Endpoints of resuscitation: what are they anyway?

Seminars in Cardiothoracic and Vascular Anesthesia http://scv.sagepub.com/

Endpoints of Resuscitation: What Are They Anyway? George S. Tseng and Michael H. Wall SEMIN CARDIOTHORAC VASC ANESTH published online 3 February 2014 DOI: 10.1177/1089253213520348 The online version of this article can be found at: http://scv.sagepub.com/content/early/2014/01/28/1089253213520348

Published by: http://www.sagepublications.com

Additional services and information for Seminars in Cardiothoracic and Vascular Anesthesia can be found at: Email Alerts: http://scv.sagepub.com/cgi/alerts Subscriptions: http://scv.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav

>> OnlineFirst Version of Record - Feb 3, 2014 What is This?

Downloaded from scv.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on May 11, 2014

520348 research-article2014

SCVXXX10.1177/1089253213520348Seminars in Cardiothoracic and Vascular AnesthesiaTseng and Wall

Article

Endpoints of Resuscitation: What Are They Anyway?

Seminars in Cardiothoracic and Vascular Anesthesia 1–11 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253213520348 scv.sagepub.com

George S. Tseng, MD1, and Michael H. Wall, MD, FCCM1

Abstract Hemodynamic optimization of surgical patients during and after surgery in the Surgical Intensive Care Unit is meant to improve outcomes. These outcomes have been measured by Length Of Stay (LOS), rate of infection, days on ventilator, etc. Unfortunately, the adaptation of modern technology to accomplish this has been slow in coming. Ever since Shoemaker described in 1988 using a pulmonary artery catheter (PAC) to guide fluid and inotropic administration to deliver supranormal tissue oxygenation, many authors have written about different techniques to achieve this “hemodynamic optimization”. Since the PAC and CVC have both gone out of favor for utilization to monitor and improve hemodynamics, many clinicians have resorted using the easy to use static measurements of blood pressure (BP), heart rate (HR), and urine output. In this paper, the authors will review why these static measurements are no longer adequate and review some of the newer technology that have been studied and proven useful. This review of newer technologies combined with laboratory measurements that have also proven to help guide the clinician, may provide the impetus to adopt new strategies in the operating rooms (OR) and SICU. Keywords analgesia, critical care, intensive care unit, monitoring, near infrared spectroscopy There are more than 234 million surgical procedures performed every year. Approximately 15% of these cases involve high-risk surgical patients accounting for 80% of deaths.1 There are also approximately 715 000 cases of sepsis each year in the United States, with 215 000 resulting in death. This costs the US health industry around $16 billion each year.1 The question is, can improvement of cardiac output (CO), tissue oxygen delivery (DO2), and mixed venous oxygen saturation (SvO2) decrease mortality, morbidity, and improve outcomes? If so, what are the mechanisms and tools that can be commonly and easily used? This article will briefly review the rationale behind goaldirected therapy (GDT), review commonly available monitoring devices that can be used to assess fluid responsiveness, and, finally, discuss some other possible physiologic endpoints of resuscitation that are also currently available. The concept of GDT is not new, and there have been numerous studies of GDT or hemodynamic optimization using many different protocols, monitors, fluids, and endpoints. Most show improvements in morbidity and mortality. Giglio et al performed a meta-analysis of 16 trials (3410 patients). The GDT groups had fewer major and minor complications.2 Gurgel and Nascimento reported a systemic review of GDT in high-risk surgical patients in 32 trials (5056 patients). They also showed a significant reduction in mortality and postoperative organ dysfunction in the GDT groups. These findings were even stronger in sicker patients (ie, there

was a greater improvement in outcome associated with GDT in patients with a control group mortality of ≥20%).3 Finally, Hamilton et al showed similar results in a systemic review and meta-analysis of GDT in moderate-risk and high-risk surgical patients in 29 trials (4805 patients) where complications and mortality were decreased in the GDT groups.4 It appears that there is a consistent improvement in outcomes in the use of GDT in surgical patients. Unfortunately, most individual studies are small, and all use different protocols, so comparison of these studies is difficult, and application is even harder, but the theme of improved oxygen delivery to tissues resulting in improved morbidity and mortality is consistent. But how do you actually do it?

