- Email: [email protected]
Tissue oxygenation in morbid obesity – The physiological and clinical perspective
Trends in Anaesthesia and Critical Care 3 (2013) 310e315
Contents lists available at ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
Tissue oxygenation in morbid obesity e The physiological and clinical perspective Adrian Alvarez a, *, Preet Mohinder Singh b, Ashish C. Sinha c a
Department of Anesthesia, Hospital Italiano de Buenos Aires, Juan D. Peron 4190, C1181ACH Buenos Aires, Buenos Aires Province, Argentina Department of Anesthesia, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India c Department of Anesthesia, Drexel University College of Medicine; Philadelphia, PA, USA b
s u m m a r y Keywords: Tissue oxygenation in morbidly obese Perioperative tissue oxygenation in obese Pathophysiology of tissue oxygen monitoring in obese
In order to reach and maintain a normal physiological performance, each cell of the human body needs an adequate quantity of oxygen. The measurement of oxygen at the cellular level is a significant early marker of local injury. Unlike global markers of oxygen deficit that often detect on-going pathology in the irreversible phase, tissue oxygenation measurement can provide an early therapeutic window for appropriate timely intervention to prevent and revert the damage. The present review describes the physiological principles guiding tissue oxygen levels in the morbidly obese. We describe how the morbidly obese are different from lean patients in terms of oxygen delivery at various tissue levels. The text highlights how pathological alterations in tissue oxygen levels during special situations like trauma, sepsis, and active bleeding can be predicted, interpreted and therapeutically targeted to improve clinical outcomes in morbidly obese patients. The utility of tissue oxygenation monitoring in relevance to morbidly obese patients during the perioperative period along with the possible clinical implications is also discussed. We present the present evidence on the topic and extrapolate the possible future role of this monitoring for various diseased states in morbidly obese patients. Ó 2013 Elsevier Ltd. All rights reserved.
In order to reach and maintain a normal physiological performance, each cell of the human body needs an adequate quantity of oxygen. Thus, it would be ideal to measure the amount of oxygen at a cellular level or as close as possible to the cell. In clinical practice this usually does not happen. Commonly used monitors evaluate the upstream component of the circulation; oxygen in blood prior to it reaching the tissue (pulse oximetry, arterial blood gas sampling) and the perfusion pressure, again prior to reaching the tissue (invasive and non-invasive arterial blood pressure monitoring). On the other hand, monitors also measure the downstream component; for oxygenation (venous oxygen saturation, mixed venous oxygen saturation) and the post perfusion pressure (central venous pressure). In any case, the ultimate aim of these monitors is to detect the amount of oxygen effectively reaching the peripheral tissues where actual utilization/metabolism takes place. In 1956, Clark described an electrode capable of measuring oxygen tension in the tissue based on polarography. Eventually this finding opened up a new dimension of understanding about the oxygen cascade.1 Subsequent developments in technology have made it possible to directly look at microcirculation; the site of
* Corresponding author. E-mail address: [email protected] (A. Alvarez). 2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tacc.2013.09.002
actual oxygen delivery and consumption. Although conventional monitors act adequately as a surrogate marker, they cannot measure the actual factors upon which tissue oxygenation depends (i.e. adequate total blood flow, even distribution of microcirculatory flow, adequate diffusion of oxygen across capillaries and the capacity of tissues to take up and utilize oxygen.)2 The idea of using such monitoring might be vital in some patient populations like the morbidly obese. In these subjects, weight gain is out of proportion to the increase in blood volume.3 In the morbidly obese, relative blood volume is lower than in lean counterparts. Subsequently actual tissue perfusion (and eventual oxygenation) on a per weight unit basis is also lower in these individuals. Although conventional monitors fail to detect any such abnormality in the obese, this persistent tissue dysoxia is now recognized as the crux of metabolic ailments seen in the morbidly obese patients.4 With that said, in this review first we will address the monitoring targets for tissue perfusion and oxygenation and discuss the factors affecting tissue oxygen tension. We will also emphasize the importance of the concept “critical oxygen delivery to tissue”. Then we will analyze the implications of tissue oxygenation derangements seen in morbidly obese individuals mainly focusing on chronic metabolic and inflammatory diseases as well as in sepsis and shock. Finally we will discuss the possible future directions for research in this field.
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
Table 1 Principles and technologies used in monitoring tissue level perfusion properties. Parameter
Concept
Technology
Microvascular flow
RBC flow velocity Percentage of total micro-vessels carrying blood Tissue PaO2
Laser Doppler flowmetry Orthogonal polarization spectral imaging Or dark field imaging Oxygen electrodes or optode sensors Reflectance spectrometry
Tissue Oxygen availability
Microvascular physiological function
Relative Oxyhemoglobin concentration Hb/HbO2 and cytochrome aa3 in tissues Changes in tissue vessel permeability
Near infrared spectroscopy Venous occlusion plethysmography
1. Monitoring targets for tissue perfusion and oxygenation As the insights into oxygen delivery and consumption are growing, the advancements in the monitoring systems now target microcirculation for monitoring oxygenation. The current available technology is capable of quantifying changes in the microcirculation at three levels, namely5 1. Measuring microvascular flow 2. Tissue oxygen availability 3. Microvascular physiological function The principles and technology used in the above measurement are shown in Table 1. It must be realized that all the above methods are based on electrophysiological or electromagnetic wave based principles and penetration into tissue (past the skin and subcutaneous tissue) is a prerequisite for accurate measures. Thus the accuracy of these monitoring methods is debated in the morbidly obese. Either a site of measurements is chosen, that is least affected by body fat (e.g. palms) or specific modifications need to be made in this equipment to compensate for this physiological derangement. 2. Factors affecting tissue oxygen tension Partial pressure of oxygen exerted in the interstitial compartment (extravascular space) is labeled as tissue oxygen tension or tPO2.6 It is a measure of balance between capillary oxygen delivery and mitochondrial oxygen consumption. The percentage of “oxygen saturated hemoglobin” in the microcirculation blood perfusing the tissue is called the tissue oxygen saturation or the StO2. (Fig. 1) A complex relationship exists between the above two variables (tO2 and StO2). The oxygen dissociation curve is sigmoid and for available normograms, if the value of one of the above variables is available the other can be easily calculated. Most of the noninvasive technologies (other than Clark’s electrode) measure StO2 and estimate tissue oxygen tension. The measured value of tO2 or StO2 represents a balance between oxygen delivery and utilization. When the oxygen delivery decreases and consumption is maintained or falls to a lesser degree, then tissue oxygen tension falls. On the other hand if oxygen delivery increases but oxygen consumption is maintained or increases to a lesser degree, then the tPO2 value will increase. In morbidly obese subjects, blood flow to nonvital organs and fat is lower than in lean counterparts. As a result, basal tPO2 and StPO2 values are also lower.7 Thus the measurement of tissue oxygen tension can provide an insight into the demand/ supply ratios for organs at watershed zones and for organs where local oxygen delivery and consumption fluctuate on a regular basis
311
(e.g. kidney). This demand/supply mismatch, once estimated via tissue oxygen levels can also evaluate the local organ-specific disease process that can eventually be used to prognosticate during the treatment of critical illness states.8 As an example, the oxygen supply to the renal medulla is physiologically low to maintain interstitial solute gradient that may otherwise be washed off by high blood flow. So in such tissue, demand and supply are matched at a nadir and any further pathological insult may manifest as lowered tissue oxygenation due to decreased blood flow. Thus monitoring demand and supply changes at such tissue levels may add to a very early diagnosis of an evolving pathological process. 3. The concept of critical oxygen delivery to tissue Oxygen supply to tissue routinely matches the demands of the perfused tissue. Physiologically, when demand increases it usually promotes a raise in blood flow (metabolites/CO2 leads to vasodilatation). Thus the oxygen supply to the tissue is a “demand dependent supply” with a large margin of safety. When the tissue perfusion falls without an increase in oxygen content, it is compensated for by an increased oxygen extraction ratio from the hemoglobin. Cain demonstrated that initially when a drop in blood flow happens by increasing the extraction ratio, oxygen consumption by the tissue remains unaffected.9 However, once this blood flow (or the total oxygen delivered to tissue) falls below a “critical level”, the oxygen consumption by the tissue decreases promoting anaerobic metabolism. This occurs when the extraction ratio reaches a maximum possible value and further unloading of oxygen from hemoglobin is not possible. This unloading or extraction ratio varies with the tissue properties. These properties depend on factors like CO2 tension, acid-base status, concentration of 2,3-DPG (diphosphoglycerate) etc. In other words, the critical point of oxygen delivery for different tissues in the body is not the same. Consequently, the chances to shift to an anaerobic metabolism (inefficient metabolism) vary for different organs. High oxygen consumption organs (unless capable of increasing extraction ratio to extreme values) are likely to suffer metabolic insult much earlier (like the central nervous system) than organs with low requirements (musculoskeletal system) or even organs with high extraction ratio (heart).10 So if global markers of hypoxia are measured in blood, due to dilution, no marker changes or abnormality may be found, when actually one of the organ systems may have already reached a critical limit. The markers of anaerobic metabolism drained into the blood become significantly diluted to bring about measurable changes in whole blood concentration (which analyzers measure in the lab). In view of the varying critical points for different tissue, a fall in regional oxygen tensions acts as an early marker of physiological insult.11 In situations of “global fall of oxygen delivery”, organ systems consuming more oxygen will be affected prior to other organ systems consuming less oxygen. Global markers of anaerobic metabolism will not be able to distinguish this differential fall in tissue oxygen levels. However, if oxygen levels are measured at an individual tissue/organ system level, this variation will become evident soon and this pathological state affecting specific organs can be detected much earlier eventually promoting restorative measures in time. 4. Tissue oxygen tension in the morbidly obese: implications for chronic metabolic and inflammatory diseases Recent insight into the pathophysiology of obesity-related metabolic disorders has implicated persistent low tissue oxygenation (adipose) levels as the prime inciting cause.12 Adipose tissue development is closely linked to vascularization. It is likely that the expansion of adipose tissue mass during the progressive
312
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
Fig. 1. Schematic diagram showing the site of measurement of tissue oxygen tension and tissue oxygen saturation.
