Monitoring mitochondrial PO2: the next step

PURPOSE OF REVIEW: To fully exploit the concept of hemodynamic coherence in resuscitating critically ill one should preferably take into account information about the state of parenchymal cells. Monitoring of mitochondrial oxygen tension (mitoPO2) has emerged as a clinical means to assess information of oxygen delivery and oxygen utilization at the mitochondrial level. This review will outline the basics of the technique, summarize its development and describe the rationale of measuring oxygen at the mitochondrial level. RECENT FINDINGS: Mitochondrial oxygen tension can be measured by means of the protoporphyrin IX-Triplet State Lifetime Technique (PpIX-TSLT). After validation and use in preclinical animal models, the technique has recently become commercially available in the form of a clinical measuring system. This system has now been used in a number of healthy volunteer studies and is currently being evaluated in studies in perioperative and intensive care patients in several European university hospitals. SUMMARY: PpIX-TSLT is a noninvasive and well tolerated method to assess aspects of mitochondrial functio

Diagnostic Errors Induced by a Wrong a Priori Diagnosis: A Prospective Randomized Simulator-Based Trial

Preventive strategies against diagnostic errors require the knowledge of underlying mechanisms. We examined the effects of a wrong a priori diagnosis on diagnostic accuracy of a focussed assessment in an acute myocardial infarction scenario. One-hundred-and-fifty-six medical students (cohort 1) were randomized to three study arms differing in the a priori diagnosis revealed: no diagnosis (control group), myocardial infarction (correct diagnosis group), and pulmonary embolism (wrong diagnosis group). Forty-four physicians (cohort 2) were randomized to the control group and the wrong diagnosis group. Primary endpoint was the participants’ final presumptive diagnosis. Among students, the correct diagnosis of an acute myocardial infarction was made by 48/52 (92%) in the control group, 49/52 (94%) in the correct diagnosis group, and 14/52 (27%) in the wrong diagnosis group (p p = 0.023). In the wrong diagnosis group, 31/52 (60%) students and 6/23 (19%) physicians indicated their initially given wrong a priori diagnosis pulmonary embolism as final diagnosis. A wrong a priori diagnosis significantly increases the likelihood of a diagnostic error during a subsequent patient encounter

Fluid resuscitation does not improve renal oxygenation during hemorrhagic shock in rats

Background: The resuscitation strategy for hemorrhagic shock remains controversial, with the kidney being especially prone to hypoxia. Methods: The authors used a three-phase hemorrhagic shock model to investigate the effects of fluid resuscitation on renal oxygenation. After a 1-h shock phase, rats were randomized into four groups to receive either normal saline or hypertonic saline targeting a mean arterial pressure (MAP) of either 40 or 80 mmHg. After such resuscitation, rats were transfused with the shed blood. Renal macro-and microcirculation were monitored with cortical and outer-medullary microvascular oxygen pressure, renal oxygen delivery, and renal oxygen consumption measured using oxygen-dependent quenching of phosphorescence. Results: Hemorrhagic shock was characterized by a drop of aortic blood flow, MAP, renal blood flow, renal oxygen delivery, renal oxygen consumption, and renal microvascular PO2. During the fluid resuscitation phase, normal saline targeting a MAP = 80 mmHg was the sole strategy able to restore aortic blood flow, renal blood flow, and renal oxygen consumption, although without improving renal oxygen delivery. However, none of the strategies using either normal saline or hypertonic saline or targeting a high MAP could restore the renal microvascular Po2. Blood transfusion increased microvascular Po2 but was unable to totally restore renal microvascular oxygenation to baseline values. Conclusions: This experimental rat study shows that (1) high MAP-directed fluid resuscitation (80 mmHg) does not lead to higher renal microvascular Po2 compared with fluid resuscitation targeted to MAP (40 mmHg); (2) hypertonic saline is not superior to normal saline regarding renal oxygenation; and (3) decreased renal oxygenation persists after blood transfusion

In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique

Mitochondrial oxygen tension (mitoPO2) is a key parameter for cellular function, which is considered to be affected under various pathophysiological circumstances. Although many techniques for assessing in vivo oxygenation are available, no technique for measuring mitoPO2in vivo exists. Here we report in vivo measurement of mitoPO2and the recovery of mitoPO2histograms in rat liver by a novel optical technique under normal and pathological circumstances. The technique is based on oxygen-dependent quenching of the delayed fluorescence lifetime of protoporphyrin IX. Application of 5-aminolevulinic acid enhanced mitochondrial protoporphyrin IX levels and induced oxygen-dependent delayed fluorescence in various tissues, without affecting mitochondrial respiration. Using fluorescence microscopy, we demonstrate in isolated hepatocytes that the signal is of mitochondrial origin. The delayed fluorescence lifetime was calibrated in isolated hepatocytes and isolated perfused livers. Ultimately, the technique was applied to measure mitoPO2in rat liver in vivo. The results demonstrate mitoPO2values of ∼30-40 mmHg. mitoPO2was highly sensitive to small changes in inspired oxygen concentration around atmospheric oxygen level. Ischemia-reperfusion interventions showed altered mitoPO2distribution, which flattened overall compared to baseline conditions. The reported technology is scalable from microscopic to macroscopic applications, and its reliance on an endogenous compound greatly enhances its potential field of applications

