Baseline Lactate Levels Research Articles

Impact of inhaled nitric oxide therapy in patients with cardiogenic shock treated with veno-arterial extracorporeal membrane oxygenation combined with Impella: a retrospective cohort study

BackgroundThe mortality rate of patients with cardiogenic shock (CS) requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) combined with Impella (ECPELLA) support remains high. Inhaled nitric oxide (iNO) improves right ventricular (RV) function, resulting in increased Impella flow, which may facilitate early withdrawal of VA-ECMO and improve survival. This study investigated the prognostic impact of iNO therapy in ECPELLA patients.MethodsWe retrospectively analyzed the data of consecutive patients with CS supported by ECPELLA from September 2019 to March 2024 at our hospital. Changes in pulmonary artery pulsatility index (PAPi) and Impella flow over time were evaluated, and VA-ECMO withdrawal rate, time to withdrawal, and 30-day survival were compared between ECPELLA patients with and without iNO therapy.ResultsOf the 48 ECPELLA patients, 25 were treated with iNO. There were no significant differences between the groups in baseline characteristics or lactate levels at mechanical circulatory support induction. Patients with iNO therapy demonstrated significant improvements in the PAPi over time and a trend toward increased Impella flow, as well as a significantly higher VA-ECMO withdrawal rate (88% vs. 48%, P = 0.002) and a shorter time to VA-ECMO withdrawal (5 [3–6] days vs. 7 [6–13] days, P = 0.0008) than those without iNO therapy. Kaplan–Meier analysis demonstrated that the 30-day survival rate was significantly higher in patients with iNO than in those without (76% vs. 26%, P = 0.0002).ConclusionsiNO therapy in patients with CS requiring ECPELLA was associated with short-term prognosis by improving RV function and facilitating weaning from VA-ECMO.Trial registration Retrospectively registered in UMIN-CTR (Reference No. R00006352).

Mortality prediction model from combined serial lactate, procalcitonin and calprotectin levels in critically ill patients with sepsis: A retrospective study according to Sepsis-3 definition

Objective1) To evaluate the ability of baseline and on 24 h serum calprotectin, in comparison to canonical biomarkers (lactate and procalcitonin), for prognosis of 28-day mortality in critically ill septic patients; and 2) To develop a predictive model combining the three biomarkers. DesignA single-center, retrospective study. SettingIntensive Care Unit of a university hospital. Patients or participantsOne hundred and seventy three septic pacientes were included. InterventionsMeasurement of baseline lactate, procalcitonin and calprotectin level and procalcitonin and calprotectin levels on 24 h. Main variables of interestDemographics and comorbidities, SOFA score on ICU admission, baseline lactate, procalcitonin and calprotectin on admission and on 24 h and 28-day mortality. Results1) On ICU admission, lactate was the only biomarker achieving a significant accuracy (AUC: 0.698); 2) On 24 h, no differences were found on procalcitonin and calprotectin levels. Procalcitonin and calprotectin clearances were significantly lower in non-survivors and both achieved a moderate performance (AUCs: 0.668 and 0.664, respectively); 3) A biomarker based-model achieved a significant accuracy (AUC: 0.766), trending to increase (AUC: 0.829) to SOFA score alone; y 4) Baseline lactate levels and procalcitonin and calprotectin clearance were independent predictors for the outcome. Conclusions1) Baseline and on 24 h calprotectina and procalcitonin levels lacked ability in predicting 28-day mortality; 2) Accuracy of clearance of both biomarkers was moderate; and 3) Combination of SOFA score and the predictive biomarker based-model showed a high prognostic accuracy.

Developing a predictive nomogram for mortality in patients with extrapulmonary acute respiratory distress syndrome: the prognostic value of serum soluble thrombomodulin, lung ultrasound score, and lactate.