Measurements of Fluid Response Routinely used indices such as blood pressure (BP), heart rate (HR), and urine output (UOP) have proven inadequate markers for optimizing CO and SvO2. The BP and HR may not change until almost 25% of intravascular volume has been lost. Even the venerable central venous pressure 1

University of Minnesota, Minneapolis, MN, USA

Corresponding Author: Michael H. Wall, B515 Mayo 420 Delaware St. S.E. Minneapolis, MN 55455, USA. Email: [email protected]


2

Seminars in Cardiothoracic and Vascular Anesthesia

(CVP) has been found wanting. Over the last 30 years, evidence has been accumulated against using static pressure measurements such as CVP, pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP), and left ventricular end diastolic area (LVEDA). These values, even when used in conjunction with HR, BP, and UOP, have not been useful markers for delineating intravascular volume status and left ventricular (LV) fluid responsiveness.5,6 Studies have consistently confirmed that the correlation between CVP and preload responsiveness is very poor at best, misleading at worst. In 2008, a systemic review of CVP usage found that such static values were not useful in identifying which patients needed more fluid or were fluid responsive. The authors concluded that CVP should no longer be routinely used in the intensive care unit (ICU), operating rooms (ORs), or emergency departments (EDs)!5 Marik and Cavallazzi published, in 2013, an updated meta-analysis of 43 studies evaluating CVP and fluid responsiveness, and again they concluded that the use of CVP to guide fluid therapy be abandoned.6 This recommendation came despite the promise of early goal directed therapy (EGDT) in the emergency department using CVP as one of its parameters for early resuscitation.7 It is also pertinent to point out that the meta-analysis reviews of GDT studies includes a vast array of both “static” and “dynamic” variables as goals. But the evidence is growing that the “static” measurements of fluid therapy is inadequate. Static measurements such as with the BP, HR, and CVP do not adequately correlate with fluid responsiveness during resuscitation. The pulmonary artery catheter (PAC) has also fallen out of favor due to recent studies demonstrating that PAOP is a poor predictor of preload and volume responsiveness.8-10 Because of this, clinicians had to find other simple and reliable means of predicting fluid responsiveness during fluid resuscitation and use new endpoints of resuscitation. These new endpoints of resuscitation need to account for the observations of Shoemaker and others that supranormal hemodynamic values such as oxygen delivery greater than 600 mL/min/m2 in high-risk patients improved outcomes and survival.11 The endpoints also need to balance the recent finding of Vincent et al,12 which have shown positive fluid balance is associated with increased morbidity, mortality, and other negative outcomes. The endpoints also need to simply and accurately identify patients who are fluid responsive versus those who are not. Fortunately, over the past 20 years, a number of minimally invasive CO devices have emerged making determinations of fluid responsiveness easier and more reliable. Monitors such as the esophageal Doppler monitor (EDM) and devices based on bioreactance, bioimpedance, and arterial pressure waveform analysis now provide near continuous real-time stroke volume variation (SVV) and pulse pressure variation (PPV) information. Serum lactate,

Figure 1. Measurement of plural responsiveness along the Starling curve.

mixed venous oxygen saturation (SvO2), central venous oxygen saturation (ScvO2), tissue oxygenation using nearinfrared spectroscopy (NIRS), and tissue oximetry (StO2) have been used to guide resuscitation and are available rapidly or continuously.13,14 These indicators of tissue perfusion and oxygenation are what Marik describes as “downstream” indices that cannot be provided for by “upstream” indices of resuscitation such as BP, CO, and DO2.15 These downstream indices of tissue oxygenation could be used as markers of adequate resuscitation guided by the above techniques (Figure 1). We have been taught that CVP describes the pressure of blood in the vena cava near the right atrium; it must follow that these pressures are a good indicator of right ventricular (RV) preload, RV stroke volume, LV preload, and LV stroke volume (SV) as classically shown in the Frank-Starling curve in Figure 1. Unfortunately, the physiology of the patient in the ICU is fraught with byproducts of sepsis, such as decreased ventricular compliance, and changes in vascular tone. The need to ventilate an acutely ill patient introduces changes to the transthoracic and transpulmonary pressures creating a poor relationship between the CVP and RV end diastolic volume (RVEDV).16 The end result is that the RVEDV may not reflect the patient’s position on the Frank–Starling curve and therefore may not reflect fluid responsiveness to a volume challenge.5 It has become generally acknowledged that estimates of intravascular volume based on a given level of filling pressure do not reliably predict a patient’s response to fluid challenges.5,6,17

Upstream Measurements of Fluid Responsiveness Despite positive pressure ventilation contributing to unreliable data from the CVP, positive pressure ventilation causes the dynamic variables of pulse pressure variation (PPV) and stroke volume variation (SVV) that have been


3

Tseng and Wall

Figure 2. Spectral Doppler tracings of aortic blood flow recorded with esophageal Doppler cardiac output monitoring. The velocity–time waveform shape reflects alterations in contractility (mainly affecting peak velocity and mean acceleration), preload (mainly affecting systolic flow time corrected for heart rate [FTc]), and afterload (which affects FTc, mean acceleration, and peak flow velocity).

