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Aplikasi NIR Dan MRS Untuk Menilai Oksigenasi Dan Metabolisme Organ

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Aplikasi NIR Dan MRS Untuk Menilai Oksigenasi Dan Metabolisme Organ
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  Oxidative metabolism in muscle M. FERRARI  , T. BINZONI     V.   UARESIMA   Department of Biomedical Sciences and     echnologies ,  Uni   ersit     of L ’ Aquila ,  67100 L ’ Aquila ,  Ital     Departments of Ph   siolog    and Radiolog   ,  Uni   ersit     of Gene  e ,  1211 Gene  e 4 ,  S   it   erland  SUMMARY Oxidative metabolism is the dominant source of energy for skeletal muscle. Near-infrared spectroscopyallows the non-invasive measurement of local oxygenation, blood flow and oxygen consumption.Although several muscle studies have been made using various near-infrared optical techniques, it is stilldifficult to interpret the local muscle metabolism properly. The main findings of near-infraredspectroscopy muscle studies in human physiology and clinical medicine are summarized. The advantagesand problems of near-infrared spectroscopy measurements, in resting and exercising skeletal musclesstudies, are discussed through some representative examples. 1. INTRODUCTION Oxidative metabolism is the dominant source of energyfor skeletal muscle. The major physiological variablesin O   utilization are expressed in the Fick equation:oxygen utilization ( V  O  )  (arteriovenous (a  v) O  difference)  (blood flow). The demand for O   is metby an increase in the O   delivery ( D O  ) and by anincrease of O   extraction from oxyhaemoglobin(HbO  ). From rest to intense exercise, systemic a  vO  differenceincreasesfromabout5toabout15 mldl −  and O   saturation of venous blood falls from 75 to25%. O   delivery by blood circulation is closely linkedto the cardiac output and to the rate of muscle O  utilization during exercise (Wittenberg & Wittenberg1989).Although the use of optical methods, exploitingvisible light (400–650 nm) to investigate muscle oxi-dative metabolism, dates back to 1937, when Millikan(Millikan 1937) demonstrated muscle deoxygenationon stimulation, its application is limited by thepoor penetration depth. Conversely, near-infrared(650–1100 nm; NIR) spectroscopy (NIRS), a rela-tively new non-invasive technique, allows the sim-ultaneous measurement of changes in intravascular(haemoglobin) and mitochondrial (cytochrome  aa  )oxygenation in 2–6 cm   of the limb muscles. Recentfindings raise new arguments about the possibility of measuring muscle cytochrome  aa   (Bradley 1996),while changes in the concentration of oxyhaemoglobin[HbO  ], deoxyhaemoglobin [Hb] and total haemo-globin ([Hbtot]  [HbO  ]    [Hb]) can be easilycalculated by a modification of the Beer–Lambert law(Cope & Delpy 1988). In addition, with some simplephysiological manoeuvres, it is possible to quantifymuscle  V  O   (Cheatle  et al  . 1991; De Blasi  et al  . 1993),flow (Edwards  et al  . 1993; De Blasi  et al  . 1994; Homma et al  . 1996 a ) and venous saturation (Yoxall &Weindling 1996, 1997).Various NIR optical techniques, differing in thetype of light source (lamps, lasers, light-emittingdiodes) and in the modality of the light sources(continuous wave, NIR CWS ; continuous wave spatiallyresolved,NIRS SRS ;pulsed,NIR TRS ;phasemodulation,NIR PMS ) have been used for muscle studies. Althoughthese studies reported interesting pathophysiologicalfindings, it is still difficult to interpret the localmetabolism properly due to the impossibility of distinguishing the srcin of the signal. It is expectedthat the main contributor to the NIR signal is thevenoushaemoglobin.However, arecentstudyreportedthat, in cycling exercise, muscle oxygenation measure-ments by NIRS do not reflect the venous saturation(Costes  et al  . 1996).The aim of this paper is to review the main findingsof NIR muscle studies and to discuss, through somerepresentative examples, the advantages and problemsof NIRS measurement of resting and exercising humanskeletal muscle. 2. NIRS STUDIES OF HEALTHY MUSCLES The first NIR absorption spectrum of the humanmuscle was produced by Norris at the USA De-partment of Agriculture Research Service (Smith1977). The spectral features of the haemoglobin, waterand fat were identified and a chemometric algorithmwas developed to quantify body fat (Conway  et al  .1984). Myoglobin has similar absorption spectra tohaemoglobin. However, the ratio of haemoglobin tomyoglobin in human skeletal muscle is approximatelyten (Seiyama  et al  . 1988).In the Eighties several NIR CWS  prototypes were built(Jo   bsis 1977; Giannini  et al  . 