Objective: This study aimed to elucidate the prognostic significance of serum soluble thrombomodulin (sTM), lung ultrasound score (LUS), and lactate levels in patients with extrapulmonary acute respiratory distress syndrome (ARDS), with the goal of refining mortality risk prediction in this cohort. Methods: In a prospective cohort of 95 patients with extrapulmonary ARDS admitted to the intensive care unit, we investigated the primary endpoint of 28-day mortality. Utilizing Lasso-Cox regression analysis, we identified independent prognostic factors for mortality. A predictive nomogram was developed incorporating these factors, and its performance was validated through several statistical measures, including the consistency index, calibration plot, internal validation curve, decision curve analysis, interventions avoided analysis, receiver operating characteristic curve analysis, and Kaplan-Meier survival analysis. We further conducted a subgroup analysis to examine the impact of prone positioning on patient outcomes. Results: The study identified baseline serum sTM, LUS, and lactate levels as independent predictors of 28-day mortality in extrapulmonary ARDS patients. The predictive nomogram demonstrated superior prognostic accuracy compared to the use of sTM, LUS, or lactate levels alone, and outperformed traditional prognostic tools such as the Acute Physiology and Chronic Health Evaluation II score and the partial pressure of arterial oxygen to fractional inspired oxygen ratio. The subgroup analysis did not show a significant impact of prone positioning on the predictive value of the identified biomarkers. Conclusion: Our study results support the development and validation of a novel prognostic nomogram that integrates key clinical biomarkers and ultrasound imaging scores to predict mortality in patients with extrapulmonary ARDS. While our research is preliminary, further studies and validation are required.

Serial daily lactate levels association with 30-day outcome in cardiogenic shock patients treated with VA-ECMO: a post-hoc analysis of the HYPO-ECMO study

BackgroundReliable predictors of outcomes in venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy are limited. While elevated lactate levels over time have been linked to outcomes in cardiogenic shock (CS), their significance in VA-ECMO-treated patients remains inconclusive.MethodsWe conducted a post hoc analysis of data from the HYPO-ECMO trial, which compared normothermia to moderate hypothermia in CS patients supported by VA-ECMO. We examined daily lactate levels collected over a week to assess their correlation with 30-day mortality.ResultsAmong the 318 out of 334 patients (95%) with baseline lactate measurements, 66 had normal levels (< 2.2 mmol/l, 21%). No difference was found in lactate course between moderate hypothermia and normothermia groups. Lactate levels were consistently higher in non-survivors at each time point (p = 0.0002). Baseline hyperlactatemia was associated with an increased risk of death (Hazard Ratio [HR]: 1.85 (1.12–3.05), p = 0.016). When considering all time points, lactate levels during the ICU stay were significantly and gradually associated with a higher risk of death (p < 0.0001). In the overall population, a decrease in lactate levels was not linked to 30-day mortality. However, patients with baseline hyperlactatemia exhibited a more significant decrease in lactate levels from day one to seven (p < 0.0001). In this group, survivors had a significantly greater decrease in lactate levels at day 1 compared to non-survivors (63% (48–77) versus 57% (21–75), p = 0.026). Patients experiencing a secondary increase in lactate (24%) had a worse prognosis (Hazard Ratio: 1.78 (1.21–2.61), p = 0.004), regardless of both baseline lactate levels and the occurrence of severe ischemic adverse events (intestinal and/or limb ischemia).ConclusionsThe consistent and significant association between lactate levels, whether assessed at baseline or during ICU treatment, and the risk of mortality underscores the pivotal prognostic relevance of lactate levels in patients with CS undergoing VA-ECMO therapy. The study findings provide some novel insights, regarding the trend profile and the relevance of a second peak during the 7 day period after ECMO start.Trial Registration identifier NCT02754193 registered on 2016–04–12.

Evaluation of Blood Lactate Level as a Predictor of In-hospital Morbidity and Mortality in Patients Undergoing Surgery for Bowel Perforation: A Prospective Cohort Study

