Description of mitochondrial oxygen tension and its variability in healthy volunteers.

OBJECTIVES: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. DESIGN: Prospective cohort study. SETTING: Measurements were performed in Leiden University Medical Center, the Netherlands. PARTICIPANTS: Healthy volunteers enrolled from July to September 2020. INTERVENTIONS: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. PRIMARY AND SECONDARY OUTCOME MEASURES: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. RESULTS: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). CONCLUSIONS: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. TRIAL REGISTRATION: ClinicalTrials.gov with trial number NCT04626661.

A simulation of skin mitochondrial Po2 in circulatory shock.

Circulatory shock is the inadequacy to supply mitochondria with enough oxygen to sustain aerobic energy metabolism. A novel noninvasive bedside measurement was recently introduced to monitor the mitochondrial oxygen tension in the skin (mitoPo2). As the most downstream marker of oxygen balance in the skin, mitoPo2 may provide additional information to improve shock management. However, a physiological basis for the interpretation of mitoPo2 values has not been established yet. In this paper, we developed a mathematical model of skin mitoPo2 using a network of parallel microvessels, based on Krogh's cylinder model. The model contains skin blood flow velocity, heterogeneity of blood flow, hematocrit, arteriolar oxygen saturation, and mitochondrial oxygen consumption as major variables. The major results of the model show that normal physiological mitoPo2 is in the range of 40-60 mmHg. The relationship of mitoPo2 with skin blood flow velocity follows a logarithmic growth curve, reaching a plateau at high skin blood flow velocity, suggesting that oxygen balance remains stable while peripheral perfusion declines. The model shows that a critical range exists where mitoPo2 rapidly deteriorates if skin perfusion further decreases. The model intuitively shows how tissue hypoxia could occur in the setting of septic shock, due to the profound impact of microcirculatory disturbance on mitoPo2, even at sustained cardiac output. MitoPo2 is the result of a complex interaction between all factors of oxygen delivery and microcirculation. This mathematical framework can be used to interpret mitoPo2 values in shock, with the potential to enhance personalized clinical trial design.NEW & NOTEWORTHY This is the first paper to simulate mitochondrial oxygen tension in skin in circulatory shock. The relationships of mitoPo2 with parameters of (microcirculatory) oxygen delivery aid in the understanding of noninvasive bedside measurement of mitoPo2 values and show that mitochondrial oxygen tension is two orders of magnitude higher than classically assumed. The model can be used to enhance clinical trial design investigating mitoPo2 as a resuscitation target in circulatory shock.

Prediction of Inhospital Mortality in Critically Ill Patients With Sepsis: Confirmation of the Added Value of 24-Hour Lactate to Acute Physiology and Chronic Health Evaluation IV.

We previously reported the added value of 24-hour lactate concentration alone and in combination with 24-hour lactate clearance and lactate concentration at admission for the prediction of inhospital mortality in critically ill patients with sepsis. We aimed to validate this finding. DERIVATION COHORT: The derivation cohort from Leiden, The Netherlands, consisted of 451 critically ill patients with sepsis. VALIDATION COHORT: The validation cohort consisted of 4,440 critically ill adult patients with sepsis from the Medical Information Mart for Intensive Care cohort admitted to the ICU of Beth Israel Deaconness Medical Center, Boston, MA, between January 2006 and 2018. PREDICTION MODEL: Predictors of mortality were: age, chronic comorbidities, length of stay pre-ICU, Glasgow Coma Scale, and Acute Physiology Score. Lactate concentration at 24-hour alone, in combination with 24-hour lactate clearance and in combination with lactate concentration at admission, was added to assess improvement of the prediction model. The outcome was inhospital mortality. RESULTS: Inhospital mortality occurred in 160 patients (36%) in the derivation cohort and in 2,347 patients (53%) in the validation cohort. The Acute Physiology and Chronic Health Evaluation (APACHE) IV model had a moderate discriminative performance (recalibrated C-statistic, 0.62; 95% CI, 0.60-0.63). Addition of 24-hour lactate concentration increased the recalibrated C-statistic to 0.64 (95% CI, 0.62-0.66). The model with 24-hour lactate concentration and lactate concentration at admission showed the best fit as depicted by the smallest Akaike Information Criterion in both the derivation and validation data. CONCLUSION: The 24-hour lactate concentration and lactate concentration at admission contribute modestly to prediction of inhospital mortality in critically ill patients with sepsis. Future updates and possible modification of APACHE IV should consider the incorporation of lactate concentration at baseline and at 24 hours.

