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Noninvasive Cellular Oxygenation Measurement During Graded Hypoxia Using Visible–Near-Infrared Spectroscopy

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Abstract

In critically ill patients, direct knowledge of intracellular pO 2 would allow for identification of cellular hypoxia, which when prolonged leads to organ failure. We have developed a visible–near-infrared optical system that noninvasively measures myoglobin saturation, which is directly related to intracellular pO 2 , from the surface of the skin. We used an animal model of graded hypoxia from low levels of inspired oxygen ( n = 5) and verified that low intracellular pO 2 is correlated with high steady-state serum lactate values. In addition, the pO 2 gradient between arterial blood and inside muscle cells was 83 mm Hg at 21% O 2 , but fell to 24 mm Hg at 8% O 2 . Continuous myoglobin saturation measurement in skeletal muscle displayed the same trends as cerebral oxygenation with no lag in changes over time, demonstrating its relevance as a measure of systemic oxygenation.

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There is increasing interest in the application of near infrared spectroscopy (NIRS) as a noninvasive monitor of cerebral oxygenation. This review will briefly describe the principles of NIRS and examine current evidence for its clinical application as a monitor of the adequacy of cerebral oxygenation in adults. There has been a recent surge of interest in the clinical application of NIRS following studies that have quantified the benefits of NIRS-guided management of cerebral oxygenation during cardiopulmonary bypass. However, there are limited data to support its widespread application in other clinical scenarios. New NIRS systems are being introduced to the market and technological advancements have improved their accuracy and extended the range of variables measured. NIRS offers noninvasive monitoring of cerebral oxygenation over multiple regions of interest in a wide range of clinical scenarios. It has many potential advantages over other neuromonitoring techniques, but further technological advances are necessary before it can be introduced more widely into clinical practice.
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A method to simultaneously measure oxygenation in vascular, intracellular, and mitochondrial spaces from optical spectra acquired from muscle has been developed. In order to validate the method, optical spectra in the visible and near-infrared regions (600-850 nm) were acquired from solutions of myoglobin, hemoglobin, and cytochrome oxidase that included Intralipid as a light scatterer. Spectra were also acquired from the rabbit forelimb. Three partial least squares (PLS) analyses were performed on second-derivative spectra, each separately calibrated to myoglobin oxygen saturation, hemoglobin oxygen saturation, or cytochrome aa3 oxidation. The three variables were measured from in vitro and in vivo spectra that contained all three chromophores. In the in vitro studies, measured values of myoglobin saturation, hemoglobin saturation, and cytochrome aa3 oxidation had standard errors of 5.9%, 7.4%, and 12.2%, respectively, with little cross-talk between the in vitro measurements. In the progression from normal oxygenation to ischemia in the rabbit forelimb, hemoglobin desaturated first, followed by myoglobin, while cytochrome aa3 reduction occurred last. The ability to simultaneously measure oxygenations in the vascular, intracellular, and mitochondrial compartments will be valuable in physiological studies of muscle metabolism and in clinical studies when oxygen supply or utilization are compromised.
Neurologic dysfunction is a problem in patients with congenital heart disease. Near infrared spectroscopy (NIRS) may provide a real-time window into cerebral oxygenation. Enthusiasm for NIRS has increased in hopes of reducing neurologic dysfunction. However, potential gains need to be evaluated relative to cost and potential detriment of intervention before routine implementation. Responding to data in ways that seem intuitively beneficial can be risky when the long-term impact is unknown. Many centers, and even entire countries, have adopted NIRS as standard of care. Available data suggest that multimodality monitoring, including NIRS, may be a useful adjunct. However, the current literature on the use of NIRS alone does not demonstrate improvement in neurologic outcome. Data correlating NIRS findings with indirect measures of neurologic outcome or mortality are limited. Although NIRS has promise for measuring regional tissue oxygen saturation, the lack of data demonstrating improved outcomes limits the support for wide-spread implementation.
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Myoglobin (Mb) saturation was measured spectroscopically in 1,950 randomly selected cells from dog gracilis muscles frozen in situ during the transition from rest to steady twitch contraction at approximately 70% maximum rate of O2 consumption (VO2max). Measurements were made at the center of muscle-cell profiles in cross section, with spatial resolution approximately 5 X 5 X 3 micron. PO2 was calculated from saturation by use of the oxymyoglobin dissociation curve. Flow increased more rapidly than VO2 (half-times 5 and 14 s, respectively). Mb saturation changed little through 15 s. Saturation was lowest at 30 s and rose somewhat between 30 s and steady state. The lowest intracellular PO2 at any time or location was 1.5 Torr, and only 5% of loci were below 2 Torr. Since 1.5 Torr is about 10 times the minimum PO2 required for the observed VO2 (Connett et al. An upper bound on the minimum PO2 for O2 consumption in red muscle in vivo. Adv. Exp. Med. Biol. In press.), neither anoxia nor hypoxia was present. The observed fall in saturation and intracellular PO2 during exercise permits Mb to 1) promote transcapillary O2 flux, 2) facilitate intracellular O2 diffusion, 3) minimize convective and diffusive shunting, and 4) buffer intracellular PO2 above the tension that limits cytochrome turnover.
Article
Abstract A quantitative method of determining the content of myoglobin and hemoglobin in human muscle is described. A piece of muscle, 1–4 g, is ground with dry ice, homogenized and extracted with 0.02 M phosphate buffer, pH 7.4. After being centrifuged at 15,000 × g, the solution is concentrated by dialysis against 25% polyethylene glycol solution. The hemoproteins are separated by gel filtration on Sephadex G 75, identified by the absorption spectra of their carbon monoxide compounds and quantitatively determined by the pyridine hemochrome method. The content of hemoprotein is calculated as per cent of dry weight, the latter being determined on the original homogenate. In an autopsy material, mainly consisting of patients in upper age-groups with chronic disease and modest physical activity, average values of 0.9 g myoglobin per 100 g dry muscle were found in hearts (left ventricle), whereas corresponding values for diaphragm, abdominal muscle and muscles of the thigh were 1.1, 1.6 and 2.2 g per 100 g dry muscle. It is assumed that values in healthy adults may well be somewhat higher. From these values it is calculated that the total amount of myoglobin in an adult male is in the range of 120–150 g, corresponding to an iron pool of 0.37-0.47 g or approximately 7/5 of the amount of hemoglobin iron. Comparisons with determinations arrived at by other methods are made, and some aspects of the physiology of myoglobin and other hematin compounds are discussed. The insoluble or “residual” hematin has been determined. It could be shown that the major part of this hematin can be accounted for by the mitochondrial hemoproteins, the remaining part in all probability deriving from hemoglobin.
Article
The assumption that cellular oxygen pressure (PO2) is close to zero in maximally exercising muscle is essential for the hypothesis that O2 transport between blood and mitochondria has a finite conductance that determines maximum O2 consumption. The unique combination of isolated human quadriceps exercise, direct measures of arterial, femoral venous PO2, and 1H nuclear magnetic resonance spectroscopy to detect myoglobin desaturation enabled this assumption to be tested in six trained men while breathing room air (normoxic, N) and 12% O2 (hypoxic, H). Within 20 s of exercise onset partial myoglobin desaturation was evident even at 50% of maximum O2 consumption, was significantly greater in H than N, and was then constant at an average of 51 +/- 3% (N) and 60 +/- 3% (H) throughout the incremental exercise protocol to maximum work rate. Assuming a myoglobin PO2 where 50% of myoglobin binding sites are bound with O2 of 3.2 mmHg, myoglobin-associated PO2 averaged 3.1 +/- .3 (N) and 2.1 +/- .2 mmHg (H). At maximal exercise, measurements of arterial PO2 (115 +/- 4 [N] and 46 +/- 1 mmHg [H]) and femoral venous PO2 (22 +/- 1.6 [N] and 17 +/- 1.3 mmHg [H]) resulted in calculated mean capillary PO2 values of 38 +/- 2 (N) and 30 +/- 2 mmHg(H). Thus, for the first time, large differences in PO2 between blood and intracellular tissue have been demonstrated in intact normal human muscle and are found over a wide range of exercise intensities. These data are consistent with an O2 diffusion limitation across the 1-5-microns path-length from red cell to the sarcolemma that plays a role in determining maximal muscle O2 uptake in normal humans.
Article
The use of a pulse oximeter to monitor arterial oxygen saturation (SaO2) is considered accurate and reliable in the range of 90% to 100%. However, differing reports exist about the accuracy with desaturation. Thus, the suitability of pulse oximetry in desaturated patients was evaluated using a Nellcor N-100 oximeter. In 56 children with cyanotic congenital heart disease, the pulse oximeter reading was compared with the direct measurement of SaO2 by a CO-oximeter OSM 3. The influence of high hematocrit values on the accuracy at low saturation was also investigated. All oxygen saturation measurements (two per child) were carried out after induction of anesthesia (ketamine, fentanyl, pancuronium) during a "steady state" before the surgical procedure. The results indicate that at low levels of saturation (SaO2 below 80%), pulse oximetry is not as accurate as at higher saturations, and overestimates the true value. Bias and precision between saturations measured by the pulse oximeter and the CO-oximeter were 5.8 and 4.8 in the group with a saturation below 80%, and 0.5 and 2.5 in the group with a saturation over 90%, respectively. Because the margin of safety for a patient is small when arterial saturation levels are under 80%, it is advisable under this condition to check the SaO2 measurements by a CO-oximeter. High hematocrit levels did not seem to be responsible for impaired accuracy of pulse oximetry at saturation values below 80%.
Article
Multiwavelength optical spectroscopy was used to determine the oxygen-binding characteristics for equine myoglobin. Oxygen-binding relationships as a function of oxygen tension were determined for temperatures of 10, 25, 35, 37, and 40 degrees C, at pH 7.0. In addition, dissociation curves were determined at 37 degrees C for pH 6.5, 7.0, and 7.5. Equilibration was achieved with a myoglobin solution, at the desired temperature and pH, and 16 oxygen-nitrogen gas mixtures of known oxygen fraction. Correction for the inevitable presence of metmyoglobin was made by using a three-component least squares analysis and by correcting the end point oxymyoglobin spectra for the presence of metmyoglobin. The PO2 at which myoglobin is half-saturated with O2 (P50) was determined to be 2.39 Torr at pH 7.0 and 37 degrees C. The myoglobin dissociation curve was well fit by the Hill equation [saturation = PO2/(PO2 + P50)].
Article
To evaluate the performance of two pulse oximeters in the measurement of arterial hemoglobin saturation in hypoxemic children. Prospective, repeated-measures observational study. A 16-bed pediatric intensive care unit in a children's tertiary hospital. Sixty-six patients with arterial saturation of <90%. Three arterial blood samples were taken from each subject during a 48-hr period. Pulse oximeter measurements of arterial saturation were compared with arterial saturation determined by cooximetry. Arterial saturation was measured using one or both pulse oximeters (SpO2) and compared with the arterial hemoglobin saturation determined by cooximetry (SaO2). Sixty-two subjects were studied, using the Ohmeda pulse oximeter giving 185 data points (78 with saturations <75% [defined by the average of pulse oximeter and cooximeter]); 53 subjects were studied, using the Hewlett-Packard pulse oximeter yielding 155 data points (60 with saturations <75%). SpO2 ranged from 24% to 94%. Bias and precision of the Ohmeda pulse oximeter were -2.8% and 4.8% >75% and -0.8% and 8.0% <75%. Bias and precision of the Hewlett-Packard pulse oximeter were -0.5% and 5.1% >75% and 0.4% and 4.6% <75%. Intrapatient regression coefficient (r) for the differences between pulse oximeter and cooximeter was 0.58 for the Ohmeda and 0.59 for the Hewlett-Packard. Regression coefficients for predicting change in cooximeter value given a change in the Ohmeda pulse oximeter were 0.59 and 0.71 <75% and >75%, respectively. Similar coefficients for the Hewlett-Packard pulse oximeter were 0.50 and 0.70, respectively. The performance of the Ohmeda pulse oximeter deteriorated below an SpO2 of 75%. The Hewlett-Packard pulse oximeter performed consistently above and below an SpO2 of 75%. The ability of both pulse oximeters to reliably predict change in SaO2 based on change in pulse oximetry was limited. We recommend measurement of PaO2 or SaO2 for important clinical decisions.
Article
Skeletal muscles consist of slow-twitch and fast-twitch muscle fibers, which have distinct physiological and biochemical properties. The muscle fiber composition determines the contractile velocity and fatigability of a particular skeletal muscle. We analyzed the systemic distribution of slow muscle fibers in all rodent skeletal muscles by myosin ATPase staining and found that only seven hindlimb skeletal muscles were extremely rich in slow muscle fibers. These included the mouse piriformis (56.5%), gluteus minimus (35.7%), vastus intermedius (24.7%), quadratus femoris (69.9%), adductor brevis (44.3%), gracilis (24.6%), and soleus muscles (35.1%). In mice, the relative proportion of slow muscle fibers did not exceed 15% in skeletal muscles in other regions. The distribution of slow muscle fibers was well conserved in rats and rabbits. The soleus muscle is an important antigravity muscle in both rodents and humans; therefore, these skeletal muscles rich in slow muscle fibers might play an important role in sustaining neutral alignment of the lower extremity.
