Evidence-Based Review and Consensus Statement On Monitoring of Hemodynamics and Oxygen Transport Balance

Introduction
The Pediatric Cardiac Intensive Care Society evidence-based review and consensus statement on monitoring of hemodynamics and oxygen transport balance
Paul A. Checchia, MD, FCCM, FACC; Ronald A. Bronicki, MD
very 2 yrs, the Pediatric Cardiac Intensive Care Society convenes a group of experts to develop and publish a scientic statement based on the available evidence and consensus opinion. Previous versions have dealt with the diagnosis and management of myocarditis and the acute management of pulmonary hypertension. This version addresses the monitoring of hemodynamics and oxygen transport balance in critically ill children. The primary objective in managing critically ill patients is to make a timely and accurate assessment of tissue oxygenation. Studies in children and adults have demonstrated that the assessment of cardiovascular function and tissue oxygenation based on the interpretation of conventional clinical data, such as the
From the St. Louis Childrens Hospital (PAC), Washington University School of Medicine, St. Louis, MO; Childrens Hospital of Orange County (RAB), University of California, Orange, CA; and the David Geffen School of Medicine at the University of California (RAB), Los Angeles, CA. Dr. Checchia has received honoraria from Edwards Lifesciences and Medimmune and grants from Ikaria. Dr. Bronicki has not disclosed any potential conicts of interest. Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e318220e64f
physical examination, blood pressure, and central venous pressure, is often discordant from measured values. A writing committee was formed to examine the evidence and develop recommendations for various monitoring modalities. The ndings were presented at the eighth International Meeting of the Pediatric Cardiac Intensive Care Society in December 2010. This supplement is meant to bring the reader from standard hemodynamic measurements such as blood pressure and heart rate through pulmonary artery catheters and ultimately to emerging technologies just entering the marketplace. In addition to the presentation of the available evidence and recommendations, we sought to express an editorial opinion on the use of each modality. These are represented as perspectives and insights from leaders in the elds of neonatology, pediatric critical care medicine, pediatric cardiac critical care medicine, and pediatric critical care nursing. Additionally, we sought to interpret the evidence and recommendations from the perspective of critical care practitioners outside the boundaries of the United States. This supplement represents the results of the work of the committee. As the Chairmen of the Writing Committee and Guest Editors of this supplement to Pediatric Critical Care Medicine, we would
like to thank each committee member for his or her substantial efforts. Writing Committee: Paul A. Checchia, MD, FCCM, FACC, Cochair; Ronald A. Bronicki, MD, Cochair; Meredith Allen, MBBS, FRACP, FRCPCH, PhD, London, UK; Nick Anas, MD, Orange, CA; Jon T. Berger, MD, Washington, DC; Desmond Bohn, MB BCh, FFARCS, MRCP, FRCPC, Toronto, Ontario, Canada; David S. Cooper, MD, St. Petersburg, FL; Heidi J. Dalton, MD, Phoenix, AZ; Michelle Domico, MD, Orange, CA; Neil N. Finer, MD, San Diego, CA; Avihu Z. Gazit, MD, St. Louis, MO; Nancy S. Ghanayem, MD, Milwaukee, WI; Mary Fran Hazinski, MSN, FAAN, FAHA, BERC, Nashville, TN; George M. Hoffman, MD, Milwaukee, WI; John P. Kinsella, MD, Denver, CO; Niranjan Kissoon, MD, FRCPC, Vancouver, British Columbia, Canada; Darren Klugman, MD, MMS, Washington, DC; Peter C. Laussen, MBBS, Boston, MA; Graeme MacLaren, MBBS, FCICM, FRACP, FCCM, Melbourne, Australia, and Singapore; Duncan J. Macrae, MB ChB, London, UK; Ronald M. Perkin, MD, MA, Greenville, NC; V. Ben Sivarajan, MD, FRCPC, Toronto, Ontario, Canada; Neil Spenceley, MB ChB, MRCPCH, Glasgow, Scotland; Dawn Tucker, MSN, CPNP-PC/ AC, Kansas City, MO; Gil Wernovsky, MD, Philadelphia, PA; and Hector R. Wong, MD, Cincinnati, OH.
Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
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Hemodynamic Monitoring
Monitoring of standard hemodynamic parameters: Heart rate, systemic blood pressure, atrial pressure, pulse oximetry, and end-tidal CO2
V. Ben Sivarajan, MD, FRCPC; Desmond Bohn, MB, FRCPC
Background: Continuous monitoring of various clinical parameters of hemodynamic and respiratory status in pediatric critical care medicine has become routine. The evidence supporting these practices is examined in this review. Methodology: A search of MEDLINE, EMBASE, PubMed, and the Cochrane Database was conducted to nd controlled trials of heart rate, electrocardiography, noninvasive and invasive blood pressure, atrial pressure, end-tidal carbon dioxide, and pulse oximetry monitoring. Adult and pediatric data were considered. Guidelines published by the Society for Critical Care Medicine, the American Heart Association, the American Academy of Pediatrics, and the International Liaison Committee on Resuscitation were reviewed, including further review of references cited. Results and Conclusions: Use of heart rate, electrocardiography, noninvasive and arterial blood pressure, atrial pressure, pulse oximetry, and end-tidal carbon dioxide monitoring in the pediatric critical care unit is commonplace; this practice, however, is not supported by well-controlled clinical trials. Despite the majority of literature being case series, expert opinion would suggest that use of routine pulse oximetry and end-tidal carbon dioxide is the current standard of care. In addition, literature would suggest that invasive arterial monitoring is the current standard for monitoring in the setting of shock. The use of heart rate, electrocardiography. and atrial pressure monitoring is advantageous in specic clinical scenarios (postoperative cardiac surgery); however, the evidence for this is based on numerous case series only. (Pediatr Crit Care Med 2011; 12[Suppl.]:S2S11) KEY WORDS: hemodynamic monitoring; heart rate; systemic blood pressure; atrial pressure; pulse oximetry; end-tidal CO2
linical assessment and frequent reassessment is essential in critically ill children because normal parameters are less guided by published population curves (Table 1) and more by trends established during monitoring of the individual patient. The goal of such monitoring is to allow anticipatory management of infants and children. Relationships between specic hemodynamic variables are complex
From the Divisions of Cardiac Critical Care and Cardiology (VBS), Departments of Critical Care Medicine and Paediatrics, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada, and the Department of Critical Care Medicine and Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Department of Critical Care Medicine (DB), Hospital for Sick Children, Professor of Anaesthesia and Paediatrics, University of Toronto, Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: ben.sivarajan@sickkids.ca Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e318220e7ea
enough in states of health. In disease states, the specic responses of heart rate, central venous pressure, and blood pressure to treatments are essential to rapid diagnosis and curative therapy. Appropriate monitoring allows one to comprehend etiologic and compensatory factors contributing to shock pathophysiology. This allows the clinician to calculate secondary parameters (Table 2) that are paramount in executing specic therapeutic strategies (1). However, the primacy of monitoring lies in documentation of improved outcomes based on hemodynamic monitor-driven treatments in controlled clinical studies. The question of whether there is sufcient scientic evidence supporting or discouraging standard monitoring practices in pediatric critical care is the basis for this review.
Guidelines published by the Society for Critical Care Medicine, the American Heart Association, the American Academy of Pediatrics, and the International Liaison Committee on Resuscitation were reviewed, including further review of references cited.
Background
As the discipline of critical care medicine evolved out of the battleelds of Normandy and the MASH (Mobile Army Surgical Hospital) units of Korea, the importance of objective vital sign monitoring became singularly apparent. In 1952, a study by Ibsen (2, 3) had demonstrated that operating room techniques such as tracheotomy and curare could be used in an intensive care unit setting. In 1953, he converted the surgical recovery ward in Copenhagens Kommunehospital into the rst intensive care unit (ICU) (2, 4). The ICU established by Dr. Peter Safar at Baltimore City Hospital emphasized bedside resuscitative interventions and the primary importance of maintenance of airway and breathing (5). At the University of Southern California, Drs. Max Weil and Herbert Shubin became interested in why patients died suddenly after a myocardial
Process
MEDLINE, EMBASE, PubMed, and Cochrane Database searches were conducted to nd controlled trials regarding the use of heart rate, noninvasive and invasive pressure, end-tidal carbon dioxide, and pulse oximetry monitoring. Adult and pediatric data were considered.
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Table 1. Vital signs at various ages Heart Rate (beats/min) 120170 100150 90120 80120 70110 65110 6095 5585 Blood Pressure (mmHg) (systolic/diastolic) 5575/3545 6585/4555 7090/5065 80100/5565 90105/5570 95110/6075 100120/6075 110135/6585 Respiratory Rate (breaths/min) 4070 3555 3045 2540 2030 2025 1422 1218
Age Premature 03 mo 36 mo 612 mo 13 yr 36 yr 612 yr 12 yr
Adapted from Mathers LH, Frankel LR. The acutely ill child. In: Nelson Textbook of Pediatrics 17th edition. Berhman, Kliegman, Jenson (Eds). Philadelphia, PA, Saunders, an Imprint of Elsevier Science, 2003.
Table 2. Primary and derived hemodynamic parameters from hemodynamic monitoring Primary hemodynamic parameters HR, beats/min MAP, mm Hg CVP or RAP, mm Hg LAP or PAOP, mm Hg PAP, mm Hg CO, L/mina SaO2, % SpO2 as an estimate of SaO2, % SvO2, % Hb, g/L Height and weight needed to calculate BSA, m2 Derived hemodynamic parameters CI CO/BSA, L/min/m2 Stroke volume CO/HR 1000, mL/min Stroke index stroke volume/BSA, mL/m2 LV stroke work stroke volume (MAP PAOP), mL mm Hg LV stroke work index LV stroke work/BSA, mL mm Hg/m2 Total peripheral resistance (MAP/CO) 80, dyne s/cm5 Systemic vascular resistance ( MAP RAP )/CO 80, dyne s/cm5 Pulmonary vascular resistance ( PAP PAOP /CO) 80, dyne s/cm5 Global DO2b CO (SaO2 SvO2) Hb 1.36 1000, mL oxygen/min Global DO2 indexb CI (SaO2 SvO2) Hb 1.36, mL oxygen/min Global VO2b CO SaO2 Hb 1.36 1000, mL oxygen/min Global VO2 indexb CI SaO2 Hb 1.36 1000, mL oxygen/min MAP, mean arterial pressure; CVP, central venous pressure; HR, heart rate; RAP, right atrial pressure; LAP, left atrial pressure; PAOP, pulmonary arterial occlusion pressure; PAP, mean pulmonary artery pressure; CO, cardiac output; SaO2, arterial oxygen saturation; SvO2, central/mixed venous oxygen saturation; Hb, hemoglobin; BSA, body surface area; CI, cardiac index; VO2, oxygen consumption; DO2, systemic oxygen delivery. a Continuous measurement not reliable in small children and in those with shunt lesions; b SpO2 can be substituted for arterial oxygen saturation in these calculations.
Figure 1. The value of trend heart rate monitoring is illustrated here in differentiating the cause of tachycardia. Patient A has an abrupt onset and termination diagnostic of a re-entrant mechanism, whereas patient B has the gradual increase associated with an automatic focus (most commonly sinus tachycardia).
infarction, serious illness, or in the postoperative period (6). They realized that the absence of continuous vital sign assessment practically precluded the opportunities for lifesaving measures. The establishment of their initial four-bed shock unit, that combined efforts of dedicated ICU physicians, nurses, engineers, and technicians, was one of the rst to focus on monitoring, measurement, and alarms in real time to target appropriate lifesaving interventions (6, 7).
Pulse, heart rate, and electrocardiographic monitoring

Galen rst provided physiological descriptions of pulse in the second century AD; however, its use was noted by the early Egyptians (8). In the Western world, assessment of vital signs continued to be dismissed as quackery as recently as the mid-19th century. The advent of coro-
nary care units, resuscitative practices, and denitive therapies made continuous vital sign assessment necessary and practical (9, 10). Pulse assessment is currently provided by a number of complementary methods: intermittent assessment using direct palpation or cuff sphygmomanometry, or continuous assessment through pulse oximetry or invasive arterial pressure monitoring. Recognizing the nuances of pulse contour and strength can provide instantaneous insights into the underlying pathologic process. With the advent of widespread application of pulse oximetry technology, continuous pulse monitoring became practicable and provided earlier clues to potential bradycardic or tachycardic states (11). Conrmation of these states and their potential effects on cardiac output, systemic oxygen delivery, and tissue perfusion still requires a complementary clinical assessment. Heart rate trend review, available on bedside monitors since the early 1990s, provides insight into underlying mechanisms of disease. For example, a period of postoperative tachycardia can be reviewed and decisions can be made regarding the pathologic process and its appropriate therapy (Fig. 1). Electrocardiographic monitoring became routinely used in adult critical care throughout the 1970s and in the 1980s, bedside arrhythmia analysis and bed-tobed switching allowed its widespread use so that a central monitoring station was not required. Widespread adoption in pediatric ICUs did not occur until the late 1980s with the advent of modular units that allowed input from various devices. At this time the potential for arrhythmia in postoperative cardiac (12) and various organ dysfunction states was becoming appreciated. Focused attention to STsegment changes has been commonplace after operations that involve manipulation of the coronary origins such as the arterial switch operation and the Ross operation (Fig. 2). This potential use of ST-segment analysis needs to be balanced by the limitations of algorithms used by currently available software for this purpose in the pediatric population. Evidenced-based guidelines were recently published for electrocardiographic monitoring in adults and children, suggesting that all patients requiring intensive care and children after cardiac surgery have class I indications for such monitoring. However, the references proS3
Figure 2. Demonstration of midprecordial ST-segment elevation after an arterial switch operation. These ndings should prompt urgent investigation and therapy directed toward establishing the adequacy of the coronary anastomosis.
Figure 3. A, Vierordts sphygmograph, invented in 1854. Pad b is applied over the radial artery. Weights are placed in the large cup until the pulse wave is traced; then weights are placed in the smaller cup which acts as a ne adjuster. B, A direct sphygmograph attributed to Marey, circa 1881. Reproduced with permission from the Wellcome Institute for the History of Medicine and Booth J: A short history of blood pressure measurement. Proc R Soc Med 1977; 70:793799.
vided do not support this level of assertion in the pediatric population (13). Evidence and recommendations for the use of heart rate and electrocardiographic monitoring. Pulse and heart rate monitoring with 12- to 15-lead electrocardiographic monitoring has been adopted as a standard during surgery (cardiac or otherwise), cardiac catheterization, and for postoperative ICU care. It improves diagnostic precision and is a major enhancement to patient safety and quality care. There is sufcient evidence to support its routine use in these situations but, like many monitoring devices, this recommenS4
dation is based on case series and observational studies (level of evidence: IV; grade of recommendation: C).
Blood pressure monitoring

History. Despite the observation of blood pulsating from shorn blood vessels throughout recorded history, it was not until the mid-18th century when the rst recorded measurements of invasive blood pressure were made on a horse by Stephen Hale (14). In 1828, Poiseuille described the use of a mercury manometer connected to an
arterial cannula to measure arterial pressure as part of his doctoral dissertation (15). Poiseulles innovation enabled Carl Ludwig to develop the kymograph (or wave-writer) in 1847. This advance paved the way for modications used today such as the myograph (developed by Helmholtz in 1850 for recording muscle movements) and the sphygmograph (developed by Vierordt in 1855). Noninvasive Blood Pressure Measurement. Until 1855, a noninvasive method of blood pressure assessment in the clinical situation remained elusive. Vierordt hypothesized that indirect assessment might be made by assessing the counter pulsation necessary to cause cessation of the arterial pulse. Although his device was somewhat cumbersome, a modication by Marey gained wide acceptance in medical practice (Fig. 3). In the 1870s, von Basch developed the idea of sphygmomanometry, the presentday technique of which is based on RivaRoccis method reported in 1896 (16). The advantages of this technology are: ease of application; rapidity in action; precision; and patient comfort. This method was useful for systolic pressure measurement but was useless for accurate diastolic pressure measurement. Hill and Barnard (17) subsequently developed a small portable apparatus that used the oscillatory method with a needle pressure gauge sensitive enough to precisely record the diastolic pressure. In 1905, Korotkoff, a Russian surgeon, reported the auscultatory method, in which he controlled the pressure in the Riva-Rocci cuff while listening with a monaural device that was a direct descendant of Laennecs rod (16). Current Noninvasive Methods of Blood Pressure Assessment in the Pediatric ICU. Use of the oscillometric method with devices such as the Dinamap (Device for Indirect Non Invasive Measurement of Blood Pressure; GE Healthcare, Waukesha, WI) represents the usual standard for noninvasive measurement in most pediatric settings. Park and colleagues established in a number of landmark studies the degree of reproducibility and reliability of this technique for pediatric age groups (18 22) in the outpatient setting. Friesen and Lichtor (23) were the rst to show the high degree of precision and reliability of oscillometric systolic blood pressure compared with indwelling arterial lines in a series of neonates. A study by Cullen et al subsequently analyzed 260 paired comparisons from 16 neonates
with indwelling arterial lines during anesthesia. A regression analysis over a wide range of blood pressures demonstrated high correlation for heart rate and systolic blood pressure with moderate correlation for mean blood pressure and poor correlation for diastolic blood pressure. They concluded that the oscillometric technique represented an accurate trend monitor for heart rate and blood pressure for stable neonates with greater bias at lower blood pressures. It is important to take pause to note that the goal is to monitor and optimize cardiac output; however, we generally rely on clinical examination and monitoring of surrogates such as heart rate and blood pressure. Thus, a good blood pressure does not always indicate adequate cardiac output. It is a well-recognized phenomenon that lowering blood pressure (with afterload reduction) improves cardiac output in selected clinical situations. However, a number of studies have demonstrated that inadequately treated hypotension and arterial hypoxemia can be predictive of mortality in various shock states (24 26) and after cardiac arrest (2730). Thus, in these critically ill patients, it is vital to ensure the most appropriate modalities of monitoring. A number of emergency department and operating room-based studies in adults have recently shown that oscillometric methods may have a role (3133) in mild shock. Regardless of age group, traditional noninvasive methods have been shown to be unreliable and inadequate for diastolic pressure assessment as well as in patients with low cardiac output, hypotension, and/or dysrhythmias (34 38). Despite current guidelines supporting invasive arterial pressure monitoring in septic shock (39), a recent survey of adult intensivists (40) indicated that in hypotensive and frank shock states, 73% and 47%, respectively, relied solely on noninvasive methods. The standard in these clinical situations continues to be invasive arterial pressure measurement. Invasive Arterial Blood Pressure Measurement: Principles and Technique. Despite renements over the centuries, the technique of arterial pressure measurement is essentially unchanged from the methods described in the study by Hale (14). Invasive arterial measurement continues to constitute the gold standard for measurement in critically ill patients both in pediatrics and adults. The invasive arterial pressure monitor allows titration of both inspired oxygen (by
monitoring the alveolararterial PO2 gradient) and vasoactive medications. Invasive pressure monitoring, however, has technical limitations that can make the displayed information inaccurate. Invasive pressure measurement systems are indirect and thus require calibration to a reference (41) (right atrium for cardiovascular pressures, tragus of the ear for intracranial pressure monitoring). Monitoring systems are based on the principle of transmitting pressure changes from a column of uncompressible uid (in an ideally incompressible tube) to a mechanical transducer. The mechanical transducer is basically a displaceable diaphragm, which converts physical uid displacement into a proportional electrical signal, which can be processed and displayed. Factors that may affect the quality of measurement include the compliance, resistance, and impedance of the system; this can result in the alteration of the recorded signal. Seemingly minor issues such as bubbles in the tubing can result in dampening of the pressure waveform. Other important factors include the frequency response of the system and the sampling rate. The usual sites of arterial pressure monitoring in pediatrics include the radial, femoral, and posterior tibial arteries. Less frequently used sites, especially in smaller infants, include the brachial and axillary arteries. During a 6-yr period, Mortenson and colleagues (42) collected details and follow-up on almost 3200 arterial cannulations in 2360 patients. This study informed renement of access techniques and locations both for monitoring and catheterization studies. Cannulations were performed by percutaneous needle puncture, a percutaneous Seldinger technique, or cutdown arteriotomy. The overall minor complication rate (pain, bleeding, transient loss of pulse) was approximately 10% with major complication rates of 1% to 2% (distal ischemia, loss of limb). The complication rate was increased with the Seldinger technique, use of the brachial arterial site, and in children aged 10 yrs (the complication rate approached 30% in this population). Contemporary studies have also discouraged cannulation of the brachial artery based on higher complication rates (43, 44). Evidence and Recommendations for the Use of Blood Pressure Monitoring. Routine blood pressure monitoring has become an accepted standard for all pediatric patients undergoing surgery, as
well as for those patients who warrant postoperative monitoring in an ICU environment. The choice of frequency and modality are based on the severity of illness as well as the need for additional data such as an accurate diastolic blood pressure or arterial blood gases. Invasive arterial pressure monitoring in all intraoperative and postoperative ICU patients (especially those requiring cardiac surgery) continues to be the accepted standard. In addition, most patients during cardiac catheterization and all patients with shock should have attempts to secure invasive arterial pressure monitoring. There is sufcient evidence to support its routine use in these situations (level of evidence: IV; grade of recommendation: C).
Central venous and left atrial pressure monitoring

Central Venous Pressure Monitoring. Continuous assessment of pressure waveforms and lling pressures is provided by central venous pressure monitoring. The central venous pressure is often used inappropriately to assess the intravascular volume status. It is important to note that the truly important intravascular volume parameter is the left ventricular end-diastolic volume because this directly impacts stroke volume and ultimately systemic cardiac output. Assessing at the bedside on a continuous basis is both imprecise and impractical. As a result, because the instantaneous relationship between pressure and volume is known (assuming loading conditions do not change and the patient is maintained on the same pressurevolume curve), monitoring of left ventricular enddiastolic pressure can impart this same information. In the absence of signicant mitral valve stenosis, the left atrial pressure also provides this information. Monitoring catheters in the proximal circulation (i.e., central venous pressure or Swan-Ganz as opposed to direct left atrial pressure) are routinely placed at the bedside by intensivists. Catheters in these positions minimize complication rates and reduce dependence on surgical placement; however, such measures are often poor estimates of left ventricular enddiastolic volume as a result of the multiple additional assumptions as well as the effect of cardiopulmonary interactions. As a result, central venous pressure is best used to assess the relative impedance to systemic venous return imposed by the
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Figure 4. The top frame demonstrates a wide complex regular rhythm consistent with a ventricular tachycardia. The bottom frame demonstrates the atrial pressure waveform showing occasional cannon A-waves (arrows) conrming atrioventricular dissociation. The lack of atrial contribution to cardiac output during these beats is evidence from the concomitant drop in blood pressure as evidenced in the arterial blood pressure tracing (middle frame). Reproduced with permission from Sharkey SW: Beyond the wedge: Clinical physiology and the Swan-Ganz catheter. Am J Med 1987; 83:111122.
tion of patent ductus arteriosus and simple coarctation repair) will not require postoperative central access and thus do not derive any benet from such monitoring. However, the majority of postoperative cardiac surgical patients will continue to have central venous pressure monitoring through central lines that also serve as access for vasoactive infusions and central venous saturation monitoring. In addition, ICU patients who require central venous access for management should routinely have central venous pressure monitoring to guide uid and vasoactive therapy. Location of monitoring is guided by available access recognizing that the femoral site does not provide for accurate central venous saturation monitoring. Left atrial pressure monitoring plays a valuable role in monitoring those patients with concerns regarding left ventricular function or size. Its use should be guided by the clinical situation (level of evidence: IV; grade of recommendation: C).
right heart. If the central venous pressure is high, the patient will require a higher mean circulatory lling pressure (either by infusion of volume or by augmenting venoconstriction) to maintain right ventricular preload. In addition, the change in central venous pressure to a uid challenge is also a valuable assessment of ventricular compliance. High reliability and correlation with direct right atrial pressure assessment has been shown with infrarenal venocaval lines placed through the femoral approach (45, 46). These lines, however, are not reliable for mixed venous saturation sampling (47). Continuous central venous pressure monitoring also allows the astute intensivist to diagnose dysrhythmias (Fig. 4) or even pathologies such as signicant atrioventricular valve regurgitation or impending pericardial tamponade (48). Standard central venous catheters have risks that have been well described, including hematoma formation, vessel dissection, thrombosis, pneumothorax, and even hemothorax and hemopericardium (49, 50). In recent years, certain centers have advocated direct atrial pressure catheters in the place of internal jugular catheters after cardiac surgery; these catheters are placed at the end of the operation but have a 1% to 2% complication rate usually associated with bleeding and tamponade.
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Left Atrial Pressure Monitoring. As preoperative evaluation has become more sophisticated and thorough, intraoperative placement of left atrial catheters has become more selective. Left atrial pressure monitoring is now usually reserved for the following indications: after biventricular repairs in which the left ventricular adequacy for size or compliance may be borderline; complicated or late anatomic repairs of transposition of the great arteries; after repair of anomalous coronary origins in which there is myocardial dysfunction; and postoperatively in patients with pulmonary vascular disease. Some centers may variably use left/ common atrial catheters after a cavopulmonary anastomosis or Fontan operation; however, central venous pressure monitoring through the cavopulmonary connection is usually sufcient when combined with thorough intraoperative echocardiography. In fact, routine intraoperative transesophageal echocardiography (51, 52) has revolutionized intraoperative and postoperative care in pediatric cardiology. Evidence and Recommendations for the Use of Central Venous and Left Atrial Pressure Monitoring. Routine central venous pressure monitoring is an accepted standard for all pediatric patients undergoing cardiac surgery requiring cardiopulmonary bypass. Selected cases (liga-
Pulse oximetry monitoring: Physiology and principles

