Review | Open | Published:
Principles of fluid management and stewardship in septic shock: it is time to consider the four D’s and the four phases of fluid therapy
Annals of Intensive Carevolume 8, Article number: 66 (2018)
In patients with septic shock, the administration of fluids during initial hemodynamic resuscitation remains a major therapeutic challenge. We are faced with many open questions regarding the type, dose and timing of intravenous fluid administration. There are only four major indications for intravenous fluid administration: aside from resuscitation, intravenous fluids have many other uses including maintenance and replacement of total body water and electrolytes, as carriers for medications and for parenteral nutrition. In this paradigm-shifting review, we discuss different fluid management strategies including early adequate goal-directed fluid management, late conservative fluid management and late goal-directed fluid removal. In addition, we expand on the concept of the “four D’s” of fluid therapy, namely drug, dosing, duration and de-escalation. During the treatment of patients with septic shock, four phases of fluid therapy should be considered in order to provide answers to four basic questions. These four phases are the resuscitation phase, the optimization phase, the stabilization phase and the evacuation phase. The four questions are “When to start intravenous fluids?”, “When to stop intravenous fluids?”, “When to start de-resuscitation or active fluid removal?” and finally “When to stop de-resuscitation?” In analogy to the way we handle antibiotics in critically ill patients, it is time for fluid stewardship.
In patients with septic shock, hemodynamic stabilization using intravenous fluids remains a major therapeutic challenge as numerous questions remain regarding the type, dose and timing of fluid administration. In these patients, fluids play an important role beyond hemodynamic stabilization and resuscitation. Intravenous fluids should be prescribed as any other drug we give to our patients: we should take into account the indications and contraindications for different types of fluids [2,3,4,5,6,7,8]. We should only prescribe fluids when they are clearly indicated and should balance the risk of not administering enough with the increasingly apparent risks of too much fluid.
In this review, we will expand on the concept of the “four D’s” of fluid therapy (drug, duration, dosing and de-escalation). We will also focus on the recent concept defining four different phases in the time course of septic shock (resuscitation, optimization, stabilization and evacuation). Each phase requires a different therapeutic attitude regarding fluid administration. Taking into account both of these concepts in combination with other suggested ideas may promote more rational fluid administration aimed at avoiding both too little and too much. In analogy to the way we handle antibiotic usage in the critically ill, it is now time for fluid stewardship.
The risk of fluid overload
Treating a patient with septic shock inevitably results in some degree of salt and water overload. First and foremost, this is the result of the initial fluid resuscitation with the aim of restoring intravascular volume, increasing cardiac output, augmenting oxygen delivery and improving tissue oxygenation. Salt and water overload can also result from the administration of large volumes of fluid as drug diluents, artificial nutrition and maintenance fluids. The capillary leak that is inherent to sepsis promotes the extravasation of large amounts of fluid, inducing relative central hypovolemia that often requires further fluid administration, despite interstitial oedema. Capillary leak represents the maladaptive, often excessive, and undesirable loss of fluid and electrolytes with or without protein into the interstitium that generates anasarca and end-organ oedema causing organ dysfunction and eventually failure . Fluid overload should be avoided in this setting.
The four D’s of fluid therapy
When prescribing fluids in patients with septic shock, we must take into account their composition and their pharmocodynamic and pharmacokinetic properties. In practice, we should consider the “four D’s” of fluid therapy: drug, dosing, duration and de-escalation (Table 1) . Many clinicians already use these four D’s for the prescription of antibiotics (Table 1).
We should consider the different compounds: crystalloids versus colloids, synthetic versus blood derived, balanced versus unbalanced, intravenous versus oral. The osmolality, tonicity, pH, electrolyte composition (chloride, sodium, potassium, etc.) and levels of other metabolically active compounds (lactate, acetate, malate, etc.) are all equally important. Clinical factors (underlying conditions, kidney or liver failure, presence of capillary leak, acid–base equilibrium, albumin levels, fluid balance, etc.) must all be taken into account when choosing the type and amount of fluid for a given patient at a given time. Moreover, the type of fluid is different depending on the reason why they are administered. There are only four indications for fluid administration, namely resuscitation, maintenance, replacement and nutrition, or a combination.
Resuscitation fluids are given to correct an intravascular volume deficit in the case of absolute or relative hypovolemia. In theory, the choice between colloids and crystalloids should take into account the revised Starling equation and the glycocalyx model of transvascular fluid exchange . When capillary pressure (or transendothelial pressure difference) is low, as in hypovolemia or sepsis and especially septic shock, or during hypotension (after induction and anaesthesia), albumin or plasma substitutes have no advantage over crystalloid infusions, since they all remain intravascular. However, the glycocalyx layer is a fragile structure and is disrupted by surgical trauma-induced systemic inflammation or sepsis, but also by rapid infusion of fluids (especially saline). Under these circumstances, transcapillary flow (albumin leakage and risk of tissue oedema) is increased, as is the risk to evolve to a state of global increased permeability syndrome (GIPS) .
