResultsMicrocirculatory flow variables correlated negatively with pre-transfusion flow variables (ΔMFI: ρ = − 0.821, p < 0.001; ΔPPV: ρ = − 0.778, p < 0.001). Patients with good initial microcirculation (cutoffs: MFI > 2.84, PPV > 88%) showed a deteriorated microcirculation after red blood cell transfusion. An impaired microcirculation improved after transfusion. At both transfusion thresholds, approximately one third of the patients showed an initially impaired microcirculation. In contrast, one third in every group had good microcirculation above the cutoff variables and did not profit from the transfusion.ConclusionThe data suggest that the established transfusion thresholds and other hemodynamic variables do not reflect microcirculatory perfusion of patients. Blood transfusion at both thresholds 75 g/l and 90 g/l hemoglobin can either improve or harm the microcirculatory blood flow, questioning the concept of arbitrary transfusion thresholds.

Intestinal Mucosal and Serosal Microcirculation at the Planned Anastomosis during Abdominal Surgery

Introduction: Intestinal blood flow is often named as a key factor in the pathophysiology of anastomotic leakage. The distribution between mucosal and serosal microperfusion during surgery remains to be elucidated. Objective: The aim of this study was to assess if the mucosal microcirculation of the intestine is more vulnerable to a surgical hit than the serosal microcirculation during surgery. Methods: In an observational cohort study (n = 9 patients), the microcirculation of the bowel serosa and mucosa was visualized with incident dark-field imaging during surgery. At the planned anastomosis, the following microcirculatory parameters were determined: microvascular flow index (MFI), percentage of perfused vessels (PPV), perfused vessel density (PVD), and total vessel density (TVD). Data are presented as median (interquartile range [IQR]). Results: Perfusion parameters and vessel density were significantly higher for the mucosa than the serosal microcirculation at the planned site for anastomosis or stoma. Mucosal MFI was 3.00 (IQR 3.00–3.00) compared to a serosal MFI of 2.75 (IQR 2.21–2.94), p = 0.03. The PPV was 99% (IQR 98–100) versus 92% (IQR 66–94), p = 0.01. The TVD was 16.77 mm/mm² (IQR 13.04–18.01) versus 10.42 mm/mm² (IQR 9.36–11.81), p = 0.01, and the PVD was 15.44 mm/mm² (IQR 13.04–17.78) versus 9.02 mm/mm² (IQR 6.43–9.43), p = 0.01. Conclusions: The mucosal microcirculation was preserved, while lower perfusion of the serosa was found at the planned anastomosis or stoma during surgery. Further research is needed to link our observations to the clinically relevant endpoint of anastomotic leakage.

Resuscitation with Hydroxyethyl Starch Maintains Hemodynamic Coherence in Ovine Hemorrhagic Shock.

Fluid resuscitation in hemorrhagic shock aims to restore hemodynamics and repair altered microcirculation. Hemodynamic coherence is the concordant performance of macro- and microcirculation. The present study on fluid therapy in hemorrhagic shock hypothesized that the choice of fluid (0.9% sodium chloride [saline group] or balanced 6% hydroxyethyl starch 130/0.4 [hydroxyethyl starch group]) impacts on hemodynamic coherence. After instrumentation, 10 sheep were bled up to 30 ml/kg body weight of blood stopping at a mean arterial pressure of 30 mmHg to establish hemorrhagic shock. To reestablish baseline mean arterial pressure, they received either saline or hydroxyethyl starch (each n = 5). Hemodynamic coherence was assessed by comparison of changes in mean arterial pressure and both perfused vessel density and microvascular flow index. Bleeding of 23 ml/kg blood [21; 30] (median [25th; 75th percentile]) in the saline group and 24 ml/kg [22; 25] (P = 0.916) in the hydroxyethyl starch group led to hemorrhagic shock. Fluid resuscitation reestablished baseline mean arterial pressure in all sheep of the hydroxyethyl starch group and in one sheep of the saline group. In the saline group 4,980 ml [3,312; 5,700] and in the hydroxyethyl starch group 610 ml [489; 615] of fluid were needed (P = 0.009). In hemorrhagic shock perfused vessel density (saline from 100% to 83% [49; 86]; hydroxyethyl starch from 100% to 74% [61; 80]) and microvascular flow index (saline from 3.1 [2.5; 3.3] to 2.0 [1.6; 2.3]; hydroxyethyl starch from 2.9 [2.9; 3.1] to 2.5 [2.3; 2.7]) decreased in both groups. After resuscitation both variables improved in the hydroxyethyl starch group (perfused vessel density: 125% [120; 147]; microvascular flow index: 3.4 [3.2; 3.5]), whereas in the saline group perfused vessel density further decreased (64% [62; 79]) and microvascular flow index increased less than in the hydroxyethyl starch group (2.7 [2.4; 2.8]; both P < 0.001 for saline vs. hydroxyethyl starch). Resuscitation with hydroxyethyl starch maintained coherence in hemorrhagic shock. In contrast, saline only improved macro- but not microcirculation. Hemodynamic coherence might be influenced by the choice of resuscitation fluid.