Pulse oximetry, introduced into medical care in the 1980s to detect changes in oxygen saturation during anesthesia, was regarded as a major innovation in patient safety. The device operates by estimating the absorption of two different wavelengths of light. This changes depending on the amount of blood in tissue and the relative amounts of oxygenated and deoxygenated hemoglobin. Measuring the changes in light absorption that occurs with pulsatile ow allows for the estimation of heart rate. Close agreement between the heart rate on the cardiac monitor and the pulse oximeter rate is a means of checking that the device is providing accurate information of the saturation. The accuracy of pulse oximeters in being able to measure true arterial oxygen saturation in critically ill children has been a major challenge. Movement artifact, poor tissue perfusion, temperature, abnormal hemoglobins, tissue pigmentation, probe site, and articial light are all known to affect the accuracy of pulse oximeters (5358). Perhaps the most important from a pediatric cardiac critical care perspective is their accuracy in the presence of cyanosis. These devices measure the absorption spectra of the two wavelengths of light and then average them over a short period and compare the average with a calibration curve
of arterial saturations developed from experiments on volunteers (59). These experiments were not done at the low saturations seen in cyanotic congenital heart disease, and hence there will be some discrepancy between pulse oximetry and directly measured saturations in this group of patients. Most of these case series consist of 50 patients of different age groups and consist of a mixture of cyanotic and acyanotic forms of congenital heart disease. When saturations are 90%, most devices have a precision of approximately 2%. However, in the range of signicant desaturation ( 80%), an increasing bias has been observed with a tendency for pulse oximeters to overread the true saturation when compared with direct arterial sampling (11, 60 67). The accuracy of devices has also been shown to be enhanced by applying the probe to the nger rather than the foot (68, 69). Pulse Oximetry in the Perioperative Setting and During Cardiac Catheterization. An extensive experience has been accumulated in the use of pulse oximeters during pediatric surgery and cardiac catheterization. One of the original studies that secured its widespread acceptance as an essential monitoring device in pediatric anesthesia was the single-blind study by Cote et al (70) in 1988 in which 152 children undergoing elective surgery were divided into two groups. In one group the oximeter data and alarms were available to the anesthesia team, and in the second group a trained observer recorded all episodes of drop in saturation on the monitor but only informed the anesthesia team of major events, i.e., when the pulse oximetry was 85%. There were three times as many events in the trained observer group and these were most common in children 2 yrs of age. The patients in this study did not include children with congenital heart disease; however, since then, pulse oximeters have been used extensively in monitoring patients undergoing heart surgery, in the postoperative period in the ICU, or during cardiac catheterization (11, 58 62, 64 69, 7177). Evidence and Recommendations for the Use of Pulse Oximetry. Pulse oximetry has been adopted as a standard monitoring device during cardiac surgery, postoperative ICU care, and cardiac catheterization and is a major enhancement to patient safety. There is sufcient evidence to support its routine use in these situations but, as with many monitoring
devices, this recommendation is based on case series and observational studies (level of evidence: IV; grade of recommendation: C).
Capnography and end-tidal CO2 monitoring: Physiology and principles

The concentration of CO2 measured in the expired gas will vary on the amount produced by the tissues as well as the alveolar ventilation and pulmonary blood ow. Infrared devices that can detect exhaled CO2 have been used since the 1970s and can both measure the concentration expressed in mm Hg (capnometry) and display it graphically (capnography). Two different methods are available: in line where the sensor is connected to the endotracheal tube (78) and sidestream sampling where a small sample of expired gas is aspirated and sampled. The rst part of the normal expiratory capnogram shows a sharp rise in CO2 level as alveolar gas mixes with dead space gas (Fig. 5). This levels off through expiration to form a plateau and reaches an end-expiratory point before abruptly falling to zero at the beginning of the inspiratory cycle. In situations in which there is a normal match between ventilation and perfusion, the alveolar CO2 (PACO2) level will equal the PaCO2 and there will be a minimum gradient between this and the end-tidal CO2 level measured in mm Hg, commonly referred to as the PaCO2PETCO2 (Fig. 6). In situations in which there is a poor match between ventilation and perfusion as a result of either lung disease that adversely affects pulmonary blood ow or low cardiac output, the PaCO2PETCO2 will increase. When cardiac arrest occurs, the capnogram will show no exhaled CO2, which will reappear with effective cardiopulmonary resuscitation. End-tidal CO2 monitoring did not gain wide acceptance in ventilated pediatric ICU patients because the original detectors were bulky and added signicantly to dead space. There was also a feeling that with the common use of uncuffed tubes in children the difference between PaCO2 and PETCO2, normally 12 mm Hg in ventilated patients in the absence of signicant lung disease, would be too variable for it to be used as a reliable monitor. However, the introduction of the newer generation of end-tidal CO2 monitors and the more widespread use of cuffed tubes renders the data more reliable in the
Figure 5. Normal capnogram showing the initial upstroke (increasing amount of alveolar gas) and the expiratory plateau. In situations in which there is signicant lung parenchymal lung disease, a plateau in the capnogram may not be reached. Reproduced with permission from Hess DR, Kacmarek RM: Essentials of Mechanical Ventilation. New York, McGraw-Hill, 1996.
Figure 6. The relationship between alveolar CO2 (PACO2) and pressure of end-tidal CO2 (PETCO2) in different states of ventilation/perfusion (V/Q) matching. Reproduced with permission from Hess DR, Kacmarek RM: Essentials of Mechanical Ventilation. New York, McGraw-Hill, 1996.
management of children with congenital heart disease. Information that can be derived from capnography and PETCO2 measurements includes: 1) changes in alveolar ventilation; 2) conrmation of endotracheal tube placement; 3) degree of right to left intracardiac shunt; 4) change in pulmonary blood ow; and 5) effectiveness of cardiopulmonary resuscitation. End-Tidal CO2 Monitoring in Surgery and Anesthesia. Noninvasive CO2 measurement as a monitor of effective alveolar ventilation has become standard practice in operating rooms, and PETCO2 as a routine monitoring device has been a cornerstone of safe anesthesia practice for 30 yrs (79). In pediatric practice it has been used by anesthesiologists during surgery for congenital heart disease and cardiac catheterization for 20 yrs (80 85). A study by Burrows (80) examined the PaCO2PETCO2, physiological dead space, and venous admixture in 41 inS7
fants and children undergoing heart surgery. Patients were divided into acyanotic with normal or increased pulmonary blood ow and cyanotic with either right to left intracardiac shunts or complete mixing lesions. He found that in the acyanotic lesions the PaCO2PETCO2 difference was minimal but that the PETCO2 underestimates the PaCO2 in children with cyanotic congenital heart disease attributable largely to venous admixture, a nding conrmed by another study (83). Both the study by Fletcher (81) and the study by Wilson et al (86) have conrmed the increase in PaCO2PETCO2 in children with cyanotic coronary heart disease and right to left intracardiac shunts and theorized that there would be a relationship between this increase and reduced saturation levels (87), a nding conrmed by others (72). Both the study by Yates et al (88) and the study by Tugrul et al (89) in which PETCO2 was monitored during the insertion of systemic to pulmonary artery shunts showed that the effectiveness of the procedure could be demonstrated by a rise in SaO2 coincident with a reduction in PaCO2PETCO2. This observation can also be applied in the ICU when there is concern about possible shunt occlusion as a widening of the PaCO2PETCO2 gradient may be observed even before there is a change in hemodynamics or a fall in saturation (85). PETCO2 can change dramatically when pulmonary blood ow is compromised as reported in a 7-monthold patient with tetralogy of Fallot and a pulmonary valve replacement in which obstruction of the main pulmonary artery by a transesophageal probe resulted in the PETCO2 reading falling rapidly to zero (90). A study by Smolinsky et al (91), in which capnography was used during pulmonary artery banding procedures in patients with excessive pulmonary blood ow, demonstrated an average reduction of 3.8 mm Hg in the PETCO2 at the end of the procedure. However, any inferences about pulmonary blood ow drawn from the use of PETCO2 should take into account the state of the lung parenchyma. Despite previous studies about PaCO2 PETCO2 values being increased in cyanotic coronary heart disease, a study by Short et al (92) found that in children undergoing cardiac surgery, there was a higher than predicted PaCO2PETCO2 gradient in those patients with heart failure with high pulmonary blood ow and pulmonary congestion probably due to increased ventilationperfusion mismatch.
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Capnography and PETCO2 Monitoring in Critical Care. Although end-tidal CO2 monitoring is part of routine care in adult ICUs, its adoption has been slower in pediatrics because of concerns about its accuracy when uncuffed tubes are used. A study by McDonald et al (93) evaluated the comparison between PaCO2 and PETCO2 in 129 ventilated children in a pediatric ICU, 30% of whom had cardiac disease. They found that the PaCO2 PETCO2 difference was within 5 mm Hg in 54% of paired samples but that the difference increased with increasing severity of oxygenation failure as manifested by a reduction in the PaO2/FIO2 ratio. Despite this, there are many reasons to support its use as a routine monitor in ventilated pediatric postoperative cardiac patients; the most compelling is that the cardiac ICU is an extension of the care provided in the operating room. The importance of this is illustrated in the study of patients undergoing sternal closure in the ICU (94) in which expired tidal volume and CO2 elimination 30 mins before and after sternal closure in 17 patients decreased by 17% and 29%, respectively. This reects a decrease in effective alveolar ventilation resulting from a reduction in respiratory system compliance. The same strictures apply to use of end-tidal CO2 monitoring during the performance of transesophageal echocardiography in infants who are being ventilated because the probe can obstruct either the endotracheal tube or vascular structures within the mediastinum (95, 96). In both situations, this can be detected by a fall in PETCO2. Capnography During Pediatric Emergencies. End-tidal CO2 monitoring has a number of applications in emergency situations in children, including conrmation of endotracheal tube placement (97). The American Society of Anesthesiologists guidelines for the management of the difcult airway recommend that conrmation of correct placement of the tube into the trachea is veried by either standard infrared capnometry or the use of a disposable colorimetric CO2 detector (2). A study by Roberts et al (98) on neonates undergoing urgent or emergent intubation used a capnograph with sidestream sampling to detect CO2 and was able to identify correctly 39 of 40 esophageal intubations by capnography. The disposable colorimetric CO2 connector is now more commonly used in emergency situations. This is a portable device that is connected to the endotracheal tube and
changes color from purple (0.03 to 0.5%, area A) to tan (0.5 to 2.0%, area B) or yellow (2.0 to 5%, area C) in the presence of CO2. It has been shown to accurately identify correct tube placement in infants and small children (99). If no color change from the purple zone is noted during emergency airway placement and the tube is conrmed to be in the trachea by other means, then the likely explanation is that no CO2 is being produced during loss of cardiac output. Capnography and end-tidal CO2 concentration have been used to identify both the effectiveness of cardiopulmonary resuscitation and as a prognostic indicator for the return of a perfusing cardiac rhythm (100 103). In studies of cardiac arrest in adults, a PETCO2 level of 15 mm Hg has been associated with effective cardiopulmonary resuscitation and restoration of cardiac output (100, 101). In the study of pediatric emergency intubations and resuscitations by Bhende and Thompson (104) in which the colorimetric CO2 detector method was used during cardiopulmonary resuscitation, only patients with a reading in the C range had return of spontaneous circulation and survived to ICU admission. This use of capnography and colormetric CO2 detection form part of the American Heart Association guidelines for cardiopulmonary resuscitation in children (105). Finally, capnography is an important part of the monitoring of ventilation during pediatric transport both within the hospital and in the prehospital setting (78, 102, 106, 107). Studies have shown that in situations in which tight control of PaCO2 is required, this is more readily achieved by monitoring end-tidal CO2 (78, 108). Evidence and Recommendations for the Use of Capnography and End-Tidal CO2 Monitoring. End-tidal CO2 monitoring is routinely used during anesthesia for cardiac surgery and cardiac catheterization as a measure of effective ventilation and is recommended because it adds signicantly to patient safety. There is also a signicant amount of evidence that supports its routine use in ventilated patients in ICU or during transport. Capnography is also recommended to verify the correct placement of endotracheal tubes and the effectiveness of cardiopulmonary resuscitation. Like many monitoring devices, the evidence to support these recommendations is based on case series and observational studies (level of evidence: IV; grade of recommendation: C).
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Pulmonary artery catheters

Ronald M. Perkin, MD, MA; Nick Anas, MD
Background: After its introduction in 1970, the use of the pulmonary artery catheter became a central part of the management of critically ill patients in adult and pediatric intensive care units. However, because it was introduced as a class II device, efcacy for its safety and clinical benet did not exist during the early years of use. This review describes the pulmonary artery catheter and reviews the literature supporting its use. Methodology: A search of MEDLINE, PubMed, and the Cochrane Database was made to nd literature about pulmonary artery catheter use. Literature for both adult and pediatric patients was reviewed. Guidelines published by the Society for Critical Care Medicine and the American Heart Association were reviewed, including further review of references cited. Results and Conclusions: The evidence supporting the use of the pulmonary artery catheter is mostly limited to level IV (nonrandomized, historical controls, and expert opinion) and level V (case series, uncontrolled studies, and expert opinion). A higher level of evidence supports the use of the pulmonary artery catheter in selected pediatric patients, especially those with pulmonary arterial hypertension and shock refractory to standard uid resuscitation and vasoactive agents. There are no data to suggest that use of the pulmonary artery catheter increases mortality in children. (Pediatr Crit Care Med 2011; 12[Suppl.]:S12S20) KEY WORDS: pulmonary artery; catheter; pediatric; acute lung injury; shock; pulmonary hypertension
n 1970, the introduction of the pulmonary artery (PA) catheter revolutionized the care of critically ill patients by allowing the clinician to directly measure important cardiovascular variables at the bedside (1, 2). As a result, the use of the PA catheter became a central part of the management of critically ill patients in adult and pediatric intensive care units (37). The standard PA catheter has four lumens, which allow assessment of the patients hemodynamic condition through direct intracardiac and PA pressure monitoring (Tables 1 and 2; Fig. 1). The directly measured physiological data available from the PA catheter include the pressures in the right atrium, right ventricle, PA, and PA occlusion pressure; mixed venous oxygenation; and temperature (Figs. 2 and 3). From these variables and three other measured variables, namely systemic arterial pressure, heart
From the Department of Pediatrics (RMP), Brody School of Medicine at East Carolina University, Greenville, NC; and Pediatric Critical Care (NA), Childrens Hospital of Orange County, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: PERKINR@ecu.edu Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e318220f079
rate, and cardiac output, a large array of calculated information is available, including stroke volume, systemic vascular resistance, pulmonary vascular resistance, oxygen transport, oxygen consumption, and oxygen extraction ratio (Table 3). There are several technologies available for the measurement of cardiac output. The thermodilution technique for determining cardiac output is applied widely and represents a major use of the PA catheter. The procedure can be performed rapidly, and clinical studies have shown good correlation between thermodilution cardiac outputs and the Fick or dye dilution method. This technique takes advantage of the fact that cold water can be injected into the central circulation and that venous return (cardiac output) may be estimated by examining the dilution of cold water with warm blood (8). There are several principles of thermodilution measurement of cardiac output. A known quantity of cold injectate is introduced into the circulation at one point (right atrium), becomes adequately mixed (two heart chambers), and the resultant change in intravascular temperature is measured downstream. Recording of the resulting cooling curve at the downstream site allows calculation of net blood ow. Cardiac output is inversely proportional to the fall in temperature. In practice, a known quantity of cooled glu-
cose or saline is injected into the proximal part of the PA catheter. The thermistor, located distantly, allows recording of baseline PA temperature and the subsequent cooling curve. This temperaturetime curve is similar to the one produced by the indicator dilution method. The temperature change integrated over time (Stuart-Hamilton equation) yields the cardiac output (8). A normal curve characteristically shows a sharp upstroke from rapid injection of the injectate. This is followed by a smooth curve and slightly prolonged downslope back to the baseline. Because this curve is representing a change from warmer temperature to cooler and then back to warmer temperature, the actual curve is in a negative direction. For continuity of most graphs, the curve is produced in an upright fashion. The area under the curve is inversely proportional to the cardiac output. When cardiac output is low, more time is required for the temperature to return to baseline, producing a larger area under the curve. With high cardiac output, the cooler injectate is carried faster through the heart, and the temperature returns to baseline faster. This produces a smaller area under the curve (Fig. 4). A modied Stewart-Hamilton equation is used to calculate the cardiac output taking into consideration the change in temperature as the indicator; modiPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
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Table 1. PA catheter port locations and port functions Location Distal Function Monitors PA pressure Monitors wedge pressure Allows sampling of blood for mixed venous oxygen saturation determination Monitors RA pressure Used for cardiac output injectate uid Syringe used to inate balloon for placement and obtain wedge pressure value Measures blood temperature 4 cm from distal tip (7F) or 2.5 cm from distal tip (5F)
Proximal Balloon gate value Thermistor connector
PA, pulmonary artery; RA, right atrium. Table 2. Standard pulmonary artery catheter comparisons 5F Length 75 cm Proximal injectate port 15 cm (distance from tip) Recommended 6 or 6.5 introducer (French size) Balloon volume 0.8 cc Thermodilution 3, 5, 10 cc injectate volume 7F 110 cm 30 cm 8.5 or 9
1.5 cc 5, 10 cc
cations include the measured temperature of the injectate and the patients blood temperature along with the specic gravity of the solution injected. CO V (TB A SI) (SI (SB CI) CB) 60 CT 1 K
Where CO cardiac output; V volume of injectate (mL); A area of thermodi-
lution curve in square millimeters divided by paper speed (mm/sec); K calibration constant in mm/C; TB, TI temperature of blood (B) and injectate (I); SB, SI specic gravity of blood and injectate; CB, CI specic heat of blood (SI CI) and injectate; 1.08 when 5% (SB CB) dextrose is used; 60 60 sec/min; and CT correction factor for injectate warming. The thermistor port of the catheter is attached to a computer or monitor. Calculations are performed internally with the results displayed on the screen. Some computers and monitors can also display the actual cardiac output timetemperature curve. By observing the actual thermodilution curve, assessment of injection technique and artifactual inuences can be noted (Fig. 4). It is important to enter the computation constant into the computer or monitor. The correct computation will be dependent on the injectate temperature, injectate volume, catheter model, and injectate system (9). The temperature of the injectate can be iced or room temperature. Available
Figure 1. Standard four-lumen pulmonary artery catheter.
data suggest that there will be less variability in cardiac output determinations if iced solution is used. The computer is registering a change (signal) in temperature from the patients baseline (noise). In some conditions, a variation in temperature of 0.05C may occur with respirations. This decreases the signal-tonoise ratio and may produce an abnormally low cardiac output value (10). Conditions in which the thermodilution method may produce unreliable results are those that have a backward ow of blood on the right side, tricuspid or pulmonic valve regurgitation, and ventricular or atrial septal defects (8 12). The advantages of this technique over the other methods previously mentioned are the reliability and ease of performing at the bedside. Also, serial cardiac outputs are performed without requiring blood sampling. Accuracy of the thermodilution technique involves very rapid injection rates, accurate measurement of the injectant temperature and volume, thorough mixing of the injectant and venous return, and no loss of injectant. Falsely elevated cardiac output will occur with slow injection rates and small injectant volumes. Falsely depressed cardiac output values occur with the use of solutions cooler than or injectant volumes greater than values initially programmed on the cardiac output computer. The principle on which the thermodilution technique is based assumes a constant blood ow during the time the indicator solution travels from the right atrium to the thermistor. Also, the normal pulsatile nature of blood ow and respiratory variations in intrathoracic pressures may affect all thermodilution determinations (8 12). To reduce the impact of this latter problem, most investigators recommend averaging three consecutive measurements performed in the same phase of the respiratory cycle. Cardiac output measurements in children are further complicated for the following reasons: 1) Multiple measurements of cardiac output may result in uid overload in a small child. The injected volume can be as little as 3 mL; however, the tradeoff is a greater likelihood of an erroneous measurement; 2) The position of the proximal port of the PA catheter affects the accuracy of both thermodilution cardiac output determinations and RA pressure measurements (13). In small children, the proximal port may be in the right ventricle.
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Figure 2. The pulmonary artery catheter: how it moves through the heart and what it measures. A, The catheter enters the right atrium (RA) of the heart, usually through the superior vena cava. Once the catheter is in the RA, a pressure tracing like the one above should appear. Normal RA pressures range from 1 to 6 mm Hg (in spontaneous breathing patients, the RA pressure may be negative during inspiration). They reect mean RA lling (diastolic) pressure (equivalent to central venous pressure) and right ventricle (RV) end-diastolic pressure (pressure at the end of the lling cycle, just before contraction). B, After the catheter enters the RA, the balloon is inated, and the catheter follows the blood ow through the tricuspid valve into the RV. An RV tracing like the one above should appear. RV pressures normally range from 20 to 30 mm Hg systolic and from 0 to 5 mm Hg diastolic. C, From the RV, the catheter passes through the pulmonary semilunar valve into the pulmonary artery (PA), at which time a PA tracing should appear on the monitor. Normal PA pressures range from 20 to 30 mm Hg systolic and from 8 to 12 mm Hg diastolic. PA pressures give an estimate of the venous pressure within the lungs and the mean lling pressure of the left atrium and ventricle, information that is fundamental to detecting pulmonary congestion. They also reect RV function because, in the absence of pulmonary stenosis, PA systolic pressure usually equals RV systolic pressure. D, When the catheter reaches a branch of the PA with a smaller diameter than that of the balloon, it wedges in the vessel and a pulmonary capillary wedge (PCW) pressure tracing appears on the monitor. Once the PCW pressure has been recorded, the balloon is deated and the PA tracing reappears. Normal PCW pressure ranges from 4 to 12 mm Hg. In most patients with no signicant pulmonary vascular disease, PCW pressure equals PA diastolic pressure; even nondiseased patients, however, commonly show a 3 to 5 mm Hg gradient between the PCW and PA diastolic pressures. A gradient of 5 mm Hg is abnormal. Because PCW pressure is usually equal to left atrial pressures, it is a good index of left heart function. The PCW pressure may also be referred to as the pulmonary artery wedge pressure, the pulmonary artery occlusion pressure, or the pulmonary wedge pressure. Modied from Lalli SM: The complete Swan-Ganz. RN Magazine September 1978.
(The authors have had customized PA catheters made that placed the proximal port in the RA. Most commonly a 5F catheter with the proximal port at 20 cm was requested.) 3) The position of the PA catheter can lead to erroneous results if the thermistor bead rests against the PA wall; this is not uncommon when small catheters are advanced into a small branch on the right or left PA. 4) The presence of intracardiac shunts will not necessarily be detected when using thermodilution, and measurement of pulmonary blood ow using thermodilution will not reect systemic blood ow in the presence of such shunts. In the presence of a right-to-left intracardiac shunt, some of the indicator (cold injectate) goes out the aorta without passing the thermistor. This gives spuriously high values for cardiac output. Similarly, in the presence of left-to-right shunts, recirculation of the cold injectate gives a second peak, which cannot be handled by the computer. 5) The rapid circulation time in infants can lead to errors in integration. Other uses of PA catheters have included cardiac pacing, segmental PA angiography, diagnosing left-to-right intracardiac shunts by step changes in oxygenation, and diagnosing emboli of tumor and other nonthrombus material (2, 14). The directly measured and calculated variables, in turn, serve as the basis for diagnosing and determining the mechanism of many of the important cardiovascular and pulmonary derangements that dominate the clinical course of patients in intensive care units (i.e., disorders that fundamentally alter oxygen transport balance) (2). It has now been 40 yrs since the PA catheter was introduced in a study by Swan et al (1). Although the use in pediatric patients was less frequent, it did become a routine part of pediatric intensive care even for small infants (37). It was thought, and literature supported the belief, that substantial value existed from the information made available by the use of the PA catheter in select groups of critically ill infants and children as outlined subsequently: 1) clarication of the cardiopulmonary distress in the newborn (5, 6); 2) diagnosis and management of shock (1523); 3) assessment of selected new therapies (24 27); 4) evaluation in the postoperative cardiac surgery patient (28 30); 5) evaluation of patients suspected to have pulmonary hypertension (31, 32); 6) diagnosis of uncertain causes of pulmonary edema (cardiogenic vs. noncardiogenic)
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Figure 3. The continuous pressure monitoring trace as a pulmonary artery catheter is advanced through the heart. Table 3. Derived values from pulmonary artery catheterization Variable Hemodynamic Stroke index Cardiac index Systemic vascular/resistance index Formula Normal Range
SI CI/HR 3060 mL/m2 CI CO/BSA 3.55.5 L/min/m2 SVRI 79.9 (MAPCVP) 8001600 dynes sec/cm5/m2 CI Pulmonary vascular/resistance index PVRI 79.9 (mPAPPWP) 80240 dynes sec/cm5/m2 CI Note: The PVRI may be expressed in units: PVRI mPAPPWP 13 units/m2 CI In the rst week of life, the PVRI is considerably higher and may be 810 units/m2; it then falls rapidly and by 68 weeks of life it is at adult value Oxygen transport Arterial oxygen content Mixed venous oxygen content Oxygen content difference Oxygen availability Oxygen consumption (Hgb)(1.34)(% sat) (PaO2)(0.003) CVO2 (Hgb)(1.34)(% sat) (PVO2) (0.003) avDO2 CaO2CVO2 O2 avail CI CaO2 10 VO2 CI avDO2 10 CaO2 1720 mL/dL 1215 mL/dL 35 mL/dL 550650 mL/min/m2 120200 mL/min/m2
HR, heart rate; BSA, body surface area; CO, cardiac ouput; MAP, mean arterial pressure; CVP, central venous pressure; mPAP, mean pulmonary arterial pressure; PWP, pulmonary wedge pressure; Hgb, hemoglobin; % sat, saturation; PVO2, venous oxygen pressure.
Figure 4. Thermodilution curves.
(3336); and 7) evaluation and management of acute lung injury/cardiopulmonary interaction during mechanical ventilation (4, 37, 38). These studies demonstrate that we learned a great deal about hemodynamics in critically ill pediatric patients with the use of the PA catheter; this should not be ignored or forgotten. Also, these studies that used the PA catheter without reporting complications from its use support that it is
a safe procedure in the pediatric population. It should be noted that in the United States, the PA catheter was introduced as a class II device and, as a consequence, was not required to undergo assessment before clinical use. As a result, evidence for its efcacy and safety does not exist (39). Great controversy has developed regarding the use of the PA catheter (39, 40). Proponents argue that its unique ability to allow accurate measurement of
cardiac output and other hemodynamic variables improved diagnosis and management of circulatory instability (41, 42). Critics, however, pointed to complications associated with its insertion and use, inaccuracies in measurement, and difculties with interpretation of data (40, 43 48). Furthermore, a lack of positive outcome benets in the critically ill adult patient and some suggestions of increased mortality from retrospective analyses indicated potential problems with the PA catheter (40, 49 51). In 1996, a large, nonrandomized, riskadjusted study in adult patients indicated an increased 30-day mortality rate associated with PA catheter use in the rst 24 hrs after admission to intensive care (52). This fresh uncertainty encouraged further study of the use of the PA catheter in both adult and pediatric patients. Consensus on the use of PA catheter has been summarized in the Society of Critical Care Medicine Pulmonary Artery Catheter Consensus Conference document (53). This document suggests that the PA catheter claries cardiopulmonary physiology in selected pediatric patients with the following characteristics: 1) pulmonary hypertension; 2) shock refractory to uid resuscitation and/or low-tomoderate doses of vasoactive agents; 3) severe respiratory failure requiring high airway pressures; and 4) multiple organ dysfunction on rare occasions. In these patients, data derived from the PA catheter may improve outcome. However, the evidence supporting the use of the PA catheter in these situations was limited to level IV (nonrandomized, historical controls, and expert opinion) and level V (case series, uncontrolled studies, and expert opinion) evidence. There were no data to suggest that use of the PA catheter increases mortality in children. The committee did recommend that the PA catheter in pediatric patients should be used judiciously and for the shortest time necessary. The PA catheter should be placed under the direct supervision of an experienced, attending-level physician. Interpretation of the PA catheter-derived data and subsequent management decisions should be supervised in a similar fashion. It should be emphasized that the PA catheter is a monitoring device, not a therapeutic modality (54). As a monitor, the PA catheter is directly attributable to very little in the way of morbidity and mortality (55). Complications of the PA catheter are rare (Table 4). Any adverse affects associated with the PA catheter are
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Table 4. Complications of pulmonary artery catheter placement Problems with vessel cannulation Arterial puncture Pneumothorax Hemothorax Hydrothorax Air embolism Thoracic injury Bronchial injury Insertion problems Arrhythmias Cardiac conduction disturbances Catheter looping and knotting Pulmonary artery perforation Valve damage Maintenance problems Pulmonary infarction Venous thrombosis Infections Aseptic endocarditis Thrombocytopenia Balloon rupture
likely, therefore, to be related to the therapeutic changes associated with the data obtained from the monitor. Clinicians must interpret that data provided by the PA catheter and use that data with relevant protocols (42, 54). It is this altered therapeutic strategy that will favorably alter outcome, not the PA catheter (53). With these categories in mind, a review of more recent evidence is discussed.
Pulmonary Hypertension
Pulmonary arterial hypertension in children is a critical determinant of morbidity and mortality in diverse pediatric cardiac and pulmonary disorders as well as diseases affecting coagulation, inammation, and immunity (56 59). Structure and function of the pulmonary circulation can be altered by primary aberrations of lung growth and development or secondary to injury associated with acute respiratory failure, chronic lung disease after premature birth, chronic hypoventilation, congenital heart disease, and chronic hemolysis. Whereas the impact of pulmonary arterial hypertension on the clinical course of children with congenital heart disease and persistent pulmonary hypertension of the newborn are clearly appreciated, the contribution of pulmonary arterial hypertension to the course and ultimate outcome of children with lung disease is
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often overlooked or underestimated (56). Without therapy, high pulmonary vascular resistance contributes to progressive right ventricular failure, low cardiac output, and high mortality (56, 57). Determining the etiology of pulmonary hypertension is the key to initial management strategies (58). The goals of diagnostic evaluations are to characterize the etiology and severity of pulmonary hypertension, recognize and correct underlying causes, ascertain the reversibility of the pulmonary hypertension, determine initial treatment strategy, and assess the prognosis (58). Right heart or PA catheterization is the gold standard for the diagnosis of pulmonary hypertension (58, 60 66). PA catheterization is necessary for the hemodynamic differential diagnosis of pulmonary arterial hypertension; presently no noninvasive tests are available for the accurate diagnosis of precapillary, postcapillary, and mixed types of pulmonary arterial hypertension (41). Despite current controversies regarding the use of PA catheters in the intensive care unit, hemodynamic data are valuable in the care of critically ill patients with pulmonary hypertension (60, 66). Severe tricuspid regurgitation and elevated PA pressure often make placing a PA catheter challenging, and many necessitate the use of uoroscopy. Accurate determination of cardiac output by thermodilution may be limited in patients with tricuspid regurgitation or low cardiac output (9, 67 69). Complications of PA catheterization in patients with pulmonary hypertension can be life-threatening. In pediatric patients, two studies have found that major complications, including arrhythmia, pulmonary hypertensive crisis, and cardiac arrest, were 5% and 6%, respectively (70, 71). Standard diagnostic criteria for pulmonary hypertension include the presence of mean pulmonary artery pressure 25 mm Hg with pulmonary artery occlusion pressure 15 mm Hg and pulmonary vascular resistance 3 Wood units/m 2 (58). Hemodynamics determined at the time of catheterization may also reect prognosis (58, 72); elevated mean pulmonary artery pressure and reduced cardiac index predict a less favorable prognosis. Angiography at catheterization should include evaluation of pulmonary vessels for PA morphology, pulmonary vein ow, and aortogram to
exclude signicant aortopulmonary connections. Patients beneting from therapies that serve as nitric oxide donors or from long-term calcium channel blockers may be identied by acute vasodilator challenge during right heart catheterization (58). Potential agents used in testing may include inhaled nitric oxide, intravenous adenosine, or intravenous epoprostenol. Additional medications may also be tested, acutely, including oral sildenal, oral nifedipine, and inhaled prostacyclin (63). Response to vasodilator therapy is dened as mean pulmonary artery pressure decrease by 10 mm Hg to reach a mean pulmonary artery pressure of 40 mm Hg with normal or high cardiac output. Children are more likely to respond to acute vasodilator testing than adults and response to acute vasodilator testing predicts both response to long-term vasodilator therapy and survival (58). Recommendations for the use of right heart or PA catheterization in the assessment of pediatric pulmonary hypertension are as follows (58, 72): 1) hemodynamic catheterization is recommended to conrm the diagnosis and establish severity (class I, level of evidence C); and 2) right heart catheterization with vasodilator testing is recommended to guide initial determination of therapy (class I, level of evidence B).
Shock
The primary physiological task of the cardiovascular system is to deliver enough O2 to meet the metabolic demands of the body. Shock and tissue hypoxia occur when the cardiorespiratory system is unable to meet the metabolic demand adequately. Sustained tissue hypoxia is one of the most important cofactors in the pathophysiology of organ dysfunction (73). Therefore, determining the adequacy of tissue oxygenation in critically ill patients is central to ascertaining the health of the patient and the response to therapy. Unfortunately, normal values in blood pressure, central venous pressure, heart rate, and blood gases do not rule out tissue hypoxia or imbalances between whole-body oxygen supply and demand (7375). This discrepancy has led to increased interest in more direct indicators of adequacy of tissue oxygenation such as mixed and central venous oxygen saturations. PA catheterization allows obtaining true mixed venous oxygen saturation, whereas measuring central venous oxygen
Table 5. Cardiopulmonary failure patterns CO Hypovolemic Cardiogenic Obstructive Septic High output Low output 2 2 2 1 2 PCWP 2 1 1 2 1 SVR 1 1 1 2 1 C(aVO2) 1 1 1 2 1 PV O2 2 2 2 1 2 O2Ext 1 1 1 2 1
C(aVO2), arteriovenous oxygen content difference; PVO2 mixed venous oxygen partial pressure; O2Ext, oxygen extraction; CO, cardiac output; PCWP, pulmonary capillary wedge pressure; SVR, systolic vascular resistance.
livery beyond the point of oxygen consumption plateau (77, 80, 84, 85). Recommendations for the use of PA catheterization in the assessment and management of shock are that the PA catheter can be used in those patients who remain in shock despite therapies directed to clinical signs of perfusion, mean arterial pressure central venous pressure, central venous oxygen saturation, and echocardiographic analyses (class IIa, level of evidence C) (79).
Acute Lung Injury

