Review article: Biomedical intelligence

The value of volume substitution in patients with septic and haemorrhagic shock with respect to the microcirculation

Publication Date: 04.02.2019
Swiss Med Wkly. 2019;149:w20007

Martin Siegemund, Alexa Hollinger, Eva C. Gebhard, Jonas D. Scheuzger, Daniel Bolliger

Departement für Anästhesie, Operative Intensivbehandlung, präklinische Notfallmedizin und Schmerztherapie, Universitätsspital Basel, Departement klinische Forschung, Universität Basel, Switzerland


After decades of ordinary scientific interest, fluid resuscitation of patients with septic and haemorrhagic shock took centre stage in intensive care research at the turn of the millennium. By that time, resuscitation fluids were the mainstay of haemodynamic stabilisation, avoidance of vasopressors and treatment of hypovolaemia in patients in shock, but were accompanied by adverse events such as excessive tissue oedema. With the spread of early goal-directed therapy research intensified and it was realised that type, volume and timing of resuscitation fluids might affect the course and outcome of critically ill patients. At the same time, the importance of microvascular blood flow as target of resuscitation was accepted.

Today, once-forbidden albumin is the recommended colloid in severe sepsis and septic shock, and the European Medical Agency is considering the removal of starch solutions from the European market because of an increased incidence of acute kidney injury and mortality. This is unprecedented, especially because the administration of low-molecular-weight starches seems to have advantages in indications other than sepsis, and because practices in fluid resuscitation have changed fundamentally since the negative starch studies. Crystalloids are still the mainstay of hypovolaemia treatment in critically ill patients, but awareness is increasing that electrolyte composition, strong ion gap, tonicity and the bicarbonate-substituting anion may have an effect on adverse effects and outcome. In haemorrhagic shock, the utilisation of crystalloids and colloids is retreating, and plasma and erythrocyte concentrates are gaining more importance in the resuscitation of the patient with acute bleeding. However, there are still influential voices warning against the liberal usage of plasma concentrates and erythrocytes in trauma and haemorrhagic shock.

This review describes the evidence relating to fluid resuscitation in sepsis, septic shock and massive haemorrhage. Beside the scientific evidence based on clinical trials, possible effects on the microcirculation and, therefore, organ function will be illustrated and areas of future research highlighted. The critical appraisal of the existing evidence should enable the reader to choose the optimal volume substitution for an individual patient.

Keywords: shock, septic haemorrhagic shock, serum albumin microcirculation, physiopathology, hydroxyethyl starch, balanced crystalloids


Hypovolaemia is an essential part of virtually all types of shock, sometimes even in cardiogenic shock. In haemorrhagic and hypovolaemic shock, an absolute volume deficit exists owing to absolute blood or fluid loss, whereas in septic and anaphylactic shock vasodilatation and extravasation of fluid cause relative hypovolaemia. Both relative and absolute hypovolaemia lead to decreased vascular filling and wall tension, and cardiac output [1]. The reduced cardiac output attenuates microvascular organ blood-flow, resulting in tissue hypoxia, anaerobic metabolism and acidosis [2]. Rapid fluid resuscitation is, therefore, a mainstay of the treatment of this common pathway of shock. In this respect, an ideal resuscitation fluid should normalise intravascular and cardiac filling and improve microvascular blood flow without propagating capillary permeability and impairing endothelial integrity [3].

Erythrocyte and plasma concentrates, colloids and crystalloids all normalise intravascular and cardiac filling to a greater or lesser extent and according to the timing of administration [4]. The effects of resuscitation fluid on the microcirculation of organs are critical for the volume expanding effect under different pathological conditions [3]. Under physiological conditions, fluid shift out of capillaries is a tightly regulated mechanism that depends upon endothelial cells, endothelial cell junctions and the endothelial glycocalyx [5]. The endothelial glycocalyx is a luminal network of membranous glycoproteins and proteoglycans of vessel-proportional thickness [6]. Under physiological conditions, the space between endothelial glycocalyx and endothelial cells is free of proteins and blood cells, preventing the escape of large amounts of plasma protein-containing fluid. Organ-specific gaps within the endothelial cell junctions constitute the pathways for trans-vascular fluid and protein exchange [7]. The classic Starling principle assumes that hydrostatic pressure promotes leakage whereas oncotic pressure promotes the reabsorption of fluid along the length of microvascular blood vessels. The so-called revised Starling equation additionally considers the endothelial glycocalyx, stating that an intact glycocalyx prevents protein extravasation into the interstitial space independent of capillary pressure, and that the low oncotic pressure between glycocalyx and endothelial cells determines fluid exchange [7]. This implies that an increased plasma oncotic pressure will not promote reabsorption of interstitial fluid but rather counteract fluid extravasation, and that lymphatic vessels clear all interstitial fluids back into the venous system via the thoracic duct.

High venous pressure, therefore, increases oedema in two ways; on one hand, high venous outflow pressure transmits to intracapillary pressure promoting fluid extravasation and on the other side, a high central venous pressure hinders thoracic duct lymphatic drainage.

The microcirculatory blood flow provides oxygenation and nutrition to, and removes metabolic products from, the organs. In sepsis and haemorrhagic shock, the integrity of the microcirculation is severely abnormal due to the existing hypovolaemia, dysfunctional vascular tone, activated coagulation, increased leucocyte adherence and activation [8], and shedding of the glycocalyx. In 2002, de Backer and colleagues showed that the microcirculation in septic patients is severely disturbed and that nonsurvivors had less perfused small vessels than survivors [9]. The same group showed in a subsequent study that the microcirculation in nonsurvivors of septic shock did not improve, despite resolution of the clinical signs of shock [10]. The administration of fluid in shock states improves microvascular perfusion and increases capillary pressure (fig. 1). Unfortunately, the endothelial glycocalyx is disrupted by lipopolysaccharides [11] and other inflammatory conditions such as trauma [12] and ischaemia reperfusion [13], as a result of oxidative stress [4]. At the same time, sepsis increases endothelial permeability by a disassembling of intercellular junctions, promoting the extravasation of smaller proteins such as albumin [14, 15]. Finally, the inadequate administration of bolus fluid and hence hypervolaemia increase the level of atrial natriuretic peptide, causing enhanced shedding of the glycocalyx and alteration of the microcirculation [16]. This leaves a narrow path in fluid resuscitation of septic and haemorrhagic shock, with the recovery of microvascular flow by optimal capillary filling on the one hand and the exacerbation of fluid extravasation and tissue oedema by volume overloading on the other hand. Fluid extravasation and oedema alone may lead to pulmonary oedema [17], or abdominal compartment syndrome [18], and contribute to acute kidney injury (AKI) [19].

