Chapter outlines

TIMING AND RATE OF FLUID ADMINISTRATION

TYPE OF FLUIDS FOR RESUSCITATION

THE PHYSIOLOGY OF FLUID SELECTION

SELECTING IV FLUID FOR RESUSCITATION

• Crystalloids: The most widely used first-line therapy in managing hypovolemic shock comprises crystalloids such as normal saline, Ringer’s lactate, and PlasmaLyte.
• Colloids: Colloids are second-line resuscitation therapy used in selected patients with hypotension. Among colloids, the use of natural colloids like albumin, which is safe but highly expensive, is recommended in specific clinical settings. However, the use of synthetic colloids such as hydroxyethyl starch, dextran, and gelatin is not recommended, and they are avoided or discouraged due to their harmful effects and lack of benefits.
• Blood Products: Packed red blood cells or blood substitutes are essential for effective resuscitation for patients with significant blood loss or anemia associated with hypotension.

Each type of fluid comes with its characteristics and is chosen based on the specific needs and conditions of the patient.

CRYSTALLOID RESUSCITATION: FIRSTLINE THERAPY

• Composition of commonly used IV crystalloids.
• Physiological basis, advantages, disadvantages, and preferred indications for using normal saline and balanced crystalloids.
• A literature review to address the ongoing controversy between saline and balanced crystalloids.
• Conclusions and current recommendations for appropriate use of crystalloids.

The composition of commonly used IV crystalloids

A. Normal saline

Advantages

• Availability and compatibility: It is readily available, cost-effective, and compatible with the co-infusion of blood products and medications like ceftriaxone [15].
• Volume expansion: With 154 mEq/L of sodium, it effectively expands intravascular volume and corrects hypotension.
• Safe for specific conditions: It is the preferred option for patients with brain injury, hypochloremia, hypovolemic hyponatremia, and metabolic alkalosis. As the osmolarity of normal saline is 308 mOsm/L (compared to normal plasma osmolality of about 285 mOsm/kg), its use for resuscitation in neurological patients is without the risk of cerebral edema.
• Glucose-free: Ideal for scenarios with unknown glycemic statuses due to its lack of glucose content.

Disadvantages

1. It has a significantly higher chloride concentration (154 versus 109 mEq/L).
2. It lacks a buffer, essential for maintaining pH.
3. It does not contain several electrolytes, like potassium and calcium, that are present in plasma.

Hyperchloremic metabolic acidosis

• The SID of normal saline is zero; therefore, its infusion decreases plasma SID, leading to metabolic acidosis (SID: Normal value = 40; Normal saline = 0; RL = 28, PlasmaLyte = 50) [16, 29].
• Administering a large volume of normal saline reduces renal bicarbonate reabsorption, decreasing bicarbonate levels [30].
• Using large volumes of bicarbonate-free fluids like normal saline dilutes the bicarbonate concentration in the body, inducing dilutional acidosis [2, 31].

Risk of acute kidney injury (AKI)

