Vol 27, No 6

December 2013

EDITORIAL G oa l - D i r e c t e d Th e r ap y i n C a r di a c Su r g e r y : Ar e W e T h e r e Ye t ?

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OAL-DIRECTED THERAPY (GDT) is the practice of using hemodynamic parameters, beyond standard ones such as heart rate and blood pressure, to optimize oxygen delivery. These parameters might include stroke volume (SV), cardiac output (CO), and central venous oxygen saturation (ScO2), or dynamic ones such as stroke volume variation or pulse pressure variation. Optimization of oxygen delivery using such parameters was described by Shoemaker in the 1980s. He observed that shock survivors had significantly higher cardiac index (CI), oxygen delivery (DO2), and oxygen consumption (VO2) than non-survivors.1 He then hypothesized that setting supranormal hemodynamic goals in high-risk surgical patients would compensate for increased perioperative metabolism, leading to decreased morbidity and mortality. His landmark study in 19882 showed significant reductions in mortality and hospital length of stay (LOS) in high-risk surgical patients managed with GDT. Other investigators have reported similar results, although the supranormal approach is still debated. Anesthetic management using hemodynamic goals is something all anesthesiologists do daily. Conventional parameters such as mean arterial pressure (MAP), heart rate (HR), urine output (UOP), and, occasionally, central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) may serve as surrogates for CO, DO2, and preload. These variables are manipulated with volume administration, vasoactive drugs, and inotropes to achieve and maintain goal values. For low-tomoderate-risk patients and surgeries, normalization of these markers probably is adequate for maintaining tissue perfusion. However, tissue hypoxia may manifest in high-risk surgical patients despite normal conventional parameters. There are numerous studies that show that markers such as PCWP,3 CVP,4 UOP,5 HR,6 and BP7 often do not reflect end-organ perfusion. Tissue hypoxia is a key component in activating the systemic inflammatory response in post-surgical patients and may not manifest clinically for days. The objective of GDT is to use flow-directed hemodynamic parameters to guide fluid and inotrope administration to maintain adequate circulating volume, tissue blood flow, and oxygen delivery. Theoretically,

normal tissue perfusion helps prevent systemic inflammation and end-organ dysfunction and thus reduces perioperative morbidity and mortality. GDT has been evaluated in numerous randomized controlled trials with the vast majority showing improvement in outcomes in high-risk patients undergoing noncardiac surgery. An obvious next step is to evaluate the effectiveness of GDT in the cardiothoracic surgical population. These patients represent a high-risk group that theoretically should benefit from hemodynamic optimization using “alternative” parameters. Unfortunately, the data on GDT in cardiac surgery are sparse. There are 5 studies to date that specifically address the effectiveness of GDT in cardiac surgery. The first is a prospective, randomized trial by Mythen et al8 looking at the effect of perioperative volume expansion on gut mucosal pH during cardiac surgery. Low gut mucosal pH, a surrogate for gut hypoperfusion, has been shown to be a sensitive predictor of poor outcome in cardiac surgery. Mythen et al enrolled 60 American Society of Anesthesiologists (ASA) class 3 patients who presented for elective cardiac surgery and had an ejection fraction (EF) 450% and randomly allocated them to control and protocol groups. The anesthetic management of the control group was based on the standard practice at their institution using HR, MAP, UOP, and CVP. Patients in the protocol group, in addition to the standard practice, received 200 milliliter (mL) boluses of 6% hydroxyethyl starch solution based on CVP and SV measurements using esophageal Doppler monitoring. Colloid boluses were administered repeatedly throughout the pre- and postbypass periods if there was evidence of an increase in SV without a significant increase in CVP. Gut mucosal perfusion (pH) was assessed by gastric tonometry. Mythen et al found that the incidence of gut mucosal hypoperfusion was significantly reduced in the

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Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 6 (December), 2013: pp 1075–1078