development of obesity leads to a relative oxygen deficient state in certain parts of the adipose tissue due to insufficient angiogenesis to maintain normoxia in the entire adipose tissue.13 Deoxyribonucleic acid (DNA) microarray based gene expression profiling has shown an increase in adipose tissue mass which parallels the down regulation of mitochondrial energy handling capability both in visceral and abdominal fat (proportionate to the relative deficiency of vascularity).14 Persistent decreased tissue oxygen content has a clear association with the up regulation of GLUT-1 (Glucose transporter-1) and hypoxia inducible factor (HIF), this not only alters glucose utilization but also induces a state of chronic tissue inflammation.15 These pro-inflammatory cytokines spill over to the circulation causing malfunction of non-adipose tissue as well.16 Morbidly obese patients also have a high incidence of OSA (obstructive sleep apnea)17 and undergo severe episodic desaturations during sleep. The tissue develops extremely low oxygen tension during these obstructive episodes that lead to the down regulation of “adiponectin” expression.18,19 Adiponectin is a protein that affects glucose and fatty acid metabolism to lower fat content and to reduce local inflammation.20 Animal studies (diet-induced mutant obese mice) and cell-culture experiments (human adipocytes) strongly support the role of tissue level hypoxia in modulating the production of several inflammation-related adipokines, like increased IL-6, leptin and macrophage migratory inhibition factor production simultaneously with low adiponectin synthesis. These events have a significant contribution to the altered adipocyte physiology in morbidly obese patients and contribute to the adverse metabolic milieu associated with obesity.21 In the near future, unlike non-obese patients where tissue oxygenation levels have only found utility in acute physiological insults, in obese tissue oxygen tension estimations may also find a predictive role for longterm outcomes as well. 5. Tissue oxygen tension in healthy state Under resting conditions oxygen tension varies not only amongst different organs but also within the organ itself. The values are lower for higher oxygen consuming (metabolically active) organs like the heart, brain, liver etc. and high in organs with a low consumption e.g. the bladder. For example in the kidneys, within the organ, the values within the renal medulla due to high oxygen demand are much lower than those found in the renal cortex.22 As a result of these physiological variations, the
development of normal routine values is challenging. Minor variations in basal requirements can significantly alter the measured results without any actual pathological association and can give a false indication of an associated pathology. Generally, basal oxygen tension values are lower in deeper tissue and in centrally located organs with high metabolic activity. The basal values measured at tissue level bear no direct relation to the percentage of cardiac output that an organ is perfused with, rather it is a strong predictor of the ratio of oxygen consumption to the total blood flow. So organs with high blood flow but high oxygen consumption may have very low baseline values. Another factor that determines the basal value in tissue is the degree of arterio-venous shunting (AV shunt) that results in blood bypassing the tissue without providing oxygen. In such cases the oxygen values measured in a vein draining the tissue will be high, whereas the actual tissue suffers from a dearth of oxygen.8,23 Such AV shunts are known to play a vital role in maintaining high renal medullary osmolarity, while simultaneously contributing to significantly low oxygen tension in the renal medulla. Pasarica and colleagues found that healthy obese patients had around 44% lesser capillary density in subcutaneous tissue signifying lower perfusion. They were not, however, able to correlate it to any pathological significance.24 Increasing the body fat quantity has been shown to correlate inversely with basal subcutaneous tissue oxygen levels. More research is needed targeting the obese subgroup to determine the possible range of ‘normal’ values in various tissues. 6. Tissue oxygen tension in the diseased state Peripheral tissue oxygenation shows a fall much earlier than central organs, as basal oxygen delivery to peripheral tissues is much lower. So any pathological insult has a smaller buffering capacity in the periphery, and can thus be used for early detection of on-going insult. Extrapolating these pathophysiological alterations to the morbidly obese has significant clinical implications. Obese patients have much higher subcutaneous tissue volume compared to lean patients. A redistribution of blood flow towards central circulation away from this peripheral adipose tissue is likely to leave a larger amount of hypoxic tissue in comparison to similar redistributions that occur in non-obese patients. During diseased states this higher volume of subcutaneous tissue rapidly becomes underperfused and eventually produces more inflammatory/hypoxic markers. It is known that these markers in normal patients trigger a cascade of reactions that form the pathophysiological basis
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
of disease progression during hypoxic states. The above translates into the possibility of morbidly obese patients showing a much more rapid clinical deterioration with physiological insults that may not be very significant in lean patients. Measuring the peripheral tissue oxygenation in morbidly obese patients could thus provide an early window of opportunity for treatment by initiating therapeutic steps before the actual clinical symptomatology/deterioration occurs. Additionally, as maintaining optimal oxygen supply to vital organs is the primary goal; measuring tissue oxygenation at a central level may help to quantify the maximal permissible ischemia time (intraoperative) without long-term sequelae. Multiple trials have evaluated the use of tissue oxygenation measurement (peripheral/ central) in the following pathological states:
313
Fig. 2. Diagram showing evidence-based protocol to treat hemorrhagic shock on the basis of measured StO2 (tissue oxygen saturation) values and its trends.