Introduction: Perforation peritonitis is associated with significant Morbidity and Mortality (M&amp;M). The predictive performance of blood lactate levels and their clearance varies depending on the timing of measurement, and the optimal time for measurement remains unclear. Aim: To evaluate perioperative lactate levels and their clearance as predictors of in-hospital M&amp;M in bowel perforation surgery. Materials and Methods: The present prospective cohort study was conducted in the Department of Anaesthesiology and Critical Care, Pt. BD Sharma PGIMS, Rohtak, Haryana, India, from March 2023 to December 2023. Study was conducted on 40 adult patients undergoing surgery for bowel perforation, and clinical and various laboratory parameters were observed from admission until discharge. Baseline and perioperative lactate levels were recorded up to 24 hours postoperatively. The association of M&amp;M with different scores such as the Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Mannheim Peritonitis Index (MPI), as well as, lactate levels and lactate clearance, was assessed. The diagnostic accuracy of lactate levels and lactate clearance at different time points in the perioperative period to predict M&amp;M was calculated, and finally, the ‘Bidirectional Stepwise Selection’ (BSS) was used to select the most useful predictor of M&amp;M. Results: Total 40 participants were included in the study, of which 34 were males and 6 were females. The overall M&amp;M rates were 50% and 30%, respectively. On univariate analysis, there was a significant difference between non survivors and survivors in terms of age (50.92 vs 38.07 years, p-value=0.004), APACHE II score (10.00 vs 6.46, p-value=0.028), preoperative serum creatinine (1.41 vs 1.13 mg/dL, p-value=0.043), 24-hour postoperative lactate (4.75 vs 1.54 mmol/L, p-value=0.005), and lactate clearance (-28.97 vs 24.83%, p-value=0.03). Patients with or without morbidity showed a significant difference in age (47.7 vs 36.15 years, p-value=0.005), MPI score (22.45 vs 18.6, p-value=0.048), preoperative serum creatinine (1.40 vs 1.03 mg/dL, p-value=0.028), and 24-hour postoperative lactate (3.65 vs 1.35, p-value=0.002). In BSS analysis, age and 24-hour postoperative lactate were identified as good predictors of M&amp;M, with the latter being the best predictor. Conclusion: The incidence of M&amp;M is quite high in perforation peritonitis. Among all predictors, 24-hour postoperative lactate is the strongest predictor of M&amp;M and may be useful in risk stratification and optimising treatment accordingly

Acute kidney injury during extracorporeal life support in cardiogenic shock: Does flow matter?

This study examines the role of extracorporeal life support flow in the development of acute kidney injury in cardiogenic shock. We performed a retrospective analysis of 465 patients placed on extracorporeal life support at our institution between January 2015 and December 2020 for cardiogenic shock. Flow index was calculated by dividing mean flow by body surface. Stages of acute kidney injury were determined according to Kidney Disease: Improving Global Outcomes (KDIGO) organization guidelines. There were 179 (38.5%) patients who developed acute kidney injury, 63.1% of which were classified as Stage 3--the only subgroup associated with 1-year mortality (hazard ratio = 2.03, p < .001). Risk of kidney injury increased up to a flow index of 1.6L/min/m2, and kidney injury was more common among patients with flow index greater than 1.6L/min/m2 (p = .034). Those with kidney injury had higher baseline lactate levels (4.4 vs 3.1, p = .04), and Stage 3 was associated wit higher baseline creatinine (p < .001). In our cohort, kidney injury was common and Stage 3 kidney injury was associated with worse outcomes compared to other stages. Low flow was not associated with increased risk of kidney injury. Elevated baseline lactate and creatinine among patients with acute kidney injury suggest underlying illness severity, rather than flow, may influence kidney injury risk.

The relationship between initial lactate levels and outcomes in patients diagnosed with diabetic ketoacidosis in the emergency department

Background/Aim: Diabetic ketoacidosis (DKA) is an endocrinological emergency frequently seen in emergency departments (ED). It can result in mortality if not treated appropriately. The aim of this study was to examine the relationship between baseline lactate levels and patient outcomes in DKA patients admitted to the emergency department (ED). Methods: This retrospective cohort study was carried out in the ED of a tertiary hospital between May 2022 and November 2022 using the data of patients diagnosed with DKA. Patients with missing data, patients transferred from another hospital, patients with a diagnosis other than DKA, and patients who could not be followed up were excluded from the study. The primary outcome of the study was admission to the intensive care unit (ICU) and/or in-hospital mortality. The area under the curve (AUC) was calculated by receiver operating characteristic (ROC) regression analyses to predict critically ill patients with lactate levels. Results: The study was completed with 95 patients. The mean age of the patients was 53.1 years and n = 46 were female. Twenty (21.1%) of these patients were admitted to the intensive care unit and 22 (23.2%) died. The statistical analysis showed that lactate levels were statistically significant in predicting critically ill patients (P &lt; 0.001). ROC analysis showed that a lactate level of 2.6 mmol/dL could predict critically ill patients. The area under the curve was 0.823 (95% confidence interval: 0.731-0.894, sensitivity: 71.4, Specificity: 69.8), the Youden index was 0.476, and the P-value was 0.001. Conclusion: According to the results of this study, there is a significant relationship between the initial lactate levels in DKA patients and patients who will require critical care. Therefore, lactate can be used as an appropriate follow-up tool in the management of DKA patients.