saturation through a central venous catheter reects principally the degree of oxygen extraction for the brain and the upper part of the body. A study by Ceneviva et al categorized 50 children with uid-refractory septic shock according to hemodynamic state (based on hemodynamic data obtained with the pulmonary artery catheter) into one of three possible cardiovascular derangements: 1) hyperdynamic state characterized by high cardiac output ( 5.5 L/min/m2 body surface area) and low systemic vascular resistance (SVR) ( 800 dynessec/cm5) (classically referred to as warm shock); 2) a hypodynamic state characterized by low cardiac output ( 3.3 L/min/m2 body surface area) and low SVR; or 3) a hypodynamic state characterized by low cardiac output and high SVR ( 1200 dynessec/cm5) (classically referred to as cold shock) (76). In contrast to adults in which the early stages of septic shock are characterized by high cardiac output and low SVR, most of these children were in a hypodynamic state characterized by low cardiac output and high SVR (cold shock) and required the addition of vasodilators to decrease SVR, increase cardiac output, decrease myocardial oxygen consumption, and improve peripheral perfusion (76). Children with low cardiac output (as dened by a cardiac index 2.0 L/min/m2 body surface area) had the highest risk of mortality. This study as well as literature referred to early in this article supports the use of the PA catheter to dene the exact hemodynamic state in the patient with refractory shock (Table 5) (77). The new information gained allows for therapies to be tailored to address the hemodynamic derangements determined to be present on institution of PA catheter monitoring. An independent review of this topic interpreted the results in the Ceneviva study to support the use of the
PA catheter in the select group of children with septic shock whose hemodynamic prole and clinical condition were not improved by the application of therapies based on the data obtained by peripheral arterial and central venous pressure and oxygen saturation monitoring (78). In the clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock article, Carcillo and colleagues (77) recommended that a PA catheter should be considered when poor perfusion, including reduced urine output, acidosis, or hypoperfusion, persists despite use of hemodynamic therapies guided by clinical examination, blood pressure analysis, echocardiographic analysis, and arterial and superior vena cava oxygen saturation analysis. Once the PA catheter is placed, therapy should be adjusted to maintain mixed venous oxygen saturation 70%, cardiac index 3.3 L/min/m2, and a normal perfusion pressure for age (mean arterial pressure central venous pressure) with the ultimate goal of restoration of normal perfusion (77). These recommendations were considered a level II recommendation (reasonably justied by scientic evidence and strongly supported by expert critical care opinion). These goals were reafrmed in the 2007 clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock (79). At one time, hemodynamic therapy aimed at achieving supranormal values for cardiac index and oxygen delivery was encouraged for critically ill patients (80, 81). This therapeutic strategy was based on the observations that patients who survived had values for cardiac index and oxygen delivery that were higher than those of patients who died and, more important, higher than standard physiological values (82, 83). Recent studies fail to show a benet of increasing oxygen de-
A common diagnostic indication for the use of a PA catheter is pulmonary edema when there is doubt concerning the nature or cause (i.e., cardiogenic vs. noncardiogenic pulmonary edema) (3336). The diagnosis of noncardiogenic pulmonary edema or the acute respiratory distress syndrome (ARDS) is based on physical and radiologic evidence of bilateral pulmonary inltrates consistent with edema, refractory hypoxemia, and normal left ventricular lling pressure (38). Almost all currently available forms of mechanical ventilation can have pronounced direct and/or indirect effects on a patients circulatory function and cardiopulmonary reserve (86). Biphasic uctuations in airway and intrathoracic pressures change the preload conditions on the right side of the heart by altering venous return, transmural pressure gradients, and pulmonary vascular resistance. Altering positive end-expiratory pressure in the management of patients with ARDS may signicantly affect pulmonary blood ow and ventilation/ perfusion matching; these changes in physiology will best be determined by the data obtained from the PA catheter. Patients with ARDS may have an unpredictable response to mechanical ventilation and the physical ndings may not be helpful in assessment of the adequacy of tissue oxygen delivery (8790). Continuous arterial pressure monitoring with measurement of systemic blood ow and PA catheterization with mixed venous oxyhemoglobin saturation monitoring may prove valuable in these vulnerable patients (87, 88). It has been postulated that monitoring both right and left ventricular lling pressures (right atrial and pulmonary capillary wedge pressures) and cardiac output will facilitate the maintenance of volume status and regulation of vasopressor and inotropic therapy in patients with ARDS (41). It has
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been suggested that such hemodynamic monitoring with the use of PA catheters is superior to the use of central venous catheters to monitor central venous pressure alone and is likely to produce a better outcome. Indeed, many nonrandomized clinical studies have recommended, for routine bedside hemodynamic monitoring, the use of PA catheters for management of ARDS (89). However, in adult patients, a recent study suggested that PA catheter-guided therapy in patients with acute lung injury did not improve survival or organ function but was associated with more complications than central venous pressure-guided therapy (91). Similar studies do not exist in children. Strategies for managing ARDS include not only the manipulation of mechanical ventilation, but also nonventilatory modalities such as uid restriction and selective use of pulmonary vasodilators (92, 93). Fluid administration increases hydrostatic pressure in the lungs and promotes uid ltration and edema formation, particularly in states of increased microvascular permeability such as ARDS. In randomized clinical trials, a conservative uid management strategy for patients with ARDS resulted in lower intravascular pressure, less extravascular lung water, shorter duration of mechanical ventilation, and shorter intensive care unit length of stay (93, 94). The exact uid strategy will vary from patient to patient; in some patients, the use of the PA catheter may be necessary to achieve the optimal cardiac hemodynamic prole. Pulmonary hypertension, resulting from vasoconstriction and occlusion of the pulmonary microvasculature, is widely recognized as a characteristic feature of ARDS (95, 96). Pulmonary hypertension contributes to impaired right ventricular performance and cardiac output in patients with ARDS, leading to a reduction in systemic oxygen delivery. Pharmacologic manipulation of pulmonary vascular tone is feasible in patients with ARDS but will require carefully performed clinical trials and close characterization of the hemodynamic prole. Recommendations for the use of a PA catheter in the management of patients with ARDS or pulmonary edema are: 1) the PA catheter may be useful in selected pediatric patients with ARDS (class IIb, level of evidence C) (53); and 2) the PA catheter may be useful in the diagnosis and management of uncertain causes of pulmonary edema (class IIb, level of evidence C) (3336).
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Conclusion
The PA catheter may be useful in the management of selected pediatric patients, especially those with pulmonary arterial hypertension and shock refractory to standard uid resuscitation and vasoactive agents. Data obtained from the PA catheter can delineate the patients hemodynamic prole, can be followed to evaluate the response to therapeutic interventions, and in certain circumstances may improve outcome and/or be of prognostic importance. If a properly trained physician believes that invasive hemodynamic data are necessary for the management of a specic patient, then the use of the PA catheter is justied in that patient (42). Once a PA catheter is in place, one must insist on correct measurement, correct interpretation, and correct application of the data obtained.
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Venous oximetry and the assessment of oxygen transport balance

Ronald A. Bronicki, MD
Objective: To review the principles of venous oximetry; the physiology of oxygen transport balance; clinical studies on venous oximetry; and the assignment of a classication of recommendation and level of evidence. Data Source: A MEDLINE-based literature source. Conclusion: One of the tenets of critical care medicine is to provide a timely and accurate assessment of tissue oxygenation. In conjunction with other monitoring modalities, the routine deployment of central venous catheters readily enables the clinician to complete this task. (Pediatr Crit Care Med 2011; 12[Suppl.]: S21S26) KEY WORDS: oxygen delivery; oxygen consumption; oxygen extraction ratio; oxygen transport balance; venous oximetry; shock
ne of the tenets of critical care medicine is to ensure adequate tissue oxygenation. This assessment must be timely and accurate to optimize outcomes. This determination is often based on clinical parameters such as the physical examination and standard hemodynamic parameters, including blood pressure, central venous pressure, and urine output. However, studies have demonstrated signicant discordance between assessments based on these parameters and those based on measurements of cardiac output (CO) and venous oximetry (13). The routine use of central venous catheters readily enables the clinician to assess oxygen extraction, oxygen transport balance, and the adequacy of tissue oxygenation. To accurately interpret and appreciate the use and limitations of venous oximetry requires an understanding of the determinants of tissue oxygenation; the relationship between oxygen requirements and oxygen delivery or oxygen transport balance; and the compensatory circulatory responses to alterations in oxygen transport balance. These principles as well as the evidence supporting the use of venous oximetry are reviewed.
Physiology of Tissue Oxygenation and Oxygen Transport Balance

According to the Fick equation, total body oxygen consumption (VO2) is equal to the product of CO and the difference in arterialvenous oxygen content (CaO2 CvO2) or the volume of oxygen extracted per minute (Table 1). Because oxygen is poorly soluble in water, the amount of oxygen dissolved in blood is minimal and inconsequential except in cases of severe anemia. By ignoring the amount of oxygen dissolved in blood, the Fick equation SmvO2 may be simplied to: SaO2 VO2/DO2, where SaO2 is the arterial oxygen saturation; SmvO2 is the mixed venous oxygen saturation, which is obtained from the pulmonary artery and is the weighted average of venous return from all viscera; and DO2 is oxygen delivery, the product of CO and arterial oxygen content. SaO2 SmvO2 is the percent oxygen extraction; however, in the presence of arterial hypoxemia, oxygen extraction is assessed by calculating the oxygen extraction ratio (OER) (Table 2A). By measuring oxygen extraction, the relationship between oxygen demand and DO2 or oxygen transport balance can be assessed and the adequacy of tissue oxygenation determined (Table 1). If oxygen requirements were to remain constant, as DO2 decreases, oxygen extraction increases to maintain adequate tissue oxygenation and VO2 remains unchanged (Fig. 1). Below a given DO2, oxygen extraction continues to increase but oxygen demands exceed oxygen availability. At this point VO2 falls, anaerobic metabolism ensues, and lactate begins to accumulate (Table 2B). This represents the critical
From the Childrens Hospital of Orange County, Orange, CA; and David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA. The author has not disclosed any potential conict of interest. For information regarding this article, E-mail: rbronicki@choc.org Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3182211667
DO2, which is the same regardless of whether the decrease in DO2 resulted from anemia, hypoxemia, and/or low CO (4). The corresponding percent oxygen extraction represents the critical OER. If oxygen requirements were to change, the critical DO2 would change in parallel; however, the indicator of the adequacy of tissue oxygenation, the critical OER, remains constant between 50% and 60% (Fig. 2) (57). For most viscera, ow is tightly coupled to metabolism. Local metabolic regulation of vasomotor tone provides the homeostatic mechanism by which metabolic demand inuences perfusion. As a result, regional and global OERs remain fairly constant despite modest changes in the determinants of oxygen transport balance (Table 3). Increases in oxygen requirements or decreases in oxygen content resulting from hypoxemia or anemia are compensated for by increases in blood ow and the OER remains normal (8 11). The OER increases appreciably with signicant increases in oxygen requirements or decreases in oxygen content and when CO is limited. The primary compensatory mechanism to maintain tissue oxygenation in a low CO state is an increase in oxygen extraction. Thus, as long as the OER is not signicantly elevated, DO2 is adequate and aerobic metabolism is maintained. The exception to this occurs in pathologic states characterized by impaired oxygen use such as cyanide poisoning. In this condition, serum lactate levels are signicantly elevated despite an elevated DO2 and narrowed OER. Like with cyanide poisoning, some patients in septic shock also appear to have impaired oxygen utilization. In these paS21
Table 1. Oxygen transport balance Fick equation: VO2 CO CaO2 CvO2 By ignoring the amount of oxygen dissolved in blood, the Fick equation may be simplied to: SaO2 SmvO2 VO2/DO2 oxygen transport balance VO2, oxygen consumption (cc/min); CO, cardiac output (L/min); CaO2, arterial O2 content (cc O2/dL); CvO2, venous O2 content (cc O2/dL); SaO2, arterial O2 saturation; SmvO2, mixed venous O2 saturation; DO2, oxygen delivery (CO CaO2; O2/min). Table 2. Oxygen extraction ratioa A. Oxygen Extraction Ratio (OER) OER SaO2 SmvO2 SAO2 Figure 1. The relationship between oxygen delivery (DO2), oxygen consumption (VO2), and oxygen (O2) extraction. Initially, as DO2 decreases, VO2 remains constant as a result of an increase in O2 extraction (i.e., VO2 is independent of DO2). As DO2 decreases further, O2 extraction increases further but not enough to maintain a constant VO2 (i.e., VO2 becomes dependent on DO2). Without a change in O2 demand, the critical DO2 is dened when VO2 begins to fall.
SaO2, arterial O2 saturation; SmvO2, mixed venous O2 saturation B. Oxygen Extraction Ratios 25% 30% to 40% 40% to 50% 50% to 60%
a
Normal Increased Impending shock Shock, lactic acidosis

O2
Based on mixed venous
saturation.
tients, serum lactate levels are elevated despite the fact that the OER is less than critical. Furthermore, increasing DO2 does not increase measured VO2 (12). That said, it is unclear if the lactic acidosis is the result of impaired oxygen utilization because the OER increases as DO2 decreases; the critical DO2 and critical OER are the same as those seen in critically ill nonseptic patients; and as the OER rises above critical, serum lactate levels rise even further (1316). Further confounding the discussion, serum lactate levels may be elevated as a result of impaired clearance (17). In any case, the lactic acidosis seen in patients with septic shock in conjunction with an OER less than critical is not responsive to an increase in DO2.
Figure 2. The curvilinear relationship between cardiac index and oxygen extraction as oxygen consumption (VO2) varies. The critical oxygen extraction ratio remains the same; however, the critical oxygen delivery increases as O2 demand increases.
The OxygenHemoglobin Dissociation Curve

The shape and position of the oxygen hemoglobin dissociation curve relates the partial pressure of oxygen to the percent oxygen bound to hemoglobin and in doing so graphically depicts the afnity of oxygen for hemoglobin. The P50 is the partial pressure of oxygen at which 50%
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of hemoglobin is saturated. A shift in the oxygen hemoglobin dissociation curve to the right, or an increased P50, represents a decrease in the afnity of oxygen for hemoglobin, whereas a shift to the left is reective of an increase in afnity of oxygen for hemoglobin. The relevance of the oxygen hemoglobin dissociation curve to a review of venous oximetry is that in critical illness, the afnity of oxygen for hemoglobin is frequently altered, which may affect the loading and unloading of oxygen and the interpretation of venous oximetry. A decrease in the afnity of oxygen for hemoglobin is thought to be teleological in shock because it increases the efciency of oxygen extraction. If this were true, a shift in the oxygen hemoglobin dissociation curve to the right would increase and a shift to the left would decrease the critical OER. However, this does not appear
to be the case. Regardless of the P50, the OER increases in proportion to decreases in CO/DO2. Whether the P50 is reduced (18) or increased (19), the efciency of oxygen extraction and the critical OER remain unchanged. At the critical OER, the venous partial pressure of oxygen will be lowest in those with a reduced P50, intermediate in those with a normal P50, and highest in those with an increased P50. However, the critical OER remains the same across all groups.
Compensatory Mechanisms to Maintain Tissue Oxygenation

As CO and DO2 decrease and/or VO2 increases, three separate but interrelated processes attempt to maintain oxygen transport balance: CO is augmented, blood ow is redistributed between organs, and microcirculatory changes enPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
Table 3. Compensatory circulatory responses to changes in O2 transport balance Increased metabolism VO21 3 CO/DO21 3 OER normal VO211 3 CO/DO211, OER13 O2 demands met Hypoxic or anemic hypoxia CaO2 23 CO13 DO2 maintained, OER normal CaO2 223 CO11, DO21 OER13 O2 demands met Stagnant hypoxia CO2 3 OER13 O2 demands met CO223 OER113 VO2 falls Histotoxic hypoxia VO223 CO/DO213 OER22, lactic acidosis OER, oxygen extraction ratio; VO2, oxygen consumption; CO, cardiac output; CaO2, arterial oxygen content; DO2, oxygen delivery. Table 4. Factors responsible for increasing requirements Catecholamines, endogenous and exogenous Systemic inammatory response Fever Consciousness, pain and anxiety Spontaneous respiration Enteral nutrition
O2
large percentage of CO under normal conditions, and an increase in ow as oxygen requirements increase. Finally, although there may be alterations in vascular resistance that reduce blood ow, all organs are capable of microcirculatory adjustments that lead to vascular recruitment and a compensatory increase in oxygen extraction. The local accumulation of adenosine, a byproduct of adenosine-5 -triphosphate utilization, and a decrease in tissue oxygen tension, for example, have been shown to mediate these changes. Vascular recruitment increases capillary density. As a result, the diffusion distance for oxygen decreases and the capillary surface area available for gas exchange increases. In addition, the cross-sectional area of the individual vessel and of the vascular bed increases; because the linear velocity of blood is inversely related to the cross-sectional area, red blood cell velocity decreases and its transit time increases, increasing oxygen diffusion times and oxygen extraction.
Regional Oxygen Transport Balance

An understanding of regional oxygen transport balance enables the clinician to accurately interpret venous oximetry from different sites under normal conditions and in limited CO states. Cerebral blood ow is tightly coupled to cerebral metabolism providing a fairly constant cerebral OER (20). The exception to this occurs when cerebral blood ow is limited, in which case the cerebral OER increases, and when changes in the PaCO2 occur. Irrespective of cerebral metabolic demands and systemic hemodynamics, cerebral blood ow changes in parallel with PaCO2. The normal cerebral OER is 35% (jugular bulb) and the critical cerebral OER (corresponding to the onset of neurologic decits and a rise in brain lactate levels) is similar to the global critical OER at approximately 50% (21). However, as CO becomes limited, the global OER increases rst and to a greater extent than does the cerebral OER. Total blood ow to the gastrointestinal system is approximately 20% to 25% of CO in the unfed sate and may increase by as much as 200% above baseline levels with ingestion of nutrients (22). The normal splanchnic OER is approximately 25% to 35% and the critical OER is similar to the global critical OER at roughly 50% to 60% (23). However, as CO falls, the splanchnic OER increases rst and
hance tissue extraction of oxygen. As DO2 and CO become limited, cardiopulmonary receptors, arterial baroreceptors, and chemoreceptors are stimulated. This leads to activation of neurohormonal systems and an increase in circulating levels of catecholamines, angiotensin II, aldosterone, and vasopressin; direct adrenergic stimulation of the myocardium also occurs. These vasoactive substances cause venoconstriction, thereby reducing venous capacitance, and stimulate uid retention, both of which serve to increase venous return and ventricular lling; additionally, they increase heart rate, enhance myocardial function, and increase arterial vascular tone. The net result is an increase in CO, DO2, and arterial pressure. When CO is limited, the redistribution of blood ow between organs represents an additional mechanism by which to optimize DO2. Less vital organs (such as the mesentery and dermis) and organs with considerable ow reserve (such as the kidneys) experience an increase in vascular resistance and therefore a reduction in perfusion. Vital organs such as the brain, myocardium, and diaphragm do not experience an increase in vascular resistance and perfusion is maintained. This represents an important compensatory mechanism, because these vital organs have high resting oxygen extraction, necessitating a relatively
becomes critical sooner than does the global OER (23). The kidneys are second only to the heart in terms of VO2. The vast majority of renal VO2 occurs with the active resorption of ltrate and because renal sodium transport is coupled to renal blood ow, changes in renal VO2 are met by corresponding changes in renal oxygen delivery. This phenomenon coupled with the fact that the kidneys receive a very high blood ow (approximately 20% of CO) produces a very low OER of approximately 10% to 15% (24). As a result, the renal OER increases appreciably only with signicant decreases in renal DO2 (25). These differences in regional oxygen transport balance are responsible for the ranges of venous oximetry obtained from different sites under normal conditions and in low CO states. Under normal conditions, venous saturations range from 80% to 85% in the inferior vena cava (IVC), 70% to 75% in the superior vena cava (SVC), 65% to 70% in the jugular vein, and a normal SmvO2 is 75% (26). As CO decreases, IVC saturations fall rst, which is accompanied by a less severe drop in SmvO2. As CO falls further, SVC and jugular saturations begin to decrease (27, 28).
Advantages and Limitations of Venous Oximetry