Outcome of a rabbit model for late irradiation effects in mandibular oral mucosa and bone: a pilot study

Late side effects of radiotherapy (RT) in the treatment for head and neck (HN) malignancies involve an inadequate healing response of the distressed tissue due to RT-induced hypovascularity. The aim of this study was to develop a pilot model in which vascular alterations associated with the onset of late irradiation (IR) injury could be measured in rabbit oral mucosa and mandibular bone. Eight male New Zealand white rabbits were divided over four treatment groups. Group I-III received four fractions of RT (5.6 Gy, 6.5 Gy, and 8 Gy, respectively) and Group IV received 1 fraction of 30 Gy. Oral microcirculatory measurements were performed at baseline (before RT) and once a week during 11 consecutive weeks after RT assessing perfusion parameters, that is, total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). Post-mortem histopathology specimens were analyzed. Five weeks after RT, TVD, and PVD in all groups showed a decrease of >10% compared to baseline, a significant difference was observed for Groups I, II, and IV (P<0.05). At T11, no lasting effect of decreased vessel density was observed. PPV and MFI remained unaltered at all-time points. Group IV showed a marked difference in scattered telangiectasia such as microangiopathies, histological necrosis, and loss of vasculature. No significant lasting effect in mucosal microcirculation density due to IR damage was detected. Observed changes in microcirculation vasculature and histology may align preliminary tissue transition towards clinical pathology in a very early state associated with late IR injury in the oral compartment. Enhancing knowledge on the onset of late vascular IR injury in the HN region could help the development, monitoring, and timing of therapies that act on prevention, discontinuation, or repair of radiation pathology.

IgM-enriched immunoglobulins (Pentaglobin) may improve the microcirculation in sepsis: a pilot randomized trial

BackgroundPolyclonal or IgM-enriched immunoglobulins may be beneficial during sepsis as an adjuvant immunomodulatory therapy. We aimed to test whether the infusion of IgM-enriched immunoglobulins improves microvascular perfusion during sepsis.MethodsSingle-centre, randomized, double-blind, placebo-controlled phase II trial including adult patients with a diagnosis of sepsis or septic shock for less than 24 h. Patients received an intravenous infusion of 250 mg/kg (5 mL/kg) per day of IgM-enriched immunoglobulins (Pentaglobin, n = 10) for 72 h or placebo (NaCl 0.9%, n = 9). At baseline and after 24 and 72 h of infusion, the sublingual microcirculation was assessed with Incident Dark Field videomicroscopy. Thenar near-infrared spectroscopy (NIRS) was applied with a vascular occlusion test to assess tissue oxygenation and microvascular reactivity. Levels of interleukin (IL) 1-beta, IL-6, IL-8, IL-10 and tumour necrosis factor alpha were measured in the serum.ResultsThe perfused vessel density (PVD) for small vessels (diameter < 20 micron) increased in the Pentaglobin group (from 21.7 ± 4.7 to 25.5 ± 5.1 mm/mm2) and decreased in the placebo group (from 25 ± 5.8 to 20.7 ± 4.1 mm/mm2, p for interaction < 0.001, two-way analysis of variance). The absolute between-group difference at 72 h was 4.77 (standard error 2.34), p = 0.140. The microvascular flow index for small vessels increased at 24 h in the Pentaglobin group (from 2.68 [2.38–2.78] to 2.93 [2.82–3], p < 0.01) and decreased at 72 h in the placebo group (from 2.83 [2.60–2.97] to 2.67 [2.48–2.73], p < 0.05). Changes in general parameters, cytokines and NIRS-derived parameters were similar between the two groups, except for IL-6 and IL-10 that significantly decreased at 72 h only in the Pentaglobin group.ConclusionsA 72-h infusion of IgM-enriched immunoglobulins (Pentaglobin) in patients with sepsis or septic shock may be associated with an increase in sublingual microvascular perfusion. Further studies are needed to confirm our findings.Trial registration NCT02655133, www.ClinicalTrials.gov, date of registration 7th January 2016, https://www.clinicaltrials.gov/ct2/show/NCT02655133.