6.1. Hemorrhagic shock Belzberg et al. in their analysis of 625 obese trauma patients showed that early cardiac index and tissue oxygenation reduction, strongly correlates with survival. They concluded that using tissue oxygenation as a therapeutic target could be used to determine the adequacy of resuscitation. Nelson et al. also showed that obese patients due to having relative low blood volume (ml/kg) are at an increased risk of developing hypovolemic-hemorrhagic shock and recommended using tissue oxygenation to institute early therapeutic measures.25 During blood loss the peripheral vascular resistance increases and leads to shunting of blood to vital organs. Consequently, multiple studies have reported a consistent fall in peripheral tissue oxygenation in vascular beds like the stomach, gut, skin and mucosa, preceding any classical hemodynamic parameters detecting any change.26 As already stated above, a higher volume of subcutaneous tissue is likely to represent redistribution associated hypoxia much earlier and thus may eventually find a vital role for monitoring of hemorrhagic shock in the morbidly obese during future trials. Eventually if the bleeding (volume loss) continues, the delivery to central organs also suffers and it is at this point that most of the established monitors (blood pressure and CVP) detect an on-going shock.27 Another unique feature of quantifying the ongoing shock using tissue oxygen tension that distinguishes it from measures of global oxygenation is that until the hypovolemia is treated, an increase in the inspired oxygen percentage does not fallaciously lower markers of hypoxia. Organs with high oxygen demand (like the kidney) start to suffer from the consequences of lowered oxygen delivery much earlier. The liver rapidly metabolizes lactates (global marker of tissue ischemia) added from the ischemic organ. Increasing the blood oxygen content by increasing inspired oxygen concentration further enhances this metabolism. Thus when ischemic markers are measured from the central compartment, false assuring results may be obtained. If global markers like lactate are measured, increased oxygen in the blood (increasing inspired concentration) stimulates aerobic metabolism (despite persistent low volume state), lactate is metabolized by central, well perfused organs like the liver giving a false assurance of adequate treatment. Peripheral tissue oxygen tension does not show much change on increasing inspired oxygen as vasoconstriction persists till volume status returns to normal and these tissues continue to have low perfusion related low oxygen tension.28 Noninvasive technologies like NIRS (Near Infrared Spectrometry) based studies measuring peripheral tissue hemoglobin saturation have been validated in multiple trials for assessing the treatment of hemorrhagic shock in non-obese patients.29,30 A suggested basic plan of management targeting tissue hemoglobin saturation close to 75% is shown in Fig. 2. Tissue oxygenation values recorded at the commencement of treatment have a strong
prognostic significance. The lower the values, the worse is the likely outcome and the more aggressive should be the volume replacement.30 Based upon physiological principles, the trends of changes in NIRS in morbidly obese patients are likely to parallel those of the lean population. While using NIRS in the morbidly obese, one must keep in mind the possibility of a decreased representation of deeper tissue (fat decreases near infrared wave penetration). Additionally, the obese are in a state of chronically lower tissue oxygen levels, thus the actual measured values may persistently remain slightly lower in obese patients. Therefore, during the diseased state, NIRS may show further lower values in the obese. Until concrete evidence is available and more studies shed light on the utility of NIRS in the obese, it must be used in these patients with the above limitations in mind. 6.2. Sepsis Conflicting results exist concerning the effect of sepsis on tissue oxygen levels. Some trials have reported increased tissue PO2 in the bladder and gut,31 whereas others reported decreases in values from the skeletal muscle and liver.32 A possible explanation for these inconsistent results is that the initial phase of sepsis leads to systemic vasodilatation and is compensated for by increasing the cardiac output. If measurements are taken during this initial phase (where blood flow is actually increased as a result of physiological compensation), one may find increased oxygen delivery to peripheral tissue despite on-going pathology. Subsequently, cardiac compensation fails and a possible mitochondrial dysfunction begins.33 The peripheral oxygen delivery falls and thus the measurements now show lower than normal values.8 Pathological tissue hypo-perfusion persists even in the presence of normal blood pressure and adequate cardiac output, a state referred to as “cryptic shock”.34 This hypo-perfusion is the potential result of blood flow at the regional or microvascular level. It may also be a result of mitochondrial dysfunction in the presence of an adequate oxygen supply.35 Baseline StO2 values during sepsis may have a significant overlap with normal patients but one thing that consistently distinguishes sepsis-related pathology is an inconsistent increase in tissue oxygen tension upon increasing inspired oxygen concentration. This phenomenon is probably attributable to sepsis-related mitochondrial dysfunction.36 Another possible hypothesis explaining normal or nearnormal values during sepsis is microcirculatory disturbance with blood stagnation in the capillaries or associated A-V shunting that gives a factitious reading of raised tissue oxygen levels.37 A low StO2 value at the outset of sepsis predicts poor outcome with a high degree of sensitivity and specificity.38 Despite multiple trials evaluating the treatment response to sepsis, no direct correlation could
314
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
be established between patient improvement and actual values of tissue oxygenation. A positive outcome that can be drawn from the above unpredictability is in patients with hemodynamic shock of cardiogenic origin (cardiac failure). This subgroup of patients will always have low tissue perfusion without tissue mitochondrial dysfunction and will always have low tissue oxygenation levels, whereas sepsis-related hypotension could present with both increased or decreased tissue oxygen levels.8 Almost no literature on tissue oxygenation changes in sepsis exists for obese patients. There is however no reason that these morbidly obese patients should behave differently in this aspect. Until studies addressing sepsis-related changes in the obese are available, these results could logically be extrapolated to that conclusion. 7. Tissue oxygenation in the morbidly obese during the perioperative period The perioperative period is one of the most studied phases of utility of tissue oxygenation in morbidly obese patients. Consistently it has been established that tissue perfusion in morbidly obese patients is impaired in the perioperative period. It has been attributed to local as well as systemic factors. Cardiac output, circulating blood volume, and resting oxygen consumption are all increased in obese individuals, which probably lowers oxygen tension reaching the tissue.39 An increased incidence of wound infection in the morbidly obese possibly has a direct bearing on lower tissue oxygen tension. Oxidative killing by the neutrophils is the primary defense against the surgical site related pathogens. Thus in low availability of tissue oxygen, this mechanism suffers and oxidative killing is hampered.40 Evidence supports that the risk of surgical wound infection is inversely related to perioperative tissue oxygen partial pressure.41 It is a known fact that tissue repair after surgical incision is also strongly dependent upon subcutaneous tissue oxygen tension.42 Thus, morbidly obese patients are at a higher risk of surgical site infection and delayed wound healing. Fleischmann et al. reported significantly low tissue oxygenation levels in obese patients undergoing laparoscopic surgery when compared to their non-obese counterparts. They concluded that obese patients required higher inspired oxygen concentrations to maintain similar levels of tissue oxygenation. A possible mechanism to explain the higher incidence of wound infections in these patients could be subcutaneous tissue hypo-oxygenation.43 Obesity is actually associated with an increased incidence of surgical site infection and delayed wound healing. This has been noted in a retrospective review of perioperative complications in morbidly obese patients published by Dindo et al.44 Pain promotes sympathetic stimulation, subsequent increased metabolism and oxygen consumption. Adequate analgesia may prevent this pathophysiological cascade. Epidural analgesia offers a dual advantage for improving tissue oxygenation levels, it lowers tissue oxygen demand by alleviating pain and further by vasodilatation (when local anesthetics are used) it also increases the regional blood flow thereby simultaneously improving both demand and supply. Data suggests that thoracic epidural anesthesia blunts the decrease of subcutaneous tissue oxygen tension caused by surgical stress and adrenergic vasoconstriction during major abdominal surgery. According to Kabon and coworkers, combined general and epidural anesthesia may help to provide sufficient tissue oxygenation.45 Deliberate moderate hypercapnia is another measure utilized to improve tissue oxygenation in obese patients. Hager et al. evaluated the effect of intraoperative hypercapnia in morbidly obese patients undergoing open gastric bypass. These authors found significantly improved tissue oxygen levels in their patients.46 On the other hand Kabon et al. (evaluating the effect of postoperative oxygen supplementation leading to increased tissue oxygen tension) failed to
show significant improvement on wound infection rates.40 Further research on this may add more insight into this aspect and improve clinical outcomes. 8. Future directives Non-invasive monitoring of tissue oxygenation needs to be fully explored in morbidly obese individuals. Concerns about excessive subcutaneous tissue affecting the accuracy of tissue oxygenation measurements have been expressed. Nevertheless, once basal values are available in obese subjects, these problems can easily be offset. The chronic lower basal levels of tissue oxygen in obese patients with associated extremely low values during episodes of OSA distinguish them from their nonobese counterparts. Studies evaluating OSAS and associated diseases may provide further insight into obesity-related metabolic derangements. An incompletely explored field involving obesity, sepsis and tissue oxygenation may become instrumental in predicting and improving the outcomes of obese patients developing sepsis. Perioperative monitoring of tissue oxygenation in the obese extends a possibility of discovering methods to improve ventilatory strategies in these patients. Postoperative pulmonary complications often present as clinical hypoxia after significant insults, and the capability of measuring these tissue level changes before they affect vital organs. A window therefore exits that if utilized appropriately may give us an opportunity to significantly improve outcomes. Future studies addressing the perioperative requirement of transfusion in the obese may be able to give an objective marker of therapeutic end points. Such studies will also be vital in targeting fluid requirements in the obese. Long term follow-up trials can help to establish therapeutic interventions that may bring down cellular inflammation which is the common pathway of pathophysiology in morbidly obese patients. Conflicts of interest None for any of the authors. References 1. Severinghaus JW. First electrodes for blood PO2 and PCO2 determination. J Appl Physiol 2004;97(5):1599e600. 2. Shoemaker WC, Wo CC, Chan L, Ramicone E, Kamel ES, Velmahos GC, et al. Outcome prediction of emergency patients by noninvasive hemodynamic monitoring. Chest 2001;120(2):528e37. 3. Lemmens HJM, Bernstein DP, Brodsky JB. Estimating blood volume in obese and morbidly obese patients. Obes Surg 2006;16(6):773e6. 4. Goossens GH, Blaak EE. Adipose tissue oxygen tension: implications for chronic metabolic and inflammatory diseases. Curr Opin Clin Nutr Metab Care 2012;15(6):539e46. 5. Sakr Y. Techniques to assess tissue oxygenation in the clinical setting. Transfus Apher Sci 2010;43(1):79e94. 6. Duling BR, Berne RM. Longitudinal gradients in periarteriolar oxygen tension. A possible mechanism for the participation of oxygen in local regulation of blood flow. Circ Res 1970;27(5):669e78. 7. Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 2008;100(2):227e35. 8. Dyson A, Singer M. Tissue oxygen tension monitoring: will it fill the void? Curr Opin Crit Care 2011;17(3):281e9. 9. Soni N, Fawcett WJ, Halliday FC. Beyond the lung: oxygen delivery and tissue oxygenation. Anaesthesia 1993;48(8):704e11. Erratum in: Anaesthesia 1993;48(12):1123. 10. Wolff CB. Normal cardiac output, oxygen delivery and oxygen extraction. Adv Exp Med Biol 2007;599:169e82. 11. Bateman RM, Sharpe MD, Ellis CG. Bench-to-bedside review: microvascular dysfunction in sepsisehemodynamics, oxygen transport, and nitric oxide. Crit Care 2003;7(5):359e73. 12. Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, et al. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 2008;118(9):968e76. 13. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92(3):347e55.