Abstract 14870: Adrenomedullin in Patients With Out-of-Hospital Cardiac Arrest

Introduction: Adrenomedullin (ADM) is a free circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of adrenomedullin in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA) of non-traumatic origin. Methods: Mid-regional pro-ADM (MR-proADM) concentrations were measured in OHCA patients after successful ROSC on admission. The outcome of interest was all-cause death. Patients were characterized by quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, and baseline eGFR. Results: A total of 232 patients were included in the present study (28% women, 67 years, SAPS II score 80). In total, 132 patients (56.9%) died, and 24 patients had an unfavorable neurologic outcome (i.e., a CPC score of 3-4). The median MR-proADM and lactate levels were 1.4 nmol/L (IQR 0.8 to 2.8 nmol/L) and 4.8 mmol/L (IQR 2.8 to 7.4 mmol/L), respectively. MR-proADM concentrations correlated weakly with lactate levels (r=0.23, P&lt;0.001). High (Q4) versus low (Q1-Q3) MR-proADM concentration was associated with an increased rate of death at 28 days (45.4% vs. 75.9%; P&lt;0.001; Fig A ). After multivariable adjustment (including baseline lactate levels), higher MR-proADM levels were significantly associated with an increased risk of death (Q4 vs. Q1-Q3: adjusted HR 1.84, 95% CI 1.21 to 2.77; adjusted HR for 1 unit increase in standardized biomarker 1.55, 95% CI 1.28 to 1.86). The combination of high MR-proADM and high lactate (Q4) concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; Fig B ). Conclusions: Higher MR-proADM concentration are associated with an increased risk of death in patients with OHCA of non-traumatic origin. The combination of high MR-proADM and high lactate levels identifies patients at distinctly elevated risk.

Acute Low Force Electrically Induced Exercise Modulates Post Prandial Glycemic Markers in People with Spinal Cord Injury.

Regular exercise involves daily muscle contractions helping metabolize up to 70% of daily ingested glucose. Skeletal muscle increases glucose uptake through two distinct pathways: insulin signaling pathway and muscle contraction mediated AMPK pathway. People with paralysis are unable to contract their muscles which atrophy, transform into insulin resistant glycolytic muscle, and develop osteoporosis. Our goal is to determine if low force electrically induced exercise (LFE) will modulate the post prandial insulin and glucose response in people with and without spinal cord injury (SCI). 18 people with SCI and 23 without SCI (Non-SCI) participated in an assessment of metabolic biomarkers during passive sitting (CTL) and a bout of LFE delivered to the quadriceps/hamstring muscle groups after a glucose challenge. Baseline fasting insulin (p = 0.003) and lactate (p = 0.033) levels were higher in people with SCI, but glucose levels (p = 0.888) were similar compared to the non-SCI population. After 1-h of muscle contractions using LFE, heart rate increased (p &lt; 0.001), capillary glucose decreased (p = 0.004), insulin decreased (p &lt; 0.001), and lactate increased (p = 0.001) in the SCI population. These findings support that LFE attenuates certain metabolic blood biomarkers during a glucose challenge and may offer a lifestyle strategy to regulate metabolic responses after eating among people with SCI.

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial

BackgroundRecently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.MethodsIn the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE.ResultsA continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004).ConclusionsAdjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints.Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994).