Abstract 173: The Neuroprotective Effect Of JZL184 is Comparable With Therapeutic Hypothermia in a Rat Model of Cardiac Arrest

Introduction: JZL184 is a synthetic monoacylglycerol lipase inhibitor that reduces brain edema, infarct size and alleviates inflammation following cerebral ischemia in experimental studies. In this study, we compared its cerebral protective effects with therapeutic hypothermia following cardiopulmonary resuscitation (CPR) in a rat model. Hypothesis: JZL184 will have similar neuroprotective effects to therapeutic hypothermia after cardiac arrest (CA) by reducing brain and blood brain barrier (BBB) injury and preserving cerebral microcirculation following CPR. Methods: Thirty six male Sprague-Dawley rats weighing between 450-550 g were randomized: 1) control 2) hypothermia 3) JZL184. Ventricular fibrillation was induced and untreated for 6 min for all rats. Resuscitation was attempted with a 4 Joule defibrillation after 8 min of CPR. Immediately following resuscitation, either hypothermia (33+0.5 o C) or JZL184 (16 mg/k, IP) was administered. Cerebral microcirculation, S-100β, NSE and Evan’s Blue (EB) concentrations were analyzed at 6hrs after resuscitation. Results: NSE and S-100β levels were higher in control compared to hypothermia and JZL18 at 6hr post ROSC (p &lt; 0.001) (Fig. 1). Compared with control, there was a significant decrease in brain permeability to EB in Hypothermia and JZL184 after 6hr post ROSC (p&lt;0.001) (Fig. 2). Microvascular flow index (MFI) was reduced in control compared with hypothermia and JZL184 6hr post ROSC (p &lt;0.01). Conclusions: JZL184 administered following resuscitation reduced brain and BBB injury and preserved cerebral microcirculation at 6 hr post arrest to the same extent as hypothermia in a rat model of cardiac arrest.

Abstract 174: Effects of Melatonin (N-Acetyl-5-Methoxytryptamine) on Inflammation and Cerebral Microcirculation After Cardiopulmonary Resuscitation in a Rat Model of Cardiac Arrest

Introduction: Cerebral ischemia-reperfusion injury produces inflammation and cerebral microcirculatory dysfunction after cardiopulmonary resuscitation (CPR). Melatonin (N-acetyl-5-methoxytryptamine) has both anti-inflammatory and anti-oxidative properties. In this study, we investigated the effects of melatonin on inflammation and cerebral microcirculation after cardiopulmonary resuscitation in a rat model of cardiac arrest. Hypothesis: Melatonin decreases the systemic inflammatory response after cardiopulmonary resuscitation and will preserve cerebral microcirculation in a rat model of cardiac arrest. Method: Eighteen male Sprague Dawley rats weighing between 450-550 g were randomized into three groups: 1) sham: no ventricular fibrillation (VF) and CPR; 2) CPR control: untreated VF for 6 min followed by 8 min CPR; 3) CPR+melatonin: untreated VF for 6 min followed by 8 min CPR. Melatonin (10 mg/kg) was administered intraperitoneal (IP) in line with hypoxia-ischemia animal studies after return of spontaneous circulation (ROSC). Serum TNF- α, IL-1 β and cerebral microcirculation were measured at baseline and 6 h following ROSC. Result: Serum TNF-α and IL-1β were significantly lower in the CPR+melatonin group at 6h after ROSC compared to CPR controls ( p &lt;0.01, Fig. 1). Animals treated with melatonin had improved cerebral microcirculation including perfused vessel density (PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI) compared to control animals ( p &lt;0.05, Fig. 2). Conclusion: In a rat model of cardiac arrest, melatonin reduced systemic inflammation and preserved cerebral microcirculation following resuscitation.

The vaginal microcirculation after prolapse surgery.