shown to predict fluid responsiveness. On insufflation during mechanical ventilation, the RV preload decreases due to less venous return secondary to increases in pleural pressure while RV afterload increases due to increases to transpulmonary pressure.10 This leads to decreased RV stroke volume. The decrease in venous return is thought to be the main mechanism for the inspiratory reduction in RV ejection.18 After a lag of 2 or 3 heart beats, a decrease in LV filling is seen resulting in decreased LV stroke volume. This cyclic change in stroke volume due to mechanical ventilation is greater when the ventricles operate on the steep part of the Frank–Starling curve. Therefore, the magnitude of the respiratory changes in LV stroke volume is an indicator of biventricular preload dependence.10 A systematic review of 29 clinical studies demonstrated that the PPV and SVV could predict with a high degree of accuracy those patients who were fluid responsive to a fluid challenge.15 A PPV/SVV threshold of 12% to 13% proved remarkably consistent in these studies. This consistency and accuracy was independent of ventricular function and compliance as well as pulmonary pressures and mechanics.15 It was also noted that PPV was a better predictor of volume responsiveness than SVV. Unfortunately, arrhythmias and spontaneous breathing will make PPV and SVV unreliable for predicting fluid responsiveness. Small tidal volumes (less than 8 cc/kg) also affect the accuracy and reliability of SVV/PVV and fluid responsiveness. For accuracy, reproducibility, and consistency, it is suggested that a tidal volume of 8 to 10 mL/kg of ideal body weight be used for measurement of PPV/SVV.15 In another study of 443 patients under general anesthesia and mechanical ventilation, Cannesson et al19 found that PPV values

between 9% and 13% could not accurately predict fluid responsiveness. This is in accordance with numerous other studies that show PPV monitoring may be affected by ventilator-patient dyssynchrony, arrhythmias, low tidal volume ventilation, altered chest wall and pulmonary compliance, pulmonary hypertension, and increased intraabdominal pressure.20-24 In the “gray zone” area of PPV (values between 9% and 13%) fluid responsiveness cannot be predicted. It has been suggested that in routine clinical practice (where patients may be spontaneously breathing, tidal volumes are small, in LV failure, etc), in both the ORs and ICUs, caution must be used in interpreting dynamic indices of preload responsiveness.25 The esophageal Doppler monitor (EDM) probe works by measuring blood flow in the descending aorta. This is accomplished by using a Doppler transducer tipped probe placed in the esophagus. Cardiac output and SV are calculated based on aortic diameter, measured flow velocity of blood in the aorta, and distribution of the cardiac output to the descending aorta13,14 (Figure 2). Using the PAC as a standard, Dark and Singer found an 86% correlation of cardiac output with the EDM.26 Though correlation between them was modest, there was excellent correlation between the changes in CO with therapeutic interventions.26 In a randomized trial with patients undergoing proximal femur repair, intraoperative fluid optimization using the EDM was compared with a control group (Figure 3). Using SV optimization using the corrected flow time (FTc), which is a surrogate for SV, and the change in FTc following a fluid challenge, Sinclair et al found the EDM group to have faster postoperative recovery and reduced hospital stay as compared with the control


4


Figure 3. Typically, optimization is achieved through the use of a fluid management algorithm. Stroke volume (SV) or stroke distance (SD) responses to fluid challenges may help guide further interventions. Such algorithms have been used routinely in outcome studies with Deltex medical esophageal Doppler monitors.

group.27 In a study with trauma patients using an EDMbased protocol, Chytra et al demonstrated lower blood lactate levels, lower infectious complications, and lower ICU and hospital length of stay (LOS) in the EDM group.28 Similarly, the use of the EDM in other studies have shown decreased time to discharge, earlier time to oral intake, reduced unplanned ICU admissions, and fewer major or intermediate complications.27,29-32 Abbas and Hill published a systematic review of EDM in major abdominal surgery. They included 5 studies (420 patients). The EDM intervention group showed reduced hospital LOS, fewer complications and ICU admissions, and less need for inotropes. In addition, return of bowel function occurred sooner.33 Although the EDM has been shown to be useful in fluid optimization, its technology has been slow in adaptation. This may be due to several factors, including a long learning curve, requirement for the clinician to obtain a Doppler signal, the “fiddle factor” in the continued ongoing manipulation of the EDM probe, and the problem related to the probe being in the esophagus during certain types of surgery (Figure 4). Another promising technology on the rise is the use of bioreactance, bioimpedance, or phase shift in voltage across the thorax. The monitor contains a highly sensitive phase detector that continuously captures thoracic phase shifts, which results in a signal. Cardiac output and SV data, among others, are then calculated from this signal13,14 (Figure 5). The CO measured has been shown to highly

Figure 4. Fluid management algorithm: esophageal Doppler/ bioreactance. Fluid optimization protocol as used by BarnesJewish Hospital Department of Anesthesiology.

correlate with that measured by thermodilution and pulse contour analysis.34-37 Bioreactance technology has also been shown to track changes in CO more accurately than thermodilution.36 In comparison with the EDM, there was good agreement between the 2 technologies for fluid responsiveness. Additional controlled studies with patients utilizing this technology in fluid resuscitation are still needed to show improved patient outcomes (Figure 6).

