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 function at the bedside. It allows doctors to look beyond the macrocirculation and microcirculation and to take the oxygen balance at the cellular level into account in treatment strategies.

Bedside hand vein inspection for noninvasive central venous pressure assessment.

Rapid estimates of the central venous pressure (CVP) can be helpful to administer early fluid therapy or to manage cardiac preload in intensive care units, operating rooms or emergency rooms in order to start and monitor an adequate medical therapy. Invasive CVP measurements have inherent and non-negligible complication rates as well as great expenditures. Several noninvasive methods of CVP measurements, like ultrasound-guided techniques, are available, but require trained skills and special equipment which might not be at hand in all situations. Our purpose was to evaluate the feasibility and accuracy of CVP estimates assessed upon the height of hand veins collapse (HVC) using invasively measured CVP as the gold standard. The HVC was determined by slowly lifting the patient's hand while watching the dorsal hand veins to collapse. The vertical distance from the dorsal hand to a transducer air zero port was noted and converted to mmHg. The observer was blinded to the simultaneously measured CVP values, which were categorized as low (<7 mmHg), normal (7-12 mmHg) and high (>12 mmHg). Measurements were performed in 82 patients who had a median [IQR] age of 67 [60;74]. Median CVP was 12 [8;15] mmHg and the median absolute difference between the measured HVC and CVP was 4 [2;7] mmHg. The Spearman correlation coefficient between CVP and HVC was 0.55, 95%-CI [0.35;0.69]. Overall CVP categorization was correct in 45% of the cases. HVC had a sensitivity of 92% for a low CVP with a negative predictive value of 98%. A high HVC had a sensitivity of 29% but a high specificity of 94% for a high CVP. The overall performance of observing the hand vein collapse to estimate CVP was only moderate in the intensive care setting. However, the median difference to the CVP was low and HVC identifies a low CVP with a high sensitivity and excellent negative predictive value.

The introduction of a standardised national licensing exam as a driver of change in medical education: A qualitative study from Switzerland.

INTRODUCTION: Only a few studies have described the impacts, strengths and needs for further development of national licensing exams (NLE). To gain such insights regarding the Swiss NLE, which includes a multiple-choice and a standardised clinical skills exam, we explored the perceptions of involved experts and stakeholders. METHODS: We explored participants' perceptions in four focus group discussions. The interviews were recorded, transcribed verbatim and qualitatively analysed using a thematic analysis approach. RESULTS: The analysis resulted in five perceived impacts, two strengths and two needs for further developments of the NLE. Perceived impacts were (1) steering students' learning behaviour, (2) supporting teachers and assessors to align teaching to competencies, (3) elevating the importance of the Swiss Catalogue of Learning Objectives, (4) setting incentives for the further development of curricula, and (5) fostering the collaboration between the faculties of medicine. Perceived strengths were the blend of assessment formats, including their competency-based orientation, and the collaborative development approach. Perceived needs lay in the NLE's further development to sustain its fit for purpose and in incentives for people involved. CONCLUSION: According to our study, this NLE had, and has, notable impacts on medical education in Switzerland. Our insights can be useful for others planning a similar undertaking.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

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 (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 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.

Increased in vivo mitochondrial oxygenation with right ventricular failure induced by pulmonary arterial hypertension: mitochondrial inhibition as driver of cardiac failure?