AimsOxygen plays a crucial role in wound healing after prolapse surgery. Trauma to the vaginal vasculature might limit the delivery of oxygen to the surgical wound, which may negatively affect wound healing and regeneration of connective tissue. This possibly increases the future risk of recurrence. We aimed to determine the effects of vaginal prolapse surgery on the microcirculation of the vaginal wall.MethodsWe evaluated the vaginal microcirculation in healthy participants without known vascular disease undergoing anterior and/or posterior colporrhaphy. We used incident dark‐field imaging for in vivo assessment before and after (1 day, 2 weeks, and 6 weeks) surgery. We studied perfusion (microvascular flow index [MFI]), angioarchitecture (morphology/layout of microvessels) and capillary density.ResultsTen women were included. Interindividual differences were observed 1 day postoperatively with regard to perfusion and angioarchitecture. Microvascular flow at the surgical site was absent or significantly reduced in some participants, whereas normal microvascular flow was observed in others (MFI range 0–3). Perfusion and angioarchitecture had been restored in all participants after 6 weeks (MFI range 2–3), regardless of the extent of vascular trauma 1 day postoperatively.ConclusionsThe difference in the extent of vascular trauma between women undergoing seemingly identical surgical procedures suggests that some individuals are more susceptible to vascular trauma than others. Delivery of oxygen to the wound and subsequent wound healing may be compromised in these cases, which could be related to the development of anatomical recurrence. Future studies should investigate whether there is a relationship between the vaginal microvasculature and the recurrence of prolapse.

Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis

BackgroundThe endothelial glycocalyx (eGC) covers the luminal surface of the vascular endothelium and plays an important protective role in systemic inflammatory states and particularly in sepsis. Its breakdown leads to capillary leak and organ dysfunction. Moreover, sepsis-induced alterations of sublingual microcirculation are associated with a worse clinical outcome. The present study was performed to investigate the associations between eGC dimensions and established parameters of microcirculation dysfunction in sepsis.MethodsThis observational, prospective, cross-sectional study included 40 participants, of which 30 critically ill septic patients were recruited from intensive care units of a university hospital and 10 healthy volunteers served as controls. The established microcirculation parameters were obtained sublingually and analyzed according to the current recommendations. In addition, the perfused boundary region (PBR), an inverse parameter of the eGC dimensions, was measured sublingually, using novel data acquisition and analysis software (GlycoCheck™). Moreover, we exposed living endothelial cells to 5% serum from a subgroup of study participants, and the delta eGC breakdown, measured with atomic force microscopy (AFM), was correlated with the paired PBR values.ResultsIn septic patients, sublingual microcirculation was impaired, as indicated by a reduced microvascular flow index (MFI) and a reduced proportion of perfused vessels (PPV) compared to those in healthy controls (MFI, 2.93 vs 2.74, p = 0.002; PPV, 98.53 vs 92.58, p = 0.0004). PBR values were significantly higher in septic patients compared to those in healthy controls, indicating damage of the eGC (2.04 vs 2.34, p < 0.0001). The in vitro AFM data correlated exceptionally well with paired PBR values obtained at the bedside (rs = − 0.94, p = 0.02). Both PBR values and microcirculation parameters correlated well with the markers of critical illness. Interestingly, no association was observed between the PBR values and established microcirculation parameters.ConclusionOur findings suggest that eGC damage can occur independently of microcirculatory impairment as measured by classical consensus parameters. Further studies in critically ill patients are needed to unravel the relationship of glycocalyx damage and microvascular impairment, as well as their prognostic and therapeutic importance in sepsis.Trial registrationRetrospectively registered: Clinicaltrials.gov, NCT03960307

Microcirculatory Differences in Children With Congenital Heart Disease According to Cyanosis and Age.

