- Email: [email protected]
Fluid management in the critically ill
review
www.kidney-international.org
Fluid management in the critically ill Jean-Louis Vincent1 1
Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
Fluid therapy, which is provided to restore and maintain tissue perfusion, is part of routine management for almost all critically ill patients. However, because either too much or too little fluid can have a negative impact on patient outcomes, fluid administration must be titrated carefully for each patient. The “salvage, optimization, stabilization, de-escalation” (SOSD) mnemonic should be used as a general guide to fluid resuscitation, and fluid administration should be adapted according to the course of the disease. In the initial salvage phase, lifesaving fluid should be administered generously. Once hemodynamic monitoring is available, fluid administration should be optimized by determining the patient’s fluid status and the need for further fluid. This determination can be difficult, however; clinical indicators of hypovolemia, such as heart rate, blood pressure, and urine output, may not detect early hypovolemia, and edema is a late sign of fluid overload. Dynamic tests of fluid responsiveness such as pulse pressure or stroke volume variation can be used in only a small percentage of critically ill patients, and thus a fluid challenge technique is most frequently used to assess ongoing fluid requirements. Once a patient has been stabilized, efforts should start to concentrate on removing excess fluid. Which fluid should be used remains a matter of some debate. Crystalloid solutions are cheaper than colloid solutions, but colloid solutions remain in the intravascular space for a longer period, making edema less likely. Thus crystalloids and colloids should be used together, especially in patients likely to require large fluid volumes. Human albumin is a natural colloid and may have beneficial effects in patients with sepsis in addition to its volume effects. Fluids should be prescribed as are other medications, taking into account individual patient factors, disease processes, and other treatments. Kidney International (2019) 96, 52–57; https://doi.org/10.1016/ j.kint.2018.11.047 KEYWORDS: albumin; colloid; crystalloid; fluid challenge; hypovolemia Copyright ª 2019, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Correspondence: Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. E-mail: [email protected] Received 13 April 2018; revised 20 November 2018; accepted 28 November 2018; published online 4 March 2019 52
F
luid management in critically ill patients is both a simple and a complex process. It can be considered “simple” because inserting a catheter and allowing a solution to run into a vein is really not a very sophisticated procedure. Fluid administration represents one of the core interventions in the management of acutely ill patients, with about one third of patients in the intensive care unit (ICU) receiving resuscitation fluids on a specific day1 and many more receiving maintenance fluids. However, although administering fluids in critically ill patients is a common intervention, it is far from simple if it is performed correctly. Determining the optimal type and amount of fluid for each patient at any specific moment in his or her ICU course is actually rather complex. Because colloid fluids can be administered in smaller amounts than can crystalloid fluids to produce the same effect, the amount and type of fluid are related. However, for the sake of simplicity we will consider these 2 aspects separately.2 Amount of fluid
The amount of fluid required by any one patient depends on several factors, including the patient’s diagnosis and severity of disease. We need to find the ideal balance between too little and too much fluid in all patients, because both these conditions are associated with worse outcomes3 (Figure 14). Too little fluid leads to hypovolemia, which can result in inadequate cardiac output and thus decreased tissue perfusion. Hypovolemia ultimately leads to multiple organ failure and death. However, too much fluid leads to hypervolemia, which can result in edema. Edema can result in altered organ function. Importantly, altered capillary permeability and hypo-oncocity can contribute to edema formation even when the effective circulating blood volume is not increased, which is why the term “fluid overload” should be used with great caution.5 The effects of lung edema are perhaps the most obvious clinically, with altered gas exchange rapidly apparent. However, edema in other organs can lead to delirium, abdominal compartment syndrome, and impaired wound healing, to mention just a few possible consequences. The kidney, being an encapsulated organ, is also sensitive to the effects of edema. Increases in venous pressure have been associated with the development of acute renal failure,6 and fluid overload is associated with an increased risk of acute renal failure7 and worse outcomes in patients with acute renal failure.7,8 In the Sepsis Occurrence in Acutely Ill Patients study, a positive fluid balance was an independent predictor of poor outcome in patients with acute renal failure (hazard ratio: 1.21; 95% confidence interval: 1.13–1.28; P < 0.001).8 Kidney International (2019) 96, 52–57
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J-L Vincent: Fluid management in the critically ill
Important interactions between organs also can occur.9 For example, altered cardiac function can further reduce tolerance to fluids, with increases in cardiac filling pressures. In intensive care medicine, the interaction between the lungs and the kidneys is often an important consideration (Figure 2). Generally it is preferable to keep the lungs dry to limit lung edema and preserve gas exchange, but the kidneys need to be well perfused to maintain function. Whereas the lungs do not suffer much from fluid restriction, the kidneys do suffer from fluid restriction. Unfortunately one cannot use global formulas to decide how much fluid a patient requires; this process requires individualization guided by hemodynamic monitoring. Moreover, the time factor is of great importance and varies according to the phase of resuscitation. Four phases can be recognized: salvage, optimization, stabilization, and deescalation.10 Salvage. Salvage is the initial phase during which a patient needs rapid resuscitation for profound alterations in tissue perfusion as a result of multiple conditions, including sepsis, hemorrhage, and profound dehydration. During this very early phase, a plentiful amount of fluids must be administered rapidly to facilitate effective resuscitation. Often the need to act quickly means there is no time to position complex monitoring systems to guide fluid administration. The Surviving Sepsis Campaign guidelines were strongly criticized for recommending administration of 30 ml/kg of fluid over 3 hours, which is too long a period. The updated 1hour Surviving Sepsis Campaign bundle11 is still suboptimal, because it only states that one should “begin” administration of fluid within the first hour. One should rather consider giving 500 ml to 1 L of fluid over a short period, definitely less than 1 hour. Authors of a recent study reported increased mortality rates in patients with sepsis who received initial fluid resuscitation more than 2 hours after diagnosis.12 As additional monitoring devices are utilized and we move into the next phase of optimization, the amount of fluid administered can quickly be individualized to the patient’s needs. Importantly, in patients with severe hypotension, vasopressor therapy should be started along with fluid administration because a clear relation exists between the magnitude and duration of hypotension and patient outcomes.13,14 Moreover, in patients with septic shock, hypotension is in large part the result of decreased vascular tone, which is not corrected by fluid administration alone.15 Indeed, it is often difficult to determine the prevalent pathophysiologic process underlying the hemodynamic failure or shock, which can include some degree of increased endothelial permeability (in which case fluids are required) and/or vasodilation (requiring vasopressor agents). Therapeutic strategies that can decrease permeability alterations by protecting the endothelium are being studied, but currently fluid administration is the only effective option. Vasopressin (and vasopressin derivatives), interferon-b, and thrombomodulin are potential candidates for endothelial cell protection,16 but it is difficult to evaluate permeability Kidney International (2019) 96, 52–57
Risk of complications
