Effects of restrictive fluid therapy on the time to resolution of hyperlactatemia in ICU patients with septic shock. A secondary post hoc analysis of the CLASSIC randomized trial.

PURPOSE: The aim of this study was to examine the effects of intravenous (IV) fluid restriction on time to resolution of hyperlactatemia in septic shock. Hyperlactatemia in sepsis is associated with worse outcome. Sepsis guidelines suggest targeting lactate clearance to guide fluid therapy despite the complexity of hyperlactatemia and the potential harm of fluid overload. METHODS: We conducted a post hoc analysis of serial plasma lactate concentrations in a sub-cohort of 777 patients from the international multicenter clinical CLASSIC trial (restriction of intravenous fluids in intensive care unit (ICU) patients with septic shock). Adult ICU patients with septic shock had been randomized to restrictive (n = 385) or standard (n = 392) intravenous fluid therapy. The primary outcome, time to resolution of hyperlactatemia, was analyzed with a competing-risks regression model. Death and discharge were competing outcomes, and administrative censoring was imposed 72 h after randomization if hyperlactatemia persisted. The regression analysis was adjusted for the same stratification variables and covariates as in the original CLASSIC trial analysis. RESULTS: The hazard ratios (HRs) for the cumulative probability of resolution of hyperlactatemia, in the restrictive vs the standard group, in the unadjusted analysis, with time split, were 0.94 (confidence interval (CI) 0.78-1.14) at day 1 and 1.21 (0.89-1.65) at day 2-3. The adjusted analyses were consistent with the unadjusted results. CONCLUSION: In this post hoc retrospective analysis of a multicenter randomized controlled trial (RCT), a restrictive intravenous fluid strategy did not seem to affect the time to resolution of hyperlactatemia in adult ICU patients with septic shock.

Comparing the accuracy of prediction models to detect clinically relevant post-hepatectomy liver failure early after major hepatectomy.

BACKGROUND: Arterial lactate measurements were recently suggested as an early predictor of clinically relevant post-hepatectomy liver failure (PHLF). This needed to be evaluated in the subgroup of major hepatectomies only. METHOD: This observational cohort study included consecutive elective major hepatectomies at Karolinska University Hospital from 2010 to 2018. Clinical risk factors for PHLF, perioperative arterial lactate measurements and routine lab values were included in uni- and multivariable regression analysis. Receiver operating characteristics and risk cut-offs were calculated. RESULTS: In total, 649 patients constituted the study cohort, of which 92 developed PHLF grade B/C according to the International Study Group of Liver Surgery (ISGLS). Lactate reached significantly higher intra- and postoperative levels in PHLF grades B and C compared to grade A or no liver failure (all P < 0.002). Lactate on postoperative day (POD) 1 was superior to earlier measurement time points in predicting PHLF B/C (AUC 0.75), but was outperformed by both clinical risk factors (AUC 0.81, P = 0.031) and bilirubin POD1 (AUC 0.83, P = 0.013). A multivariable logistic regression model including clinical risk factors and bilirubin POD1 had the highest AUC of 0.87 (P = 0.006), with 56.6% sensitivity and 94.7% specificity for PHLF grade B/C (cut-off ≥0.32). The model identified 46.7% of patients with 90-day mortality and had an equally good discriminatory potential for mortality as the established ISGLS criteria for PHLF grade B/C but could be applied already on POD1. CONCLUSION: The potential of lactate to predict PHLF following major hepatectomy was inferior to a prediction model consisting of clinical risk factors and bilirubin on first post-operative day.

A retrospective multicenter cohort study of the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19.