Use in hyperkalemia

B. Balanced crystalloids

Balanced electrolyte composition

Provides buffer to prevent or correct metabolic acidosis

Reduces the risks of hyperchloremia

Effect of RL on serum lactate levels

Use in lactic acidosis misconceptions and facts

Safety in hyperkalemia

Safety in neurological disorders

Use in liver disorders

Use in diabetic ketoacidosis

Precautions

C. Saline vs. balanced crystalloids: A review of literature

1. Trials suggestive of the superiority of balanced crystalloids

• Shaw et al. (Ann Surg 2012) compared adult patients undergoing major open abdominal surgery who received either normal saline (30,994 patients) or a PlasmaLyte (926 patients) on the day of surgery. This study concluded that PlasmaLyte was associated with less postoperative morbidity than normal saline [66].
• Yunus et al. (JAMA 2012) compared the association of a chloride-restrictive vs. chloride-liberal IV fluid strategy with AKI in 760 critically ill patients. This study concluded that the chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and the use of RRT [20].
• McCluskey et al. (Anesth Analg 2013) compared the impact of postoperative hyperchloremia in 22,851 patients undergoing noncardiac surgery. This study concluded that postoperative hyperchloremia was associated with increased mortality, renal dysfunction, and length of hospital stay [67].
• Raghunathan et al. (Crit Care Med 2014) compared the outcome after resuscitation with balanced versus non-balanced fluids in 53,448 patients with sepsis in an ICU. This study concluded that among critically ill adults with sepsis, resuscitation with balanced crystalloids was associated with a lower risk of in-hospital mortality [68].
• SMART Trial (Semler et al. NEJM 2018) is a very large study that compared normal saline with balanced crystalloids among 15,802 critically ill adults. This study concluded that using balanced crystalloids resulted in a lower rate of death from any cause, RRT, or persistent renal dysfunction than using saline [69].
• SALT-ED Trial (Self et al. NEJM 2018) compared normal saline with balanced crystalloids among 13,347 noncritically ill adults. This study concluded that there was no difference in hospital-free days between both groups, but the use of balanced IV fluid resulted in a lower rate of death from any cause, RRT, or persistent renal dysfunction than the use of saline [70].

2. Trials and analysis suggestive of no difference between both groups

• The SPLIT Trial (Young et al. JAMA 2015) compared normal saline with PlasmaLyte in 2278 ICU patients and concluded that using a buffered crystalloid compared with saline did not reduce the risk of AKI [71]. A major limitation of this study was the median administration of a small volume of saline (<2 liters) and, therefore, a lesser risk of developing hyperchloremia.
• The SALT Trial (Semler et al. Am J Respir Crit Care Med 2017) compared normal saline with balanced crystalloids in 974 ICU patients and concluded no difference in the overall incidence of AKI or major adverse kidney events [72].
• The BaSICS Trial (Zampieri et al. JAMA 2021), a multicenter, double-blind RCT involving 11,000 patients, compared normal saline with balanced crystalloids and concluded that there were no significant differences in mortality rates or AKI incidence [73].
• The PLUS Study (Finfer et al. NEJM 2022), a multicenter, double-blind RCT involving 5,000 patients, compared normal saline to balanced crystalloids and concluded that the balanced crystalloid group did not demonstrate reduced mortality or kidney injury [74].

3. Meta-analysis and society guidelines

• Krajewski et al. (Br J Surg 2015) reported in a meta-analysis of 21 studies involving 6,253 patients that the use of high-chloride fluids in perioperative or intensive care settings was associated with an increased risk of acute kidney injury, with no observed benefits on mortality [32].
• Cochrane Database Syst Rev. (2017) reported that perioperative administration of buffered versus non-buffered crystalloid fluids showed insufficient evidence of impacting mortality and organ system function but noted a significant reduction in postoperative hyperchloremia and metabolic acidosis with the use of buffered fluids [75].
• Surviving sepsis campaign guidelines (Evans et al. Crit Care Med 2021): The guidelines advise using crystalloids for both initial resuscitation and ongoing intravascular volume replenishment in adult patients with sepsis and septic shock [4]. The previous Surviving sepsis guidelines (2017) [76] suggested using either balanced crystalloids or saline, but in 2021, guidelines suggested using balanced crystalloids instead of normal saline for resuscitation [4].
• Hammond NE et al. (NEJM Evid 2022) conducted a Systematic Review with Meta-Analysis comparing balanced crystalloids to saline in critically ill adults and demonstrated reduced mortality in patients who received balanced crystalloids [77].
• Beran A et al. (J Clin Med 2022) demonstrated in their systematic review and meta-analysis that adults with sepsis treated with balanced crystalloids showed reduced mortality and AKI compared to those who received normal saline [78].
• Isha et al. (Front Med 2023) conducted a retrospective analysis that compared normal saline with balanced crystalloids in 2022 patients and found no significant difference in mortality rates, hospital stay, ICU admission rates, mechanical ventilation needs, oxygen therapy, and renal replacement therapy [79].
• Zampieri et al. (Lancet Respir Med. 2024) conducted a systematic review and meta-analysis, demonstrating lower in-hospital mortality associated with the use of balanced solutions compared to saline in the ICU [80].
• European Society of Intensive Care Medicine (ESICM) clinical practice guideline (Intensive Care Med. 2024): Recent ESICM Guidelines recommends the use balanced crystalloids instead of normal saline for resuscitation in severe volume depletion or hypovolemic shock in critical patients, and in patients with sepsis or kidney injury [56].