Hypervolemia
Hypovolemia Altered tissue perfusion Renal failure Anastomosis leakage Confusion, risk of CVA Splanchnic ischemia MOF
Edema Intra-abdominal hypertension Respiratory failure Impaired healing Altered mobilization MOF
Volume status
Figure 1 | The relationship between blood volume and the risk of complications. Both hypo- and hypervolemia should be avoided because these 2 extremes are associated with a greater risk of complications. CVA, cerebrovascular accident; MOF, multiple organ failure. Modified from Vincent JL, Pelosi P, Pearse R, et al. Perioperative cardiovascular monitoring of high-risk patients: a consensus of 12. Crit Care. 2015;19:224.4 Copyright ª 2015 Vincent et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
changes in patients and thus to establish who may benefit from these therapies; the techniques of weighing, measuring fluid balance using in-out charts, and biomarkers are all unreliable. When vasopressors are used, norepinephrine is the vasopressor of choice in critically ill patients.17 Optimization. As soon as is possible, in addition to performing a reliable assessment of heart rate and arterial pressure, an echocardiogram should be obtained to assess the degree of filling and function of the cardiac chambers, because clinical assessment of ventricular function is often inaccurate.18 Echography should be repeated periodically to monitor the response to treatment. Every physician involved in the management of acutely ill patients should be able to perform an echocardiogram, and mobile point-of-care devices are now widely available.19 Blood lactate levels, which are increased in patients with shock and reflect tissue oxygenation, should be measured serially (at least every hour) as an indicator of the effectiveness of therapy and resolution of shock.20 In terms of fluid administration, the optimization phase consists of the administration of a limited amount of i.v. fluid, with careful evaluation of the patient’s response. Signs of fluid responsiveness before any additional fluid is given can be very valuable to avoid giving fluids to patients who may not benefit from them. Importantly, such tests of fluid responsiveness should be used only if it is unclear whether a patient needs fluids. If a patient clearly needs fluid—for example, if he or she has acute bleeding or hypotension that recurs as soon as the fluid administration rate is slowed—then time should not be wasted in assessing fluid responsiveness. However, in 53
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J-L Vincent: Fluid management in the critically ill
Table 1 | Requirements for use of pulse pressure variation and stroke volume variation to assess fluid responsiveness
Renal dysfunction Pre-renal
Renal
Maximize fluids + vasoactive agents?
Maximize fluids + vasoactive agents?
Hemodynamic
Nonhemodynamic
Minimize fluids + vasoactive agents?
Minimize fluids + vasoactive agents?
Lung edema
Figure 2 | The lung/kidney dilemma during fluid resuscitation. Restricting fluid administration may reduce the risk of lung edema but also can reduce renal perfusion, leading to renal dysfunction. However, providing sufficient fluid to maintain renal function can result in pulmonary edema with reduced gas exchange.
patients for whom the added benefit of fluid is unclear, assessment of fluid responsiveness can be useful. Several techniques have been proposed for this purpose. In patients undergoing mechanical ventilation, changes in the arterial pulse pressure (pulse pressure variation) during the respiratory cycle can reflect the sensitivity of cardiac filling. Likewise, some hemodynamic monitoring systems assess the variation in stroke volume during the respiratory cycle. However, these measures have several limitations, which are listed in Table 1. The most important limitation is that these measures are only reliable during controlled mechanical ventilation, when the patient does not trigger the ventilator. This restriction may be possible when anesthesia is induced in the operating room but not under other conditions, because we try to avoid use of sedative agents as much as possible in ICUs today.21 In addition, the use of low tidal volumes is recommended today not only in patients with acute respiratory distress syndrome but in all patients undergoing mechanical ventilation, but the use of low tidal volumes decreases the magnitude of the signal, making it less reliable. Given the limitations of these signs of fluid responsiveness, central venous pressure (CVP) measurement can still be helpful. Importantly, a single measurement of CVP may not provide much information about the patient’s response to fluid, and changes in CVP values should be measured during a fluid challenge to evaluate the dynamic response to fluid.22 The Surviving Sepsis Campaign guidelines23 recommend that fluid challenge be the first method used to guide fluid administration in patients with sepsis. Nevertheless, fluid challenges must be conducted correctly, with a predefined amount of fluid (100 to 200 ml) given as a slow bolus while monitoring the response to ensure that preset safety limits, such as a specific CVP value, are not exceeded. In a patient with hypovolemia, the fluid challenge will result in an increase in cardiac output with a small increase in CVP; in a patient with adequate or excessive filling, however, the CVP will increase considerably while the cardiac output remains unchanged.24 Importantly, to correctly interpret these 54
Mechanical ventilation Relatively large tidal volume No spontaneous breathing activity No major arrhythmia No significant tachypnea No right ventricular failure No intra-abdominal hypertension
changes, close monitoring is required and the patient must receive no other interventions during the procedure. Fluid responsiveness also can be assessed by an “internal” or “endogenous” fluid challenge using a passive leg raising test, which results in transfer of blood from the legs to the intrathoracic compartment. This technique is more complex than simply “raising the legs.”25 Importantly, one cannot use an arterial pressure measurement alone to monitor the response to passive leg raising; stroke volume needs to be monitored closely in a quiet environment, because the result is dependent on detecting a transient increase in stroke volume. Whichever technique is used, it must be remembered that the presence of fluid responsiveness does not necessarily mean that fluids should be administered (indeed, healthy persons are fluid responsive), but lack of fluid responsiveness suggests that fluid administration should be stopped, similar to the situation in which there is no response to a fluid challenge. A simple algorithm to evaluate the need for fluid is presented in Figure 3. Stabilization. Importantly, the optimization methods previously described better serve to identify when to stop fluids than when to start them. Once the patient is stable, or when the patient no longer responds to fluid, aggressive fluid administration must be stopped, and only minimal, if any, maintenance fluid is required. Too often, clinicians continue to administer fluids when they are no longer indicated. Persisting positive fluid balance is associated with worse outcomes,26 more so than a positive fluid balance early during resuscitation. In the large Intensive Care Over Nations study of 1808 patients with sepsis in the ICU, it was observed that a higher cumulative fluid balance at 72 hours after ICU admission but not during the first 24 hours was independently associated with an increase in the hazard of death.26 If fluid removal can be accomplished without needing to increase doses of vasopressor agents, this may be attempted, but withdrawing fluid while increasing the dose of vasopressors can be dangerous. De-escalation. When the patient is well stabilized, he or she enters the de-escalation phase and should not receive much fluid; rather, excess fluids should be eliminated to remove any edema that has formed. During this phase, diuretics can be administered if a negative fluid balance is not achieved spontaneously. Loop diuretics, such as furosemide, are most widely used but can lead to hypernatremia if sodium excretion is not adequate.27 Although diuretics have been associated with worse outcomes in patients with acute kidney Kidney International (2019) 96, 52–57
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J-L Vincent: Fluid management in the critically ill
Crystalloids
Problem that could be alleviated by fluid administration (hypotension, tachycardia, or oliguria)
Very low cardiac filling (pressures or volumes) and/or context of hypovolemia (bleeding, diarrhea, ...)
