Although rapid and adequate administration of fluid is largely accepted as a mainstay of resuscitation in the critically ill patient, there is still an ongoing debate on the merits of colloids against crystalloids as first line plasma expanders. The underlying biologic rationale calls for rapid restoration of fluid losses to maintain circulating blood volume and organ perfusion.
The main arguments in favor of colloids are that they restore hemodynamic parameters faster and with less volume load than crystalloids, remain in the intravascular space longer, and lead to less pulmonary and tissue edema. An increased volume load or positive fluid balance may favor tissue edema and decrease survival. However, recent studies in patients with capillary leak syndrome have shown that extravascular lung water or pulmonary SOFA score were not influenced by type of colloid or crystalloid fluid administered [1,2]. Moreover, colloids have beneficial effects on microcirculation and rheology, and exert potential anti-inflammatory effects. In comparison to albumin, synthetic colloids are less costly.
Crystalloid supporters argue that crystalloids are safe, do not interfere with coagulation beyond the effect of hemodilution, are not taken up and stored in the body, and are inexpensive to use.
Until recently, available information was based on comparison of fluids in terms of their physiological effect in small, under-powered studies with short observation periods. Meta-analyses based on these studies have consistently confirmed that crystalloids and colloids are equally effective plasma expanders . The choice of an ideal plasma volume expander is often founded on personal belief as well as special ty and location of practice, and use of these compounds varies considerably throughout the world, with starches predominating in Europe, particularly Germany and the Netherlands as well as in Canada, while albumin is preferred in the USA and Australia. Gelatin is favored more in the UK. In the USA, by request of the FDA gelatin was removed from the market due to coagulatory side effects, whereas tetrastarch (HES 130/0.4) was recently introduced to the market .
In the meanwhile, however, clinical trials with suitable design and power were undertaken to study the effect of crystalloids or colloids in critically ill patients and the results provide new insights, especially on the safety of these compounds in these patients.
Albumin is a natural plasma protein which contributes strongly towards plasma oncotic pressure. Albumin has an excellent long-term safety record and serious adverse events reported from its use are rare . A highly controversial meta-analysis which focused on albumin alone found an increased mortality risk in critically ill patients  and led to a steep decline in use of albumin. However, this was neither confirmed by subsequent meta-analyses nor randomized controlled trials. The large interventional Saline versus Albumin Fluid Evaluation (SAFE) study was the first adequately designed study to investigate the outcome of albumin administration in critically ill patients . Nearly 7,000 patients were randomized to receive either 4% iso-osmotic albumin or normal saline for resuscitation according to clinical status and response to treatment. In addition, patients received maintenance fluids, specific replacement fluids, and enteral or parenteral nutrition and blood products as necessary. Patients in the two groups received similar volumes of non-study fluid during the first 4 days except for the albumin group, which received 71.0 ml more of packed red cells. All outcomes in both groups were comparable, in particular the lengths of stay, number of organ failures, duration of mechanical ventilation, or 28-day all cause mortality [20.9% vs. 21.1%, the relative risk of death being 0.99; 95% confidence interval (CI), 0.91–1.09; p = 0.87].
The relative risk of death tended to be reduced in a subgroup of 603 patients with severe sepsis after resuscitation with albumin (30.7%) in comparison to saline (35.3%, p = 0.06 by the test for a common relative risk).
In a subgroup of patients with trauma, however, the relative risk of death during 28 days was higher in the albumin group (N = 1,186, 13.6% vs. 10.0%, 95% CI 0.99–1.86, p = 0.06). This was due to the greater number of patients with associated brain injury who died after random assignment to albumin as opposed to saline. A follow-up study of the enrolled patients with severe brain injury confirmed a significantly higher mortality at 24 months after treatment with albumin (N = 460, 33.2% vs. 20.4%, RR 1.88, 95% CI, 1.31–2.70; p <0.001) .
In summary, 4% iso-osmotic albumin is safe to use in the intensive care unit (ICU), except in patients with traumatic brain injury, and may have some potential
benefit in patients with severe sepsis. Further trials are needed to determine the relevance of this observation.