BACKGROUND: Patients with critical COVID-19 have a high risk of thromboembolism, but intensified thromboprophylaxis has not been proven beneficial. The activity of low-molecular-weight heparins can be monitored by measuring anti-Factor Xa. We aimed to study the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19. METHOD: This retrospective cohort study included adult patients with critical COVID-19 admitted to an intensive care unit at three Swedish hospitals between March 2020 and May 2021 with at least one valid peak and/or trough anti-Factor Xa value. Within the peak and trough categories, patients' minimum, median, and maximum values were determined. Logistic regressions with splines were used to assess associations. RESULTS: In total, 408 patients had at least one valid peak and/or trough anti-Factor Xa measurement, resulting in 153 patients with peak values and 300 patients with trough values. Lower peak values were associated with thromboembolism for patients' minimum (p = 0.01), median (p = 0.005) and maximum (p = 0.001) values. No association was seen between peak values and death or bleeding. Higher trough values were associated with death for median (p = 0.03) and maximum (p = 0.002) values and with both bleeding (p = 0.01) and major bleeding (p = 0.02) for maximum values, but there were no associations with thromboembolism. CONCLUSIONS: Measuring anti-Factor Xa activity may be relevant for administrating low-molecular-weight heparin to patients with critical COVID-19. Lower peak values were associated with an increased risk of thromboembolism, and higher trough values were associated with an increased risk of death and bleeding. Prospective studies are needed to confirm the results. TRIAL REGISTRATION: The study was retrospectively registered at Clinicaltrials.gov, NCT05256524, February 24, 2022.

Prevalence and impact of chronic dysglycaemia among patients with COVID-19 in Swedish intensive care units: a multicentre, retrospective cohort study.

OBJECTIVE: Using glycated haemoglobin A1c (HbA1c) screening, we aimed to determine the prevalence of chronic dysglycaemia among patients with COVID-19 admitted to the intensive care unit (ICU). Additionally, we aimed to explore the association between chronic dysglycaemia and clinical outcomes related to ICU stay. DESIGN: Multicentre retrospective observational study. SETTING: ICUs in three hospitals in Stockholm, Sweden. PARTICIPANTS: COVID-19 patients admitted to the ICU between 5 March 2020 and 13 August 2020 with available HbA1c at admission. Chronic dysglycaemia was determined based on previous diabetes history and HbA1c. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was the actual prevalence of chronic dysglycaemia (pre-diabetes, unknown diabetes or known diabetes) among COVID-19 patients. Secondary outcome was the association of chronic dysglycaemia with 90-day mortality, ICU length of stay, duration of invasive mechanical ventilation (IMV) and renal replacement therapy (RRT), accounting for treatment selection bias. RESULTS: A total of 308 patients with available admission HbA1c were included. Chronic dysglycaemia prevalence assessment was restricted to 206 patients admitted ICUs in which HbA1c was measured on all admitted patients. Chronic dysglycaemia was present in 82.0% (95% CI 76.1% to 87.0%) of patients, with pre-diabetes present in 40.2% (95% CI 33.5% to 47.3%), unknown diabetes in 20.9% (95% CI 15.5% to 27.1%), well-controlled diabetes in 7.8% (95% CI 4.5% to 12.3%) and uncontrolled diabetes in 13.1% (95% CI 8.8% to 18.5%). All patients with available HbA1c were included for the analysis of the relationship between chronic dysglycaemia and secondary outcomes. We found no independent association between chronic dysglycaemia and 90-day mortality, ICU length of stay or duration of IMV. After excluding patients with specific treatment limitations, no association between chronic dysglycaemia and RRT use was observed. CONCLUSIONS: In our cohort of critically ill COVID-19 patients, the prevalence of chronic dysglycaemia was 82%. We found no robust associations between chronic dysglycaemia and clinical outcomes when accounting for treatment limitations.

[Challanges and possibilities with space travel]. / Rymdmedicin: utmaningar och möjligheter med rymdfärder.

Human space flight poses several challenges to human health, such as microgravity, space radiation, and prolonged confinement. Humans are anatomically and physiologically adapted to the gravitation on earth, and microgravity affects crucial functions. We review the pathophysiological consequences of spaceflight on the sensomotoric, cardiovascular, cerebral, and musculoskeletal systems, as well as effects of space radiation and psychosocial considerations. We also look at the medical capabilities in space, and different research methods on earth and in space.

Frequency of blood lactate elevation following esophagectomy and its association to postoperative complications.