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315 14. Klimcáková E, Roussel B, Márquez-Quiñones A, Kovácová Z, Kováciková M, Combes M, et al. Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response. J Clin Endocrinol Metab 2011;96(1):E73e82. 15. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007;293(4):E1118e28. 16. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008;94(2):206e18. 17. Wadhwa A, Singh PM, Sinha AC. Airway management in patients with morbid obesity. Int Anesthesiol Clin 2013;51(3):26e40. 18. Wree A, Mayer A, Westphal S, Beilfuss A, Canbay A, Schick RR, et al. Adipokine expression in brown and white adipocytes in response to hypoxia. J Endocrinol Invest 2012;35(5):522e7. 19. Yu J, Shi L, Wang H, Bilan PJ, Yao Z, Samaan MC, et al. Conditioned medium from hypoxia-treated adipocytes renders muscle cells insulin resistant. Eur J Cell Biol 2011;90(12):1000e15. 20. Kim DH, Kim C, Ding EL, Townsend MK, Lipsitz LA. Adiponectin levels and the risk of hypertension: a systematic review and meta-analysis. Hypertension 2013;62(1):27e32. 21. Wood IS, de Heredia FP, Wang B, Trayhurn P. Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 2009;68(4):370e7. 22. Whitehouse T, Stotz M, Taylor V, Stidwill R, Singer M. Tissue oxygen and hemodynamics in renal medulla, cortex, and corticomedullary junction during hemorrhage-reperfusion. Am J Physiol Renal Physiol 2006;291(3):F647e53. 23. Izumi Y, Sakai H, Hamada K, Takeoka S, Yamahata T, Kato R, et al. Physiologic responses to exchange transfusion with hemoglobin vesicles as an artificial oxygen carrier in anesthetized rats: changes in mean arterial pressure and renal cortical tissue oxygen tension. Crit Care Med 1996;24(11):1869e73. 24. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 2009;58(3):718e25. 25. Nelson J, Billeter AT, Seifert B, Neuhaus V, Trentz O, Hofer CK, et al. Obese trauma patients are at increased risk of early hypovolemic shock: a retrospective cohort analysis of 1,084 severely injured patients. Crit Care 2012;16(3):R77. 26. Drucker W, Pearce F, Glass-Heidenreich L, Hopf H, Powell C, Ochsner MG, et al. Subcutaneous tissue oxygen pressure: a reliable index of peripheral perfusion in humans after injury. J Trauma 1996;40(3 Suppl.):S116e22. 27. Vollmar B, Conzen PF, Kerner T, Habazettl H, Vierl M, Waldner H, et al. Blood flow and tissue oxygen pressures of liver and pancreas in rats: effects of volatile anesthetics and of hemorrhage. Anesth Analg 1992;75(3):421e30. 28. Nordin A, Mildh L, Mäkisalo H, Härkönen M, Höckerstedt K. Hepatosplanchnic and peripheral tissue oxygenation during treatment of hemorrhagic shock: the effects of pentoxifylline administration. Ann Surg 1998;228(6):741e7. 29. Cohn SM, Nathens AB, Moore FA, Rhee P, Puyana JC, Moore EE, et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation. J Trauma 2007;62(1):44e54 discussion 54e5.
315
30. Lima A, van Bommel J, Jansen TC, Ince C, Bakker J. Low tissue oxygen saturation at the end of early goal-directed therapy is associated with worse outcome in critically ill patients. Crit Care 2009;13(Suppl. 5):S13. 31. VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995;23(7):1217e26. 32. Anning PB, Sair M, Winlove CP, Evans TW. Abnormal tissue oxygenation and cardiovascular changes in endotoxemia. Am J Respir Crit Care Med 1999;159(6): 1710e5. 33. Singh PM, Borle A, Trikha A. Diagnostic dilemma: rare case of recurrent d-lactic acidosis leading to recurrent acute cardiac failure. Acta Anaesthesiol Taiwan 2013;51(2):94e6. 34. Donnino MW, Nguyen B, Jacobsen G, Tomlanovich M, Rivers E. Cryptic septic shock: a sub-analysis of early, goal-directed therapy. Chest 2003;124 (4_ MeetingAbstracts):90Seb. 35. Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit Care 2005;9(Suppl. 4):S20e6. 36. Creteur J, Carollo T, Soldati G, Buchele G, De Backer D, Vincent JL. The prognostic value of muscle StO2 in septic patients. Intensive Care Med 2007;33(9): 1549e56. 37. De Backer D, Ospina-Tascon G, Salgado D, Favory R, Creteur J, Vincent JL. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010;36(11): 1813e25. 38. Mesquida J, Gruartmoner G, Martínez ML, Masip J, Sabatier C, Espinal C, et al. Thenar oxygen saturation and invasive oxygen delivery measurements in critically ill patients in early septic shock. Shock 2011;35(5):456e9. 39. Di Girolamo M, Skinner Jr NS, Hanley HG, Sachs RG. Relationship of adipose tissue blood flow to fat cell size and number. Am J Physiol 1971;220(4):932e7. 40. Kabon B, Rozum R, Marschalek C, Prager G, Fleischmann E, Chiari A, et al. Supplemental postoperative oxygen and tissue oxygen tension in morbidly obese patients. Obes Surg 2010;20(7):885e94. 41. Hopf HW, Hunt TK, West JM, Blomquist P, Goodson 3rd WH, Jensen JA, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997;132(9):997e1004 discussion 1005. 42. Greif R, Akça O, Horn EP, Kurz A, Sessler DI., Outcomes Research Group. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. N Engl J Med 2000;342(3):161e7. 43. Fleischmann E, Kurz A, Niedermayr M, Schebesta K, Kimberger O, Sessler DI, et al. Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg 2005;15(6):813e9. 44. Dindo D, Muller MK, Weber M, Clavien P- A. Obesity in general elective surgery. Lancet 2003;361(9374):2032e5. 45. Kabon B, Fleischmann E, Treschan T, Taguchi A, Kapral S, Kurz A. Thoracic epidural anesthesia increases tissue oxygenation during major abdominal surgery. Anesth Analg 2003;97(6):1812e7. 46. Hager H, Reddy D, Mandadi G, Pulley D, Eagon JC, Sessler DI, et al. Hypercapnia improves tissue oxygenation in morbidly obese surgical patients. Anesth Analg 2006;103(3):677e81.