Maintenance fluids are given, specifically, to cover the patient’s daily basal requirements of water, glucose and electrolytes. As such, they are intended to cover daily needs. The basic daily needs are water, in an amount of 25–30 mL/kg of body weight, 1 mmol/kg potassium, 1–1.5 mmol/kg sodium per day and glucose or dextrose 5 or 10% 1.4–1.6 g/kg (to avoid starvation ketosis) .
Some specific maintenance solutions are commercially available, but they are far from ideal. There is a lot of debate whether isotonic or hypotonic maintenance solutions should be used. Data in children showed that hypotonic solutions carry the risk of hyponatremia and neurologic complications [32, 33]. However, studies in adults are scarce and indicate that administration of isotonic solutions will result in a more positive fluid balance as compared to hypotonic solutions . This was confirmed in a recent pilot study in healthy volunteers showing that isotonic solutions caused lower urine output, characterized by decreased aldosterone concentrations indicating (unintentional) volume expansion, than hypotonic solutions. Despite their lower sodium and potassium content, hypotonic fluids were not associated with hyponatremia or hypokalemia .
Replacement fluids are administered to correct fluid deficits that cannot be compensated by oral intake. Such fluid deficits have a number of potential origins, like drains or stomata, fistulas, hyperthermia, open wounds, polyuria (salt-wasting nephropathy, cerebral salt wasting, osmotic diuresis or diabetes insipidus) .
Data on replacement fluids are also scarce. Several recent guidelines advise matching the amount and composition of fluid and electrolytes as closely as possible to the fluid that is being or has been lost [35, 36]. An overview of the composition of the different body fluids can be found in the NICE guidelines . Replacement fluids are usually isotonic balanced solutions. In patients with fluid deficit due to a loss of chloride-rich gastric fluid, high-chloride solutions, like saline (0.9% NaCl), might be used as replacement fluid.
Often overlooked, it is about time to consider parenteral nutrition as another source of intravenous fluids that may contribute to fluid overload. Likewise, nutritional therapy in the critically ill should be seen as “medication” helping the healing process. As such, we might consider also the four D’s of nutritional therapy in analogy to how we deal with antibiotics and fluids : drug (type of feeding), dose (caloric and protein load), duration (when and how long) and de-escalation (stop enteral nutrition and/or parenteral nutrition when oral intake improves) .
Combination of fluids
A combination of different types of fluids is often justified. For example, numerous combinations may be used in daily practice with regard to resuscitation fluids: blood and crystalloids (trauma), crystalloids early (post-operative hypovolemia), albumin late (sepsis). Similarly, maintenance fluids are often a combination of enteral and parenteral nutrition, other glucose-containing solutions, saline and/or balanced crystalloids to dissolve medications.
The longer the delay in fluid administration, the more microcirculatory hypoperfusion and subsequent organ damage related to ischaemia–reperfusion injury. In patients with sepsis , Murphy and colleagues compared outcomes related to early adequate versus early conservative and late conservative versus late liberal fluid administration and found that the combination of early adequate and late conservative fluid management carried the best prognosis  (Fig. 4). Combined data from other studies confirm that late conservative is maybe more important than early adequate fluid therapy [39,40,41].
As Paracelsus nicely stated: “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous” Like other drugs, it is the dose of fluids that make them poisonous. As stated before, the risk of excessive fluid overload is well established.
Similar to other drugs, choosing the right dose implies that we take into account the pharmacokinetics and pharmacodynamics of intravenous fluids (Table 1). Pharmacokinetics describes how the body affects a drug resulting in a particular plasma and effect site concentration . Pharmacokinetics of intravenous fluids depends on distribution volume, osmolality, tonicity, oncoticity and kidney function. Eventually, the half-time depends on the type of fluid, but also on the patient’s condition and the clinical context (Table 2). When administering 1 L of fluid only, 10% of glucose solution, versus 25–30% of an isotonic crystalloid solution, versus 100% of a colloid solution will remain intravascularly after 1 h, but as stated above the half-life is dependent on other conditions (like infection, inflammation, sedation, surgery, anaesthesia, blood pressure) (Fig. 3) [29, 43].
Volume kinetics is an adaptation of pharmacokinetic theory that makes it possible to analyse and simulate the distribution and elimination of infusion fluids . Applying this concept, it is possible, by simulation, to determine the infusion rate that is required to reach a predetermined plasma volume expansion. Volume kinetics may also allow the quantification of changes in the distribution and elimination of fluids (and calculation of the half-life) that result from stress, hypovolemia, anaesthesia and surgery .
