Remote ischemic preconditioning improves tissue oxygenation in a porcine model of controlled hemorrhage without fluid resuscitation

Remote ischemic preconditioning (RIPC) involves deliberate, brief interruptions of blood flow to increase the tolerance of distant critical organs to ischemia. This study tests the effects of limb RIPC in a porcine model of controlled hemorrhage without replacement therapy simulating an extreme field situation of delayed evacuation to definitive care. Twenty-eight pigs (47 ± 6 kg) were assigned to: (1) control, no procedure (n = 7); (2) HS = hemorrhagic shock (n = 13); and (3) RIPC + HS = remote ischemic preconditioning followed by hemorrhage (n = 8). The animals were observed for 7 h after bleeding without fluid replacement. Survival rate between animals of the RIPC + HS group and those of the HS group were similar (HS, 6 of 13[46%]-vs-RIPC + HS, 4 of 8[50%], p = 0.86 by Chi-square). Animals of the RIPC + HS group had faster recovery of mean arterial pressure and developed higher heart rates without complications. They also had less decrease in pH and bicarbonate, and the increase in lactate began later. Global oxygen delivery was higher, and tissue oxygen extraction ratio lower, in RIPC + HS animals. These improvements after RIPC in hemodynamic and metabolic status provide essential substrates for improved cellular response after hemorrhage and reduction of the likelihood of potentially catastrophic consequences of the accompanying ischemia.

MO821OXYGEN EXTRACTION RATIO AND MORTALITY RISK IN HAEMODIALYSIS PATIENT: A MULTICENTRE STUDY

Background and Aims Patients on haemodialysis (HD) suffer a very high rate of cardiovascular mortality with some evidence suggesting a possible association with decreasing blood oxygen saturation (SO2) during sessions. The ratio between arterial SO2 (SaO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents an estimate of the amount of oxygen claimed by peripheral tissues and of the haemodialysis related hypoxic stress, might represent a new prognostic factor. Method We evaluate the relationship between OER values and mortality risks in HD patients in a prospective multicentre observational study. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand and SaO2 is available with a peripheral oxymeter. OER ([(SaO2−ScvO2)/SaO2]×100) was measured before and after HD at enrolment (HD OER sessions) in each patients, and a one-year follow-up was planned to record the number of deaths. Results In 101 patients (age 71.5 ± 14 years on dialysis for 47 ± 38 months), during 9 ± 6 months of follow up, we recorded 35 deaths. Patients were then divided into two groups, above or below the median value of pre-HD OER, which was 30%. In these groups, the average incidence of deaths was 12% (24 deaths) and 5,5% (11 deaths) respectively (p<0.05), with significantly different survival curves (Kaplan-Meier log rank test = 0.04, fig). No difference in mortality was evident if we divided patients according to the median intradialytic change in OER value. Conclusion Patients with pre-HD OER > 30% have a higher mortality risk, most probably secondary to reduced capability to respond to HD related oxygen requirements. OER is novel biomarker to identify patients at greatest clinical risk.

Remote Ischemic Preconditioning Improves Tissue Oxygenation in a Porcine Model of Controlled Hemorrhage Without Fluid Resuscitation

Purpose Remote Ischemic preconditioning (RIPC) involves deliberate, brief interruptions of blood flow to increase the tolerance of distant critical organs to ischemia. This study tests the effects of limb RIPC in a porcine model of controlled hemorrhage without replacement therapy simulating an extreme field situation of delayed evacuation to definitive care.Methods Twenty-eight pigs (47±6kg) were assigned to: (1) control, no procedure (n=7); (2) HS=hemorrhagic shock (n=13); and (3) RIPC+HS=remote ischemic preconditioning followed by hemorrhage (n=8). The animals were observed for 7 hours after bleeding without fluid replacement. Results Survival rate between animals that underwent RIPC before bleeding and those bled without prior RIPC were similar (HS, 6 of 13[46%]-vs-RIPC+HS, 4 of 8[50%], p=0.86 by Chi-square). Animals with prior RIPC had faster recovery of mean arterial pressure and developed higher heart rates without complications. Those with RIPC had less decrease in pH and bicarbonate, and the increase in lactate began later. Global oxygen delivery was higher, and tissue oxygen extraction ratio lower, in animals bled after RIPC. Conclusions These improvements after RIPC in hemodynamic and metabolic status provide essential substrates for improved cellular response after hemorrhage and reduction of the likelihood of potentially catastrophic consequences of the accompanying ischemia.