Downstream Indices of Perfusion It now appears clear that optimizing intravascular volume using dynamic markers (PPV/SVV) of fluid responsiveness is preferred over static markers (CVP/PAOP), and there are several monitoring technologies available to do this accurately. The next question is, “Are there other markers of resuscitation that should be used?” Next, we will discuss the role of lactate, SvO2, ScvO2, oxygen extraction ratios (O2ER), and tissue oxygen tension (StO2) using NIRS as goals of resuscitation.


5

Tseng and Wall

Figure 5. Electrical velocimetry for calculating cardiac output.

A small sinusoidal current is passed between a pair of electrodes, and the impedance to electrical flow conducted by the red cell mass within the thoracic cavity is measured (left). Shown are a representative electrocardiogram (ECG) tracing, ECG impedance waveform −dZ(t), first derivative of the impedance waveform dZ(t)/dt, and pulse oximetry waveform SpO2. The first derivative of the impedance waveform (dZ(t)/dt) is used with an ECG to determine the beginning of electrical systole (Q), aortic valve opening (B), maximal deflection of the dZ(t)/dt waveform (C), and the closing of the aortic valve (X). Stroke volume and cardiac output are calculated from these reference points. A high degree of correlation between cardiac output measured by Doppler and electrical velocimetry has been demonstrated. Abbreviation: LVET, left ventricular ejection time.

Under hypoxic conditions, anaerobic glycolysis provides much needed energy used by the body. This increases the production of cellular lactate that diffuses into the blood stream. Elevated levels of lactate in the bloodstream should indicate inadequate tissue oxygenation due to decreased delivery or increased consumption.38 Clinicians have used lactate levels as a prognostic indicator of tissue hypoperfusion. Lactate levels are also useful as a screening tool to stratify and prognosticate those patients who are hemodynamically stable but with suspected infection.39 It is well known that nonsurvivors of sepsis usually have higher initial levels of lactate, regardless of whether the patient was or was not in shock.40 In a retrospective cohort study of ED patients with severe sepsis, Mikkelsen et al41 reported that the association between lactate level and mortality was independent of clinically apparent organ dysfunction and shock. Jansen et al studied a protocol of GDT plus lactate clearance versus GDT alone in 348 ICU patients. The lactate clearance group received more fluids and vasodilators. The lactate clearance group’s mortality and organ failure scores were lower, and ventilator

weaning occurred sooner.42 While these studies do not conclusively prove that lactate or lactate clearance should be used as the gold standard endpoint in resuscitation, they do show that an elevated serum lactate level should prompt the clinician to look for occult hypoperfusion despite the normalization of signs of apparent shock. Rivers et al studied 263 patients with severe sepsis who were randomized into 2 groups of therapy in the first 6 hours. The standard care groups’ targets were: CVP ≥ 8 to 12 mm Hg, MAP ≥ 65 mm Hg, and UOP ≥ 0.5 cc/kg/h. The EGDT group had these same targets and had the additional goal of ScvO2 ≥ 70%. EDGT (using ScvO2 ≥ 70%) decreased mortality from 46.5% to 30.5% (P = .009).7 Varpula et al retrospectively reviewed the impact of hemodynamic variables and outcome in patients (n = 111) with septic shock. They showed that the best predictive thresholds for 30-day mortality was the hypotensive area for MAP less than 65 mm Hg (area under curve [AUC] 0.85, 95% confidence interval [CI] 0.77 to 0.93) and time under SvO2 of 70% (AUC 0.75, 95% CI 0.62 to 0.88) in the initial 48 hours.43 Textoris et al retrospectively analyzed 111


6


Figure 6. Fluid management algorithm: pulse pressure variation or stroke volume variation. Fluid optimization protocol as used by Barnes-Jewish Hospital Department of Anesthesiology.

patients with septic shock and showed nonsurvivors were associated with a higher maximum ScvO2 level in the first 72 hours (ScvO2 max 85% vs 79%, P = .009). The authors speculate that elevated ScvO2 in sepsis may reflect impaired oxygen utilization in more severe shock.44 Marty et al investigated the prognostic value of ScvO2 in patients treated with EGDT as described by Rivers et al.7 In their study, there were no differences in ScvO2 between survivors and nonsurvivors during the first 24 hours in the ICU (ScvO2 was greater than 70% at all-time points in both groups). However, lactate was higher and lactate clearance was lower in the first 24 hours in nonsurvivors. The authors speculated that elevated lactate in the presence of normal ScvO2 may indicate more severe shock or occult tissue hypoperfusion and that adding lactate clearance to EGDT with a target ScvO2 ≥ 70% may improve outcomes.45 Jones et al prospectively studied EGDT in 300 patients with severe sepsis with one group targeted to ScvO2 ≥ 70% and the other group targeted to a lactate clearance ≥10% per hour for the initial 6 hours of therapy in both groups. They found no differences in the treatment related adverse events or outcomes between the 2 groups. Mortality was 23% (95% CI 17% to 30%) in the ScvO2 group versus 17%