4. Trials suggestive of the superiority of normal saline

• To date, not a single study has demonstrated the superiority of saline over balanced crystalloids in the selection of appropriate resuscitation fluids. The absence of evidence establishing the superiority of saline indirectly reinforces the preference for using balanced crystalloids. This is consistent with the existing body of evidence highlighting the efficacy of balanced crystalloids in fluid resuscitation, even in the absence of high-quality reference evidence.

D. Crystalloids: conclusions and current recommendations

1. Balanced crystalloids preferred firstline modality

• The current trend in literature, including the recent Surviving Sepsis Campaign guideline (2021) and the European Society of Intensive Care Medicine fluid therapy guideline (2024), favors the use of isotonic, balanced crystalloids as the preferred resuscitation fluids [56, 69, 85–97]. The benefits of using balanced crystalloids are more evident in patients with sepsis, metabolic acidosis, hyperchloremia, increased creatinine, or those at risk of kidney injury [4, 56, 98].
• Ringer’s lactate is suggested as the preferred resuscitation fluid in sepsis [37, 42, 84], acutely ill critical patients [99–101], surgical patients [66, 102], trauma [103, 104], high risk for acute kidney injury [105], acute pancreatitis [106–108], diarrhea, burns [109]. Benefits of balanced solutions are more evident when administering fluid in large volumes, particularly for septic patients [110, 111].
• Patients with metabolic acidosis should receive balanced crystalloids with an “alkalinizing” effect, while patients with metabolic alkalosis and hypochloremia should be treated with normal saline [112].
• Ringer’s lactate should be avoided or used with caution in patients with severe metabolic alkalosis and hypochloremia (e.g., due to profound vomiting) [18], those with frank hepatic failure [113], and individuals with traumatic brain injury or at risk of increased intracranial pressure [18, 53].
• Although lactate metabolism may be impaired in patients with severe lactic acidosis, sepsis, or liver failure, Ringer’s lactate does not cause or aggravate lactic acidosis [49, 50].
• Besides the fact that balanced crystalloids contain a small amount of potassium, the risk of hyperkalemia is significantly lower compared to normal saline [18, 35, 50].

2. Normal saline: selective use preferred

• Infusion of large quantities (>2 L) of supraphysiologic chloride containing normal saline can cause hyperchloremic metabolic acidosis, acute kidney injury [114], coagulopathy, increased hemodynamic instability, and potential mortality and therefore is harmful [115].
• Avoid administering large volumes of chloride-rich normal saline to all patients, especially those at high risk for AKI or incipient AKI, due to the potential risk of acute kidney injury [105, 116].
• Small to moderate amounts of normal saline do not increase the incidence of acute kidney injury [71]. Thus, modest volumes of normal saline can be administered to patients with normal kidney function in the absence of hyperchloremia and sepsis [117–119].
• Normal saline is the fluid of choice for patients with metabolic alkalosis, hypovolemia due to vomiting or upper gastrointestinal suction, traumatic brain injury, and those receiving blood products [18, 39, 56, 90, 112–122].

SELECTION OF BALANCED CRYSTALLOID

• Understanding the difference between lactate and Acetate buffer.
• Physiological basis for limitations of Ringer’s lactate.
• Understanding the composition of PlasmaLyte and its advantages.
• Evidence comparison of Ringer’s lactate vs. PlasmaLyte.
• Summary and clinical indications of newer balanced crystalloids.

A. Understanding the difference between lactate and acetate buffer

B. Physiological basis for limitations of Ringer’s lactate

• Use of lactate as a buffer: In cases of severe liver impairment, hypoxia, acidaemia, or shock, the body’s ability to convert lactate into bicarbonate is compromised [123, 124]. This impairment leads to not only a lack of buffering benefits but also lactate accumulation and a rise in serum lactate levels [44]. Consequently, using lactate levels as markers for resuscitation effectiveness becomes challenging.
• Lower osmolality: As RL is a hypotonic fluid (osmolality of RL 278 mOsmol/L vs. plasma osmolality 290 mOsmol/L), use it with caution in neurological patients with cerebral edema [39].
• Lower sodium content: Since RL contains less sodium than plasma (130 mEq/L vs. 140 mEq/L serum sodium), administering it in large volumes can lead to hyponatremia.
• Calcium content: The presence of calcium in RL can lead to precipitation when mixed with citrate in blood transfusions [15]. 