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protocol group (7% v 56%). In addition, the protocol group had fewer patients with major complications (0 v 6), shorter hospital LOS (6.4 d v 10.1 d), and spent fewer days in the ICU (1 d v 1.7 d). The protocol group received significantly more colloid than the control group. Mythen et al suggested that volume expansion based on SV and CVP can reduce gut hypoperfusion, and thus perioperative complications, in cardiac surgery. Of note, despite significant differences in SV and gastric pH at the end of surgery, the BP and HR were similar between groups. Of note, the CVP was lower in the protocol group even with the increase in fluid administration. This suggests that BP, HR, and CVP are not, in themselves, effective measures of oxygen delivery and preload. Polonen et al9 studied mixed venous oxygen saturation (SvO2) and lactate as parameters for GDT in the 8 hours following cardiac surgery. Four hundred three elective cardiac surgical patients presenting for coronary revascularization were assigned randomly to control and protocol groups. The control group was treated based on standard institutional practice including maintenance of CI 42.5 L/min/m2, PCWP between 12 and 18 mmHg, and MAP between 60 and 90 mmHg. The goals of the protocol group were to maintain the SvO2 greater than 70% and the lactate concentration below 2.0 mmol/L using fluids, and dobutamine if fluid administration alone was ineffective. Although discharge time from the ICU was similar, in both groups, the patients in the protocol group had a shorter mean hospital LOS (6 d v 7 d) and had less morbidity at the time of discharge (1.1% v 6.1%). Mortality between the groups was statistically similar, but showed a trend towards a reduction in the protocol patients at 28 days (2 deaths in the protocol group v 6 in the control group), 6 months (3 v 7), and 12 months (4 v 9). One issue with this study is that both groups were managed in a “goaldirected” manner. The outcome differences between the groups may reflect the effectiveness of the chosen goals in the respective groups and not GDT itself. Also, outcomes between the control and protocol groups were similar when hemodynamic targets were met. Only about half the protocol patients achieved the predetermined goals. In addition, a significant portion of the control group also achieved these goals despite a lack of directed therapy. Patients who achieved these goals in both groups tended to be younger, have a better EF, and were less likely to have diabetes. All patients who achieved these targets had better outcomes. Therefore, it may be that the therapy itself was not the cause of the improved outcome. Rather, the ability to achieve the hemodynamic goals is a marker for healthier patients who will thus enjoy better outcomes. McKendry et al10 studied how GDT applied in the postoperative period affects outcome. They randomly allocated 174 post-cardiac surgery patients to either conventional hemodynamic management using BP, HR, CVP, UOP, and arterial base deficit, or protocol-driven management using a stroke volume index (SVI) 435 mL/m2 as the goal. The protocol was nursedirected in the ICU using esophageal Doppler. The primary method of optimizing the SVI was 200 mL colloid boluses although, if unsuccessful, vasodilator or inotropic therapy was to be used. With this protocol, McKendry et al showed a reduction in the hospital LOS (11.4 d v 13.9 d). There was also a trend towards a reduction in ICU LOS and a reduction in major complications (17% v 26%), including atrial fibrillation