Article
Intracellular oxygen (O2) availability and the impact of ambient hypoxia have far reaching ramifications in terms of cell signalling and homeostasis; however, in vivo cellular oxygenation has been an elusive variable to assess. Within skeletal muscle the extent to which myoglobin desaturates (deoxy-Mb) and the extent of this desaturation in relation to O2 availability provide an endogenous probe for intracellular O2 partial pressure (P(iO2)). By combining proton nuclear magnetic resonance spectroscopy (1H NMRS) at a high field strength (4 T), assessing a large muscle volume in a highly efficient coil, and extended signal averaging (30 min) we assessed the level of skeletal muscle deoxy-Mb in 10 healthy men (30 +/- 4 years) at rest in both normoxia and hypoxia (10% O2). In normoxia there was an average deoxy-Mb signal of 9 +/- 1%, which, when converted to P(iO2) using an O2/Mb half-saturation (P50) of 3.2 mmHg, revealed an P(iO2) of 34 +/- 6 mmHg. In ambient hypoxia the deoxy-Mb signal rose to 13 +/- 3% (P(iO2) = 23 +/- 6 mmHg). However, intersubject variation in the defence of arterial oxygenation (S(aO2)) in hypoxia (S(aO2) range: 86-67%) revealed a significant relationship between the changes in S(aO2) and P(iO2)(r2 = 0.5). These data are the first to document resting intracellular oxygenation in human skeletal muscle, highlighting the relatively high P(iO2) values that contrast markedly with those previously recorded during exercise (approximately 2-5 mmHg). Additionally, the impact of ambient hypoxia on P(iO2) and the relationship between changes in S(aO2) and P(iO2) stress the importance of the O2 cascade from air to cell that ultimately effects O2 availability and O2 sensing at the cellular level.
Article
The aim of this study was to examine the effects of assuming constant reduced scattering coefficient (mu'(s)) on the muscle oxygenation response to incremental exercise and its recovery kinetics. Fifteen subjects (age: 24 +/- 5 yr) underwent incremental cycling exercise. Frequency domain near-infrared spectroscopy (NIRS) was used to estimate deoxyhemoglobin concentration {[deoxy(Hb+Mb)]} (where Mb is myoglobin), oxyhemoglobin concentration {[oxy(Hb+Mb)]}, total Hb concentration (Total[Hb+Mb]), and tissue O(2) saturation (Sti(O(2))), incorporating both continuous measurements of mu'(s) and assuming constant mu'(s). When measuring mu'(s), we observed significant changes in NIRS variables at peak work rate Delta[deoxy(Hb+Mb)] (15.0 +/- 7.8 microM), Delta[oxy(Hb+Mb)] (-4.8 +/- 5.8 microM), DeltaTotal[Hb+Mb] (10.9 +/- 8.4 microM), and DeltaSti(O(2))(-11.8 +/- 4.1%). Assuming constant mu'(s) resulted in greater (P < 0.01 vs. measured mu'(s)) changes in the NIRS variables at peak work rate, where Delta[deoxy(Hb+Mb)] = 24.5 +/- 15.6 microM, Delta[oxy(Hb+Mb)] = -9.7 +/- 8.2 microM, DeltaTotal[Hb+Mb] = 14.8 +/- 8.7 microM, and DeltaSti(O(2))= -18.7 +/- 8.4%. Regarding the recovery kinetics, the large 95% confidence intervals (CI) for the difference between those determine measuring mu'(s) and assuming constant mu'(s) suggested poor agreement between methods. For the mean response time (MRT), which describes the overall kinetics, the 95% confidence intervals were MRT - [deoxy(Hb+Mb)] = 26.7 s; MRT - [oxy(Hb+Mb)] = 11.8 s, and MRT - Sti(O(2))= 11.8 s. In conclusion, mu'(s) changed from light to peak exercise. Furthermore, assuming a constant mu'(s) led to an overestimation of the changes in NIRS variables during exercise and distortion of the recovery kinetics.
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