Hydroxyethyl starch (HES) is the most widely used synthetic colloid and has been on the market for many decades. Previous meta-analyses concluded that HES does not improve clinical outcome compared to either other colloids or crystalloids [3,9]. Only few clinical studies in ICU patients have focused on patient-related outcome measures, and most of them were carried out only recently [1,2,10–13]. These studies compared fluid therapy with HES against crystalloid and confirmed that HES administration does not confer a clinical benefit. Moreover, they provide evidence that HES administration in ICU patients carries the risk of severe adverse effects and shows dose-related toxicity with increased long-term mortality. Meanwhile, the use of HES in critically ill patients is highly controversial [14,15].
The recent Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study (VISEP) was undertaken to test the hypothesis that HES resuscitation would lead to a better outcome in patients with severe sepsis . This prospective multicenter study randomized 537 patients to either 10% HES 200/0.5 or modified Ringer’s lactate to achieve a central venous pressure (CVP) >8 mmHg; in addition, patients received maintenance fluids, enteral or parenteral nutrition, and blood products. Twenty-eight-day mortality did not differ between the HES and the crystalloid group (26.7% vs. 24.1%, p = 0.48) but 90-day mortality tended to be higher in the HES group (41.0% vs. 33.9%, p = 0.09). Further analyses revealed that this was due to a substantial subgroup of patients (N = 100) who had received high doses of HES on at least 1 day (defined as >22 ml/kg body weight/day, 20 ml/kg/day being the dose limit recommended by the manufacturer). These patients also had received a cumulative dose of 136.0 ml/kg bodyweight and had an excessively high mortality rate of 57.9%, compared to the lower dose group with a median cumulative dose of 48.3 ml HES/kg and a mortality rate of 30.9%, p <0.001.
Wills et al. conducted a single center, randomized, double-blind comparison of Ringer’s lactate, 6% dextran 70, and 6% HES 200/0.5 for emergency resuscitation of children with Dengue shock syndrome stratified according to pulse pressure. The primary outcome measure was requirement for rescue colloid which was similar across treatment groups, the relative risk being 1.08 (95% CI 0.66–1.17; p = 0.38) for Ringer’s compared with either colloid solution .
Hypervolemic hemodilution is a widely accepted therapy in patients with acute ischemia of the brain. In order to test its efficacy, a recent double-blind, placebo-controlled study randomized 200 patients within 6 h of a first ischemic stroke localized in the middle cerebral artery territory to 10% HES 200/0.5 or Ringer’s lactate over a study period of 5 days. Primary outcome was clinical improvement within 7 days as measured by the Graded Neurologic Scale. An interim analysis showed that neurological recovery was similar between the groups at 7 days and 3 months and the study
was terminated early for futility . The total dose of HES used was 2,500 ml within 5 days, which amounts to approximately 33 ml/kg cumulative dose in a 75 kg adult. Two subsequent small studies, which were undertaken with 10% and 6% HES 130/0.4 also failed to show a neurological outcome benefit over crystalloid [16,17].
There is now considerable evidence that HES can impair renal function in ICU patients, ranging from acute renal failure in prospective multicenter studies in septic patients [2,10] to chronic nephrotoxicity with secondary renal failure in liver transplant patients as long as 10 years after HES administration . In patients with severe sepsis, administration of 6% HES 200/0.62 compared to 3% gelatin resulted in increased occurrence of renal impairment, defined as a twofold increase in serum creatinine from baseline or need for renal replacement therapy (N = 129; 42% vs. 23%, p = 0.028). The mean cumulative dose of HES was 31 ml/kg . In the VISEP study, 10% HES 200/0.5 recipients had a higher risk of acute renal failure (34.9% vs. 22.8%, p = 0.002) and twofold days on renal replacement therapy (650 of 3,554 vs. 321 of 3,471 total days, or 18.3% vs. 9.2%). Renal impairment correlated with the cumulative dose of HES, but not of Ringer’s lactate. Importantly, patients who always received HES doses below the manufacturer’s daily dose limit still had a higher risk of renal failure than patients receiving crystalloid (p = 0.04) .