FERGERSON AND MANECKE JR

and acute renal failure. The protocol group had significantly higher CO, SV, and colloid administration. Although not statistically significant, there were fewer deaths in the control group (2 v 4). It is important to note that only 61% of the protocol patients achieved a target SVI 435 mL/m2, attesting to the fact that achieving the goals in GDT can be difficult. Also of note is that 44% of the control group achieved an SVI 435 mL/m2. Kapoor et al11 studied 27 patients with a EuroSCORE Z3 undergoing on-pump coronary artery bypass graft (CABG) surgery. They randomly divided patients into control and GDT groups. Both groups were monitored and treated throughout the intraoperative period and up to 8 hours postoperatively. As with the earlier studies, the control group management was guided by BP, HR, CVP, and UOP. In addition to these parameters, the GDT group was managed with pulse contour-based technology (FloTracTM Edwards Lifesciences, Irvine, CA) and central venous oximetry (PreSepTM, Edwards Lifesciences) to maintain the CI 2.5-4.2 L/min/m2, SVI 30-65 mL/beat/m2, systemic vascular resistance index (SVRI) 1500-2500 dynes/s/cm5/m2, oxygen delivery index (DO2I) 450-600 mL/min/m2, ScO2 470%, and stroke volume variation (SVV) o10%. Fluids, packed red blood cells (if the hematocrit was o30%), and inotropic and vasodilator agents were administered in efforts to achieve the goals. The GDT group received more fluids and more adjustments to their inotropic agents. The patients in the GDT group had a shorter average duration of mechanical ventilation (13.8 h v 20.7h), fewer days of use of inotropic agents (1.6 vs. 3.8), shorter ICU LOS (2.6 d v 4.9 d), and shorter hospital LOS (5.6 d v 8.9 d). Morbidity was low in both groups and there were no deaths. The authors stated the data in their study were inconclusive in showing the benefit of GDT in cardiac surgery patients, although the study size was so small as to make any conclusions difficult. Of note, although the inotropic agents were adjusted more frequently in the GDT group, the overall duration of inotrope use was less, indicating that identifying and monitoring for clear hemodynamic endpoints when using cardiovascular drugs may actually limit the duration of their use. Smetkin et al12 studied 40 patients presenting for off-pump coronary artery bypass surgery and randomized them to a control group in whom therapy was guided by CVP (6-14 mmHg), MAP (60-100 mmHg), and HR (o90 beats per minute), and a GDT group guided by MAP, HR, ScO2 (460%), and intrathoracic blood volume index (850-1,000 mL/m2) assessed by transpulmonary thermodilution.13 Measurements were performed pre-, intra-, and 2, 4, and 6 hours postoperatively. The parameters in the GDT group were optimized by volume administration (hydroxyethyl starch) and dobutamine. The GDT group received more colloid and dobutamine with resultant increases in ScO2, CI, and DO2. ICU and hospital LOS were decreased by 15% and 25%, respectively, in the GDT group, although these differences were not statistically significant. There were no deaths in either group. This paper, like Kapoor et al's, suggests that GDT may be beneficial in cardiac surgery patients and indicates that larger trials are in order. Cecconi et al14 performed a systematic review and metaanalysis of GDT in cardiac surgery using these 5 articles. Taken together, these studies evaluated 699 patients and revealed reductions in postoperative complication rates (21 patients in the GDT group v 51 in the control), and hospital LOS (2.21

EDITORIAL

fewer days). As mentioned above, 2 of the trials had no reported deaths, leaving only 632 patients for mortality comparison. The overall effect on mortality was not statistically significant. In a similar meta-analysis, Giglio et al15 confirmed Cecconi et al’s conclusion that these trials revealed a reduction in postoperative complications using GDT, but no reduction in mortality. Cecconi et al’s cited several limitations of the data pooled from these trials. None of these trials was considered to have high methodologic quality because of difficulty in doubleblinding. All the studies were single-centered and subject to the effects of the patient population, operative team experience, and complexity of the surgeries performed. The overall sample size in each was small; which, in the setting of a low baseline operative mortality, may explain why there was no effect on mortality despite the fact that GDT used in high-risk noncardiac surgery has been reported to reduce mortality.16 The effect of the small sample size might have been reduced with pooling of the data had there not been significant heterogeneity among the 5 trials. Nevertheless, these trials taken as a whole suggest that GDT in cardiac surgery can reduce postoperative complication rates and, thus, hospital LOS. Given that the data on the effects of GDT in improving outcome in noncardiac surgery were so robust, where do the comparatively modest results of GDT in cardiac surgery leave medical professionals? The first thing to consider is whether or not an alternative to the current management model is even needed. Mortality is relatively low in cardiac surgery despite the high-risk nature of the procedures and the severity of illness in the patients. Welsby et al17 found a mortality rate of approximately 3.6% in cardiac patients who underwent a procedure using cardiopulmonary bypass (CPB). Shoemaker suggested that GDT is best applied to high-risk surgical patients with a predicted mortality of upwards of 20%. If mortality is the primary reason to use GDT, the current mortality rate in cardiac surgery might not warrant its use. The rate of complications in cardiac surgery, however, remains high. Approximately 36.5% of the patients studied in Welsby’s article had complications and 15.7% had an adverse outcome. In the cardiac surgery GDT trials noted above, even those with no mortality had relatively high rates of noncardiac organ dysfunction. Welsby also showed that patients who suffered noncardiac complications had more than twice the mortality rate of those with cardiac complications alone and nearly 7 times that of patients without complications. Looking at causes of prolonged ICU LOS after CABG, Michalopoulos et al18 suggested that low-cardiac-output syndrome, as evidenced by the need for multiple inotropes, was the primary cause of postoperative complications and, thus, prolonged ICU LOS. Goepfert et al19 showed that GDT in cardiac surgery reduced the need for vasopressor and inotropic support. It appears from these articles that tissue hypoperfusion secondary to low-cardiac-output and the organ dysfunction that ensues are the primary cause of complications, prolonged ICU stays, and, likely, postoperative mortality. It may be that GDT, with its primary goal being to improve cardiac output, reduces the prevalence of low-cardiac-output syndrome and, thus, noncardiac complications and hospital LOS. Given this, it is not unreasonable to expect that larger trials would show a reduction in overall mortality.

