It is important to note that the pragmatic study design in trials 6S and CHEST meant that clinicians used fluids without explicit algorithms. The concept of volume responsiveness is critical because fluid therapy administered to “volume nonresponders” is potentially harmful.42 In both CHEST and 6S trials, initial resuscitation had occurred before randomization. Hence, the quantitative harm from receipt of unnecessary fluids may have been compounded by the qualitative harm from fluid type (in this case, HES). Recently, the CRISTAL trial reported a practical randomized comparison of crystalloids versus colloids among patients with acute hypovolemia23 but had potential for bias due to a lack of blinding. The primary 28-day mortality outcome was equivalent, while the secondary 90-day mortality outcome showed an advantage for colloids (0.88; 95% confidence interval, 0.77–0.99). The colloid group also had more days alive and more days without vasopressor therapy and mechanical ventilation at 7 and 28 days. Proponents of HES may cite the lack of a mortality difference in CHEST and highlight better mortality outcomes among acutely hypovolemic patients in the CRISTAL trial, emphasizing the importance of volume context during administration of HES. However, the possible benefits in secondary outcomes observed in CRISTAL need to be confirmed in further studies.
What inferences regarding use of HES in the intraoperative period can one make based on RCTs conducted on ICU populations? We believe that context is crucial: the population at-risk; interventions being compared; and outcomes being evaluated need to be carefully contrasted in order for clinicians to weigh the situational risks and benefits of therapy in the OR versus in the ICU.43 More than 2800 patients randomized in CHEST were in the ICU postoperatively (after emergent or elective noncardiac and nonliver transplantation surgery). As subset results are not yet available, it is unclear whether outcomes in this subset were similar to that of the entire cohort. Regardless, these data may not adequately inform clinicians about the risks versus benefits of intraoperative volume optimization with HES. The traditional Starling model of forces governing IV fluid disposition is being revised with increasing insight into the role of the endothelial glycocalyx layer and volume context,44,45 and physiologic appraisal suggests that traditional colloid-crystalloid distinctions may be of less importance than previously thought. The risk of using modern tetrastarch in the setting of an intact glycocalyx in the patient undergoing intravascular volume optimization early during major surgery may be potentially different than risks associated with severe sepsis where there is significant glycocalyx shedding and disruption. From a clinical standpoint: first, patients presenting for preemptive volume optimization (the population-at-risk) have a lower predicted mortality at baseline (compared with ICU patients). Assessment of mortality risks associated with use of HES during GDT would require a very large RCT (rare outcome). Second, HES during GDT is restricted to those instances where flow improves with fluid administration.4,5 As suggested by the CRISTAL trial, safety outcomes may be equivalent or favor colloids when patients are volume responsive. Third, safety risks from HES might not be relevant if the alternative is potentially harmful such as the empiric use of large volumes of saline.40,46 It is possible that the risk of harm could actually increase when albumin or saline boluses are used.47 By addressing occult hypovolemia early during major surgery, GDT could improve outcomes and lower the risk of harm from HES.
As the trend in perioperative fluid therapy moves toward a more restrictive approach, it may become even more difficult to appreciate outcome differences between different fluid types. The total administered volume may be more important than the type of fluid given.48 We suggest that Bellamy’s49 as well as Kehlet and Bundgaard-Nielsen’s50 descriptions of the relationship between toxicity (risk) and fluid dose (or volume status) may help clinicians conceptualize these potential differences. This dose-toxicity curve may be modified by patient characteristics (cardiovascular disease and other comorbidities, critical illness), surgical factors (inadequate modulation of the surgical stress response), and fluid choice. Curves may be U shaped in the OR and V shaped in the ICU, reflecting narrow physiologic reserves in the critically ill and a greater safety margin in the OR. Individualized goals target the augmentation of preload to achieve euvolemia. In contrast, a traditional arterial blood pressure and urine output-guided approach may be associated with increased risks. For example, the clinician’s response to low blood pressure or oliguria may be fluid therapy although vasopressors (in distributive shock states like neuraxial blockade) or inotropes/diuretics (cardiogenic shock state) may be indicated.