Contents lists available at ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
Tissue oxygenation in morbid obesity e The physiological and clinical perspective Adrian Alvarez a, *, Preet Mohinder Singh b, Ashish C. Sinha c a
Department of Anesthesia, Hospital Italiano de Buenos Aires, Juan D. Peron 4190, C1181ACH Buenos Aires, Buenos Aires Province, Argentina Department of Anesthesia, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India c Department of Anesthesia, Drexel University College of Medicine; Philadelphia, PA, USA b
s u m m a r y Keywords: Tissue oxygenation in morbidly obese Perioperative tissue oxygenation in obese Pathophysiology of tissue oxygen monitoring in obese
In order to reach and maintain a normal physiological performance, each cell of the human body needs an adequate quantity of oxygen. The measurement of oxygen at the cellular level is a significant early marker of local injury. Unlike global markers of oxygen deficit that often detect on-going pathology in the irreversible phase, tissue oxygenation measurement can provide an early therapeutic window for appropriate timely intervention to prevent and revert the damage. The present review describes the physiological principles guiding tissue oxygen levels in the morbidly obese. We describe how the morbidly obese are different from lean patients in terms of oxygen delivery at various tissue levels. The text highlights how pathological alterations in tissue oxygen levels during special situations like trauma, sepsis, and active bleeding can be predicted, interpreted and therapeutically targeted to improve clinical outcomes in morbidly obese patients. The utility of tissue oxygenation monitoring in relevance to morbidly obese patients during the perioperative period along with the possible clinical implications is also discussed. We present the present evidence on the topic and extrapolate the possible future role of this monitoring for various diseased states in morbidly obese patients. Ó 2013 Elsevier Ltd. All rights reserved.
In order to reach and maintain a normal physiological performance, each cell of the human body needs an adequate quantity of oxygen. Thus, it would be ideal to measure the amount of oxygen at a cellular level or as close as possible to the cell. In clinical practice this usually does not happen. Commonly used monitors evaluate the upstream component of the circulation; oxygen in blood prior to it reaching the tissue (pulse oximetry, arterial blood gas sampling) and the perfusion pressure, again prior to reaching the tissue (invasive and non-invasive arterial blood pressure monitoring). On the other hand, monitors also measure the downstream component; for oxygenation (venous oxygen saturation, mixed venous oxygen saturation) and the post perfusion pressure (central venous pressure). In any case, the ultimate aim of these monitors is to detect the amount of oxygen effectively reaching the peripheral tissues where actual utilization/metabolism takes place. In 1956, Clark described an electrode capable of measuring oxygen tension in the tissue based on polarography. Eventually this finding opened up a new dimension of understanding about the oxygen cascade.1 Subsequent developments in technology have made it possible to directly look at microcirculation; the site of
* Corresponding author. E-mail address: [email protected] (A. Alvarez). 2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tacc.2013.09.002
actual oxygen delivery and consumption. Although conventional monitors act adequately as a surrogate marker, they cannot measure the actual factors upon which tissue oxygenation depends (i.e. adequate total blood flow, even distribution of microcirculatory flow, adequate diffusion of oxygen across capillaries and the capacity of tissues to take up and utilize oxygen.)2 The idea of using such monitoring might be vital in some patient populations like the morbidly obese. In these subjects, weight gain is out of proportion to the increase in blood volume.3 In the morbidly obese, relative blood volume is lower than in lean counterparts. Subsequently actual tissue perfusion (and eventual oxygenation) on a per weight unit basis is also lower in these individuals. Although conventional monitors fail to detect any such abnormality in the obese, this persistent tissue dysoxia is now recognized as the crux of metabolic ailments seen in the morbidly obese patients.4 With that said, in this review first we will address the monitoring targets for tissue perfusion and oxygenation and discuss the factors affecting tissue oxygen tension. We will also emphasize the importance of the concept “critical oxygen delivery to tissue”. Then we will analyze the implications of tissue oxygenation derangements seen in morbidly obese individuals mainly focusing on chronic metabolic and inflammatory diseases as well as in sepsis and shock. Finally we will discuss the possible future directions for research in this field.
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
Table 1 Principles and technologies used in monitoring tissue level perfusion properties. Parameter
Concept
Technology
Microvascular flow
RBC flow velocity Percentage of total micro-vessels carrying blood Tissue PaO2
Laser Doppler flowmetry Orthogonal polarization spectral imaging Or dark field imaging Oxygen electrodes or optode sensors Reflectance spectrometry
Tissue Oxygen availability
Microvascular physiological function
Relative Oxyhemoglobin concentration Hb/HbO2 and cytochrome aa3 in tissues Changes in tissue vessel permeability
Near infrared spectroscopy Venous occlusion plethysmography
1. Monitoring targets for tissue perfusion and oxygenation As the insights into oxygen delivery and consumption are growing, the advancements in the monitoring systems now target microcirculation for monitoring oxygenation. The current available technology is capable of quantifying changes in the microcirculation at three levels, namely5 1. Measuring microvascular flow 2. Tissue oxygen availability 3. Microvascular physiological function The principles and technology used in the above measurement are shown in Table 1. It must be realized that all the above methods are based on electrophysiological or electromagnetic wave based principles and penetration into tissue (past the skin and subcutaneous tissue) is a prerequisite for accurate measures. Thus the accuracy of these monitoring methods is debated in the morbidly obese. Either a site of measurements is chosen, that is least affected by body fat (e.g. palms) or specific modifications need to be made in this equipment to compensate for this physiological derangement. 2. Factors affecting tissue oxygen tension Partial pressure of oxygen exerted in the interstitial compartment (extravascular space) is labeled as tissue oxygen tension or tPO2.6 It is a measure of balance between capillary oxygen delivery and mitochondrial oxygen consumption. The percentage of “oxygen saturated hemoglobin” in the microcirculation blood perfusing the tissue is called the tissue oxygen saturation or the StO2. (Fig. 1) A complex relationship exists between the above two variables (tO2 and StO2). The oxygen dissociation curve is sigmoid and for available normograms, if the value of one of the above variables is available the other can be easily calculated. Most of the noninvasive technologies (other than Clark’s electrode) measure StO2 and estimate tissue oxygen tension. The measured value of tO2 or StO2 represents a balance between oxygen delivery and utilization. When the oxygen delivery decreases and consumption is maintained or falls to a lesser degree, then tissue oxygen tension falls. On the other hand if oxygen delivery increases but oxygen consumption is maintained or increases to a lesser degree, then the tPO2 value will increase. In morbidly obese subjects, blood flow to nonvital organs and fat is lower than in lean counterparts. As a result, basal tPO2 and StPO2 values are also lower.7 Thus the measurement of tissue oxygen tension can provide an insight into the demand/ supply ratios for organs at watershed zones and for organs where local oxygen delivery and consumption fluctuate on a regular basis
311
(e.g. kidney). This demand/supply mismatch, once estimated via tissue oxygen levels can also evaluate the local organ-specific disease process that can eventually be used to prognosticate during the treatment of critical illness states.8 As an example, the oxygen supply to the renal medulla is physiologically low to maintain interstitial solute gradient that may otherwise be washed off by high blood flow. So in such tissue, demand and supply are matched at a nadir and any further pathological insult may manifest as lowered tissue oxygenation due to decreased blood flow. Thus monitoring demand and supply changes at such tissue levels may add to a very early diagnosis of an evolving pathological process. 3. The concept of critical oxygen delivery to tissue Oxygen supply to tissue routinely matches the demands of the perfused tissue. Physiologically, when demand increases it usually promotes a raise in blood flow (metabolites/CO2 leads to vasodilatation). Thus the oxygen supply to the tissue is a “demand dependent supply” with a large margin of safety. When the tissue perfusion falls without an increase in oxygen content, it is compensated for by an increased oxygen extraction ratio from the hemoglobin. Cain demonstrated that initially when a drop in blood flow happens by increasing the extraction ratio, oxygen consumption by the tissue remains unaffected.9 However, once this blood flow (or the total oxygen delivered to tissue) falls below a “critical level”, the oxygen consumption by the tissue decreases promoting anaerobic metabolism. This occurs when the extraction ratio reaches a maximum possible value and further unloading of oxygen from hemoglobin is not possible. This unloading or extraction ratio varies with the tissue properties. These properties depend on factors like CO2 tension, acid-base status, concentration of 2,3-DPG (diphosphoglycerate) etc. In other words, the critical point of oxygen delivery for different tissues in the body is not the same. Consequently, the chances to shift to an anaerobic metabolism (inefficient metabolism) vary for different organs. High oxygen consumption organs (unless capable of increasing extraction ratio to extreme values) are likely to suffer metabolic insult much earlier (like the central nervous system) than organs with low requirements (musculoskeletal system) or even organs with high extraction ratio (heart).10 So if global markers of hypoxia are measured in blood, due to dilution, no marker changes or abnormality may be found, when actually one of the organ systems may have already reached a critical limit. The markers of anaerobic metabolism drained into the blood become significantly diluted to bring about measurable changes in whole blood concentration (which analyzers measure in the lab). In view of the varying critical points for different tissue, a fall in regional oxygen tensions acts as an early marker of physiological insult.11 In situations of “global fall of oxygen delivery”, organ systems consuming more oxygen will be affected prior to other organ systems consuming less oxygen. Global markers of anaerobic metabolism will not be able to distinguish this differential fall in tissue oxygen levels. However, if oxygen levels are measured at an individual tissue/organ system level, this variation will become evident soon and this pathological state affecting specific organs can be detected much earlier eventually promoting restorative measures in time. 4. Tissue oxygen tension in the morbidly obese: implications for chronic metabolic and inflammatory diseases Recent insight into the pathophysiology of obesity-related metabolic disorders has implicated persistent low tissue oxygenation (adipose) levels as the prime inciting cause.12 Adipose tissue development is closely linked to vascularization. It is likely that the expansion of adipose tissue mass during the progressive
312
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
Fig. 1. Schematic diagram showing the site of measurement of tissue oxygen tension and tissue oxygen saturation.