Figure 1

Changes of the microcirculation under the tongue of a patient in shock with incident dark field (IDF) imaging (CytoCam-IDF, Braedius Medical, Huizen, The Netherlands). Panel A shows the normal microcirculation with normal flow in capillaries and venules. Panel B illustrates the different microcirculatory flow patterns during shock. Very few normally perfused (green lines) next to intermittently perfused (orange lines) vessels. Almost half of the vessels show no-flow (red lines), meaning that the blood cells do not move. Fluid resuscitation of shock aims to improve or normalise microvascular blood flow.

The objective of this review article is to discuss commonly used resuscitation fluids, to present the scientific evidence related to volume resuscitation in septic and haemorrhagic shock and to classify the different findings with respect to impact on the microcirculation.

Fluid replacement in septic patients

In 2001, the landmark paper of Rivers et al. [20] started a new approach to volume resuscitation in septic patients and intensive care medicine in general. In this single-centre randomised controlled trial, early goal-directed therapy entailing fluid resuscitation (according to central venous and mean arterial pressure), transfusions and inotropic support during the first 6 hours of therapy improved 30-day survival by 16%. Surprisingly, not much weight was given to the 24% increase in the numbers of patients receiving blood transfusions to improve central venous saturation with early goal-directed therapy, although the total amount of fluid was equal after 3 days. Because in this study the types of fluid used for early goal-directed therapy were not specified and there was a sceptical attitude to erythrocyte transfusions in intensive care in general [21], a decade of intense research to find the optimal volume of replacement fluid began. Although the concept of early goal-directed therapy has since been abandoned because its mortality benefit could not be confirmed in three large randomised trials [2224] and two meta-analysis [25, 26], the search for the best type, volume and time of resuscitation fluid is still ongoing (table 1).

Table 1

Advantages and risks of preparations for volume resuscitation in septic and haemorrhagic shock.

 Molecular weight
Osmolarity (mosm/l)Chloride (mmol/l)AdvantagesRisksVolume effect
Albumin66291140Human protein
Transport capacities for proteins and drugs
Antioxidant potential
Hyperoncotic preparations may increase risk for AKI
Increased bleeding and mortality in haemorrhagic shock
Rapid microcirculatory plasma escape rate in septic shock
Modern semi-synthetic colloids130297-308110–118Improve micro-vascular blood flow
In high doses increased risk of mortality
Increased risk of AKI and renal replacement therapy
Itching and rash
Volume effect longer than duration of infusion
Gelatines30284103–120 Allergic reactions
Increased risk of AKI and renal replacement therapy
Insufficient data for mortality risk
Rapid degradation and temporary volume effect
Sodium chloride (“normal saline”) 308154High osmolarityHyperchloraemic acidosis
Decreased renal blood flow
Rapid emergence of tissue oedema
Volume effect only during infusion
Balanced crystalloid solutions 273–29498–112Inert
Comparable electrolyte composition to plasma
Rapid emergence of tissue oedemaVolume effect only during infusion
Pooled fresh frozen plasma50–34032273–79Coagulation factors
Human proteins
Transfusion associated lung injury (very low risk with pooled preparations)
Transfusion associated circulatory overload
Low risk of infection
Good volume expanding effect and long intravascular stay

AKI = acute kidney injury

Recommendations for the application of resuscitation fluids in different types of shock are summarised in table 2.

Table 2

Recommendations for the application of resuscitation fluids in different types of shock.

Type of shockFirst ChoiceAlternativeComments
Hypovolaemic Balanced crystalloidsAlbuminIn patients with a high chloride loss (e.g., hyperemesis) NaCl 0.9% may be indicated.
HaemorrhagicWith apparent severe bleedingErythrocyte concentrates
Balanced crystalloidsAlbumin and all synthetic colloid solutions have the potential to increase bleeding, especially with large wound areas.
Without apparent bleedingBalanced crystalloidsErythrocyte concentrates and plasma
HES (130/0.4) or gelatines
Here applies the same as mentioned above.
With traumatic brain injuryNaCl 0.9%HES (130/0.4) or gelatines
Erythrocyte concentrates and plasma
Hypo-oncotic albumin solutions may increase bleeding and mortality.
Septic Balanced crystalloidsAlbuminConsider erythrocytes and plasma at low haematocrit and disturbed coagulation parameters.
Synthetic colloids compromise kidney function and may increase mortality.
Anaphylactic Balanced crystalloidsAlbumin
HES (130/0.4)
Fluid resuscitation only for correction of anaphylaxis-related relative hypovolaemia (usually 1–2 L crystalloids).
Cardiogenic Balanced crystalloidsAlbuminIn cardiogenic shock, small volume boluses may improve cardiac output due to correction of relative hypovolaemia. Especially in cases with preserved ejection fraction.
HES = hydroxylethyl starch


At a first glance, albumin seems to be the ideal reference colloid. This small endogenous protein, synthesised in the liver, has antioxidant properties, transports electrolytes, drugs and hormones/cytokines, provides 80% of the plasma oncotic pressure and interacts with the endothelial glycocalyx [27]. Albumin continuously leaks into the interstitial space, where 40% of total body albumin is located, and is brought back to the circulation by lymphatic return. The normal plasma escape rate of albumin is 5% per hour, increases by at least 200% in patients with septic shock and returns to baseline after 2 days [28]. This is an obvious disadvantage of albumin administration in the very early phase of septic shock when capillary leak is substantial. However, the latest guidelines from the Surviving Sepsis Campaign recommend albumin for fluid resuscitation in sepsis and septic shock patients who require substantial amounts of crystalloids (weak recommendation) [29]. The American College of Critical Care Medicine recommended 20 ml/kg fluid boluses of either isotonic crystalloids or 5% albumin (level 1C) for early fluid resuscitation in children and neonates with septic shock [30].