Oxygen extraction ratio to identify patients at increased risk of intradialytic hypotension

Intradialytic hypotension (IDH) is a hemodynamic phenomenon recently associated with decreased blood oxygen saturation (SO2). The ratio between peripheral oxygen saturation (SpO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents a roughly estimate of the amount of oxygen claimed by peripheral tissues, might be used to estimate haemodialysis (HD) related hypoxic stress. Aim of this pilot study was to evaluate the relationship between OER increments during dialysis sessions (ΔOER) and episodes of IDH. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand. OER ([(SpO2 − ScvO2)/SpO2] × 100) was measured in three consecutive HD sessions (HD OER sessions) before HD, after 15′, 30′ and 60′ min and at the end of HD. Then, a one-year follow-up was planned to record the number of IDH episodes. In the 28 enrolled patients (age 74 ± 2.6 years), during 12 ± 1.2 months of follow up, incidence of IDH was 3.6%. We divided patients into two groups, above or below the median value of ΔOER at the end of HD, which was 36%. In these groups, the average incidence of IDH was 7% and 2% respectively (p < 0.01), while OER values before HD were not different. Notably, in the high ΔOER group the OER increment was evident since after 15′ and was significantly higher than in the low ∆OER group (∆OER-15′ = 19 ± 3.0% vs. 9.0 ± 3.0%; p < 0.05). By comparison, blood volume changes overlapped in the two groups (average change − 9 ± 0.8%). Values of ∆OER > 19% after only 15′ of HD treatment or > 36% at the end of the session characterize patients with higher rates of hypotension. Intradialytic ∆OER, a parameter of tissue hypoxic stress, identifies more fragile patients at greater risk of IDH.

Oxygen Extraction Ratio to Identify Patients at Increased Risk of Intradialytic Hypotension.

Intradialytic hypotension (IDH) is a hemodynamic phenomenon recently associated with decreased blood oxygen saturation (SO2). The ratio between arterial SO2 (SaO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents a roughly estimate of the amount of oxygen claimed by peripheral tissues, might be used to estimate haemodialysis (HD) related hypoxic stress. Aim of this pilot study was to evaluate the relationship between OER increments during dialysis sessions (ΔOER) and episodes of IDH. Methods. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand. OER ([(SaO2−ScvO2)/SaO2]×100) was measured in three consecutive HD sessions (HD OER sessions) before HD, after 15’, 30’ and 60’ minutes and at the end of HD. Then, a one-year follow-up was planned to record the number of IDH episodes. Results. In the 28 enrolled patients (age 74±2.6 years), during 12±1.2 months of follow up, incidence of IDH was 3.6%. We divided patients into two groups, above or below the median value of ΔOER at the end of HD, which was 36%. In these groups, the average incidence of IDH was 7% and 2% respectively (p<0.01), while OER values before HD were not different. Notably, in the high ΔOER group the OER increment was evident since after 15’ and was significantly higher than in the low ∆OER group (∆OER-15’ = 19±3.0% vs. 9.0±3.0%; p<0.05). By comparison, blood volume changes overlapped in the two groups (average change -9±0.8%). Conclusion. Values of ∆OER >19% after only 15’ of HD treatment or >36% at the end of the session characterize patients with higher rates of hypotension. Intradialytic ∆OER, a parameter of tissue hypoxic stress, identifies more fragile patients at greater risk of IDH.