C. Understanding the composition of PlasmaLyte and its advantages

• Use of acetate as a buffer in PlasmaLyte: PlasmaLyte replaces the lactate in RL with anions like acetate, gluconate, and maleate as bicarbonate precursors. Acetate’s ability to be metabolized both in the liver and other tissues of the body allows it to ensure the conversion to bicarbonate even in severe liver failure and shock [42, 125]. PlasmaLyte has better buffering agents and effects. Furthermore, PlasmaLyte doesn’t affect serum lactate levels, ensuring accurate readings during shock.
• Osmolality equal to plasma: PlasmaLyte, having an osmolality equal to plasma (290 mOsmol/L), does not carry the risk of causing cerebral edema, unlike hypotonic fluids.
• Sodium concentration similar to plasma: The sodium concentration in PlasmaLyte is identical to that of plasma (140 mEq/L), reducing the risk of hyponatremia or hypernatremia during large-volume fluid infusion [42].
• Free of calcium content: Being free of calcium, PlasmaLyte mitigates the risk of calcium overload and avoids complications associated with the co-administration of blood products containing citrate, which can lead to calcium precipitation.
• Magnesium content: Hypomagnesemia is common in critically ill patients, and PlasmaLyte, containing 1.5 mmol/L of magnesium, can be beneficial in these cases. However, it should be used cautiously in patients at risk for hypermagnesemia.

D. A comparative review of literature on Ringer’s lactate vs. acetate buffered solutions

Evidence suggesting Acetate buffered solutions/PlasmaLyte is superior

• Curran et al. (2021): This systematic review with a meta-analysis of 24 trials noted that PlasmaLyte led to lower serum chloride and lactate levels and a higher base excess compared to Ringer’s lactate, although the evidence is of low certainty [128].
• Ellekjaer et al. (2022): Another systematic review with a meta-analysis of five RCTs involving 390 patients found very limited, low-quality evidence supporting the use of acetate over lactate-buffered solutions in hospitalized patients for all-cause mortality [129].
• Priyanka et al. (2023): A study involving 80 children indicated a preference for PlasmaLyte over RL during perioperative fluid therapy for abdominal surgeries due to enhanced acid-base, serum electrolytes, and blood lactate profiles [130].
• Abdellatif et al. (2023): In a study with 80 children undergoing cardiac surgery, PlasmaLyte showed better lactate and calcium levels than Ringer’s lactate when used as a priming solution [131].
• The inclusion of PlasmaLyte as a balanced crystalloid in recent major saline vs. balanced crystalloid trials such as SPLIT (2015), SALT (2017), SMART (2018), SALT-ED (2018), BaSICS (2021), and PLUS (2022) emphasizes its recognition and utility as a valuable option among balanced crystalloids [69–74].

Evidence suggesting equal effectiveness of Ringer’s lactate and Acetate buffered solutions

• Weinberg et al. (2018): In a trial with 50 adults, PlasmaLyte and Hartmann’s solution showed no significant differences in plasma bicarbonate levels, complications, or length of ICU and hospital stays during elective cardiac surgery with CPB [132].
• Pfortmueller et al. (2019): In a study of seventy-five patients undergoing cardiac surgery, the use of RL and Ringer’s acetate showed similar effects on hemodynamic stability and the progression of acid-base parameters [133].
• Rawat et al. (2020): A study of fifty adult ICU patients with metabolic acidosis revealed no significant advantage of acetate solution over RL in either the speed or extent of acidosis correction [134].
• Chaussard et al. (2020): A comparison involving twenty-eight burn patients showed similar alkalinizing effects between PlasmaLyte and Ringer’s lactate during fluid resuscitation. However, using PlasmaLyte resulted in significantly lower ionized calcium levels [135].