Correlation between Intraoperative Serum Lactate and New-Onset Postoperative Neurodeficits in Patients Undergoing Elective Craniotomies

Background:Elevated lactate levels in neurosurgical patients are seen in brain tumors, traumatic brain-injury, brain infarction, and subarachnoid hemorrhage. Hyperlactatemia during craniotomy may be caused by hypotension due to multiple factors. Recently, intraoperative hyperlactatemia has been associated with fresh-onset neurodeficits.Aims:We studied the prevalence of hyperlactatemia in patients undergoing craniotomy and relationship between intraoperative hyperlactatemia and development of new postoperative neurodeficit.Study Design:Eighty-six patients, American Society of Anesthesiologists Classes I,II and III, undergoing elective craniotomy for neurosurgical indications were included in this prospective, observational study in a tertiary care center.Materials and Methods:Baseline, intraoperative, and postoperative (upto 12 h) lactate levels were noted. Neurological examination to detect new-onset neurodeficits was done at intervals up to 72 h postoperatively. Lactate levels were compared between patients who developed neurodeficits and those who did not develop neurodeficits postoperatively.Statistical Analysis:Statistical analysis of the correlation between intraoperative hyperlactatemia and fresh postoperative neurodeficit was done using the Chi-square test.Results:The prevalence of intraoperative hyperlactatemia was found to be 52.3% and that of fresh-onset postoperative neurodeficits was 31.4%. The relationship between the two was statistically insignificant (P > 0.05).Conclusion:The intraoperative hyperlactatemia is not correlated with the development of fresh-onset postoperative neurodeficit.Implications:There may be no relationship between the intraoperative lactate levels and fresh-onset postoperative neurodeficits. Multifactorial reasons may be responsible for increased lactate levels which need to be identified by further research.

Carboxyhemoglobin, Methemoglobin and Lactate Levels in Patients with Systemic Inflammatory Response Syndrome

Background: Systemic inflammatory response syndrome (SIRS) is a common, severe inflammatory condition. This condition forms the basis of the definitions of sepsis, severe sepsis, septic shock, and multiple organ failure syndromes. The diagnosis can be made earlier with arterial blood gas analysis, which can provide a lot of information within minutes. This study aimed to determine the value of carboxyhemoglobin (COHb), methemoglobin (metHb), and lactate levels in the prognosis and mortality of patients with SIRS. Methods: Patients who met the SIRS criteria with the first vital signs and laboratory values and who had arterial blood gas analysis according to the clinician’s decision were included in the study. The demographic characteristics, prognosis and correlation of 1-month mortality rates of patients with baseline COHb, metHb and lactate levels were investigated. Results: Among non-smoker patients, no significant difference was found between fCOHb values and age, gender, presence of infection, blood pressure, department of hospitalization, and 1-month mortality rates (p>0.05). Also, the relationship between fCOHb values and length of stay in the hospital was not statistically significant (r = -0.013, p = 0.883). Among the patients included in the study; there was no significant difference in metHb values between age groups (p = 0.9941), gender (p = 0.6422), presence of infection (p = 0.1311), blood pressure (p = 0.7711), length of stay in hospital (p = 0.737), inpatient clinics (p = 0.6722) and 1-month mortality (p = 0.8752). Lactate values were found to be correlated with the 1-month mortality of the patients (p = 0.005). Lactate levels were significantly higher in patients who died within 1-month compared to those who survived. Conclusions: In patients with SIRS, initial COHb and metHb values cannot be considered a predictor for prognosis and mortality. However, lactate values may be useful to predict SIRS mortality even during hospital admission.

Predictive Relevance of Baseline Lactate and Glucose Levels in Patients with Spontaneous Deep-Seated Intracerebral Hemorrhage.

(1) Background: As elements of the standard admission blood panel, lactate and glucose represent potential biomarkers for outcome prediction. In patients with intracranial hemorrhage (ICH), data on the predictive value of these blood values is exceedingly sparse. (2) Methods: Between 2014 and August 2020, all patients with deep-seated ICH referred to the neurovascular center at the authors’ institution were included in the subsequent study. Serum levels of lactate and glucose at the time of admission were compared with mortality at 90 days. In addition, a multivariate analysis was performed in order to identify independent admission predictors for 90-day mortality. (3) Results: Among the 102 patients with deep-seated ICH, elevated lactate and glucose levels on admission were significantly associated with increased mortality at 90 days. Multivariate logistic regression analysis identified “ICH score ≥3” (p = 0.004) along with “admission hyperlactatemia” (p = 0.025) and “admission hyperglycemia” (p = 0.029) as independent and significant predictors of 90-day mortality in patients with deep-seated ICH. (4) Conclusions: Initially elevated lactate and glucose levels after spontaneous intracerebral hemorrhage are associated with poor outcome, suggesting a potential application for future prognostic models when considered in conjunction with other parameters.