BACKGROUND: Esophagectomy is a major surgical intervention and a cornerstone in the treatment of esophageal cancer. There is clinical experience that blood lactate concentration often is elevated in the period following esophagectomy, but the incidence and clinical consequences are sparsely studied. METHODS: We extracted data from all patients undergoing esophagectomy at Karolinska University Hospital 2016-2018, n = 153. Most were performed with minimally invasive technique, n = 130. Blood lactate values directly after surgery, highest value during the first night, and morning level on postoperative day one were recorded. Primary outcome was hospital length of stay and secondary outcome was a composite of postoperative infection, additional surgery, or intensive care during the hospital stay. Development of anastomotic leak was analyzed separately. RESULTS: Postoperative hyperlactatemia was common as 93% of patients had peak lactate concentration >1.6 mmol/L and 27% >3.5 mmol/L in the first night following operation. Median hospital length of stay was 14 days. Blood lactate showed a weak correlation to hospital stay and intensive care the morning following surgery, but not at arrival to postoperative ward. There were no statistical differences between those with and without anastomotic leak at any of the time points. Elevated lactate in the first 12-16 h postoperatively was related to surgical factors (open technique, surgery time, and perioperative bleeding) but not to patient related factors (ASA-class, Charlson comorbidity index, sex, age) or cumulative fluid balance. CONCLUSION: In conclusion, elevated blood lactate in the immediate time following esophagectomy showed a weak association to intensive care and length of stay but not anastomotic leak.

Characteristics and outcomes of patients with COVID-19 admitted to ICU in a tertiary hospital in Stockholm, Sweden.

BACKGROUND: Information on characteristics and outcomes of intensive care unit (ICU) patients with COVID-19 remains limited. We examined characteristics, clinical course and early outcomes of patients with COVID-19 admitted to ICU. METHODS: We included all 260 patients with COVID-19 admitted to nine ICUs at the Karolinska University Hospital (Stockholm, Sweden) between 9 March and 20 April 2020. Primary outcome was in-hospital mortality among patients with definite outcomes (discharged from ICU or death), as of 30 April 2020 (study end point). Secondary outcomes included ICU length of stay, the proportion of patients receiving mechanical ventilation and renal replacement therapy, and hospital discharge destination. RESULTS: Of 260 ICU patients with COVID-19, 208 (80.0%) were men, the median age was 59 (IQR 51-65) years, 154 (59.2%) had at least one comorbidity, and the median duration of symptoms preceding ICU admission was 11 (IQR 8-14) days. Sixty-two (23.8%) patients remained in ICU at study end point. Among the 198 patients with definite outcomes, ICU length of stay was 12 (IQR, 6-18) days, 163 (82.3%) received mechanical ventilation, 28 (14.1%) received renal replacement therapy, 60 (30.3%) died, 62 (31.3%) were discharged home, 47 (23.7%) were discharged to ward, and 29 (14.6%) were discharged to another health care facility. On multivariable logistic regression analysis, older age and admission from the emergency department was associated with higher mortality. CONCLUSION: This study presents detailed data on clinical characteristics and early outcomes of consecutive patients with COVID-19 admitted to ICU in a large tertiary hospital in Sweden.

Thromboembolism, Hypercoagulopathy, and Antiphospholipid Antibodies in Critically Ill Coronavirus Disease 2019 Patients: A Before and After Study of Enhanced Anticoagulation.

To determine the prevalence of thrombotic events, functional coagulation tests, inflammatory biomarkers, and antiphospholipid antibodies before and after enhanced anticoagulation in critically ill coronavirus disease 2019 patients. DESIGN: Retrospective. SETTING: Tertiary intensive care unit. PATIENTS: Two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients were included before (cohort 1, n = 12) and after (cohort 2, n = 14) enhanced prophylactic anticoagulation strategy. INTERVENTIONS: Before and after study of enhanced anticoagulation. MEASUREMENTS AND MAIN RESULTS: Thromboelastometry point-of-care coagulation tests were performed by thromboelastography (Tem International GmbH, Munich, Germany), standard blood tests were extracted from patient charts, and presence of antiphospholipid antibodies in plasma was measured. All patients were males on mechanical ventilation. In cohort 1 (low-molecular-weight heparin dose: 129 ± 53 U/kg/24 hr), 50% had pulmonary embolism, and thromboelastography analysis revealed hypercoagulation in a majority of patients and greater than 80% had detectable antiphospholipid antibodies. In the second cohort (enhanced low-molecular-weight heparin dose: 200 ± 82 U/kg/24 hr; p = 0.04 vs cohort 1), we found a nonsignificantly lower prevalence of pulmonary embolism (21%; p = 0.22), lower fibrinogen (6.3 ± 2.5 vs 8.7 ± 2.0; p = 0.02), reduced fibrinogen-dependent thromboelastography (p < 0.001), and lower inflammatory markers. CONCLUSIONS: In these two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients, thromboembolic complications, hypercoagulation, and antiphospholipid antibodies were common. A more aggressive anticoagulation regime was associated with a reduction in inflammatory biomarkers including plasma fibrinogen and a reduction in fibrinogen-dependent hypercoagulation, as indicated by thromboelastography analyses.

Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients.

BACKGROUND: A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. METHOD: In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500-4500 IU tinzaparin or 2500-5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. RESULTS: A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13-0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43-1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. CONCLUSIONS: Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. TRIAL REGISTRATION: Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

Lactate kinetics in ICU patients using a bolus of 13C-labeled lactate.

BACKGROUND: Plasma lactate concentrations and their trends over time are used for clinical prognosis, and to guide treatment, in critically ill patients. Although heavily relied upon for clinical decision-making, lactate kinetics of these patients is sparsely studied. AIM: To establish and validate a feasible method to study lactate kinetics in critically ill patients. METHODS: Healthy volunteers (n = 6) received a bolus dose of 13C-labeled lactate (20 µmol/kg body weight), and 43 blood samples were drawn over 2 h to determine the decay in labeled lactate. Data was analyzed using non-compartmental modeling calculating rates of appearance (Ra) and clearance of lactate. The area under the curve (AUC) was calculated using a linear-up log-down trapezoidal approach with extrapolation beyond 120 min using the terminal slope to obtain the whole AUC. After evaluation, the same protocol was used in an unselected group of critically ill patients (n = 10). RESULTS: Ra for healthy volunteers and ICU patients were 12.8 ± 3.9 vs 22.7 ± 11.1 µmol/kg/min and metabolic clearance 1.56 ± 0.39 vs 1.12 ± 0.43 L/min, respectively. ICU patients with normal lactate concentrations showed kinetics very similar to healthy volunteers. Simulations showed that reducing the number of samples from 43 to 14 gave the same results. Our protocol yielded results on lactate kinetics very similar to previously published data using other techniques. CONCLUSION: This simple and user-friendly protocol using an isotopically labeled bolus dose of lactate was accurate and feasible for studying lactate kinetics in critically ill ICU patients. TRIAL REGISTRATION: ANZCTR, ACTRN12617000626369, registered 8 March 2017. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372507&isReview=true.

COVID-19 critical illness in Sweden: characteristics and outcomes at a national population level.

Objective: During the coronavirus disease 2019 (COVID-19) pandemic, baseline demographics and comorbidities of patients with COVID-19 have been presented, but there are limited data on outcomes of severely ill patients. We aimed to examine the association between patient characteristics and 30-day mortality among patients with COVID-19 treated in the intensive care unit (ICU). Design: Population-based cohort study. Setting: ICUs in Sweden. Participants: All consecutive patients with COVID-19 admitted to Swedish ICUs from 6 March to 5 April 2020. Main outcome measures: The primary outcome was 30-day mortality after ICU admission. Patient demographics, comorbidities and clinical characteristics were also retrieved. Results: A total of 604 patients were included. The median age was 61 years (interquartile range [IQR], 52-70 years) and 458 patients (76%) were males. The most common comorbidities were hypertension (35.9%) and diabetes (25.7%), whereas 36.4% of patients had no comorbidities. Median Simplified Acute Physiology Score (SAPS) 3 was 53 (IQR, 46-60). Of 573 patients with available respiratory support data, 487 (85.0%) received invasive mechanical ventilation. Among 518 patients with available data, 117 (22.6%) received renal replacement therapy. Median length of stay was 13 days (IQR, 6-20 days). Mortality at 30 days was 32.6%. In the multivariable Cox regression model, age (hazard ratio [HR] 1.06; 95% CI, 1.04-1.07 per year), the presence of one or more comorbidities (HR, 1.80; 95% CI, 1.20-2.68), chronic obstructive pulmonary disease or asthma (HR, 1.68; 95% CI, 1.12-2.50), hypertension (HR, 1.41; 95% CI, 1.01-1.99), and acute illness severity (SAPS 3 excluding age and comorbidity) (HR, 1.06; 95% CI, 1.04-1.09) were associated with 30-day mortality. Conclusions: This population-based cohort study presents 30-day mortality of 604 ICU patients with COVID-19. The higher mortality was explained by older age, the presence chronic illness, and acute illness severity.