It is not until the critical OER is reached and the production of lactate exceeds its clearance that the serum lactate level begins to rise (Table 2B). Therefore, venous oximetry is more sensitive at detecting impaired oxygen transport balance and impending tissue hypoxia than an elevated serum lactate level. Oxygen demand is an important determinant of oxygen transport balance; however, it is impractical to measure and it varies considerably between and within disease states (Table 4). Thus, a determination of CO and DO2 does not provide an indication of whether they are adequate to meet metabolic demand. Venous oximetry assesses oxygen transport balance and the adequacy of DO2. Similarly, changes in oxygen extraction do not necessarily reect changes in CO and DO2 because oxygen demand may vary over time. The relationship between CO and venous oxygen saturations is curvilinear (Fig. 2). Thus, for a given VO2, venous oximetry is relatively insensitive at detecting changes in CO as it falls from normal values. It is when CO becomes low that further decreases produce a
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large increase in oxygen extraction. Systemic hemodynamic parameters (e.g., CO) and global indicators of oxygen transport balance, such as SmvO2 and serum lactate levels, do not necessarily reect the adequacy of regional tissue oxygenation. This is exemplied in the comparison of systemic and splanchnic indicators of oxygen transport balance in low CO states, as discussed previously (29, 30).
Central Venous Oximetry

Mixed venous oximetry is often not available. Placement of a pulmonary arterial catheter is difcult in neonates and infants. Pulmonary artery saturations are rendered useless in the presence of leftto-right cardiac shunting. Alternative sites for monitoring venous oxygen saturations include the right atrium (RA), so long as there is no left-to-right atrial shunt, IVCRA junction, and the SVC. Right atrial saturations are close to and track changes in SmVO2; however, they may vary some from SmvO2 if inadequate mixing occurs (10, 28, 31, 32). IVC saturations should be obtained from the IVCRA junction to optimize mixing of venous return from abdominal viscera. In addition to giving consideration to where the samples are obtained from, central venous saturations should be interpreted in their clinical context, because these values vary considerably from site to site under normal conditions and as CO and regional oxygen transport balance are altered, as described previously.
Clinical Studies
Venous oximetry has been studied extensively in severe sepsis and septic shock with the seminal study published by Rivers and colleagues in 2001 (3). On presentation to the emergency department, adults with severe sepsis and septic shock were eligible for enrollment if their systolic blood pressure was 90 mm Hg despite 20 30 mL/kg of uid or if their serum lactate level was 4 mmol/L (n 263). Patients were randomized to receive either 6 hrs of standard therapy (interventions based on central venous pressure, blood pressure, and urine output) or early goal-directed therapy (EGDT), which included the targeting of a central venous oxygen saturation (ScvO2; SVC saturations) of 70%. The group randomized to EGDT had signicantly less severe organ dysfunction and
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improved survival with an inhospital mortality of 30.5% (vs. 46.5%, p .009) and 28-day mortality of 33.3% (vs. 49.2%, p .01). The author concluded that the significant impact on morbidity and mortality in the EGDT group was the result of an early and accurate diagnosis of the severity of illness and the implementation of a timely and aggressive resuscitation. This approach has been shown to improve outcomes in other critical illness, including trauma, acute myocardial infarction, and ischemic stroke (3335). At the core of this approach is an appreciation of the fact that estimations of CO and tissue oxygenation based on the physical examination and standard clinical parameters (e.g., central venous pressure, blood pressure, and urine output) are often discordant from measured values, whereas targeting a parameter such as Sv O 2 represents a more denitive resuscitation strategy (13). These notions are supported by the fact that during the initial 6 hrs of therapy, the ScvO2 was signicantly higher and a ScvO2 of 70% was achieved in signicantly more patients in the EGDT group than in the standard practice group, and those receiving EGDT received signicantly more uid, red blood cell transfusions, and inotropic support. Furthermore, although the EGDT group had a signicantly higher mean blood pressure during the initial 6 hrs, all patients in both groups reached the goal mean blood pressure and there was no difference between groups for heart rate or central venous pressure. Several studies since the original report by Rivers and colleagues have evaluated the impact of EGDT on outcomes in adults with severe sepsis and septic shock. These studies differed in that they relied on historical controls and their protocols were not limited to optimizing hemodynamics but included additional therapies such as antibiotics, which were bundled into the resuscitation protocols (36). Eight singlecenter studies (37 43) and one national study (44) demonstrated a signicant reduction in mortality following implementation of EGDT, whereas two inadequately powered studies did not demonstrate improved outcomes (45, 46). In the study by Castellanos-Ortega and colleagues, the only single intervention with impact on mortality was the achievement of a ScvO2 of 70% (43). A study by Rivers et al (47) also found the ScvO2 component of the bundle to have the greatest impact on survival of any bundle element.
A study similar to that conducted by Rivers and colleagues was carried out by de Oliveira and colleagues in children with severe sepsis (48). Patients were recruited from the emergency department, inpatient unit, and pediatric intensive care unit (n 102). Eligibility criteria were severe sepsis or uid-refractory shock despite 40 mL/kg of uid. Severe sepsis was dened as evidence of infection and sepsis inammatory response syndrome criteria and at least one of the following: altered mental status, hypoxemia, increased serum lactate level, oliguria, or hypotension. The duration of the resuscitation protocols was 72 hrs and the intervention group targeted a SvO2 of 70%, which was obtained from the RA, or SVCRA, or IVCRA junction. Those patients randomized to the SvO2 group had signicantly less mortality at 28 days (11.8 vs. 39.2%, p .002) and less organ dysfunction than the group targeting standard hemodynamic parameters alone. As was the case in the study by Rivers and colleagues, during the initial 6 hrs, the group targeting SvO2 received signicantly more uid, red blood cell transfusions, and vasoactive support and were much more likely to reach a SvO2 70% (37.9 vs. 12.5%, p .02). Furthermore, there was no difference in heart rate, mean blood pressure, or central venous pressure between groups. Venous oximetry has not been studied extensively in cardiac surgical patients. A prospective randomized study was conducted by Polonen and colleagues (49) of 403 adult patients undergoing cardiac surgery. The protocol-driven group that targeted a SmvO2 of 70% had signicantly reduced hospital length of stay and less postoperative organ dysfunction than the control group. Two additional small prospective randomized studies in adults undergoing cardiac surgery found a decrease in length of stay in their respective groups that targeted SvO2 (50, 51). Data supporting the use of venous oximetry in pediatric cardiac patients is also limited. Tweddell and colleagues (52) performed a retrospective analysis of outcomes for 115 consecutive patients undergoing the Norwood procedure. From 1992 to 1996, the survival rate for the Norwood procedure at their institution was 53%. Commensurate with the implementation of new treatment strategies in 1996, the survival rate increased to 93% from 1996 to 2001. Multivariate analysis identied continuous SsvcO2 monitoring
as a signicant factor responsible for improved survival. In addition to the prospective randomized studies in severe sepsis conducted by Rivers and colleagues and by de Oliveira and colleagues, a study by Donati and associates (53) randomized adult patients (n 135) undergoing major abdominal surgery to receive either goal-directed therapy, which targeted ScvO2 during surgery up until postoperative day 1, or standard care. Although patients in both group received similar amounts of uid and packed red blood cells during the study, those in the goal-directed group received a greater amount of each during surgery as well as signicantly more inotropic support during and after surgery. The goal-directed group had signicantly higher ScvO2 and lower serum lactate levels at the conclusion of surgery and developed signicantly less organ failure and had a greater reduction in hospital length of stay.
6.
7. 8.
9.
10.
11.
12.
Conclusion
One of the tenets of critical care medicine is to provide a timely and accurate assessment of tissue oxygenation. In conjunction with other monitoring modalities, the routine deployment of central venous catheters readily enables the clinician to complete this task.
13.
14.
Classication of recommendations and level of evidence

Class I and level of evidence: B. ScvO2 should be monitored in critically ill pediatric patients and a ScvO2 of 70% should be targeted. In patients with arterial hypoxemia, a normal oxygen extraction ratio should be targeted.
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17.
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Near-infrared spectroscopy as a hemodynamic monitor in critical illness

Nancy S. Ghanayem, MD; Gil Wernovsky, MD; George M. Hoffman, MD
Background: Near-infrared spectroscopy has moved from a research tool to a widely used clinical monitor in the critically ill pediatric patient over the last decade. The physiological and clinical evidence supporting this technology in practice is reviewed here. Methodology: A search of MEDLINE and PubMed was conducted to nd validation studies, controlled trials, and other reports of near-infrared spectroscopy use in children and adults in the clinical setting. Guidelines published by the American Heart Association, the American Academy of Pediatrics, and the International Liaison Committee on Resuscitation were reviewed including further review of references cited. Results: The biophysical properties of near-infrared spectroscopy devices allow measurement of capillaryvenous oxyhemoglobin saturation in tissues a few centimeters beneath the surface sensor with validated accuracy in neonates, infants, and small patients. The biologic basis for the relationship of capillary venous oxyhemoglobin saturation to cerebral injury has been described in animal and human studies. Normal ranges for cerebral and somatic capillaryvenous oxyhemoglobin saturation have been described for normal newborns and infants and children with congenital heart disease and other disease states. The capillaryvenous oxyhemoglobin saturation from both cerebral and somatic regions has been used to estimate mixed venous saturation and to predict biochemical shock, multiorgan dysfunction, and mortality in different populations. The relationship of cerebral capillaryvenous oxyhemoglobin saturation to neuroimaging and functional assessment of outcome is limited but ongoing. Although there are numerous conicting reports in small populations, expert opinion would suggest that special use may exist for near-infrared spectroscopy in patients with complex circulatory anatomy, with extremes of physiology, and in whom extended noninvasive monitoring is useful. Conclusions: Class II, level B evidence supports the conclusion that near-infrared spectroscopy offers a favorable risk benet prole and can be effective and benecial as a hemodynamic monitor for the care of critically patients. (Pediatr Crit Care Med 2011; 12[Suppl.]:S27S32) KEY WORDS: NIRS; spectroscopy; hemodynamic monitoring; hemoglobin saturation; electrophysiologic monitoring
onventional hemodynamic monitoring (typically measured continuously such as blood pressure or heart rate) and laboratory evidence of anaerobic metabolism or organ dysfunction (typically measured intermittently such as acid-base status or serum lactate levels) are often relatively late indicators of shock, resulting in delayed recognition of serious illness and potentially suboptimal outcomes (112). A continuous, noninvasive indicator of the changes in regional circulation that occur
early in developing shock states would ll a gap in standard evaluation and treatment of these circulatory abnormalities (1316). In patients with the potential for (or with established) shock and critical illness, the addition of near-infrared spectroscopy (NIRS) monitoring to traditional hemodynamic and electrophysiological monitoring helps characterize regional and global circulatory function with growing evidence for improved outcomes.
NIRS technology
Near-infrared spectroscopy uses a modied Beer-Lambert law for measurement of concentration of a substance according to the absorption and scatter of light. Current clinically useful NIRS devices provide a noninvasive assessment of tissue oxygenation through quantitative assessment of the color of hemoglobin in blood. Unlike pulse oximetry, NIRS devices do not look for an arterial pulsatile signal, but for the average or nonpulsatile optical component, which is highly related to capillaryvenous hemoglobin saturation (rSO2). An optical window of 700 900 nm allows light to pass
From the Division Critical Care in Department of Pediatrics (NSG, GMH) and the Department of Anesthesiology (GMH), Medical College of Wisconsin, Childrens Hospital of Wisconsin, Milwaukee, WI; and the Division of Pediatric Cardiology (GW), The Childrens Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: ghoffman@mcw.edu Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e318221173a
through skin or bone into underlying tissue; the differential absorption of at least two light wavelengths of light, and a dualdetector system that can reduce by subtraction the effects of shallow signals, allows a NIRS device to continuously and noninvasively estimate the hemoglobin oxygen saturation within tissues deep to the sensor. The depth of the optical eld is approximately half the source-detector distance, which is 4 cm in the most widely used device (Invos; Somanetics Inc, Troy, MI). This source-detector distance and the subtraction algorithm allow the device to estimate rSO2 in a tissue sample approximately 1 cm3 centimeter in volume and approximately 23 cm beneath the sensor. This venous-weighted measurement provides an estimation of the regional oxygen supply demand relationship. Continuous, realtime changes in rSO2 reect changes either in metabolic demand or in supply in the sampled region, a function of systemic cardiac output, arterial oxygen content, and total and regional resistance. Near-infrared spectroscopy has been extensively studied in animal and human
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models for the past four decades. The biophysical characteristics of the device and underlying tissue determine the optical eld that is measured, and the technique permits very good approximation of capillaryvenous hemoglobin saturation (17). Clinical studies have initially focused on cerebral NIRS and have validated NIRS cerebral rSO2 with jugular bulb venous saturation measurements (18 21). In a study of 30 infants and children with congenital heart disease, correlation between cerebral rSO2 and jugular bulb venous saturation was excellent with r .93 (18). A similar series in patients before cardiac catheterization or cardiac surgery found good correlation between rSO2 and jugular bulb venous saturation, however, with the strongest correlation in infants 10 kg (r .83) (20). Several studies have reported the relationship among cerebral rSO2, somatic rSO2, and venous saturation from the superior vena cava (SvO2). Because the mixed venous saturation is the owweighted average of regional venous saturations, attempts to show a univariate correlation between single-site rSO2 and a mixed venous measure (2225) should be viewed as oversimplied compared with multivariate models including multiple sites (Fig. 1) (26 28). The relationship between hypoxia detectable by NIRS and organ injury has been established for a number of tissues. In animal models of cerebral injury, cerebral hypoxia below a normothermic rSO2 threshold of 45% is associated progressively with increased lactate production, intracellular anaerobic metabolism, depletion of adenosine triphosphate, electroencephalographic slowing, and nally silence (29). Similarly, relative thresholds for cerebral injury in adults have been established in prospective observational studies of adults undergoing cardiac surgery. Absolute cerebral rSO2 50% or a 20% decline from baseline is associated with a higher likelihood of cognitive decline, frontal lobe injury, increased incidence of stroke, electroencephalographic silence, prolonged mechanical ventilation, and prolonged hospitalization (30 34). In a randomized, prospective study of adults having coronary artery bypass grafting, prolonged cerebral desaturation was associated with greater incidence of multisystem organ dysfunction (35). A higher likelihood of adverse neurologic outcomes has been associated with lower intraoperative cerebral rSO2 saturation in children. A study by Austin et al reported
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Figure 1. Estimation of venous saturation (SvO2) from cerebral and somatic near-infrared spectroscopy (NIRS) in 10 patients with hypoplastic left heart syndrome after stage 1 palliation with an average of 31 measures per patient in the rst 48 postoperative hours. Central venous oxygen saturation (ScvO2) was measured by an oximetric catheter (Oxycath, Abbott Laboratories, North Chicago, IL) in the superior vena cava. Cerebral and somatic capillaryvenous oxyhemoglobin saturation (rSO2) were measured by NIRS (Invos 4100A, Somanetics Inc, Troy, MI) with probes in the midline frontal and right T12L2 ank region. The best linear model was t as SVO2 3 0.46*rSO2C 0.46*rSO2R. This can be transformed as SVO2 0.92* (average of cerebral and somatic rSO2) 3. Modied from a study by Hoffman et al (26). CI, condence interval.
the inuence of multimodal neurophysiological monitoring during pediatric cardiac surgery on acute neurologic injury in 250 pediatric cardiac surgery patients who had intraoperative multimodality neurophysiological monitoring. Conditions of neurologic vulnerability were observed in 70% of patients, with NIRS alone identifying 60% of these abnormalities. Patients who had interventions that successfully treated the identied abnormalities had signicantly fewer neurologic complications and shorter hospitalizations than either historical controls or those patients whose identied abnormalities were not corrected, and the outcome of patients with successfully treated abnormalities was not different from that of patients without abnormalities detected on neurophysiological monitoring (36). This study was not randomized, so other factors may have inuenced the ndings, although the authors felt compelled to abandon a nonintervention arm because the identied abnormalities frequently alerted them to undesirable conditions despite otherwise deliberate intraoperative management.
Application of multisite NIRS in the intensive care unit

Baseline or Normal rSO2 Values. Multisite cerebral and somatic NIRS monitoring of patients in critical care units
provides continuous, noninvasive, realtime assessment of regional perfusion in patients at risk for multiorgan dysfunction and death. Application of this technology relies on knowledge of normal rSO2 values in well patients as well as knowledge of baseline, and potentially abnormal values, in patients with underlying vulnerable physiology. In a study of healthy adults, mean baseline cerebral rSO2 was 70% compared with 65% in adults just before cardiac surgery (37). Early work by Kurth established baseline values for cerebral rSO2 in infants and children with and without congenital heart disease. Healthy children and those with acyanotic heart disease had baseline cerebral rSO2 values similar to the adult population with an arterial saturation cerebral rSO2 difference of approximately 30%. In patients with cyanotic heart disease, cerebral rSO2 values were 46% to 57% with a wider arterial saturation rSO2 difference of nearly 40% in patients with hypoplastic left heart syndrome (38). A study by Fenton et al reported pediatric cardiac patients with clinical evidence of left-to-right shunts with or without cyanosis had lower baseline cerebral rSO2 compared with those without left to right shunts regardless of arterial saturation (39). Recently, simultaneous baseline cerebral and somatic rSO2 have been reported in healthy neonates and in
neonates before stage 1 palliation for hypoplastic left heart syndrome. A study by Bernal et al reported resting and postprandial cerebral and somatic rSO2 values in healthy neonates with normal arterial saturation. The at-rest average cerebral rSO2 was 78% with a somatic rSO2 of 88% demonstrating higher oxygen extraction across the cerebral bed compared with the somatic bed. Changes in cerebral and somatic tissue oxygenation during feeding in healthy neonates was not signicant as would be expected with good physiological reserve (40). In a series of 45 neonates with hypoplastic left heart syndrome before stage 1 palliation, mean arterial saturation was 92% with mean cerebral rSO2 of 68% and mean somatic rSO2 of 70% demonstrating similar extraction across somatic and cerebral vascular beds as would be expected with relatively limited systemic perfusion (41).
Figure 2. Predicted probability of complications, biochemical shock, and mortality in 79 neonates with hypoplastic left heart syndrome. A somatic-cerebral capillaryvenous oxyhemoglobin saturation (rSO2) difference 10 during rst 48 postoperative hours after stage 1 palliation is associated with an increase risk of biochemical shock and postoperative complications. A somatic cerebral rSO2 difference of zero or less is associated with an increased risk of mortality. Modied from a study by Hoffman et al (43). CI, condence interval.
Critical illness in patients with structural heart disease

Use of NIRS for monitoring and management of critical illness in intensive care units has predominated in infants and children. Several prospective observational studies of infants and children with congenital heart disease requiring surgery have evaluated the relationship of multisite NIRS and SvO2 or indicators of anaerobic metabolism (Fig. 1) (26 28, 42 44). In a series of 20 infants and children, dorsal lateral ank and anterior abdominal rSO2 exhibited a strong correlation with SvO2 and lactate within 48 hrs of surgery (23). In a similar study of 23 infants, cerebral, splanchnic, renal, and muscle rSO2 values were recorded every 30 secs and correlated to lactate measurements during the rst 24 hrs after surgery. rSO2 from each site was associated with elevated lactate with the strongest inverse relationship between cerebral rSO2 and lactate. In this series, averaged two-site (cerebral and renal) rSO2 65% in acyanotic children predicted serum lactate 3 mmol/L with 95% sensitivity and 83% specicity (44). In a series of 30 neonates with hypoplastic left heart syndrome, 48 hrs of postoperative physiological data including cerebral and somatic rSO2 were used to detect the distribution of systemic perfusion during periods of low cardiac output dened by low SvO2 and metabolic acidosis. Actual cerebral and somatic rSO2 were loosely related with SvO2 but more closely related when considering both rSO2 in a multilinear
relationship. A somatic rSO2 cerebral rSO2 difference of 10, indicating redistribution of perfusion away from somatic regions, predicted anaerobic metabolism (42). In a series of 79 patients who underwent stage 1 palliation, somatic rSO2 60%, and an progressive somatic ischemia indicated by a somatic cerebral rSO2 difference approaching zero predicted biochemical shock, complications, and longer intensive care unit length of stay (Fig. 2) (43). The relatively recent application of NIRS monitoring precludes evaluation of its predictive validity for important longer-term outcomes, particularly for the central nervous system. There are increasing reports of a favorable association of improved rSO2 values with improved neurodevelopmental measurements in infants and preschool-aged children; however, studies in this age group have very limited correlation with important neurodevelopmental outcomes in schoolaged children and adolescents. Longterm functional outcome studies that demonstrate a relationship to any measured physiological parameter, including cerebral rSO2, arterial blood pressure, or arterial saturation, remain absent from the literature. Few studies have correlated low rSO2 to magnetic resonance imaging abnormalities and early childhood developmental outcomes, and the results have been equivocal. Specically, in a prospective observational assessment of infants with congenital heart disease after cardiac surgery, Dent et al reported new or worsened
postoperative magnetic resonance imaging lesions in 73% study subjects, typically abnormalities of the white matter. These new or worsened lesions were correlated with a prolonged cerebral rSO2 decline (rSO2 45% for 180 mins) (45). In a prospective series, Andropoulos and colleagues reported results in a cohort of neonates with complex congenital heart disease (with either one or two ventricles) requiring surgery shortly after birth. The patients had intraoperative and postoperative cerebral NIRS monitoring and targeted interventions to maintain cerebral rSO2 50%. The investigators found new postoperative magnetic resonance imaging lesions in 36% of the cohort. In contrast to the report by Dent et al, this study did not identify an association between new magnetic resonance imaging ndings and cerebral rSO2, although rSO2 was maintained 45% for 96% of the monitored period (46). Most recently, a study by Kussman et al reported an intraoperative prospective study of 104 infants who underwent biventricular repair without aortic arch obstruction with 1-yr development assessment and magnetic resonance imaging. Lower Psychomotor Development Index (Bayley Scale) scores were associated with lower rSO2 60 mins after separation from cardiopulmonary bypass (Fig. 3). The study was limited to measuring values in the operating room, thus not measuring the continued vulnerability of the central nervous system in the intensive care unit (47). In addition to identication of global and organ-specic hypoxicischemic
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Figure 3. Perioperative periods of diminished cerebral capillaryvenous oxyhemoglobin saturation (rSO2) associated with neurologic ndings in infants undergoing reparative cardiac surgery. Lower cerebral rSO2 in the 60 mins after separation from cardiopulmonary bypass (CPB) is associated with the Psychomotor Development Index (Bayley Scale) at age 1 yr (A) and brain hemosiderin on magnetic resonance imaging (B). Modied with permission from a study by Kussman et al (47).
states, NIRS can be used to trend these conditions noninvasively in less intense environments or before invasive or laboratory measures can be obtained (41, 48, 49). In conditions of limited global oxygen delivery, optimizing the distribution of cardiac output is a critical goal that can be achieved with the regional measures provided by NIRS. For example, NIRS can guide changes in cerebral rSO2 and systemic perfusion with changes in the fraction of inspired oxygen and changes in carbon dioxide (50, 51). Consequently, changes in pulmonary and system ows can be approximated by trending systemic and pulmonary arteriovenous differences with SvO2 or noninvasively with NIRS. The patient with a single ventricle in a shock or cardiac arrest state may particularly benet from information obtained from NIRS (52, 53). In this subset of patients, optimization of the pulmonary to systemic ow ratio (minimizing steal of systemic cardiac output into the pulmonary circulation) can be critical to avoid end-organ injury and treatment can be guided more easily with the information derived from venous-side measures provided by NIRS monitoring.
Critical illness in patients without structural heart disease

