Authors: Adrianna Levesque, MD (Senior EM Resident at SAUSHEC, US Army) and Brit Long (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)

**THE FIRST IN A 2-PART SERIES**

An 86 year-old male is brought in by ambulance with a chief complaint of subjective fever for 24 hours with chills, rigors, generalized weakness, and decreased appetite for the past day. His wife reports that he is normally very high functioning, walks without assistance, and drives. However, today he did not have enough strength to get out of bed.

His initial vital signs include temperature of 103°F, pulse of 112, blood pressure 134/86, respiratory rate of 22, and saturating 98% on room air. Exam reveals suprapubic tenderness and right sided costovertebral tenderness (CVA). Laboratory values reveal leukocytosis with 17,000 WBCs, BUN/sCr of 28/1.4 and all other values within normal limits. Urinalysis returns markedly positive for nitrites, WBCs, and bacteria.

In order to treat this patient’s sepsis, you order intravenous (IV) antibiotics and fluids. As ER physicians, we understand the importance of adequate fluid resuscitation, along with source control and antimicrobials. Intravenous fluids are a key component of resuscitation, and all fluids increase intravascular volume to varying degrees based on several components.

Does your choice of fluids for resuscitation in sepsis matter? Multiple studies have been performed to determine whether septic patients benefit from colloid versus crystalloid IV fluids, and other studies have specifically looked at the different kinds of fluids within those specific groups. Debate now exists as to which fluid will improve patient outcomes.

The most important aspect of fluid resuscitation is to remember that IV fluids should be viewed as a medication!

What are crystalloids and colloids? A crystalloid is an aqueous solution of water-soluble molecules/ions, while colloids are solutions containing larger molecules, thought to not easily cross endothelial membranes. The most common crystalloid used is normal saline (NS), which has a sodium of 154 mmol/L and chloride of 154 mmol/L. The use of large quantities of normal saline in resuscitation has been shown to cause hyperchloremic metabolic acidosis and is associated with renal injury.1 A trial by Yunos et al. showed decreased acute renal injury and use of renal replacement therapy in ICU patients resuscitated with a chloride restrictive strategy.2 A recent push for “balanced fluids” has been advocated. Balanced crystalloid solutions have lower chloride and sodium and more closely resemble plasma composition (such as Lactated Ringer’s (LR) and acetate solutions).1 Unfortunately no fluid can exactly replicate extracellular fluid composition, and excess administration of any of them can have adverse effects. Excess LR can cause metabolic alkalosis, hyponatremia, and hypoosmolarity, as well as interfere with serum lactate testing. Fluids containing acetate can be cardiotoxic at high doses, and microthrombi can result if given with blood.

Albumin 4% NS LR Plasma-lyte Sodium 148 mmol/L 154 mmol/L 130 mmol/L 140 mmol/L Chloride 128 mmol/L 154 mmol/L 109 mmol/L 98 mmol/L Potassium 4 mmol/L 5 mmol/L Calcium – – 1.5 mmol/L – Magnesium – – – 3 mmol/L Lactate – – 28 mmol/L – Acetate – – – 27 mmol/L Gluconate – – – 23 mmol/L Tonicity 250 mOsml/L 308 mOsml/L 280 mOsml/L 294 mOsml/L

Table 1 – Comparison of IV fluids

Colloids include compounds such as albumin and synthetic compounds such as hydroxyethyl starch (HES) solutions, gelatin, or dextran. Albumin is the most commonly used colloid fluid during resuscitation, but it is used less often due to increased cost and theoretical risk of blood product exposure. Starches are made through the modification of polymeric glucose molecules with the goal of prolonged intravascular circulation due to resistance to enzyme degradation. However, starches can deposit in the liver, kidney, and other organ systems. The FDA has placed a black box warning on usage of HES for its risk of increased renal injury and reported higher mortality rates in critically ill patients.3

IV fluids are medications, and each fluid has different pros and cons. A recent meta-analysis suggested that albumin is superior to saline, and balanced crystalloids are also superior to saline. However, a crude analysis of the data showed no significant difference between colloids versus crystalloids in resuscitation of critically ill patients.1 The CRISTAL randomized trial showed no difference in 28-day mortality in patients resuscitated with crystalloids vs. colloids; however, it did show that there were more days alive without mechanical ventilation and without vasopressor therapy in the colloid group vs. the crystalloid group by a mean of 7 days.4

When choosing a fluid for resuscitation, you should evaluate your patient’s needs while considering the different fluid options. Normal saline will benefit a patient that is hypovolemic, hyponatremic, hypochloremic, and/or alkalotic. As discussed previously, normal saline is actually far from “physiological normal” and can potentially cause renal injury as well as hyperchloremic metabolic acidosis.5 This acidosis is extensively due to its strong ion difference (SID), which refers to ions that dissociate at the pH of the solution such as sodium and chloride. A normal difference is 38. If the difference is below 38, the solution becomes more acidotic, while a difference of greater than 38 increases pH. NS possesses a SID of 0, increasing acidosis. Even though this solution is not physiologically “normal,” it is cheap, is accessible, and will improve intravascular volume.