development of obesity leads to a relative oxygen deficient state in certain parts of the adipose tissue due to insufficient angiogenesis to maintain normoxia in the entire adipose tissue.13 Deoxyribonucleic acid (DNA) microarray based gene expression profiling has shown an increase in adipose tissue mass which parallels the down regulation of mitochondrial energy handling capability both in visceral and abdominal fat (proportionate to the relative deficiency of vascularity).14 Persistent decreased tissue oxygen content has a clear association with the up regulation of GLUT-1 (Glucose transporter-1) and hypoxia inducible factor (HIF), this not only alters glucose utilization but also induces a state of chronic tissue inflammation.15 These pro-inflammatory cytokines spill over to the circulation causing malfunction of non-adipose tissue as well.16 Morbidly obese patients also have a high incidence of OSA (obstructive sleep apnea)17 and undergo severe episodic desaturations during sleep. The tissue develops extremely low oxygen tension during these obstructive episodes that lead to the down regulation of “adiponectin” expression.18,19 Adiponectin is a protein that affects glucose and fatty acid metabolism to lower fat content and to reduce local inflammation.20 Animal studies (diet-induced mutant obese mice) and cell-culture experiments (human adipocytes) strongly support the role of tissue level hypoxia in modulating the production of several inflammation-related adipokines, like increased IL-6, leptin and macrophage migratory inhibition factor production simultaneously with low adiponectin synthesis. These events have a significant contribution to the altered adipocyte physiology in morbidly obese patients and contribute to the adverse metabolic milieu associated with obesity.21 In the near future, unlike non-obese patients where tissue oxygenation levels have only found utility in acute physiological insults, in obese tissue oxygen tension estimations may also find a predictive role for longterm outcomes as well. 5. Tissue oxygen tension in healthy state Under resting conditions oxygen tension varies not only amongst different organs but also within the organ itself. The values are lower for higher oxygen consuming (metabolically active) organs like the heart, brain, liver etc. and high in organs with a low consumption e.g. the bladder. For example in the kidneys, within the organ, the values within the renal medulla due to high oxygen demand are much lower than those found in the renal cortex.22 As a result of these physiological variations, the
development of normal routine values is challenging. Minor variations in basal requirements can significantly alter the measured results without any actual pathological association and can give a false indication of an associated pathology. Generally, basal oxygen tension values are lower in deeper tissue and in centrally located organs with high metabolic activity. The basal values measured at tissue level bear no direct relation to the percentage of cardiac output that an organ is perfused with, rather it is a strong predictor of the ratio of oxygen consumption to the total blood flow. So organs with high blood flow but high oxygen consumption may have very low baseline values. Another factor that determines the basal value in tissue is the degree of arterio-venous shunting (AV shunt) that results in blood bypassing the tissue without providing oxygen. In such cases the oxygen values measured in a vein draining the tissue will be high, whereas the actual tissue suffers from a dearth of oxygen.8,23 Such AV shunts are known to play a vital role in maintaining high renal medullary osmolarity, while simultaneously contributing to significantly low oxygen tension in the renal medulla. Pasarica and colleagues found that healthy obese patients had around 44% lesser capillary density in subcutaneous tissue signifying lower perfusion. They were not, however, able to correlate it to any pathological significance.24 Increasing the body fat quantity has been shown to correlate inversely with basal subcutaneous tissue oxygen levels. More research is needed targeting the obese subgroup to determine the possible range of ‘normal’ values in various tissues. 6. Tissue oxygen tension in the diseased state Peripheral tissue oxygenation shows a fall much earlier than central organs, as basal oxygen delivery to peripheral tissues is much lower. So any pathological insult has a smaller buffering capacity in the periphery, and can thus be used for early detection of on-going insult. Extrapolating these pathophysiological alterations to the morbidly obese has significant clinical implications. Obese patients have much higher subcutaneous tissue volume compared to lean patients. A redistribution of blood flow towards central circulation away from this peripheral adipose tissue is likely to leave a larger amount of hypoxic tissue in comparison to similar redistributions that occur in non-obese patients. During diseased states this higher volume of subcutaneous tissue rapidly becomes underperfused and eventually produces more inflammatory/hypoxic markers. It is known that these markers in normal patients trigger a cascade of reactions that form the pathophysiological basis
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
of disease progression during hypoxic states. The above translates into the possibility of morbidly obese patients showing a much more rapid clinical deterioration with physiological insults that may not be very significant in lean patients. Measuring the peripheral tissue oxygenation in morbidly obese patients could thus provide an early window of opportunity for treatment by initiating therapeutic steps before the actual clinical symptomatology/deterioration occurs. Additionally, as maintaining optimal oxygen supply to vital organs is the primary goal; measuring tissue oxygenation at a central level may help to quantify the maximal permissible ischemia time (intraoperative) without long-term sequelae. Multiple trials have evaluated the use of tissue oxygenation measurement (peripheral/ central) in the following pathological states:
313
Fig. 2. Diagram showing evidence-based protocol to treat hemorrhagic shock on the basis of measured StO2 (tissue oxygen saturation) values and its trends.