Application of NIRS has expanded beyond perioperative cardiac care to areas of neurovascular disease, plastic and vascular surgery, general surgery, emergency medicine, sports medicine, sleep disorders, and neonatology. Many studies in adults have used a supercial muscle
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(thenar eminence) and a shallow-detecting NIRS measure (Inspectra; Hutchinson Technology, Hutchinson, MN) in identifying perfusion derangements incurred from traumatic injury, sepsis, and dehydration. Low shallow-detecting NIRS measure in early traumatic injury has been linked to increased risk of multiorgan dysfunction syndrome and mortality (54 57). Additionally, good correlation between acute blood loss and NIRS has been reported (58, 59). In septic shock, low shallow-detecting NIRS measure identies patients at increased risk of mortality (60, 61) and is signicantly related to anaerobic metabolism, venous oximetry, and reperfusion derangements (62 65). Reports of NIRS effectiveness in detecting and managing perfusion abnormalities in pediatric patients without cardiac disease are limited. Few studies have evaluated regional perfusion during apneic or hypoxic events in preterm neonates. Fortune applied NIRS-derived cerebral and mesenteric rSO 2 in 39 neonates to evaluate the risk of developing necrotizing enterocolitis. NIRS values were expressed as absolute rSO2 for each site and as a somatic/cerebral ratio. When the ratio was 0.75, indicating severely increased somatic oxygen extraction, there was an eight times greater risk of developing necrotizing enterocolitis with 90% sensitivity. The somatic/ cerebral ratio was more predictive of necrotizing enterocolitis than the mesenteric signal alone (66). In children with acute dehydration, a study by Hanson used cerebral and somatic (ank, renal,
or muscle rSO2) NIRS to assess changes in perfusion with rehydration. In children with moderate dehydration, cerebral rSO2 was preserved and unchanged with rehydration, whereas somatic rSO2 increased signicantly from 79% to 87% (p .001) with concomitant decrease in somatic regional oxygen extraction (19% to 11%, p .001). Most signicant observations were seen in patients who were 15 kg and in patients who received a higher volume of rehydration (49). Although increasingly used, no studies have reported the effectiveness of NIRS technology for triage or management of pediatric patients with isolated sepsis or septic shock syndrome.
Recommendations
Over the last decade, there have been approximately 400 reports from human studies (approximately 100 in children) that include use of NIRS; however, not all these studies assess its effectiveness as a hemodynamic monitor. The most extensive reports in pediatrics investigate the use of NIRS as a perioperative cerebral monitor during cardiac surgery. A single randomized controlled study in adults undergoing coronary artery bypass grafting has demonstrated improved outcome with NIRS-driven intervention. Many prospective observational studies, with a subset of randomized studies, validate NIRS rSO2 in relationship to venous oximetry and anaerobic metabolism with some studies that link NIRS-derived rSO2 to intermediate patient outcomes, whereas others show little effect. There
are two principle questions that need to be answered in the coming years as NIRS is adopted with increasing frequency in general pediatric and cardiac intensive care units. The rst is the uncertainty about critical thresholds both absolute values and durationthat should be avoided to minimize the risk of secondary organ dysfunction in a low-output/ delivery state. The second is that future studies must be performed to assess the benetand risk of management strategies targeted to improve NIRS rSO2 values. Management protocols that include transfusions, increased sedation, and changes in mechanical ventilation must be carefully designed to assess the relative risks (short-term) of the treatment strategies to the potential benets of improved long-term outcomes. We should continue to evaluate the relationship to outcome of all monitoring modalities NIRS, pulse oximetry, blood pressure, capnographyto use the technologies only where they add value, recognizing the potential to harm by inappropriate intervention or nonintervention. Future studies might use both the pressure and oxygenation dimension to better characterize circulatory status and identify risk conditions. The current evidence of NIRS monitoring in human studies over the past decade is consistent with class II recommendations according to the American Heart Association and the American College of Cardiology Task Force on Practice Guidelines. The lack of randomized, blinded, interventional trials that study the impact of NIRS as a hemodynamic monitor along with some studies reporting equivocal outcomes associated with NIRS classies the evidence at level B. Specically, NIRS appears to have a favorable risk benet prole and can be effective and benecial as a hemodynamic monitor for the care of critically patients.
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Biomonitors of cardiac injury and performance: B-type natriuretic peptide and troponin as monitors of hemodynamics and oxygen transport balance
Michelle Domico, MD; Paul A. Checchia, MD, FCCM, FACC
Serum biomarkers, such as B-type natriuretic peptide and troponin, are frequently measured in the cardiac intensive care unit. A review of the evidence supporting monitoring of these biomarkers is presented. Design: A search of MEDLINE, PubMed, and the Cochrane Database was conducted to nd literature regarding the use of B-type natriuretic peptide and troponin in the cardiac intensive care setting. Adult and pediatric data were considered. Results and Conclusion: Both B-type natriuretic peptide and troponin have demonstrated utility in the intensive care setting but there is no conclusive evidence at this time that either biomarker can be used to guide inpatient management of children with cardiac disease. Although B-type natriuretic peptide and troponin concentrations can alert clinicians to myocardial stress, injury, or hemodynamic alterations, the levels can also be elevated in a variety of clinical scenarios, including sepsis. Observational studies have demonstrated that perioperative measurement of these biomarkers can predict postoperative mortality and complications. Recommendation and Level of Evidence: (class IIb, level of evidence B): The use of B-type natriuretic peptide and/or troponin measurements in the evaluation of hemodynamics and postoperative outcome in pediatric cardiac patients may be benecial. (Pediatr Crit Care Med 2011; 12[Suppl.]:S33S42) KEY WORDS: B-type natriuretic peptide; biomarkers; cardiac disease; hemodynamics; troponin
biomonitor is dened in ecology as any organism that provides quantitative information on the quality of its environment. It is tempting to think that biomonitors could be used to monitor the hemodynamic environment of the patient in a critical care setting. The use of serum measurements of organ injury or dysfunction is utilized in a variety of scenarios in medicine. Biomarkers specic to the cardiovascular system have included cardiac troponin and natriuretic peptides. While these measures have been utilized as markers of injury and dysfunction, it has yet to be determined if they can be utilized as a monitoring strategy
that can guide management decisions in a pediatric critical care setting.
Process
MEDLINE, Embase, PubMed, and Cochrane Database searches were conducted to nd controlled trials regarding the use of heart rate, noninvasive and invasive pressure, end-tidal CO2, and pulse oximetry monitoring. Adult and pediatric data were considered. Guidelines published by the Society for Critical Care Medicine, the American Heart Association, the American Academy of Pediatrics, and the International Liaison Committee on Resuscitation were reviewed, including further review of references cited.
B-Type Natriuretic Peptide

From the Childrens Hospital of Orange County (MD), Orange, CA, David Geffen School of Medicine at the University of California, Los Angeles, CA; and St. Louis Childrens Hospital (PAC), Washington University School of Medicine, St. Louis, MO. Dr. Checchia has received honoraria from MedImmune and Edwards Lifesciences, and grants from Ikaria. Dr. Domico has not disclosed any potential conicts of interest. For information regarding this article, E-mail: pchecchia@wustl.edu Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e318221178d
Over the last decade, B-type natriuretic peptide (BNP) has generated interest as a promising biomarker in the evaluation, management, and treatment of adults and children with a variety of cardiac diseases. The role of BNP and its cleaved inactive metabolite, aminoterminal pro-BNP (NT-proBNP), has been well studied in adults with congestive heart failure (CHF). The utility of BNP in the pediatric population and in critical care units is less well dened. This review
of the evidence will serve as a guideline to augment understanding and interpretation of BNP levels for practitioners of pediatric cardiac intensive care. In 1988, BNP was rst identied in the extracts of porcine brain and originally termed brain natriuretic peptide (1). Subsequent investigations have demonstrated that BNP is a neurohormone secreted predominantly by ventricular myocytes. BNP is synthesized as a larger precursor prohormone (proBNP) of 108 amino acids, which is cleaved into the biologically active BNP (32 amino acids) and an inactive NT-proBNP peptide (76 amino acids) (Fig. 1). The regulation of BNP synthesis and secretion takes place at the transcriptional level on chromosome 1. The main impetus for BNP secretion is increased ventricular enddiastolic pressure and ventricular wall tension (2). BNP is a member of the natriuretic peptide family, which includes atrial natriuretic peptide, BNP, C-type natriuretic peptide, and Dendroaspis natriuretic peptide (2, 3). BNP has similar physiologic activity to atrial natriuretic peptide and exerts its actions through natriuretic peptide receptors A and B, ultimately increasing intracellular levels of cyclic guanosine monophosphate. BNP binds
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Figure 1. Diagram depicting cleavage of prohormone cleaved into an active 32 amino acid structure, B-type natriuretic peptide (BNP), and an inactive amino-terminal pro-BNP fragment, (NT-proBNP).
preferentially to natriuretic peptide receptor A located in the vascular endothelium, brain, adrenal glands, and kidneys (4). The end result of BNP is to promote diuresis, natriuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system (5). Natriuretic peptides also inhibit broblast proliferation and regulate ventricular remodeling (6, 7). Excretion of BNP is via three different mechanisms: internalization and enzymatic degradation facilitated by natriuretic peptide receptor C, cleavage by neural endopeptidases (present in vascular and renal tubular cells), and renal excretion (2, 8). Intrinsic renal dysfunction has been shown to affect BNP concentration; peptide levels increase as glomerular ltration rate decreases (9).
Normal values in children

In the pediatric population, BNP concentration is signicantly related to age, with higher levels in the younger age groups (11). BNP varies widely in the rst few days of life during the transition from fetal to postnatal circulation. Mean BNP levels of 231 pg/mL have been demonstrated in healthy newborns, which markedly declines to 20 pg/mL in early adolescence. In the rst 72 hrs of life, the mean concentration of NT-proBNP can be up to 3183 pg/mL in healthy neonates, decreasing to 70 pg/mL by early childhood. A summary of natriuretic peptide levels in healthy children from various studies is listed in Table 1.
vational cohort studies (2224). The Better Not Pout Children! Study (23) demonstrated that BNP can reliably diagnose signicant structural or functional cardiovascular diseases in children. In neonates with cardiac disease, the median BNP was 526 pg/mL vs. 96 pg/mL for those without disease (p .001). A BNP concentration of 170 pg/mL in neonates yielded a sensitivity of 94% and a specicity of 73%. In older children with cardiac pathology, the median BNP was 122 pg/mL as compared to 22 pg/mL in those without (p .001). Using a value of 41 pg/mL for the older age group, sensitivity and specicity were 87% and 70%, respectively (23). Since symptoms of pediatric cardiac disease are protean, a biomarker alerting the clinician toward a cardiac diagnosis can be very useful. For instance, Koulouri et al (24) reported that BNP helped differentiate between cardiac or pulmonary etiologies in 49 children with acute respiratory distress. They found that patients with CHF (n 23) had BNP levels of 693 pg/mL ( 501.6 pg/mL), signicantly higher than those with lung disease (BNP 45 64 pg/mL [p .001]). A cutoff value of 40 pg/mL demonstrated a positive predictive value of 78% and a negative predictive value of 91% in differentiating CHF from respiratory pathology (24).
BNP concentrations in children with various cardiac conditions

Natriuretic peptide levels vary depending on the structure and severity of the congenital heart lesion. In theory, it seems prudent to use each patient as their own control. BNP concentrations vary among types of defects and at various time points (preoperative vs. postoperative, compensated vs. noncompensated), therefore the absolute number may not be as useful as the overall trend. In general, children with systolic dysfunction tend to have higher BNP levels than children with anatomical cardiac defects. Koulouri and colleagues (24) demonstrated that BNP concentrations were higher in patients with systolic dysfunction than in those with volume overload (1181 487 pg/mL vs. 433 471 pg/mL, p .007). This nding was also supported by Westerlind et al (25), who evaluated 137 children with various types of cardiac defects and found patients with systolic dysfunction to have the highest elevation of BNP (median 613 pg/mL [range 813910 pg/mL]), followed by volPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
Common causes of elevated BNP levels

There are various well-studied conditions that elevate BNP concentration in adults, especially CHF and acute coronary syndrome. BNP is more accurate than any historical feature, physical exam nding, or laboratory value for identifying CHF as the cause of dyspnea (12). The diagnostic accuracy of BNP at a cutoff of 100 pg/mL was 83%, with a negative predictive value of 96%, at peptide levels 50 pg/mL. Other scenarios in which BNP levels are elevated in both adults and children include: pulmonary hypertension, acute pulmonary embolus, acute respiratory distress syndrome, septic shock, and renal failure (1321). Known causes of elevated BNP concentrations are listed in Table 2. The ability of BNP to diagnose significant cardiac pathology in children has been demonstrated in prospective obser-
BNP vs. NT-proBNP

The decision to use BNP vs. its inactive metabolite NT-proBNP for testing is generally based on institutional preference. Although both peptides are produced in equimolar amounts, there are some notable differences in their respective clearances and half-lives. Clearance of BNP is via three different mechanisms as mentioned above, while evidence suggests that NT-proBNP is cleared solely by passive renal excretion (8). During periods of cardiac strain, BNP levels are elevated within 212 hrs (10), enabling BNP to measure rapid changes, whereas NT-proBNP can assess changes over a longer period of time (5). NT-proBNP is biologically inert with a more stable halflife of 12 hrs, where BNP has a half-life of approximately 20 mins (5).
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Table 1. Values of B-type natriuretic peptide (BNP) and amino-terminal pro BNP (NT-proBNP) in healthy neonatal and pediatric populations Number of Patients (Age Range) 34 (136 months) 70 (3 days6 years) 190 (116 years) 195 (0 days17 years)
Study Walsh et al 2008 Maher et al 2008 Zhang et al 2006 Koch et al 2006
Cardiac Peptide BNP BNP BNP BNP
Results 105 78 pg/mL range 17.4 pg/mL (mean); 5174 pg/mL range 51.9 46.3 pg/mL range 231 pg/mL (mean): 01 days 48.6 pg/mL (mean): 26 days 8.3 pg/mL (females), 8.5 pg/mL (males) mean: 10 years 12.1 pg/mL (females), 5.1 pg/mL (males) mean: 10 years 35.5 pg/mL (median); 10289 pg/mL range 57 pg/mL (mean); 14157 pg/mL rangea 202 pg/mL (mean): 09 yearsa 151 pg/mL (mean): 1014 yearsa 98 pg/mL (mean): 1519 yearsa 3,183 pg/mL (mean); 26013,224 pg/mL range: 02 days 2,210 pg/mL (mean); 287,250 pg/mL range: 311 days 141 pg/mL (mean); 51,121 pg/mL range: 112 months 129 pg/mL (mean); 31675 pg/mL range: 12 years 70 pg/mL (mean); 5391 pg/mL range: 26 years 52 pg/mL (mean); 5391 pg/mL range: 614 years 34 pg/mL (mean); 5363 pg/mL range: 1418 years
Koch et al 2006 Eerola et al 2009 Mir et al 2006 Nir et alb 2009
46 (0.417 years) 64 (0.615 years) 332 (019 years) 690 (018 years)
NT-proBNP NT-proBNP NT-proBNP NT-proBNP
converted from fmol/mL to pg/mL; bpooled data from four separate studies.
Table 2. Known causes of elevated serum B-type natriuretic peptide concentration Cardiac Etiology Congestive heart failure Acute coronary syndrome Cardiomyopathy Myocarditis Congenital heart disease Kawasaki disease Atrial brillation/utter Diastolic dysfunction/restrictive physiology Anthracycline toxicity Acute rejection in transplanted hearts Noncardiac Etiology Sepsis/septic shock Pulmonary embolus Pulmonary hypertension Acute respiratory distress syndrome Pneumonia Chronic obstructive pulmonary disease with cor pulmonale Sleep apnea Renal failure Hyperthyroidism Dexamethasone administration Anemia
4 167 pg/mL] vs. mean 57 pg/mL [range 14 157 pg/mL], respectively) (30).
Plasma BNP and pulmonaryto-systemic blood ow ratio

Since BNP is elevated in volume overload lesions, it is logical to question whether levels reect the degree of highoutput heart failure, i.e., pulmonary-tosystemic blood ow ratio (Qp/Qs). Kunii and colleagues (31) explored this possibility in 154 children with volume-loaded lesions. Serum BNP correlated signicantly with Qp/Qs values measured in the catheterization lab in 91 children with a ventricular septal defect (r .75, p .0001), in 29 with a PDA (r 089, p .0001), and in patients with an atrial septal defect (r .69, p .001). A cutoff BNP level of 40 pg/mL corresponded to a Qp/Qs of 2:1, with a sensitivity of 88% and specicity of 76% (31). This nding was corroborated by Suda et al (32), demonstrating a signicant positive correlation between BNP levels and Qp/Qs (r .65) in 59 children with a ventricular septal defect.
ume overload lesions (i.e., ventricular septal defect, atrial septal defect, or patent ductus arterious [PDA]), with median BNP concentration of 29 pg/mL (range 5352 pg/mL). Children with pressure overload lesions (i.e., aortic or pulmonic stenosis) had only slightly higher elevations than controls (median 17 pg/mL [range 0 315 pg/mL] vs. 4 pg/mL [range 0 17 pg/mL]) (25). BNP levels are higher when the volume overload is at the level of the ventricles (dilated cardiomyopathy patients) as compared to the atria (mitral stenosis patients), with levels of 333 405 pg/mL vs. 147 54 pg/mL, respectively (p .01) (26). Diastolic dysfunction also produces elevated BNP levels, but not to the same degree as systolic dysfunction (2729). Perhaps the ventricular hypertrophy that accompanies diastolic dysfunction does not permit the stretch stimulus for BNP, only the strain.
NT-proBNP levels follow similar trends as BNP. Eerola et al (30) examined serum NT-proBNP levels in 128 children with different types of loading conditions, including atrial septal defect (right-sided volume load lesion), PDA (left-sided overload), coarctation of the aorta (pressure load), and children with Mulibrey nanism (restrictive cardiomyopathy). The highest levels of NT-proBNP were seen in children with Mulibrey nanism (mean 280 pg/mL, range 18 9170 pg/mL), followed by left-sided overload lesion (PDA), producing levels ranging from 31 to 6027 pg/mL (mean 154 pg/mL). NT-proBNP concentrations were lower in right-sided volume load lesion (mean 90 pg/mL, range 5 458 pg/mL). Interestingly, in this particular study, patients with leftsided pressure load (coarctation of the aorta) did not have a statistically signicant elevation of NT-proBNP as compared to controls (mean 50 pg/mL [range
The single-ventricle patient and BNP

Lechner and associates (33) studied 78 single-ventricle patients with a bidirectional cavopulmonary anastomosis to obtain baseline NT-proBNP concentrations. Thirty-one of those children had CHF (based on the New York University
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Pediatric Heart Failure Index score), and all had signicantly elevated NT-proBNP levels (median 670 pg/mL, range 29039,763 pg/mL) vs. bidirectional cavopulmonary anastomosis patients without CHF (median 171 pg/mL, range 32355 pg/mL) (33). It has been postulated that after bidirectional cavopulmonary anastomosis, children with univentricular defects and without signs of heart failure have intrinsic dysfunction in the natriuretic peptide system, since their BNP concentrations are nearly equivalent to healthy children. Natriuretic peptide system dysfunction in patients with a single ventricle may be related to hypoplastic ventricular development (34); however, when in failure, univentricular patients are able to increase BNP synthesis and secretion. Evidence for this was provided by Nozohoor and colleagues (35), who reported that a doubling of plasma BNP was associated with an odds ratio for heart failure of 2.17 (95% condence interval 1.10 to 4.3, p .026) in patients with a single ventricle. Law et al (36) also demonstrated elevated BNP concentrations (mean 714 912 pg/mL) in singleventricle patients with symptomatic heart failure (n 18) as compared to those (n 8) with no heart failure (mean 22 12 pg/mL, p .001).
uretic peptide levels provide powerful information, predicting adverse outcomes and mortality in adult patients with acute coronary syndrome, cardiogenic shock, critical illness, and after coronary artery bypass grafting (46 50). There are also adult data demonstrating that a high predischarge BNP concentration ( 700 pg/mL) is a strong, independent predictor of death or readmission after decompensated CHF (51). Although the pediatric literature is not as robust, preoperative NT-proBNP levels correlate with postoperative inotrope score, duration of mechanical ventilation, and duration of intensive care unit (ICU) stay, hence showing promise as a prognostic predictor for children undergoing cardiac surgery (5254). New evidence suggests that the biological activity of the natriuretic hormone system may be transiently decreased following cardiopulmonary bypass, but the mechanism is unknown (55). Nonetheless, postoperative BNP concentrations are useful after cardiopulmonary bypass; correlating with duration of cardiopulmonary bypass, postoperative inotrope score, presence of low cardiac output syndrome, cardiac index, duration of mechanical ventilation, and hospital length of stay in neonates and children with a variety of congenital heart defects (11, 55 64).
are needed to identify the utility of BNP as an adjunctive marker to determine extubation readiness.
Therapy targeted to BNP concentration

Natriuretic peptide-guided therapy has been shown to signicantly reduce all-cause mortality in patients with CHF as compared to usual care in both the outpatient and inpatient setting (67 69). A BNP level of 300 pg/mL in pediatric outpatients with chronic left ventricular heart failure increased the risk of having an adverse cardiovascular event (such as cardiac death or cardiac-related hospitalization) within 90 days (adjusted hazard ratio 63.6; p .0001) (40). Unfortunately, there are no data to suggest that BNP-guided therapy can alter outcome in children with anatomical cardiac defects. Unlike adults, the pathophysiology in the pediatric cardiac ICU is diverse, including systolic dysfunction, diastolic dysfunction, and volume or pressure overload of either ventricle and/or atria.
Limitations
The use of BNP measurements are handicapped by a wide variety of clinical scenarios in which natriuretic peptide levels can be elevated, including cardiac pathology, lung disease, and septic shock. Therefore, increased BNP concentrations should be interpreted with caution and practitioners should consider the clinical situation in total, rather than focus solely on cardiac pathology.
BNP as a surrogate marker for other hemodynamic measurements

Several pediatric studies mirror the adult experience and report an inverse correlation between BNP levels and left ventricular ejection fraction in a variety of clinical scenarios (18, 21, 37 41). Circulating levels of BNP have also been shown to correlate with mean pulmonary arterial pressure and pulmonary vascular resistance (13, 32, 42). Overall, there are no adequate data to support the utility of BNP as a surrogate marker for hemodynamic measurements, with the exception of ejection fraction as measured by echocardiography.
BNP in the periextubation period

Cardiopulmonary interactions are of vital importance in the cardiac ICU. Positive pressure ventilation is highly benecial to a compromised systemic ventricle. Conversion from positive pressure ventilation to negative pressure ventilation following extubation increases afterload on the left ventricle (65) and may be a difcult transition for cardiac patients. A few small studies suggest that BNP may be a useful adjunct to predict success of extubation in patients with possible cardiovascular instability. Chien and colleagues (66) evaluated BNP concentration along with a spontaneous breathing trial in adults recovering from acute respiratory failure and concluded that measuring the percentage change in BNP may improve weaning outcome. Berry and associates (63) noted that BNP levels increased within 48 hrs of extubation in 12 of 13 patients after the Norwood procedure. This could be a reection of the cardiopulmonary stress extubation elicits on the systemic ventricle. Further studies
Conclusion for BNP

BNP is a useful adjunctive biomarker in children with cardiac pathology. This biomarker can be elevated in several conditions, such as systolic dysfunction, diastolic dysfunction, and various congenital heart defects causing volume and/or pressure load on the heart. There is evidence to support that BNP concentrations parallel Qp/Qs measurements and inversely correlate with ejection fraction. A recent application for natriuretic peptides is measurement in the perioperative period to prognosticate morbidity and mortality in cardiac surgical patients. Further studies are required in children to dene the role of natriuretic peptides in the perioperative setting. Current pediatric evidence suggests that BNP levels are related to postoperative complications,
The utility of plasma BNP levels in the perioperative setting

There is strong evidence (level 1 A) in the adult population supporting elevated preoperative BNP or NT-proBNP measurement as an independent predictor of mortality and major adverse cardiovascular events following vascular and noncardiac surgery (43 45). Preoperative natriS36
such as prolonged duration of mechanical ventilation and hospital length of stay. Future studies in the cardiac ICU evaluating preoperative, postoperative, and predischarge BNP levels while trending these values in an individual patient may help prognosticate outcome. This neurohormone may prove to be invaluable as a diagnostic tool and therapeutic agent in the future of pediatric cardiac intensive care.
Cardiac Troponin
The myocardial sarcomere is composed of the contractile proteins myosin, tropomyosin, and the troponin complex. The cardiac troponin (cTn) complex is made up of three distinct subtypes: troponin C, troponin I, and troponin T. Together, this complex controls the interaction of the thick and thin laments and, ultimately, muscular contraction. Specically, calcium binds to the troponin C subunit, resulting in a conformational change allowing actin-myosin cross-bridge formation. The utility of troponin as a marker of myocardial injury stems from its origin specically from cardiac muscles. While the troponin complex is found throughout all muscle cells, the I and T subunits found in the cardiac myocyte are immunologically distinct from their skeletal muscle forms. The N-terminus amino chain is unique in the cardiac subunits and has resulted in the development of monoclonal antibodies as markers in the serum of patients (70 73). The sensitivity and specicity of both the I and T isoforms are similar except for their detectable half-lives (74).
most diagnostically sensitive and specic biomarkers of myocardial injury (82 84). Based on this sensitivity and specicity prole, cTn is recommended for the diagnosis of acute myocardial infarction by the National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines, and the International Committee of Experts in Epidemiology, Pathology, Clinical, and Laboratory Medicine (85 87). Serial sampling, including a baseline sample and follow-up examination 8 to 12 hrs after symptom onset, is recommended (88). Although cTnI is cleared more quickly from the circulation than cTnT, both isoforms remain elevated in the serum for several days after injury, allowing for diagnostic conrmation even in patients presenting with delayed symptoms. For similar reasons, its utility as a monitor of ongoing cardiac injury is limited.
Troponin in pediatrics
There are specic issues related to the use of troponin measurements in the pediatric population. The fetal heart contains two cTnI isoforms: the adult cTnI and an isoform similar to one found in adult slow-twitch skeletal muscle. The latter, which is predominant in the fetus, is replaced with maturation, so at term, only the adult cTnI is detectable (89). Troponin concentrations in normal children are higher in the rst year of life, being highest after birth, and gradually decreasing to adult concentrations toward the end of the rst year (90, 91). These ranges appear to require at least one standard deviation above the normal reference range, depending on specic assay characteristics. Additionally, troponin measurements in the perinatal period and in premature infants may be limited by these issues (9297). These factors reinforce the recommendation for serial measurements in the neonatal period.
Troponin in cardiac injury

Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are released as a result of myocardial cell injury and are highly sensitive and specic markers of myocardial damage (75). As early as 1981, studies suggested that troponin subunits are released from the endocardium of the infarcted region relatively early (4 hrs after coronary artery occlusion) in patients with myocardial infarction (76). This nding prompted some studies to suggest the use of cTn as a clinically important marker of cardiac injury and infarction (77 81). cTn measurements are superior to that of creatine kinase MB, with higher sensitivity and specicity (70, 77). Several studies in the adult patient population have shown that cTnI and cTnT are the
Troponin in nonischemic cardiac conditions

Critically ill patients may have elevated cTn levels in various nonacute coronary syndrome disorders (98 104). Several studies have demonstrated that the presence of elevated troponin levels in critically ill septic patients predicts the presence of myocardial dysfunction and an increased mortality rate (105, 106). In a study of 37 consecutive patients with
septic shock (107), the 16 (43%) patients with elevated serum cTnI had a signicantly lower ejection fraction and significantly higher mortality than the others. Preexisting coronary artery disease and demand ischemia could account for cTn release in sepsis. However, it has been shown that cTn release can also occur in patients in whom signicant coronary artery disease has been excluded with sensitive methods (98). Babuin et al (100) evaluated the shortterm and long-term prognostic value of measurement cTnT levels in 1,657 medical ICU patients. Admission (within 6 hrs) cTnT measurement of at least 0.01 g/L was considered elevated. Positive cTnT levels were available in 929 (56.1%) patients, of which 570 (61.4%) had elevated levels. During hospitalization, 12.5% of patients with negative cTnT died, compared with 29.5% with elevated cTnT. Mortality rate at 30 days was 13.7% in patients with negative, compared with 34.6% in patients with positive, cTnT. The expected probability of mortality at 1-yr, 2-yr, and 3-yr follow-up was higher in patients with elevated cTnT. After adjustment for severity of illness using the Acute Physiology and Chronic Health Evaluation III prognostic system, positive cTnT levels were independently associated with in-hospital, and short- and long-term mortality. Interestingly, the prognostic value of cTnT elevations was similar (or even slightly better) in patients with noncardiovascular etiologies of their acute illness and in patients who were less ill according to Acute Physiology and Chronic Health Evaluation III. Elevated cTnT was associated with shortterm and long-term mortality, indicating that even after successful treatment and discharge, there still may be opportunities to improve outcomes if mechanisms responsible for the cardiac injury are identied. These data further support published studies that underlined the prognostic impact of elevated cTn in different settings of critically ill patients (108 112). In another study of 46 patients with septic shock, increased plasma concentrations of cTnI and cTnT were found in 50% and 36% of patients, respectively (113). Left ventricular functional assessment revealed that both cTnI and cTnT were exclusively associated with left ventricular dysfunction (p .0001). However, the usefulness of elevated troponin levels in identifying septic patients with myocardial dysfunction is limS37
ited, since many other conditions commonly observed within the ICU, such as acute coronary syndrome, acute kidney injury, and pulmonary embolism, are also associated with an increase in troponin levels (75). As such, there is no evidence to support the use of inotropes in patients with elevated troponin levels in an effort to enhance myocardial performance. Indeed, this approach may be harmful (114). Nevertheless, an elevated troponin level in the critically ill is associated with an adverse prognosis irrespective of the underlying cause (98, 108, 115, 116). Fenton et al (101) demonstrated increased cTnI in children with septic shock admitted to a pediatric ICU, a nding similar to studies in adults (105, 106, 117). Other pediatric data have shown that children with meningococcal septic shock had a signicant increase in cTnI (118). In another series of children with meningococcal sepsis, Thiru and colleagues (119) found that cTnI was increased at admission to a degree similar to that we have found in septic shock (24% at admission, 62% within the rst 2 days of illness), but ischemic heart disease was not excluded in these children. Additionally, troponin elevation has been demonstrated in children with a septiclike picture associated with respiratory syncytial virus infection (120, 121).
match. It is possible that smaller, immunoreactive troponin fragments are cleared by the kidney, but this remains to be claried. Improvement in renal function after renal transplant does not appear to alter the occurrence of elevated serum troponin (126). Even if the kidneys were partially responsible for troponin clearance, it does not explain why troponin is released from the heart. During myocardial necrosis, the elimination rate and apparent half-life of serum cTnI is not signicantly different in patients with normal renal function or end-stage renal disease (127). Additionally, preliminary results from Western blot analysis fail to implicate renal tissue as the source of serum cTnT in patients with renal failure (128). Notably, it has been repeatedly conrmed that troponin T is a powerful death predictor, and a recent metaanalysis has nicely shown that high troponin T ( 0.1 ng/mL) conveys a 2.6 times higher risk of death in asymptomatic dialysis patients (129).
Troponin in perioperative cardiac patients