Following a Cochrane Review conducted in 1998 that suggested increased mortality associated with albumin use in critically ill patients [31], albumin infusion underwent a period of nearly total avoidance in intensive care. The albumin tide was turning in 2006 when a large blinded randomised controlled trial in almost 7000 patients compared 4% albumin with 0.9% sodium chloride for fluid resuscitation in intensive care units (SAFE trial) [32]. The two heterogeneous groups of critically ill patients showed no difference in 28-day mortality, days on mechanical ventilation and renal replacement therapy (RRT), and length of intensive care and hospital stay. On the contrary, in the predefined subgroup of severely septic patients with complete baseline data (919/1218; 75.5%), the adjusted odds ratio for death with albumin versus saline was 0.71 (95% confidence interval [CI] 0.52–0.97) without increased renal or other organ impairment [33]. Despite a significantly higher mortality rate in the subgroup of traumatic brain injury patients resuscitated with hypo-oncotic albumin [34] and a relatively small fluid saving effect, the results of the SAFE trial corroborated the belief in the beneficial effects of colloids for resuscitation in severe sepsis and septic shock.

A prospective, multicentre open-label trial tested the potential of albumin replacement in severe sepsis and septic shock in 1818 patients randomised to receive either albumin and crystalloids or crystalloids alone [35]. This study targeted a serum albumin concentration of 30 g/l with the infusion of 3 × 100 ml of hyperoncotic albumin 20% per day. During the early phase of volume resuscitation, fluid administration in both groups was according to early goal-directed therapy guidelines. There was no difference in 28- and 90-day mortality or in the appearance and severity of organ dysfunction; however, a post hoc subgroup analysis showed a decreased mortality with albumin in patients with shock at enrolment (relative risk [RR] 0.87; 95% CI 0.77–0.99) [35]. The total fluid volume infused after 7 days was not different, although albumin administration resulted in faster haemodynamic stabilisation. A third randomised open-label multicentre study compared 3 ×100 ml albumin 20% daily with saline boluses in patients with septic shock [36]. This French trial (abstract only available) also showed faster circulatory stabilisation and no difference in mortality between the two groups.

Representative of the urgent wish for a safe and effective colloid are not fewer than eight meta-analyses for the use of albumin in patients with sepsis published between 2011 and 2014, based mainly on the results from the three studies described above [37]. The largest meta-analysis, by Patel et al. [38], included 16 prospective randomised clinical trials published between 1982 and 2014 with patients having sepsis of any severity who received albumin for volume resuscitation compared with a control fluid (crystalloid or colloid; n = 4190). Presenting an overall moderate quality of evidence, the analysis showed a similar risk of death for albumin groups and control fluid groups (RR 0.94; 95% CI 0.87–1.01). There was no indication of harm from albumin in patients with sepsis of any severity. Strong evidence of no difference was found in 3878 patients when albumin was compared with crystalloids only (RR 0.93; 95% CI 0.86–1.01). In contrast, Xu and colleagues found a decreased 90-day mortality with albumin compared with crystalloids for resuscitation in septic shock patients [39]. Overall, this meta-analysis of five studies comparing the effects of albumin with those of crystalloid or saline therapy on mortality exclusively in patients with severe sepsis (n = 3658) and septic shock (n = 2180) observed a trend toward reduced 90-day mortality in the albumin group.

In summary, it can be said that the application of human albumin for resuscitation in severe sepsis and septic shock is an option for supporting haemodynamic stabilisation in patients with high fluid requirements, without negative effects on survival. The significance of albumin in the very early phase of fluid resuscitation with marked capillary leakage and the impact on oedema generation needs further evaluation.

Semisynthetic colloid solutions

After the results of the Rivers study [20] and the almost significant improved survival of septic patients treated with albumin in the SAFE trial [32], semisynthetic colloid solutions (hydroxyethyl starch [HES], gelatines) were adopted as ideal resuscitation fluids for early goal-directed therapy. The allegedly reduced amount of resuscitation fluid with colloid solutions was thought to reduce the interstitial oedema accompanying high volume fluid therapy and lacked the high costs of albumin [40]. Initial concerns about the use of HES for volume resuscitation in severe sepsis appeared after two studies with HES solutions of higher molecular weight and grade of substitution (200 kD / 0.5–0.66). Both studies showed an increased risk of AKI and RRT but no difference in mortality compared with either gelatine 3% or Ringer’s lactate [41, 42]. Specifically, the Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was criticised because a substantial proportion of patients received more than the maximum recommended amount of hyperoncotic HES [42]. At about the same time as this unsettling result, new iso-oncotic HES solutions with a lower molecular weight and degree of substitution (130 / 0.4–0.42) were developed [4].

