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Pediatric Anesthesiology
Section Editor: Peter J. Davis

Review Article

Perioperative Crystalloid and Colloid Fluid M...
Figure 1. The original graph from the
published new fasting guidelines for elective surgery.     to the operating room. The more recent studies on this
Current ...
extracellular fluid volume was redistributed or seques-         chemical, pharmacokinetic, and pharmacodynamic
tered into ...
in the ICU or hospital, days of mechanical ventilation,
and days of renal replacement therapy) between the
groups. However...
Table 2. Hydroxyethyl Starch (HES) Solutions Properties and Availability
                                      HES 450/0.7...
addition, Paul et al.92 noted no differences between the    hyperchloremia resulting from HES infusion might
groups with r...
the United States since 1978 because of a high inci-          differences regarding success in the treatment of shock
The greatest concern with hypertonic saline solu-         still a dearth of evidence supporting any particular
tions is th...
Table 3. Clinical Settings Associated with Increased Antidiuretic Hormone Production
             Hemodynamic stimuli     ...
desalination. and may be the etiology of the slight
Table 4. Composition of Frequently Used IV Fluids in the United States
                                 Glucose    Na     ...
19. Bevan JC, Burn MC. Acid-base and blood glucose levels of            43. Kehlet H. Goal-directed perioperative fluid ma...
Perioperative crystalloid and colloid fluid management in children where are we and how did we get here
Perioperative crystalloid and colloid fluid management in children where are we and how did we get here
Perioperative crystalloid and colloid fluid management in children where are we and how did we get here
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Perioperative crystalloid and colloid fluid management in children where are we and how did we get here

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Perioperative crystalloid and colloid fluid management in children where are we and how did we get here

  1. 1. Pediatric Anesthesiology Section Editor: Peter J. Davis Review Article Perioperative Crystalloid and Colloid Fluid Management in Children: Where Are We and How Did We Get Here? Ann G. Bailey, MD*† It has been more than 50 yr since the landmark article in which Holliday and Segar (Pediatrics 1957;19:823–32) proposed the rate and composition of parenteral Peggy P. McNaull, MD*† maintenance fluids for hospitalized children. Much of our practice of fluid administration in the perioperative period is based on this article. The glucose, electrolyte, and intravascular volume requirements of the pediatric surgical patient Edmund Jooste, MBCHB, DA‡ may be quite different than the original population described, and consequently, use of traditional hypotonic fluids proposed by Holliday and Segar may cause Jay B. Tuchman, MD‡ complications, such as hyperglycemia and hyponatremia, in the postoperative surgical patient. There is significant controversy regarding the choice of isotonic versus hypotonic fluids in the postoperative period. We discuss the origins of perioperative fluid management in children, review the current options for crystalloid fluid management, and present information on colloid use in pediatric patients. (Anesth Analg 2010;110:375–90) F luid management of the pediatric surgical patient presents challenges to both the anesthesia and surgical either isotonic saline or lactated Ringer’s solution (LR) to “detoxify” dehydrated children. Their institution of IV teams. Typically, the intraoperative management is therapy decreased the current mortality rate for child- the responsibility of the anesthesiologist, whereas hood dehydration from 63% to 23%.2 Over the next 30 postoperative orders are written by the surgeons. Both yr, work by Gamble, Darrow, Crawford, Wallace, and groups rely on formulas and concepts once thought to others further defined the nature of the body’s extracel- be certain, but these are presently being examined and lular fluid and the rationale for fluid therapy.3– 6 challenged, especially in the pediatric literature. The The 1957 publication by Holliday and Segar7 first purpose of this review is to outline the history sup- presented a practical method for clinicians to prescribe porting current fluid management strategies and to IV fluids. The suggestions made in this classic article discuss the effect of recent controversies on future evolved into what is now termed the “4-2-1 rule” for practice decisions. maintenance fluid therapy in children. Based on ear- lier research done by their peers, the authors described CRYSTALLOIDS the intimate relationship between physiologic fluid losses and caloric expenditure. The physiologic defi- The “4-2-1 Rule” cits from urine output and insensible losses of the skin Fluid therapy for the ill child was first described in and respiratory tract are equal to approximately 100 the early 20th century. In 1918, Blackfan and Maxcy1 mL per 100 kcal metabolized per day. Simply stated, 1 reported instilling 0.8% isotonic saline intraperitone- mL of “water” is required for every 1 kcal of energy ally to successfully treat infants with diarrheal dehy- expended. Based on the computed caloric needs of the dration. Karelitz and Schick, in 1931, administered a average hospitalized patient (Fig. 1), the daily fluid continuous IV solution of 5% dextrose combined with requirements, as proposed by Holliday and Segar, for From the Departments of *Anesthesiology, and †Pediatrics, patients weighing 0 –10 kg are 100 mL/kg, for patients University of North Carolina, Chapel Hill, North Carolina; and 11–20 kg are 1000 mL 50 mL/kg for each kilogram ‡Department of Anesthesiology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania. between 11 and 20 kg, and for patients weighing more Accepted for publication June 19, 2009. than 20 kg are 1500 mL 20 mL/kg for each kilogram Reprints will not be available from the author. over 20 kg.7 A weight-based, hourly IV fluid rate, Address correspondence to Ann G. Bailey, MD, Department of extrapolated from the above formulas, led to what is Anesthesiology, CB# 7010, 223 Burnett-Womack, Chapel Hill, NC most frequently used today in pediatric practice, 27599-7010. Address e-mail to hence the “4-2-1 rule”8 (Table 1). Copyright © 2010 International Anesthesia Research Society In this article, the authors also defined daily main- DOI: 10.1213/ANE.0b013e3181b6b3b5 tenance electrolyte requirements. Considering the Vol. 110, No. 2, February 2010 375
  2. 2. Figure 1. The original graph from the Holliday and Segar article. The upper and lower lines were plotted from pre- vious data measuring caloric needs with normal activity and for basal met- abolic rate at 50th percentile weights. The middle line represents computed caloric needs based on the average hospitalized pediatric patient. Under normal conditions, 1 mL of water is required to metabolize 1 kcal, account- ing for insensible and urinary losses. Hence, caloric requirements mirror wa- ter requirements. (Reproduced from Holliday and Segar7 with permission.) Table 1. Daily and Hourly Fluid Requirements Based on Body Weight Daily fluid requirement Hourly fluid requirement 3–10 kg: 100 mL/kg 3–10 kg: 4 mL/kg/h 10–20 kg: 1000 mL 50 mL/kg for each kg from 11 to 20 kg 10–20 kg: 40 mL/h 2 mL/kg/h for each kg from 11 to 20 kg 20 kg: 1500 mL 20 mL/kg for each kg 20 kg 20 kg: 60 mL/h 1 mL/kg/h for each kg 20 kg Adapted from Paut O, Lacroix F, Curr Opin Anaesthesiol, 2006, 19, 268 –77. electrolyte composition of human milk and cow’s above. However, considerable debate has occurred re- milk, they recommended 2 mEq 100 kcal 1 d 1 of garding the amount of deficit generated by the nil per os both potassium and chloride and 3 mEq 100 (NPO) status and the existence of “third space losses.” kcal 1 d 1 of sodium. These electrolyte requirements As a result of the fasting state, children are pre- are theoretically met by the hypotonic maintenance sumed to develop preoperative fluid deficits second- fluid more commonly used in hospitalized children in ary to continuing insensible losses and urine output. the United States today, 5% dextrose with 0.2% nor- In 1975, Furman et al.9 proposed calculating the pre- mal saline. In their conclusions, it was emphasized operative deficits by multiplying the hourly rate, as that “these figures provide only maintenance needs dictated by the Holliday and Segar method, by the for water. It is beyond the scope of this paper to number of hours the patient was NPO. They then consider repair of deficits or replacement of continu- suggested replacing half of this volume during the ing abnormal losses of water.”7 Unfortunately, clini- first hour of surgery, followed by the other half over cians may often extrapolate the “4-2-1 rule” and the the next 2 h. This practice was adopted for many years accompanying hypotonic solutions to clinical situa- without questioning its utility. However, in 1986, tions where they may not be appropriate and could, in Berry10 simplified