Pharmacodynamics relates the drug concentrations to its specific effect. For fluids, the Frank–Starling relationship between cardiac output and cardiac preload is the equivalent of the dose effect curve for standard medications. Because of the shape of the Frank–Starling relationship, the response of cardiac output to the fluid-induced increase in cardiac preload is not constant . The effective dose 50 (ED50), in pharmacology, is the dose or amount of drug that produces a therapeutic response or desired effect in 50% of the subjects receiving it, whereas lethal dose 50 (LD50) will result in death of 50% of recipients. Translated to IV fluids, this would be the dose of fluid that induces, respectively, a therapeutic response or death in 50% of the patients. The problem is that the therapeutic response varies from one patient to another. Fluid administration can be toxic (or even lethal) at a high enough dose, as demonstrated in 2007 when a California woman died of water intoxication (and hyponatremia) in a contest organized by a radio station (http://articles.latimes.com/2007/jan/14/local/me-water14). The difference between toxicity and efficacy is dependent upon the particular patient and the specific condition of that patient, although the amount of fluids administered by a physician should fall into the predetermined therapeutic window. Unanswered questions remain: what is an effective dose of IV fluids? What is the exact desired therapeutic effect? What is the therapeutic window? In some patients, volume expansion increases the mean systemic filling pressure (the backward pressure of venous return), but it increases the right atrial pressure (the forward pressure of venous return) to the same extent, such that venous return and, hence, cardiac output do not increase . Hence, venous congestion and backward failure may even play a more important and currently underestimated role . The probability of the heart to “respond” to fluid by a significant increase in cardiac preload varies along the shock time course, and thus, pharmacodynamics of fluids must be regularly evaluated. At the very early phase, fluid responsiveness is constant. After the very initial fluid administration, only one half of patients with circulatory failure respond to an increase in cardiac output .
Like for antibiotics (Table 1), the duration of fluid therapy must be as short as possible, and the volume must be tapered when shock is resolved. However, many clinicians use certain triggers to start, but are unaware of triggers to stop fluid resuscitation, increasing the potential for fluid overload. As with duration of antibiotics, although there is no strong evidence, there is a trend towards shorter duration of intravenous fluids .
The four phases of fluid therapy
Not only are the characteristics of fluids important, but also the strategy for their administration. This strategy fundamentally changes along with the time course of septic shock. Recently a three-hit, or even four-hit model of septic shock was suggested trying to answer four basic questions, in which we can recognize four distinct dynamic phases of fluid therapy : resuscitation, optimization, stabilization and evacuation (de-resuscitation) (the acronym ROSE) (Table 3, Fig. 5). The four questions that will be discussed in the next section are “When to start intravenous fluids?”, “When to stop intravenous fluids?”, “When to start de-resuscitation or active fluid removal?” and finally “When to stop de-resuscitation?”
First phase: Resuscitation
After the first hit which can be sepsis, but also burns, pancreatitis or trauma, the patient will enter the “ebb” phase of shock. This life-threatening phase of severe circulatory shock can occur within minutes and is characterized by a strong vasodilation leading to a low mean arterial pressure and microcirculatory impairment (Table 3). It may be accompanied by high (hyperdynamic circulatory shock as seen in sepsis, burns, severe acute pancreatitis, liver cirrhosis, thiamine deficiency, etc.) or low cardiac output (e.g. septic shock with severe hypovolemia or septic shock with sepsis-induced cardiomyopathy).
At this initial phase, usually during the first 3–6 h after the initiation of therapy, fluid resuscitation is commonly administered according to an early, adequate, goal-directed, fluid management strategy. The modalities of fluid administration at this early phase have been a matter of great debate. In the study by Rivers et al. , a protocol-based fluid management called early goal-directed therapy (EGDT) was associated with a significant reduction in mortality compared to standard care. Since this publication, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients . As a result, EGDT was incorporated as a “resuscitation bundle” into the first 6 h of sepsis management adopted by the Surviving Sepsis Campaign. As such, it has been disseminated internationally as the standard of care for early sepsis management. Recently, a trio of trials (ProCESS , ARISE  and ProMISe ), while reporting an all-time low sepsis mortality, showed no improvement in outcomes with EGDT, questioning the need and pointing towards the potential dangers of protocolized care for patients with severe and septic shock [54, 55]. A recent study employing a combined Bayesian and frequentist methodological approach to evaluate 12 randomized trials and 31 observational studies found that EGDT was potentially harmful in the patients with the highest disease severity . In addition, although conducted in sub-Saharan Africa, three recent trials have demonstrated worse outcomes when administering fluid boluses for resuscitation in patients with septic shock [57,58,59]. What remains from the EGDT debate is that the rapidity of fluid administration and of the achievement of hemodynamic goals for initial resuscitation is important, even though this aspect has also recently been called into question .
In fact, rather than infusing a predefined given amount of fluid, the goal should be individualized for every patient, based on the evaluation of the need for fluids and on the patient’s premorbid conditions [16, 55, 61,62,63,64]. In this phase, on an individual basis for each patient, we try to find an answer to the first question: “When to start fluid therapy?”