RCTs powered for short-term efficacy outcomes may not offer any insight into safety. For instance, in the CRYSTMAS trial that was conducted to fulfill a postmarketing regulatory requirement, Guidet et al.51 compared VoluvenTM with saline in patients suffering from severe sepsis, and the primary outcome was the fluid amount required to achieve initial hemodynamic stability. Investigators found that slightly less HES was needed but also concluded that there was no evidence of long-term harm, which was inconsistent with the results of the larger 6S trial where long-term harm was demonstrated. Similarly, Feldheiser et al.52 compared balanced tetrastarch with balanced crystalloids within a GDT context, finding a modest and proximal efficacy advantage. There is no GDT trial large enough with a follow-up period long enough, to draw definitive conclusions regarding the risks of intraoperative HES. There is a significant likelihood of type II errors for safety outcomes. Benefit may be modest and plateau early, while toxicity may be cumulative and occur late. Rather than draw conclusions about intraoperative safety from underpowered studies, we believe that clinicians should ask if an adequately powered trial should be designed for that specific clinical context. As shown by Yates et al.,53 crystalloids can be used for GDT, but more volume will be needed. For patients in whom this excess in volume may need to be avoided, HES might offer benefits potentially without (measurable) harm. Hence, the gap in the literature, the relationship between use of colloid during GDT and long-term patient-centered outcomes, needs to be filled. We recommend that future RCTs focus on safety outcomes over an extended postoperative period as suggested by Myles and Devereaux54 (disability-free survival at 1 year). In addition, we also suggest that future studies on fluid choice examine the effects of variable chloride content and strong ion difference.
Careful consideration of quantitative and qualitative toxicities is needed. Timing of therapy, volume context, fluid type, patient comorbidities, mortality risk, and the type of surgical procedure (effects on the endothelial glycocalyx) are all relevant but beyond the scope of this discussion. There may yet be a role for perioperative HES but precisely who will benefit and how much is unclear. To work within the recent regulatory restrictions placed on HES, clinicians may find the following considerations helpful:
* Define the problem that IV fluid therapy is intended to solve. For example, volume responsiveness does not equal volume deficiency. Conversely, volume deficiency should be assessed by testing for volume responsiveness rather than assumed based on changes in blood pressure or urine output.
* Define the goal of therapy. This may vary according to the clinical setting. With active bleeding, for example, the goal may be to allow moderate hypotension until surgical control is established rather than to volume load with crystalloids. In contrast, the goal with preemptive GDT is to fluid load for maximal stroke volume.
* Determine the type of fluid to use. We believe that balanced crystalloid solutions may be a safe default for most situations. Colloids may be indicated in specific settings such as to avoid large crystalloid volumes during the management of acute hypovolemia or in preemptive GDT.
* Delineate starting and stopping points with monitoring for response during treatment. This implies measuring end-organ perfusion, recognizing that this varies by organ.
We would like to thank Dr. Jonathan Mark and Kathy Gage, both from the Department of Anesthesiology, Duke University Medical Center, for their thoughtful comments and help with the preparation of this manuscript. We would also like to thank the editor and reviewers of Anesthesia & Analgesia for their constructive and detailed review.
1. Raghunathan K, Shaw AD, Bagshaw SM. Fluids are drugs: type, dose and toxicity. Curr Opin Crit Care. 2013;19:290–8
2. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, Du B, McArthur C, Myburgh JSAFE TRIPS Investigators. . Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care. 2010;14:R185
3. Cannesson M, Pestel G, Ricks C, Hoeft A, Perel A. Hemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologists. Crit Care. 2011;15:R197
4. Corcoran T, Rhodes JE, Clarke S, Myles PS, Ho KM. Perioperative fluid management strategies in major surgery: a stratified meta-analysis. Anesth Analg. 2012;114:640–51
5. Hamilton MA, Cecconi M, Rhodes A. A systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients. Anesth Analg. 2011;112:1392–402
6. Grocott MP, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan KOptimisation Systematic Review Steering Group. . Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database Syst Rev. 2012;11:CD004082
7. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013;2:CD000567
8. Rhee P. Shock, Electrolytes and Fluids. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice, 18th edition. 2012 Philadelphia, PA Elsevier Health Sciences:66–119
9. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton RSAFE Study Investigators. . A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–56
10. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SACHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. . Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–11
11. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. 2001;72:527–33
12. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911–6
13. Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2010;1:CD007594
14. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart KGerman Competence Network Sepsis (SepNet). . Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–39