Metabolic fatigue in resuscitators using personal protection equipment against biological hazard.

Objective. To describe the effects of wearing individual protection equipment against biological hazard when performing a simulated resuscitation.Methods. Uncontrolled quasi-experimental study involving 47 volunteers chosen by random sampling stratified by sex and professional category. We determined vital signs, anthropometric parameters and baseline lactate levels; subsequently, the volunteers put on level D individual protection equipment against biological hazard and performed a simulated resuscitation for 20 minutes. After undressing and 10 minutes of rest, blood was extracted again to determine lactate levels. Metabolic fatigue was defined as a level of lactic acid above 4 mmol/L at the end of the intervention.Results. 25.5% of the participants finished the simulation with an unfavorable metabolic tolerance pattern. The variables that predict metabolic fatigue were the level of physical activity and bone mass -in a protective form- and muscle mass. People with a low level of physical activity had ten times the probability of metabolic fatigue compared to those with higher levels of activity (44% versus 4.5%, respectively).Conclusion. Professionals who present a medium or high level of physical activity tolerate resuscitation tasks better with a level D individual biological protection suit in a simulated resuscitation.

First-in-Human Mitochondrial Augmentation of Hematopoietic Stem Cells in Pearson Syndrome

▪Background:Pearson Syndrome (PS) is an ultra-rare disease caused by de-novo mitochondrial DNA (mtDNA) deletions. Patients present at infancy with sideroblastic anemia and later develop a multisystem metabolic disorder, leading to death in early or late childhood. No disease-modifying treatments are available for PS. Ex-vivo enrichment of functional mitochondria into various cells has been previously demonstrated, as has inter-cellular mitochondrial transfer. In preclinical models of mitochondrial and lysosomal disorders, hematopoietic stem and progenitor cells (HSCs) have been shown capable of carrying and transferring normal organelles into diseased tissues, thereby altering disease phenotype. Here, we show enrichment of PS-derived HSCs with wild-type mitochondria, a process termed mitochondrial augmentation. We further report on three patients with PS treated with autologous HSCs following ex-vivo mitochondrial augmentation.Methods:Diagnosis of PS was confirmed by MLPA and deletion-specific dPCR. Colony formation assays were performed on PS patient-derived HSCs, prior to and after mitochondrial augmentation. HSC mobilization was performed with GCSF alone (n=1) or with plerixafor (n=2) prior to leukapheresis. Autologous CD34+ cells were positively-selected using a CliniMACS system, followed by ex-vivo mitochondrial augmentation of the cells with maternal cryopreserved mitochondria carrying normal mtDNA as confirmed by MLPA. Enriched cells were intravenously infused without conditioning. Level of heteroplasmy (relative normal to deleted mtDNA) was determined by deletion-specific dPCR of DNA from peripheral blood. Patients were followed for a period of up to 1 year including clinical and metabolic evaluations. Adverse events were reported as per CTCAE v4.03. Cellular mitochondrial function was studied on peripheral blood mononuclear cells (PBMCs) by ATP content, O2 consumption and flow cytometry for TMRE (tetramethylrhodamine ethyl ester) and MTG (mitotracker green).Results:Three patients were treated with production and safety data available, and in two patients efficacy data is available. PS-patient derived HSCs have a diminished capacity to form colonies in vitro (median, 360 colonies per 5x104 cells vs. 1090 in healthy donors). HSC colony forming capacity increased by an average of 30% after mitochondrial augmentation. Target cell dose (4x106 CD34+ cells/kg) was not reached despite two leukapheresis procedures in patients 1 and 2, who received 1.1 and 1.8 million CD34+ cells/kg recipient, respectively. Patient 3 received 2.8 million cells/kg following a single apheresis. Mitochondrial enrichment in the products was 156%, 162% and 114% for patients 1, 2 and 3. To date, the only treatment-related adverse events noted were leukapheresis related, including anemia, hypocalcemia and alkalosis.In two patients with more than 3 months follow-up, we observed in vivo mitochondrial enrichment starting 3-4 months after cellular therapy, and throughout the follow-up period (Figure). Metabolic function of PBMCs showed improvement at 5 months post-treatment in lymphocyte ATP content, O2 consumption and TMRE:MTG ratio, indicating improved mitochondrial respiratory capacity. Improvement in mitochondrial heteroplasmy and function was in line with clinical findings. Following cell therapy, no events of metabolic crisis occurred, along with normalization of a pre-treatment negative base excess in patient 1 and ongoing improvement in baseline lactate levels in patient 2. Aerobic ability and fine motor functions were superior compared to baseline in both patients. Importantly, quality of life, as measured by the International Pediatric Mitochondrial Disease Score (IPMDS), was greatly improved after treatment.Conclusion:We report a first in human study with a novel form of cellular therapy, mitochondrial augmentation, in which we enrich HSCs with organelles encoding non-mutated version of the mtDNA sequence. We show the ability of mitochondrial augmentation to improve in vitro PS-derived HSC function, and improvement in metabolic determinants, aerobic capacity and quality of life of two patients treated. Together, these preliminary clinical data suggest that mitochondrial augmentation therapy is safe, and may alter the clinical course for patients with mitochondrial deletions/mutations including PS. [Display omitted] DisclosuresJacoby:Novartis Israel: Consultancy. Blumkin:Minovia Therapeutics: Employment. Sher:Minovia Therapeutics: Employment. Yivgi Ohana:Minovia Therapeutics: Employment. Toren:Novartis Israel: Consultancy.