Background: Congenital heart disease (CHD) is one of the main causes of morbidity and mortality in children. Microcirculatory changes in CHD patients have previously been investigated using a variety of techniques. Handheld videomicroscopy enables non-invasive direct visualization of the microcirculatory bed. The aim of our study was to determine if there are microcirculatory differences among CHD patients based on age and the presence of cyanosis.Methods: A prospective observational study was carried out. Patients with CHD undergoing corrective surgery were evaluated after anesthetic induction prior to surgery. Microcirculation was evaluated using sidestream dark field (SDF) imaging. Hemodynamics and respiratory, biochemical, and tissue perfusion parameters were analyzed.Results: A total of 30 patients were included, of whom 14 were classified as cyanotic and 16 as non-cyanotic. Cyanotic patients had a higher total vessel density (TVD) (p = 0.016), small vessel density (p = 0.004), and perfused small vessel density (p = 0.013), while their microvascular flow index (MFI) was lower (p = 0.013). After adjustment for age and PaO2, cyanotic patients showed increased TVD (p = 0.023), and small vessel density (p = 0.025) compared to non-cyanotic patients but there were no differences on the MFI. Age was directly correlated with total MFI (spearman's rho = 0.499, p = 0.005) and small vessel MFI (spearman's rho = 0.420, p = 0.021). After adjustment for the type of CHD (cyanotic vs. non-cyanotic) patients with MFI and small MFI vessels <3 were younger than those with values ≥3 (p = 0.033 and p = 0.037).Conclusions: SDF-based evaluation of microcirculation in CHD patients showed that patients with cyanotic defects had higher vascular density, as compared to patients with non-cyanotic defects. Younger patients were more likely to have a low MFI regardless of their type of CHD.

The effect of mild hypothermia on the myocardial and microcirculatory dysfunction induced by epinephrine during early post-resuscitation

Objective To investigate the effect of mild hypothermia on the myocardial and microcirculation dysfunction induced by epinephrine during early post-resuscitation in a rat model of cardiac arrest and cardiopulmonary resuscitation (CPR). Methods Transesophageal cardiac pacing was performed in order to elicit cardiac arrest for 5 min in SD male rats. Totally 40 rats were randomly (random number) divided into 4 groups (n=10): normothermic control group (N), normothermic epinephrine group (N+E), hypothermic control group (H), and hypothermic epinephrine group (H+E). Chest compression was then initiated. Epinephrine (0.02 mg/kg) or saline was administrated at 1 min during CPR. Restoration of spontaneous circulation (ROSC) was recorded, and the rates of ROSC were observed. Myocardial and microcirculatory function were observed at 1, 2, 3, and 4 h during early post-resuscitation. Serum lactate level was assessed at baseline and ROSC 4 h. Results The ROSC rates were 10/10 in the H+E group, 9/10 in the N+E group, 4/10 in the H group, and 1/10 in the N group, respectively. Ejection fraction (EF) and cardiac output (CO) in the H+E group were significantly higher than that of other groups (P<0.05). Total vessel density, perfused vessel density, proportion of perfused vessels, and microvascular flow index in the H+E group were also significantly higher than those of other groups during early post-resuscitation. The serum lactate level in the H+E group was significantly lower than that in the N+E and H groups.. Conclusions Both epinephrine and mild hypothermia can improve the success rate of resuscitation. However, mild hypothermia can improve the epinephrine induced myocardial and microcirculatory dysfunction during postresuscitation in the rat cardiac arrest. Key words: Cardiac arrest; Cardiopulmonary resuscitation; Epinephrine; Mild hypothermia; Myocardial dysfunction; Microcirculation

Effects of topical estrogen therapy on the vaginal microcirculation in women with vulvovaginal atrophy.

AimsThis study aims to assess vaginal wall angioarchitecture and function in women with vulvovaginal atrophy (VVA) and determine the effect of topical estrogen on the vaginal microcirculation.Materials and MethodsIn this prospective observational study, incident dark field imaging was used to assess the vaginal microcirculation. In patients with VVA, measurements were performed before and after treatment with topical estrogen and compared to measurements performed in women without VVA. Vaginal angioarchitecture was studied by assessing microcirculatory architecture and capillary tortuosity scores at four regions of the vaginal wall. In addition, the capillary density and microvascular flow index (MFI) were obtained.ResultsSeventeen women were included in this study. Of these, eight women were diagnosed with VVA and nine women were considered healthy controls. Significant differences were observed between groups with regard to microcirculatory architecture scores. The architecture of the microvasculature in women with VVA was characterized by the appearance of a vascular network without capillary loops, whereas an array of capillary loops was predominantly seen in women without VVA. After estrogen treatment, no difference in architecture scores between patients and healthy controls was observed. Capillary tortuosity, capillary density, and MFI were similar in both groups before and after estrogen treatment.ConclusionsThe architecture of vaginal microvasculature is altered in patients with VVA. In case of similar vascular architecture, capillary tortuosity and density seem to be comparable. Treatment with topical estrogen results in restoration of the angioarchitecture.

Preload Dependence Is Associated with Reduced Sublingual Microcirculation during Major Abdominal Surgery.