the method of Furman et al. by fact, be harmful. delivering a bolus of basic salt solution to otherwise healthy children over the first hour of surgery. Berry Perioperative Fluid Requirements concluded that children 3 years and younger should Historically, accepted intraoperative practice has receive 25 mL/kg, whereas children 4 years and older been to administer IV fluids to meet maintenance should receive 15 mL/kg. requirements as well as to replace preoperative The methods of both Furman et al. and Berry were deficits and ongoing losses incurred during the surgical developed based on the assumption that patients had procedure. Today, most anesthesiologists have adopted been NPO for at least 6 to 8 hours. Fortunately, the the use of either normal saline or LR for both mainte- debate about the significance of preoperative dehydra- nance and deficit fluid replacement in the operating tion secondary to NPO status has become less impor- room setting. There has been little controversy regarding tant due to the liberalization of fasting requirements. the acceptable maintenance fluid rate as described In 1999, the American Society of Anesthesiologists 376 Perioperative Fluid Management in Pediatric Patients ANESTHESIA & ANALGESIA
  3. 3. published new fasting guidelines for elective surgery. to the operating room. The more recent studies on this Current recommendations allow administration of topic estimate the incidence of preoperative hypogly- clear liquids up to 2 h before procedures requiring cemia to be between 0% and 2.5% and usually associ- anesthesia.11 Despite the revised guidelines, patients ated with fast durations from 8 to 19 h, well beyond may still present to the operating room having been the current American Society of Anesthesiologists NPO for more than the recommended 2 h or having recommended guidelines.23 significant deficits related to their disease process. Hyperglycemia has also been recognized as detri- Whereas there are no data to determine the exact mental for the brain. In the presence of ischemia or amount of fluid deficit that occurs in normal fasting hypoxia, it is proposed that the impaired metabolism children, strong evidence suggests that healthy adult of excess glucose causes an accumulation of lactate, a patients will maintain normal intravascular volumes decrease in intracellular pH, and subsequently se- despite a prolonged fast.12 verely compromised cellular function that may result in cell death.13 Hyperglycemia can also induce an Perioperative Dextrose: The Risks of Hypoglycemia osmotic diuresis that may lead to dehydration and Weighed Against the Risks of Hyperglycemia electrolyte abnormalities.23–25 Furthermore, there is In the early 1900s, Karelitz and Schick reported that evidence in the pediatric literature suggesting that the addition of glucose to IV fluids in dehydrated hyperglycemia, especially in the setting of an ischemic children allowed them “to fall into a restful sleep.” or hypoxic event, worsens neurologic outcomes as The authors used a 5% dextrose solution to render the well as morbidity and mortality statistics in the pedi- IV fluid isosmolar and to prevent hypoglycemia.2 atric population.17,26 –28 Intraoperative dextrose infusion subsequently became In the 1986 study by Welborn et al., the patients common practice in the pediatric population. Although were randomized to intraoperatively receive either LR researchers and clinicians acknowledged the deleterious or 5% dextrose in LR (D5LR). Both the LR and D5LR effects of hypoglycemia, Holliday and Segar 7 and groups had statistically significant increases in blood Furman et al.9 warned that the hyperglycemia often glucose. However, the D5LR group had a much larger occurring subsequent to glucose administration is not increase in blood glucose (83 14 mg/dL preopera- without risk. tively to 244 60 mg/dL postoperatively) than the LR Hypoglycemia, depending on the severity, can group (85 14 mg/dL preoperatively to 111 22 have devastating effects on the central nervous sys- mg/dL postoperatively).22 tem, especially in neonates. Low blood glucose in- Based on these results and those of other studies, vokes a stress response and alters cerebral blood flow there is a growing consensus to selectively administer and metabolism.13 Permanent neurodevelopmental intraoperative dextrose only in those patients at great- impairment can result if hypoglycemia goes unrecog- est risk for hypoglycemia and, in such situations, to nized and untreated. In 1967, Anderson et al.14 first consider the use of fluids with lower dextrose