Increased cTn has been reported to occur after virtually every open-heart surgery (70, 130, 131). However, release of cTn in the postoperative cardiac setting may not only reect acute myocardial infarction related to coronary syndromes, but could also result from myocardial cell injury attributable to incomplete myocardial protection, reperfusion injury, unavoidable surgical trauma, intramyocardial vessel manipulation, and debrillation (132, 133). Previous studies demonstrated that all children with intracardiac surgery showed a postoperative increase in cTnT. Children with extracardiac surgery of the great vessels showed no postoperative increase of cTnT (134). Increases in creatine kinase MB and cTnT have been reported to be about ve times greater than those previously reported in adult patients (135). The association between increased postoperative troponin release and clinical postoperative outcomes is controversial (136 140). Nesher et al (139) found that moderate elevations in troponin are common after cardiac operations in adults, and specically, a cTnT level exceeding eight times the upper limit of normal ( 0.8 g/L) was found to be an independent predictor of increased major adverse cardiac events. Mildh et al (141), using a forward stepwise logistic regres-
sion, showed that troponin T measured on the rst postoperative day was a strong independent predictor of death at 30 days. Levels of troponin T 5.9 /L on the rst postoperative day predicted death, as did an admission lactate level 5.2 mmol/L. No other variable, including postoperative creatine kinase MB concentration, age, diagnosis, surgical procedure, presence of cyanosis, chromosomal anomaly or ventriculotomy, duration of cardiopulmonary bypass, or aortic cross-clamp, had any independent effect on 30-day survival. Additionally, Lipshultz et al (142) demonstrated an association between a score of increasing surgical severity and the mean level of postoperative cTnT. Postoperative cTnT levels were signicantly elevated in children who completed cardiovascular surgery with an open chest compared with those with a closed chest. In addition, cTnT levels before cardiovascular surgery predicted postoperative survival. Finally, perioperative troponin measurements have been used as a gauge of therapeutic success with a variety of intraoperative protocols (142148).
Recommendation and Level of Evidence Class IIb, level of evidence B

The use of BNP and/or troponin measurements in the evaluation of hemodynamics in pediatric patients may be considered and may be benecial.
Troponin and renal disease

In apparently asymptomatic, stable dialysis patients, multivessel coronary artery disease diagnosed by angiography is more prevalent with progressively greater quartiles of troponin (122), and it is a strong predictor of death and cardiovascular events. It is unlikely that elevated serum troponin is the result of decreased clearance by the failing kidney. Free troponin T and bound troponin T are relatively large molecules (37 and 77 kDa, respectively), similar in molecular weight to albumin (60 kDa), making it improbable that the kidney would be responsible for their clearance. Creatine kinase and its isoforms are of similar size and are mainly cleared by the reticuloendothelial system (123), whereas myoglobin is smaller (18 kDa) and cleared by the kidney (124). Indeed, in asymptomatic hemodialysis patients, troponin T rises in parallel with left ventricular mass and mirrors declining left ventricular systolic function (125). These relationships probably reect subtle myocardial cell ischemia brought about by perfusion misS38
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Lactate and acid base as a hemodynamic monitor and markers of cellular perfusion
Meredith Allen, MB, BS, FRACP, FRCPCH, PhD
Background: The intra- and postoperative monitoring of lactate and acid-base has been advocated in pediatric cardiac critical care as surrogate markers of cardiac output, oxygen delivery, and cellular perfusion. Many clinicians use lactate and base excess routinely as markers of tissue perfusion and to assess the effectiveness of their intervention. This review discusses the strengths and weaknesses of using these measurements in pediatric cardiac critical care. Methodology: A search of MEDLINE, EMBASE, PubMed, and the Cochrane Database was conducted to nd controlled trials of lactate and base excess. Adult and pediatric data were considered. Guidelines published by the Society of Critical Care Medicine, the American Heart Association, the American Academy of Pediatrics, and the International Liaison Committee on Resuscitation were reviewed including further review of references cited. Results and Conclusions: Many factors other than tissue hypoxia may contribute to hyperlactemia in critical illness. Although the presence of hyperlactemia on admission appears to be associated with intensive care unit mortality and morbidity in some retrospective analyses, signicant overlap between survivors and nonsurvivors means that nonsurvivors cannot be predicted from admission lactate measurement. Persistently elevated postoperative lactate is associated with increased morbidity and mortality in the pediatric cardiac population. To date there is no randomized control trial of goal-directed therapy in adult or pediatric cardiac care that includes normalization of lactate as a target. Overall equivalent time measurements of base excess, anion gap, and pH have a low predictive value for morbidity and mortality in children after cardiac surgery. Lactate is one of a cluster of markers of cellular perfusion and oxygen delivery. Alone, as a single measurement, it has minimal predictive value and is nondiscriminatory for survival. (Pediatr Crit Care Med 2011; 12[Suppl.]:S43S49) KEY WORDS: lactate; base excess; biomarkers; cardiac output; cell perfusion; oxygenation
linical and hemodynamic parameters such as heart rate, blood pressure, toe-core temperature difference, urine output, and central venous pressure are unreliable or late signs of inadequate tissue perfusion and hence their use is limited in guiding timely therapy. An ideal biomarker would identify states of diminished cardiac output/oxygen delivery before hemodynamic instability, facilitating early therapeutic intervention and improving patient outcome. The intra- and postoperative monitoring of lactate, acid-base, and mixed venous oxygenation (SvO2) have been advocated in pediatric cardiac critical care as surrogate markers of cardiac output, oxygen delivery, and cellular perfusion.
Many clinicians use lactate and base excess routinely as markers of tissue perfusion and to assess the effectiveness of their intervention. This review discusses the strengths and weaknesses of using these measurements in pediatric cardiac critical care.
Lactate Shuttle
Lactate (2-hydroxypropanoic acid) was rst discovered in 1780 (1) in samples of sour milklacticand rst isolated from the blood of two women who died from puerperal fever in 1843 (2). An intermediary of carbohydrate metabolism, lactate is formed from pyruvate by lactate dehydrogenase in the nal step of glycolysis (Fig. 1). Under normal aerobic conditions, lactate is constantly being produced and consumed (metabolized) by cells in the body. The majority of lactate produced (70% to 75%) is converted back to pyruvate by oxidation (Fig. 2) in the mitochondria with a smaller percentage (20%) providing the predominant precursor for glyconeogenesis. The production (glycolysis), exchange (oxidation), and use (gluconeogenesis) of lactate within or between cells is known as
the lactate shuttle and believed to represent a form of cell cell signaling (3). Normal circulating lactate levels in the body are 1.5 mmol/L and 2 mmol/L in critical illness. It is normally produced in skeletal muscle (fast-glycolytic type IIB bers), brain, renal medulla, and red blood cells and metabolized by the liver (50%), renal cortex (20%), skeletal muscle (slow-oxidative type I bers), heart, and brain (4). At very high levels, lactate is actively excreted by the kidney.
Critical Illness
During critical illness, plasma lactate levels can be increased by a number of mechanisms; only some of these represent cellular hypoperfusion (Table 1). The distinction between hypoxic or nonhypoxic production of lactate is critical for the correct interpretation of lactate values and selection of appropriate therapy. Although initially thought to be exclusively the result of tissue hypoxia, hyperlactemia in critical illness may also result from reduced lactate clearance relative to production during critical illness or accelerated aerobic glycoS43
From Paediatric Intensive Care and the SPRinT Program, Royal Brompton Hospital, London, UK. The author has not disclosed any potential conicts of interest. For information regarding this article, E-mail: meredith.allen@rch.org.au Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3182211aed
lysis that exceeds the oxidative capacity of mitochondria (e.g., cytokine or catecholamine-driven) (5, 6).
Lactate after cardiopulmonary bypass and cardiac surgery

Although lactate is normally extracted from the circulation by the myocardium as a cellular fuel (7, 8), in the setting of surgical trauma, lactate extraction decreases (9) and production is increased as a result of anaerobic glycolysis. Lactate release from the infant myocardium has been shown to be greater after crystalloid cardioplegia compared with blood cardioplegia (10). Studies show a delay of 30 40 mins between release of a cross-clamp/reperfu-
sion and reduction in lactate release by heart muscle into the coronary sinus, suggesting that, after ischemia, anaerobic cellular metabolism within the myocardium continues for some time (10). With restoration of blood ow, a washout of lactate from regional tissues has been shown to occur in animal and human models, especially from the coronary and renal circulations (11, 12). A paradoxic increase in blood lactate concentration after the release of the aortic cross-clamp or completion of surgery may reect improvement rather than deterioration of cellular perfusion; however, high or sustained levels of lactate should not be accredited to washout. Pulmonary lactate levels rise signicantly after exposure to surgical trauma and cardiopulmonary bypass and may contribute signicantly to circulating lactate levels up to 6 hrs postoperatively (13,14). Although pulmonary lactate levels have not been shown to correlate with cardiopulmonary bypass time, a statistically signicant correlation has been shown between pulmonary lactate release and postoperative alveolararterial oxygen gradient (13).
Lactate and cellular hypoxia

Figure 1. Lactate oxidation. Lactate is converted to pyruvate in the presence of cytosolic or mitochondrial lactate dehydrogenase by oxidation.
Under hypoxic conditions or if the rate of cellular glycolysis exceeds the mito-
chondrial capacity, pyruvate is converted to lactate in the cytosol (through lactate dehydrogenase) to regenerate NAD and support continued adenosine-5 -triphosphate regeneration from glycolysis. Although less energy-efcient than mitochondrial respiration, this adaptive process maintains cellular energy (Fig. 3). The metabolic acidosis observed with this process is caused by the increased cellular reliance on nonmitochondrial adenosine-5 -triphosphate turnover. An increase in circulating lactate in critically ill patients in the setting of supply dependency may be viewed as a positive feature indicating the presence of functioning adaptive metabolic pathways. With timely correction of cellular perfusion, there is restoration of mitochondrial respiration and minimal cell death is seen in affected organs. However, if cellular hypoxia persists, apoptosis and necrosis occur and organ failure emerges (15, 16). With cell death, lactate production may cease and plasma lactate levels may fall (provided clearance is not impaired). High circulating levels of lactate can be divided into two groups according to the following etiology: 1) type A: increased lactate secondary to reduced cellular perfusion/hypoxia. Lactate production is in excess of pyruvate and lactate: pyruvate ratio increases; and 2) type B: conditions that increase the amount of lactate in the blood unrelated to a decreased availability of oxygen. Pyruvate synthesis increases in proportion to lactate and ratio remains normal (10:1). In cardiac critical care, hyperlactemia may be the result of a combination of both type A and type B etiologies.
Prognostic Signicance of Early Postoperative Lactate

Protagonists of lactate measurement in critical illness have suggested that lactate levels reect the degree of global tissue anoxia, thus acting as a marker of organ damage and eventual outcome. There are many studies that show an association between plasma lactate levels and subsequent mortality/morbidity in critically ill adults, children, and neonates (16 27). Many of these are in the pediatric cardiac population (20, 23, 28 36). For lactate to have a practical use during the early postoperative period, it has to have a high predictive value. The positive predictive value of a high admission lactate for postoperative mortality is supported by some single-center retrospecPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
Figure 2. Cellular respiration. Glycolysis is the rst part of aerobic (and anaerobic) respiration and takes part in the cytosol. Lactate is formed from pyruvate in the nal step of glycolysis. The predominant monocarboxylate entering the mitochondrial intermembrane space is lactate. Entry of lactate and pyruvate into the mitochondrial matrix is facilitated by monocarboxylate transporters. Lactate is then oxidized to pyruvate through mitochondrial lactic dehydrogenase. In the presence of oxygen, pyruvate enters the Krebs cycle to generate cellular energy by mitochondrial respiration.
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Table 1. Mechanism of increased plasma lactate levels in critical illness Inhibition of mitochondrial respiration Inhibition of mitochondrial respiration White blood cell production Anaerobic Hypoxiasystemic (66), regional (67), or microcirculatory Lactate is produced from pyruvate by cells functioning in reduced oxygen conditions provided cells are supplied with sufcient glucose Impaired activity of pyruvate dehydrogenase is seen with sepsis (12, 6871), thiamine deciency (72) Drugs that induce mitochondrial cytopathy or inhibit oxidative phosphorylation White blood cells, when activated by endotoxin, produce large amounts of lactate by anaerobic glycolysis (81) Although generated by anaerobic metabolism, this increase in lactate is not the result of hypoxia In inammatory processes 3 large amounts of lactate may be produced without tissue hypoxia Liver dysfunction (74) Maturation of liver enzymes may in part explain high lactate concentrations seen in perinatal studies (72) Blood lactate levels are normal in very severely impaired liver patients; therefore, production must be high in addition to impaired clearance Cytokines increase in aerobic glycolysis resulting in levels of pyruvate that exceed the oxidative capacity of mitochondria (pyruvate dehydrogenase capacity) (75) 1Pyruvate concentration drives lactate production and lactate:pyruvate ratio remains normal Epinephrine increases glycogenolysis, glycolysis and stimulates Na K adenosine triphosphatase membrane ion pump (76,77) Epinephrine has been shown to increase plasma lactate levels under fully aerobic conditions in healthy control subjects at rest and during exercise (78,79) oradrenaline does not have these effects (80) Hyperglycemia results in increased production of pyruvate through aerobic glycolysis that exceeds the oxidative capacity of mitochondria (pyruvate dehydrogenase capacity) Lung has been shown to be an important source of lactate in pulmonary and extrapulmonary disease (12 14,81,82) Probably reects a response to inammatory mediators Alkalosis increases cellular lactate efux via the cell membrane H - linked carrier mechanism (83) Nucleoside reverse transcriptase inhibitors Methanol Biguanides (e.g., metformin) Cyanide Ethylene-glycol Blood not kept on ice or measured immediately may be falsely elevated by in vitro red blood cell lactate production
Aerobic
Anaerobic (but not hypoxic)
2 Lactate clearance
Aerobic
Cytokine-mediated cellular uptake of glucose Catecholamine stimulated
Aerobic
Aerobic
Hyperglycemia Lung production
Aerobic Aerobic
Alkalosis Drugs
Aerobic
Incorrect whole blood processing
Figure 3. Aerobic vs. anaerobic metabolism. Under hypoxic conditions or if the rate of cellular glycolysis exceeds mitochondrial capacity (e.g., catecholamine/cytokine driven), pyruvate is converted to lactate via cytosolic lactate dehydrogenase. This regeneration of NAD enables continued (but less efcient) adenosine-5- -triphosphate generation from glycolysis.
tive studies (19, 28, 3235) but not observed in others (20, 31, 36, 37). Although low lactate levels are highly predictive of survival (97%), high lactate levels have only a modest and variable predictive value for nonsurvival (43%) (20). The limitations of lactate as a predictor reects the fact that hyperlactemia early after cardiopulmonary bypass may represent intraoperative factors, early postoperative tissue oxygen debt, impaired lactate clearance, or a combination of these. Reduced cardiopulmonary bypass ow ( 100 mL/kg/min 1) and oxygen delivery (38), duration of bypass and circulatory arrest, temperature, hematocrit during and after surgery, and host systemic inammatory response have all been shown to affect postoperative lactate (20, 30, 31, 39). In addition, increased catecholamines (intrinsic and extrinsic) may increase glycolysis with increased lactate production beyond the capacity of pyruvate dehydrogenase, independent of the adequacy of cellular perfusion (type B).
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Figure 4. Postoperative lactate levels reect surgical complexity. The study by Hannan et al looked at 155 retrospectively pediatric cardiac patients and plotted postoperative lactate measurements over the rst 48 postoperative hours according to Risk Adjustment for Congenital Heart Surgery (RACHS) category. There was a denable trend in lactate pattern in RACHS category 1 4 vs. 6 with RACHS 1 4 having a steady decline in lactate from admission, whereas RACHS 6 has an initial increase in lactate over the rst 12 hrs and then a decline. Reproduced with permission from Hannan et al (40).
Recommendation. Class IIbAlthough the presence of hyperlactemia on admission appears to be associated with intensive care unit (ICU) mortality and morbidity in some retrospective analysis, signicant overlap between survivors and nonsurvivors means that nonsurvivors cannot be predicted from admission lactate (23, 32) (level of evidence: B).
Relationship Between Lactate and Surgical Complexity

A correlation between Risk Adjustment for Congenital Heart Surgery (RACHS) category and postoperative lactate levels has been shown by a number of studies with more complex surgical procedures having an initial increase in lactate levels over the rst postoperative hours before decline (Fig. 4) (32, 40). Although the receiver operating curve for lactate on admission to the pediatric ICU for predicting survival was slightly better in one study than RACHS alone (area under the curve 0.881 vs. 0.777), the addition of admission lactate level to RACHS score made a minimal impact (area under the curve 0.881 vs. 0.882) (32).
ture, failure of lactate levels to fall to normal values during critical illness had been shown be more predictive of mortality than initial levels (22, 25, 41 43). In sepsis, a reduction in lactime by goaldirected therapy has been shown to be signicantly associated with a reduction in mortality, morbidity, and circulating inammatory biomarkers (43, 44). A failure of lactate to fall over 48 hrs after pediatric cardiac surgery was proposed to have a better predictive value of morbidity and mortality than a single initial lactate level (34, 45, 46). In a small single-center study by Kalyanaraman et al (n 129, mortality rate 4.6%), lactime was shown to be the strongest predictor of mortality (p .03) (46). Although these studies show an association between persistently abnormal lactate levels, inammation, and poor outcome, no causal relationship has been shown. Recommendation. Class IPersistently elevated postoperative lactate is associated with increased morbidity and mortality in the pediatric cardiac population (level of evidence: B).
Lactate as a Target in GoalDirected Therapy

Goal-directed therapy (GDT) uses explicit protocols to target predened physiological or laboratory goals to be achieved in a set time period in an effort to improve outcome. Although GDT is now well established in pediatric and adult sepsis, it has only just started to appear in the pediatric cardiac ICU. The selection of a specic goal must take into account the ease and reliability
Lactate Clearance vs. Admission Lactate as a Predictive Value

Failure of a single lactate level to predict pediatric cardiac surgical outcome in the 1990s resulted in increasing interest in the prognostic value of lactime (time during which the lactate remains elevated 2 mmol/L). In the adult literaS46
of measurement and the association of that goal with improved outcome. Lactate has recently been considered in GDT (44, 4751) with hyperlactemia being a trigger to initiate/escalate therapies that increase oxygen delivery or decrease oxygen demand (44, 48, 5154). Although lactate 4 mmol/L is a trigger for entry into the Surviving Sepsis Campaign, neither the adult 2008 nor pediatric 2007 American College of Critical Care Medicine clinical guidelines include lactate as a target goal (49, 50). In 2010, two randomized control trials in adult ICU populations were published in which lactate was considered a target in GDT. A study of 300 septic patients in a study by Jones et al (47) substituted lactate for SvO2 as the goal in the Surviving Sepsis guidelines. As the third/last resuscitation goal in the protocol, targeting lactate clearance of 10% in the rst 2 hrs was at least as safe and effective as targeting SvO2 of 70% in the resuscitation of sepsis. However, only 10% of patients required escalation of therapy based on lactate clearance (comparable to only 8% in SvO2 group), which is significantly lower than Rivers original study. A study by Jansen et al (53) showed that targeting a reduction of elevated lactate in the early resuscitation of mixed ICU patients was associated with more uid and inotrope administration and reduced hospital mortality (34% vs. 43%). Although both groups were treated with resuscitation measures and physiological targets similar to those in current Surviving Sepsis guidelines, only the lactate group had continuous SvO2 monitoring. Thus, this study leaves it unclear as to whether SvO2 monitoring or lactate levels were the primary driver for the increased therapy. A randomized controlled trial study by Polonen et al was published of GDT targeting both SvO2 70% and lactate 2 mmol/L over the rst 8 hrs of postoperative care of 403 adult cardiac surgical patients (52). The GDT group had a shorter hospital stay (7 vs. 6 days, p .05) but no signicant difference in ICU length of stay. In post hoc analysis, there was reduced organ dysfunction at hospital discharge in the GDT group (1% vs. 5.6%, p .01). Of note, only 57% of the protocol group achieved the SvO2 and lactate targets in the 8-hr study period, whereas a signicant proportion of patients in the control group achieved these same targets (42%) with standard care. To date, no randomized control trial of GDT involving lactate in the postoperative management of pediatric cardiac paPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
tients has been undertaken. This may be in part because monitoring of postoperative lactate has become embedded in our daily practice without prospective proof of clear benet. A study by Rossi et al in (48) 2005 compared the outcome of 710 pediatric cardiac patients (RACHS 1 6) managed with GDT involving lactate against a historical cohort (1995 2001). In the GDT group, blood lactate was measured hourly for the rst 4 6 hrs in neonates and 4 hourly in older children. Escalation of therapy was indicated for persistently abnormal or rising lactate levels. Overall mortality was signicantly different in the GDT cohort compared with historical controls (1.8 vs. 3.7%, p .02) with the greatest difference seen in the neonatal group (3.75 vs. 15%, p .001) and RACHS 4 6 category patients (p .006). However clinical extrapolation from this study should be limited as a result of the use of historical controls and lack of explicit treatment protocol. Recommendation. Class IIbTo date, there is no randomized control trial of GDT in adult or pediatric cardiac care that includes normalization of lactate as a target. There are limited data using a historical cohort for control that suggest escalation of ICU therapy in the setting of persistently abnormal or rising lactate improves mortality in pediatric cardiac critical care patients (level of evidence: B).
(BE) can, in part, be explained using the Stewarts acid-base classication.
Stewarts acid-base classication

Stewart showed that three independent variables control pH: strong ion difference, the partial pressure of carbon dioxide in blood, and the sum of the weak acids and proteins in the plasma. A raised value for strong ion difference is dened as 3 mEq/L. Lactate is an unmeasured anion (UMA) in the Stewart equation. An increased lactate level reduces strong ion difference, which has an acidifying effect. However, in Stewarts model, raised lactate alone does not necessarily result in metabolic acidosis because other simultaneous alterations in UMA, weak acids and proteins (particularly albumin), or partial pressure of carbon dioxide in blood can all inuence pH (60, 64). Some authors have looked at UMA and strong ion difference as alternative markers to lactate as outcome predictors. Considering lactate is an UMA, it is not surprising that studies have shown that UMA make a signicant contribution to acidosis immediately after pediatric cardiac surgery or that UMA increase with surgical complexity (RACHS) and higher postoperative levels have an association with increased risk of major adverse events and patient death (UMA 6 mEq/L; relative risk of mean absolute error, 2.13 [95% condence interval {CI}, 1.33.4]) (37, 65). Like lactate, the majority of patients with elevated UMA had uneventful postoperative courses and no level of UMA has been identied above which the predictive ability is useful. A study by Durwood et al found that admission strong ion difference 3.2 mEq/L was marginally superior to lactate 3 mmol/L or BE 5 mEq/L as a mortality predictor (receiver operating curve, 0.85; [95% CI, 0.74 0.95] vs. 0.71 [95% CI, 0.44 0.98] and 0.73 [95% CI, 0.431], respectively) (64). Recommendation. Class IIIOverall equivalent time measurements of BE, anion gap, and pH have a low predictive value for morbidity and mortality in children after cardiac surgery (19, 29) (level of evidence: B).
a metabolic acidosis. Although hyperlactemia has been frequently associated with metabolic acidosis, this relationship is not causal. Many factors other than tissue hypoxia may contribute to hyperlactemia in critical illness. Failing to recognize the correct etiology of hyperlactemia may result in initiation/ escalation of therapies, which may worsen the hyperlactemia. The presence or absence of coexisting metabolic acidosis is important in distinguishing aerobic from anaerobic hyperlactemia (39, 65). Early recognition of hypoxic hyperlactemia is essential and interventions designed to improve tissue oxygenation (GDT) have been shown to both reduce lactime as well as improve morbidity, mortality, and inammatory biomarkers. Although it might be hypothesized that reducing duration of hyperlactemia improves outcome through minimizing time of tissue oxygen debt and thereby reduce apoptosis and tissue necrosis, this causal relationship has never been shown. Perhaps it is too much to ask a single isolated biochemical measurement to predict the course of a complex critically ill patient. Lactate is one of a cluster of markers of cellular perfusion and oxygen delivery. Alone, as a single measurement, it has minimal predictive value and is nondiscriminatory for survival.
Relationship Among Lactate, pH, and Base Excess in Critical Illness