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Even if GDT does not prove to reduce postoperative mortality in cardiac patients, the fact that it is associated with decreased morbidity warrants its consideration, from medical and economic standpoints. Depending on a hospital’s caseload, a 1-day reduction in average LOS can amount to hundreds of thousands to several million dollars saved annually. In addition, reduced ICU and bed usage would allow for more cases and thus more revenue generation. Probably, most importantly, a reduction in complications significantly reduces the costs associated with those complications. For example, respiratory failure requires mechanical ventilation, renal failure requires dialysis, and neurocognitive dysfunction requires rehabilitation—very expensive interventions. A reduction in such complications can result in enormous cost savings to hospitals and the healthcare system at large. The current preliminary data for GDT in cardiac surgery argue for larger trials to determine its effectiveness. One factor to consider is whether or not additional fluid load often (although not always) associated with GDT is dangerous for cardiac surgical patients with compromised physiology. The Frank-Starling mechanism describes how CO varies in relation to preload. The heart increases its force of contraction in response to increases in preload, up to a point. After this point, the Starling curve levels off, and additional fluid does not enhance SV. Heart failure is associated with a “stretching” of the myocardium that leads to a reduction in overlapping actin and myosin units. This flattens the Starling curve, causing the point of diminishing returns and potential complications to be reached at a lower preload. For this reason, as well as the fact that CPB systems are “primed” with fluid, many physicians restrict fluids in their cardiac surgical patients. There are, however, several limitations to a “blind” fluid restriction approach, even in patients with poor cardiac function. The first is that the contractile response of the heart to preload is not based solely on stretching of the sarcomere. It is multifactorial and includes calcium homeostasis, neurohormonal responses, and alterations in genetic expression.20 There is no single curve on which a ventricle operates. The contractile state of the heart can vary day to day and even minute to minute. The second limitation is that although the Starling curve in heart failure is flatter, it is still a curve. Even the compromised myocardium can improve its contraction in response to volume. Lastly, hypo- or hypervolemia is nearly impossible to predict from conventional parameters and cannot be assumed based on preoperative fasting, theoretic “thirdspacing,” or estimated blood loss.21 Cardiac surgical patients can be hypovolemic and the extra fluid associated with CPB may not optimize myocardial performance. Using a flow-based parameter to determine the hemodynamic status in cardiac surgical patients, therefore, makes physiologic sense. GDT, although protocol based, allows individual management of cardiovascular status, offering additional parameters to help determine what level of venous return an individual heart requires. GDT involves use of CO or other end-organ perfusion measures to determine the result of fluid administration. Moreover, fluid restriction is not at odds with the concept of GDT. Clinicians can restrict fluids by significantly limiting the background fluid administration and guide volume resuscitation solely by flow-related parameters. The key point in GDT is individualization of volume administration and not high-