Mitochondrial oxygen tension within the heart

By using a newly developed optical technique which enables non-invasive measurement of mitochondrial oxygenation (mitoPO2) in the intact heart, we addressed three long-standing oxygenation questions in cardiac physiology: 1) what is mitoPO2 within the in vivo heart?, 2) is mitoPO2 heterogeneously distributed?, and 3) how does mitoPO2 of the isolated Langendorff-perfused heart compare with that in the in vivo working heart? Following calibration and validation studies of the optical technique in isolated cardiomyocytes, mitochondria and intact hearts, we show that in the in vivo condition mean mitoPO2 was 35 ± 5 mm Hg. The mitoPO2 was highly heterogeneous, with the largest fraction (26%) of mitochondria having a mitoPO2 between 10 and 20 mm Hg, and 10% between 0 and 10 mm Hg. Hypoxic ventilation (10% oxygen) increased the fraction of mitochondria in the 0–10 mm Hg range to 45%, whereas hyperoxic ventilation (100% oxygen) had no major effect on mitoPO2. For Langendorff-perfused rat hearts, mean mitoPO2 was 29 ± 5 mm Hg with the largest fraction of mitochondria (30%) having a mitoPO2 between 0 and 10 mm Hg. Only in the maximally vasodilated condition, did the isolated heart compare with the in vivo heart (11% of mitochondria between 0 and 10 mm Hg). These data indicate 1) that the mean oxygen tension at the level of the mitochondria within the heart in vivo is higher than generally considered, 2) that mitoPO2 is considerably heterogeneous, and 3) that mitoPO2 of the classic buffer-perfused Langendorff heart is shifted to lower values as compared to the in vivo heart

International Study on Microcirculatory Shock Occurrence in Acutely Ill Patients

Objectives: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. the prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables.Design: Multicenter observational point prevalence study.Setting: the Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide.Patients: A heterogeneous ICU population consisting of 501 patients.Interventions: None.Measurements and Main Results: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index ( 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. in reference to microvascular flow index, a significant interaction was observed with tachycardia. in patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients.Conclusions: in a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.Erasmus MC Univ Med Ctr, Dept Intens Care Adults, Rotterdam, NetherlandsMed Ctr Leeuwarden, Dept Intens Care, Leeuwarden, NetherlandsUniv Politecn Marche, Dept Biomed Sci & Publ Hlth, Ancona, ItalyServ Terapia Intens Sanatorio Otamendi & Miroli, Buenos Aires, DF, ArgentinaBeth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USABarts & London Queen Marys Sch Med & Dent, London, EnglandUniversidade Federal de São Paulo, São Paulo, BrazilUniv Klinikum RWTH Aachen, Klin Anesthesiol, Aachen, GermanyKosuyolu Univ, K Kosuyolu High Specialty Educ & Res Hosp, Istanbul, TurkeyLithuanian Univ Hlth Sci, Dept Intens Care, Kaunas, LithuaniaCooper Univ Hosp, Sect Cardiol, Camden, NJ USAUniv Basel Hosp, Med Intens Care Unit, CH-4031 Basel, SwitzerlandSt Antonius Hosp, Dept Anesthesiol Intens Care & Pain Manag, Nieuwegein, NetherlandsOnze Lieve Vrouw Hosp, Dept Intens Care, Amsterdam, NetherlandsSt Louis Univ Hosp, Mercy Hosp St Louis, St Louis, MO USAUniv Plymouth, Peninsula Sch Med, Derriford Hosp, Plymouth PL4 8AA, Devon, EnglandHacettepe Univ, Intens Care Unit, Ankara, TurkeyUDELAR, Sch Med, Hosp Espanol ASSE, Intens Care Unit, Montevideo, UruguayNew Cross Hosp, Intens Care Unit, Wolverhampton, W Midlands, EnglandUniv Paris 07, Hop Lariboisiere, AP HP, Dept Anesthesiol Crit Care & SMUR, Paris, FranceCanberra Hosp, Intens Care Unit, Canberra, ACT, AustraliaRoyal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, AustraliaIspat Hosp, Intens Care Unit, Rourkela, Orissa, IndiaUniv Pittsburgh, Pittsburgh, PA USAUniv Calif San Diego, Sch Med, San Diego, CA 92103 USAJoan XXIII Univ Hosp, Dept Crit Care, Tarragona, SpainPontificia Univ Catolica Chile, Fac Med, Escuela Med, Dept Med Intens, Santiago, ChileHosp San Martin, Intens Care Unit, La Plata, Buenos Aires, ArgentinaUniv Paris 11, Hop Bicetre, AP HP, Hop Univ Paris Sud,Dept Anesthesie Reanimat, Paris, FranceGelre Ziekenhuizen, Intens Care Unit, Apeldoorn, NetherlandsRoyal Marsden Hosp, Intens Care Unit, London SW3 6JJ, EnglandRoyal Devon & Exeter Hosp, Intens Care Unit, Exeter EX2 5DW, Devon, EnglandSanta Maria Angeli Hosp, Intens Care Unit, Pordenone, ItalyUniv Jena, Univ Klinikum Jena, Dept Internal Med 1, Jena, GermanyRoyal Free Hosp, Intens Care Unit, London NW3 2QG, EnglandDipartimento Anestesia Rianimaz & Terapia Intens, Treviso, ItalyUniv Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, NetherlandsUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc