Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

CHEST

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The role of the circulation is to deliver adequate oxygen and nutrients to meet tissue metabolic

demands. 1 Circulatory shock represents inadequate cellular oxygen supply (hypoxia), and/or impaired oxygen use (dysoxia). This can, if not corrected promptly, progress to organ dysfunction and failure. Early resus-citation regimens targeted toward prespecifi ed hemo-dynamic values improve outcomes in patients with severe sepsis or undergoing high-risk surgery. 2 , 3 This strategy does not, however, benefi t patients in estab-lished organ failure. 4 , 5 Thus, a relatively narrow window of opportunity exists to provide tissues with suffi cient oxygen to restore cellular metabolism and prevent/ame-liorate further organ dysfunction.

Assessment of the adequacy of oxygen delivery and use is therefore key to early identifi cation and inter-vention. Traditional markers such as urine output and BP remain in common use to evaluate tissue hypop-erfusion yet are nonspecifi c and often change belatedly. 6 Newer techniques, although superior, still have limi-tations. For example, mixed or central venous oxygen saturation refl ects the global oxygen supply-demand balance yet may not recognize any local mismatch,

particularly in “canary organs” whose perfusion may be compromised before others. Organs vary in their metabolic activity and the blood fl ow they receive. As exemplars, 70% to 75% of hepatic blood fl ow arises from the portal vein that carries blood already deoxy-genated after passage through the gut. Renal blood fl ow accounts for 20% to 25% of cardiac output yet only consumes 7% to 8% of total oxygen consump-tion. The kidney regions also vary markedly in terms of oxygen delivery and metabolic rate, resulting in marked intrarenal differences in oxygen tension. 7 Oxygen extraction by the resting heart exceeds 55%, so sub-stantial increases in myocardial oxygen supply require signifi cant (up to fi vefold) increases in coronary blood fl ow. 8 Hyperlactatemia, the product of an imbalance between lactate production and metabolism, is also frequently used as a marker of tissue hypoperfusion. Although sensitive, it too is a somewhat nonspecifi c marker of global tissue hypoxia. 9

Recognition of the limitations of global “whole body” monitoring techniques has stimulated efforts to develop devices that evaluate regional tissue perfusion and oxygenation. Characteristics of the ideal monitoring

Monitoring Tissue Perfusion, Oxygenation, and Metabolism in Critically Ill Patients

Nasirul J. Ekbal , MBBS ; Alex Dyson , PhD ; Claire Black , MSc ; and Mervyn Singer , MD

Alterations in oxygen transport and use are integral to the development of multiple organ failure; therefore, the ultimate goal of resuscitation is to restore effective tissue oxygenation and cellular metabolism. Hemodynamic monitoring is the cornerstone of management to promptly identify and appropriately manage (impending) organ dysfunction. Prospective randomized trials have confi rmed outcome benefi t when preemptive or early treatment is directed toward maintaining or restoring adequate tissue perfusion. However, treatment end points remain controversial, in large part because of current diffi culties in determining what constitutes “optimal.” Information gained from global whole-body monitoring may not detect regional organ perfusion abnormal-ities until they are well advanced. Conversely, the ideal “canary” organ that is readily accessible for monitoring, yet offers an early and sensitive indicator of tissue “unwellness,” remains to be fi rmly identifi ed. This review describes techniques available for real-time monitoring of tissue perfusion and metabolism and highlights novel developments that may complement or even supersede current tools. CHEST 2013; 143 ( 6 ): 1799 – 1808

Abbreviations : ATP 5 adenosine triphosphate ; COX 5 cytochrome oxidase ; LDF 5 laser Doppler fl owmetry ; MRS 5 magnetic resonance spectroscopy ; NADH 5 reduced form of nicotinamide adenine dinucleotide ; NIRS 5 near-infrared resonance spectroscopy ; PCr 5 phosphocreatine ; Pi 5 inorganic phosphate ; SDF 5 sidestream dark fi eld ; St o 2 5 tissue oxygen saturation ; tP o 2 5 tissue oxygen tension

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system are summarized in Table 1 . For any monitor of a regional bed, an important consideration is whether it refl ects changes occurring in other organs during a systemic insult. Preferably, this should occur concur-rently or, ideally, beforehand to provide an early warn-ing system enabling prompt intervention and correction of the problem. This is particularly pertinent when using an accessible site such as mouth (sublingual), bladder, muscle, or subcutaneous tissue as a surro-gate for deeper “vital” organs such as liver, brain, and kidney. This is complicated by physiologic differences specifi c to certain organs, as described previously, and to pathophysiologic or compensatory mechanisms.

Techniques that monitor regional perfusion target different compartments ( Fig 1 ). This review highlights key principles underlying these techniques and their current usefulness. Some are available as clinical tools, whereas others are still at the animal or early human testing stage. No commercial device has yet been enshrined as “standard of care” within (inter)national management protocols. This is often because of their relative lack of user friendliness as a bedside tool, and/or an inability to deliver quantitative data, and/or a paucity of multicenter trial outcomes data to make an overwhelming case for their incorporation as a routinely used bedside device.

Microcirculation Measurements

The microcirculation is defi ned as vessels with diam-eters , 100 m m (ie, arterioles, capillaries, and venules). 10 Several techniques can monitor or visualize the micro-circulation in situ and are available for patient use.

Microcirculatory Hemoglobin Oxygenation

Near-infrared resonance spectroscopy (NIRS) is a noninvasive optical technique based on passage of infrared light (680-800 nm) through biologic tissues. By the Beer-Lambert law, the NIRS signal is limited to

interrogating small vessels ( , 1 mm diameter) only. The amount of light recovered after illumination depends on the degree of scattering within the tissue and by the three molecules known to affect near-infrared light absorption, namely hemoglobin, myoglobin, and mito-chondrial cytochrome oxidase (COX). Differential absorption patterns depend on whether these chromo-phobes are oxygen bound ( Fig 2 ). Predefi ned algo-rithms generate concentrations; as the contributions of myoglobin and COX to light attenuation is relatively minor, NIRS predominantly assesses microvascular oxyhemoglobin and deoxyhemoglobin. Some special-ized machines can generate a COX signal (see later).

Tissue oxygen saturation (St o 2 ) is calculated from the fractions of oxyhemoglobin and deoxyhemoglo-bin. As 75% of blood within skeletal muscle is venous, the NIRS St o 2 value mostly represents local venous oxyhemoglobin saturation rather than that of tissue. It thus refl ects both local supply-demand balance and any arteriovenous shunting present.

The thenar eminence, a superfi cial muscle with little interference from overlying fat and subcutaneous tissue, is the main site used for St o 2 monitoring. Edema may result in artifact and be problematic, with venous congestion, hypoalbuminemia, and/or increased endo-thelial leak. Brain St o 2 monitoring has been success-fully applied in neonates 11 and animal models 12 but is more challenging in adults because of interference from scalp blood fl ow. 13 An issue with thenar muscle NIRS monitoring is the wide range (52%-98%) found in healthy subjects. 14 NIRS values are also affected by age, BMI, sex, race, and smoking.

As changes in St o 2 refl ect changes in fl ow and/or metabolism, a proportional change may leave St o 2 unaltered. This may explain why absolute values fell outside the normal range in severely shocked trauma patients 14 and in septic shock only when oxygen delivery fell markedly. 15 , 16

More utility can be derived from a dynamic vascu-lar occlusion test to evaluate the St o 2 response to a sudden loss of oxygen supply. 17 , 18 The rate of fall of St o 2 following arterial and/or venous occlusion is decreased in shocked compared with nonshocked septic patients or healthy volunteers The St o 2 recov-ery slope seen on reperfusion evaluates both the limb’s

Table 1 —Key Properties of an Ideal Monitor for Organ Hypoperfusion

Provides accurate and reproducible results High sensitivity and specifi city delivered at an early point Easy to use Noninvasive or minimally invasive and causes no harm Provides continuous and interpretable data Not only refl ects regional data but also useful as an early indicator of

systemic hypoperfusion Provides information to guide therapeutic interventions

Manuscript received July 23 , 2012 ; revision accepted November 27 , 2012 . Affi liations: From the Bloomsbury Institute of Intensive Care Med-icine, Division of Medicine, University College London, London, England . Funding/Support: The authors work at University College London Hospitals/University College London, which receives a propor-tion of its funding from the UK Department of Health’s National Institute for Health Research Biomedical Research Centre’s fund-ing scheme. Dr Ekbal is funded by the Medical Research Council and Claire Black by the UK National Institute for Health Research . Correspondence to: Prof Mervyn Singer, MD, Bloomsbury Institute of Intensive Care Medicine, University College London, Cruciform Bldg, Gower St, London, WC1E 6BT, England; e-mail: m.singer@ucl.ac.uk © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-1849

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oxygen content and the capacity to recruit arterioles and venules (microvascular reserve). The slope may be altered by different pathologies or therapeutic inter-ventions ( Fig 3 ). In sepsis, the alterations seen sug-gest both microcirculatory dysfunction and impaired use of oxygen (mitochondrial dysfunction � reduced metabolism). 17 , 18

Laser Doppler Flowmetry

Laser Doppler fl owmetry (LDF) uses wavelengths of visible and infrared light to measure tissue perfu-sion by exploiting changes in wavelength frequency (Doppler shifts) that moving erythrocytes impart to light. The chosen wavelength is usually 780 nm, as this is near the isobestic point (800 nm) where the absorp-tion spectra of oxyhemoglobin and deoxyhemoglobin intersect ( Fig 2 ); changes in blood oxygenation have little effect on measurement. Laser light is delivered fi beroptically and diffusely scattered by stationary tissue, with some being refl ected back with no change in wave-length. However, photons that encounter moving RBCs experience a Doppler shift, which is also detected. This signal is proportional to perfusion (or fl ux) and represents microvascular blood cell transport. 19

In porcine hemorrhagic shock, changes in skin LDF fl ux occurred earlier than heart rate, BP, arterial lac-tate, or base defi cit. 20 After abdominal surgery or endo-toxin administration, no effect was seen in intestinal microcirculation despite fl uid resuscitation and nor-epinephrine to restore BP and regional blood fl ow to baseline levels or above. 21 , 22 By contrast, titrating nor-epinephrine to obtain a mean arterial pressure of 90 mm Hg in patients with established septic shock signifi cantly increased red cell fl ux to deltoid muscle. 23

LDF monitoring has several drawbacks. Outputs are obtained as arbitrary perfusion units and not

Figure 1. Techniques for monitoring regional perfusion. LDF 5 laser Doppler fl owmetry; MRS 5 magnetic resonance spectroscopy; NIRS 5 near-infrared resonance spectroscopy; O 2 5 oxygen; SDF 5 sidestream dark fi eld; tPO 2 5 tissue oxygen tension.

Figure 2. NIRS absorption spectra for HbO 2 and Hb, MbO 2 , and Mb. The spectrum for COx represents the oxidized minus the reduced form. Line A and line B correspond to peak Hb and HbO 2 absorption wavelength, respectively. Line C corresponds to the isobestic point. COx 5 cytochrome oxidase; Hb 5 deoxy-hemoglogin; HbO 2 5 oxyhemoglobin; Mb 5 deoxymyoglobin; MbO 2 5 oxymyoglobin. See Figure 1 legend for expansion of other abbreviation.

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absolute blood fl ow; thus, only trends can be assessed. The result is a net vector fl ow in line with the direc-tion of the incoming Doppler-shifted signal. As this signal may contain components from blood fl owing through multiple vessels at varying angles to the probe, results may vary considerably. This may also be seen in tissues with a heterogeneous microcirculation. It is thus important to fi x the probe in position or to use a multifi ber array to increase the surface area being captured.

Microvideoscopic Techniques

Historically, intravital microscopy was considered the gold standard for microcirculation imaging. How-ever, this is restricted to transilluminable tissues, such as the nailfold bed, or requires specifi c dyes not licensed for human use. Videomicroscopic imaging devices such as sidestream dark fi eld (SDF) imaging have sup-planted intravital microscopy as a clinical tool to visu-alize the microcirculation. 24 , 25 Light is refl ected by superfi cial tissue layers but absorbed by hemoglobin contained within erythrocytes. A 530-nm wavelength is usually chosen, as this corresponds to the other isobestic point in the absorption spectra of deoxyhemo-globin and oxyhemoglobin. Absorbed light is refl ected back, allowing erythrocytes to be viewed as gray/black bodies moving against a white background ( Fig 4 ). Tissue perfusion can be characterized in individual vessels or averaged over an area within the device’s fi eld of vision. Studies have mainly focused upon the sublingual circulation, although brain, eye, and diges-tive tract have also been assessed in patient studies. 26 , 27