Optimal cut-off for hourly lactate reduction in ICU-treated patients with septic shock.

BACKGROUND: A decrease in lactate concentration over time during septic shock is associated with favourable outcomes. However, if this applies to hourly intervals during the initial time period in the ICU is unknown. The aim of this study was to investigate whether there is an early hourly reduction rate of lactate that is related to clinical outcome in septic shock patients treated in the ICU. METHODS: A cohort of adult septic shock patients admitted to the ICU with an initial lactate level >2 mmol/L and receiving vasopressor was retrospectively analysed. Mean hourly reduction rate of lactate (ΔLact/h) was calculated individually from all lactate concentrations measured from inclusion until normalization of lactate (≤1.5 mmol/L) within 24 hours. The mortality at 30 days following ICU admission was evaluated. RESULTS: Among 1405 ICU admissions during 2 years, 104 patients were eligible. Mortality rate at 30 days was 34%. The optimal cut-off values of baseline lactate and ΔLact/h for 30-day mortality were 4 mmol/L and 2.5%/h. When stratifying the patients by these cut-points, those with baseline lactate > 4 mmol/L and ΔLact/h < 2.5%/h had lowest probability of survival (27%). Multivariable logistic regression showed that ΔLact/h <2.5%/h, baseline lactate >4 mmol/L and high Simplified Acute Physiology Score III were independent risk factors of 30-day mortality. CONCLUSIONS: In this retrospective pilot cohort, a mean reduction rate of lactate <2.5%/h within the first 24 hours of ICU stay was associated with an increased risk of 30-day mortality in septic shock patients.

An attenuated rate of leg muscle protein depletion and leg free amino acid efflux over time is seen in ICU long-stayers.

BACKGROUND: There is extensive documentation on skeletal muscle protein depletion during the initial phase of critical illness. However, for intensive care unit (ICU) long-stayers, objective data are very limited. In this study, we examined skeletal muscle protein and amino acid turnover in patients with a prolonged ICU stay. METHODS: Patients (n = 20) were studied serially every 8-12 days between days 10 and 40 of their ICU stay as long as patients stayed in the ICU. Leg muscle protein turnover was assessed by measurements of phenylalanine kinetics, for which we employed a stable isotope-labeled phenylalanine together with two-pool and three-pool models for calculations, and results were expressed per 100 ml of leg volume. In addition, leg muscle amino acid flux was studied. RESULTS: The negative leg muscle protein net balance seen on days 10-20 of the ICU stay disappeared by days 30-40 (p = 0.012). This was attributable mainly to an increase in the de novo protein synthesis rate (p = 0.007). It was accompanied by an attenuated efflux of free amino acids from the leg. Leg muscle protein breakdown rates stayed unaltered (p = 0.48), as did the efflux of 3-methylhistidine. The arterial plasma concentrations of free amino acids did not change over the course of the study. CONCLUSIONS: In critically ill patients with sustained organ failure and in need of a prolonged ICU stay, the initial high rate of skeletal muscle protein depletion was attenuated over time. The distinction between the acute phase and a more prolonged and more stable phase concerning skeletal muscle protein turnover must be considered in study protocols as well as in clinical practice. TRIAL REGISTRATION: Australian New Zealand Trial Registry, ACTRN12616001012460 . Retrospectively registered on 1 August 2016.

Muscle metabolism.