At the very initial phase of septic shock, answering the question is easy: fluid administration will significantly increase cardiac output in almost all cases. Nevertheless, after the first boluses of fluid, the likelihood of preload unresponsiveness is high. Therefore, at this stage, fluid administration should be conditioned to the positivity of indices and tests predicting fluid responsiveness. However, it must be noted that the state of responsiveness can only be determined a posteriori (after the intervention with administration of fluid bolus) and when a hemodynamic monitoring device is in place to estimate or calculate cardiac output. Therefore, we advocate the use of specific tests to increase the a priori probability and likelihood for a favourable event/outcome, as fluid administration should be limited to responders.
Second phase: Optimization
The second hit occurs within hours and refers to ischaemia and reperfusion (Table 3). At this phase, fluid accumulation reflects the severity of illness and might be considered a “biomarker” for it . The greater the fluid requirement, the sicker the patient and the more likely organ failure (e.g. acute kidney injury) may occur [71, 72].
In this phase, we must try to find an answer to the second question: “When to stop fluid therapy?” avoiding fluid overload. Indices of fluid responsiveness are again of utmost importance, since fluid administration should be stopped when these indices become negative . Second, the clinical context must be taken into account. Obviously, more fluid is needed in septic shock from peritonitis than from pneumonia. Third, the decision to refrain from fluid administration should be based on indices that indicate the risk of excessive fluid administration. The presence of lung impairment is the condition that is most likely to be associated with the worst consequences of fluid overload. To estimate the pulmonary risk of further fluid infusion, one may consider the pulmonary artery occlusion pressure measured with the Swan–Ganz catheter. Nonetheless, this does not take into account the degree of lung permeability, which is a key factor in the mechanisms of pulmonary oedema formation . Extravascular lung water measured by transpulmonary thermodilution, as well as the pulmonary vascular permeability index which is inferred from it, might reflect the pulmonary risk of fluid infusion more directly [40, 48, 74]. Intra-abdominal hypertension is also a potential consequence of too much fluid administration . The intra-abdominal pressure should be cautiously monitored in patients at risk .
Third phase: Stabilization
With successful treatment, stabilization should follow the optimization phase (homoeostasis), evolving over the next few days (Table 3). It is distinguished from the prior two by the absence of shock or the imminent threat of shock. As previously described, the focus is now on organ support and this phase reflects the point at which a patient is in a stable steady state [1, 76] (Table 3).
Fluid therapy is now only needed for ongoing maintenance in the setting of normal fluid losses (i.e. renal, gastrointestinal, insensible) and replacement fluids if the patient is experiencing ongoing losses because of unresolved pathologic conditions [1, 76]. Since persistence of a positive daily fluid balance over time is strongly associated with a higher mortality rate in septic patients [11, 77], clinicians should also be aware of the hidden obligatory fluid intake, as it may contribute more than a litre daily .
Fourth phase: Evacuation
After the second hit, the patient may either further recover, entering the “flow” phase with spontaneous evacuation of the excess fluids that have been administrated previously, or, as is the case in many critically ill patients, the patient remains in a “no-flow” state followed by a third hit, usually resulting from global increased permeability syndrome with ongoing fluid accumulation due to capillary leak [17, 79]. In any case, the patient enters a phase of “de-resuscitation” (Table 3). This term was first suggested in 2012  and finally coined in 2014 . It specifically refers to late goal-directed fluid removal and late conservative fluid management.
Late goal-directed fluid removal involves aggressive and active fluid removal using diuretics and renal replacement therapy with net ultrafiltration. It is characterized by the discontinuation of invasive therapies and a transition to a negative fluid balance . Late conservative fluid management describes a moderate fluid management strategy following the initial treatment in order to avoid (or reverse) fluid overload. Recent studies showed that two consecutive days of negative fluid balance within the first week of the intensive care unit stay is a strong and independent predictor of survival .
In this de-resuscitation phase, we try to find an answer to the third and fourth question: “When to start fluid removal?” and “When to stop fluid removal?” in order to find the balance between the benefits (reduction in second and third space fluid accumulation and tissue oedema) and risk (hypoperfusion) of fluid removal. To answer these questions, testing preload responsiveness may still be useful. Indeed, if no preload responsiveness is detected, it is reasonable to assume that fluid removal will not induce a reduction in cardiac output . On the opposite, positive indices of preload responsiveness might indicate the limit of fluid removal and could even be a target to reach when removing fluids.
Obviously, the risk at this phase is to be too aggressive with fluid removal and to induce hypovolemia, which may trigger a “fourth hit” for hemodynamic deterioration and hypoperfusion (Fig. 5). If fluid is needed at this phase, the use of albumin seems to have positive effects on vessel wall integrity facilitates achieving a negative fluid balance in hypoalbuminemia and may be less likely to cause nephrotoxicity .