Systemic perfusion assessment in patients with univentricular hemodynamics based on blood gas parameters

The objective: to identify laboratory markers of systemic perfusion in newborns with functional single ventricle on mechanical ventilation after surgical correction. Subjects and methods. Blood gas parameters were retrospectively analyzed in 52 newborns with congenital heart defects with univentricular hemodynamic after surgical correction. All samples were divided into three groups based on arterial blood saturation (SaO2): Group 1 – hypoxia (SaO2 ≤ 65%); Group 2 – normoxemia (SaO2 = 65-85%); Group 3 – hyperoxemia (SaO2 > 85%). Stroke volume and cardiac index were evaluated with echocardiography. The oxygen consumption and carbon metabolism were evaluated by arterial and venous blood gases. Results. The mixed central venous pO2 (PvO2) > 29.5 mm Hg, mixed central venous O2 (SvO2) > 54.5%, arteriovenous difference in saturation (Sa-vO2) < 15.8%, total oxygen content in venous blood (CvO2) > 119 ml/l, oxygen extraction ratio (O2ER) < 19% and the arteriovenous difference in partial pressure of carbon dioxide (dPCO2) < 5.4 mm Hg are cut off criteria for adequate systemic perfusion. PvO2 < 26 mm Hg, SvO2 < 44.5%, Sa-vO 2 > 27%, CvO2 < 88 ml/l, O2ER > 27.7%, dPCO2> 7.9 mm Hg have been associated with decreased systemic perfusion. The logistic regression model including combination of O2ER and dPCO2 predicts adequate systemic flow accuracy of 94.3% (sensitivity 87.5%, specificity 94.7%, p = 0.001). Graphics allow to adapt the mathematical model to clinical practice to verify systemic hypoperfusion in newborns with functional single ventricle. Conclusion: The following cut off parameters allow to assess systemic perfusion in newborns with functional single ventricle: PvO2, SvO2, CvO2, Sa-vO 2, O2ER, and dPCO2. The model for predicting the adequacy of systemic perfusion can be used as an effective tool to monitor hemodynamic status in newborns with functional single ventricle.

P1435RELATIONSHIP BETWEEN INTRA-DIALYTIC OXYGEN EXTRACTION RATIO (OER) CHANGE AND IDH

Background and Aims Intradialytic hypotension (IDH) involves a reduced tolerance to hemodialysis (HD), a poor quality of life and is associated with mortality. Intradialytic monitoring systems (blood pressure, heart rate, volemia) are not able to identify patients at greater risk of IDH. IDH is a hemodynamic phenomenon and attention has recently been given to the evaluation of oxygen saturation to evaluate its role in IDH. Oxygen Extraction Ratio (OER), the ratio between SaO2 and ScvO2, is a parameter used to monitor parenchyma oxygen consumption and stress. Recent evidence showed that HD patients with a greater delta OER (ΔOER) during HD (threshold 40%)had higher mortality risk. OER could be a new monitoring instrument to measure hemodialysis induced sub-clinical parenchyma hypoxia and stress, two elements included in the pathogenesis of IDH. The aim of the study was to evaluate the relationship between OER and IDH incidence. Method Inclusion criteria: age ≥18 years, chronic HD treatment by means of permanent jugular CVC, no evidence of acute underlying illness. We evaluated OER ([(SaO2 − ScvO2)/SaO2] × 100) before HD and at 15’, 30’, 60’ and post HD in three HD sessions (HD OER sessions). For the statistic analysis we considered for each patient the median OER value obtained from the three HD OER sessions. Then we started the follow-up study with a minimum follow-up of three months and end follow-up of two years, to record IDH (defined according to K/DOQI guidelines) for each patient. We divided the population in two groups using as a threshold the median percentage number of IDH in our population and evaluate the differences between the obtained two groups in pre HD OER, Delta OER and intradialytic OER trends. Results During the follow-up period (mean 12 ± 1.2 months), we enrolled 28 patients with permanent jugular CVC: 13 males and 15 females, aged 74±2.6 years, HD vintage 46 ± 6.5 months. The HD OER sessions for each patient were asymptomatic. Pre HD OER was 34 ± 1.4, post HD OER 46 ± 1.8, with a Delta OER of 39 ± 5 %. OER change during HD was evident since after 15 minutes (OER% 15’: 40 ± 1.2 p&lt;.001) and continued to increase progressively (OER% end HD 46 ± 1.8; p&lt;.0001). During the follow up period we monitored 4342 HD sessions of which 186 with IDH, the median incidence of IDH was 3.6% of all HD sessions. We divided patients into two groups based on the median value of IDH incidence: (IDH % ≤ 3.6 and IDH % &gt; 3.6). The two groups were not different for age (76 ± 2.4 vs 73 ± 3.0 years; p &lt;ns), HD vintage (52 ± 8.6 vs 40 ± 4.0 months; p &lt;ns), systolic (125 ± 3.2 vs 129 ± 4.0 mmHg; p &lt;ns) and diastolic blood pressure (67 ± 2.2 vs 70 ± 2.2 mmHg; p &lt;ns) and heart rate (70 ± 2.2 vs. 76 ± 2.3 bpm; p &lt;ns) (Tab. 2). The IDH % &gt;3.6 group had 159 IDH out of a total of 1911 sessions (9%), while IDH % ≤ 3.6 group had 27 IDH out of 2431 sessions (0.9%). Pre HD OER values were not different between the groups while the IDH % &gt;3.6 group had greater delta OER% than the IDH % ≤ 3.6 group (43 ± 4.8 vs. 35 ± 3.0 %; p &lt;.05) (Figure). Evaluating the OER trend during HD session a higher ΔOER% was found at 15 minutes of HD treatment in the IDH % &gt; 3.6 group (ΔOER 20± 3.0 % vs. 8.0 ± 3.0 %; IDH % &gt; 3.6 group vs. IDH % ≤ 3.6 group, p &lt;.05), data confirmed at 30' (24 ± 3.0 % vs. 13 ± 5.0 %; p &lt;.05), and post HD (43 ± 5.0 % vs 35 ± 3.0 %; p &lt;.05), but not at 60 minutes of HD treatment (19 ± 4.0 % vs. 17 ± 4.6 %; p &lt;ns). Conclusion Our data show that intradialytic ΔOER, representative of the extent of tissue hypoxic stress, identifies patients at greater risk of IDH. In particular, a ΔOER of 20% after the first 15 minutes of HD and of 43% at the end of the HD session characterizes the more hemodynamically fragile patients. The measurement of the OER can be a new and easy monitoring instrument to identify the most hemodynamically fragile patients already after the first 15 minutes of HD treatment.

Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy: implication in neuroinflammation in hypoxemic adult rats

Background: Hypoxemia is a typical symptom of acute respiratory distress syndrome (ARDS). Ventilations are always needed for correcting hypoxemia. To avoid pulmonary morbidity, low tidal volume ventilation is often applied. The ventilation strategy will certainly result in hypercapnia. Our previous study found that hypercapnia could induce IL-1β overproduction in hypoxia-activated microglia. However, the underlying mechanism has remained unclear. This study aimed to explore whether hypercapnia would promote microglial pyroptosis via inhibiting mitophagy in adult rats with hypoxemia. Methods: Cerebral oxygen extraction ratio (CERO2), partial pressure of brain tissue oxygen (PbtO2), and reactive oxygen species (ROS) production in brain tissue in a rat model of hypercapnia/hypoxemia were evaluated. Along with this, the oxygen consumption rate (OCR) and ROS production of BV-2 microglial cells were evaluated after 15% CO2/0.2% O2 treatment. Mitophagy was observed using transmission electron microscopy (TEM). The protein expression level of LC3-II/I, p62, caspase-1, gasdermin D-N domains (GSDMD-N), IL-1β and IL-18 in microglial cells were detected before and after application of a ROS scavenger in vivo and in vitro. Results: PbtO2 level was elevated by hypercapnia in the hypoxemic rats in the first 1.5 h, but it was significantly decreased 2 h after ventilation. This was further evident by the increased levels of CERO2 at 3 h after ventilation. Besides, a high concentration of CO2 treatment could increase the levels of OCR in hypoxic BV-2 microglial cells in vitro. Expression levels of LC3-II were reduced, while those of p62 were increased by hypercapnia in the hypoxic hippocampus and BV-2 microglia. Autophagosomes could be seen in hypoxia treated microglial cells under TEM, while those were rarely observed in hypercapnia + hypoxia treated microglia. Hypercapnia markedly increased the production of ROS and the expression of caspase-1, GSDMD-N, IL-1β, and IL-18 in hypoxia-activated microglia both in vivo and in vitro. Pharmacological scavenging ROS inhibited microglial pyroptosis and expression of IL-1β and IL-18.Conclusion: Hypercapnia-induced mitophagy inhibition may promote pyroptosis and enhance IL-1β and IL-18 release in hypoxia-activated microglia.