(95% CI 11% to 24%) in the lactate clearance groups, which was not significant.46 It appears that an initial ScvO2 less than 70% is associated with mortality and is an appropriate tool for initial resuscitation. However, after initial resuscitation, ScvO2 does not predict mortality—in fact higher ScvO2 may predict mortality following initial resuscitation! Marty et al concluded “ScvO2 seems to be a necessary but not sufficient parameter to guide therapeutic intervention in the ICU after initial resuscitation.”45 Based on these studies and others, the most recent sepsis treatment guidelines recommend an SvO2 ≥ 65% or ScvO2 ≥ 70% in the early resuscitation of sepsis.47 As a precursor to rising lactate levels, Donati et al48postulated that maintaining an oxygen extraction (O2ER) < 27% (equivalent to 1 − ScVO2) would decrease the incidence of organ failure and hospital LOS. The threshold of 27% for oxygen extraction estimate (O2ERe = SaO2 − ScvO2/SaO2) had been established by other authors as a predictor of survival in high-risk surgical patients.49 Predefined goals of MAP greater than 80 mm Hg, urine output greater 0.5 mL/kg/h, and CVP 8 to 12 cm H2O until the first postoperative day were met for both the control and study groups. For the protocol group, fluid challenges with colloids were used to maintain a CVP to greater than10 cm H2O, and dobutamine and/or preload red blood cells (PRBC) were used to keep the O2ERe less than 27%. In their study of 135 patients, Donati et al showed a decrease in hospital LOS and organ failure when early and aggressive treatment kept the O2ERe less than 27%. The authors commented that the total amount of fluid and PRBC was the same in both groups—the O2ERe group got them earlier. Also, the O2ERe group received more dobutamine. They postulated that earlier and more aggressive resuscitation (using O2ERe) should be considered in high-risk surgical patients.48 NIRS has also been used for measuring downstream indices of resuscitation (Figure 7). This technique has been used to provide a noninvasive and continuous monitor of the balance between cerebral oxygen delivery and consumption.50,51 NIRS has been deployed in various disciplines such as neurosurgery, trauma, vascular surgery, and cardiac surgery to detect cerebral ischemia during periods of hypoperfusion. Several excellent recent reviews and pro/con articles have been written on this topic.52-54 During carotid artery stenting, Matsumoto et al55 found that measurements using NIRS could be an excellent predictor of cerebral hyperperfusion syndrome. A case study by Santo et al56describes using NIRS during a hybrid aortic arch replacement. They described being able to track regional oxygen saturation while the left common carotid artery was manipulated. An eventual decline in regional oxygen saturation prompted a re-exploration of the left common carotid artery graft where a thrombus was found. Besides cerebral oxygenation, NIRS is also used to monitor another


7

Tseng and Wall

Figure 7. Operating principles of the use of near-infrared spectroscopy.

(A) The electrodes are positioned in the forehead. (B) Signals from both hemispheres are transmitted to a display. (C) The signals are coming from an optode that has 1 transmitter and 2 receptors. The signal originating from the proximal receptors are subtracted from the distal ones. Therefore, only information from the deeper part of the brain is displayed. (D) On the screen, the large number indicates the ongoing brain oximetry values and the small number the baseline value obtained at the beginning of the recording from both the right (R) and the left (L) hemisphere.

downstream indicator of upstream resuscitation of skeletal muscle tissue oxygen saturation (StO2). Using StO2 to guide resuscitation in the ED, Miner et al, in their preliminary study, showed a decreased LOS.57 Another study showed the corollary that low StO2 predicted increased hospital and ICU LOS.58 Of course, using NIRS has its own limitations. Ischemia can occur in nonmonitored sites, more so for cerebral than skeletal muscle tissue. NIRS monitoring can be interfered with by electrocautery and cannot differentiate the cause of regional oxygen saturation change. This has led Denault et al to come up with an algorithm to help optimize factors during cardiopulmonary bypass that can affect cerebral oxygen.59 This algorithm includes the following: 1. 2. 3. 4. 5. 6. 7. 8.