Safety of HES in critically ill patients has never yet been proven in adequately designed clinical studies. Studies called upon to rule out negative effects of HES solutions on renal function are flawed by inadequate comparators, e.g., other synthetic colloids like different HES solutions or gelatin, too-short observation periods, and inadequate endpoints for renal dysfunction [4, 19]. With observation periods of 5 days or less and creatinine serum levels as marker of renal dysfunction, neither the Schortgen  nor the VISEP study  would have revealed the higher incidence of renal failure after HES administration.
Similarly, findings from a recent European multicenter study which claimed that HES was not associated with increased renal replacement therapy are inconclusive because the study was purely observational and not designed to test the safety of HES. Patients received other colloid fluids and HES use was reported in a very low mean cumulative dose of less than 15 ml/kg . Another recent comparison in cardiac surgical patients with 60-day follow-up concluded that HES 130/0.4 was as safe as 5% albumin; however, the cumulative dose during the 48-h study period was only approximately 33 ml/kg, which is less than one recommended daily dose of 50 ml/kg .
In 2007, use of tetrastarch (HES 130/0.4) in the USA was approved by the FDA for hypovolemia during or after surgery on the basis of noninferiority studies. The underlying clinical studies, which can be publicly assessed , show that comparator fluids were mainly other starches or gelatin. Estimation of safety was based on pooled results from studies in low risk patients excluding previous cardiac surgery; anemia; a history of heart, kidney, or liver disease; diabetes or severe infectious diseases; history of coagulation disorders; known allergy to starch; BW >100 kg; pregnancy; and lactation. Mean observation period was 2 days and mean cumulative dose was 42 ml/kg, which is less than one daily allowed maximum dose of 50 ml/kg for this solution. There was no data on the safety of HES 130/0.4 in severe sepsis patients or ICU patients with pre-existing renal impairment or risk for renal dysfunction. Based on this evidence, HES 130/0.4 can only be safely recommended in small amounts and in patients with low risk . Adverse effects on renal function have been noted in various clinical conditions and for all HES solutions [22,23]. Recently, persisting renal failure with osmotic nephrosis and interstitial foam cells was observed in a previously healthy patient with severe sepsis who had received fluid resuscitation with the most modern HES 130/0.4 in a cumulative dose of 81 ml/kg within 5 days .
The mechanism of renal failure is unclear. HES and dextran are taken up by the proximal tubular cells leading to swelling and subsequent lesions called osmotic nephrosis. The pathophysiology can be described as accumulation of proximal tubular lysosomes due to administration of exogenous solutes . In the critically ill patient with hypovolemia or shock, such lesions may contribute to acute or chronic renal failure. Schortgen et al. have suggested that the use of hyperoncotic colloid solutions, i.e., starches, dextrans, and 20–25% albumin may be responsible for renal impairment .
Coagulopathy and Thrombocytopenia
HES interferes with clotting factors, thrombocytes, and prolongs bleeding time . It may lead to potentially fatal bleeding in susceptible patients. A meta-analysis investigating perioperative blood loss in 653 cardiac surgical patients from 16 trials with albumin or HES exposure found that blood loss amounted to 789 ±487 mL in the HES group compared to 693 ±350 mL in the albumin group, the pooled standardized mean difference reaching statistical significance. Interestingly, increased bleeding was equally associated with HES solutions 200 or 450 kDa; and mean cumulative doses were 15.0 ml/kg and 8.9 ml/kg, respectively. Albumin moreover resulted in significantly less bleeding than HES in comparisons involving both volume expansion and addition of colloid to the priming fluid . As a result, the FDA added a warning label on the package insert for hetastarch (HES 450 kDa), the only HES solution then on the US market, stating that this solution “is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired.” . In France, HES 200/0.62 was withdrawn from the market after a pharmacovigilance study documented three cases of fatal cerebral hemorrhage among nine patients with subarachnoid hemorrhage and acquired von Willebrand’s disease after HES exposure . In patients with acute ischemic stroke or brain injury with cumulative HES doses of approximately 70, 87, and 253 ml/kg
[16,17,30] raised safety concerns about increased incidence of intracranial bleeding [31,32]. Another group of patients at increased risk are patients with severe sepsis, where administration of 10% HES 200/0.5 compared to Ringer’s reduced the platelet count (p <0.001) and was associated with transfusion of more units of packed red cells (p <0.001) .