In 2012, three studies investigating these new HES solutions in a general intensive care population and in severe sepsis and septic shock were published. The multicentre double-blind Scandinavian 6S trial compared HES with Ringer’s acetate for the therapy of severe sepsis and septic shock patients [43]. This study found a 17% increased relative risk of 90-day mortality (95% CI 1.01–1.36) for HES, without a difference in fluid volume administered. Interestingly, the mortality rates at 28 days and at 6 and 12 months were not significantly different between HES 130/0.4 and Ringer’s acetate [44]. Despite a significant difference in short-term RRT, without an increased RRT-related mortality, the same number of patients had RRT for >5 days and an adjustment for AKI stage as covariate eliminated the significance of 90-day mortality [45]. Crystalloid versus Hydroxyethyl Starch Trial (CHEST), a randomised controlled double-blind trial (n = 7000, 1937 patients with sepsis) also found an increased risk for RRT with HES (130/0.4) as compared with sodium chloride 0.9% (RR 1.21, 95% CI 1.00–1.45) [46]. Ninety-day mortality did not differ between the groups and the patients receiving HES showed a decreased incidence of AKI assessed with the RIFLE criteria. The HES group received significantly less fluid during the first 4 days. A smaller French study compared HES 130/04 with sodium chloride for early fluid resuscitation and found that a significantly lower amount of HES was needed to achieve haemodynamic stability [47]. This study found no difference in mortality and renal failure in 196 patients with severe sepsis. The open-label, randomised controlled Colloids Versus Crystalloids for the Resuscitation of the Critically ill (CRISTAL) trial randomised 2857 patients in shock to receive either colloid or crystalloid for the initial treatment of shock [48]. In this trial, the majority of patients received HES 130/0.4 as colloid or sodium chloride as crystalloid, and the colloid group required significant less resuscitation fluid. The primary end-point of 28-day mortality was not different, although there was a small mortality benefit in favour of colloids after 90 days. No difference in the number of patients receiving RRT was observed [48].

A meta-analysis comparing only HES 140/03 with either crystalloids or albumin in sepsis found no overall increased mortality in 3546 patients. In the studies with low risk of bias (3016 patients), the relative risk of death with the use of HES was 1.11 (1.00–1.23 trial sequential analysis adjusted 95% CI 0.95–1.29) [49]. Patients receiving HES needed more RRT and showed a nonsignificant increase in the risk of AKI. Another meta-analysis comparing HES of different molecular weights, substitution and oncotic preparations with other resuscitation fluids in critically ill patients found an increased relative risk of mortality (1.09, 95% CI 1.02–1.17) and an increased risk for AKI (RR 1.27, 95% CI 1.09–1.47) and RRT (RR 1.32, 95% CI 1.15–1.50) [50]. Finally, a network meta-analysis examining the effect of different resuscitation fluids on mortality in sepsis showed with high confidence higher mortality with starches than with crystalloids [51]. Balanced crystalloids revealed with moderate confidence a lower mortality than low- and high molecular weight HES preparations.

Although gelatines are widely used semisynthetic colloids, there is a paucity of high-quality randomised controlled trials [40, 52]. In a prospective sequential fluid resuscitation analysis, gelatine 4% was an independent risk factor of AKI (OR 1.85, 95% CI 1.31–2.62) [53]. A recent meta-analysis of three studies comparing gelatine with crystalloids or albumin in 212 patients showed a 15% increased relative risk for mortality and a 35% increased risk for AKI in patients receiving gelatines [54]. Although these findings were not significant, they point to avoidance of gelatine use in septic patients.

Semisynthetic colloids, especially starches, should not be administered to patients with severe sepsis and septic shock because there is an increased risk for mortality and AKI when they are given in large amounts for volume resuscitation in critically ill septic patients. However, particularly the large, randomised controlled trials used high amounts of HES for more than 2 days partly in patients already fluid-resuscitated [42, 43, 46]. A recent meta-regression analysis of studies using HES 130/0.4 in septic patients suggested that the inappropriately high daily delta fluid balance is an important source of heterogeneity and was associated with mortality in these trials [55]. Studies using HES in the very early phase of sepsis resuscitation showed a decreased volume of fluid required in the HES group without an increased risk for mortality and AKI [47, 48]. The increased number blood products received, interpreted as to the detriment of HES [43, 46], could also be viewed as a sign of effectiveness, because haematocrit is more affected with a better plasma expanding capacity [56]. In the light of the increased mortality with higher amounts of fluid in patients with septic shock [57, 58], semisynthetic colloids and their influence on microvascular flow [59] in the initial phase of septic shock therapy deserve further investigation.

Crystalloid solutions

Crystalloids are the mainstay of volume resuscitation and maintenance in critically ill patients [29]. Crystalloids are classified as “balanced” and “unbalanced”. Balanced crystalloids are characterised by a plasma-like strong ion gap (about 24 mmol/l) [4]. Sodium chloride (saline, NaCl), the most commonly used crystalloid worldwide, has a strong ion difference of zero and is therefore called “unbalanced” [40]. Administration of large amounts of saline results in a hyperchloraemic metabolic acidosis [1]. High plasma chloride concentrations increase inflammatory markers, induce coagulopathy and decrease renal blood flow [60, 61]. In sepsis studies, crystalloid solutions are mainly used as comparator fluids for semisynthetic colloids and albumin. Direct comparisons between different balanced crystalloids are rare. No trials have evaluated the differences between different buffered crystalloids or their side effects in critically ill patients, although there are theoretical reasons for preferring acetate- to lactate-buffered solutions. In fact, nearly every human cell type is able to metabolise acetate, whereas lactate increases with declining liver function, hampering the interpretation of serum lactate levels.

A prospective, open-label, sequential period study in a single intensive care unit in Australia compared sodium chloride with balanced electrolytes [62]. In this before and after study, patients who received almost entirely balanced infusions showed a significant decrease in the incidence of AKI (adjusted OR 0.52, CI 95% 0.37–0.75) and RRT (adjusted OR 0.53, CI 95% 0.33–0.81) compared with patients treated with normal saline during an earlier period. Two retrospective studies including patients with sepsis (n = 53,448) [63] and systemic inflammatory response syndrome (n = 109,836) [64] showed a reduced in-hospital mortality with balanced infusions, a finding that was proportional to the chloride load. Patients in the sepsis cohort showed no difference in AKI. Another retrospective study in septic patients found an increased mortality in patients with hyperchloraemia on admission, independent of base deficit, cumulative fluid balance and AKI [65]. A retrospective cohort study in more than 60,000 septic shock patients compared four groups of fluid resuscitation [66]. Patients receiving saline together with balanced electrolytes had a significantly lower mortality (17.7%) than saline 0.9% alone (20.2%), saline and colloids (24.2%), and all three categories together (19.2%). In contrast to this retrospective cohort studies, two prospective, cluster randomised, crossover trials (SALT and SPLIT) comparing more than 3000 intensive care patients to either crystalloids or sodium chloride 0.9% found no difference in mortality, AKI and RRT [67, 68]. In both studies, the amount of fluid infused was rather low and the group of sepsis patients small, so that a possible negative effect on kidney function was obscured. In the SALT trial, patients administered larger volumes of saline showed a significant increase in the composite of death, AKI and RRT [68]. A retrospective study of large volume resuscitation (60 ml/kg per day) showed a significantly increased crude rate of hyperchloraemic acidosis, AKI and hospital mortality with increased chloride load [69]. After adjustment for disease severity, total fluids and age, only mortality remained significant with a 5.5% increased risk of death for each 100 mmol of administered chloride, or 11% for 2 L of sodium chloride 0.9%. Finally a recent cluster-randomised, multiple cross-over trial in 15,802 critically ill adults showed that primarily the administration of balanced fluids resulted in a lower rate of a composite outcome of death, AKI and initiation of RRT [70]. The separate analysis of the three outcomes did not reach significance. In the relatively small group of septic patients (n = 2936), the composite endpoint and the 30-day mortality were lower with balanced infusions [70].