This four-phase approach should be better characterized by some epidemiological studies. Its prognostic impact might be significant, because it may lead to a reduction in the cumulative fluid balance, which by itself is clearly associated with poor prognosis (Fig. 4). Similar principles have also been suggested by others, confirming the need for a multicenter prospective clinical trial with a biphasic fluid therapy approach, starting with initial early adequate goal-directed treatment followed by late conservative fluid management in those patients not transgressing spontaneously from the ebb to the flow phase [14, 15, 70, 76, 82,83,84,85,86]. The RADAR (Role of Active De-resuscitation After Resuscitation) trial may help to find such answers (http://www.hra.nhs.uk/news/research-summaries/radar-icu/).
There are only four major indications for fluid administration in the critically ill: resuscitation, maintenance, replacement and nutrition (enteral or parenteral). In this review, a conceptual framework is presented looking at fluids as drugs by taking into account the four D’s (drug selection, dose, duration and de-escalation) and the four phases of fluid therapy within the ROSE concept (resuscitation, optimization, stabilization and evacuation). The four hits model is presented herein. This will provide answers to the four basic questions surrounding fluid therapy: (1) When to start IV fluids? (2) When to stop fluid administration? (3) When to start fluid removal and finally (4) When to stop fluid removal? In analogy to the way we deal with antibiotics in critically ill patients, it is time for fluid stewardship.
early goal-directed therapy
global increased permeability syndrome
acronym for resuscitation–optimization–stabilization–evacuation
Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014;46(5):361–80.
Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, et al. 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(3):R94.
Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH, Elkjaer JM, Poulsen LM, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124–34.
Van Regenmortel N, Jorens PG, Malbrain ML. Fluid management before, during and after elective surgery. Curr Opin Crit Care. 2014;20(4):390–5.
Malbrain ML, Van Regenmortel N, Owczuk R. It is time to consider the four D’s of fluid management. Anaesthesiol Intensive Ther. 2015;47:1–5.
Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901–11.
Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, Preiser JC, Outin H, Troche G, Charpentier C, 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(17):1809–17.
Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(25):2462–3.
Duchesne JC, Kaplan LJ, Balogh ZJ, Malbrain ML. Role of permissive hypotension, hypertonic resuscitation and the global increased permeability syndrome in patients with severe hemorrhage: adjuncts to damage control resuscitation to prevent intra-abdominal hypertension. Anaesthesiol Intensive Ther. 2015;47(2):143–55.
Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53.
Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, Schroeder ME, Marshall JC, Vincent JL, Intensive Care Over Nations I. Higher fluid balance increases the risk of death from sepsis: results from a large international audit. Crit Care Med. 2017;45(3):386–94.
Jozwiak M, Silva S, Persichini R, Anguel N, Osman D, Richard C, Teboul JL, Monnet X. Extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome. Crit Care Med. 2013;41(2):472–80.
Pinsky MR. Hemodynamic evaluation and monitoring in the ICU. Chest. 2007;132(6):2020–9.
O’Connor ME, Prowle JR. Fluid overload. Crit Care Clin. 2015;31(4):803–21.
Benes J, Kirov M, Kuzkov V, Lainscak M, Molnar Z, Voga G, Monnet X. Fluid therapy: double-edged sword during critical care? Biomed Res Int. 2015;2015:729075.
Vandervelden S, Malbrain ML. Initial resuscitation from severe sepsis: one size does not fit all. Anaesthesiol Intensive Ther. 2015;47:44–55.
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(3):384–94.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.
Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412–21.
Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, Najafi A. Effects of normal saline vs. lactated ringer’s during renal transplantation. Ren Fail. 2008;30(5):535–9.
Langer T, Santini A, Scotti E, Van Regenmortel N, Malbrain ML, Caironi P. Intravenous balanced solutions: from physiology to clinical evidence. Anaesthesiol Intensive Ther. 2015;47:78–88.
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(15):1566–72.
Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18–24.
Van Regenmortel N, De Weerdt T, Van Craenenbroeck AH, Roelant E, Verbrugghe W, Dams K, Malbrain M, Van den Wyngaert T, Jorens PG. Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers. Br J Anaesth. 2017;118:892–900.
Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, Wang L, Byrne DW, Shaw AD, Bernard GR, et al. Balanced crystalloids versus saline in the intensive care unit. The SALT randomized trial. Am J Respir Crit Care Med. 2017;195(10):1362–72.
Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, Anderson BA, Scherer LA. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255–62.
Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829–39.
Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, Slovis CM, Lindsell CJ, Ehrenfeld JM, Siew ED, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819–28.
Hahn RG. Volume kinetics for infusion fluids. Anesthesiology. 2010;113(2):470–81.
Hahn RG. Why crystalloids will do the job in the operating room. Anaesthesiol Intensive Ther. 2014;46(5):342–9.