PURPOSE OF REVIEW: To review the recent findings on metabolic derangements leading to loss of muscle mass and function. RECENT FINDINGS: Several recent studies investigated methods to assess muscle mass and function and its clinical relevance. These are also included. A few studies confirm that a low muscle mass is related to a worse outcome but also a compromised muscle function at discharge is related to long-term survival. A low quality of muscle assessed by the density of muscle from a computed tomography scan is related to mortality. For the metabolic derangements, a compromised handling of calcium is present in muscle of animal models and might be causing a decreased muscle function in patients. Transcriptomics analyses of muscle post-ICU indicated an upregulation of regenerative pathways, but still muscle mass is not recovering in most patients. This could be due to an impairment regenerative capacity due to satellite cells dysfunction. SUMMARY: Muscle mass and function are related to outcome. New finding show that not only muscle mass but also muscle quality is important, that a compromised handling of calcium might be involved in muscle weakness and that regaining muscle could be compromised due to a defective regenerative capacity of satellite cells.

The effect of plasma from septic ICU patients on healthy rat muscle mitochondria.

BACKGROUND: Although sepsis-induced organ failure is a major cause of death in ICU worldwide, the associated mitochondrial dysfunction is not fully characterized and there is presently no evidence of causality. In this study, we examined whether a central factor in septic plasma could directly affect respiratory function of healthy rat muscle mitochondria. METHODS: ICU patients with severe sepsis or septic shock were recruited within 24 h of admission together with age-matched controls. Blood samples were centrifuged and immediately frozen. Two trials were performed, and mitochondrial respiration was analyzed using an Oxygraph chamber with a Clark-electrode. (1) Isolated mitochondria from the rat skeletal muscle were divided and incubated for 30 min with plasma from patients or postoperative controls (n = 10). Respiration was normalized for citrate synthase activity. (2) Permeabilized muscle fibers from rats were divided and incubated with plasma from patients or healthy controls, for 30 and 120 min, and analyzed for mitochondrial respiration (n = 10). Respiration was normalized for wet weight. Primary outcome was state 3 respiration, corresponding to the maximal respiration initiated by ADP and energy substrates (malate and pyruvate). T test was used for statistical comparison. RESULTS: No differences in respiratory function of the mitochondria were seen between the groups in either of the experiments. (1) State 3 respiration of isolated mitochondria were 19.9 ± 6.7 vs. 20.2 ± 8.8 nmol O2 × U CS(-1) × min(-1) for sepsis vs. control, respectively. (2) State 3 respiration for fibers incubated with septic and control plasma were after 30 min 2.6 ± 0.3 vs. 2.4 ± 0.7 and after 120 min 2.5 ± 0.4 vs. 2.5 ± 0.6 nmol O2 × mg × w.w(-1) × min(-1). Respiratory control ratios were good in all experiments (8.8-11.2), ensuring functioning mitochondria. CONCLUSIONS: These findings indicate that muscle mitochondria are not directly influenced by a factor in plasma of septic patients. The effects seen in mitochondrial function in sepsis may rather be a result of intracellular processes and signaling, such as e.g., production of reactive oxygen species.

Lactate kinetics and mitochondrial respiration in skeletal muscle of healthy humans under influence of adrenaline.

Plasma lactate is widely used as a biomarker in critical illness. The aims of the present study were to elucidate the usefulness of a three-compartment model for muscle lactate kinetics in humans and to characterize the response to an exogenous adrenaline challenge. Repeated blood samples from artery and femoral vein together with blood flow measurements and muscle biopsies were obtained from healthy male volunteers (n=8) at baseline and during an adrenaline infusion. Concentrations of lactate and enrichment of [13C]lactate were measured and kinetics calculated. Mitochondrial activity, glycogen concentration, oxygen uptake and CO2 release were assessed. The adrenaline challenge increased plasma lactate 4-fold as a result of a greater increase in the rate of appearance (R(a)) than the increase in the rate of disappearance (R(d)). Leg muscle net release of lactate increased 3.5-fold, whereas intramuscular production had a high variation but did not change. Mitochondrial state 3 respiration increased by 30%. Glycogen concentration, oxygen uptake and CO2 production remained unchanged. In conclusion a three-compartment model gives additional information to the two-compartment model but, due to its larger variation and invasive muscle biopsy, it is less likely to become a regularly used tool in clinical research. Hyperlactataemia in response to adrenergic stimuli was driven by an elevated lactate release from skeletal muscle most probably due to a redirection of a high intramuscular turnover rather than an increased production.