Elevated Baseline Cortisol Levels Are Predictive of Bad Outcomes in Critically Ill Children.

The definition of an adequate adrenal response in critically ill children continues to be controversial. We aimed to evaluate the cortisol levels at baseline and after adrenocorticotropin (ACTH) stimulation and determine their association to clinical outcome of critically ill children. All children who underwent an ACTH test in the pediatric intensive care unit (PICU) in a tertiary medical center between 2006 and 2013 were included in the study. Data on age, sex, diagnosis, vasoactive-inotropic score, length of pediatric intensive care unit stay, and mortality were obtained. Laboratory variables included hematologic and chemistry data, arterial lactate, and total plasma cortisol levels at baseline and after ACTH stimulation. Ninety-nine patients (61 males; median [range] age, 2 [0-204] months) were enrolled. The mortality rate of children with a baseline cortisol level of 600 nmol/L or greater was 36% (12/33 patients) versus 18% (12/66 patients) for children with a baseline cortisol level of less than 600 nmol/L (odds ratio, 2.6 [95% confidence interval, 1-6.6]; P = 0.05). There was a positive correlation between baseline cortisol and lactate levels (r = 0.40, P < 0.0001), vasoactive-inotropic scores (r = 0.24, P = 0.02), and mortality (P = 0.05). There was no correlation between peak cortisol measured at the ACTH test or the delta increment of cortisol from baseline and mortality. A high baseline cortisol level in critically ill children was associated with more severe illness, higher lactate level, and a higher mortality rate. Routine baseline cortisol assessment is recommended to identify patients at high mortality risk.

Lactic acidosis - update 2018

Severe hyperlactaemia in intensive care patients is most often due to underlying sepsis or septic, cardiogenic or haemorrhagic shock. Hyperlactaemia is an independent predictor of death in various groups of critically ill patients. With serum lactate values > 10 mmol/l 80 % of the patients die in intensive care, and if the severe lactic acidosis persists for 48 hours, all patients die. Increased lactate levels require immediate diagnostic work-up and classification. The new sepsis definition requires a serum lactate > 2 mmol/l for septic shock with adequate volume substitution and vasopressor administration in order to achieve a mean arterial pressure in persistent hypotension ≥ 65 mmHg. The 1-hour bundle of the Surviving Sepsis Campaign published in 2018 recommends as a first measure the determination of the lactate serum concentrations, and increased values should be closely monitored. In addition, blood culture sampling, broad-spectrum antibiotics, fluid resuscitation and vasopressor administration are recommended within the first hour. Large amounts of crystalloids should be given for increased lactate levels (≥ 4 mmol/l) and refractory hypotension, the administration of fluids can be adjusted according to lactate clearance. Lactate metabolism is prolonged in patients with liver function impairment. Lactate levels on admission to intensive care are significantly associated with the number of failing organs and mortality in patients with cirrhosis. 12-hour lactate clearance has a strong predictive prognosis for survival in patients with baseline lactate levels above 5 mmol/l, the latter remains an independent predictor for the severity of the underlying disease even after correction. The greater the decrease in lactate during the initial therapy, the better the outcome.