E. Summary and clinical indications of newer balanced crystalloids

• Diabetic ketoacidosis: The use of dextrose-free PlasmaLyte reduces the risk of hyperchloremic metabolic acidosis, corrects acidosis by providing bicarbonate, and offers benefits like early and faster acidosis resolution, and reduces ICU and hospital stays leading to decreased total cost [62, 138, 139].
• Perioperative fluid therapy: The use of PlasmaLyte may result in improved acid-base status, serum electrolytes, and blood lactate profiles [130]. It may be useful in major open GI and liver surgeries, including liver transplantation and complex cardiac surgeries [42, 140].In postoperative patients, using PlasmaLyte for fluid replacement on the day of major surgery has been linked to lower mortality than normal saline [66].
• Critically ill patients: PlasmaLyte is likely the optimal choice for fluid resuscitation in most critically ill, trauma patients, except those with traumatic brain injury [141–143].
• Priming the CPB circuit: Using PlasmaLyte for priming in cardiopulmonary bypass can be associated with reduced metabolic acidosis and improved calcium levels [131, 144].
• Deceased donor kidney transplantation: Using PlasmaLyte may reduce the incidence of delayed graft function in deceased donor kidney transplantation in adults [145] and decrease the risk of acute electrolyte disturbances in children [146]. Based on the findings of the ‘BEST-Fluids’ trial, PlasmaLyte should be preferred over normal saline as the fluid of choice in deceased donor kidney transplantation [145]. 

COLLOIDS: SECOND-LINE THERAPY FOR SELECTIVE USE

A. The rationale for using colloids in resuscitation

• Greater volume expansion: As colloid solutions remain in the vascular space, plasma volume expansion is greater with colloids as compared to crystalloids [147, 148]. As the volume of colloids required to correct hypovolemic shock is less [149, 150], colloids prevent complications associated with the large volume of crystalloids, such as hyperchloremic acidosis, dilutional coagulopathy, and tissue edema. Accumulation of crystalloids in tissues, including lungs and incision sites, can cause weight gain, anasarca, and delayed tissue healing [151, 152].
• Faster volume expansion: Colloids are statistically more effective than crystalloids in reaching resuscitative hemodynamic endpoints [153]. The benefit of speedier achievement of hemodynamic goals with colloids compared to crystalloids is less organ damage and a decreased incidence of organ failure [148].
• More prolonged volume expansion: Because of longer intravascular half-life, colloids remain in circulation for a longer period, resulting in lesser volume requirement and better hemodynamic stability compared to crystalloids [154–156].

Review of literature

1. Albumin trials

• Cochrane Injuries Group Albumin Reviewers (BMJ 1998): Administration of albumin for fluid resuscitation in critically ill patients may increase mortality [157].
• SAFE Study (Finfer et al. NEJM 2004): In ICU, using 4% albumin or saline for fluid resuscitation results in similar outcomes at 28 days [158].
• Cochrane Database Syst Rev (Roberts et al 2011): The review of 38 trials involving patients with hypovolemia concluded that there is no evidence suggesting that albumin decreases mortality among critically ill patients with burns and hypoalbuminemia. [159].
• Meta-analysis of five RCTs (Xu et al 2014): In this meta-analysis involving 3,658 patients with severe sepsis, those resuscitated with albumin, compared to crystalloid and saline, demonstrated a trend toward reduced 90-day mortality [160].
• Systematic review and meta-analysis (Patel et al 2014): In a study of 16 primary clinical trials including 4190 critically ill adults with sepsis, compared to crystalloids, albumin did not reduce all-cause mortality [161].
• ALBIOS Trial (Caironi et al. NEJM 2014): Comparing 20% albumin to crystalloid in 1800 septic patient resuscitation. No differences in mortality at 28 or 90 days [162].

2. Hydroxyethyl starch trials

• 6S Trial (Perner et al. NEJM 2012): Increased incidence of renal replacement therapy after HES and significantly higher 90-day mortality [163].
• CHEST Trial (Myburgh et al. NEJM 2012): Increased incidence of renal replacement therapy after HES [164].
• Cochrane Database Syst Rev 2013: The review highlighted an overall increased risk of AKI and RRT in individuals treated with HES, indicating the detrimental effects of HES on kidney function compared to alternative fluids [165].
• Recommendation of European Medicines Agency (PRCA 2013): HES should be used at the lowest effective dose for the shortest period. HES should not be used for more than 24 hours and monitor patients’ kidney function for 90 days. HES should no longer be used in patients with sepsis, burns, or critically ill patients. HES should only be used to treat hypovolaemia caused by acute blood loss when crystalloids alone are insufficient [166].
• Recommendation of European Medicines Agency (PRCA July 2018): Because of potential adverse effects, HES should be used with additional measures of protection in selected patients with acute blood loss, where for resuscitation, ‘crystalloids’ alone are not sufficient. HES should be used at the lowest effective dose for the shortest duration (dose less than 30 mL/kg and maximum duration <24 hours) for the initial phase of volume resuscitation [167].
• Recommendation of European Medicines Agency (July 2022): The PRAC noted the persistent use of HES solutions in contraindicated populations, increasing the risk of severe harm and mortality. Given that the associated risks outweigh the benefits, they suspended the marketing of HES and recommended opting for safer therapeutic alternatives in line with clinical guidelines [168].