concen- described 6 cases of neonatal hypoglycemia and the trations (e.g., 1% or 2.5%).23–25,29,30 It should be noted disastrous clinical and pathological sequelae associ- that there are no IV fluids with dextrose concentra- ated with prolonged low blood glucose. Animal ex- tions less than 5% commercially available in the periments have further demonstrated that cerebral United States. The populations at highest risk of injury is caused not only by severe prolonged hypo- hypoglycemia include neonates, children receiving glycemia but also mild hypoglycemia combined hyperalimentation, and those with endocrinopathies, with mild hypoxia or ischemia.15 In a recent study of in whom monitoring blood glucose levels and adjust- 35 term neonates with symptomatic hypoglycemia ing the rate of infusion is also recommended.24,25,30 (blood glucose level 45 mg/dL or 2.6 mmol/L), Routine dextrose administration is no longer advised magnetic resonance imaging detected white matter for otherwise healthy children receiving anesthesia. abnormalities in 94%, with severe abnormalities noted in 43% of the studied population. Furthermore, at Third Space Losses 18-mo follow-up, 26 of the 35 patients studied contin- “Third space losses” refers to the sequestration of ued to exhibit some level of impairment.16 Hypogly- fluid to a nonfunctional extracellular space that is cemia has also been found to be associated with an beyond osmotic equilibrium with the vascular increase in morbidity and mortality in pediatric inten- space.31,32 In the original study documenting this sive care unit (ICU) patients.17 phenomenon, 13 adults having elective major surger- In the 1970s, research suggested that fasted children ies (primarily cholecystectomies) were injected with may become hypoglycemic while under anesthe- I131-tagged serum albumin, chromate51-tagged red sia.18 –21 In 1986, Welborn et al.22 evaluated preopera- blood cells (RBCs), and sulfur35-tagged sodium sulfate tive hypoglycemia in 446 children, 1 mo to 6 yr old, to determine plasma volumes, red cell mass, and extra- scheduled for outpatient minor surgical procedures. cellular fluid volumes. Additionally, the “trauma” asso- There were 2 asymptomatic children with preopera- ciated with the surgery was rated based on the observed tive blood glucose values of 50 mg/dL. Both of these amount of necessary retraction, difficulty in exposure, children had fasted in excess of 17 h before presenting and depth of anesthesia.32 The data suggested that Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 377
  4. 4. extracellular fluid volume was redistributed or seques- chemical, pharmacokinetic, and pharmacodynamic tered into areas that no longer communicated with a properties, and consequently, these products differ with functional extracellular space and that this correlated respect to their impact on hemodynamic variables. with the observed degree of trauma. We have long assumed that the surgical trauma incurred by cell Protein Colloid: Albumin membranes causes hypoxic injury creating a loss of Albumin occurs naturally and is regarded as the integrity allowing fluids to traverse cell membranes colloid “gold standard.” Albumin is derived from indiscriminately. Isotonic fluids were recommended pooled human plasma by the Cohn cold ethanol to replace the losses from the functional extracellular fractionation process: human plasma is heated to 60°C space to the “third space.” In pediatrics, it has been for 10 h and then sterilized by ultrafiltration, thus proposed that, depending on the nature of the surgical eliminating the risk of disease transmission.46 Albu- procedure, 1 mL kg 1 h 1 to as much as 15 min has a molecular weight (MW) of approximately 69 mL kg 1 h 1 of additional isotonic fluids are neces- kDa. In the United States, albumin is produced in sary to compensate for these continuing losses. In fact, concentrations of both 5% and 25%. An albumin 5% it has been stated that up to 50 mL kg 1 h 1 is solution is osmotically equivalent to an equal volume required for premature neonates undergoing surgery of plasma, whereas a 25% solution is osmotically for necrotizing enterocolitis, a surgery associated with equivalent to 5 times its plasma volume. In other significant trauma and ischemia of the bowel.25 A words, the administration of 100 mL of 25% albumin recent review of predominantly adult literature con- will increase the intravascular volume approximately cludes that a classic “third space” does not exist.33 3–5 times the amount infused. In contrast, the admin- Several studies using