+ colloids
1.5
Intermediate/high cardiac filling (pressures or volumes)
Controlled mechanical ventilation (deep sedation — no triggering) No major arrhythmia No RV failure Fluid loading
Crystalloids
1
0.5
No Fluid challenge
Yes Pulse pressure variation (PPV) Stroke volume variation (SVV) End-expiratory pause
Internal External (passive leg raising)
Figure 3 | A simple algorithm for fluid administration in acutely ill patients. RV, right ventricular.
injury, in patients with excess fluid and acute kidney injury, diuretic use may still be beneficial by creating a negative fluid balance.28 Nevertheless, in patients with renal dysfunction, diuretics are less effective and renal replacement therapy (RRT) will likely be necessary. In a recent survey of Australia, New Zealand, and United Kingdom intensivists, RRT was preferred over diuretic therapy if a fluid-overloaded critically ill patient was oliguric or anuric or if he or she had a significant degree of acute kidney injury.29 Few published data support the use of pharmacologic or mechanical methods of fluid removal in critically ill patients. In patients treated with RRT, ultrafiltration can be used but should be performed prudently to allow equilibration between the intravascular and extravascular volumes. If performed too aggressively, the ultrafiltration can result in relative hypovolemia with the associated risk of altered tissue perfusion. Importantly, the impact on perfusion may not be easily recognized clinically because hypotension is a relatively late sign of hypovolemia and cardiac output or central venous oxygen saturation may not be regularly monitored in these already stable patients. It is difficult to monitor changes in blood volume during RRT; some systems are available during hemodialysis, but they are not reliable in critically ill patients. Unfortunately, no chemical biomarkers apart from blood lactate (discussed earlier) are available that can reliably assess tissue perfusion or fluid status. B-type natriuretic protein has been proposed but is unreliable in the critically ill patient population.30 Type of fluid
With their large molecular weight, colloids persist longer in the intravascular space, and thus the addition of colloids to fluid management can decrease the total amount of fluid required and reduce the risk and amount of edema. A Kidney International (2019) 96, 52–57
0 Figure 4 | Differences in the amount of fluid required if using crystalloid solutions alone or when combining crystalloid solution with some colloid solution.
meta-analysis of prospective randomized controlled trials (RCTs) in various patient populations indicated that the amount of fluid could be reduced by one third if colloids were given in addition to crystalloids, instead of giving crystalloids alone.2 In a large pragmatic clinical trial comparing colloids with crystalloids, the same ratio of 1/1.5 was reported.31 These differences are illustrated in Figure 4 and are clinically relevant. As just one example, abdominal compartment syndrome is almost always associated with administration of large amounts of crystalloid solutions.32 For many years, the debate was considered to be about “crystalloids versus colloids,” but the real debate is actually “crystalloids alone versus crystalloids plus colloids.” Indeed, colloids are rarely administered alone, and an excessive increase in colloid osmotic pressure may alter renal function, supporting the additional use of crystalloid solutions when colloids are administered.33 Numerous studies have attempted to compare outcomes in patients treated with crystalloids versus outcomes in patients receiving colloids. A meta-analysis of 59 RCTs indicated that there was no increased risk of mortality in patients who received colloids compared with crystalloids.34 In patients with trauma, colloids seemed to decrease the incidence of acute renal failure by about 50% (odds ratio: 0.46 [95% confidence interval: 0.23–0.90]), whereas in critically ill patients or patients with sepsis, colloids were associated with an increased risk of acute renal failure compared with crystalloids (odds ratio: 1.24 [95% confidence interval: 1.09–1.41]).34 Administration of albumin solution, the only natural colloid fluid, can have a place in fluid management and may even decrease mortality in patients with septic shock.35,36 In the Albumin Italian Outcome Sepsis open-label randomized trial, the efficacy of saline solution with and without administration of 20% albumin solution was studied in 1818 patients with sepsis. Although there were no significant differences in overall survival after 28 or 90 days, in the 55
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subgroup of 1121 patients with septic shock, albumin was associated with a significant survival advantage after 90 days (relative risk of death: 0.87; 95% confidence interval: 0.77– 0.99).37 In addition to its volume-expanding qualities, albumin has other attributes, including antioxidant effects and drug-carrying properties. Hydroxyethyl starch (HES) solutions may represent a cheaper alternative, although the financial advantage is quite limited in the United States. The potentially harmful renal effects of HES solutions have been discussed,38 but the data remain controversial, especially because the largest study, the Crystalloid versus Hydroxyethyl Starch Trial, showed that although patients who received HES solutions were more likely to need RRT than were those who received saline solution, the incidence of renal dysfunction as expressed by the “Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease” criteria was significantly lower in the HES group than in the saline solution group.39 Intriguingly, against the advice of the jury of experts that they had themselves constituted, the safety committee (Pharmacovigilance Risk Assessment Committee) of the European Medicines Agency proposed that HES solutions should no longer be available in Europe.40 The discussion about revising the package insert of HES solutions is still ongoing. Because of their smaller molecular weight, gelatin solutions are less effective and are not available in the United States. An ongoing multicenter RCT in Europe is comparing gelatin-based resuscitation with balanced crystalloid-based resuscitation (ClincialTrials.gov identifier NCT02715466). Dextran solutions have been almost entirely abandoned. Among the crystalloid solutions, saline solutions, which include large amounts of chloride (154 mEq/l), induce hyperchloremic acidosis, and evidence shows that hyperchloremia may alter renal function by impairing internal hemodynamics. This finding was first demonstrated in the classic study by Wilcox in 1983.41 Hence chloride levels must be monitored during infusion and infusion of saline