Microvascular alterations were first described in critically ill patients about 20 years ago. These alterations are characterized by a decrease in vascular density and presence of non-perfused ...capillaries close to well-perfused vessels. In addition, heterogeneity in microvascular perfusion is a key finding in sepsis. In this narrative review, we report our actual understanding of microvascular alterations, their role in the development of organ dysfunction, and the implications for outcome. Herein, we discuss the state of the potential therapeutic interventions and the potential impact of novel therapies. We also discuss how recent technologic development may affect the evaluation of microvascular perfusion.
Oxygen monitoring has been a topic of exhaustive study given its central role in the biochemistry of life. The ability to quantify the physiological distribution and real‐time dynamics of oxygen from ...sub‐cellular to macroscopic levels is required to fully understand the mechanisms associated with both normal physiology and disease states. This Review will present the most significant recent advances in the development of oxygen‐sensing materials and techniques, including polarographic, nuclear medicine, magnetic resonance, and optical approaches, that can be applied specifically for the real‐time monitoring of oxygen dynamics in cellular and tissue environments. As some of the most exciting recent advances in synthetic methods and biomedical applications have been in the field of optical oxygen sensors, a major focus will be on the development of these toolkits.
Tracking oxygen: To fully comprehend oxygen's critical role in the biochemistry of life, various techniques have been developed for the measurement of its physiological tensions in different environments. There have been exciting advances in both instrumentation and method development, leading to techniques that are capable of providing oxygenation information from sub‐cellular to macroscopic tissue levels (image: changes in oxygen consumption in a full‐thickness burn).
Near‐infrared spectroscopy (NIRS) is a common tool used to study oxygen availability and utilization during repeated‐sprint exercise. However, there are inconsistent methods of smoothing and ...determining peaks and nadirs from the NIRS signal, which make interpretation and comparisons between studies difficult. To examine the effects of averaging method on deoxyhaemoglobin concentration (HHb) trends, nine males performed ten 10‐s sprints, with 30 seconds of recovery, and six analysis methods were used for determining peaks and nadirs in the HHb signal. First, means were calculated over predetermined windows in the last 5 and 2 seconds of each sprint and recovery period. Second, moving 5‐seconds and 2‐seconds averages were also applied, and peaks/nadirs were determined for each 40‐seconds sprint/recovery cycle. Third, a Butterworth filter was used to smooth the signal, and the resulting signal output was used to determine peaks and nadirs from predetermined time points and a rolling approach. Correlation and residual analysis showed that the Butterworth filter attenuated the “noise” in the signal, while maintaining the integrity of the raw data (r = .9892; mean standardized residual −9.71 × 103 ± 3.80). Means derived from predetermined windows, irrespective of length and data smoothing, underestimated the magnitude of peak and nadir HHb compared to a rolling mean approach. Consequently, sprint‐induced metabolic changes (inferred from ΔHHb) were underestimated. Based on these results, we suggest using a digital filter to smooth NIRS data, rather than an arithmetic mean, and a rolling approach to determine peaks and nadirs for accurate interpretation of muscle oxygenation trends.
Norepinephrine is the principal vasopressor used to restore blood pressure in sepsis, but its effects on intrarenal oxygenation are unknown. To clarify this, we examined renal cortical, medullary, ...and urinary oxygenation in ovine septic acute kidney injury and the response to resuscitation with norepinephrine. A renal artery flow probe and fiberoptic probes were placed in the cortex and medulla of sheep to measure tissue perfusion and oxygenation. A probe in the bladder catheter measured urinary oxygenation. Sepsis was induced in conscious sheep by infusion of Escherichia coli for 32 hours. At 24 to 30 hours of sepsis, either norepinephrine, to restore mean arterial pressure to preseptic levels or vehicle-saline was infused (8 sheep per group). Septic acute kidney injury was characterized by a reduction in blood pressure of ∼12 mm Hg, renal hyperperfusion, and oliguria. Sepsis reduced medullary perfusion (from an average of 1289 to 628 blood perfusion units), medullary oxygenation (from 32 to 16 mm Hg), and urinary oxygenation (from 36 to 24 mm Hg). Restoring blood pressure with norepinephrine further reduced medullary perfusion to an average of 331 blood perfusion units, medullary oxygenation to 8 mm Hg and urinary oxygenation to 18 mm Hg. Cortical perfusion and oxygenation were preserved. Thus, renal medullary hypoxia caused by intrarenal blood flow redistribution may contribute to the development of septic acute kidney injury, and resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. The parallel changes in medullary and urinary oxygenation suggest that urinary oxygenation may be a useful real-time biomarker for risk of acute kidney injury.
Up to 15 billion dollars of US health care expenditure each year is consumed by treatment of poorly healing wounds whose etiologies are often associated with aberrancies in tissue oxygenation. To ...address this issue, several modes of tissue oxygen delivery systems exist, including Hyperbaric Oxygen Therapy (HBOT) and Topical Oxygen Therapy (TOT), but their efficacies have yet to be fully substantiated. Micro/nanobubbles (MNBs), which range anywhere from 100 μm to <1 μm in diameter and are relatively stable for hours, offer a new mode of oxygen delivery to wounds. The aim of this article is to systematically review literature examining the use of TOT for wound healing and use of MNBs for tissue oxygenation using the MEDLINE database. The search yielded 87 articles (12 MNB articles and 75 TOT articles), of which 52 met the inclusion criteria for this literature review (12 MNB articles and 40 TOT articles). Additionally, we present an analysis on the efficacy of our MNB generating technology and propose its use as a wound healing agent.