Herrod PJ, Awad S, Redfern A, Morgan L, Lobo DN. Hypo- and hypernatraemia in surgical patients: is there room for improvement? World J Surg. 2010;34(3):495–9.
McNab S, Duke T, South M, Babl FE, Lee KJ, Arnup SJ, Young S, Turner H, Davidson A. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet. 2015;385(9974):1190–7.
Moritz ML, Ayus JC. Maintenance intravenous fluids in acutely ill patients. N Engl J Med. 2015;373(14):1350–60.
Lobo DN, Stanga Z, Simpson JA, Anderson JA, Rowlands BJ, Allison SP. Dilution and redistribution effects of rapid 2-litre infusions of 0.9% (w/v) saline and 5% (w/v) dextrose on haematological parameters and serum biochemistry in normal subjects: a double-blind crossover study. Clin Sci (Lond). 2001;101(2):173–9.
Padhi S, Bullock I, Li L, Stroud M, National Institute for H, Care Excellence Guideline Development G. Intravenous fluid therapy for adults in hospital: summary of NICE guidance. BMJ. 2013;347:f7073.
Soni N. British consensus guidelines on intravenous fluid therapy for adult surgical patients (GIFTASUP): Cassandra’s view. Anaesthesia. 2009;64(3):235–8.
De Waele E, Honore PM, Malbrain M. Does the use of indirect calorimetry change outcome in the ICU? Yes it does. Curr Opin Clin Nutr Metab Care. 2018;21(2):126–9.
Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, Micek ST, Kollef MH. The importance of fluid management in acute lung injury secondary to septic shock. Chest. 2009;136(1):102–9.
Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42(11):1695–705.
Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Huber W, Malbrain MLNG. Fluid management in critically ill patients: the role of extravascular lung water, abdominal hypertension, capillary leak and fluid balance. Annals Intensive Care. 2012;2(Supplem 1):S1.
Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Martin G, Huber W, Malbrain ML. Aiming for a negative fluid balance in patients with acute lung injury and increased intra-abdominal pressure: a pilot study looking at the effects of PAL-treatment. Ann Intensive Care. 2012;2(Suppl 1):S15.
Elbers PW, Girbes A, Malbrain ML, Bosman R. Right dose, right now: using big data to optimize antibiotic dosing in the critically ill. Anaesthesiol Intensive Ther. 2015;47(5):457–63.
Hahn RG, Lyons G. The half-life of infusion fluids: an educational review. Eur J Anaesthesiol. 2016;33(7):475–82.
Monnet X, Marik P, Teboul JL. Prediction of fluid responsiveness: an update. Ann Intensive Care. 2017;6(1):111.
Guerin L, Teboul JL, Persichini R, Dres M, Richard C, Monnet X. Effects of passive leg raising and volume expansion on mean systemic pressure and venous return in shock in humans. Crit Care. 2015;19:411.
Verbrugge FH, Dupont M, Steels P, Grieten L, Malbrain M, Tang WH, Mullens W. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol. 2013;62(6):485–95.
Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298–309.
Jozwiak M, Teboul JL, Monnet X. Extravascular lung water in critical care: recent advances and clinical applications. Ann Intensive Care. 2015;5(1):38.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77.
Osborn TM. Severe sepsis and septic shock trials (ProCESS, ARISE, ProMISe): what is optimal resuscitation? Crit Care Clin. 2017;33(2):323–44.
Pro CI, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–93.
Investigators A, Group ACT, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506.
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Tan JC, Harvey SE, Bell D et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015;19(97):i–xxv, 1–150.
Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21.
Marik PE, Malbrain M. The SEP-1 quality mandate may be harmful: how to drown a patient with 30 mL per kg fluid! Anaesthesiol Intensive Ther. 2017;49(5):323–8.
Kalil AC, Johnson DW, Lisco SJ, Sun J. Early goal-directed therapy for sepsis: a novel solution for discordant survival outcomes in clinical trials. Crit Care Med. 2017;45(4):607–14.
Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483–95.
Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR. Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial. JAMA. 2017;318(13):1233–40.
Andrews B, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Bernard GR. Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia. Crit Care Med. 2014;42(11):2315–24.
Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–44.
Perel A, Saugel B, Teboul JL, Malbrain ML, Belda FJ, Fernandez-Mondejar E, Kirov M, Wendon J, Lussmann R, Maggiorini M: The effects of advanced monitoring on hemodynamic management in critically ill patients: a pre and post questionnaire study. J Clin Monit Comput. 2016;30(5):511–8.
Saugel B, Trepte CJ, Heckel K, Wagner JY, Reuter DA. Hemodynamic management of septic shock: is it time for “individualized goal-directed hemodynamic therapy” and for specifically targeting the microcirculation? Shock. 2015;43(6):522–9.