solutions must be stopped if hyperchloremia develops. I believe it is unfortunate that large RCTs are being conducted to compare saline solution with balanced solutions,42 because they may expose patients in the saline solution group to excessive risk. More specifically, in such a trial, if the saline solution is stopped when hyperchloremia develops, no differences will be found in outcomes between study arms, and if it is continued, there is almost no doubt that saline solution will be found to be harmful. Indeed, there is no evidence that hyperchloremia is associated with any beneficial effect; rather, it has been shown to be associated with worse outcomes.43 The recent Isotonic Solutions and Major Adverse Renal Events Trial (SMART) and Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED) RCTs indicated an increase in major adverse kidney events—a composite of death, new RRT, or persistent renal dysfunction—with saline solutions.44,45 This type of RCT thus raises ethical questions because there is no equipoise.46 Use of balanced solutions also can be criticized. Ringer’s lactate solutions (also called Hartmann’s solutions) are 56
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hypotonic and should be avoided, especially in patients with neurologic injury. Plasma-Lyte solutions contain acetate, which may have its own adverse effects. Davies et al.47 showed that the use of Plasma-Lyte as the circuit priming fluid during cardiopulmonary bypass was associated with supraphysiological plasma concentrations of acetate. My colleagues and I showed that the use of baths containing acetate during dialysis was associated with a decrease in myocardial contractility,48 and acetate was replaced by bicarbonate in dialysis baths a long time ago. However, it is unclear whether the smaller amounts of acetate received when Plasma-Lyte is used as a resuscitation fluid have similar potentially harmful effects.49 Hence i.v. fluids should be considered as drugs. Each fluid can have adverse effects, and there is no optimal fluid solution for all circumstances. Choices of fluid combinations in individual patients should be made according to various factors, including likely fluid requirements, underlying diagnoses, hemodynamic status, and laboratory results. It is important to have a variety of solutions available and to be cautious before banning the use of any specific type of solution. CONCLUSION
Optimal fluid management in the acutely ill patient remains a challenge. Although fluid administration initially may appear simple, it is actually quite complex and dependent on the pathophysiology underlying the hemodynamic instability. Intravenous fluids should be treated and prescribed as drugs, with the type and dosage adapted to each patient’s individual ongoing needs and tolerance. DISCLOSURE
The author declared no competing interests.
REFERENCES 1. Finfer S, Liu B, Taylor C, et al. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care. 2010;14:R185. 2. Orbegozo Cortes D, Gamarano Barros T, Njimi H, Vincent JL. Crystalloids versus colloids: exploring differences in fluid requirements by systematic review and meta-regression. Anesth Analg. 2015;120:389–402. 3. Balakumar V, Murugan R, Sileanu FE, et al. Both positive and negative fluid balance may be associated with reduced long-term survival in the critically ill. Crit Care Med. 2017;45:e749–e757. 4. Vincent JL, Pelosi P, Pearse R, et al. Perioperative cardiovascular monitoring of high-risk patients: a consensus of 12. Crit Care. 2015;19:224. 5. Vincent JL, Pinsky MR. We should avoid the term "fluid overload.". Crit Care. 2018;22:214. 6. Legrand M, Dupuis C, Simon C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care. 2013;17:R278. 7. Wang N, Jiang L, Zhu B, et al. Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. Crit Care. 2015;19:371. 8. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care. 2008;12:R74. 9. Lelubre C, Vincent JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018;14:417–427. 10. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369:1726– 1734. 11. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign bundle: 2018 update. Crit Care Med. 2018;46:997–1000. Kidney International (2019) 96, 52–57
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12. Leisman DE, Doerfler ME, Schneider SM, et al. Predictors, prevalence, and outcomes of early crystalloid responsiveness among initially hypotensive patients with sepsis and septic shock. Crit Care Med. 2018;46:189–198. 13. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18:532. 14. Vincent JL, Nielsen ND, Shapiro NI, et al. Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. Ann Intensive Care. 2018;8:107. 15. Hamzaoui O, Scheeren TWL, Teboul JL. Norepinephrine in septic shock: when and how much? Curr Opin Crit Care. 2017;23:342–347. 16. Vincent JL, Grimaldi D. Novel interventions—what’s new and the future. Crit Care Clin. 2018;34:161–173. 17. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779– 789. 18. Sekiguchi H, Harada Y, Villarraga HR, et al. Focused cardiac ultrasound in the early resuscitation of severe sepsis and septic shock: a prospective pilot study. J Anesth. 2017;31:487–493. 19. Michard F. A sneak peek into digital innovations and wearable sensors for cardiac monitoring. J Clin Monit Comput. 2017;31:253–259. 20. Vincent JL, Quintairos E Silva A, Couto L Jr, Taccone FS. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit Care. 2016;20:257. 21. Vincent JL, Shehabi Y, Walsh TS, et al. Comfort and patient-centred care without excessive sedation: the eCASH concept. Intensive Care Med. 2016;42:962–971. 22. De Backer D, Vincent JL. Should we measure the central venous pressure to guide fluid management? Ten answers to 10 questions. Crit Care. 2018;22:43. 23. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552. 24. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006;34: 1333–1337. 25. Monnet X, Teboul JL. Passive leg raising: five rules, not a drop of fluid! Crit Care. 2015;19:18. 26. Sakr Y, Rubatto Birri PN, Kotfis K, et al. Higher fluid balance increases the risk of death from sepsis: results from a large international audit. Crit Care Med. 2017;45:386–394. 27. Bellomo R. Issue and challenges of fluid removal in the critically ill. Br J Anaesth. 2014;113:734–735. 28. Grams ME, Estrella MM, Coresh J, et al. Fluid balance, diuretic use, and mortality in acute kidney injury. Clin J Am Soc Nephrol. 2011;6:966–973. 29. O’Connor ME, Jones SL, Glassford NJ, et al. Defining fluid removal in the intensive care unit: a national and international survey of critical care practice. J Intensive Care Soc. 2017;18:282–288. 30. Levitt JE, Vinayak AG, Gehlbach BK, et al. Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study. Crit Care. 2008;12:R3.