BACKGROUND: The leading cause of mortality due to pulmonary arterial hypertension (PAH) is failure of the cardiac right ventricle. It has long been hypothesized that during the development of chronic cardiac failure the heart becomes energy deprived, possibly due to shortage of oxygen at the level of cardiomyocyte mitochondria. However, direct evaluation of oxygen tension levels within the in vivo right ventricle during PAH is currently lacking. Here we directly evaluated this hypothesis by using a recently reported technique of oxygen-dependent quenching of delayed fluorescence of mitochondrial protoprophyrin IX, to determine the distribution of mitochondrial oxygen tension (mitoPO2) within the right ventricle (RV) subjected to progressive PAH. METHODS: PAH was induced through a single injection of monocrotaline (MCT). Control (saline-injected), compensated RV hypertrophy (30 mg/kg MCT; MCT30), and RV failure (60 mg/kg MCT; MCT60) rats were compared 4 wk after treatment. The distribution of mitoPO2 within the RV was determined in mechanically-ventilated, anaesthetized animals, applying different inspired oxygen (FiO2) levels and two increment dosages of dobutamine. RESULTS: MCT60 resulted in RV failure (increased mortality, weight loss, increased lung weight), MCT30 resulted in compensated RV hypertrophy. At 30% or 40% FiO2, necessary to obtain physiological arterial PO2 in the diseased animals, RV failure rats had significantly less mitochondria (15% of total mitochondria) in the 0-20 mmHg mitoPO2 range than hypertrophied RV rats (48%) or control rats (54%). Only when oxygen supply was reduced to 21% FiO2, resulting in low arterial PO2 for the MCT60 animals, or when oxygen demand increased with high dose dobutamine, the number of failing RV mitochondria with low oxygen became similar to control RV. In addition, metabolic enzyme analysis revealed similar mitochondrial mass, increased glycolytic hexokinase activity following MCT, with increased lactate dehydrogenase activity only in compensated hypertrophied RV. CONCLUSIONS: Our novel observation of increased mitochondrial oxygenation suggests down-regulation of in vivo mitochondrial oxygen consumption, in the absence of hypoxia, with transition towards right ventricular failure induced by pulmonary arterial hypertension.

Sex-Based Differences in Clinical Characteristics of Patients with Acute Myocarditis: A Cohort Study.

BACKGROUND: This study investigated sex differences in acute myocarditis patients during index hospitalization. METHODS: We included 365 patients with acute myocarditis, hospitalized with continuous monitoring at the intensive care unit from 2000-2023 into the Basel Myocarditis Cohort study. We compared sex differences in clinical presentation, the presenting electrocardiogram, prior medical history, inflammatory and cardiac biomarkers, cardiac imaging, arrhythmia occurrence, and short- to midterm outcomes. RESULTS: Mean age was 41.3 years, and 26.3% were female. Compared with men, women were older (median 49.7 vs 38.3 years, P < .001) at the time of diagnosis and presented more frequently with dyspnea (41 vs 26%, P = .013) and a higher Killip class (P = .011). In the presenting electrocardiogram, men had a higher occurrence of diffuse ST-elevation (38 vs 9%, P < .001) and PQ-depression (31 vs 20%, P = .042), compared with women. Women had higher N-terminal pro B-type natriuretic peptide levels (1180 vs 387 ng/L, P = .015), lower cardiac troponin T levels (389 vs 726 ng/L, P = .006), and fewer segments with nonischemic late gadolinium enhancement on cardiac magnetic resonance imaging (1 vs 3, P = .005), but similar left ventricular ejection fraction (55 vs 55%, P = .629), compared with men. Overall, hospital stay was longer in women compared with men (7 vs 5 days, P = .018), with a similar length of intensive care unit stay (2.6 vs 2.7 days, P = .922). Women more often developed severe arrhythmia (8.3 vs 2.2%, P = .015) and heart failure during the hospitalization (31.3 vs 16.4%, P = .003). CONCLUSION: Compared with men, women with acute myocarditis were older at the time of diagnosis, presented more often with heart failure, and had an increased frequency of severe arrhythmia.

Thyroid hemorrhage causing airway obstruction after intravenous thrombolysis for acute ischemic stroke.

BACKGROUND: There are several life-threatening complications associated with intravenous thrombolysis after acute ischemic stroke such as symptomatic intracerebral hemorrhage, orolingual angioedema, or less frequent, bleedings of the mucosa or ecchymosis. Aside from these known critical incidents, rare and unfamiliar complications may be even more challenging, as they are unexpected and may mimic events that appear more frequently. We report a rare and unusual acute complication of intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) (0.9 mg/kg) administered for acute ischemic stroke. METHODS: Medical records, radiologic imaging, and pathologic specimens were reviewed. RESULTS: A 86-year-old woman developed acute respiratory failure 20 h after thrombolysis with suspected angioedema triggered by intravenous rt-PA. The inspiratory stridor and dyspnea were unresponsive to bronchodilators, corticosteroids, and inhaled adrenaline. After endotracheal intubation, laryngoscopy showed no significant supraglottic narrowing. Thyroidal sonography and cervical computed tomography revealed a thyroidal mass causing a tracheal and vascular compression compatible with thyroidal hemorrhage. Sonography showed a nodular goiter of the right thyroid gland. A total thyroidectomy was performed and histologic analysis confirmed a hemorrhage of the right thyroidal lobe. CONCLUSIONS: Acute airway obstruction with respiratory failure due to thyroidal hemorrhage after intravenous thrombolysis is an important life-threatening complication, mimicking an anaphylactic reaction or a more frequent orolingual angioedema.