The microcirculation cannot be monitored contin-uously with SDF, although repeated images are gen-

erally obtainable and reproducible. Recorded video clips are measured offl ine using software that provides a semiquantitative analysis. SDF is operator depen-dent, so adequate training is needed to ensure that image acquisition is satisfactory and video clips objec-tively analyzed. A recent study found one-third of recordings by a trained investigator were technically excellent, whereas a further one-third showed pressure artifact from the probe on the tissue surface. 28 Recent design improvements may overcome such issues. 29

Notwithstanding these caveats, interesting data have been generated during surgery in shocked patients and animal models. The sickest septic patients pre-senting to an ED had the greatest sublingual micro-circulatory abnormalities, and this prognosticated for eventual outcome. 30 In a follow-up study investigating early goal-directed therapy resuscitation, an associa-tion was seen between microcirculatory improvement and better outcomes. 31 This may have been con founded by greater norepinephrine use in patients with poor outcome. In other human septic shock studies, no change in preexisting sublingual microvascular fl ow abnormalities was seen with norepinephrine, although considerable interindividual variation was reported. 23 , 32

Figure 3. NIRS derived changes in thenar StO 2 following arterial and venous occlusion in septic patients. a 5 baseline measurements; b 5 SI; c 5 reperfusion; d 5 reactive hyperemia; e 5 return to base-line. SI 5 stagnant ischemia; StO 2 5 tissue oxygen saturation. See Figure 1 legend for expansion of other abbreviation.

Figure 4. SDF imaging. A, Side view. B, Probe tip view. C, Still SDF image of rat intestine microcirculation. LED 5 light emit-ting diode. See Figure 1 legend for expansion of other abbreviation.

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Hypoperfusion and increased fl ow heterogeneity (rather than the expected hyperdynamic fl ow pattern) are the main characteristics of the sublingual micro-circulation in patients with established septic shock. 33 Similar changes were seen in a cardiogenic shock model, although the cerebral microcirculation remained unaffected. 34 Differences were also seen between sublingual and intestinal microcirculations in septic patients. 35 Nitroglycerin in septic patients 36 and fl uid loading plus dopexamine in high-risk surgical patients 37 improved microcirculatory fl ow, yet no outcome ben-efi t was forthcoming. The precise role of microcircula-tory manipulations in affecting mortality and morbidity thus remains to be elucidated.

Monitoring the Extracellular (Interstitial) Compartment

Tissue Oxygen Tension

Tissue oxygen tension (tP o 2 ) measures the partial pressure of oxygen within the interstitial (extravascular) space. It represents the balance between local oxygen delivery (from both macrocirculation and microcir-culation) and consumption. Thus, matched increases or decreases in local oxygen delivery and consumption will not impact on tP o 2. Depending upon an indi-vidual organ’s metabolic activity and blood fl ow, the tP o 2 level varies markedly between organs. 38

Traditional probes used Clark electrodes, which generally contain a platinum cathode and silver anode linked by a salt bridge. Oxygen diffusing through the electrode membrane is reduced at the cathode sur-face, completing an electrical circuit that generates a current proportional to the oxygen content. Such electrodes consume oxygen, which may be disadvan-tageous when tP o 2 is low. Newer techniques use dy-namic luminescence quenching, involving transfer of absorbed energy to oxygen from a light-excited lumi-nophore (eg, ruthenium, platinum) encased within a silicone matrix at the tip of a fi beroptic cable. 38 No oxygen is consumed by this process, and the decay half-life (“quenching”) is inversely proportional to local P o 2 . These optodes thus reliably determine low tP o 2 values. Sensors can be precalibrated before insertion, facilitating their use. We use a platinum-complex fl u-orophore sensor with an active surface area of 8 mm 2 to broaden spatial tP o 2 averaging. This sensor is now being developed for patient use.

tP o 2 monitoring has been studied widely in animal models in multiple organs, including brain, gut, kidney, liver, muscle, and bladder. 39 - 41 In small-scale patient studies, brain, conjunctiva, subcutaneous tissue, muscle, and liver have been monitored during resuscitation from hemorrhagic shock and trauma, during sepsis and cardiogenic shock, and perioperatively. 42 - 48 Outcome improvements have been reported following the use of

brain tP o 2 monitoring after traumatic brain injury 43 , 44 ; however, this requires confi rmation in larger studies.