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31. Annane D, Siami S, Jaber S, et al. 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: 1809–1817. 32. Balogh ZJ, Lumsdaine W, Moore EE, Moore FA. Postinjury abdominal compartment syndrome: from recognition to prevention. Lancet. 2014;384:1466–1475. 33. Roche AM, James MF. Colloids and crystalloids: does it matter to the kidney? Curr Opin Crit Care. 2009;15:520–524. 34. Qureshi SH, Rizvi SI, Patel NN, Murphy GJ. Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. Br J Surg. 2016;103:14–26. 35. Vincent JL, De Backer D, Wiedermann CJ. Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care. 2016;35:161–167. 36. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161: 347–355. 37. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–1421. 38. Schetz M, Shaw AD, Vincent JL. Is the literature inconclusive about the harm of HES? We are not sure. Intensive Care Med. 2017;43:1526–1528. 39. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–1911. 40. Annane D, Fuchs-Buder T, Zoellner C, et al. EMA recommendation to suspend HES is hazardous. Lancet. 2018;391:736–738. 41. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71:726–735. 42. Vincent JL, De Backer D. Saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? Crit Care. 2016;20:250. 43. Stenson EK, Cvijanovich NZ, Anas N, et al. Hyperchloremia is associated with complicated course and mortality in pediatric patients with septic shock. Pediatr Crit Care Med. 2018;19:155–160. 44. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829–839. 45. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378:819–828. 46. Vincent JL, De Backer D. We do not appreciate SALT. Am J Respir Crit Care Med. 2018;197:1361. 47. Davies PG, Venkatesh B, Morgan TJ, et al. Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution. Crit Care. 2011;15:R21. 48. Vincent JL, Vanherweghem JL, Degaute JP, et al. Acetate-induced myocardial depression during hemodialysis for acute renal failure. Kidney Int. 1982;22:653–657. 49. Semler MW, Kellum JA. Balanced crystalloid solutions. Am J Respir Crit Care Med. 2019;199:952–960.
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Fluid management in the critically ill Jean-Louis Vincent1 1
Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
Fluid therapy, which is provided to restore and maintain tissue perfusion, is part of routine management for almost all critically ill patients. However, because either too much or too little fluid can have a negative impact on patient outcomes, fluid administration must be titrated carefully for each patient. The “salvage, optimization, stabilization, de-escalation” (SOSD) mnemonic should be used as a general guide to fluid resuscitation, and fluid administration should be adapted according to the course of the disease. In the initial salvage phase, lifesaving fluid should be administered generously. Once hemodynamic monitoring is available, fluid administration should be optimized by determining the patient’s fluid status and the need for further fluid. This determination can be difficult, however; clinical indicators of hypovolemia, such as heart rate, blood pressure, and urine output, may not detect early hypovolemia, and edema is a late sign of fluid overload. Dynamic tests of fluid responsiveness such as pulse pressure or stroke volume variation can be used in only a small percentage of critically ill patients, and thus a fluid challenge technique is most frequently used to assess ongoing fluid requirements. Once a patient has been stabilized, efforts should start to concentrate on removing excess fluid. Which fluid should be used remains a matter of some debate. Crystalloid solutions are cheaper than colloid solutions, but colloid solutions remain in the intravascular space for a longer period, making edema less likely. Thus crystalloids and colloids should be used together, especially in patients likely to require large fluid volumes. Human albumin is a natural colloid and may have beneficial effects in patients with sepsis in addition to its volume effects. Fluids should be prescribed as are other medications, taking into account individual patient factors, disease processes, and other treatments. Kidney International (2019) 96, 52–57; https://doi.org/10.1016/ j.kint.2018.11.047 KEYWORDS: albumin; colloid; crystalloid; fluid challenge; hypovolemia Copyright ª 2019, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Correspondence: Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. E-mail: [email protected] Received 13 April 2018; revised 20 November 2018; accepted 28 November 2018; published online 4 March 2019 52
F
luid management in critically ill patients is both a simple and a complex process. It can be considered “simple” because inserting a catheter and allowing a solution to run into a vein is really not a very sophisticated procedure. Fluid administration represents one of the core interventions in the management of acutely ill patients, with about one third of patients in the intensive care unit (ICU) receiving resuscitation fluids on a specific day1 and many more receiving maintenance fluids. However, although administering fluids in critically ill patients is a common intervention, it is far from simple if it is performed correctly. Determining the optimal type and amount of fluid for each patient at any specific moment in his or her ICU course is actually rather complex. Because colloid fluids can be administered in smaller amounts than can crystalloid fluids to produce the same effect, the amount and type of fluid are related. However, for the sake of simplicity we will consider these 2 aspects separately.2 Amount of fluid
The amount of fluid required by any one patient depends on several factors, including the patient’s diagnosis and severity of disease. We need to find the ideal balance between too little and too much fluid in all patients, because both these conditions are associated with worse outcomes3 (Figure 14). Too little fluid leads to hypovolemia, which can result in inadequate cardiac output and thus decreased tissue perfusion. Hypovolemia ultimately leads to multiple organ failure and death. However, too much fluid leads to hypervolemia, which can result in edema. Edema can result in altered organ function. Importantly, altered capillary permeability and hypo-oncocity can contribute to edema formation even when the effective circulating blood volume is not increased, which is why the term “fluid overload” should be used with great caution.5 The effects of lung edema are perhaps the most obvious clinically, with altered gas exchange rapidly apparent. However, edema in other organs can lead to delirium, abdominal compartment syndrome, and impaired wound healing, to mention just a few possible consequences. The kidney, being an encapsulated organ, is also sensitive to the effects of edema. Increases in venous pressure have been associated with the development of acute renal failure,6 and fluid overload is associated with an increased risk of acute renal failure7 and worse outcomes in patients with acute renal failure.7,8 In the Sepsis Occurrence in Acutely Ill Patients study, a positive fluid balance was an independent predictor of poor outcome in patients with acute renal failure (hazard ratio: 1.21; 95% confidence interval: 1.13–1.28; P < 0.001).8 Kidney International (2019) 96, 52–57