Tissue Uptake and Storage
In critically ill patients with disturbed macro-und microcirculation, vascular leakage, and renal impairment, lysosomal uptake in the lysosomes of reticuloendothelial cells with subsequent tissue storage becomes a major route of elimination for HES molecules from plasma. HES thus may accumulate dose dependently in a variety of organs , particularly after repeated administration. Pruritus after HES is due to deposition in the skin, most probably in cutaneous nerve fibers  and can lead to protracted and long-lasting itching depending on the cumulative dose . Pruritus is associated with all HES solutions, and was observed after hemodilution therapy with HES 130/0.4 to a higher degree than HES 200/0.5 . Chronic administration can result in massive HES storage in macrophages, bone marrow, and liver cells with the aspect of a storage disease, manifesting as “foamy macrophage syndrome” or “acquired lysosomal storage disease” with liver failure and ascites [36, 37]. These patients had received cumulative HES doses in the range of 250 to 400 ml/kg or more for plasmapheresis or fluid therapy on the ICU.
Issue of Cumulative Dosage
It is becoming increasingly clear that HES-related toxicity is dose dependent and relates more closely to the overall cumulative rather than the maximum daily dose administered. In the VISEP study, need for renal replacement therapy increased almost linearly with cumulative doses of HES . Awareness of cumulative dosage is still low. Manufacturers mostly recommend daily dose limits but do not mention cumulative dose thresholds. Cumulative doses are not routinely reported in HES trials, and large daily doses exceeding recommendations are not unusual in clinical studies or in daily clinical practice [30,38]. Use of HES should urgently be restricted to the cumulative doses which were found to be safe in clinical studies with adequate observation periods.
Dextran and Gelatin
Dextran and gelatin are synthetic colloids which share important characteristics with starches, namely their dose-related renal and coagulatory side effects [5,26] and their inability to improve clinical outcomes compared to albumin or crystalloids [1,3,11,12,39].
Dextran is a polydispersed mixture of glucose polymers. It is associated with severe anaphylactoid reactions and has been increasingly replaced by gelatin or HES. Wills et al. compared 6% dextran 70 with Ringer’s lactate for emergency resuscitation of children with Dengue shock syndrome and found that dextran use conferred no clinical benefit .
Gelatin is a bovine collagen derivative which was withdrawn from the US market as plasma volume expander in 1978 due to increased blood viscosity, reduced blood clotting, and prolonged bleeding time (http://www.fda.gov/ohrms/dockets/ 98fr/ 100898b.txt). Similarly, A well-conducted comparison between normal saline and gelatin for resuscitation in 60 children with septic shock showed that both performed equally in terms of hemodynamic stabilization. Both fluids were titrated to blood pressure, capillary filling time, or central venous pressure . Gelatin impairs hemostasis during cardiac surgery as compared to albumin  and perioperative renal function in aortic aneurysm surgery compared to HES . Anaphylactoid reactions are 4–6 times more common after gelatin than after HES or dextran (pooled incidence rate ratio in comparison to albumin 12.4; 95% CI 6.4–24.0) . Gelatin has been found to result in a lower incidence of acute renal failure in severe sepsis in comparison to HES 200/0.62 , but comparisons to albumin or crystalloids in adult septic patients are lacking.
Crystalloids contain water and electrolytes and are fluids without oncotic pressure, including normal or isotonic saline (0.9% NaCl), acetated or lactated Ringer’s, or Hartmann’s solution.
Hypertonic saline is still considered experimental in humans, except for the treatment of raised intracranial pressure and cerebral edema following traumatic brain injury . Small volume resuscitation fluids are a combination of hypertonic crystalloid with a colloid, e.g., 7.5% sodium chloride and 6% dextran 70. A recent meta-analysis could not arrive at a conclusion about the efficacy of hypertonic crystalloids for lack of adequate data in patients with trauma, burns, or those undergoing surgery .
Saline-based fluids can lead to the development of hyperchloremic acidosis; this may not necessarily harm the patient. In surgical patients, volume therapy with normal saline required administration of bicarbonate, more total fluid, and more blood products than with Ringer’s. This, however, had no direct effect on ICU or hospital stay and adverse events .