Study protocol and pilot results of an observational cohort study evaluating effect of red blood cell transfusion on oxygenation and mitochondrial oxygen tension in critically ill patients with anaemia: the INsufficient Oxygenation in the Intensive Care Unit (INOX ICU-2) study.

INTRODUCTION: The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO2) in vivo at the bedside. MitoPO2might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study. METHODS AND ANALYSIS: We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO2, which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods. ETHICS AND DISSEMINATION: The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT03092297.

The Added Value of Lactate and Lactate Clearance in Prediction of In-Hospital Mortality in Critically Ill Patients With Sepsis.

We investigated the added predictive value of lactate and lactate clearance to the Acute Physiology and Chronic Health Evaluation IV model for predicting in-hospital mortality in critically ill patients with sepsis. DESIGN: Retrospective observational cohort study. SETTING: Mixed ICU of Leiden University Medical Center, The Netherlands. PATIENTS: Critically ill patients adult patients with sepsis who have been admitted to the ICU of Leiden University Medical Center, The Netherlands, from 2006 to January 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We fitted a baseline model with the Acute Physiology and Chronic Health Evaluation IV predictors and added 13 prespecified combinations of lactate and lactate clearance at 0, 6 and 24 hours after admission to create a set of extended models to compare with the baseline Acute Physiology and Chronic Health Evaluation IV model. Among 603 ICU admissions, 451 patients met the inclusion criteria. A total of 160 patients died in-hospital, of which 106 died in the ICU. Their lactate and lactate clearance measurements were higher at all time points than those of survivors. The Akaike Information Criterion score improved in 10 of 13 prespecified extended models, with best performance for models that included lactate at 24 hours, alone or in combination with lactate at admission or lactate clearance at 24 hours. We compared the observed and predicted probabilities of in-hospital mortality of the baseline Acute Physiology and Chronic Health Evaluation IV model with the best model in our data, lactate at 24 hours added to the Acute Physiology and Chronic Health Evaluation IV model. This resulted in an increase in specificity of 29.9% (95% CI, 18.9-40.9%). CONCLUSIONS: Lactate measurements at 24 hours after admission add predictive value to the prediction of mortality with Acute Physiology and Chronic Health Evaluation IV among ICU patients with sepsis. External validation is needed to develop extended prediction models.

Nationwide Study on the Course of Influenza A (H1N1) Infections in Hospitalized Children in the Netherlands During the Pandemic 2009-2010.

BACKGROUND: The influenza H1N1 pandemic of 2009-2010, provided a unique opportunity to assess the course of disease, as well as the analysis of risk factors for severe disease in hospitalized children (< 18 years). METHODS: Retrospective national chart study on hospitalized children with H1N1 infection during the 2009-2010 pH1N1 outbreak. RESULTS: Nine hundred forty patients (56% boys), median age 3.0 years, were enrolled; the majority were previously healthy. Treatment consisted of supplemental oxygen (24%), mechanical ventilation (5%) and antiviral therapy (63%). Fifteen patients died (1.6%), 5 of whom were previously healthy. Multivariable analyses confirmed pre-existent heart and lung disease as risk factors for intensive care unit admission. Risk factors for mortality included children with a neurologic or oncologic disease and psychomotor retardation. CONCLUSIONS: This nationwide overview of hospitalized children confirms known risk groups for severe influenza infections. However, most of the acute and severe presentations of influenza occurred in previously healthy children.

Fall risk in people with MS: A Physiological Profile Assessment study.

INTRODUCTION: The Physiological Profile Assessment (PPA) is used in research and clinical practice for assessing fall risk. We compared PPA test performance between people with multiple sclerosis (MS) and healthy controls, determined the fall-risk profile for people with MS and developed a reference database for people with MS. METHODS: For this study, 416 ambulant people with MS (51.5 ± 12.0 years) and 352 controls (52.8 ± 12.2 years) underwent the PPA (tests of contrast sensitivity, proprioception, quadriceps strength, reaction time and sway) with composite fall-risk scores computed from these measures. MS participants were followed prospectively for falls for 3 months. RESULTS: The MS participants performed significantly worse than controls in each PPA test. The average composite fall-risk score was also significantly elevated, indicating a "marked" fall risk when compared with controls. In total, 155 MS participants (37.3%) reported 2 + falls in the follow-up period. Frequent fallers performed significantly worse than non-frequent fallers in the contrast sensitivity, reaction time and sway tests and had higher PPA composite scores. CONCLUSIONS: In line with poor PPA test performances, falls incidence in people with MS was high. This study provides comprehensive reference data for the PPA measures for people with MS that could be used to inform future research and clinical practice.