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 < 0.001 vs. both other groups). Among physicians, the correct diagnosis was made by 20/21 (95%) in the control group and 15/23 (65%) in the wrong diagnosis group (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.

Brief leadership instructions improve cardiopulmonary resuscitation in a high-fidelity simulation: a randomized controlled trial.

OBJECTIVE: The influence of teaching leadership on the performance of rescuers remains unknown. The aim of this study was to compare leadership instruction with a general technical instruction in a high-fidelity simulated cardiopulmonary resuscitation scenario. DESIGN: Prospective, randomized, controlled superiority trial. SETTING: Simulator Center of the University Hospital Basel in Switzerland. SUBJECTS: Two-hundred thirty-seven volunteer medical students in teams of three. INTERVENTION: During a baseline visit, the medical students participated in a video-taped simulated witnessed cardiac arrest. Participants were thereafter randomized to receive instructions focusing either on correct positions of arms and shoulders (technical instruction group) or on leadership and communication to enhance team coordination (leadership instruction group). A follow-up simulation was conducted after 4 mos. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the amount of hands-on time, defined as duration of uninterrupted cardiopulmonary resuscitation in the first 180 secs after the onset of the cardiac arrest (hands-on time) [corrected]. Secondary outcomes were time to start cardiopulmonary resuscitation, total leadership utterances, and technical skills. Outcomes were compared based on videotapes coded by two independent researchers. After a balanced performance at baseline, the leadership instruction group demonstrated a longer hands-on time (120 secs; interquartile range, 98-135 vs. 87 secs; interquartile range, 61-108; p < .001), a shorter median time to start cardiopulmonary resuscitation (44 secs; interquartile range, 32-62; vs. 67 secs; interquartile range, 43-79; p = .018), and had more leadership utterances (7; interquartile range, 4-10; vs. 5; interquartile range, 2-8; p = .02) in the follow-up visit. The rate of correct arm and shoulder positions was higher in teams with technical instruction (59%; 19 out of 32; vs. 23%; 7 out of 31; p = .003). CONCLUSIONS: Video-assisted leadership and technical instructions after a simulated cardiopulmonary resuscitation scenario showed sustained efficacy after a 4-mo duration. Leadership instructions were superior to technical instructions, with more leadership utterances and better overall cardiopulmonary resuscitation performance.

Serum procalcitonin, C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study.

INTRODUCTION: The aim of this study was to investigate time course of procalcitonin (PCT), C-reactive protein (CRP) and white blood cell (WBC) levels in patients with therapeutic hypothermia after cardiac arrest. METHODS: We retrospectively assessed laboratory and clinical data in a consecutive cohort of patients admitted to the medical intensive-care-unit of the University Hospital in Basel, Switzerland, in whom therapeutic hypothermia was induced because of cardiac arrest between December 2007 and January 2009. Infection was considered based on microbiological evidence (restricted definition) and/or clinical evidence of infection with prescription of antibiotics (extended definition). RESULTS: From 34 included patients, 25 had respiratory tract infection based on the clinical judgment and in 18 microbiological cultures turned positive (restricted definition). PCT concentrations were highest on the first day after hypothermia and showed a steady decrease until day 7 without differences in patients with and without presumed infection. CRP concentrations increased to a peak level at days 3-4 followed by a steady decrease; CRP concentrations were higher in patients with clinical diagnosis of infection on day 4 (P = 0.02); and in patients with evidence of bacterial growth in cultures on days 4 and 5 (P = 0.01 and P = 0.006). WBC remained unchanged after hypothermia without differences between patients with and without infection. CONCLUSION: High initial values of PCT and high peak levels after 3-4 days of CRP were found in patients with induction of hypothermia after cardiac arrest. This increase was unspecific and mirrors rather an inflammatory reaction than true underlying infection, limiting the diagnostic potential for early antibiotic stewardship in these patients.