Microdialysis

Microdialysis enables monitoring of energy-related metabolites within the interstitial space. A solution of known solute concentration (eg, Hartmann solution) is slowly pumped through a thin catheter with a semi-permeable membrane sited in interstitial tissue. This is designed to mimic a capillary. Soluble small molecules up to 30,000 Da (eg, glucose, lactate, pyruvate [refl ect-ing carbohydrate metabolism] and glycerol [refl ecting lipid breakdown]) equilibrate across the membrane between extracellular space and perfusion fl uid that can be collected and analyzed. Other small molecules such as adenosine, urea, amino acids such as glutamate, hormones, and cytokines can be measured to enable evaluation of drug delivery, pharmacokinetics/dynam-ics, bioavailability, and bioequivalence.

Animal studies of sepsis 49 and hemorrhage 50 show an increased tissue lactate and, more usefully, lac-tate:pyruvate ratios. This has been reproduced in studies of patients in septic shock. 51 , 52 Changes in glu-cose, glycerol, glutamate levels, and lactate:pyruvate ratios denote the severity of brain injury and ischemia following trauma and can independently prognosti-cate. 53 Tissue cortisol and antibiotic concentrations can also be measured in patients. 54 , 55 Before introduc-tion into routine clinical practice its use as a monitoring tool needs to be validated.

CO 2 Tonometry

Tissue CO 2 represents the balance between local production and removal. A rising value likely refl ects a decrease in local blood fl ow rather than increased local production of CO 2 related to buffering of lactic acid by tissue bicarbonate. 56

Tissue CO 2 has been measured in various tissues, including subcutaneous, sublingual, small and large bowel and, most notably, the stomach. Gastric tonom-etry was in vogue as a research tool 15 to 20 years ago, prompted by the identification that an increasing gastric-arterial or gastric-end-tidal P co 2 gap or a falling gastric intramucosal pH (placing the values into a Henderson-Hasselbalch equation) were predictive of complications and mortality in patients admitted to intensive care or undergoing major surgery. 57 , 58 The original technique involved inserting saline into a semipermeable gastric luminal balloon, allowing P co 2 equilibration with the gastric mucosa over 30 min, and then aspirating the saline and measuring the P co 2 level in a blood gas analyzer. Gastric feed had to be interrupted premeasurement, and gastric acid sup-pressants were required. This proved too cumbersome

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for regular use. An automated, semicontinuous air tonometric technique using infrared spectropho-tometry to measure gastric CO 2 levels offered faster equilibration times and ease of use. However, a mul-ticenter study failed to confi rm adequate prognostic capability, 59 so the product was commercially aban-doned. Despite this checkered history, utility in early identifi cation of tissue hypoperfusion has been dem-onstrated in animal shock models using alternative locations, such as subcutaneous tissue and bladder. 50 , 60 Potentially, with newer technology offering user friend-liness and increased accuracy, this concept could be gainfully revitalized.

Mitochondrial Monitoring

Most of the body’s oxygen consumption is used by mitochondria towards production of adenosine tri-phosphate (ATP) and heat. Cell death pathways are triggered by a rapid fall in ATP levels or via specifi c mitochondrial mechanisms. Mitochondrial dysfunc-tion also appears to be integral to the development of multiorgan failure in sepsis. 61 Therefore, assessing mitochondrial function represents the holy grail of monitoring the adequacy of organ perfusion. Early identifi cation of mitochondrial stress during major surgery or critical illness from reactive species and oxygen lack would enable prompt treatment and, potentially, improved outcomes.