multiple blood samples and istration of 500 mL of 5% albumin is necessary to steady-state tracer kinetics revealed that the functional increase the intravascular volume by a similar amount fluid space is either unchanged or expanded rather than of 100 mL of 25% albumin.47 This intravascular vol- contracted after surgery.34 –36 Substantial amounts of ume expansion occurs because of fluid translocation fluid accumulate in the interstitial space secondary to from the interstitial compartment into the intravascu- factors including volume overload with crystalloid lar space. However, in subjects with increased intra- infusions and iatrogenic deterioration of the vascular vascular permeability (e.g., critically ill, sepsis, barrier.33 trauma, and burn), the translocation of fluid from the There is little evidence regarding this topic in pediat- interstitial compartment to the intravascular compart- ric patients. It is possible that our traditional practice of ment may be decreased and colloids may actually leak liberal isotonic fluid delivery in major pediatric surgeries into the interstitial space, thereby worsening edema may have adverse implications. Several studies in adults by pulling fluid from the intravascular compartment. demonstrate that, in abdominal surgery, outcomes may Side effects from albumin are rare but have been be improved by conservative fluid management in the reported. Although considered to have negligible ef- perioperative period.37–39 Individualized goal-directed fects on the coagulation cascade, albumin might still fluid management using only the amount of crystalloid have weak anticoagulation effects through inhibition and/or colloid necessary to optimize flow-related vari- of platelet aggregation48 or heparin-like effects on ables such as stroke volume can alter the incidence of antithrombin III.49 These effects are thought to be postoperative complications.40 – 43 Unfortunately, periop- clinically insignificant if volume replacement with erative studies in pediatric patients using the esophageal albumin is kept below 25% of the patient’s blood Doppler, pulse contour analysis, or mixed venous oxy- volume. Tobias et al.,50 using thromboelastography gen saturation to guide and determine optimum fluids (TEG®, Haemonetics Corp, Braintree, MA), demon- are lacking. Instead, we are left to wonder if a smaller strated that hemodilution with large amounts of albu- amount of crystalloid combined with an appropriate min ( 25% hemodilution of the blood volume) may colloid might reduce the amount of tissue edema and produce a hypocoagulable state. Allergic reactions are improve recovery from surgery previously thought to another possible complication of albumin administra- generate a third space. tion; however, albumin is associated with significantly fewer anaphylactic reactions compared with other colloids.51 COLLOIDS Albumin’s safety has been questioned in 2 sepa- When determining the particular colloid fluid to rately conducted meta-analyses.52,53 In the 2004 Saline administer, the type of fluid deficit (fluid loss or plasma versus Albumin Fluid Evaluation study, Finfer et al.54 loss) and the effect that these replacement fluids might noted no difference in outcomes between albumin and have on the intravascular volume, coagulation cascade, saline in adults. This 7000-patient multicenter, ran- microcirculation, and any possible allergic reactions domized, double-blind trial, comparing the effects of must be considered.44,45 Colloid fluids can be divided saline and albumin fluid on the 28-day patient mor- into natural protein colloids (albumin) and synthetic tality rate, showed no significant difference in mortal- colloids (hydroxyethyl starches [HESs], dextrans, and ity (726 deaths in albumin group and 729 deaths in gelatins). These products vary significantly in their saline group) or secondary end points (length of stay 378 Perioperative Fluid Management in Pediatric Patients ANESTHESIA & ANALGESIA