Crystalloids are devoid of allergic reactions or the side effects discussed above, are completely eliminated, and cheap to use. They have, however, been shunned for fear of pulmonary and tissue edema. Recent studies, however, have shown that the volume requirement for successful resuscitation is not as high as believed and considerable fluid loads did not lead to pulmonary edema. In septic patients, median respiratory SOFA score was 1.76 (interquartile range 1.00 to 2.71) in the Ringer’s group and 1.80 (IQR 0.86–2.67) in the HES group (p = 0.51) . Similarly, in a study comparing resuscitation fluids in 67 mechanically ventilated surgical patients with acute lung injury, determination of the 67Ga-transferrin pulmonary leak index and extravascular lung water showed no difference and oxygenation ratios improved in all groups. Pulmonary permeability and edema were not affected by different colloids or crystalloid administered for volume loading, despite the fact that significantly more saline than HES, albumin, or gelatin was used .
Differences in Hemodynamic Effects Between Crystalloids and Colloids
The current understanding and one of the arguments used in favor of colloids is that they expand the intravascular volume and increase myocardial preload faster than crystalloids . However, larger studies and longer observation periods reveal that this effect is marginal and does not lead to improved clinical outcome in the ICU [2,7,11]. When septic patients with below target values of CVP, central venous oxygen saturation (ScvO2), and mean arterial blood pressure (MAP) were resuscitated with HES or Ringer’s, only CVP returned to target more quickly after HES (p = 0.003). ScvO2 and MAP normalized equally fast with modified Ringer’s lactate, and clinical outcomes were comparable . Children with Dengue shock syndrome who received colloids achieved initial cardiovascular stability more rapidly and showed a faster reduction in median hematocrit values during the first 2 h (25, 22, and 9% reduction for dextran, gelatin, and Ringer’s, respectively; p <0.001). Subsequently, however, their hematocrit increased more than with Ringer’s (5% increase for dextran or gelatin, 0% for Ringer’s; p <0.001). The authors explained this as a combination of fluid effects and vascular leak, such that colloids exerted a rapid effect followed by a rebound increase in vascular leak a few hours later. Overall time to final stabilization was not different between groups .
It is commonly believed that it requires 3–5 times more crystalloid than colloid volumes to raise the circulating intravascular fluid to a similar degree . This concept was derived from small studies in surgical and septic patients with short observation periods. More recent studies reveal that considerably smaller volume ratios of colloid to crystalloid were needed in direct comparison for comparable clinical outcomes, ranging from 1 to 1.0 for HES or dextran , 1 to 1.2 for colloids , 1 to 1.4 for albumin , 1 to 1.4 for HES , 1 to 1.6 for gelatin , and 1 to 1.7 for colloids . In summary, the evidence from these more recent studies strongly suggests that resuscitation with crystalloids in critically ill patients to the same hemodynamic goals does not require several-fold volumes and longer time to achieve than with colloids. The most likely reason may be that in critically ill patients with increased vascular leakage, colloids do not remain much longer in the vasculature than crystalloids.
Recent evidence confirms that the use of gelatin, dextran, or HES as plasma volume expanders in critically ill patients does not add a survival benefit in comparison to crystalloids. All synthetic colloids are associated with dose-related harmful effects, in particular coagulopathy and renal impairment. Moreover, HES is taken up and stored in various organs; this may be detrimental in ICU patients, in particular patients with sepsis. HES also raises safety concerns in patients with brain injury. Unfortunately, adverse effects were also observed with the most modern HES solution (HES 130/0.4, Voluven®).
While a potential benefit for albumin was shown in patients with severe sepsis which has to be confirmed in further clinical trials, albumin too is very likely to be harmful in patients with traumatic brain injury. Crystalloids are as effective as colloids but safer for resuscitation in critically ill patients. Longer observation periods show that the fluid requirement to achieve similar hemodynamic goals is not considerably higher for crystalloids than colloids and frequency of pulmonary edema is not increased.
Because synthetic colloids do not improve outcomes, but can cause considerable harm, the question arises whether they still have a place as plasma expanders in these high-risk patients. Notwithstanding, use of HES should urgently be restricted to the cumulative doses which were found to be safe in clinical studies with adequate observation periods.
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