1982; Takada  et al  . 1987;Cope & Delpy 1988; Chance  et al  . 1988 a ,  b ; Hampson& Piantadosi 1988); forearm occlusion and exercisewas used to test their instrumental capabilities. Most of the NIR muscle studies have been made using a low-cost continuous dual wavelength system (RUNMAN,NIM Inc., Pennsylvania, USA), which has recentlybeen improved (Shiga  et al  . 1995). AlthoughRUNMAN gives only relative values, a strong linearrelationship was found between its values and forearmdeep vein O   saturation during exercise (Mancini  et al  . Phil  .    rans .  R .  Soc .  Lond  . B (1997)  352 , 677–683   1997 The Royal Society Printed in Great Britain 677  678 M. Ferrari and others  Oxidati   e metabolism in muscle 1994 a ). The RUNMAN has been used during varioustypes of whole body upright exercise (e.g. treadmill,rowing and bicycling). Skeletal quadriceps oxygen-ationwasinvestigatedduringconstantandincrementalwork rate bicycle exercise (Wilson  et al  . 1989; Chance et al  . 1992; Belardinelli  et al  . 1995 a , b ; Costes  et al  .1996). It has been demonstrated that the rate of O  resaturation after exercise is faster in the endurance-trained athlete (rowers) than in sedentary controls(Chance  et al  . 1992). The effect of hypoxia on muscleoxygenation during arm exercise has been investigated(Jensen-Urstad  et al  . 1995). An interesting study on theeffects of the increased sympathetic vasoconstrictordrive on muscle oxygenation in rhythmically con-tracting human forearm muscles was recently reportedby Hansen  et al  . (1996).Simultaneous application of    P magnetic resonancespectroscopy (MRS) with the RUNMAN provided aunique opportunity to investigate muscle metabolismand oxygenation (Kemp  et al  . 1994; Mancini  et al  .1994 a , c ). The kinetics of reoxygenation paralleledthose for regeneration of the high-energy compoundphosphocreatine after submaximal exercise, and rap-idly surpassed the metabolic processes after maximaleffort (McCully  et al  . 1994 b ). Proton MRS and NIRSexperiments also demonstrated that haemoglobindeoxygenation precedes myoglobin deoxygenation(Wang  et al  . 1990; Mancini  et al  . 1994 c ).More quantitative muscle studies were performedusing a three-wavelength NIR CWS  instrument (OM-100A, Shimadzu Co., Japan). This instrument wasused in several studies, i.e. to develop a forearm  V  O  method (Homma  et al  . 1996 a ), to investigate theinfluence of adipose tissue thickness on the NIRmeasurements (Homma  et al  . 1996 c ), to investigateskeletal quadriceps oxygenation during constant andincremental work rate bicycle exercise (Homma  et al  .1993) and to study changes in muscle oxygenationduring weight-lifting exercise (Tamaki  et al  . 1994).  uantitation was further improved by combining four-wavelength attenuation data, measured by theNIRO500 (Hamamatsu Photonics, Japan), with theoptical path length that can be measured from separateNIR TRS  and NIR PMS  measurements during differentconditions (Delpy  et al  . 1988; Chance  et al  . 1988 b ;Duncan  et al  . 1995 a ). Path length changes were lessthan 10% during arterial occlusion with maximalvoluntary contraction (Ferrari  et al  . 1992, 1993;Duncan  et al  . 1995 b ). The NIRO500 was used inseveral studies, i.e. to develop forearm  V  O   and flowmethods (De Blasi  et al  . 1994), to investigate the effectof the treadmill speed and slope on the quadriceps oxy-genation (  uaresima  et al  . 1995 b , 1996 a ), and to studyforearm muscle exercising simultaneously with variousleg-cycling intensities (Bradley 1996). 3. NIRS MUSCLE STUDIES ON PATIENTS The clinical significance of NIRS muscle findings indifferent diseases has been explored by several groupsusing different instrumentation. NIRS has been usedto investigate the diseases associated with impairedtissue oxygenation, like heart failure and peripheralvascular disease (PVD). It has been shown thatpatients with congestive heart failure desaturate theirmuscle at lower work levels than normal subjectsindicating an insufficient blood flow to the exercisingmuscles of these patients (Wilson  et al  . 1989; Mancini et al  . 1994 c ; Belardinelli  et al  . 1995 c ; Matsui  et al  .1995). The results indicate that NIRS can detectdifferent muscle oxygenation profiles in patients withdifferent levels of exercise intolerance.Accessory respiratory muscle oxygenation duringexercise was assessed on patients with heart failure andon heart transplant recipients (Mancini  et al  . 