Ruling out mechanical obstruction Increasing mean arterial pressure Verifying systemic oxygenation Normalizing PaCO2 Optimizing hemoglobin Evaluate cardiac function Decrease CMRO2 Other differential, including intracranial process and type of cardiopulmonary bypass used (Figure 8)

Controversies As with all emerging technology, not every study has been positive for GDT, or even fluid boluses for resuscitation. Maitland et al60 found an increase in the absolute risk in mortality by 48 hours and increased risk of death, neurologic sequelae or both at 4 weeks, in children with clinical findings of sepsis in the sub-Saharan Africa who were bolused with either saline or albumin compared to a control group that only received maintenance fluid. Of note, differentiation of the causes of severe illness was not possible at the time of admission and that recommendations regarding fluid resuscitation differ substantially among some of those illnesses. Also, no other “upstream” or “downstream” monitors were available to follow the effects of the boluses. Other than lactate levels, blood pH, and base deficits obtained at admission, most other signs of hypotension and sepsis used were static values such as blood pressure and HR or clinical signs such as capillary refill, pulse characteristics, and mucous membrane signs of pallor. In their double-blinded controlled trial of 179 patients undergoing major open or laparoscopic colorectal surgery, Challand et al61 found differences in aerobically fit and


8


Figure 8. Sample of a peripheral tissue oxygen tension monitor.

unfit individuals using GDT when measuring readiness for discharge (RfD) and LOS. Individuals underwent cardiopulmonary exercise testing (CPET) on a stationary bicycle to stratify who was fit or unfit by their anaerobic threshold (AT). AT as determined by the V slope and ventilator equivalent was used as the marker of fitness. Unfit individuals (AT 8.0-10.9 mL O2 kg−1 min−1) and fit individuals (AT >11.0 mL O2 kg−1 min−1) were stratified and randomized. Of 179 patients entered into their study, GDT patients received an average of 1360 mL more of colloids, and times to RfD and LOS were longer in the GDT group, but not statistically significant. In subgroup analysis, unfit patients’ time to RfD and LOS were similar in GDT and control groups. It was in the fit group of patients that had significantly increased median time to RfD and prolonged LOS. In their analysis of their study and why their results were in contrast to previous studies, the authors postulated that previous algorithms incorporated additional parameters such as increase in corrected flow time and increase in CVP, to signal that the circulating blood volume was replete. With the new algorithm, the patient is titrated to a stroke volume that is near the top of the Starling curve. This new algorithm may prove to be too simplistic in its rational. In their recent meta-analysis of 11 articles and 1179 cardiothoracic and vascular patients, Giglio et al2 showed that perioperative GDT was effective in reducing postoperative complications in cardiac patients but not in

postoperative vascular patients. This meta-analysis did not show any difference in mortality between GDT and conventional fluid management. The result for cardiac surgery patients was corroborated in the Aya et al62 metaanalysis of 5 GDT studies encompassing 699 patients. The authors found a reduced postoperative complication rate and decreased LOS in the GDT groups but no significance in mortality rates. However, the vast majority of studies and meta-analysis of GDT showed favorable decreases in LOS, morbidity, and complications in a wide population of patients. These studies also showed that patients receiving GDT also received more fluids than control groups, and the fluids were mostly colloids.61 These findings must be reconciled with studies showing that increased fluid balance, especially within the first 24 hours in septic patients, results in poor outcome.12,63,64 To complicate matters even more, recent literature has pushed clinicians away from using synthetic colloids. A systematic review and meta-analysis by Zarychanski et al has concluded that hydroxyl ethyl starch (HES) for acute volume resuscitation is not warranted due to serious safety concerns. The 2 major concerns were associated with increased risk of acute kidney injury and mortality.65 Also, the Consensus Statement of the ESICM (European Society of Intensive Care Medicine) task force also mirror those recommendations against HES. It has also excluded the use of albumin in head trauma patients but not severe sepsis patients.66


Tseng and Wall

9

Conclusion

8. Michard F, Teboul J. Predicting fluid responsiveness in ICU patients. Chest. 2002;121:2000-2008. 9. Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med. 2007;35:64-68. 10. Michard F, Teboul J. Using heart-lung interactions to assess fluid responsiveness during mechanical ventilation. Crit Care. 2000;4:282-289. 11. Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988;94:1176-1186. 12. Vincent J, Sakr Y, Sprung C, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34:344-353. 13. Marik PE. Noninvasive cardiac output monitors: a state-of theart review. J Cardiothorac Vasc Anesth. 2013;27:121-134. 14. Funk DJ, Moretti EW, Gan TJ. Minimally invasive cardiac output monitoring in the perioperative setting. Anesth Analg. 2009;108:887-897. 15. Marik P. Techniques for assessment of intravascular volume in critically ill patients. J Intensive Care Med. 2009;24:329-337. 16. Funk DJ, Jacobsohn E, Kumar A. Role of the venous return in critical illness and shock: Part II—shock and mechanical ventilation. Crit Care Med. 2013;41:573-579. 17. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006;34:1333-1337. 18. Theres H, Binkau J, Laule M, et al. Phase-related changes in right ventricular cardiac output under volume-controlled mechanical ventilation with positive end-expiratory pressure. Crit Care Med. 1999;27:953-958. 19. Cannesson M, Manach YL, Hofer DK, et al. Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsivness: a 'grayzone' approach. Anesthesiology. 2011;115:231-41. 20. Mahjoub Y, Pila C, Friggeri A, et al. Assessing fluid responsiveness in critically ill patients: false-positive pulse pressure variation is detected by Doppler echocardiographic evaluation of the right ventricle. Crit Care Med. 2009;37:25702575. 21. Muller L, Louart G, Bousquet PJ, et al. The influence of the airway driving pressure on pulsed pressure variation as a predictor of fluid responsiveness. Intensive Care Med. 2010;36:496-503. 22. Jacques D, Bendjelid K, Duperret S, et al. Pulse pressure variation and stroke volume variation during increased intra-abdominal pressure: an experimental study. Crit Care. 2011;15(1):R33. 23. Wyler von Ballmoos M, Takala J, Roeck M, et al. Pulsepressure variation and hemodynamic response in patients with elevated pulmonary artery pressure: a clinical study. Crit Care. 2010;14(3):R111. 24. Lakhal K, Ehrmann S, Benzekri-Lefèvre D, et al. Respiratory pulse pressure variation fails to predict fluid responsiveness in acute respiratory distress syndrome. Crit Care. 2011;15(2):R85. 25. Lansdorp B, Lemson J, van Putten MJ, et al. Dynamic indices do not predict volume responsiveness in routine clinical practice. Br J Anaesth. 2012;108:395-401.