Up-to-date randomised, controlled, double-blind trials comparing saline 0.9% with balanced crystalloids, or different crystalloid preparations are lacking. Nevertheless, the existing data seem to indicate an increased mortality risk with saline 0.9%, especially when administered in high amounts. Hyperchloraemic acidosis seems to outweigh the possible adverse effects of the slightly hypotonic balanced crystalloid solutions. The only exception may be traumatic brain injury, where hypotonic balanced solutions may increase brain oedema more than slightly hypertonic saline 0.9%.

Volume replacement in massive haemorrhage

Fluid resuscitation in uncontrolled haemorrhage aims to maintain adequate organ perfusion and tissue oxygen delivery in a system compromised by the physiological consequences of traumatic injury. However, fluid therapy is only one component of a complex haemodynamic resuscitation strategy in massively injured patients [71]. Additional therapeutic options, including the use of vasopressors, early surgical exploration with emphasis on damage control, angiographic embolisation of bleeding arteries and deliberate hypotension, are comparably important, especially in penetrating trauma [40, 72, 73]. For the latter, patients with traumatic brain injury or patients with or at risk of coronary artery or cerebrovascular disease are important exceptions.

Fluid resuscitation of trauma patients is an ongoing challenge with various recommendations regarding the use of crystalloids, colloids, blood products and clotting factor concentrates [7277]. No ideal resuscitation fluid for trauma patients exists in clinical practice [40], and the debate about this is highly emotional [76, 77]. The choice of type of resuscitation fluid is mainly based on institutional practice and clinician’s preferences, and rarely on physiological principles and study data. Further, regional variations, varying institutional protocols, availability and legal restrictions might relevantly influence the choice [74, 76].

However, there is accumulating evidence that the amount and type of fluid resuscitation might affect outcome in patients with massive haemorrhage similarly to patients with severe sepsis. Generally, it is suggested to restrict fluid administration in the prehospital period and in the emergency department [72]. Over-resuscitation with overzealous crystalloid administration leading to dilutional coagulopathy, hypothermia and potentially acidosis might further aggravate bleeding and coagulopathy [6, 16, 78].

Although their positive effect and advantage is not fully proven, crystalloids have an established role as inexpensive and widely available first-line resuscitation fluids in trauma [40]. Albeit the use of semisynthetic colloids in trauma patients is often perceived to be associated with improved haemodynamic stability, but with increased risk of coagulopathy and renal failure, a large meta-analysis could not show that one solution is relevantly safer or associated with improved survival [79, 80]. Similarly, the use of human albumin for fluid resuscitation did not improve outcome compared with crystalloid in a randomised study including nearly 7000 patients [32]. In a subgroup of patients with traumatic brain injury, the use of hypo-oncotic albumin 4% actually increased mortality [34].

The administration of colloids over a prolonged period of time and in dosages beyond any recommendations must be avoided. However, colloids might be better than crystalloids for replacing plasma deficits and avoiding acute intravascular hypovolaemia or for preventing tissue oedema [6, 76, 81]. Potentially, limited amounts of colloids in the initial resuscitation phase of haemodynamically unstable patients (fig. 2) might be beneficial, but should be continued with a “crystalloid” maintenance phase. The value of hyperosmolar saline solution is unclear [82], and the solution has been abandoned.

Figure 2

Influence of fluid resuscitation on the sublingual microcirculation. Panel A shows the microcirculation of a patient in haemorrhagic shock. Most of the visible microvessels show are intermittently perfused (orange lines) or show no flow (red lines). Panel B shows the microcirculation of the same patient after resuscitation with on unit packed red cells. The amount of microvessels with intermittent flow differs markedly. Only very view vessel parts show a no flow phenomenon.

Use of blood products

During massive haemorrhage, there is a rapid loss of red blood cells and coagulation factors, in combination with hyperfibrinolysis resulting in acute trauma coagulopathy. In the case of massive haemorrhagic shock, the transfusion of red blood cells is often unavoidable to preserve a minimal haematocrit level. However, the infusion of crystalloids and colloids will lead to further dilutional anaemia and coagulopathy.

Plasma might be an ideal resuscitation fluid as it is protein-rich and contains coagulation factors. The endothelial glycocalyx might be better preserved with less fluid loss in the interstitium and potentially lead to less additional coagulopathic deterioration by administration of plasma products [16, 83]. However, this concept has only been proven in a rodent model of haemorrhagic shock [83]. Recent German guidelines stated that plasma is contraindicated for primary volume resuscitation (recommendation grade 1C) [84]. The clinical effectiveness of fresh frozen plasma to preserve or restore coagulation deficits has been questioned by a large meta-analysis [85]. Nonetheless, despite the questionable indication and clinical benefit of plasma, and although its use had not been studied in non-trauma settings and in septic shock, the use of plasma as a “super-colloid” has been advocated by some experts [4].