Dynamic indices, such as pulse pressure variation, detect preload dependence and are used to predict fluid responsiveness. The behavior of sublingual microcirculation during preload dependence is unknown during major abdominal surgery. The purpose of this study was to test the hypothesis that during abdominal surgery, microvascular perfusion is impaired during preload dependence and recovers after fluid administration. This prospective observational study included patients having major abdominal surgery. Pulse pressure variation was used to identify preload dependence. A fluid challenge was performed when pulse pressure variation was greater than 13%. Macrocirculation variables (mean arterial pressure, heart rate, stroke volume index, and pulse pressure variation) and sublingual microcirculation variables (perfused vessel density, microvascular flow index, proportion of perfused vessels, and flow heterogeneity index) were recorded every 10 min. In 17 patients, who contributed 32 preload dependence episodes, the occurrence of preload dependence during major abdominal surgery was associated with a decrease in mean arterial pressure (72 ± 9 vs. 83 ± 15 mmHg [mean ± SD]; P = 0.016) and stroke volume index (36 ± 8 vs. 43 ± 8 ml/m; P < 0.001) with a concomitant decrease in microvascular flow index (median [interquartile range], 2.33 [1.81, 2.75] vs. 2.84 [2.56, 2.88]; P = 0.009) and perfused vessel density (14.9 [12.0, 16.4] vs. 16.1 mm/mm [14.7, 21.4], P = 0.009), while heterogeneity index was increased from 0.2 (0.2, 0.4) to 0.5 (0.4, 0.7; P = 0.001). After fluid challenge, all microvascular parameters and the stroke volume index improved, while mean arterial pressure and heart rate remained unchanged. Preload dependence was associated with reduced sublingual microcirculation during major abdominal surgery. Fluid administration successfully restored microvascular perfusion.

Effects of End-Tidal Carbon Dioxide-Guided Fluid Resuscitation on Outcomes in a Cecal Ligation and Puncture Induced Rat Model of Sepsis.

Cecal ligation and puncture (CLP) was used to cause severe sepsis in male Sprague-Dawley rats. There are four groups in this study: sham (n = 5), CLP (n = 10), end-tidal carbon dioxide (ETCO2) (n = 10), and mean arterial pressure (MAP) (n = 10). In ETCO2 group, fluid resuscitation (FR) began when ETCO2 at most 25 mmHg. In MAP group, FR began when MAP at most 100 mmHg. Electrocardiogram, aortic pressure, core temperature, and ETCO2 values were recorded at baseline, 2, 4, 6, 8, 10, and 12 h post-CLP. Lactate level, cardiac output (CO), perfused small vessel density (PSVD), and microvascular flow index (MFI) were assessed at the same time points as above. The results showed that MAP, CO, and ETCO2 gradually decreased after CLP. After FR, MAP, ETCO2, and CO in the ETCO2 group increased compared with the MAP group 12 h after CLP (all P < 0.05). Lactate level remains high in MAP group while decreasing in the ETCO2 group 8 h post-CLP. Both PSVD and MFI deteriorated after CLP in CLP group, though significantly improved in the ETCO2 group 8 h post-CLP. The average survival time in the ETCO2 group was significantly greater than MAP group (14.95 ± 3.90 h vs. 11.15 ± 1.76 h; t = 2.804, P = 0.012). Moreover, ETCO2 showed a negative correlation with lactic acid levels and a positive correlation with CO, PSVD, and MFI. In conclusion, ETCO2 can guide FR implement and improve outcomes of severe sepsis in CLP-inducted rat model. ETCO2 might be a potential index to guiding early FR in severe sepsis.

Monitoring of Conjunctival Microcirculation Reflects Sublingual Microcirculation in Ovine Septic and Hemorrhagic Shock.