Mitochondrial Redox State

The mitochondrial electron transport chain accepts electrons donated from the Krebs cycle via nicotin-amide adenine dinucleotide (NADH) (to complex I) and fl avin adenine dinucleotide H 2 (to complex II). These electrons are passed down the chain, which

consists of a series of redox reactions, with oxygen being the terminal electron acceptor at complex IV (COX). The passage of electrons allows proton move-ment across the inner mitochondrial membrane; the generated membrane potential drives ATP synthase (complex V) to generate ATP from ADP and inor-ganic phosphate (Pi) ( Fig 5 ).

The redox reaction at complex I involves conver-sion of the reduced form (NADH) to the oxidized NAD 1 . At complex IV, oxidized COX is converted to the reduced form. A lack of oxygen or a downstream block in the chain (eg, carbon monoxide or cyanide poisoning causing COX inhibition) will increase both the NADH/NAD 1 and the reduced/oxidized COX ratios. Specifi c absorbance of light by reduced NADH or oxidized COX enables ratiometric changes to be followed, assuming total NAD and COX pools remain unaltered. These properties can be used for clinical monitoring to provide a refl ection of oxygen avail-ability within the mitochondrion.

NADH Fluorometry: Conveniently, NADH (but not NAD 1 ) autofl uoresces in response to 340 nm excitation light. The emitted light (450 nm) relates to the concentration of the fl uorescent compound and represents changes in mitochondrial NADH, assuming no change in the total NADH/NAD 1 pool. Studies in animals subjected to a range of physiologic and phar-macologic insults have assessed NADH fl uorescence in various organ beds including brain, liver, kidney, heart, spinal cord, and bladder. 62 - 66 Clinical studies are still limited. Mayevsky et al 67 reported a case series of responses of bladder wall NADH fl uorescence in patients in intensive care or undergoing surgery. Falls in tissue oxygenation seen during aortic cross-clamping or cessation of spontaneous breathing led to rises in NADH. In a sequential hemorrhage rat model, 68 there were progressive rises in NADH fl uorescence intensity

Figure 5. The mitochondrial electron transport chain. I, II, III, IV, and V 5 mitochondrial respiratory chain complexes I to V; CoQ 5 conenzme Q; cyt c 5 cytochrome c; FAD 5 fl avin adenine dinucleotide; FADH 2 5 fl avin-adenine dinucleotide (reduced form); NADH 5 reduced form of nicotinamide adenine dinucleotide; P i 5 inorganic phosphate.

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to greater peaks, which then normalized through hemodynamic/metabolic compen sation. This contin-ued until hemorrhage became so severe that compen-sation was no longer possible and the NADH intensity remained elevated ( Fig 6 ).

Several challenges remain with this technique; absolute values cannot be obtained, so changes in fl u-orescence are calculated as percentage values (or arbitrary units) relative to calibrated signals made at the beginning of measurement. Only surface probes are used at present, and movement can result in changes in fl uorescence. This limits the technique at present to short-term use. Data interpretation is also complicated by distortion from tissue scattering and absorption (eg, due to changes in blood volume), requiring the need for correction techniques, which also have limitations. 69 More development is needed to improve fi xation to or within tissue before it can become a commonplace clinical tool.

COX Redox State: COX contains two heme iron (cytochrome a and a 3 ) and two copper centers (Cu A , Cu B ) whose redox state changes during electron transfer ( Fig 7 ). The Cu A center in the oxidized form strongly absorbs in the near-infrared spectrum with a cha-racteristic shape and broad peak at 830 nm. When oxygen availability falls, the Cu A center becomes more reduced. This is detectable using near-infrared spectroscopy 70 and was shown in brain and skeletal muscle to correlate well with oxygen use in animal models of hypoxemia, hemorrhage, endotoxemia, and ischemia-reperfusion. 71 - 74 By contrast, oxygen delivery and COX reduction were decoupled in trauma patients with multiple organ failure compared with those without multiple organ failure. 75

Advantages of this technique include the steady state of the total COX concentration (unlike deoxyhe-moglobin/oxyhemoglobin). However, the Cu A con-centration is , 10% that of hemoglobin, making optical detection diffi cult. Since the absolute concentration of Cu A is unknown, as with oxyhemoglobin and NADH, all measurements are expressed as absolute changes from an arbitrary zero at the start of measurement.