Saugel B, Malbrain ML, Perel A. Hemodynamic monitoring in the era of evidence-based medicine. Crit Care. 2016;20(1):401.
Muckart DJJ, Malbrain M. The future of evidence-based medicine: is the frog still boiling? Anaesthesiol Intensive Ther. 2017;49(5):329–35.
Weil MH, Henning RJ. New concepts in the diagnosis and fluid treatment of circulatory shock. Thirteenth annual Becton, Dickinson and Company Oscar Schwidetsky Memorial Lecture. Anesth Analg. 1979;58(2):124–32.
Monnet X, Teboul JL. Passive leg raising: five rules, not a drop of fluid! Crit Care. 2015;19:18.
Jozwiak M, Depret F, Teboul JL, Alphonsine JE, Lai C, Richard C, Monnet X. Predicting fluid responsiveness in critically ill patients by using combined end-expiratory and end-inspiratory occlusions with echocardiography. Crit Care Med. 2017;45(11):e1131–8.
Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della Rocca G, Aldecoa C, Artigas A, Jog S, et al. Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med. 2015;41(9):1529–37.
Hofkens PJ, Verrijcken A, Merveille K, Neirynck S, Van Regenmortel N, De Laet I, Schoonheydt K, Dits H, Bein B, Huber W, et al. Common pitfalls and tips and tricks to get the most out of your transpulmonary thermodilution device: results of a survey and state-of-the-art review. Anaesthesiol Intensive Ther. 2015;47(2):89–116.
Bagshaw SM, Brophy PD, Cruz D, Ronco C. Fluid balance as a biomarker: impact of fluid overload on outcome in critically ill patients with acute kidney injury. Crit Care. 2008;12(4):169.
Wang N, Jiang L, Zhu B, Wen Y, Xi XM, Beijing Acute Kidney Injury Trial W. Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. Crit Care. 2015;19:371.
Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lee J, Lo S, McArthur C, McGuiness S, Norton R, et al. An observational study fluid balance and patient outcomes in the randomized evaluation of normal vs. augmented level of replacement therapy trial. Crit Care Med. 2012;40(6):1753–60.
Teboul JL, Monnet X. Detecting volume responsiveness and unresponsiveness in intensive care unit patients: two different problems, only one solution. Crit Care. 2009;13(4):175.
Monnet X, Teboul JL. Transpulmonary thermodilution: advantages and limits. Crit Care. 2017;21(1):147.
Malbrain ML, Peeters Y, Wise R. The neglected role of abdominal compliance in organ-organ interactions. Crit Care. 2016;20(1):67.
Hoste EA, Maitland K, Brudney CS, Mehta R, Vincent JL, Yates D, Kellum JA, Mythen MG, Shaw AD, Group AXI. Four phases of intravenous fluid therapy: a conceptual model. Br J Anaesth. 2014;113(5):740–7.
Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251.
Bashir MU, Tawil A, Mani VR, Farooq U, DeVita A. Hidden obligatory fluid intake in critical care patients. J Intensive Care Med. 2017;32(3):223–7.
Malbrain ML, De Laet I. AIDS is coming to your ICU: be prepared for acute bowel injury and acute intestinal distress syndrome. Intensive Care Med. 2008;34(9):1565–9.
Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Ann Intensive Care. 2016;6(1):111.
Vincent JL, De Backer D, Wiedermann CJ. Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care. 2016;35:161–7.
McDermid RC, Raghunathan K, Romanovsky A, Shaw AD, Bagshaw SM. Controversies in fluid therapy: type, dose and toxicity. World J Crit Care Med. 2014;3(1):24–33.
Rivers EP. Fluid-management strategies in acute lung injury—liberal, conservative, or both? N Engl J Med. 2006;354:2598–600.
Bellamy MC. Wet, dry or something else? Br J Anaesth. 2006;97(6):755–7.
Bagshaw SM, Bellomo R. The influence of volume management on outcome. Curr Opin Crit Care. 2007;13(5):541–8.
Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726–34.
Macedo E, Bouchard J, Soroko SH, Chertow GM, Himmelfarb J, Ikizler TA, Paganini EP, Mehta RL, Program to Improve Care in Acute Renal Disease S. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care. 2010;14(3):R82.
Vaara ST, Korhonen AM, Kaukonen KM, Nisula S, Inkinen O, Hoppu S, Laurila JJ, Mildh L, Reinikainen M, Lund V, et al. Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study. Crit Care. 2012;16(5):R197.
Taylor CB, Hammond NE, Laba TL, Watts N, Thompson K, Saxena M, Micallef S, Finfer S, Myburgh J, Fluid Trips DCE. Drivers of choice of resuscitation fluid in the intensive care unit: a discrete choice experiment. Crit Care Resusc. 2017;19(2):134–41.
Aya HD, Rhodes A, Chis Ster I, Fletcher N, Grounds RM, Cecconi M. Hemodynamic effect of different doses of fluids for a fluid challenge: a quasi-randomized controlled study. Crit Care Med. 2017;45(2):e161–8.