The conjunctival region may serve as an alternative site for microcirculatory measurements. The present study was performed to investigate the correlation of sublingual and conjunctival microcirculation in ovine models of septic and hemorrhagic shock. Septic shock was induced in 10 sheep by inoculation of feces into the peritoneal cavity until mean arterial pressure (MAP) was <60 mm Hg and arterial lactate level was ≥1.8 mmol· L. In another 10 sheep, hemorrhagic shock was induced by stepwise blood withdrawal of 3×10 mL·kg. Systemic hemodynamics and parameters of blood gas analysis were analyzed. Conjunctival and sublingual microcirculation were monitored and analyzed according to current recommendations. Parameters were measured at baseline and at shock time. Septic shock resulted in a significant drop in MAP and cardiac index (CI), and an increase in arterial lactate levels. While the total vessel density (TVD) in the sublingual microcirculation was relatively well maintained, the perfused vessel density (PVD) and the microvascular flow index (MFI) were significantly reduced in septic shock. Hemorrhagic shock reduced MAP and CI, and increased arterial lactate levels. TVD was relatively unchanged in hemorrhagic shock, while PVD and MFI were significantly decreased. The conjunctival microcirculation showed similar changes to the sublingual microcirculation in both models. The findings of the current study support the proposed use of the conjunctiva as an alternative site for microcirculatory monitoring in hemorrhagic and septic shock. Further studies should focus on the impact of therapy and the loss of correlation between the different microcirculatory regions in advanced shock.

Effect of mild hypothermia on cerebral microcirculation in a murine cardiopulmonary resuscitation model.

We hypothesized that mild hypothermia may improve brain microcirculation by reducing cerebral microvascular endothelial cells apoptosis, and this effect may be maximized by moving up the initiation of mild hypothermia from after return of spontaneous circulation (ROSC) to the start of cardiopulmonary resuscitation (CPR). A total of 35 rats were randomized into the intra-arrest hypothermia group (IAH), post-resuscitation hypothermia group (PRH), normothermia group (NT), or the sham control group. A craniotomy exposed the parietal cortex for visualization of microcirculation. Ventricular fibrillation was electrically induced and untreated for 8minutes, followed by 8minutes of precordial compression and mechanical ventilation. Hypothermia (33±0.5°C) in the IAH and PRH group was induced and maintained for 6hours at the beginning of CPR or after ROSC, respectively. At baseline, 1, 3, and 6hours, hemodynamic parameters were measured and the pial microcirculations were visualized with a sidestream dark field imaging video microscope. Microvascular flow index and perfused microvessel density (PMD) were calculated. Rats were euthanized, and brain tissues were removed at 3 and 6hours separately. Expression of Bax, Bcl-2, and Caspase 3 in brain microvascular endothelial cells was examined by Western blot. Microvascular flow index and PMD were significantly reduced after cardiac arrest and resuscitation (all P<0.05), and the former was largely preserved by hypothermia regardless when the hypothermia treatment was induced (P<0.05). Bax and Caspase 3 increased and Bcl-2 decreased significantly after resuscitation, and hypothermia treatment reversed the trend partly (all P<0.05). A moderate correlation was observed between MFI and those proteins (Bcl-2/BAX: 3hours: r=0.730, P=0.002; 6hours: r=0.743, P=0.002). Mild hypothermia improves cerebral microcirculatory blood supply, partly by inhibiting endothelial cell apoptosis. Mild hypothermia induced simultaneously with CPR has shown no additional benefit in microcirculation or endothelial cell apoptosis.

Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs

Heart disease of different aetiology remains the leading cause of cardiac arrest (CA). Despite efforts to improve the quality of cardiopulmonary resuscitation (CPR), subsequent myocardial and systemic damage after CA still present a major long-term burden. Low-dose carbon monoxide (CO) is known to exert protective effects in cardiovascular pathophysiology but clinical applications are challenged by unfavourable delivery modes. We tested the hypothesis that extracorporeal resuscitation (E-CPR) in combination with controlled fast onset CO delivery results in improved cardiac physiology and haemodynamics. Damage-associated molecular pattern (DAMP) signalling may be part of the molecular mechanism. In an established porcine model, E-CPR was performed. While E-CPR leads to similar results as compared to a conventional CPR strategy, CO delivery in combination with E-CPR demonstrated significant cardioprotection. Cardiac performance analysis using echocardiography and thermodilution techniques showed a CO-dependent improved cardiac function compared to severe myocardial dysfunction in CPR and E-CPR (left ventricular ejection fraction: Sham 49 ± 5; CPR 26 ± 2; E-CPR 25 ± 2; CO-E-CPR 31 ± 4; P < 0.05). While sublingual microcirculation was significantly compromised in CPR and E-CPR, CO delivery demonstrated a significant improvement in microvascular function (microvascular flow index: Sham 2.9 ± 0.1; CPR 2.2 ± 0.1; E-CPR 1.8 ± 0.1; CO-E-CPR 2.7 ± 0.1; P < 0.01). Histological and serological myocardial damage markers were significantly reduced (hsTroponin-T Sham 0.01 ± 0.001; CPR 1.9 ± 0.2; E-CPR 3.5 ± 1.2; CO-E-CPR 0.5 ± 0.2 ng/mL; P < 0.05). DAMP signalling was decreased ipse facto leading to influence of cardioprotective heat shock and cyclooxygenase response. CO treatment restores myocardial function and improves systemic macro- and microhaemodynamics in E-CPR through a reduction in DAMPs.

LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture

BackgroundSepsis is a systemic inflammatory response syndrome caused by severe infections. LDK378, a second-generation ALK inhibitor, exhibits a potential anti-inflammatory function against sepsis. Micro- and macro-circulatory dysfunctions are pivotal elements of the pathogenesis of severe sepsis and septic shock. We hypothesized that LDK378 can improve micro- and macro-circulation of septic rats, therefore improving the outcome of survival via blocking the ALK-STING pathway to attenuate inflammatory injuries.MethodsA septic rat model was established by the cecal ligation and puncture (CLP) method. A total of 60 rats were randomized into three groups: a sham group, CLP group, and CLP + LDK378 group (n = 20 in each group). Five rats were randomly selected from each group for the mechanism study; the remaining 15 rats in each group were involved in a survival curve examination. A sidestream dark field video microscope was used to record sublingual microcirculation and mean arterial pressure (MAP) and levels of inflammatory cytokine secretion were examined at 6 h, 30 h, and 54 h after CLP surgery. Expressions of TANK binding kinase 1 (TBK1) and its downstream targets were determined, and histological alterations to the heart, lungs, and kidneys were examined at 54 h after CLP surgery.ResultsWe found the group that received LDK378 treatment showed increased MAP levels compared to the CLP group at 30 h and 54 h. Meanwhile, LDK378 ameliorated the perfused small vessel density and microvascular flow index, decreased the expression of TNF-a and IL-6, and upregulated the expression of IL-10 in comparison with the CLP group. LDK378 injections also downregulated the expression of TBK1 and its downstream targets. Furthermore, LDK378 treatment significantly reduced sepsis-induced organ injuries, therefore improving survival rates.ConclusionsThese findings demonstrate that LDK378 treatment can improve microcirculation and reduce organ injuries in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the downstream signaling components of the ALK-STING pathway.

Microcirculation dysfunction in endotoxic shock rabbits is associated with impaired S-nitrosohemoglobin-mediated nitric oxide release from red blood cells: a preliminary study

BackgroundMicrocirculation dysfunction with blood flow heterogeneity is an important characteristic in sepsis shock. We hypothesized that impaired ability of red blood cells to release nitric oxide resulted in microcirculation dysfunction in sepsis shock.Methods4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS), an inhibitor of band3 protein, was used to inhibit S-nitrosohemoglobin-mediated nitric oxide release. Rabbits were randomly divided into four groups: control (n = 6), lipopolysaccharide (LPS) (n = 6), LPS + DIDS (n = 6), and control + DIDS group (n = 6). Macrocirculation (cardiac output and mean arterial pressure) and microcirculation (microvascular flow index and flow heterogeneity index) parameters were recorded. At 2-h time point, arterial and venous S-nitrosohemoglobin concentrations were measured.ResultsThe arterial–venous difference for S-nitrosohemoglobin in the LPS group was lower than the control group (27.3 ± 5.0 nmmol/L vs. 40.9 ± 6.2 nmmol/L, P < 0.05) but was higher than the LPS + DIDS group, with a statistically significant difference (27.3 ± 5.0 nmmol/L vs. 16.0 ± 4.2 nmmol/L, P < 0.05). Microvascular flow index for the LPS group at 2 h was lower than the control group (1.13 ± 0.16 vs. 2.82 ± 0.08, P < 0.001) and higher than the LPS + DIDS group (1.13 ± 0.16 vs. 0.84 ± 0.14, P < 0.05). Flow heterogeneity index for the LPS group at 2 h was higher than the control group (1.03 ± 0.27 vs. 0.16 ± 0.06, P < 0.001) and lower than the LPS + DIDS group (1.03 ± 0.27 vs. 1.78 ± 0.46, P < 0.001).ConclusionsIn endotoxic shock rabbits, the ability of S-nitrosohemoglobin-mediated nitric oxide release from RBC was impaired, and there was an association between the ability and microcirculation dysfunction especially increased blood flow heterogeneity.