1991,1994 b , 1995, 1996).Many studies were made to investigate PVD.Cheatle  et al  . (1991) found that at rest the  V  O   of PVDpatients was half of that found in healthy controls. Astandardized treadmill exercise was used to investigatethe calf oxygenation of patients with claudicatiointermittent (Komiyama  et al  . 1994; McCully  et al  .1994 a ; Colier  et al  . 1995 a ). The patients with moresevere impairment (i.e. insufficient O   delivery)presented an earlier decrease of muscle oxygenation. Adelayed oxygenation recovery time after forearmocclusionwasfoundinpatientswithchronicsubclavianartery occlusion (Kurosawa  et al  . 1996). Tissueoxygenation was also investigated during electricallystimulated muscle contraction on patients with spinalcord injury (Monroe  et al  . 1995).Muscle NIRS might also have a role in investigatingthe therapeutic efficacy of vasoactive substances.Recently, the effect of nifedipine (vasodilator) on theestablished effects of bryostatin (antineoplastic agent)was studied on the calf of patients with disseminatedmelanoma by combining   P MRS and NIR CWS (Thompson  et al  . 1996). The assessment of the acutetherapeutic effect of dobutamine on skeletal muscleoxygenation has been reported (Mancini  et al  . 1990).Oxidative defects have been found in metabolicmyopathiesby NIR CWS  (Bank & Chance 1994; Chance& Bank 1995). The cytochrome  c  oxidase deficiencydid not provoke any deoxygenation during calf exercise. This indicates an under-utilization of delivered O  .Recently, the muscle absorption and the reducedscattering coefficients were mapped on musculardystrophy patients (  uaresima  et al  . 1996 b ). Using thesame patients, the effect of the treadmill speed andslope on the quadriceps oxygenation was investigated(  uaresima  et al  . 1995 b , 1996 a , c ). The Duchennemuscular dystrophy patients’ performances were notO   limited.Ageing might be associated with muscle blood flowreduction. It was found that elderly subjects had alonger rate of calf O   resaturation (McCully & Posner1995). 4. ADVANTAGES AND LIMITATIONS INTHE USE OF MUSCLE NIRS Figure1reportsatypicalexampleoftheoxygenationchanges in the resting muscle during ischaemia.Measurements were performed on the forearm by afour-continuous-wavelength instrument (NIRO500, Phil  .    rans .  R .  Soc .  Lond  . B (1997)  679 Oxidati   e metabolism in muscle  M. Ferrari and others 40200– 20– 40024681012time (min)    ∆     (    µ    M   ) Occlusion[Hb][Hbtot][HbO 2 ] Figure 1. Effects of the vascular occlusion and releasemeasured on the forearm by a NIR CWS  instrument(NIRO500). Sampling time: 1 s. Hamamatsu, Japan). Optodes were firmly positionedon muscle by a special support (  uaresima  et al  .1995 a ). [Hb] and [HbO  ] changes are expressed asmoles per litre of tissue. After 2 minutes of baseline anabrupt vascular occlusion was achieved by inflating apneumatic cuff (240–260 mmHg). The occlusion wasmaintained for about five minutes. No consistentvariations of [Hb] and [HbO  ] occurred duringbaseline, instead [HbO  ] decreased from the beginningof the occlusion. The [HbO  ] decrease was mirrored by[Hb] increase. No [Hbtot] variations occurred duringthe first two minutes of ischaemia. Instead [Hbtot] roseafter cuff release. Hbdiff ([HbO  ] −  [Hb]) is a goodindex of tissue oxygenation when no [Hbtot] changesoccur.  V  O   can be calculated by measuring the rate of change of [HbO  ] to [Hb] (Cheatle  et al  . 1991).  V  O  can be calculated more precisely by the linearregression of the desaturation rate occurring during thefirst 60 s of ischaemia. The same method was appliedby De Blasi  et al  . (1993, 1996 a ), Homma and Kagaya(1994) and Colier  et al  . (1995 b ) to measure  V  O   at restand during isometric exercise. The recovery time,required from the cessation of vascular occlusion toresaturate the haemoglobin to 50%, can be calculatedas described by Chance  et al  . (1992). This  V  O   methodcannot be validated; however, another method usingvenous occlusion (De Blasi  et al  . 1994) has recentlybeen validated by an invasive technique (Homma  et al  .1996 a ). Both  V  O   optical methods provide comparableresults. However, the venous occlusion method can bemore easily repeated and is clinically more acceptable.This method also offers the advantage of measuring theblood flow (De Blasi  et al  . 1994) and mean tissuesaturation (Sat) simultaneously (Yoxall & Weindling1996,1997).Thebloodflowmethodhasbeenvalidatedby plethysmography. Blood flow can be also estimatedfrom changes in NIR signals from forearm musclein response to the fractional inspired O   concentration(Edwards  et al  . 