  5. 5. in the ICU or hospital, days of mechanical ventilation, and days of renal replacement therapy) between the groups. However, there seemed to be an increased mortality in a subset of patients with traumatic brain injury (TBI). A post hoc follow-up study was under- taken (Saline versus Albumin Fluid Evaluation–TBI study) that, in fact, substantiated these findings and concluded that critically ill patients with TBI had a higher mortality rate if resuscitated acutely with albu- min as opposed to saline.55 Pediatric studies are few in number and small in size. In a study of critically ill children with meningo- coccal disease in the United Kingdom, early aggres- Figure 2. Structure of hydroxyethyl starch (HES). In this sive fluid resuscitation with albumin helped to reduce molecule, note the 3 hydroxyethyl groups and a total of 4 glucose units giving a high molar substitution of 0.75; all 3 mortality from 50% to 5%.56,57 Furthermore, in a hydroxyethyl groups are on the C2 carbon giving high C2:C6 randomized trial of 30 ventilator-dependent hy- substitution ratio which leads to prolonged action. poalbuminemic preterm infants, the administration of albumin was associated with a reduction in edema (as concerted monetary effort to encourage the use of judged by weight loss) and inspired oxygen concen- albumin.64 However, data supporting the continued tration requirements compared with infants who re- use of albumin for general fluid resuscitation in chil- ceived an equal volume of crystalloid maintenance dren are lacking, and in children with TBI, it may fluid.58 In another randomized trial of 30 children actually be harmful. Its utility may exist in specific younger than 3 yr undergoing cardiopulmonary by- subgroups such as neonates and patients undergoing pass, the urinary output was 57% lower after intravas- cardiac surgery. cular volume expansion with HES 200/0.5 than after albumin administration.59 In a separate study of chil- Nonprotein Colloids: HES dren undergoing cardiopulmonary bypass, Riegger et HESs are a class of synthetic colloids that are al.60 compared a pure crystalloid prime with an modified natural polysaccharides. Naturally occur- albumin-added prime solution. The authors noted that ring starches are unstable and are rapidly broken patients exposed to the albumin prime had a negative down by circulating amylases in the circulation. Sub- fluid balance and less weight gain after surgery. stituting hydroxyethyl groups for the naturally occur- However, there were no differences between the 2 ring hydroxyl groups at carbon positions C2, C3, and groups with regard to ICU length of stay, ventilation C6 results in a more soluble product, resistant to days, or mortality. In addition, the patients receiving hydrolysis, with subsequent prolonged effectiveness albumin actually had lower hemoglobin levels and (Fig. 2). higher transfusion requirements. Unlike other colloids, HES colloids are character- Albumin has been considered the gold standard for ized not only by their concentration and weighted maintenance of colloid osmotic pressure in infants and average mean MW in kilodalton but also by their neonates61 and continues to be the most frequently molar substitution (MS) and C2:C6 ratio (Table 2). used plasma expander in this population.62 However, Hetastarches are made in concentrations of 3%, 6%, the expense and decreased availability of albumin and 10%. Their weighted average mean MW may be have led some countries to pursue other colloids. The divided into low ( 70 kDa), medium (130 –270 kDa), Association of Pediatric Anesthetists of Great Britain and high ( 450 kDa) brackets. MS is defined as the and Ireland favor the use of gelatins and the Associa- molar ratio of the total number of hydroxyethyl tion of French Speaking Pediatric Anesthetists mem- groups to the total number of glucose units, and these bers from France frequently use hetastarch solutions,63 molar ratios may be divided into a low (0.4 – 0.5) or whereas in the United States, albumin remains the high (0.62– 0.7) molecular ratio. Finally, the C2:C6 ratio first choice. There are a multitude of alternative syn- describes the position of the hydroxyethyl groups on thetic colloid fluid options accessible in Europe that the glucose molecule. As a rule, the solutions with a are not currently available in the United States. Inter- higher MW and MS ratio have a prolonged volume estingly, in the United States, there is a reduced price effect, but are also associated with a greater side effect differential between albumin and its synthetic alterna- profile. Initially, HES solutions are broken down rap- tives (500 mL of 5% albumin [$82], Hespan (B. Braun idly by amylase. The hydroxyethyl groups specific to Medical Inc. Bethlehem, PA) [$18], Hextend (Hospira the C2 carbon position of the glucose molecule hinder Inc. Lake Forest, IL) [$28], Volvulen (Frensenius-Kabi, this breakdown and are therefore responsible for Bad Homburg, Germany) [$45] LR [$0.77]), whereas in prolonging the solution’s half-life. Therefore a higher Europe, 500 mL of 5% albumin may cost as much ratio of C2:C6 hydroxyethylation substitution results as €150 ($190) and HES fluids may cost €30 ($38). in slower enzymatic degradation and prolonged ac- Additionally, the manufacturers of albumin make a tion without increasing side effects. Hence, the Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 379