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volume resuscitation. In fact, the term “goal-directed fluid restriction” is now used by some to describe giving patients “the fluid they need but not a drop more” (Mythen, personal communication). Cardiothoracic anesthesiologists already use flow- and cardiac-volume-related parameters and presumably use goals in applying them. Management based on CO, intracardiac volume, and EF as measured by pulmonary artery catheters and echocardiography is ubiquitous in the authors’ practice. In very few noncardiac surgeries are these parameters as frequently applied as in cardiac surgery. A significant portion of the control groups in the above articles met the CO goals set for the protocol groups. In McKendry’s paper, 44% of the control patients met the SVI goal value of 435 mL/m2 at 4 hours postoperatively.10 In Polonen’s article, 42% of the control patients reached the hemodynamic goals as compared to 57% of the protocol patients. These data show 2 things: (1) the current standard of practice is geared towards optimizing SV and CO, and (2) with the chosen parameters in the GDT protocol groups, optimizing flow is difficult. The question may not be whether GDT is safe and beneficial in cardiac surgery, but instead which parameters should be used to guide management. In this issue of the Journal of Cardiothoracic and Vascular Anesthesia, a number of articles address various issues related to GDT. In addition, McGee et al22 provide an informative and thought-provoking review of GDT, with an emphasis on caring

for critically ill patients. McGee presents an algorithm that makes physiologic sense and likely will result in improved outcomes in a variety of critically ill patients and patients undergoing major surgery. Exactly how this approach, or others like it, should be applied to cardiac surgical patients remains to be seen. Cardiothoracic anesthesiologists and surgeons are left to determine this for their own practices. The authors of this editorial leave the reader with 2 points to consider. The first is that it has been shown conclusively that applying algorithms to optimize flow and/or oxygen delivery improves outcome in critically ill patients and patients undergoing major surgery. The second is that relative fluid restriction in cardiac and thoracic surgery has evolved for a reason, and it may be the GDT simply will be a method of using flow- and/or oxygen delivery-based data to determine the safe limits of fluid restriction. At this point it seems that there are many more questions than answers. It is safe to say, however, that judicious use of fluids and inotropes using flow-based parameters to optimize cardiac performance and tissue oxygenation likely will improve the outcomes of cardiac and thoracic surgeries. Byron D. Fergerson, MD Gerard R. Manecke Jr, MD Department of Anesthesiology University of California San Diego San Diego, CA

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12. Smetkin AA, Kirov MY, Kuzkov VV, et al: Single transpulmonary thermodilution and continuous monitoring of central venous oxygen saturation during off-pump coronary surgery. Acta Anaesthesiologica Scandinavica 53:505-514, 2009 13. Reuter DA, Felbinger TW, Moerstedt K, et al: Intrathoracic blood volume index measured by thermodilution for preload monitoring after cardiac surgery. J Cardiothorac Vasc Anesth 16:191-195, 2002 14. Aya HD, Cecconi M, Hamilton M, et al: Goal-directed therapy in cardiac surgery: A systematic review and meta-analysis. Br J Anaesth 110:510-517, 2013 15. Giglio M, Dalfino L, Puntillo F, et al: Haemodynamic goaldirected therapy in cardiac and vascular surgery. A systematic review and meta-analysis. Interact Cardiovasc Thorac Surg 15:878-887, 2012 16. Kern JW, Shoemaker WC: Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med 30:1686-1692, 2002 17. Welsby IJ, Bennett-Guerrero E, Atwell D, et al: The association of complication type with mortality and prolonged stay after cardiac surgery with cardiopulmonary bypass. Anesth Analg 94: 1072-1078, 2002 18. Michalopoulos A, Tzelepis G, Pavlides G, et al: Determinants of duration of ICU stay after coronary artery bypass graft surgery. Br J Anaesth 77:208-212, 1996 19. Goepfert MS, Reuter DA, Akyol D, et al: Goal-directed fluid management reduces vasopressor and catecholamine use in cardiac surgery patients. Intensive Care Med 33:96-103, 2006 20. Katz AM: The ‘modern’ view of heart failure: How did we get here? Circ Heart Fail 1:63-71, 2008 21. Doherty M, Buggy DJ: Intraoperative fluids: How much is too much? Br J Anaesth 109:69-79, 2012 22. McGee WT, Raghunathan T: Physiologic Goal-Directed Therapy in the Perioperative Period: The Volume Prescription for High-Risk Patients. J Cardioth Vasc Anesth 27:1079-1086, 2013