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.

Improvement of sidestream dark field imaging with an image acquisition stabilizer.

BACKGROUND: In the present study we developed, evaluated in volunteers, and clinically validated an image acquisition stabilizer (IAS) for Sidestream Dark Field (SDF) imaging. METHODS: The IAS is a stainless steel sterilizable ring which fits around the SDF probe tip. The IAS creates adhesion to the imaged tissue by application of negative pressure. The effects of the IAS on the sublingual microcirculatory flow velocities, the force required to induce pressure artifacts (PA), the time to acquire a stable image, and the duration of stable imaging were assessed in healthy volunteers. To demonstrate the clinical applicability of the SDF setup in combination with the IAS, simultaneous bilateral sublingual imaging of the microcirculation were performed during a lung recruitment maneuver (LRM) in mechanically ventilated critically ill patients. One SDF device was operated handheld; the second was fitted with the IAS and held in position by a mechanic arm. Lateral drift, number of losses of image stability and duration of stable imaging of the two methods were compared. RESULTS: Five healthy volunteers were studied. The IAS did not affect microcirculatory flow velocities. A significantly greater force had to applied onto the tissue to induced PA with compared to without IAS (0.25 +/- 0.15 N without vs. 0.62 +/- 0.05 N with the IAS, p < 0.001). The IAS ensured an increased duration of a stable image sequence (8 +/- 2 s without vs. 42 +/- 8 s with the IAS, p < 0.001). The time required to obtain a stable image sequence was similar with and without the IAS. In eight mechanically ventilated patients undergoing a LRM the use of the IAS resulted in a significantly reduced image drifting and enabled the acquisition of significantly longer stable image sequences (24 +/- 5 s without vs. 67 +/- 14 s with the IAS, p = 0.006). CONCLUSIONS: The present study has validated the use of an IAS for improvement of SDF imaging by demonstrating that the IAS did not affect microcirculatory perfusion in the microscopic field of view. The IAS improved both axial and lateral SDF image stability and thereby increased the critical force required to induce pressure artifacts. The IAS ensured a significantly increased duration of maintaining a stable image sequence.

Mitochondrial oxygen tension within the heart.

By using a newly developed optical technique which enables non-invasive measurement of mitochondrial oxygenation (mitoPO(2)) in the intact heart, we addressed three long-standing oxygenation questions in cardiac physiology: 1) what is mitoPO(2) within the in vivo heart?, 2) is mitoPO(2) heterogeneously distributed?, and 3) how does mitoPO(2) 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 mitoPO(2) was 35+/-5 mm Hg. The mitoPO(2) was highly heterogeneous, with the largest fraction (26%) of mitochondria having a mitoPO(2) 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 mitoPO(2). For Langendorff-perfused rat hearts, mean mitoPO(2) was 29+/-5 mm Hg with the largest fraction of mitochondria (30%) having a mitoPO(2) 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 mitoPO(2) is considerably heterogeneous, and 3) that mitoPO(2) of the classic buffer-perfused Langendorff heart is shifted to lower values as compared to the in vivo heart.

Microcirculation and mitochondria in sepsis: getting out of breath.

PURPOSE OF REVIEW: To present the recent findings obtained in clinical and experimental studies examining microcirculatory alterations in sepsis, their link to mitochondrial dysfunction, and current knowledge regarding the impact of these alterations on the outcome of septic patients. RECENT FINDINGS: Interlinked by a mutual cascade effect and driven by the host-pathogen interaction, microcirculatory and mitochondrial functions are impaired during sepsis. Mitochondrial respiration seems to evolve during the course of sepsis, demonstrating a change from reversible to irreversible inhibition. The spatiotemporal heterogeneity of microcirculatory and mitochondrial dysfunction suggests that these processes may be compartmentalized. Although a causal relationship between mitochondrial and microcirculatory dysfunction and organ failure in sepsis is supported by an increasing number of studies, adaptive processes have also emerged as part of microcirculatory and mitochondrial alterations. Treatments for improving or preserving microcirculatory, mitochondrial function, or both seem to yield a better outcome in patients. SUMMARY: Even though there is evidence that microcirculatory and mitochondrial dysfunction plays a role in the development of sepsis-induced organ failure, their interaction and respective contribution to the disease remains poorly understood. Future research is necessary to better define such relationships in order to identify therapeutic targets and refine treatment strategies.

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

Mitochondrial oxygen tension (mitoPO(2)) 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 mitoPO(2) in vivo exists. Here we report in vivo measurement of mitoPO(2) and the recovery of mitoPO(2) histograms 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 mitoPO(2) in rat liver in vivo. The results demonstrate mitoPO(2) values of approximately 30-40 mmHg. mitoPO(2) was highly sensitive to small changes in inspired oxygen concentration around atmospheric oxygen level. Ischemia-reperfusion interventions showed altered mitoPO(2) distribution, 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.

Prolonged administration of ß-lactam antibiotics - a comprehensive review and critical appraisal.

Prolonged infusion of ß-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates. The pharmacokinetics of ß-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance. This may lead to a significant decrease in plasma concentrations of ß-lactam antibiotics. As a consequence, low pharmacokinetic/pharmacodynamic (PK/PD) target attainment, which is described as the percentage of time that the free drug concentration is maintained above the minimal inhibitory concentration (MIC) of the causative organism (fT>MIC), has been documented for ß-lactam treatment in these patients when using standard intermittent bolus dosing, even for the most conservative target (50% fT>MIC). Prolonged infusion of ß-lactams has consistently been shown to improve PK/PD target attainment, particularly in patients with severe infections. However, evidence regarding relevant patient outcomes is still limited. Whereas previous observational studies have suggested a clinical benefit of prolonged infusion, results from two recent randomised controlled trials of continuous infusion versus intermittent bolus administration of ß-lactams are conflicting. In particular, the larger, double-blind placebo-controlled randomised controlled trial including 443 patients did not demonstrate any difference in clinical outcomes. We believe that a personalised approach is required to truly optimise ß-lactam treatment in critically ill patients. This may include therapeutic drug monitoring with real-time adaptive feedback, rapid MIC determination and the use of antibiotic dosing software tools that incorporate patient parameters, dosing history, drug concentration and site of infection. Universal administration of ß-lactam antibiotics as prolonged infusion, even if supported by therapeutic drug monitoring, is not yet ready for "prime time", as evidence for its clinical benefit is modest. There is a need for prospective randomised controlled trials that assess patient-centred outcomes (e.g. mortality) of a personalised approach in selected critically ill patients including prolonged infusion of ß-lactams compared with the current standard of care.

Staphylococcus aureus Endocarditis as a Complication of Toxocariasis-Associated Endomyocarditis With Fibrosis: A Case Report.

Complications associated with Toxocara canis infection are rare. We present a case of a patient with Staphylococcus aureus endocarditis as a complication of an endomyocardial fibrosis caused by T canis. The epidemiological, pathological, and clinical features of this rare complication are described here.

Oxygenation measurement by multi-wavelength oxygen-dependent phosphorescence and delayed fluorescence: catchment depth and application in intact heart.

Oxygen delivery and metabolism represent key factors for organ function in health and disease. We describe the optical key characteristics of a technique to comprehensively measure oxygen tension (PO(2)) in myocardium, using oxygen-dependent quenching of phosphorescence and delayed fluorescence of porphyrins, by means of Monte Carlo simulations and ex vivo experiments. Oxyphor G2 (microvascular PO(2)) was excited at 442 nm and 632 nm and protoporphyrin IX (mitochondrial PO(2)) at 510 nm. This resulted in catchment depths of 161 (86) µm, 350 (307) µm and 262 (255) µm respectively, as estimated by Monte Carlo simulations and ex vivo experiments (brackets). The feasibility to detect changes in oxygenation within separate anatomical compartments is demonstrated in rat heart in vivo. Schematic of ex vivo measurements.