  6. 6. Table 2. Hydroxyethyl Starch (HES) Solutions Properties and Availability HES 450/0.7 HES 670/0.7 HES 130/0.4 HES 70/0.5 ® ® ® Trade name Hespan Hextend Voluven Availability Europe/US US Europe/US Europe Concentration (%) 6 6 6 6 Volume effect (h) 5–6 5–6 2–3 1–2 Molecular weight (kD) 450 670 130 70 Molar substitution (MS) 0.7 0.75 0.4 0.5 C2/C6 ratio 4:1 4:1 9:1 4:1 newest-generation HES fluids are designed with low findings led to the conclusion that HES deposits in MW and MS ratios to minimize side effects, as well as cutaneous nerves may account for the itching seen a high C2:C6 hydroxyethylation ratio to prolong dura- after HES infusion.82 Pruritus may manifest months tion of action. after the infusion83,84 and seems to be resistant to HES solutions expand the plasma volume with current available forms of therapy.85 The incidence of effects lasting 2– 6 h, depending on the specific char- pruritus seems to be determined by the type of HES acteristics of the HES fluid. In addition to the volume solution and the volume administered,51,86 with less- expansion, HES solutions also affect the microcircula- frequent pruritic symptoms with the new-generation tion and tissue oxygenation. In a study of adult HES solutions.51,84 patients undergoing abdominal surgery, Lang et al.65 Initially, the only HES solution available in the compared a medium MW, low MS HES solution with United States was Hespan® (6% HES 450/0.7 in sa- LR. In this study, the HES solution was noted to have line). Hextend® was then introduced (6% HES improved tissue oxygenation. As with other colloids, 670/0.7) and marketed as a balanced colloid solution side effects of HES solutions may also include hypo- containing 6% hetastarch, balanced electrolytes, a lac- coagulation, renal toxicity, and pruritus.66,67 These tate buffer, and a physiological level of glucose. Hex- side effects are influenced by the specific characteris- tend seems to be as effective as 6% hetastarch in saline tics of the HES fluid.68,69 The older high MW, high MS, for the treatment of hypovolemia and seems to be a first-generation HES solutions (e.g., HES 450/0.7) better choice during major surgery than Hespan, with have more significant hemostatic side effects66,67 com- fewer negative effects on the TEG, less blood loss, and pared with the newer low MW, low MS solutions (e.g., less need for calcium supplementation.87,88 HES 130/0.4).70,71 The exact mechanism of the hypo- Voluven® is a 6% HES (130/0.4) solution in 0.9% coagulable effect associated with the HES solutions is sodium chloride. It was approved by the Food and unclear; however, HES seems to interfere with the Drug Administration in 2007 for the treatment of function of von Willebrand factor, factor VIII, and serious blood volume loss during surgery. Voluven, platelets.72,73 These hemostatic side effects may be with its lower MS and MW has relatively little effect especially concerning in cardiac surgery patients, in on hemostasis. Kozek-Langenecker89 noted that Volu- whom the use of cardiopulmonary bypass creates ven use decreased perioperative blood loss and RBC further coagulopathies and platelet dysfunction.45,74,75 transfusion requirements compared with HES solu- HES solutions may also worsen renal function75–77 tions with higher MS ratios. This was further substan- by inducing renal tubular cell swelling and creating a tiated in a pooled analysis of randomized clinical trials hyperviscous urine. Both tubular cell swelling and when Voluven 130/0.4 was compared with a second- hyperviscous urine can cause renal tubular obstruc- generation HES 200/0.5 solution.90 Furthermore, tion and medullary ischemia.78 However, the hyper- Voluven does not have the negative renal side effects viscous urine may be preventable, either by prior observed with older-generation HES solutions and adequate hydration with crystalloids or by the use of may, in fact, preserve effective renal plasma flow the newer-generation, less-oncotic HES solutions (low compared with normal saline.91 Thus, these newer MW and MS).79 – 81 rapidly degradable HES solutions seem to be a suit- Pruritus occurs in 0%–22% of patients exposed to able volume expander in the routine perioperative HES solutions and is thought to be caused by the setting because of their adequate volume efficacy and accumulation and storage