6.1. Hemorrhagic shock Belzberg et al. in their analysis of 625 obese trauma patients showed that early cardiac index and tissue oxygenation reduction, strongly correlates with survival. They concluded that using tissue oxygenation as a therapeutic target could be used to determine the adequacy of resuscitation. Nelson et al. also showed that obese patients due to having relative low blood volume (ml/kg) are at an increased risk of developing hypovolemic-hemorrhagic shock and recommended using tissue oxygenation to institute early therapeutic measures.25 During blood loss the peripheral vascular resistance increases and leads to shunting of blood to vital organs. Consequently, multiple studies have reported a consistent fall in peripheral tissue oxygenation in vascular beds like the stomach, gut, skin and mucosa, preceding any classical hemodynamic parameters detecting any change.26 As already stated above, a higher volume of subcutaneous tissue is likely to represent redistribution associated hypoxia much earlier and thus may eventually find a vital role for monitoring of hemorrhagic shock in the morbidly obese during future trials. Eventually if the bleeding (volume loss) continues, the delivery to central organs also suffers and it is at this point that most of the established monitors (blood pressure and CVP) detect an on-going shock.27 Another unique feature of quantifying the ongoing shock using tissue oxygen tension that distinguishes it from measures of global oxygenation is that until the hypovolemia is treated, an increase in the inspired oxygen percentage does not fallaciously lower markers of hypoxia. Organs with high oxygen demand (like the kidney) start to suffer from the consequences of lowered oxygen delivery much earlier. The liver rapidly metabolizes lactates (global marker of tissue ischemia) added from the ischemic organ. Increasing the blood oxygen content by increasing inspired oxygen concentration further enhances this metabolism. Thus when ischemic markers are measured from the central compartment, false assuring results may be obtained. If global markers like lactate are measured, increased oxygen in the blood (increasing inspired concentration) stimulates aerobic metabolism (despite persistent low volume state), lactate is metabolized by central, well perfused organs like the liver giving a false assurance of adequate treatment. Peripheral tissue oxygen tension does not show much change on increasing inspired oxygen as vasoconstriction persists till volume status returns to normal and these tissues continue to have low perfusion related low oxygen tension.28 Noninvasive technologies like NIRS (Near Infrared Spectrometry) based studies measuring peripheral tissue hemoglobin saturation have been validated in multiple trials for assessing the treatment of hemorrhagic shock in non-obese patients.29,30 A suggested basic plan of management targeting tissue hemoglobin saturation close to 75% is shown in Fig. 2. Tissue oxygenation values recorded at the commencement of treatment have a strong
prognostic significance. The lower the values, the worse is the likely outcome and the more aggressive should be the volume replacement.30 Based upon physiological principles, the trends of changes in NIRS in morbidly obese patients are likely to parallel those of the lean population. While using NIRS in the morbidly obese, one must keep in mind the possibility of a decreased representation of deeper tissue (fat decreases near infrared wave penetration). Additionally, the obese are in a state of chronically lower tissue oxygen levels, thus the actual measured values may persistently remain slightly lower in obese patients. Therefore, during the diseased state, NIRS may show further lower values in the obese. Until concrete evidence is available and more studies shed light on the utility of NIRS in the obese, it must be used in these patients with the above limitations in mind. 6.2. Sepsis Conflicting results exist concerning the effect of sepsis on tissue oxygen levels. Some trials have reported increased tissue PO2 in the bladder and gut,31 whereas others reported decreases in values from the skeletal muscle and liver.32 A possible explanation for these inconsistent results is that the initial phase of sepsis leads to systemic vasodilatation and is compensated for by increasing the cardiac output. If measurements are taken during this initial phase (where blood flow is actually increased as a result of physiological compensation), one may find increased oxygen delivery to peripheral tissue despite on-going pathology. Subsequently, cardiac compensation fails and a possible mitochondrial dysfunction begins.33 The peripheral oxygen delivery falls and thus the measurements now show lower than normal values.8 Pathological tissue hypo-perfusion persists even in the presence of normal blood pressure and adequate cardiac output, a state referred to as “cryptic shock”.34 This hypo-perfusion is the potential result of blood flow at the regional or microvascular level. It may also be a result of mitochondrial dysfunction in the presence of an adequate oxygen supply.35 Baseline StO2 values during sepsis may have a significant overlap with normal patients but one thing that consistently distinguishes sepsis-related pathology is an inconsistent increase in tissue oxygen tension upon increasing inspired oxygen concentration. This phenomenon is probably attributable to sepsis-related mitochondrial dysfunction.36 Another possible hypothesis explaining normal or nearnormal values during sepsis is microcirculatory disturbance with blood stagnation in the capillaries or associated A-V shunting that gives a factitious reading of raised tissue oxygen levels.37 A low StO2 value at the outset of sepsis predicts poor outcome with a high degree of sensitivity and specificity.38 Despite multiple trials evaluating the treatment response to sepsis, no direct correlation could
314
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315
be established between patient improvement and actual values of tissue oxygenation. A positive outcome that can be drawn from the above unpredictability is in patients with hemodynamic shock of cardiogenic origin (cardiac failure). This subgroup of patients will always have low tissue perfusion without tissue mitochondrial dysfunction and will always have low tissue oxygenation levels, whereas sepsis-related hypotension could present with both increased or decreased tissue oxygen levels.8 Almost no literature on tissue oxygenation changes in sepsis exists for obese patients. There is however no reason that these morbidly obese patients should behave differently in this aspect. Until studies addressing sepsis-related changes in the obese are available, these results could logically be extrapolated to that conclusion. 7. Tissue oxygenation in the morbidly obese during the perioperative period The perioperative period is one of the most studied phases of utility of tissue oxygenation in morbidly obese patients. Consistently it has been established that tissue perfusion in morbidly obese patients is impaired in the perioperative period. It has been attributed to local as well as systemic factors. Cardiac output, circulating blood volume, and resting oxygen consumption are all increased in obese individuals, which probably lowers oxygen tension reaching the tissue.39 An increased incidence of wound infection in the morbidly obese possibly has a direct bearing on lower tissue oxygen tension. Oxidative killing by the neutrophils is the primary defense against the surgical site related pathogens. Thus in low availability of tissue oxygen, this mechanism suffers and oxidative killing is hampered.40 Evidence supports that the risk of surgical wound infection is inversely related to perioperative tissue oxygen partial pressure.41 It is a known fact that tissue repair after surgical incision is also strongly dependent upon subcutaneous tissue oxygen tension.42 Thus, morbidly obese patients are at a higher risk of surgical site infection and delayed wound healing. Fleischmann et al. reported significantly low tissue oxygenation levels in obese patients undergoing laparoscopic surgery when compared to their non-obese counterparts. They concluded that obese patients required higher inspired oxygen concentrations to maintain similar levels of tissue oxygenation. A possible mechanism to explain the higher incidence of wound infections in these patients could be subcutaneous tissue hypo-oxygenation.43 Obesity is actually associated with an increased incidence of surgical site infection and delayed wound healing. This has been noted in a retrospective review of perioperative complications in morbidly obese patients published by Dindo et al.44 Pain promotes sympathetic stimulation, subsequent increased metabolism and oxygen consumption. Adequate analgesia may prevent this pathophysiological cascade. Epidural analgesia offers a dual advantage for improving tissue oxygenation levels, it lowers tissue oxygen demand by alleviating pain and further by vasodilatation (when local anesthetics are used) it also increases the regional blood flow thereby simultaneously improving both demand and supply. Data suggests that thoracic epidural anesthesia blunts the decrease of subcutaneous tissue oxygen tension caused by surgical stress and adrenergic vasoconstriction during major abdominal surgery. According to Kabon and coworkers, combined general and epidural anesthesia may help to provide sufficient tissue oxygenation.45 Deliberate moderate hypercapnia is another measure utilized to improve tissue oxygenation in obese patients. Hager et al. evaluated the effect of intraoperative hypercapnia in morbidly obese patients undergoing open gastric bypass. These authors found significantly improved tissue oxygen levels in their patients.46 On the other hand Kabon et al. (evaluating the effect of postoperative oxygen supplementation leading to increased tissue oxygen tension) failed to
show significant improvement on wound infection rates.40 Further research on this may add more insight into this aspect and improve clinical outcomes. 8. Future directives Non-invasive monitoring of tissue oxygenation needs to be fully explored in morbidly obese individuals. Concerns about excessive subcutaneous tissue affecting the accuracy of tissue oxygenation measurements have been expressed. Nevertheless, once basal values are available in obese subjects, these problems can easily be offset. The chronic lower basal levels of tissue oxygen in obese patients with associated extremely low values during episodes of OSA distinguish them from their nonobese counterparts. Studies evaluating OSAS and associated diseases may provide further insight into obesity-related metabolic derangements. An incompletely explored field involving obesity, sepsis and tissue oxygenation may become instrumental in predicting and improving the outcomes of obese patients developing sepsis. Perioperative monitoring of tissue oxygenation in the obese extends a possibility of discovering methods to improve ventilatory strategies in these patients. Postoperative pulmonary complications often present as clinical hypoxia after significant insults, and the capability of measuring these tissue level changes before they affect vital organs. A window therefore exits that if utilized appropriately may give us an opportunity to significantly improve outcomes. Future studies addressing the perioperative requirement of transfusion in the obese may be able to give an objective marker of therapeutic end points. Such studies will also be vital in targeting fluid requirements in the obese. Long term follow-up trials can help to establish therapeutic interventions that may bring down cellular inflammation which is the common pathway of pathophysiology in morbidly obese patients. Conflicts of interest None for any of the authors. References 1. Severinghaus JW. First electrodes for blood PO2 and PCO2 determination. J Appl Physiol 2004;97(5):1599e600. 2. Shoemaker WC, Wo CC, Chan L, Ramicone E, Kamel ES, Velmahos GC, et al. Outcome prediction of emergency patients by noninvasive hemodynamic monitoring. Chest 2001;120(2):528e37. 3. Lemmens HJM, Bernstein DP, Brodsky JB. Estimating blood volume in obese and morbidly obese patients. Obes Surg 2006;16(6):773e6. 4. Goossens GH, Blaak EE. Adipose tissue oxygen tension: implications for chronic metabolic and inflammatory diseases. Curr Opin Clin Nutr Metab Care 2012;15(6):539e46. 5. Sakr Y. Techniques to assess tissue oxygenation in the clinical setting. Transfus Apher Sci 2010;43(1):79e94. 6. Duling BR, Berne RM. Longitudinal gradients in periarteriolar oxygen tension. A possible mechanism for the participation of oxygen in local regulation of blood flow. Circ Res 1970;27(5):669e78. 7. Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 2008;100(2):227e35. 8. Dyson A, Singer M. Tissue oxygen tension monitoring: will it fill the void? Curr Opin Crit Care 2011;17(3):281e9. 9. Soni N, Fawcett WJ, Halliday FC. Beyond the lung: oxygen delivery and tissue oxygenation. Anaesthesia 1993;48(8):704e11. Erratum in: Anaesthesia 1993;48(12):1123. 10. Wolff CB. Normal cardiac output, oxygen delivery and oxygen extraction. Adv Exp Med Biol 2007;599:169e82. 11. Bateman RM, Sharpe MD, Ellis CG. Bench-to-bedside review: microvascular dysfunction in sepsisehemodynamics, oxygen transport, and nitric oxide. Crit Care 2003;7(5):359e73. 12. Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, et al. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 2008;118(9):968e76. 13. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92(3):347e55.