15. Bunn F, Trivedi D. Colloid solutions for fluid resuscitation. Cochrane Database Syst Rev. 2012;6:CD001319
16. Morris C, Rogerson D. What is the optimal type of fluid to be used for peri-operative fluid optimisation directed by oesophageal Doppler monitoring? Anaesthesia. 2011;66:819–27
17. Rhodes A, Cecconi M, Hamilton M, Poloniecki J, Woods J, Boyd O, Bennett D, Grounds RM. Goal-directed therapy in high-risk surgical patients: a 15-year follow-up study. Intensive Care Med. 2010;36:1327–32
18. Shafer SL. Shadow of doubt. Anesth Analg. 2011;112:498–500
19. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J6S Trial Group; Scandinavian Critical Care Trials Group. . Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34
20. Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg. 2013;116:35–48
21. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anesth. 2011;107:693–702
22. Reinhart K, Perner A, Sprung CL, Jaeschke R, Schortgen F, Johan Groeneveld AB, Beale R, Hartog CSEuropean Society of Intensive Care Medicine. . Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med. 2012;38:368–83
23. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, Preiser JC, Outin H, Troché G, Charpentier C, Trouillet JL, Kimmoun A, Forceville X, Darmon M, Lesur O, Régnier J, Abroug F, Berger P, Clec’h C, Cousson J, Thibault L, Chevret SCRISTAL Investigators. . Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310:1809–17
24. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H. Hydroxyethyl starches: different products–different effects. Anesthesiology. 2009;111:187–202
25. Mizzi A, Tran T, Karlnoski R, Anderson A, Mangar D, Camporesi EM. Voluven, a new colloid solution. Anesthesiol Clin. 2011;29:547–55
26. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet. 2012;51:225–36
27. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, Wakeling H, Moskowitz DM, Olufolabi Y, Konstadt SN, Bradford C, Glass PS, Machin SJ, Mythen MG. Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Hextend Study Group. Anesth Analg. 1999;88:992–8
28. Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology. 2005;103:654–60
29. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P. The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesth Analg. 2008;107:382–90
30. Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet. 2005;44:681–99
31. Lehmann GB, Asskali F, Boll M, Burmeister MA, Marx G, Hilgers R, Förster H. HES 130/0.42 shows less alteration of pharmacokinetics than HES 200/0.5 when dosed repeatedly. Br J Anaesth. 2007;98:635–44
32. Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet. 1996;348:1620–2
33. Bayer O, Reinhart K, Sakr Y, Kabisch B, Kohl M, Riedemann NC, Bauer M, Settmacher U, Hekmat K, Hartog CS. Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison. Crit Care Med. 2011;39:1335–42
34. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA. 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;309:678–88
35. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg. 2012;144:223–30
36. Sossdorf M, Marx S, Schaarschmidt B, Otto GP, Claus RA, Reinhart K, Hartog CS, Lösche W. HES 130/0.4 impairs haemostasis and stimulates pro-inflammatory blood platelet function. Crit Care. 2009;13:R208
37. Gandhi SD, Weiskopf RB, Jungheinrich C, Koorn R, Miller D, Shangraw RE, Prough DS, Baus D, Bepperling F, Warltier DC. Volume replacement therapy during major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology. 2007;106:1120–7
38. Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, Wetterslev J. Hydroxyethyl starch 130/0.38–0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ. 2013;346:839
39. Raghunathan K, Shaw A. Hydroxyethyl starch or saline in intensive care. N Engl J Med. 2013;368:774–5
40. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308:1566–72
41. Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, Kellum JA. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255:821–9
42. Michard F, Teboul JL. Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence. Chest. 2002;121:2000–8
43. Weiskopf RB. Equivalent efficacy of hydroxyethyl starch 130/0.4 and human serum albumin: if nothing is the same, is everything different? The importance of context in clinical trials and statistics. Anesthesiology. 2013;119:1249–54
44. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108:384–94
45. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology. 2008;109:723–40
46. McCluskey SA, Karkouti K, Wijeysundera D, Minkovich L, Tait G, Beattie WS. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117:412–21
47. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DMFEAST Trial Group. . Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364:2483–95
48. Brandstrup B, Svendsen PE, Rasmussen M, Belhage B, Rodt SÅ, Hansen B, Møller DR, Lundbech LB, Andersen N, Berg V, Thomassen N, Andersen ST, Simonsen L. Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance? Br J Anaesth. 2012;109:191–9
49. Bellamy MC. Wet, dry or something else? Br J Anaesth. 2006;97:755–7
50. Kehlet H, Bundgaard-Nielsen M. Goal-directed perioperative fluid management: why, when, and how? Anesthesiology. 2009;110:453–5
51. Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, Van Aken H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16:R94
52. Feldheiser A, Pavlova V, Bonomo T, Jones A, Fotopoulou C, Sehouli J, Wernecke KD, Spies C. Balanced crystalloid compared with balanced colloid solution using a goal-directed haemodynamic algorithm. Br J Anesth. 2013;110:231–40
53. Yates DR, Davies SJ, Milner HE, Wilson RJ. Crystalloid or colloid for goal-directed fluid therapy in colorectal surgery. Br J Anesth. 2014;112:281–9
54. Myles PS, Devereaux PJ. Pros and cons of composite endpoints in anesthesia trials. Anesthesiology. 2010;113:776–8