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Important interactions between organs also can occur.9 For example, altered cardiac function can further reduce tolerance to fluids, with increases in cardiac filling pressures. In intensive care medicine, the interaction between the lungs and the kidneys is often an important consideration (Figure 2). Generally it is preferable to keep the lungs dry to limit lung edema and preserve gas exchange, but the kidneys need to be well perfused to maintain function. Whereas the lungs do not suffer much from fluid restriction, the kidneys do suffer from fluid restriction. Unfortunately one cannot use global formulas to decide how much fluid a patient requires; this process requires individualization guided by hemodynamic monitoring. Moreover, the time factor is of great importance and varies according to the phase of resuscitation. Four phases can be recognized: salvage, optimization, stabilization, and deescalation.10 Salvage. Salvage is the initial phase during which a patient needs rapid resuscitation for profound alterations in tissue perfusion as a result of multiple conditions, including sepsis, hemorrhage, and profound dehydration. During this very early phase, a plentiful amount of fluids must be administered rapidly to facilitate effective resuscitation. Often the need to act quickly means there is no time to position complex monitoring systems to guide fluid administration. The Surviving Sepsis Campaign guidelines were strongly criticized for recommending administration of 30 ml/kg of fluid over 3 hours, which is too long a period. The updated 1hour Surviving Sepsis Campaign bundle11 is still suboptimal, because it only states that one should “begin” administration of fluid within the first hour. One should rather consider giving 500 ml to 1 L of fluid over a short period, definitely less than 1 hour. Authors of a recent study reported increased mortality rates in patients with sepsis who received initial fluid resuscitation more than 2 hours after diagnosis.12 As additional monitoring devices are utilized and we move into the next phase of optimization, the amount of fluid administered can quickly be individualized to the patient’s needs. Importantly, in patients with severe hypotension, vasopressor therapy should be started along with fluid administration because a clear relation exists between the magnitude and duration of hypotension and patient outcomes.13,14 Moreover, in patients with septic shock, hypotension is in large part the result of decreased vascular tone, which is not corrected by fluid administration alone.15 Indeed, it is often difficult to determine the prevalent pathophysiologic process underlying the hemodynamic failure or shock, which can include some degree of increased endothelial permeability (in which case fluids are required) and/or vasodilation (requiring vasopressor agents). Therapeutic strategies that can decrease permeability alterations by protecting the endothelium are being studied, but currently fluid administration is the only effective option. Vasopressin (and vasopressin derivatives), interferon-b, and thrombomodulin are potential candidates for endothelial cell protection,16 but it is difficult to evaluate permeability Kidney International (2019) 96, 52–57
Risk of complications
Hypervolemia
Hypovolemia Altered tissue perfusion Renal failure Anastomosis leakage Confusion, risk of CVA Splanchnic ischemia MOF
Edema Intra-abdominal hypertension Respiratory failure Impaired healing Altered mobilization MOF
Volume status
Figure 1 | The relationship between blood volume and the risk of complications. Both hypo- and hypervolemia should be avoided because these 2 extremes are associated with a greater risk of complications. CVA, cerebrovascular accident; MOF, multiple organ failure. Modified from Vincent JL, Pelosi P, Pearse R, et al. Perioperative cardiovascular monitoring of high-risk patients: a consensus of 12. Crit Care. 2015;19:224.4 Copyright ª 2015 Vincent et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
changes in patients and thus to establish who may benefit from these therapies; the techniques of weighing, measuring fluid balance using in-out charts, and biomarkers are all unreliable. When vasopressors are used, norepinephrine is the vasopressor of choice in critically ill patients.17 Optimization. As soon as is possible, in addition to performing a reliable assessment of heart rate and arterial pressure, an echocardiogram should be obtained to assess the degree of filling and function of the cardiac chambers, because clinical assessment of ventricular function is often inaccurate.18 Echography should be repeated periodically to monitor the response to treatment. Every physician involved in the management of acutely ill patients should be able to perform an echocardiogram, and mobile point-of-care devices are now widely available.19 Blood lactate levels, which are increased in patients with shock and reflect tissue oxygenation, should be measured serially (at least every hour) as an indicator of the effectiveness of therapy and resolution of shock.20 In terms of fluid administration, the optimization phase consists of the administration of a limited amount of i.v. fluid, with careful evaluation of the patient’s response. Signs of fluid responsiveness before any additional fluid is given can be very valuable to avoid giving fluids to patients who may not benefit from them. Importantly, such tests of fluid responsiveness should be used only if it is unclear whether a patient needs fluids. If a patient clearly needs fluid—for example, if he or she has acute bleeding or hypotension that recurs as soon as the fluid administration rate is slowed—then time should not be wasted in assessing fluid responsiveness. However, in 53
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Table 1 | Requirements for use of pulse pressure variation and stroke volume variation to assess fluid responsiveness
Renal dysfunction Pre-renal
Renal
Maximize fluids + vasoactive agents?
Maximize fluids + vasoactive agents?
Hemodynamic
Nonhemodynamic
Minimize fluids + vasoactive agents?
Minimize fluids + vasoactive agents?
Lung edema
Figure 2 | The lung/kidney dilemma during fluid resuscitation. Restricting fluid administration may reduce the risk of lung edema but also can reduce renal perfusion, leading to renal dysfunction. However, providing sufficient fluid to maintain renal function can result in pulmonary edema with reduced gas exchange.