Review / Trends in Anaesthesia and Critical Care 3 (2013) 310e315 14. Klimcáková E, Roussel B, Márquez-Quiñones A, Kovácová Z, Kováciková M, Combes M, et al. Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response. J Clin Endocrinol Metab 2011;96(1):E73e82. 15. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007;293(4):E1118e28. 16. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008;94(2):206e18. 17. Wadhwa A, Singh PM, Sinha AC. Airway management in patients with morbid obesity. Int Anesthesiol Clin 2013;51(3):26e40. 18. Wree A, Mayer A, Westphal S, Beilfuss A, Canbay A, Schick RR, et al. Adipokine expression in brown and white adipocytes in response to hypoxia. J Endocrinol Invest 2012;35(5):522e7. 19. Yu J, Shi L, Wang H, Bilan PJ, Yao Z, Samaan MC, et al. Conditioned medium from hypoxia-treated adipocytes renders muscle cells insulin resistant. Eur J Cell Biol 2011;90(12):1000e15. 20. Kim DH, Kim C, Ding EL, Townsend MK, Lipsitz LA. Adiponectin levels and the risk of hypertension: a systematic review and meta-analysis. Hypertension 2013;62(1):27e32. 21. Wood IS, de Heredia FP, Wang B, Trayhurn P. Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 2009;68(4):370e7. 22. Whitehouse T, Stotz M, Taylor V, Stidwill R, Singer M. Tissue oxygen and hemodynamics in renal medulla, cortex, and corticomedullary junction during hemorrhage-reperfusion. Am J Physiol Renal Physiol 2006;291(3):F647e53. 23. Izumi Y, Sakai H, Hamada K, Takeoka S, Yamahata T, Kato R, et al. Physiologic responses to exchange transfusion with hemoglobin vesicles as an artificial oxygen carrier in anesthetized rats: changes in mean arterial pressure and renal cortical tissue oxygen tension. Crit Care Med 1996;24(11):1869e73. 24. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 2009;58(3):718e25. 25. Nelson J, Billeter AT, Seifert B, Neuhaus V, Trentz O, Hofer CK, et al. Obese trauma patients are at increased risk of early hypovolemic shock: a retrospective cohort analysis of 1,084 severely injured patients. Crit Care 2012;16(3):R77. 26. Drucker W, Pearce F, Glass-Heidenreich L, Hopf H, Powell C, Ochsner MG, et al. Subcutaneous tissue oxygen pressure: a reliable index of peripheral perfusion in humans after injury. J Trauma 1996;40(3 Suppl.):S116e22. 27. Vollmar B, Conzen PF, Kerner T, Habazettl H, Vierl M, Waldner H, et al. Blood flow and tissue oxygen pressures of liver and pancreas in rats: effects of volatile anesthetics and of hemorrhage. Anesth Analg 1992;75(3):421e30. 28. Nordin A, Mildh L, Mäkisalo H, Härkönen M, Höckerstedt K. Hepatosplanchnic and peripheral tissue oxygenation during treatment of hemorrhagic shock: the effects of pentoxifylline administration. Ann Surg 1998;228(6):741e7. 29. Cohn SM, Nathens AB, Moore FA, Rhee P, Puyana JC, Moore EE, et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation. J Trauma 2007;62(1):44e54 discussion 54e5.
315
30. Lima A, van Bommel J, Jansen TC, Ince C, Bakker J. Low tissue oxygen saturation at the end of early goal-directed therapy is associated with worse outcome in critically ill patients. Crit Care 2009;13(Suppl. 5):S13. 31. VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995;23(7):1217e26. 32. Anning PB, Sair M, Winlove CP, Evans TW. Abnormal tissue oxygenation and cardiovascular changes in endotoxemia. Am J Respir Crit Care Med 1999;159(6): 1710e5. 33. Singh PM, Borle A, Trikha A. Diagnostic dilemma: rare case of recurrent d-lactic acidosis leading to recurrent acute cardiac failure. Acta Anaesthesiol Taiwan 2013;51(2):94e6. 34. Donnino MW, Nguyen B, Jacobsen G, Tomlanovich M, Rivers E. Cryptic septic shock: a sub-analysis of early, goal-directed therapy. Chest 2003;124 (4_ MeetingAbstracts):90Seb. 35. Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit Care 2005;9(Suppl. 4):S20e6. 36. Creteur J, Carollo T, Soldati G, Buchele G, De Backer D, Vincent JL. The prognostic value of muscle StO2 in septic patients. Intensive Care Med 2007;33(9): 1549e56. 37. De Backer D, Ospina-Tascon G, Salgado D, Favory R, Creteur J, Vincent JL. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010;36(11): 1813e25. 38. Mesquida J, Gruartmoner G, Martínez ML, Masip J, Sabatier C, Espinal C, et al. Thenar oxygen saturation and invasive oxygen delivery measurements in critically ill patients in early septic shock. Shock 2011;35(5):456e9. 39. Di Girolamo M, Skinner Jr NS, Hanley HG, Sachs RG. Relationship of adipose tissue blood flow to fat cell size and number. Am J Physiol 1971;220(4):932e7. 40. Kabon B, Rozum R, Marschalek C, Prager G, Fleischmann E, Chiari A, et al. Supplemental postoperative oxygen and tissue oxygen tension in morbidly obese patients. Obes Surg 2010;20(7):885e94. 41. Hopf HW, Hunt TK, West JM, Blomquist P, Goodson 3rd WH, Jensen JA, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997;132(9):997e1004 discussion 1005. 42. Greif R, Akça O, Horn EP, Kurz A, Sessler DI., Outcomes Research Group. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. N Engl J Med 2000;342(3):161e7. 43. Fleischmann E, Kurz A, Niedermayr M, Schebesta K, Kimberger O, Sessler DI, et al. Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg 2005;15(6):813e9. 44. Dindo D, Muller MK, Weber M, Clavien P- A. Obesity in general elective surgery. Lancet 2003;361(9374):2032e5. 45. Kabon B, Fleischmann E, Treschan T, Taguchi A, Kapral S, Kurz A. Thoracic epidural anesthesia increases tissue oxygenation during major abdominal surgery. Anesth Analg 2003;97(6):1812e7. 46. Hager H, Reddy D, Mandadi G, Pulley D, Eagon JC, Sessler DI, et al. Hypercapnia improves tissue oxygenation in morbidly obese surgical patients. Anesth Analg 2006;103(3):677e81.