LR is more physiologic and demonstrates trends towards less renal injury. It contains less chloride and sodium than NS and will not cause hyperchloremic metabolic acidosis. When choosing LR for your fluid, it is important to know if you anticipate giving blood products and consider what medications you are infusing to your patient. The American Association of Blood Banks states that LR is contraindicated as a diluent of red blood cell transfusions because the calcium in the solution binds to the citrate anticoagulant and can cause a risk for promotion of clots. The calcium in LR can also bind to Amicar, amphotericin, ampicillin, and thiopental, thus reducing their efficacy.6 Administration of increased amounts of balanced fluids may also result in a metabolic alkalosis, hypotonicity, and hyperlactatemia. Acetates have also been associated with cardiotoxicity.6,7

The recent SPLIT randomized clinical trial enrolled a total 2,278 patients with critical illness admitted to ICU. Patients were randomized to NS vs. LR with alternating protocols every seven weeks. Unfortunately, only 4% of each patient population admitted to the ICU were for sepsis. Interestingly, the incidence of renal injury, renal replacement therapy, and all-cause mortality were not statistically different between patients receiving LR vs. NS.8

Albumin is a good option for early resuscitation. It can be used in varying concentrations: 4%, 5%, 20%, and 25%. The rationale behind its use is driven by assuming it causes better intravascular expansion, as compared to crystalloids. No studies have been performed comparing the particular percentages of albumin to each other in the resuscitation of the critically ill patient. The SAFE RCT showed that 4% albumin can be used in resuscitation of the critically ill patient, but also indicated that albumin should not be used in patients with traumatic brain injury, as it can worsen patient outcomes.9 The EARSS Study indicated that 20% albumin is safe for resuscitation of patients in septic shock.10 The ALBIOS study evaluated patients with severe sepsis receiving 20% albumin in addition to crystalloids versus crystalloids alone and found that the albumin did not affect patient mortality, though patients in the albumin group demonstrated higher mean arterial pressures and albumin levels.11 Albumin may be useful in patients at risk for fluid overload (congestive heart failure, renal failure, liver failure).

Does cost matter to you? Crystalloids are universally cheaper and about the same cost across countries and continents ($1-$4 per liter), whereas albumin is significantly more expensive (with costs varying depending on location) and has a limited shelf life. Starches and gelatins have longer shelf lives, but are still more expensive and often not as readily available as crystalloid solutions. There is a lack of evidence for use of dextrans and gelatins and their use in severe sepsis.4

So, which fluid do you choose for resuscitation of your septic patient? For the majority of critically ill patients, the data seems to indicate that the usage of balanced crystalloids or albumin will be of most benefit; however, albumin is much more costly and may not be as readily available in some locations. NS is not physiologically normal and may cause hyperchloremic metabolic acidosis and increase trends towards renal injury, while plasmalyte and LR are more physiologic. For the first liter or two, NS will likely not harm the patient and provide adequate resuscitation. It is readily available and will adequately resuscitate the patient. After this point, a more physiologic solution is warranted to avoid complications and improve patient outcome. Realize when you are ordering fluids for your critically ill patient, your choice does matter and can affect patient morbidity and mortality.

References/Further Reading

Rochwerg B, Alhazani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161:347-355. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal versus chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. J Am Med Assoc. 2012;308:1566-1572. Hydroxyethyl Starch Solutions: FDA Safety Communication – Boxed Warning on Increased Mortality and Severe Renal Injury and Risk of Bleeding. 2015. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm358349.htm. Accessed October 5, 2015. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL trial. J Am Med Assoc. 2013;310:1809-1817. Lira A, Pinsky M. Choices in fluid type and volume during resuscitation: impact on patient outcomes. Ann Intensive Care. 2014;4(1). Marino P, Sutin K. The ICU Book. Philadelphia: Lippincott Williams & Wilkins; 2007. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369:1243-1251. Young P, Bailey M, Beasley R, et al. 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 Oct 7:1-10. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004, 350:2247-2256. Charpentier J, Mira JP, Group ES. Efficacy and tolerance of hyperoncotic albumin administration in septic shock patients: the EARSS study. Intensive Care Med2011;37(suppl 1):S115. 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 Med2014;370:1412-21.