In the event of haemorrhagic shock, early transfusion of plasma and platelets together with red blood cell concentrates has been advocated [72] as part of a massive transfusion protocol (MTP) aiming to transfuse “whole blood”. MTPs are also thought to prevent rather than reverse or treat trauma coagulopathy. MTPs with an approximate 1:1:1 ratio of blood components might be especially helpful in the early resuscitation phase before bleeding is controlled surgically. However, the value of MTPs has been evaluated only in retrospective analyses, most of which are associated with a relevant survivorship bias [86]. Further, even an MTP leads to relevant dilution of coagulation factors [87] and might be able to only partially limit rather than prevent further coagulopathy.

Finally, a recent study from Austria suggested that the early use of coagulation factor concentrates instead of the administration of plasma is feasible in the trauma setting and associated with less use of allogeneic blood products [88]. However, it is unclear whether such a regimen is associated with better outcome and lower morbidity and mortality.


After 15 years of intense research, no fluid resuscitation panacea has been found and the optimal type and amount of fluid for the early volume replacement should be individualised for each patient and type of shock (table 1). A very recent Cochrane review stated with moderate evidence that fluid resuscitation with starches, albumin or fresh frozen plasma shows little or no difference in mortality compared with crystalloids in critically ill patients [89]. In current surviving sepsis guidelines [29], five out of six recommendations for fluid therapy are based on moderate- or low-quality evidence. The only strong recommendation with high-quality evidence is against the use of HES. Even this recommendation should be considered with caution, because the studies comparing HES 130/0.4 with crystalloids used rather high volumes of resuscitation fluid in patients already volume resuscitated [43, 46, 56]. The two studies testing starches in the very early course of shock did not find an increased mortality or a higher risk of AKI [47, 48]. Studies with an early administration of starch also found a volume-sparing effect in a ratio of 1.2 to 1.5 in favour of colloids, which is far below the theoretical expected value of 3, and an effect that is not so obvious in studies using high amounts of fluid over >2 days [56]. A possible explanation for this weak volume expanding effect could be that the fluid requirement is context sensitive [3]. This means that after initial resuscitation of the microcirculation, further volume replacement increases tissue oedema disproportionately. The reason for this could be a direct transmission of the increased mean arterial pressure through the dilated resistance vessels to the capillaries, where the thinned out glycocalyx together with the increased number of endothelial gaps are unable to retain volume intravascularly. Ospina-Tascone and colleagues showed that infusion of either 1 L of Ringer’s lactate or 400 ml of albumin 4% only increased the proportion of perfused small microcirculatory vessels during the first 24 hours of severe sepsis but not 48 hours after the diagnosis [59]. No relation to mean arterial pressure or cardiac index was found. The study also found a direct relationship between improved microvascular perfusion and decreased serum lactate [59]. Earliest evidence for the relevance of the administered volume came from a study of patients with acute respiratory distress syndrome, predominantly from pneumonia and sepsis, where a conservative fluid therapy improved lung function and decreased duration of mechanical ventilation [17]. In 2006, a European multicentre, observational cohort study in 1177 septic patients found a positive cumulative fluid balance as the only modifiable risk factor for death [90]. In the meantime, several retrospective cohort and prospective observational studies showed an association between higher positive fluid balances from 24 hours to 8 days and mortality [9193]. In two very recent retrospective analyses of patients with severe sepsis or septic shock, the administration of more than 5 litres of resuscitation fluid on day one or a higher cumulative fluid balance on day three was associated with an increased risk of death [58, 94]. A retrospective review of fluid use in the prospective, randomised, blinded Vasopressin in Septic Shock Trial (VASST) [95] showed that a more positive fluid balance after 12 hours and 4 days was associated with a higher risk of mortality [57]. A central venous pressure of more than 12 mm Hg in the first 12 hours of resuscitation was also associated with increased mortality. Increased central venous pressure increases microvascular outflow and capillary pressure, which also increases the extravasation of fluid to the interstitium [3]. The possible positive impact of modulating microvascular in- and outflow pressure to reduce capillary pressure and thereby fluid extravasation was shown by two studies. Jansen et al. used a treatment algorithm according to which they applied vasodilators to correct microcirculatory derangement to foster decreased blood lactate concentrations [96]. Together with a minimal increased fluid volume during the first 8 hours, this modulation of microvascular outflow pressure decreased ICU and in-hospital mortality. An increase of microvascular inflow pressure with a fixed dose of vasopressin (0.03 U/min) in addition to vasopressors decreased the relative risk of 90-day mortality in patients with less severe sepsis [95]. Norepinephrine increased cardiac preload and reduced preload dependency in septic shock patients [97]. The current surviving sepsis campaign guidelines recommend 30 ml/kg body weight administered during the first 3 hours of sepsis therapy, norepinephrine as the first line vasopressor and vasopressin (0.03 U/min) as the second line to increase mean arterial pressure.


Fifteen years of intensive research have not found the optimal resuscitation fluid, as relative uncertainty remains about type and amount of fluid. Balanced crystalloids seem to be more advantageous than normal saline. Iso-oncotic albumin should be used as a colloid since the liberal use of starches over days has shown an increased incidence of AKI, RRT and mortality. The role of plasma and red blood cell concentrates is still controversial. The classic haemodynamic targets, including mean arterial pressure, cardiac output, lactate and even dynamic tests (e.g., passive leg raising), alone may not be sufficient to guide fluid administration in patients with haemorrhagic and septic shock. Direct or indirect monitoring of microcirculation including skin mottling and turgor, central venous pressure and peripheral oedema, should be considered as well, as the microcirculation it the primary target of fluid therapy.


We thank Allison Dwilewski for proofreading the manuscript.

Disclosure statement

MS has received support from Fresenius-Kabi for an investigator initiated fluid trial. No other potential conflict of interest related to this article was reported.