3. Colloids vs. crystalloids: Trials, reviews and guidelines

• CRISTAL Trial (Annane et al. JAMA 2013): No significant difference in 28-day mortality but lower 90-day mortality in patients receiving colloids [150].
• Cochrane Database Review of 78 RCTs (2013): Colloids are not associated with an improvement in survival and are much more expensive than crystalloids. Because of the lack of survival benefits and higher costs, the routine use of colloids in clinical practice cannot be justified [169].
• Cochrane Database Review (2018): Using colloids versus crystalloids probably makes little or no difference to mortality. Starches probably slightly increase the need for blood transfusion and RRT. With the use of albumin or FFP, there is little or no difference in the need for renal replacement therapy [170].
• A systematic review and meta-analysis (Martin et al. 2019): A recent meta-analysis of 55 randomized clinical trials by Martin and Bassett concluded that crystalloids were less effective than colloids in stabilizing resuscitation endpoints in patients with a critical illness (e.g., shock, trauma, and sepsis) [153].
• Surviving sepsis campaign guidelines (Evans et al. Crit Care Med 2021): The guidelines advise using crystalloids for both initial resuscitation and ongoing intravascular volume replenishment in adult patients with sepsis and septic shock [4].
• European Society of Intensive Care Medicine (ESICM) clinical practice guideline (Arabi et al. Intensive Care Med. 2024): The recent ESICM guidelines, in general, prefer the use of crystalloids over colloids for volume expansion during resuscitation, particularly for hypovolemia not caused by bleeding [56]. 

B. Colloids: Current recommendations

1. Colloids are potent but not safe or preferred over crystalloids

• Crystalloids and colloids are both effective, but evidence of comparative superiority and significant benefits of colloids are lacking; therefore, current trends and recommendations including the recent Surviving Sepsis Campaign guideline (2021) and the European Society of Intensive Care Medicine fluid therapy guideline (2024), favor crystalloids over colloids for the resuscitation of nonseptic and septic patients [56, 85, 86, 97, 103, 170–172], and no indications currently exist for the routine use of colloids over crystalloids [156].
• The potential benefit of colloids to provide better hemodynamic stability is due to their effectiveness in achieving greater, rapid, and prolonged intravascular volume expansion [173].
• During resuscitation, colloids are usually used along with crystalloids when patients are likely to require a large volume of crystalloids to expand the intravascular volume [174]. Adding colloids can achieve hemodynamic stability with a smaller fluid volume, thereby reducing the risk of positive fluid balance and the associated complications, such as fatal pulmonary edema and systemic organ dysfunction that can arise from administering larger volumes of crystalloids [153].
• Colloid solutions other than albumin (e.g., Hydroxyethyl starch dextran, gelatin) are not used routinely because of lack of benefits, safety, and potential adverse effects. Several studies have demonstrated increased risks, including tubular necrosis and acute kidney injury (AKI), associated with synthetic colloid treatment [175].