Magnetic Resonance Spectroscopy

Magnetic resonance spectroscopy (MRS) may be readily combined with MRI. MRI uses signals from pro tons to form anatomic images, whereas MRS uses radiolabeled molecules to determine metabolite con-cen trations and quantify tissue enzyme kinetics. Although not a monitor as such, MRS offers useful diagnostic capacity so will be briefl y described.

In a magnetic fi eld, nuclear magnetic resonance-active nuclei absorb electromagnetic radiation at a frequency specifi c to the isotope. Although various nuclei may be used, only phosphorus and hydrogen exist in concentrations high enough in vivo to be used for routine clinical evaluation. 76 , 77 For bioenergetic studies, 31 P-nuclear magnetic resonance is primarily used, as it measures changes in phosphocreatine (PCr), ATP, Pi, and intracellular pH during stress condi-tions (eg, administration of dobutamine, transient hypoxia). 78 , 79 Values of ATP, PCr, and Pi are obtained from characteristic peaks in the resonance spectrum. Intracellular pH is calculated from the shift in dis-tance between Pi and PCr peaks, as the Pi signal is pH-sensitive ( Fig 8 ).

PCr forms the primary ATP buffer in heart and muscle cells, transferring its phosphate to ADP. 79 Dur-ing ischemia, PCr decreases while Pi increases to maintain ATP homeostasis. Only when PCr is depleted do ATP levels fall. A decrease in PCr/ATP ratio indi-cates the level of stress to which myocardium or skeletal

Figure 6. Changes in skeletal tPO 2 , LDF, and surface NADH fl uorescence intensity following incremental hemorrhage. Due to physiologic compensation, the NADH:NAD 1 ratio recovers after each 10% hemorrhage until 50% of blood volume has been removed. See Figure 1 and 5 legends for expansion of other abbreviations.

Figure 7. NIRS interrogation of cytochrome oxidase redox state. c 5 cytochrome c; Cu A and Cu B 5 copper centers; H a and H a 3 5 heme iron centers. See Figure 1 legend for expansion of other abbreviation.

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muscle is subject. This ratio remains constant under mild to moderate stress but rapidly falls with tissue ischemia. The rate of change in PCr/ATP ratio during or on recovery from ischemia provides an index of fl ux. Using saturation transfer techniques, ATP fl ux can be measured. This fl ux is reduced in heart failure. 79

Hydrogen MRS can measure molecules and metab-olites involved in (patho)physiologic processes (eg, N-acetyl-aspartate [decreased in brain injury], creatine and phosphocreatine [involved in energy metabolism], lactate [marker of anaerobic metabolism], alanine, glu-cose, and choline compounds [markers of synthesis and breakdown of cell membranes]). It is used clin-ically for various conditions, particularly within the brain, including oncology, demyelinating infl amma-tory pathologies, infectious diseases, and metabolic pathologies such as hepatic encephalopathy and dif-fuse cerebral distress. In traumatic brain injury it can delineate the degree of injury and prognosis, as the detected metabolites are sensitive to hypoxia, energy dysfunction, neuronal injury, membrane turnover, and infl ammation. 80

Conclusions

The goals of resuscitation in critically ill patients are to ensure adequate tissue perfusion and cellular metabolism. Current clinical tools are, however, lack-ing in the sensitivity and specifi city needed to guide optimal management. Advances in technology are

providing promising noninvasive or minimally invasive techniques. These, however, require initial validation to ensure reliability and to gain the necessary confi -dence that they can be used as surrogates refl ecting or, better still, preceding changes in deeper, more vital organs. On satisfactory demonstration of the above, randomized controlled trials can assess their impact upon outcomes, and this must occur before potential implementation into management guidelines.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Ekbal holds a UK Medical Research Council Studentship to investigate NADH fl uoroscopy. Dr Dyson participated in a study funded as above to develop tissue P o 2 technology. University College London has an Intellectual Property agreement with Oxford Optronix Ltd to develop a clinical tissue P o 2 monitor. Dr Black holds a fellow-ship grant from UK National Institutes of Health Research assessing means of individualizing rehabilitation of critically ill patients. This partly involves study of metabolic monitoring, a device for which was purchased under the grant. Dr Singer holds UK gov-ernment/charitable grants to develop tissue P o 2 and NADH fl uo-rometry technologies and to study metabolic monitoring. Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

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1808 Postgraduate Education Corner

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