In critical care, plasma lactate, base excess, and pH often do not appear to be linked (55, 57 62). Metabolic acidosis is associated with differing mortality rates in critical care depending on the etiology (57, 63). Base excess (BE) is a calculated value that estimates the metabolic component of the blood pH. BE and anion gap reect lactate levels only in pure lactic acidosis. Renal failure, pre-existing acidbase disorders, decreased albumin levels, and intraoperative administration of bicarbonate or any other base may alter the specicity and sensitivity of BE (28). Signicant hyperlactemia and tissue hypoperfusion can exist despite lack of acidosis (17, 18). Similarly, many studies have shown that lactate is responsible for only a minor component of the metabolic acidosis in some critically ill patients (60, 64, 65). The weak correlation between hyperlactemia and metabolic acidosis
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CONCLUSION
In pediatric cardiac care, mortality appears to be more closely related to the nature rather than the magnitude (BE) of
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24. Hatherill M, Waggie Z, Purves L, et al: Mortality and the nature of metabolic acidosis in children with shock. Intensive Care Medicine 2003; 29:286 291 25. Bakker J, Gris P, Coffernils M, et al: Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg 1996; 171:221226 26. Howell MD, Donnino M, Clardy P, et al: Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med 2007; 33:18921899 27. Lavery RF, Livingston DH, Tortella BJ, et al: The utility of venous lactate to triage injured patients in the trauma center. J Am Coll Surg 2000; 190:656 664 28. Duke T, Butt W, South M, et al: Early markers of major adverse events in children after cardiac operations. J Thorac Cardiovasc Surg 1997; 114:10421052 29. Basaran M, Sever K, Kafali E, et al: Serum lactate level has prognostic signicance after pediatric cardiac surgery. J Cardiothorac Vasc Anesth 2006; 20:43 47 30. Hamamoto M, Uemura H, Imanaka H, et al: Relevance of the measurement of the concentration of lactate in the serum subsequent to the Fontan procedure in small children. Cardiol Young 2006; 16:275280 31. Munoz R, Laussen PC, Palacio G, et al: Changes in whole blood lactate levels during cardiopulmonary bypass for surgery for congenital cardiac disease: An early indicator of morbidity and mortality. J Thorac Cardiovasc Surg 2000; 119:155162 32. Molina HV, Gonen Y, Vardi A, et al: Blood lactate levels differ signicantly between surviving and nonsurviving patients within the same risk-adjusted classication for congenital heart surgery (RACHS-1) group after pediatric cardiac surgery. Pediatr Cardiol 2010; 31:952960 33. Shemie SD: Serum lactate predicts postoperative complications after pediatric cardiac surgery. Pediatr Res 1996; 39:54 34. Charpie JR, Dekeon MK, Goldberg CS, et al: Serial blood lactate measurements predict early outcome after neonatal repair or palliation for complex congenital heart disease. J Thorac Cardiovasc Surg 2000; 120:73 80 35. Cheifetz IM, Kern FH, Schulman SR, et al: Serum lactates correlate with mortality after operations for complex congenital heart disease. Ann Thorac Surg 1997; 64:735738 36. Hatherill M, Sajjanhar T, Tibby SM, et al: Serum lactate as a predictor of mortality after paediatric cardiac surgery. Arch Dis Child 1997; 77:235238 37. Murray D, Grant D, Murali N, et al: Unmeasured anions in children after cardiac surgery. J Thorac Cardiovasc Surg 2007; 133: 235240 38. Abraham BP, Prodhan P, Jaquiss RD, et al: Cardiopulmonary bypass ow rate: A risk factor for hyperlactatemia after surgical repair of secundum atrial septal defect in children. J Thorac Cardiovasc Surg 2010; 139: 170 173
39. Ranucci M, De TB, Isgro G, et al: Hyperlactatemia during cardiopulmonary bypass: Determinants and impact on postoperative outcome. Crit Care 2006; 10:R167 40. Hannan RL, Ybarra MA, White JA, et al: Patterns of lactate values after congenital heart surgery and timing of cardiopulmonary support. Ann Thorac Surg 2005; 80:1468 1473 41. Meregalli A, Oliveira RP, Friedman G: Occult hypoperfusion is associated with increased mortality in hemodynamically stable, highrisk, surgical patients. Crit Care 2004; 8:R60 R65 42. Vincent JL, Dufaye P, Berre J, et al: Serial lactate determinations during circulatory shock. Crit Care Med 1983; 11:449 451 43. Nguyen HB, Loomba M, Yang JJ, et al: Early lactate clearance is associated with biomarkers of inammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock. J Inamm (Lond) 2010; 7:6 44. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368 1377 45. Robertson CM, Joffe AR, Sauve RS, et al: Outcomes from an interprovincial program of newborn open heart surgery. J Pediatr 2004; 144:86 92 46. Kalyanaraman M, DeCampli WM, Campbell AI, et al: Serial blood lactate levels as a predictor of mortality in children after cardiopulmonary bypass surgery. Pediatr Crit Care Med 2008; 9:285288 47. Jones AE, Shapiro NI, Trzeciak S, et al: Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial. JAMA 2010; 303: 739 746 48. Rossi AF, Khan DM, Hannan R, et al: Goaldirected medical therapy and point-of-care testing improve outcomes after congenital heart surgery. Intensive Care Med 2005; 31: 98 104 49. Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296 327 50. Brierley J, Carcillo JA, Choong K, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666 688 51. Blow O, Magliore L, Claridge JA, et al: The golden hour and the silver day: Detection and correction of occult hypoperfusion within 24 hours improves outcome from major trauma. J Trauma 1999; 47:964 969 52. Polonen P, Ruokonen E, Hippelainen M, et al: A prospective, randomized study of goaloriented hemodynamic therapy in cardiac surgical patients. Anesth Analg 2000; 90: 10521059 53. Jansen TC, van Bommel J, Schoonderbeek FJ, et al: Early lactate-guided therapy in in-
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Echocardiography as a hemodynamic monitor in critically ill children

Darren Klugman, MD, MMS; John T. Berger, MD
Echocardiography is a widely used modality to assess myocardial structure and function in pediatric intensive care settings. While the use of echocardiography for diagnostic purposes remains important, its use as a hemodynamic monitoring tool has not been well established. The benets of echocardiography are in its widespread availability, relative ease of use, and importance in diagnosing structural disease and simple changes in myocardial function. However, echocardiography in pediatric critical care is limited in its use because it requires the acquisition of quality images and the accurate interpretation of the study. To date, the literature on echocardiography in pediatric critical care is limited. The purpose of this review is to examine the scientic evidence for the usefulness of echocardiography as a hemodynamic monitoring tool in pediatric critical care. (Pediatr Crit Care Med 2011; 12[Suppl.]:S50 S54) KEY WORDS: cardiac function; Doppler imaging; echocardiography; hemodynamic monitoring
chocardiography is a modality often utilized for the assessment of myocardial function in the pediatric intensive care unit (ICU) due to its widespread availability, ability to be performed at the bedside, and its noninvasiveness. Further, simple assessments of pericardial uid and myocardial function can be performed by noncardiologists (1). While echocardiography provides excellent information about valvar and other structural abnormalities in children with acquired or congenital heart disease (CHD), and has become the diagnostic test of choice in pediatric cardiology, its use for the ongoing assessment of cardiac function has less utility. In the pediatric or cardiac ICU, many of the factors inuencing cardiac performance are dynamic and thus not tracked well by intermittent echocardiograms. Other limitations include the need for echocardiographic expertise to answer complex questions relating to structure and function, inadequate
acoustic windows, and misinterpretation. Despite its limitations as a real-time monitor, echocardiography remains an important tool to diagnose the presence and etiologies of myocardial dysfunction in critically ill children. The purpose of this manuscript is to examine the scientic evidence for the use of echocardiography as a hemodynamic monitoring tool in pediatric critical care.
FS and EF
FS and EF are two echocardiographic measures of stroke volume. FS is determined using the parasternal short-axis view and is calculated using the enddiastolic dimension (EDD) and endsystolic dimension of the ventricle with the equation: FS (EDD end-systolic dimension)/EDD. Measurements are made using M-mode along a line from the intraventricular septum to the inferolateral wall at the level of the papillary muscles. The advantages of this technique include the interobserver reliability and ease of performance. Since the measurement is made along a single line, regional abnormalities, such as septal dyskinesis and arrhythmias, will greatly affect the measurement. Loading conditions, i.e., preload and afterload, will also affect FS. Increased preload will increase the EDD, falsely elevating FS, while increased afterload will alter systolic dimensions and therefore result in a decreased FS. As preload increases, the EDD will increase and potentially increase the FS; however, this does not reect any positive or negative alteration in intrinsic myocardial function. Further, an increase in afterload may cause early closure of the aortic valve, thus altering end-systolic dimension and falsely decreasing the EF. Echocardiographic assessment in septic shock has demonstrated myocardial dysfunction (2, 4, 5) similar to that which has been shown with more invasive measures (6), and may be useful in patients with septic shock whose management ofPediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)
Two-Dimensional Echocardiography
Many standard two-dimensional echocardiography (2DE) techniques are used to assess ventricular function. The term ventricular function is often used interchangeably to describe both contractility and global myocardial performance; however, these two terms are not synonymous. Contractility is the shortening of sarcomeres, a load-independent measure of myocardial performance, and is only indirectly assessed by echocardiography. Global myocardial performance is inuenced by preload, afterload, heart rate, and contractility. While 2DE can over or underestimate contractility due to frequent changes in a patients preload, afterload, heart rate, and contractility, 2DE can be useful as a diagnostic tool to assess etiologies of cardiac dysfunction, such as hypovolemia, pulmonary hypertension, and structural heart disease (2, 3) (Table 1). The most frequently used parameters to assess systolic function are the ejection phase indices fractional shortening (FS) and ejection fraction (EF).
From the Department of Critical Care Medicine and Cardiology, Childrens National Medical Center, Washington, DC; and Department of Pediatrics, The George Washington University School of Medicine, Washington, DC. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: DKlugman@cnmc.org Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3182211c17
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Table 1. Diagnoses identiable with echocardiography Hypovolemia Infarcts Dilated Cardiomyopathy/Myocarditis Pericardial Disease Pulmonary Hypertension/Acute Right Heart Failure Structural/Congenital Disease
ten includes manipulation of preload and afterload. FS has also been shown to correlate well with alterations in ventricular function related to variations in preload following the arterial switch operation (7, 8). EF is an echocardiographic determination of stroke volume and can be performed using 2DE, M-mode, or threedimensional echocardiography (3DE). The standard echocardiographic view utilized for determination of EF is performed in the apical four- or twochambered view. The recommended method for this calculation is the Simpson or modied Simpson method (9), which divides the left ventricle into cylinders, or disks, and uses the radius and length of the multiple disks measured to calculate a left ventricle volume. Measurements are derived by tracing the left ventricular endomyocardial surface at end diastole and end systole. Limitations of this method include: dependence on an elliptical or bullet-shaped chamber (limiting its use to assessments of the left ventricle only), optimal delineation of the endocardial-blood interface, and potential foreshortening of the left ventricle length. Further, in children with high heart rates, the echocardiogram may not capture the true ends of the cardiac cycle. Despite these limitations, images for EF are easy to acquire and EF accounts for regional wall motion abnormalities. The clinical utility of EF in pediatrics has been established in multiple studies. EF has been used to assess ventricular function immediately following cardiopulmonary bypass, and has correlated well with invasive measures of function longitudinally (10 13). In addition, EF has been shown to correlate with cellular markers of myocardial injury in children with septic shock (5). Due to ease of image acquisition and wide availability, EF and FS should be calculated when assessing baseline left ventricular function (9). However, because of dependence on loading conditions, inuence of ventricular geometry,
Figure 1. Pulsed tissue Doppler mitral annulus. This typical tracing of the mitral annular velocity shows the measurements that can be obtained. Ea represents mitral velocity in early diastole and Aa is the mitral velocity during atrial contraction. The S wave is the mitral velocity during early systole. Its presence above the baseline indicates its reection into the left atrium during ventricular systole. Isovolumic relaxation (IR) and contraction (IC) times are also shown. IR is from the end of the S wave to the onset of the Ea wave, and IC is from the end of atrial contraction to the onset of systolic velocity.
and reliance on angle of acquisition, these measurements should not be used as absolute values. Rather, FS and EF should be interpreted with respect to the clinical condition of the patient and are best used to follow physiologic changes over time.
Tissue Doppler Imaging

Tissue Doppler imaging (TDI) allows for a quantitative assessment of regional and global myocardial function by detecting regional changes in myocardial deformation based on tissue velocities (16). Myocardial deformation is described by strain and strain rate. Strain represents the percent change in the length of a segment of myocardium, and strain rate, the speed at which it occurs. Myocardial deformation has been shown to correlate well with global and regional ventricular contractility in animals (17, 18) and humans (19). TDI is also extremely valuable in assessing diastolic function. Because the myocardium shortens most in a longitudinal plane, TDI is optimally acquired from the apical two- or four-chamber view. During the cardiac cycle, the atrioventricular valve moves toward and away from the apex during systole and diastole, respectively, and there is limited lateral motion of the ventricular myocardium, making these views ideal to assess longitudinal annular velocities of the atrioventricular valve. Two methods of TDI are available: pulsed-wave TDI and color Doppler myocardial imaging. Pulsedwave Doppler interrogation is performed of the myocardium rather than on blood ow. The ultrasound beam is aligned parS51
Velocity of circumferential ber shortening

Velocity of circumferential ber shortening (VCF) is measured during systolic ejection, the only time ber shortening occurs during the cardiac cycle, using the formula: VCF %FS/ejection time. When corrected for heart rate, the variable is termed VCFc, and is preload independent (14). Small single-center studies have investigated changes in VCFc in children following repair of CHD and have demonstrated decreases in VCFc, which likely reect known myocardial depression following cardiopulmonary bypass (7, 8). Further, in pediatric septic shock, VCFc has been shown to reect alterations in cellular dysfunction (5) and loading conditions (2, 15). VCFc is easily performed on standard echocardiographic images and is preload independent, making it preferable to EF and FS in the critical care setting.
allel to the myocardium, and a Doppler interrogation of a small segment of myocardium or atrioventricular valve annulus is obtained. A velocity waveform is generated, which is the peak instantaneous velocity of that segment throughout the cardiac cycle (Fig. 1). While the spatial resolution of this modality is poor, the temporal resolution is high, allowing for the evaluation of brief events, such as isovolumic contraction during systole and isovolumic relaxation during diastole. In children, TDI is useful because it is independent of ventricular geometry and is easily obtained with limited training. However, like all Doppler techniques, TDI is highly dependent on the angle of insonation. TDI has been shown to accurately detect transient changes in right and left ventricular function in children undergoing percutaneous device closure of atrial septal defects (20). Further, in a heterogeneous group of children following cardiopulmonary bypass, TDI accurately reects alterations in myocardial
performance across a range of congenital heart defects (21). Others have shown that postoperative changes in TDIderived indices correlate with myocardial injury and duration of postoperative ventilator days (22). In a single-center trial, TDI was shown to be useful to follow ventricular parameters in patients with single right ventricles through the rst two stages of palliation (23). Longitudinal assessment of changes in ventricular systolic and diastolic performance is also possible with TDI, as shown in studies of patients with repaired tetralogy of Fallot (24,25), transposition of the great vessels (26), and palliated single ventricles (27). TDI has also been shown to demonstrate signicant changes in myocardial function in the immediate post-transplant period (28) and has demonstrated utility in detecting early graft failure (29). In the postoperative and post-transplant period, TDI is a reliable tool to assess myocardial function, and can be used to trend alterations in myocardial function.
Two-dimensional strain echocardiography

During the cardiac cycle, the heart contracts and relaxes in multiple planes, and also has a subtle twisting motion. Two-dimensional strain echocardiography (2DSE) tracks myocardial movement in these planes throughout the cardiac cycle. Tracings of the ventricular endocardial and epicardial surface in the apical four-chamber and short-axis views allow for tracking alterations in velocity and deformation of single myocardial points on the endocardial surface to attain data on strain and strain rate comparable to TDI (30, 31) (Fig. 2). 2DSEs advantages over TDI include angle independence, shorter postprocessing time, better reproducibility, and technical ease. Disadvantages of 2DSE compared to TDI include lower temporal resolution at higher heart rates and undersampling in patients with poor acoustic windows. 2DSE has been validated against magnetic resonance imaging as a measure of
Figure 2. Two-dimensional strain echocardiography (2SDE). This tracing of 2DSE shows the ability to track alterations in myocardial strain. Global and regional measurements of strain are calculated and differentiated by color coding.
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myocardial function in human and animal models (32, 33), and is superior to TDI inasmuch as it is unaffected by angle of acquisition. Investigations of myocardial function in the intensive care setting using 2DSE are limited. The need for manual postacquisition data processing, technical difculties of data acquisition, and variability in data between vendor packages have limited the use of this method for realtime assessment of cardiac function (34). As a result, further research is needed to make 2DSE a useful diagnostic tool in the pediatric critical care setting.
Conclusion
The role of echocardiography in the ICU is invaluable. Echocardiography is noninvasive, portable, and widely available as a diagnostic tool, particularly to assess structural/mechanical causes of alterations in cardiac function and cardiac output. As a result, the echocardiographic assessment of myocardial function in the ICU should remain a mainstay of clinical practice. The strength of echocardiography lies in its qualitative rather than quantitative assessment of the myocardium. When assessing cardiac function in the ICU, one must answer three fundamental questions: 1) What is the cardiac function? 2) Is the cardiac function normal for this clinical scenario? 3) If the cardiac function is abnormal, why? Echocardiography is a very effective tool to assist in answering the third question of why the cardiac function is abnormal; however, it only intermittently answers the question of cardiac function, thus limiting its utility as a hemodynamic monitor. For example, echocardiography is irreplaceable in the care of children with CHD as a diagnostic tool before the surgical repair and to assess alterations in postoperative cardiac function, which may result following the surgical intervention. Further, in the hemodynamically unstable child, echocardiography can often provide assessment of preload and systolic function necessary to make informed management decisions. The current evidence of echocardiography as a hemodynamic monitoring device in critically ill children is consistent with class II recommendations according the American Heart Association and the American College of Cardiology Task Force on Practice Guidelines. The total body of evidence in pediatrics for the use of echocardiography as a hemodynamic monitor has not been widely studied, with randomized controlled trials placing the level of evidence at C. There are, however, notable exceptions when echocardiography must be performed: the diagnosis of CHD, the hemodynamically unstable child without denitive etiology or unresponsive to routine resuscitation, the postoperative patient with CHD and suspected residual/new intracardiac shunts or hemodynamic instability, and the child with suspected new structural heart disease (i.e., tamponade, myocardial infarction, and cardiomyopathy). Newer modalities such as 3DE and 2DSE
remain limited in their use in the ICU, and additional research is needed to prove the viability of these modalities.
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1. Spurney CF, Sable CA, Berger JT, et al: Use of a hand-carried ultrasound device by critical care physicians for the diagnosis of pericardial effusions, decreased cardiac function, and left ventricular enlargement in pediatric patients. J Am Soc Echocardiogr 2005; 18: 313319 2. Feltes TF, Pignatelli R, Kleinert S, et al: Quantitated left ventricular systolic mechanics in children with septic shock utilizing noninvasive wall-stress analysis. Crit Care Med 1994; 22:16471658 3. Rychik J, Jacobs ML, Norwood WI Jr: Acute changes in left ventricular geometry after volume reduction operation. Ann Thorac Surg 1995; 60:12671273; discussion 1274 4. Knoester H, Sol JJ, Ramsodit P, et al: Cardiac function in pediatric septic shock survivors. Arch Pediatr Adolesc Med 2008; 162: 1164 1168 5. Fenton KE, Sable CA, Bell MJ, et al: Increases in serum levels of troponin I are associated with cardiac dysfunction and disease severity in pediatric patients with septic shock. Pediatr Crit Care Med 2004; 5:533538 6. Pollack MM, Fields AI, Ruttimann UE: Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985; 13:454 459 7. Bryant RM, Shirley RL, Ott DA, et al: Left ventricular performance following the arterial switch operation: Use of noninvasive wall stress analysis in the postoperative period. Crit Care Med 1998; 26:926 932 8. Colan SD, Boutin C, Castaneda AR, et al: Status of the left ventricle after arterial switch operation for transposition of the great arteries. Hemodynamic and echocardiographic evaluation. J Thorac Cardiovasc Surg 1995; 109:311321 9. Lopez L, Colan SD, Frommelt PC, et al: Recommendations for quantication methods during the performance of a pediatric echocardiogram: A report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010; 23:465 495; quiz 576 577 10. Di Donato RM, Wernovsky G, Walsh EP, et al: Results of the arterial switch operation for transposition of the great arteries with ventricular septal defect. Surgical considerations and midterm follow-up data. Circulation 1989; 80:1689 1705 11. Elkins RC, Knott-Craig CJ, Ahn JH, et al: Ventricular function after the arterial switch operation for transposition of the great arteries. Ann Thorac Surg 1994; 57:826 831 12. Okuda H, Nakazawa M, Imai Y, et al: Comparison of ventricular function after Senning
3DE
3DE allows acquisition of images in a pyramidal set, which allows for multiplane acquisition. Multiple plane image acquisition provides signicant improvement in resolution, which is particular advantageous in patients with CHD: improved quantication of left and right ventricular mass/volumes (35, 36), valve assessment (37, 38), and guidance of surgical and catheter-based procedures. Furthermore, magnetic resonance imaging is superior to standard 2DE for the assessment of the right ventricle in patients with CHD disease (39), and 3DE correlates well with magnetic resonance imaging assessment of right ventricular volumes and function (40 42). Images can be processed in real time (43) or processed postacquisition. Currently, there is limited research on the utility of 3DE to assess cardiac output in the pediatric ICU in children with or without congenital or acquired heart disease. However, there are multiple studies demonstrating the utility of 3DE for the longitudinal assessment of children with CHD (40, 42, 44). In a single-center trial of transesophageal 3DE in a CHD center, Baker et al (45) demonstrated the feasibility and utility of 3DE in the catheterization laboratory, the ICU, and operating room. 3DE is particularly useful in pediatrics for the assessment of valve structure and function, and right and left ventricular volumes and indices. Recent studies of the use of real-time 3DE in the cardiac catheterization lab and operating room support its continued use in these clinical settings. Additional research is needed in the critical care setting to advance the use of 3DE for children with and without heart disease.
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24. Vogel M, Sponring J, Cullen S, et al: Regional wall motion and abnormalities of electrical depolarization and repolarization in patients after surgical repair of tetralogy of Fallot. Circulation 2001; 103:1669 1673 25. Harada K, Toyono M, Yamamoto F: Assessment of right ventricular function during exercise with quantitative Doppler tissue imaging in children late after repair of tetralogy of Fallot. J Am Soc Echocardiogr 2004; 17: 863 869 26. Vogel M, Derrick G, White PA, et al: Systemic ventricular function in patients with transposition of the great arteries after atrial repair: A tissue Doppler and conductance catheter study. J Am Coll Cardiol 2004; 43: 100 106 27. Hershenson JA, Zaidi AN, Texter KM, et al: Differences in tissue Doppler imaging between single ventricles after the fontan operation and normal controls. Am J Cardiol 2010; 106:99 103 28. Mahle WT, Cardis BM, Ketchum D, et al: Reduction in initial ventricular systolic and diastolic velocities after heart transplantation in children: Improvement over time identied by tissue Doppler imaging. J Heart Lung Transplant 2006; 25:1290 1296 29. Fyfe DA, Ketchum D, Lewis R, et al: Tissue Doppler imaging detects severely abnormal myocardial velocities that identify children with pre-terminal cardiac graft failure after heart transplantation. J Heart Lung Transplant 2006; 25:510 517 30. Dhooge J, Heimdal A, Jamal F, et al: Regional strain and strain rate measurements by cardiac ultrasound: Principles, implementation and limitations. Eur J Echocardiogr 2000; 1:154 170 31. Helle-Valle T, Crosby J, Edvardsen T, et al: New noninvasive method for assessment of left ventricular rotation: Speckle tracking echocardiography. Circulation 2005; 112: 3149 3156 32. Amundsen BH, Helle-Valle T, Edvardsen T, et al: Noninvasive myocardial strain measurement by speckle tracking echocardiography: Validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol 2006; 47:789 793 33. Marwick TH, Leano RL, Brown J, et al: Myocardial strain measurement with 2-dimensional speckle-tracking echocardiography: Denition of normal range. JACC Cardiovasc Imaging 2009; 2:80 84 34. Friedberg MK, Mertens L: Tissue velocities, strain, and strain rate for echocardiographic assessment of ventricular function in congenital heart disease. Eur J Echocardiogr 2009; 10:585593 35. Lu X, Xie M, Tomberlin D, et al: How accurately, reproducibly, and efciently can we measure left ventricular indices using M-
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mode, 2-dimensional, and 3-dimensional echocardiography in children? Am Heart J 2008; 155:946 953 Bu L, Munns S, Zhang H, et al: Rapid full volume data acquisition by real-time 3-dimensional echocardiography for assessment of left ventricular indexes in children: A validation study compared with magnetic resonance imaging. J Am Soc Echocardiogr 2005; 18:299 305 Lang RM, Mor-Avi V, Sugeng L, et al: Threedimensional echocardiography: The benets of the additional dimension. J Am Coll Cardiol 2006; 48:20532069 Hlavacek AM, Crawford FA Jr, Chessa KS, et al: Real-time three-dimensional echocardiography is useful in the evaluation of patients with atrioventricular septal defects. Echocardiography 2006; 23:225231 Helbing WA, Bosch HG, Maliepaard C, et al: Comparison of echocardiographic methods with magnetic resonance imaging for assessment of right ventricular function in children. Am J Cardiol 1995; 76:589 594 van der Zwaan HB, Helbing WA, McGhie JS, et al: Clinical value of real-time threedimensional echocardiography for right ventricular quantication in congenital heart disease: Validation with cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2010; 23:134 140 Lu X, Nadvoretskiy V, Bu L, et al: Accuracy and reproducibility of real-time threedimensional echocardiography for assessment of right ventricular volumes and ejection fraction in children. J Am Soc Echocardiogr 2008; 21:84 89 Khoo NS, Young A, Occleshaw C, et al: Assessments of right ventricular volume and function using three-dimensional echocardiography in older children and adults with congenital heart disease: Comparison with cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2009; 22:1279 1288 De Castro S, Caselli S, Papetti F, et al: Feasibility and clinical impact of live threedimensional echocardiography in the management of congenital heart disease. Echocardiography 2006; 23:553561 Riehle TJ, Mahle WT, Parks WJ, et al: Realtime three-dimensional echocardiographic acquisition and quantication of left ventricular indices in children and young adults with congenital heart disease: Comparison with magnetic resonance imaging. J Am Soc Echocardiogr 2008; 21:78 83 Baker GH, Shirali G, Ringewald JM, et al: Usefulness of live three-dimensional transesophageal echocardiography in a congenital heart disease center. Am J Cardiol 2009; 103: 10251028
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Emerging technologies
Avihu Z. Gazit, MD; David S. Cooper, MD
Hemodynamic monitoring in critically ill patients has been considered part of the standard of care in managing patients with shock and/or acute lung injury, but outcome benet, particularly in pediatric patients, has been questioned. There is difculty in validating the reliability of monitoring devices, especially since this validation requires comparison to the pulmonary artery catheter, which has its own problems as a measurement tool. Interpretation of the available evidence reveals advantages and disadvantages of the available hemodynamic monitoring devices. (Pediatr Crit Care Med 2011; 12[Suppl.]:S55S61) KEY WORDS: cardiac output; circulation; hemodynamics; monitoring
he primary goal of hemodynamic monitoring in critically ill patients is to assess the adequacy of systemic perfusion. Since the introduction of the balloon oatation-assisted pulmonary artery catheter (PAC) in the 1970s, hemodynamic monitoring has been considered part of the standard of care in managing patients with shock and/or acute lung injury (1). Recent studies, however, question the PACs outcome benet (2, 3), particularly in pediatric patients. The implications of these outcome studies are not clear, but question whether alternative hemodynamic monitoring strategies available today can replace the PAC. The commercially available hemodynamic monitoring systems can be divided into three categories: 1) calibrationdependent pulse contour analysis devices (1) such as the Pulse Contour Cardiac Output (PiCCO, Pulsion, Munich, Germany) and LiDCO (LiDCO, Cambridge, UK) systems; 2) noncalibrated pulse contour analysis devices (2) such as the FloTrac system (FloTrac/Vigileo, Edwards Life Sciences, Irvine, CA), Pressure Recording Analytical Method (PRAM, Vytech Health, Padova, It-
aly), and LiDCOrapid (LiDCO, Cambridge, UK); and 3) alternative techniques (3) such as Doppler ultrasound methods, pulse dye densitometry, bioimpedance cardiography, and partial CO2 rebreathing. In general, the method described by Bland and Altman (4) seems to be the most appropriate when comparing measurements obtained by one method against another method whose accuracy is questionable. This method uses the mean of the two methods as the yardstick, and reports accuracy in terms of the mean difference (bias) between the two methods 2 standard deviations; the latter, also termed the limits of agreement, is an indicator of precision. Critchley and Critchley (5) recommend that limits of agreement between the new and reference technique of up to 30% should be accepted. The purpose of this review is to assess the theoretical basis of these strategies and their possible benet in guiding the therapy of critically ill children.
Calibration-Dependent Pulse Contour Analysis Devices PiCCO
From the Divisions of Critical Care and Cardiology (AZG), Department of Pediatrics, St. Louis Childrens Hospital, Washington University, St. Louis, MO; and The Congenital Heart Institute of Florida, Divisions of Critical Care and Cardiology (DSC), All Childrens Hospital, University of South Florida College of Medicine, St. Petersburg, FL. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: gazit_a@kids.wustl.edu Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3182211c2b
This device utilizes a standard central venous catheter as well as a proprietary thermistor-tipped arterial catheter to assess a variety of hemodynamic parameters via transpulmonary thermodilution. A 3F or 4F arterial catheter is available for cannulation of the femoral artery in children. To compensate for interindividual differences in compliance and resistance of the arterial vessel system, and to track changes of these variables as a result of changing clinical conditions,
manual calibrations are necessary. The temperature-time curves obtained during transpulmonary thermodilution measurements are broader and lower in magnitude than when obtained via a PAC. Thus these measurements are more vulnerable to errors caused by baseline drift and miscorrections for indicator recirculation. The transpulmonary technique is less vulnerable to errors caused by respiratory variation in blood temperature. A high degree of correlation between transpulmonary thermodilution measurements of cardiac output (CO) and the direct Fick principle has been established in critically ill children (6, 7). However, Bein and colleagues (8) observed large differences between the arterial waveform-based CO and reference methods during hemorrhage, shock, and vasodilatation. It has become more and more evident that frequent recalibration is necessary in these patients to obtain reasonable accuracy (8, 9). Indicator dilution methods (including thermodilution) can be used not only to measure ow but also to measure the volume through which ow is measured. The distribution volume for the indicator is the product of the CO multiplied by the mean transit time for the indicator. A detailed discussion of the measurements of intrathoracic thermal volumes can be found elsewhere (10). PiCCO measures both static and dynamic hemodynamic variables. Based on recent studies, changes in intrathoracic blood volume and global end-diastolic volume reect both changes in volume status and the resulting alteration in CO. LichtwarckAschoff and colleagues (11) demonstrated in a group of ventilated patients with acute respiratory failure a better correlaS55
tion between changes in intrathoracic blood volume index and cardiac index (CI) than between changes in either central venous pressure or pulmonary artery occlusion pressure and CI. Lopez-Herce and colleagues (12) evaluated the response to acute hypovolemia, rapid blood volume expansion, and epinephrine administration in an infant animal model and showed that intrathoracic blood volume index and global end-diastolic volume index were more sensitive to changes in blood volume than central venous pressure or pulmonary artery occlusion pressure. A prospective, multicenter, multinational study performed by Uchino and colleagues (13) in 331 critically ill adult patients monitored by PAC or PiCCO, showed that the choice of monitoring did not inuence major outcomes. The use of PiCCO, however, was associated with a greater uid balance and fewer ventilator-free days. A recent meta-analysis performed by Marik and colleagues (14) revealed that dynamic PiCCO variables, such as the pulse pressure variability and stroke volume variability, have better correlation with uid responsiveness in different adult patient populations. This meta-analysis revealed that the diagnostic accuracy of the pulse pressure variability (directly measured) was signicantly greater (p .001) than that for stroke volume variability (calculated). These data suggest that the pulse pressure variability may be the preferred arterial waveform-derived variable for assessment of volume status. The PiCCO method may give incorrect thermodilution measurements in patients with intracardiac shunts, aortic aneurysm, aortic stenosis, pneumonectomy, macro lung embolism, and extracorporeal circulation (if blood is either extracted from or infused back into the cardiopulmonary circulation). It is therefore of limited use in the perioperative care of children with complex congenital heart defects, but may be useful in children with normal cardiac anatomy who present with cardiogenic shock, or in the postoperative care of children after heart transplantation or biventricular repair.
sis monitor. The technique requires a standard arterial catheter and central or peripheral venous access (15). A small intravenous dose (0.002 0.004 mmol/kg) of isotonic lithium chloride solution (150 mM) is injected. The resulting lithium concentration-time curve is recorded by the ow of blood (4 mL/min) through a special disposable sensor that is attached to the patients arterial catheter. The CO is calculated from the lithium dose and the area under the curve before recirculation (16). The advantages of lithium are its safety prole related to the minute dose required to achieve an adequate reading, no signicant rst-pass metabolism, and rapid distribution (17, 18).
termittent and continuous CO values determined using the LiDCO system showed good agreement with those obtained by intermittent PAC thermodilution (22).
Noncalibrated Pulse Contour Analysis Devices FloTrac/Vigileo