Prof. Dr. med. Martin Siegemund, Chefarzt Stv, Operative Intensivbehandlung, Departement für Anästhesie, Operative Intensivbehandlung, präklinische Notfallmedizin und Schmerztherapie, Spitalstr. 21, CH-4031 Basel, martin.siegemund[at]


1 Semler MW, Rice TW. Sepsis Resuscitation: Fluid Choice and Dose. Clin Chest Med. 2016;37(2):241–50. doi:. PubMed

2 Siegemund M, van Bommel J, Ince C. Assessment of regional tissue oxygenation. Intensive Care Med. 1999;25(10):1044–60. doi:. PubMed

3 Tatara T. Context-sensitive fluid therapy in critical illness. J Intensive Care. 2016;4(1):20. doi:. PubMed

4 Chang R, Holcomb JB. Choice of Fluid Therapy in the Initial Management of Sepsis, Severe Sepsis, and Septic Shock. Shock. 2016;46(1):17–26. doi:. PubMed

5 Ince C, Mayeux PR, Nguyen T, Gomez H, Kellum JA, Ospina-Tascón GA, et al.; ADQI XIV Workgroup. The Endothelium in Sepsis. Shock. 2016;45(3):259–70. doi:. PubMed

6 Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology. 2008;109(4):723–40. doi:. PubMed

7 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. doi:. PubMed

8 Stiel L, Meziani F, Helms J. Neutrophil Activation During Septic Shock. Shock. 2018;49(4):371–84. doi:. PubMed

9 De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98–104. doi:. PubMed

10 Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825–31. doi:. PubMed

11 Marechal X, Favory R, Joulin O, Montaigne D, Hassoun S, Decoster B, et al.Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock. 2008;29(5):572–6. PubMed

12 Rahbar E, Cardenas JC, Baimukanova G, Usadi B, Bruhn R, Pati S, et al.Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med. 2015;13(1):117. doi:. PubMed

13 Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, et al.Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116(17):1896–906. doi:. PubMed

14 Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med. 2010;363(7):689–91. doi:. PubMed

15 Liang Y, Li X, Zhang X, Li Z, Wang L, Sun Y, et al.Elevated levels of plasma TNF-α are associated with microvascular endothelial dysfunction in patients with sepsis through activating the NF-κB and p38 mitogen-activated protein kinase in endothelial cells. Shock. 2014;41(4):275–81. doi:. PubMed

16 Chappell D, Bruegger D, Potzel J, Jacob M, Brettner F, Vogeser M, et al.Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx. Crit Care. 2014;18(5):538. doi:. PubMed

17 Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, et al., National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564–75. doi:. PubMed

18 Balogh Z, McKinley BA, Cocanour CS, Kozar RA, Valdivia A, Sailors RM, et al.Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg. 2003;138(6):637–42, discussion 642–3. doi:. PubMed

19 Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol. 2018;14(4):217–30. doi:. PubMed

20 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al.; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77. doi:. PubMed

21 Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al.A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409–17. doi:. PubMed

22 Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al., ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506. doi:. PubMed

23 Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, et al., ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–93. doi:. PubMed

24 Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al.; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11. doi:. PubMed

25 Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, et al.A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015;41(9):1549–60. doi:. PubMed

26 Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, Canter RR, et al., PRISM Investigators. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223–34. doi:. PubMed

27 Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic potential. Hepatology. 2005;41(6):1211–9. doi:. PubMed

28 Fleck A, Hawker F, Wallace PI, Raines G, Trotter J, Ledingham IM, et al.Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury. Lancet. 1985;325(8432):781–4. doi:. PubMed

29 Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al.Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304–77. doi:. PubMed

30 Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, et al.American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med. 2017;45(6):1061–93. doi:. PubMed

31 Reviewers CIGA, Reviewers CIGA; Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317(7153):235–40. doi:. PubMed

32 Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247–56. doi:. PubMed

33 Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Norton R; SAFE Study Investigators. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37(1):86–96. doi:. PubMed

34 Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, et al., George Institute for International Health. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357(9):874–84. doi:. PubMed

35 Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al.; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412–21. doi:. PubMed

36 Charpentier J, Mira J-P. Efficacy and tolerance of hyperoncotic albumin administration in septic shock patients: the EARSS study. Intensive Care Med. 2011;37(Suppl 1):S115. [abstract 0438].

37 Caironi P, Langer T, Gattinoni L. Albumin in critically ill patients: the ideal colloid?Curr Opin Crit Care. 2015;21(4):302–8. doi:. PubMed

38 Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349(jul22 10):g4561. doi:.. Correction in: BMJ. 2014;349:g4850. doi: PubMed

39 Xu JY, Chen QH, Xie JF, Pan C, Liu SQ, Huang LW, et al.Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18(6):702. doi:. PubMed

40 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243–51. doi:. PubMed

41 Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, et al.Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357(9260):911–6. doi:. PubMed

42 Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al.; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125–39. doi:. PubMed

43 Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, et al.; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124–34. doi:. PubMed

44 Perner A, Haase N, Winkel P, Guttormsen AB, Tenhunen J, Klemenzson G, et al.Long-term outcomes in patients with severe sepsis randomised to resuscitation with hydroxyethyl starch 130/0.42 or Ringer’s acetate. Intensive Care Med. 2014;40(7):927–34. doi:. PubMed

45 Müller RB, Haase N, Lange T, Wetterslev J, Perner A. Acute kidney injury with hydroxyethyl starch 130/0.42 in severe sepsis. Acta Anaesthesiol Scand. 2015;59(3):329–36. doi:. PubMed

46 Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901–11. doi:. PubMed

47 Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, 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. doi:. PubMed

48 Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, et al.; CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310(17):1809–17. doi:. PubMed

49 Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, et al.Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ. 2013;346(feb15 1):f839. doi:. PubMed

50 Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, et al.Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309(7):678–88. doi:. PubMed

51 Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, et al.; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347–55. doi:. PubMed

52 Perner A, Prowle J, Joannidis M, Young P, Hjortrup PB, Pettilä V. Fluid management in acute kidney injury. Intensive Care Med. 2017;43(6):807–15. doi:. PubMed

53 Bayer O, Reinhart K, Kohl M, Kabisch B, Marshall J, Sakr Y, et al.Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med. 2012;40(9):2543–51. doi:. PubMed

54 Moeller C, Fleischmann C, Thomas-Rueddel D, Vlasakov V, Rochwerg B, Theurer P, et al.How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. J Crit Care. 2016;35:75–83. doi:. PubMed