patients for whom the added benefit of fluid is unclear, assessment of fluid responsiveness can be useful. Several techniques have been proposed for this purpose. In patients undergoing mechanical ventilation, changes in the arterial pulse pressure (pulse pressure variation) during the respiratory cycle can reflect the sensitivity of cardiac filling. Likewise, some hemodynamic monitoring systems assess the variation in stroke volume during the respiratory cycle. However, these measures have several limitations, which are listed in Table 1. The most important limitation is that these measures are only reliable during controlled mechanical ventilation, when the patient does not trigger the ventilator. This restriction may be possible when anesthesia is induced in the operating room but not under other conditions, because we try to avoid use of sedative agents as much as possible in ICUs today.21 In addition, the use of low tidal volumes is recommended today not only in patients with acute respiratory distress syndrome but in all patients undergoing mechanical ventilation, but the use of low tidal volumes decreases the magnitude of the signal, making it less reliable. Given the limitations of these signs of fluid responsiveness, central venous pressure (CVP) measurement can still be helpful. Importantly, a single measurement of CVP may not provide much information about the patient’s response to fluid, and changes in CVP values should be measured during a fluid challenge to evaluate the dynamic response to fluid.22 The Surviving Sepsis Campaign guidelines23 recommend that fluid challenge be the first method used to guide fluid administration in patients with sepsis. Nevertheless, fluid challenges must be conducted correctly, with a predefined amount of fluid (100 to 200 ml) given as a slow bolus while monitoring the response to ensure that preset safety limits, such as a specific CVP value, are not exceeded. In a patient with hypovolemia, the fluid challenge will result in an increase in cardiac output with a small increase in CVP; in a patient with adequate or excessive filling, however, the CVP will increase considerably while the cardiac output remains unchanged.24 Importantly, to correctly interpret these 54
Mechanical ventilation Relatively large tidal volume No spontaneous breathing activity No major arrhythmia No significant tachypnea No right ventricular failure No intra-abdominal hypertension
changes, close monitoring is required and the patient must receive no other interventions during the procedure. Fluid responsiveness also can be assessed by an “internal” or “endogenous” fluid challenge using a passive leg raising test, which results in transfer of blood from the legs to the intrathoracic compartment. This technique is more complex than simply “raising the legs.”25 Importantly, one cannot use an arterial pressure measurement alone to monitor the response to passive leg raising; stroke volume needs to be monitored closely in a quiet environment, because the result is dependent on detecting a transient increase in stroke volume. Whichever technique is used, it must be remembered that the presence of fluid responsiveness does not necessarily mean that fluids should be administered (indeed, healthy persons are fluid responsive), but lack of fluid responsiveness suggests that fluid administration should be stopped, similar to the situation in which there is no response to a fluid challenge. A simple algorithm to evaluate the need for fluid is presented in Figure 3. Stabilization. Importantly, the optimization methods previously described better serve to identify when to stop fluids than when to start them. Once the patient is stable, or when the patient no longer responds to fluid, aggressive fluid administration must be stopped, and only minimal, if any, maintenance fluid is required. Too often, clinicians continue to administer fluids when they are no longer indicated. Persisting positive fluid balance is associated with worse outcomes,26 more so than a positive fluid balance early during resuscitation. In the large Intensive Care Over Nations study of 1808 patients with sepsis in the ICU, it was observed that a higher cumulative fluid balance at 72 hours after ICU admission but not during the first 24 hours was independently associated with an increase in the hazard of death.26 If fluid removal can be accomplished without needing to increase doses of vasopressor agents, this may be attempted, but withdrawing fluid while increasing the dose of vasopressors can be dangerous. De-escalation. When the patient is well stabilized, he or she enters the de-escalation phase and should not receive much fluid; rather, excess fluids should be eliminated to remove any edema that has formed. During this phase, diuretics can be administered if a negative fluid balance is not achieved spontaneously. Loop diuretics, such as furosemide, are most widely used but can lead to hypernatremia if sodium excretion is not adequate.27 Although diuretics have been associated with worse outcomes in patients with acute kidney Kidney International (2019) 96, 52–57
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J-L Vincent: Fluid management in the critically ill
Crystalloids
Problem that could be alleviated by fluid administration (hypotension, tachycardia, or oliguria)
Very low cardiac filling (pressures or volumes) and/or context of hypovolemia (bleeding, diarrhea, ...)
+ colloids
1.5
Intermediate/high cardiac filling (pressures or volumes)
Controlled mechanical ventilation (deep sedation — no triggering) No major arrhythmia No RV failure Fluid loading
Crystalloids
1
0.5
No Fluid challenge
Yes Pulse pressure variation (PPV) Stroke volume variation (SVV) End-expiratory pause
Internal External (passive leg raising)
Figure 3 | A simple algorithm for fluid administration in acutely ill patients. RV, right ventricular.
injury, in patients with excess fluid and acute kidney injury, diuretic use may still be beneficial by creating a negative fluid balance.28 Nevertheless, in patients with renal dysfunction, diuretics are less effective and renal replacement therapy (RRT) will likely be necessary. In a recent survey of Australia, New Zealand, and United Kingdom intensivists, RRT was preferred over diuretic therapy if a fluid-overloaded critically ill patient was oliguric or anuric or if he or she had a significant degree of acute kidney injury.29 Few published data support the use of pharmacologic or mechanical methods of fluid removal in critically ill patients. In patients treated with RRT, ultrafiltration can be used but should be performed prudently to allow equilibration between the intravascular and extravascular volumes. If performed too aggressively, the ultrafiltration can result in relative hypovolemia with the associated risk of altered tissue perfusion. Importantly, the impact on perfusion may not be easily recognized clinically because hypotension is a relatively late sign of hypovolemia and cardiac output or central venous oxygen saturation may not be regularly monitored in these already stable patients. It is difficult to monitor changes in blood volume during RRT; some systems are available during hemodialysis, but they are not reliable in critically ill patients. Unfortunately, no chemical biomarkers apart from blood lactate (discussed earlier) are available that can reliably assess tissue perfusion or fluid status. B-type natriuretic protein has been proposed but is unreliable in the critically ill patient population.30 Type of fluid
With their large molecular weight, colloids persist longer in the intravascular space, and thus the addition of colloids to fluid management can decrease the total amount of fluid required and reduce the risk and amount of edema. A Kidney International (2019) 96, 52–57
0 Figure 4 | Differences in the amount of fluid required if using crystalloid solutions alone or when combining crystalloid solution with some colloid solution.