Monnet X, Persichini R, Ktari M, Jozwiak M, Richard C, Teboul JL. Precision of the transpulmonary thermodilution measurements. Crit Care. 2011;15(4):R204.
Monnet X, Osman D, Ridel C, Lamia B, Richard C, Teboul JL. Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients. Crit Care Med. 2009;37(3):951–6.
Monnet X, Dres M, Ferre A, Le Teuff G, Jozwiak M, Bleibtreu A, Le Deley MC, Chemla D, Richard C, Teboul JL. Prediction of fluid responsiveness by a continuous non-invasive assessment of arterial pressure in critically ill patients: comparison with four other dynamic indices. Br J Anaesth. 2012;109(3):330–8.
Biais M, Larghi M, Henriot J, de Courson H, Sesay M, Nouette-Gaulain K. End-expiratory occlusion test predicts fluid responsiveness in patients with protective ventilation in the operating room. Anesth Analg. 2017;125(6):1889–95.
Cuthbertson DP. Post-shock metabolic response. Lancet. 1942;1:433–7.
Peeters Y, Lebeer M, Wise R, Malbrain ML. An overview on fluid resuscitation and resuscitation endpoints in burns: past, present and future. Part 2—avoiding complications by using the right endpoints with a new personalized protocolized approach. Anaesthesiol Intensive Ther. 2015;47:15–26.
MLNGM designed the initial version of the paper, BDT, PJVG, BS, XM, OJB participated in drafting the second version of the paper, MLNGM, BS, BDT, PJVG, OJB, JLT, XM, TWR and MM participated in drafting the final manuscript, and all authors read and approved the final manuscript.
This article is endorsed by the International Fluid Academy (IFA). The mission statement of the IFA is to foster education, promote research on fluid management and hemodynamic monitoring, and thereby improve survival of critically ill by bringing together physicians, nurses and others from throughout the world and from a variety of clinical disciplines. The IFA is integrated within the not-for-profit charitable organization iMERiT, International Medical Education and Research Initiative, under Belgian law. The IFA website (http://www.fluidacademy.org) is now an official SMACC-affiliated site (Social Media and Critical Care), and its content is based on the philosophy of FOAM (Free Open Access Medical education—#FOAMed). The site recently received the HONcode quality label for medical education (https://www.healthonnet.org/HONcode/Conduct.html?HONConduct519739).
Manu Malbrain is founding President of WSACS (the Abdominal Compartment Society, www.wsacs.org) and current Treasurer. He is also member of the medical advisory Board of Getinge (Pulsion Medical Systems) and consults for Baxter, Maltron, ConvaTec, Acelity, Spiegelberg and Holtech Medical. Niels Van Regenmortel has received honoraria for giving lectures from Baxter Belgium and resided in a medical advisory board organized by Baxter Healthcare, USA. Manu Malbrain and Niels Van Regenmortel are co-founders of the International Fluid Academy (IFA, www.fluidacademy.org). Bernd Saugel is a member of the medical advisory board of Getinge (Pulsion Medical Systems). He received honoraria for giving lectures from Pulsion Medical Systems and CNSystems Medizintechnik AG. He received refund of travel expenses from Pulsion Medical Systems, Tensys Medical Inc and CNSystems Medizintechnik AG. He received research grants and unrestricted research grants from Tensys Medical Inc and received research support from Edwards Lifesciences. Olivier Joannes-Boyau is consultant for Baxter and BBraun. Jean-Louis Teboul and Xavier Monnet are members of the medical advisory board of Pulsion Medical Systems (part of Maquet Getinge group). They received honoraria for giving lectures from Pulsion Medical Systems, Edwards Lifesciences, Cheetah Medical and Masimo. Monty Mythen is Director of the UCL Discovery Lab. His University Chair is sponsored by Smiths Medical. He is Co-Director Duke-UCL Consortium (The Morpheus Project); a paid Consultant for Deltex Medical and Edwards Lifesciences; a Director of the Bloomsbury Innovation Group (BiG); a Director and Chair of Evidence Based Perioperative Medicine (EBPOM) Community Interest Company; Share holder and Scientific Advisor Medical Defense Technologies LLC (Gastrostim and Entarik); Share holder and Director Clinical Hydration Solutions ltd (Patent holder “QUENCH”); GIFTASUP guidelines—Senior Author; NICE—Expert Advsior IV Fluids—Guideline 174. The other authors have no potential conflict of interest with regard to the content of this review paper.
Availability of data and materials
Consent for publication
All authors have read and approved the manuscript.
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
- Fluid therapy
- Fluid management
- Fluid stewardship
- Four D’s
- Four indications
- Four hits
- Four phases
- Four questions
- Goal-directed therapy
- Fluid responsiveness
- Passive leg raising