1993). All the methods using venous 90807060504010080604020Occlusion    H   b   t  o   t   (    µ    M   )   S  a   t   (   %   ) 604020015129630 time (min)    ∆     (    µ    M   ) [HbO 2 ][Hb] Figure 2. Effects of the vascular occlusion and releasemeasured on the quadriceps by a NIR PMS  instrument(OMNIA). Sampling time: 4.8 s. occlusion can be applied only at rest. These methodshave been used to investigate forearm flow  V  O  relationship on shock patients (De Blasi  et al  . 1996 b ).Figure 2 reports a typical example of a quadricepsoxygenation measurement performed on the restingmuscle during thigh occlusion (450 mmHg) by aNIR PMS  instrument (OMNIA, ISS Inc. Urbana,Illinois, USA). This instrument has the advantage of measuring the absorption and scattering coefficients attwo wavelengths and calculating the absolute values of [Hb] and [HbO  ] (De Blasi  et al  . 1995). From these itis possible to calculate Sat and [Hbtot]. A plateau wasreached when Sat decreased by about 20%. Thisindicates that O   stores are not depleted. A similarfinding was recently obtained using a portable NIR TRS instrument (Liu  et al  . 1995; Hamaoka  et al  . 1996). Satcan also be measured by NIR SRS  instruments (Matcher et al  . 1995 b ; Homma & Kagaya 1996 b ). AlthoughMatcher found unexpected low Sat values at rest, Satdecreased by the same order of magnitude (about30%) in ischaemia. The unexpected high saturationvalues found during prolonged ischaemia might beexplained by several factors, such as (i) incompleteocclusion; (ii) absence of water and lipids contribution Phil  .    rans .  R .  Soc .  Lond  . B (1997)  680 M. Ferrari and others  Oxidati   e metabolism in muscle 403020100– 10403020100– 10403020100– 10– 1001530456075– 10 o    ∆     [   H   b   ]   (    µ    M   )    ∆     [   H   b   O    2    ]   (    µ    M   )    ∆     [   H   b   t  o   t   ]   (    µ    M   ) 02468101214161820time (min) Figure 3. Effects of gravitational changes, at different anglesof the tilting bed, measured on the calf by a NIR CWS instrument (NIRO500). Sampling time: 2 s. in the algorithm (Matcher  et al  . 1995 b ); (iii) wrongassumptions (homogeneous medium); and (iv) differ-ent diffusion of O   in the capillaries and veins.AlthoughthereproducibilityofthisNIR PMS instrumentis satisfactory, the reliability of the data obtained fromthese instruments is still controversial. The NIR PMS ,NIR TRS  and NIR SRS  instruments offer such undoubtedpotential advantages that they should replace NIR CWS instrumentation in the near future.Figure 3 reports an example of the calf [Hb] and[HbO  ] changes during whole body passive posturalvariations ( 10  up to 75  , 15  increments). The subjectwas fixed on the bed to avoid any supplementary effortwhen the position was changed. Measurements wereperformed by a NIRO500. Negligible [HbO  ] changesoccurredduringtheprotocol;instead[Hb]consistentlyand gradually increased withthe bed angle increments.[Hb] rapidly recovered to baseline values when thebed was repositioned at   10  . [Hbtot] graduallyincreased as well, and it reflected only the [Hb]changes. Considering that no  V  O   changes areexpected at rest, [Hbtot] rise (about 20  µ M) is 20100– 10    ∆     [   H   b   ]   (    µ    M   )    ∆     [   H   b   O    2    ]   (    µ    M   )    ∆     [   H   b   t  o   t   ]   (    µ    M   ) 20100– 1020100– 1070110150190230270W0102030405060708090100time (min) Figure 4. Effects of a series of square wave exercises on thequadriceps of an untrained cycling subject. Measurementsperformed with a NIR CWS  (NIRO500). Sampling time: 2 s. attributable to blood volume increases in the capacityof the venous vessels. This result suggests that posturalchanges should be taken into account in the in-terpretation of NIR findings and could be used toinvestigate the vascular compliance in healthy subjectsand patients.Figure 4 reports an example of increasing workloads.Measurements were performed on the quadriceps by aNIRO500. A series of square wave exercises performedon a cycloergometer were alternated with freewheel.The first exercise (70 W) provoked a rapid and gradualincrease of [Hbtot]. The first four minutes were due to[Hb] rise, while the last minute was due to [HbO  ]rise. During the second exercise (110 W), [HbO  ] risecontributed more than [Hb] to the [Hbtot] increase.During the third exercise, the contribution to [Hbtot]rise was mainly due to [Hb] rise. In the followingexercise steps [Hbtot] remained constant. During eachfreewheel recovery phase, [Hb] promptly returned tobaseline values, while [HbO  ] reached different levels(each one higher than the previous one) up to 150 W. Phil  .    rans .  R .  Soc .  Lond  . B (1997)
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