meta-analysis of prospective randomized controlled trials (RCTs) in various patient populations indicated that the amount of fluid could be reduced by one third if colloids were given in addition to crystalloids, instead of giving crystalloids alone.2 In a large pragmatic clinical trial comparing colloids with crystalloids, the same ratio of 1/1.5 was reported.31 These differences are illustrated in Figure 4 and are clinically relevant. As just one example, abdominal compartment syndrome is almost always associated with administration of large amounts of crystalloid solutions.32 For many years, the debate was considered to be about “crystalloids versus colloids,” but the real debate is actually “crystalloids alone versus crystalloids plus colloids.” Indeed, colloids are rarely administered alone, and an excessive increase in colloid osmotic pressure may alter renal function, supporting the additional use of crystalloid solutions when colloids are administered.33 Numerous studies have attempted to compare outcomes in patients treated with crystalloids versus outcomes in patients receiving colloids. A meta-analysis of 59 RCTs indicated that there was no increased risk of mortality in patients who received colloids compared with crystalloids.34 In patients with trauma, colloids seemed to decrease the incidence of acute renal failure by about 50% (odds ratio: 0.46 [95% confidence interval: 0.23–0.90]), whereas in critically ill patients or patients with sepsis, colloids were associated with an increased risk of acute renal failure compared with crystalloids (odds ratio: 1.24 [95% confidence interval: 1.09–1.41]).34 Administration of albumin solution, the only natural colloid fluid, can have a place in fluid management and may even decrease mortality in patients with septic shock.35,36 In the Albumin Italian Outcome Sepsis open-label randomized trial, the efficacy of saline solution with and without administration of 20% albumin solution was studied in 1818 patients with sepsis. Although there were no significant differences in overall survival after 28 or 90 days, in the 55
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subgroup of 1121 patients with septic shock, albumin was associated with a significant survival advantage after 90 days (relative risk of death: 0.87; 95% confidence interval: 0.77– 0.99).37 In addition to its volume-expanding qualities, albumin has other attributes, including antioxidant effects and drug-carrying properties. Hydroxyethyl starch (HES) solutions may represent a cheaper alternative, although the financial advantage is quite limited in the United States. The potentially harmful renal effects of HES solutions have been discussed,38 but the data remain controversial, especially because the largest study, the Crystalloid versus Hydroxyethyl Starch Trial, showed that although patients who received HES solutions were more likely to need RRT than were those who received saline solution, the incidence of renal dysfunction as expressed by the “Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease” criteria was significantly lower in the HES group than in the saline solution group.39 Intriguingly, against the advice of the jury of experts that they had themselves constituted, the safety committee (Pharmacovigilance Risk Assessment Committee) of the European Medicines Agency proposed that HES solutions should no longer be available in Europe.40 The discussion about revising the package insert of HES solutions is still ongoing. Because of their smaller molecular weight, gelatin solutions are less effective and are not available in the United States. An ongoing multicenter RCT in Europe is comparing gelatin-based resuscitation with balanced crystalloid-based resuscitation (ClincialTrials.gov identifier NCT02715466). Dextran solutions have been almost entirely abandoned. Among the crystalloid solutions, saline solutions, which include large amounts of chloride (154 mEq/l), induce hyperchloremic acidosis, and evidence shows that hyperchloremia may alter renal function by impairing internal hemodynamics. This finding was first demonstrated in the classic study by Wilcox in 1983.41 Hence chloride levels must be monitored during infusion and infusion of saline solutions must be stopped if hyperchloremia develops. I believe it is unfortunate that large RCTs are being conducted to compare saline solution with balanced solutions,42 because they may expose patients in the saline solution group to excessive risk. More specifically, in such a trial, if the saline solution is stopped when hyperchloremia develops, no differences will be found in outcomes between study arms, and if it is continued, there is almost no doubt that saline solution will be found to be harmful. Indeed, there is no evidence that hyperchloremia is associated with any beneficial effect; rather, it has been shown to be associated with worse outcomes.43 The recent Isotonic Solutions and Major Adverse Renal Events Trial (SMART) and Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED) RCTs indicated an increase in major adverse kidney events—a composite of death, new RRT, or persistent renal dysfunction—with saline solutions.44,45 This type of RCT thus raises ethical questions because there is no equipoise.46 Use of balanced solutions also can be criticized. Ringer’s lactate solutions (also called Hartmann’s solutions) are 56
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hypotonic and should be avoided, especially in patients with neurologic injury. Plasma-Lyte solutions contain acetate, which may have its own adverse effects. Davies et al.47 showed that the use of Plasma-Lyte as the circuit priming fluid during cardiopulmonary bypass was associated with supraphysiological plasma concentrations of acetate. My colleagues and I showed that the use of baths containing acetate during dialysis was associated with a decrease in myocardial contractility,48 and acetate was replaced by bicarbonate in dialysis baths a long time ago. However, it is unclear whether the smaller amounts of acetate received when Plasma-Lyte is used as a resuscitation fluid have similar potentially harmful effects.49 Hence i.v. fluids should be considered as drugs. Each fluid can have adverse effects, and there is no optimal fluid solution for all circumstances. Choices of fluid combinations in individual patients should be made according to various factors, including likely fluid requirements, underlying diagnoses, hemodynamic status, and laboratory results. It is important to have a variety of solutions available and to be cautious before banning the use of any specific type of solution. CONCLUSION
Optimal fluid management in the acutely ill patient remains a challenge. Although fluid administration initially may appear simple, it is actually quite complex and dependent on the pathophysiology underlying the hemodynamic instability. Intravenous fluids should be treated and prescribed as drugs, with the type and dosage adapted to each patient’s individual ongoing needs and tolerance. DISCLOSURE
The author declared no competing interests.
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31. Annane D, Siami S, Jaber S, et al. 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: 1809–1817. 32. Balogh ZJ, Lumsdaine W, Moore EE, Moore FA. Postinjury abdominal compartment syndrome: from recognition to prevention. Lancet. 2014;384:1466–1475. 33. Roche AM, James MF. Colloids and crystalloids: does it matter to the kidney? Curr Opin Crit Care. 2009;15:520–524. 34. Qureshi SH, Rizvi SI, Patel NN, Murphy GJ. Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. Br J Surg. 2016;103:14–26. 35. Vincent JL, De Backer D, Wiedermann CJ. Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care. 2016;35:161–167. 36. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161: 347–355. 37. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–1421. 38. Schetz M, Shaw AD, Vincent JL. Is the literature inconclusive about the harm of HES? We are not sure. Intensive Care Med. 2017;43:1526–1528. 39. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–1911. 40. Annane D, Fuchs-Buder T, Zoellner C, et al. EMA recommendation to suspend HES is hazardous. Lancet. 2018;391:736–738. 41. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71:726–735. 42. Vincent JL, De Backer D. Saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? Crit Care. 2016;20:250. 43. Stenson EK, Cvijanovich NZ, Anas N, et al. Hyperchloremia is associated with complicated course and mortality in pediatric patients with septic shock. Pediatr Crit Care Med. 2018;19:155–160. 44. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829–839. 45. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378:819–828. 46. Vincent JL, De Backer D. We do not appreciate SALT. Am J Respir Crit Care Med. 2018;197:1361. 47. Davies PG, Venkatesh B, Morgan TJ, et al. Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution. Crit Care. 2011;15:R21. 48. Vincent JL, Vanherweghem JL, Degaute JP, et al. Acetate-induced myocardial depression during hemodialysis for acute renal failure. Kidney Int. 1982;22:653–657. 49. Semler MW, Kellum JA. Balanced crystalloid solutions. Am J Respir Crit Care Med. 2019;199:952–960.
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