55 Ma PL, Peng XX, Du B, Hu XL, Gong YC, Wang Y, et al.Sources of Heterogeneity in Trials Reporting Hydroxyethyl Starch 130/0.4 or 0.42 Associated Excess Mortality in Septic Patients: A Systematic Review and Meta-regression. Chin Med J (Engl). 2015;128(17):2374–82. doi:. PubMed

56 Orbegozo Cortés 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(2):389–402. doi:. PubMed

57 Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259–65. doi:. PubMed

58 Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43(5):625–32. doi:. PubMed

59 Ospina-Tascon G, Neves AP, Occhipinti G, Donadello K, Büchele G, Simion D, et al.Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med. 2010;36(6):949–55. doi:. PubMed

60 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® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18–24. doi:. PubMed

61 Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and physiological Hartmann’s solution: a randomized double-blind crossover study. Clin Sci (Lond). 2003;104(1):17–24. PubMed

62 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. doi:. PubMed

63 Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, et al.Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med. 2014;42(7):1585–91. doi:. PubMed

64 Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer CR. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Med. 2014;40(12):1897–905. doi:. PubMed

65 Neyra JA, Canepa-Escaro F, Li X, Manllo J, Adams-Huet B, Yee J, et al.; Acute Kidney Injury in Critical Illness Study Group. Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med. 2015;43(9):1938–44. doi:. PubMed

66 Raghunathan K, Bonavia A, Nathanson BH, Beadles CA, Shaw AD, Brookhart MA, et al.Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock. Anesthesiology. 2015;123(6):1385–93. doi:. PubMed

67 Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al.; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701–10. doi:. PubMed

68 Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, et al.; SALT Investigators * and the Pragmatic Critical Care Research Group; SALT Investigators. Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial. Am J Respir Crit Care Med. 2017;195(10):1362–72. doi:. PubMed

69 Sen A, Keener CM, Sileanu FE, Foldes E, Clermont G, Murugan R, et al.Chloride Content of Fluids Used for Large-Volume Resuscitation Is Associated With Reduced Survival. Crit Care Med. 2017;45(2):e146–53. doi:. PubMed

70 Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al.; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829–39. doi:. PubMed

71 Cannon JW. Hemorrhagic Shock. N Engl J Med. 2018;378(4):370–9. doi:. PubMed

72 Dutton RP. Management of traumatic haemorrhage--the US perspective. Anaesthesia. 2015;70(Suppl 1):108–11, e38. doi:. PubMed

73 Wise R, Faurie M, Malbrain MLNG, Hodgson E. Strategies for Intravenous Fluid Resuscitation in Trauma Patients. World J Surg. 2017;41(5):1170–83. doi:. PubMed

74 Jabaley C, Dudaryk R. Fluid resuscitation for trauma patients: crystalloids versus colloids. Curr Anesthesiol Rep. 2014;4(3):216–24. doi:.

75 Schöchl H, Voelckel W, Schlimp CJ. Management of traumatic haemorrhage--the European perspective. Anaesthesia. 2015;70(Suppl 1):102–7, e35–7. doi:. PubMed

76 Chappell D, Jacob M. Hydroxyethyl starch - the importance of being earnest. Scand J Trauma Resusc Emerg Med. 2013;21(1):61. doi:. PubMed

77 Haase N, Perner A. Hydroxyethyl starch for resuscitation. Curr Opin Crit Care. 2013;19(4):321–5. doi:. PubMed

78 Bickell WH. Are victims of injury sometimes victimized by attempts at fluid resuscitation?Ann Emerg Med. 1993;22(2):225–6. doi:. PubMed

79 Bunn F, Trivedi D. Colloid solutions for fluid resuscitation. Cochrane Database Syst Rev. 2012;(7):CD001319. PubMed

80 Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013;(2):CD000567. doi:. PubMed

81 Rehm M, Haller M, Brechtelsbauer H, Akbulut C, Finsterer U. Extra protein loss not caused by surgical bleeding in patients with ovarian cancer. Acta Anaesthesiol Scand. 1998;42(1):39–46. doi:. PubMed

82 de Crescenzo C, Gorouhi F, Salcedo ES, Galante JM. Prehospital hypertonic fluid resuscitation for trauma patients: A systematic review and meta-analysis. J Trauma Acute Care Surg. 2017;82(5):956–62. doi:. PubMed

83 Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al.Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289–95. doi:. PubMed

84 Bundesärztekammer. Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. Bundesärztekammer, editor: Deutscher Ärzte Verlag; 2015.

85 Kozek-Langenecker S, Sørensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care. 2011;15(5):R239. doi:. PubMed

86 Ho AM, Dion PW, Yeung JH, Holcomb JB, Critchley LA, Ng CS, et al.Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology. 2012;116(3):716–28. doi:. PubMed

87 Armand R, Hess JR. Treating coagulopathy in trauma patients. Transfus Med Rev. 2003;17(3):223–31. doi:. PubMed

88 Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, et al.Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial. Lancet Haematol. 2017;4(6):e258–71. doi:. PubMed

89 Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, et al.Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8:CD000567. doi:. PubMed

90 Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al.; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53. doi:. PubMed

91 Micek ST, McEvoy C, McKenzie M, Hampton N, Doherty JA, Kollef MH. Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Crit Care. 2013;17(5):R246. doi:. PubMed

92 Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC. Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock. 2015;43(1):68–73. doi:. PubMed

93 Besen BA, Taniguchi LU. Negative Fluid Balance in Sepsis: When and How?Shock. 2017;47(1S, Suppl 1):35–40. doi:. PubMed

94 Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, et al.; Intensive Care Over Nations Investigators. Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Crit Care Med. 2017;45(3):386–94. doi:. PubMed

95 Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al.; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–87. doi:. PubMed

96 Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, et al.; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182(6):752–61. doi:. PubMed

97 Monnet X, Jabot J, Maizel J, Richard C, Teboul JL. Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients. Crit Care Med. 2011;39(4):689–94. doi:. PubMed

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