This system consists of a sensor (FloTrac, Edwards) and a processing/display unit (Vigileo, Edwards). The latter applies a proprietary algorithm to the digitized arterial wave, and reports CO and other hemodynamic parameters. If a central venous pressure catheter has been placed, its signal can be interfaced with the Vigileo, allowing for the calculation of indexed systemic vascular resistance. When used with a central venous oximetry catheter, the Vigileo also provides continuous central venous oxygen saturation. The direct proportionality between arterial pulsatility and the stroke volume in conjunction with heart rate is used to calculate CO. Individual demographic data including height, weight, age, and sex are used to correct for interindividual differences in arterial compliance based on the model proposed by Langewouters and colleagues (23). A recent meta-analysis (24) showed overestimation of CO by FloTrac/Vigileo in the setting of signicant aortic regurgitation. Of note, studies involving rapidly changing hemodynamic proles and continuous thermodilution were not included in the meta-analysis. Other single-center studies showed underestimation of CO by this device in high-output, vasodilatory states (25, 26).
PulseCO system
The PulseCO Hemodynamic Monitor (LiDCO, London, UK) was developed in conjunction with LiDCO to give a beatto-beat estimate of stroke volume and CO derived from the arterial pressure waveform. The proprietary algorithm of the PulseCO is based on pulse power analysis rather than on the shape of the arterial waveform or the area under the curve for calculating CO. The assumption is that the pulse power is proportional to the stroke volume. Rhodes (19) published a detailed description of the underlying algorithm. The lithium dilution technique is of sufcient accuracy when there is constant blood ow, homogeneous mixing of blood, and when there is no indicator loss due to abnormal shunt between the site of injection and the detection site (20). The recalibration interval recommended by the manufacturer is 8 hrs; however, recent data suggest calibration whenever major hemodynamic changes occur (21). A recent study by Costa and colleagues (22) examined the level of agreement between intermittent CO monitoring by the lithium dilution technique, continuous CO monitoring using the arterial pressure waveform, and intermittent thermodilution using the PAC. This work revealed technical limitations related to the calibration of the LiDCO system, including the need for accurate measurements of serum sodium and hemoglobin concentration, limited number of calibrations based on a maximum daily lithium dose of 3 mM, and inability to calibrate within 15 to 30 mins of neuromuscular blockade administration due to the reaction with the lithium sensor. The conclusion of the study was that, in patients with hyperdynamic circulation, in-
PRAM
Different from the FloTrac/Vigileo system, the evaluation of CO by Most-Care (powered by PRAM; Vytech Health, Padova, Italy) does not require anthropometric data. It is based on the morphologic analysis of both the pulsatile and continuous components of the arterial pressure waveform. The concept behind PRAM is based on the physics theory of perturbations (27). Another important characteristic of the PRAM methodology is the 1000 Hz sampling frequency, different from other pulse contour analysis technologies that usually use a sampling frequency of 100 Hz. A detailed description of the method is published elsewhere (28). This morphology-based analysis
LiDCO
Lithium dilution CO is a minimally invasive indicator dilution technique. It was primarily developed as a simple calibration for the PulseCO (LiDCO, London, UK) continuous arterial waveform analyS56
makes the system susceptible to sources of error, as may be seen in stenosis of the arterial tree, for example. Furthermore, dampened waveforms and inadequate pulse detection associated with severe arrhythmias or catheter obstruction/dislodgment may inuence the precision of the waveform analysis (29). Although this technology is considered accurate in conditions of hemodynamic stability (30, 31), its accuracy is still questionable when profound hemodynamic changes occur. A recent study by Romagnoli and colleagues (32), performed in a swine model, investigated the reliability of Most-Care in conditions of hemodynamic instability in comparison with PAC thermodilution and transesophageal echocardiography. The study showed that Most-Care was less accurate during the low stroke volume states; however, it was not inuenced by variations in vascular tone. Since only a few validation studies have been published so far, a conclusive appraisal cannot yet be made.
LiDCOrapid
LiDCOrapid (LiDCO, Cambridge, UK) was recently launched. It applies the known LiDCO pulse power analysis algorithm without the need for calibration by lithium chloride. No scientic evidence exists so far.
Alternative Techniques Doppler ultrasound methods

The concepts behind hemodynamic evaluation via transesophageal Doppler monitoring were rst introduced by Side and Gosling (33), and later rened by Singer and colleagues (34). The technique of probe insertion is straightforward, with low inter- and intra-observer variability, and most operators become procient after 10 12 probe insertions (35, 36). Recommended absolute contraindications include recent esophageal surgery or the presence of congenital or acquired esophageal abnormalities. The accuracy of velocity measurement requires a good alignment between the Doppler beam and blood ow, and knowledge of the angle between the ultrasound beam and the blood ow vector (angle of insonation). Proper alignment of the probe is best assessed subjectively by optimizing the quality of the obtained signal with the aid of the visual display of the instantaneous velocity waveform and
the Doppler sound. The area under each waveform (the integral of velocity during the ejection time) is called the stroke distance, i.e., the distance traveled by blood in the descending aorta during each systole. Stroke volume (cm3) is the product of stroke distance (cm) multiplied by the cross-sectional area of the aortic lumen (cm2). The validity of this computation requires a at descending aorta velocity prole (i.e., the velocity should be the same at any given point across the aortic lumen), and crosssectional area should be constant during systole. Whereas ow in the descending aorta may be somewhat parabolic, with faster ow at the center of the vessel compared to the periphery (37), the differences in the absence of aortic pathology that would create turbulent ow are unlikely to be signicant (38). Bedside measurement of the cross-sectional area of the descending aorta can only be performed by using transesophageal echocardiography. This technique is not available everywhere, and the manufacturers of the transesophageal Doppler probe have incorporated a nomogram to estimate the cross-sectional area of the descending aorta based on the patients age, weight, and height. Because blood ow in the descending aorta is only a fraction of total CO, a constant proportion of the blood ow between the descending aorta (approximately 70%) and the coronary and brachiocephalic arteries (approximately 30%) needs to be assumed to estimate stroke volume and CO; however, the partition of blood ow between cephalic and caudal territories may also vary according to hemodynamic conditions, reex activation, or metabolic activity within different organs. Therefore, the assigned constant ratio of 70%:30% may become inaccurate under a variety of pathophysiologic conditions (39, 40). The extent to which this partition of CO is altered by or during critical illness has not been studied. CO as measured by the esophageal Doppler technique has been compared with CO obtained by thermodilution in multiple clinical settings, including the operating room and the medical/surgical intensive care unit. Dark and Singer (41) published a meta-analysis of validity studies comparing CO measurements obtained from the esophageal Doppler monitor (EDM, trademarked Cardio Q, previously ODM), the echo-esophageal Doppler (Echo-ED, trademarked HemoSonic100, previously Dynemo 3000),
and the PAC between 1989 and 2003. The authors concluded that EDM has minimal bias when estimating absolute values of CO, but limited clinical agreement with PAC thermodilution estimates. In addition, EDM has high validity (no bias and high clinical agreement) for monitoring changes in CO during the management of critically ill patients in both the operating room and intensive care unit. There were an insufcient number of studies to assess the validity of Echo-ED in estimating cardiac output.
Pulse dye densitometry

A recently developed and clinically introduced device (DDG2001 analyzer; Nihon Kohden, Tokyo, Japan) allows CO measurement based on transcutaneous indocyanine green (ICG) concentration curves obtained after bolus venous injection (42, 43). ICG distributes exclusively in the intravascular space via binding to 1-lipoproteins. Its concentration in the arterial blood after passage through the pulmonary circulation can be detected via a ngertip sensor that emits light with wavelengths of 805 and 890 nm. The ratio of ICG concentration measured at these two wavelengths is used to calculate the ICG concentration-time curve. CO is calculated from the observed dye dilution curve according to the StewartHamilton principle. Besides CO, this system has been suggested to allow measurement of total blood volume and central blood volume. Since appropriate signal detection is mandatory, poor peripheral circulation, movement artifacts, or ambient light inuences are inherent limitations of this technique. The ICG dye is nontoxic, except for rare cases of anaphylaxis and allergic reactions. It is exclusively cleared by the liver without undergoing either intrahepatic or enterohepatic metabolism. Usually, the ICG concentration decreases to 1% of the initial concentration after 20 mins, enabling a new measurement. The majority of recently published validation studies reported only moderate agreement with intermittent thermodilution measurements (44 46).
Thoracic electrical bioimpedance

The methodology for calculating CO from changes in electrical impedance over the thoracic area has improved over the last decade. The initial impedance
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measurements used the Kubicek equation (47). Bernstein (48) proposed a modied stroke volume equation for thoracic bioimpedance. It was based on the theory that the base thoracic impedance, which depends on the thoracic morphology and gas/uid distribution, shows pulsatile variations during the heart cycle. It was assumed that these changes were caused by systolic dilation of the aorta and its major branches. The different bioimpedance techniques and their agreement with invasive thermodilution techniques are discussed below. Cylinder- and Cone-based Bioimpedance Algorithms. The thoracic electrical bioimpedance technique involves the analysis of intrabeat variations in transthoracic voltage in response to applied high-frequency transthoracic currents. A recent study by de Waal and colleagues (49) assessed three common cylinderand cone-based bioimpedance algorithms in comparison with the thermodilution technique during the perioperative period in coronary artery bypass graft patients. This study revealed signicant deviations between bioimpedance and thermodilution stroke volume index. Bernstein and Osypka (50) substantially modied the basic equation to improve the reliability of impedance measurements, so that the maximum rate of change of impedance is related to the peak aortic blood acceleration. This method is called electrical velocimetry. Electrical Velocimetry Technique. This new bioimpedance cardiography technique interprets the changes in thoracic electrical bioimpedance as the ohmic equivalent of the mean aortic blood ow acceleration. The impedance recordings and calculations of CO, stroke volume, and CI are obtained with a new cardiovascular monitor (Aesculon Electrical Velocimetry, Osypka Medical Gmbh, Berlin, Germany) that transforms the ohmic equivalent of the mean aortic blood ow acceleration into an equivalent of mean aortic blood ow velocity. A comparison of this new method with invasive thermodilution methods (PAC or PiCCO) in 50 critically ill adult patients revealed a very small bias and acceptable limits of agreement ( 30%) (51). Bioreactance Technology. This method, applied in the NICCOM system (Cheetah Medical, Indianapolis, IN), involves the analysis of intrabeat variations in voltage phase shifts in response to high-frequency transthoracic currents. A recent multicenter study (52) used this
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device to test the accuracy of bioreactance-based CO measurement in the cardiac catheterization laboratory and in medical and cardiac intensive care units compared to thermodilution. The study showed that this device has acceptable accuracy in these varied and challenging clinical environments. Partial CO2 Rebreathing. The noninvasive cardiac output (NICO) monitor (Respironics Novametrix, Wallingford, CT) estimates CO by applying the CO2 version of the Fick equation. Fick postulated that oxygen uptake in the lungs is entirely transferred to the blood. Therefore, CO can be calculated as the ratio between oxygen consumption and arteriovenous oxygen difference. The Fick principle allows substitution with a multiple of substitutes for oxygen consumption, including CO2 clearance, and can be represented mathematically: Q VCO2/ (CvCO2-CaCO2); where Q is the CO (mL/ min), VCO2 is the CO2 elimination; and CvCO2 and CaCO2 are the venous and arterial CO2 contents (mL/100 mL blood), respectively (53). VCO2 can be calculated by the difference in CO2 content between expired and inspired gases. The Fick equation can then be further modied by use of a partial CO2 rebreathing technique. This involves a transitory interruption of CO2 elimination by the addition of dead space to the ventilatory circuit, which leads to a progressive increase in end-tidal CO2 that approximates the mixed venous partial CO2 value (54 57). The change in VCO2 is then calculated by comparing normal and rebreathing values. The change in CaCO2 content can then be approximated by the change in end-tidal CO2 multiplied by the slope of the CO2 dissociation curve, which is linear between 15 and 70 mm Hg of partial pressure of CO2 (57, 58). Because intrapulmonary shunts can affect estimates of CO with this technique, an arterial blood sample is required to enter arterial oxygen tension values for shunt estimation. The NICO monitor is characterized as minimally invasive for intubated, mechanically ventilated patients and is easy to setup with operator-independent performance. Older versions of the monitor were found to have moderate accuracy based on most validation studies (59 63). This was attributed to inadequate rebreathing time, recirculation, the difference in CO2 between alveolus and proximal airway, as well as the difference between arterial and alveolar CO2 (64).
Recent validation studies using newer software demonstrated better results. Gueret and colleagues (65) looked at the use of NICO for monitoring patients undergoing repeat total hip replacement. They reported that the bias precision of the NICO monitor with version 4.2 software against continuous CO monitoring was 0.3 1.1 L/min. The bias was smaller when mean CO was below 3 L/min. A recent study by Kotake and colleagues (66) investigated the accuracy of the NICO monitor with versions 4.2 and 5 in patients undergoing elective aortic reconstruction. Similar to Gueret and colleagues, this study revealed a smaller bias precision compared to the previous NICO software version, however, the level of agreement with the measurements obtained with the PAC failed to meet the criteria set by Critchley and Critchley (5). In pediatric patients, validation studies are scarce and not sufcient to make decisions in regards to implementation of the NICO monitor in clinical practice. Levy and colleagues (67) concluded that NICO is clinically acceptable in children with a body surface area of 0.6 m2 and a tidal volume 300 mL, whereas discrepancies with thermodilution were more important in smaller patients. Botte and colleagues (68) evaluated 21 mechanically ventilated children, weighing 15 kg, in stable respiratory and hemodynamic conditions. CO values obtained with this technique were in agreement with those obtained with Doppler echocardiography. Although NICO evaluation has yet to be completed in children in unstable respiratory and hemodynamic conditions, this would seem to be a reasonable endeavor for future investigations.
Discussion
Maintenance of adequate oxygen delivery in critically ill children is the main goal of the pediatric intensivist. Unfortunately, physical examination ndings and basic bedside monitoring devices do not always provide sufcient data to aid in meeting this goal. The PAC is still considered the de facto gold standard for hemodynamic monitoring; however, its invasive nature is associated with significant complications, and its appropriate placement, which is crucial to the adequacy of hemodynamic data derived from it, is operator dependent and requires signicant experience and expertise, particularly in pediatric patients. To ll this
monitoring gap, several devices were developed and introduced into the clinical arena over the course of the last 2 decades. These devices are minimally invasive and allow continuous and intermittent hemodynamic measurements. In general, their use is not complicated and does not require signicant training or expertise. The main problem we face as intensivists is the difculty to validate the reliability of these devices, especially since this validation requires comparison to the PAC, which by itself is problematic as a measurement tool. Elaborate and somewhat articial statistical methods were devised by Bland and Altman (4) and modied by Critchley and Critchley (5) to optimize this validation process, and indeed, these are the tools that we currently use. Another signicant problem is the lack of large-scale randomized validation studies in adults and especially in children. This obstacle is tackled by the use of meta-analysis studies, which, in spite of the meticulous nature of their preparation, introduce more confounding factors to the already hazy picture. Interpretation of the evidence available to us points toward advantages and disadvantages of the available hemodynamic monitoring devices, and we hereby summarize our recommendations for the use of these devices in the critical care environment. PiCCO. The use of this monitor in children is overall simple and, based on our experience, requires minimal training. In hemodynamically unstable patients it requires frequent recalibrations to obtain reasonable accuracy (9). The data in children are minimal but suggest good correlation of PiCCO CI measurements and calculations based on the Fick principle (6, 7). Both the dynamic and static variables measured by the PiCCO were shown to have good correlation with CI and uid responsiveness, respectively (69). PiCCO monitoring is inaccurate in children with intracardiac shunts, limiting its utility in congenital heart disease. LiDCO/PulseCO. The use of this system is problematic due to the complexity of its calibration. The available data support its use in patients with hyperdynamic circulation; however, its validity in patients with low CO has not been studied. Overall it appears that more data are required before use of this system in critically ill children. FloTrac/Vigileo. The agreement of the second-generation operating system of this device (1.07 and higher) with CO measurements of other devices was found
to be adequate. The evidence for the use of this technology in the pediatric intensive care unit is lacking. PRAM. This systems accuracy is unclear in unstable clinical states (32). LiDCOrapid. This is a new system. No scientic evidence exists so far that would allow us to make any recommendations. EDM (trademarked Cardio Q, previously ODM) and Echo-ED (trademarked HemoSonic100, previously Dynemo3000). Insertion and alignment of the probe is simple and requires minimal training to achieve prociency (35, 36). The current evidence (41) reveals that EDM has minimal bias when estimating absolute values of CO, but limited clinical agreement with PAC thermodilution estimates. It has high validity (no bias and high clinical agreement) for monitoring changes in CO during the management of critically ill patients in both operating rooms and intensive care units. There were an insufcient number of studies to assess the validity of Echo-ED in estimating cardiac output. Pulse Dye Densitometry (DDG2001 Analyzer; Nihon Kohden, Tokyo, Japan). Current evidence is limited and reveals only moderate agreement with the intermittent thermodilution technique (44 46). Cylinder- and Cone-based Bioimpedance Algorithms. Evidence suggests it is not acceptable as a hemodynamic monitoring technique. Electrical Velocimetry Technique (Aesculon Electrical Velocimetry, Osypka Medical Gmbh, Berlin, Germany). Limited data (51) reveal small bias and acceptable limits of agreement comparing the measurements obtained by this technique and measurements obtained by thermodilution (PAC or PiCCO). Bioreactance Technology (NICCOM System; Cheetah Medical, Indianapolis, IN). New technology. Limited data (61) reveal acceptable measurement accuracy in the cardiac catheterization laboratory and intensive care unit compared to thermodilution. Partial CO2 Rebreathing (NICO; Respironics Novametrix, Wallingford, CT). This monitor is easy to setup with operator-independent performance. However, its use is limited to sedated and mechanically ventilated patients, and the level of agreement of CO measurements obtained by the newer software versions of this monitor (4.2 and 5) compared to thermodilution measurements fail to meet the accept-
able criteria. Validation studies in children are currently insufcient (67, 68).
Conclusion
Minimally invasive hemodynamic monitoring devices are commercially available but their role in the evaluation of systemic perfusion in critically ill children is not well established. Largescale validation studies are required to examine their applicability in pediatric patients.
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Evidence-Based Review and Consensus Statement On Monitoring of Hemodynamics and Oxygen Transport Balance

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Evidence-Based Review and Consensus Statement On Monitoring of Hemodynamics and Oxygen Transport Balance

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Introduction

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Age Premature 03 mo 36 mo 612 mo 13 yr 36 yr 612 yr 12 yr

Pulse, heart rate, and electrocardiographic monitoring

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Blood pressure monitoring

Central venous and left atrial pressure monitoring

Pulse oximetry monitoring: Physiology and principles

Capnography and end-tidal CO2 monitoring: Physiology and principles

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pulmonary artery catheters

Proximal Balloon gate value Thermistor connector

Where CO cardiac output; V volume of injectate (mL); A area of thermodi-

Figure 1. Standard four-lumen pulmonary artery catheter.

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Figure 4. Thermodilution curves.

Acute Lung Injury

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Venous oximetry and the assessment of oxygen transport balance

Physiology of Tissue Oxygenation and Oxygen Transport Balance

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Normal Increased Impending shock Shock, lactic acidosis

Based on mixed venous

The OxygenHemoglobin Dissociation Curve

Compensatory Mechanisms to Maintain Tissue Oxygenation

Regional Oxygen Transport Balance

Advantages and Limitations of Venous Oximetry

Central Venous Oximetry

Classication of recommendations and level of evidence

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Near-infrared spectroscopy as a hemodynamic monitor in critical illness

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Application of multisite NIRS in the intensive care unit

Critical illness in patients with structural heart disease

Critical illness in patients without structural heart disease

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

that can guide management decisions in a pediatric critical care setting.

B-Type Natriuretic Peptide

Pediatr Crit Care Med 2011 Vol. 12, No. 4 (Suppl.)

Normal values in children

BNP concentrations in children with various cardiac conditions

Common causes of elevated BNP levels

BNP vs. NT-proBNP

Study Walsh et al 2008 Maher et al 2008 Zhang et al 2006 Koch et al 2006

Cardiac Peptide BNP BNP BNP BNP

Koch et al 2006 Eerola et al 2009 Mir et al 2006 Nir et alb 2009

NT-proBNP NT-proBNP NT-proBNP NT-proBNP

Plasma BNP and pulmonaryto-systemic blood ow ratio

The single-ventricle patient and BNP

Therapy targeted to BNP concentration

BNP as a surrogate marker for other hemodynamic measurements

BNP in the periextubation period

Conclusion for BNP

The utility of plasma BNP levels in the perioperative setting

Troponin in cardiac injury

Troponin in nonischemic cardiac conditions