Examining Lactate Changes during High Intensity Spinning&lt;sup&gt;&amp;reg;&lt;/sup&gt; Training

The aim of the study was to examine the changes in the acute blood lactate levels of elite taekwondo players when carrying out high-intensity interval training on Spinning® bikes. Twenty elite-level taekwondo athletes participated in the study. The subjects were selected from athletes who had been competitors for at least six years. Their average age, height and weight values were determined to be 18.89±2.07 years, 176.8 ± 8.73 cm and 70.59 ± 12.13 kg respectively. In the present study the subjects carried out high-intensity interval training using Spinning bikes based on the Tabata protocol. The loads were applied as a total of four sets of eight repetitions with the principle of 20 seconds of load followed by 10 seconds of rest with one-minute's rest given between sets. The subjects' lactate levels were measured from their fingers using the Accutrend Lactate portable lactate analyzer with the help of the strips provided. Lactate measurements were made five times: before training (Pre), after Set 1 (1S), after Set 2 (2S), after Set 3 (3S) and once the exercise was over (Post). The heart rates (HR) of the athletes were monitored by their coaches before and during exercise. The data were analyzed using One Way ANOVA in the SPSS 22 package program. A statistically significant difference was found among the baseline lactate levels, the 1S, 2S, 3S and post lactate levels in the study (p 0.05). As a result of the study it was observed that Spinning® training carried out using the high-intensity interval training method caused a rapid increase in acute lactic acid accumulation. In the case of performance athletes, we can say that this exercise could be part of the lactate tolerance training used to counter fatigue.

Immune profiles and clinical outcomes between sepsis patients with or without active cancer requiring admission to intensive care units.

BackgroundImmunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU.MethodsA combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016.ResultsOf the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals).ConclusionsAmong patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.

Central activation of the A1 adenosine receptor in fed mice recapitulates only some of the attributes of daily torpor.

Mice enter bouts of daily torpor, drastically reducing metabolic rate, core body temperature (T b), and heart rate (HR), in response to reduced caloric intake. Because central adenosine activation has been shown to induce a torpor-like state in the arctic ground squirrel, and blocking the adenosine-1 (A1) receptor prevents daily torpor, we hypothesized that central activation of the A1 adenosine receptors would induce a bout of natural torpor in mice. To test the hypothesis, mice were subjected to four different hypothermia bouts: natural torpor, forced hypothermia (FH), isoflurane-anesthesia, and an intracerebroventricular injection of the selective A1 receptor agonist N6-cyclohexyladenosine (CHA). All conditions induced profound hypothermia. T b fell more rapidly in the FH, isoflurane-anesthesia, and CHA conditions compared to torpor, while mice treated with CHA recovered at half the rate of torpid mice. FH, isoflurane-anesthesia, and CHA-treated mice exhibited a diminished drop in HR during entry into hypothermia as compared to torpor. Mice in all conditions except CHA shivered while recovering from hypothermia, and only FH mice shivered substantially while entering hypothermia. Circulating lactate during the hypothermic bouts was not significantly different between the CHA and torpor conditions, both of which had lower than baseline lactate levels. Arrhythmias were largely absent in the FH and isoflurane-anesthesia conditions, while skipped beats were observed in natural torpor and periodic extended (>1s) HR pauses in the CHA condition. Lastly, the hypothermic bouts showed distinct patterns of gene expression, with torpor characterized by elevated hepatic and cardiac Txnip expression and all other hypothermic states characterized by elevated c-Fos and Egr-1 expression. We conclude that CHA-induced hypothermia and natural torpor are largely different physiological states.