How do clinicians strike a balance of using “upstream” and “downstream” indices in GDT with the evidence that overzealous fluid administration and adherence of overly simplified algorithms may be detrimental? Also, the management of intensive care patients has been characterized as reactive to downstream indices and the operating room management as proactive. Could the use of a strategy of using upstream dynamic indices prior to downstream information allow the intensivist to stay ahead of the indicators of poor perfusion and inflammation. In review, it is clear that static measurements of fluid responsiveness are inadequate and should not be used alone. Instead, the best strategy may be to use dynamic upstream measures of fluid responsiveness in addition to downstream measures of tissue perfusion. This strategy may improve oxygen delivery while minimizing fluid volume, with the overall goal being to optimize (rather than maximize) each individual patient on their own Starling curve and own goaldirected resuscitation endpoint. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Shepherd SJ, Pearse RM. Role of central and mixed venous oxygen saturation measurement in perioperative care. Anesthesiology. 2009;111:649-656. 2. 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. 2012;15:878-887. 3. Gurgel S, Nascimento P. Maintaining tissue perfusion in high-risk surgical patients: a systematic review of randomized clinical trials. Anesth Analg. 2011;112:1384-1391. 4. Hamilton M, Cecconi M, Rhodes A. A systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and highrisk surgical patients. Anesth Analg. 2011;112:1392-1402. 5. Marik P, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? Chest. 2008;134:172-178. 6. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013;41:17741781. 7. 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.


10


26. Dark P, Singer M. The validity of trans-esophageal Doppler ultrasonography as a measure of cardiac output in critically ill adults. Intensive Care Med. 2004;30:2060-2066. 27. Sinclair S, James S, Singer M. Intraoperative intravascular volume optimization and length of hospital stay after repair of proximal femoral fracture: randomised controlled trial. BMJ. 1997;315:909-912. 28. Chytra I, Pradl R, Bosman R, et al. Esophageal Dopplerguided fluid management decreases blood lactate levels in multiple-trauma patients: a randomized controlled trial. Crit Care. 2007;11(1):R24. 29. Venn R, Steele A, Richardson P, et al Randomized controlled trial to investigate influence of the fluid challenge on duration of hospital stay and perioperative morbidity in patients with hip fractures. Br J Anaesth. 2002;88:65-71. 30. Mythen M, Webb A. Perioperative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg. 1995;130:423-429. 31. Gan TJ, Soppitt A, Maroof M, et al. Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery. Anesthesiology. 2002;97:820-826. 32. Noblett SE, Snowden CP, Shenton BK, et al. Randomized clinical trial assessing the effect of Doppler-optimized fluid management on outcome after elective colorectal resection. Br J Surg. 2006;93:1069-1076. 33. Abbas SM, Hill AG. Systematic review of the literature for the use of oesophageal Doppler monitor for fluid replacement in major abdominal surgery. Anaesthesia. 2008;63:44-51. 34. Keren H, Burkhoff D, Squara P. Evaluation of a noninvasive continuous cardiac output monitoring system based on thoracic bioreactance. Am J Physiol Heart Circ Physiol. 2007;293:H583-H589. 35. Raval NY, Squara P, Cleman M, et al. Multicenter evaluation of noninvasive cardiac output measurement by bioreactance technique. J Clin Monit Comput. 2008;22:113-119. 36. Squara P, Denjean D, Estagnasie P, et al Noninvasive cardiac output monitoring (NICOM): a clinical validation. Intensive Care Med. 2007;33:1191-1194. 37. Heerdt PM, Wagner CL, DeMais M, et al. Noninvasive cardiac output monitoring with bioreactance as an alternative to invasive instrumentation for preclinical drug evaluation in beagles. J Pharmacol Toxicol Methods. 2011;64:111-118. 38. Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation. 1970;41:989-1001. 39. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med. 2005;45:524-528. 40. Howell M, Donnino M, Clardy P, et al. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med. 2007;33:1892-1899. 41. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009;37: 1670-1677. 42. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients. Am J Respir Crit Care Med. 2010;182:752-761.