The ability to quickly diagnose hemorrhagic shock is critical for favorable patient outcomes. Therefore, it is important to understand the time course and involvement of the various physiological ...mechanisms that are active during volume loss and that have the ability to stave off hemodynamic collapse. This review provides new insights about the physiology that underlies blood loss and shock in humans through the development of a simulated model of hemorrhage using lower body negative pressure. In this review, we present controlled experimental results through utilization of the lower body negative pressure human hemorrhage model that provide novel insights on the integration of physiological mechanisms critical to the compensation for volume loss. We provide data obtained from more than 250 human experiments to classify human subjects into two distinct groups: those who have a high tolerance and can compensate well for reduced central blood volume (e.g. hemorrhage) and those with low tolerance with poor capacity to compensate.We include the conceptual introduction of arterial pressure and cerebral blood flow oscillations, reflex-mediated autonomic and neuroendocrine responses, and respiration that function to protect adequate tissue oxygenation through adjustments in cardiac output and peripheral vascular resistance. Finally, unique time course data are presented that describe mechanistic events associated with the rapid onset of hemodynamic failure (i.e. decompensatory shock).
Impact Statement
Hemorrhage is the leading cause of death in both civilian and military trauma. The work submitted in this review is important because it advances the understanding of mechanisms that contribute to the total integrated physiological compensations for inadequate tissue oxygenation (i.e. shock) that arise from hemorrhage. Unlike an animal model, we introduce the utilization of lower body negative pressure as a noninvasive model that allows for the study of progressive reductions in central blood volume similar to those reported during actual hemorrhage in conscious humans to the onset of hemodynamic decompensation (i.e. early phase of decompensatory shock), and is repeatable in the same subject. Understanding the fundamental underlying physiology of human hemorrhage helps to test paradigms of critical care medicine, and identify and develop novel clinical practices and technologies for advanced diagnostics and therapeutics in patients with life-threatening blood loss.
Determinations of renal oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in chronic kidney disease (CKD) patients have given heterogeneous results, possibly due ...to the lack of a reproducible method to analyse BOLD-MRI. It therefore remains uncertain whether patients with CKD have a reduced renal tissue oxygenation. We developed a new method to analyse BOLD-MRI signals and applied it to CKD patients and controls.
MRI was performed under standardized conditions before and 15 min after IV furosemide in 104 CKD patients, 61 hypertensives and 42 controls. MR images were analysed with the new twelve-layer concentric objects method (TLCO) that divides renal parenchyma in 12 layers of equal thickness. The mean R2* value of each layer was reported, along with the change in R2* between successive layers, as measured by the slope steepness of the relevant curve.
Inter-observer variability was 2.3 ± 0.9%, 1.9 ± 0.8% and 3.0 ± 2.3% in, respectively, controls, moderate and severe CKD. The mean R2* of the outer (more cortical) layers was significantly higher in CKD, suggesting lower cortical oxygenation as compared with controls. In CKD patients, the response to furosemide was blunted in the inner (more medullary) layers, and the R2* slope was flatter. In multivariable regression analysis, the R2* slope correlated positively with estimated glomerular filtration rate (eGFR) in patients with an eGFR <90 mL/min/1.73 m2 (P < 0.001).
Using the new TLCO method, we confirm the hypothesis that renal cortical oxygenation is reduced in CKD in humans, and that the level of cortical oxygenation correlates with CKD severity.
Haemodynamic oscillations occurring at frequencies below the rate of respiration have been observed experimentally for more than a century. Much of the research regarding these oscillations, observed ...in arterial pressure and blood flow, has focused on mechanisms of generation and methods of quantification. However, examination of the physiological role of these oscillations has been limited. Multiple studies have demonstrated that oscillations in arterial pressure and blood flow are associated with the protection in tissue oxygenation or functional capillary density during conditions of reduced tissue perfusion. There is also evidence that oscillatory blood flow can improve clearance of interstitial fluid, with a growing number of studies demonstrating a role for oscillatory blood flow to aid in clearance of debris from the brain. The therapeutic potential of these haemodynamic oscillations is an important new area of research which may have beneficial impact in treating conditions such as stroke, cardiac arrest, blood loss injuries, sepsis, or even Alzheimer's disease and vascular dementia.
figure legend Oscillations in arterial pressure and blood flow at frequencies around 0.1 Hz and 0.05 Hz increase under conditions of tissue hypoperfusion. Accumulating evidence suggests these haemodynamic oscillations are important in preserving tissue oxygenation, increasing functional capillary density, and increasing tissue fluid clearance, which has potential therapeutic implications.
This article provides a snapshot of muscle near-infrared spectroscopy (NIRS) at the end of 2010 summarizing the recent literature, offering the present status and perspectives of the NIRS ...instrumentation and methods, describing the main NIRS studies on skeletal muscle physiology, posing open questions and outlining future directions. So far, different NIRS techniques (e.g. continuous-wave (CW) and spatially, time- and frequency-resolved spectroscopy) have been used for measuring muscle oxygenation during exercise. In the last four years, approximately 160 muscle NIRS articles have been published on different physiological aspects (primarily muscle oxygenation and haemodynamics) of several upper- and lower-limb muscle groups investigated by using mainly two-channel CW and spatially resolved spectroscopy commercial instruments. Unfortunately, in only 15 of these studies were the advantages of using multi-channel instruments exploited. There are still several open questions in the application of NIRS in muscle studies: (i) whether NIRS can be used in subjects with a large fat layer; (ii) the contribution of myoglobin desaturation to the NIRS signal during exercise; (iii) the effect of scattering changes during exercise; and (iv) the effect of changes in skin perfusion, particularly during prolonged exercise. Recommendations for instrumentation advancements and future muscle NIRS studies are provided.
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