2. Albumin: Safe, potent but costly option, use selectively

• Albumin is not recommended as the first-line fluid for resuscitation in both nonseptic and septic patients; instead, it should be considered a second-line option for fluid resuscitation, along with crystalloids [4, 56, 176], and in patients with cirrhosis [56]. Albumin is indicated as an adjunct to crystalloids when a patient is unresponsive to crystalloids, requires substantial amounts of crystalloids to achieve hemodynamic endpoints, or cannot tolerate large-volume crystalloid resuscitation [4, 90, 153, 177]. Albumin helps to reduce the total infused volume of crystalloids for hemodynamic stability [4, 136, 178]. IV human albumin solution is more effective for resuscitation when patients have hypoalbuminemia [178]. In septic patients, early administration of the combination of albumin (particularly 20% albumin) with balanced crystalloids within the first 24 hours of treatment decreases mortality [95, 179–181]. The use of albumin is recommended in treatment of spontaneous bacterial peritonitis, hepatorenal syndrome, large-volume paracentesis (>5 L) [176], and in patients with cirrhosis [56].
• The 30 to 100 times higher cost of albumin compared to crystalloids, along with occasional supply shortages, serves as a significant limiting factor for its use [156, 182–185].
• Avoid albumin for resuscitation in patients with severe traumatic brain injury (TBI) [54–56, 95, 186–188]. The most likely mechanism of increased mortality in patients with severe TBI is the increased intracranial pressure associated with using albumin for resuscitation. 4% albumin is hypotonic (260 mOsmol/kg) and therefore increases brain edema [120].

3. Hydroxyethyl starch is harmful; avoid it

• Hydroxyethyl starch (HES) was once the most commonly used colloid, but due to its adverse effects, current recommendations are against its use [189]. HES is currently indicated as an adjuvant therapy for treating hypovolemia induced by acute blood loss when crystalloids alone are insufficient [190].
• HES is associated with several adverse effects including an increased risk of acute kidney injury, a higher need for renal replacement therapy, excessive postoperative bleeding, an increased need for blood transfusions, and a higher mortality rate [163].
• Strict limitations and cautious use of HES: Both the US Food and Drug Administration (FDA) [191] and the European Medicines Agency (EMA) have raised concerns about the safety of HES due to its significant harmful effects. Responding to these concerns, the EMA issued guidelines in 2013 restricting the use of HES, and these guidelines were further tightened in July 2018 [167]. According to the revised guidelines, HES should only be administered during the initial phase of fluid resuscitation, and its dosage should not exceed 30 mL/kg. Additionally, the treatment duration should be as short as possible, not extending beyond 24 hours, and it is mandatory to monitor the patient’s kidney function for at least 90 days following the administration of HES [167].
• Advise against using HES: Despite implementing risk minimization measures in 2018, the use of HES persisted in populations where it posed significant health risks, including an increased mortality rate. Owing to non-compliance with product guidelines and its misuse beyond approved recommendations, the EMA suspended the use of HES on 24 June 2022 [192].

4. Dextrans and gelatins are not recommended

• Gelatin use is associated with an increased risk of anaphylaxis, AKI, bleeding, and mortality [173, 193–195]. Given that the side effects outweigh the potential benefits [82], the Surviving Sepsis Campaign Guidelines (2021) advise against using gelatin for acute resuscitation in adults with sepsis and septic shock [4].
• Dextrans are frequently utilized in vascular surgery due to their beneficial effects, such as reducing blood viscosity and potentially enhancing microvascular circulation, particularly following grafting procedures [90]. However, their use is restricted due to associated adverse effects like antithrombotic actions [196], renal dysfunction [197], hypersensitivity reactions [198], and interference with blood grouping and cross-matching. Notably, dextrans present a higher risk of severe anaphylactic reactions compared to gelatines or starches [147].

GUIDELINES FOR BLOOD TRANSFUSION IN HYPOVOLEMIC SHOCK

1. In hospitalized, hemodynamically stable adult patients, blood transfusion is necessary if the hemoglobin level drops to ≤7 gm/dL (hematocrit ≤21%) [199].
2. In patients at high risk of adverse effects, including those undergoing cardiac surgery or exhibiting evidence of myocardial or other organ ischemia, a blood transfusion is required if hemoglobin drops to ≤8 gm/dL, aiming to maintain the hemoglobin level at ≥8 gm/dL.
3. In patients with ongoing significant bleeding and hypovolemia, the need for transfusion is determined based on pulse and blood pressure, the rate of bleeding, and estimated blood loss rather than solely relying on serial hemoglobin measurements. When a large volume of blood is needed, infuse one unit of plasma, one unit of platelets, and one unit of red blood cells (1:1:1 ratio), as suggested by the massive transfusion protocol [200].
4. Avoid liberal blood transfusion; hemoglobin and hematocrit should not be raised over 10 gm/dL and 30%, respectively [201]. A higher hematocrit level is unnecessary for oxygen transport and may increase blood viscosity, leading to stasis in the already impaired capillary circulation. 

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