43. Varpula M, Tallgren M, Saukkonen K, et al. Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005;31:1066-1071. 44. Textoris J, Fouché L, Wiramus S, et al. High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality. Crit Care. 2001;15(4):R176. 45. Marty P, Roquilly A, Vallee F, et al. Lactate clearance for death-prediction in severe sepsis or septic shock patients during the first 24 hours in intensive care unit. An observational study. Ann Intensive Care. 2013;3(1):3. 46. 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;303:739746. 47. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580637. 48. Donati A, Loggi S, Preiser JC, et al. Goal-directed intraoperative therapy reduces morbidity and length of hospital stay in high-risk surgical patients. Chest. 2007;132:1817-1824. 49. Bland RD, Shoemaker WC, Abraham E, et al. Hemodynamic and oxygen transport patterns in surviving and nonsurviving postoperative patients. Crit Care Med. 1985;13:85-90. 50. Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters. Science. 1977;198:1264-1267. 51. Edmonds HL, Austin EH. Cerebral oximetry for cardiac and vascular surgery. Semin Cardiothorac Vasc Anesth. 2004;8:147-166. 52. Ghosh A, Elwell C, Smith M. Cerebral near-infrared spectroscopy in adults: a work in progress. Anesth Analg. 2012;115:1373-1383. 53. Zheng F, Sheinberg R, Yee MS, et al. Cerebral near-infrared spectroscopy monitoring and neurologic outcomes in adult cardiac surgery patients: a systematic review. Anesth Analg. 2013;116:663-676. 54. Vernick WJ, Gutsche JT. Pro: cerebral oximetry should be a routine monitor during cardiac surgery. J Cardiothorac Vasc Anesth. 2013;27:385-389. 55. Matsumoto S, Nakahara I, Higashi T, et al. Near-infrared spectroscopy in carotid artery stenting predicts cerebral hyperperfusion syndrome. Neurology. 2009;72:1512-1518. 56. Santo KC, Barrios A, Dandekar U, et al. Near-infrared spectroscopy: an important monitoring tool during hybrid aortic arch replacement. Anesth Analg. 2008;107:793-796. 57. Miner J. The effect of near infrared spectroscopy monitoring on the treatment of patients presenting in shock to the emergency department. Crit Care Med. 2010;38:S861. 58. Conway T. Low StO2 measurements in ICU patients predicts increased hospital and ICU length of stay. Crit Care Med. 2011;39:S236. 59. Denault A, Deschamps A, Murkin JM. A proposed algorithm for the intraoperative use of cerebral near-infrared spectroscopy. Semin Cardiothorac Vasc Anesth. 2007;11:274-281. 60. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364:2483-2495.


11

Tseng and Wall 61. Challand C, Struthers R, Sneyd JR, et al. Randomized controlled trial of intraoperative goal-directed fluid therapy in aerobically fit and unfit patients having major colorectal surgery. Br J Anaesth. 2012;108:53-62. 62. Aya HD, Cecconi M, Hamilton M, et al. Goal-directed therapy in cardiac surgery: a systematic review and metaanalysis. Br J Anaesth. 2013;110:510-517. 63. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39:259-265.

64. Sadaka F, Juarez M, Naydenov S, et al. Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality [published online February 27, 2013]. J Intensive Care Med. 65. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309:678-688. 66. Reinhart K, Perner A, Sprung C, et al. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med. 2012;38:368-383.


Endpoints of resuscitation.

Nursing elements: what are they?

Predatory Journals: What are they?

Commentary: What are behavior systems and what use are they?

CPT® Codes: What Are They, Why Are They Necessary, and How Are They Developed?

Guidelines: what are they and how will they be used?

What is the P-value anyway?

Parasites: what are they good for?

Things are seldom what they seem.

Peer reviewers: "What are they thinking?".

Pollen aquaporins: What are they there for?

Audit officers: what are they up to?

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

Hypolipidaemic agents: What are they good for?

Emerging properties of adhesion complexes: what are they and what do they do?

Small-area variations: what are they and what do they mean? Health Services Research Group.

What is a placental mammal anyway?

Linguistic markers of emotion in mothers of sickle cell carrier infants: what are they and what do they mean?

At what cost are resuscitation discussions avoided in general practice?

psychogenic movement disorders: do we know what they are?

Processes of believing: Where do they come from? What are they good for?

Medical clinic referral letters. Do they say what they mean? Do they mean what they say?

Processes of believing: Where do they come from? What are they good for?

What are karrikins and how were they 'discovered' by plants?