of the HES solution in the low risk of hemostatic derangements. skin. Metze et al.82 demonstrated the formation of Pediatric studies involving synthetic colloids are intracytoplasmic vacuoles in the skin after HES fluid scant. Paul et al.92 noted, in a randomized controlled administration. The number and size of these vacuoles study of children aged 1–38 mo undergoing urologic were noted to be dose dependent. Patients experienc- surgery longer than 2 h duration, that the administra- ing pruritus consistently showed additional deposits tion of 20 mL/kg of 6% HES (70/0.5) during the first of HES in the small peripheral cutaneous nerves, with hour of the procedure resulted in a larger decrease in symptomatic clinical improvement closely associated hemoglobin concentration (more effective plasma ex- with the resolution of these neural vacuoles. These pansion) compared with a similar volume of LR. In 380 Perioperative Fluid Management in Pediatric Patients ANESTHESIA & ANALGESIA
  7. 7. addition, Paul et al.92 noted no differences between the hyperchloremia resulting from HES infusion might groups with regard to amounts of intraoperative fluid have negative effects on arterial blood pressure,100 administration, postoperative edema, weight changes, renal blood flow,101 and postoperative nausea and or incidence of pruritus. vomiting.102 Earlier studies in pediatric tumor resection noted In pediatric cardiac surgery, the data are quite that HES was well tolerated and effective in preserv- varied. When comparing HES to albumin for postop- ing global tissue oxygenation during normovolemic erative intravascular volume expansion after pediatric hemodilution in children.93,94 In a prospective, random- cardiopulmonary bypass, there were no differences ized, double-blind pilot study involving 26 neonates found in the amount of required replacement fluids or without cardiac, renal, or hemostatic abnormalities un- coagulation variables in children receiving 20 mL/kg dergoing central line placement, the use of 6% HES did or less of either colloid replacement therapy. Although not increase creatinine or bleeding when compared with an increase in prothrombin time was noted in children neonates receiving an equal volume of 5% albumin.95 who received more than 20 mL/kg of 6% hetastarch, However, in another small sample size, prospective, no differences in clinical bleeding or blood product randomized, blinded study by the same investigators, requirement were demonstrated.103 Similarly, in a no improvement in cardiac output could be shown in randomized trial of 42 patients aged 6 mo to 10 yr, 21 hypotensive neonates with low cardiac output comparing the administration of 10 mL/kg of HES states after the administration of HES, isotonic saline, (130/0.4) or fresh frozen plasma (FFP) after cardiopul- or 5% albumin.96 Similarly, in a prospective random- monary bypass, Chong Sung et al.104 reported only a ized study comparing the new third-generation 6% HES minor effect on coagulation variables. Specifically, (130/0.4) (Voluven) and 5% albumin, Standl et al.97 there was a prolonged international normalized ratio noted no difference in perioperative hemodynamic in the HES group, but no differences were shown stability, coagulation variables, blood gas, or other between the groups with regard to activated partial laboratory values in 81 pediatric patients undergoing thromboplastin time values, transfusion requirements, elective noncardiac surgery. Concerns regarding this or blood loss. Haas et al.,105 in a study measuring study relate to the fact that cardiac surgical patients coagulation variables with TEG, compared the effects and preterm patients were not included. Thus, the of 15 mL/kg 5% albumin, 4% gelatin, and HES applicability of these results is limited. (130/0.4) administered to 42 infants. In this study, A European prospective, multicenter, observa- there was an increase in activated partial thrombo- tional, postauthorization safety study was designed to plastin time values with the use of all fluids but a evaluate the safety of HES (130/0.42) for perioperative greater reduction of maximal clot firmness (MA value) plasma replacement in children. The study was only after gelatin administration when compared with al- performed in countries where the use of HES was bumin. Median TEG values for both albumin and approved and HES was already indicated for pediatric gelatin, however, remained within the normal range. volume replacement.98 Three hundred sixteen chil- Patients administered HES, however, exhibited a de- dren, aged 3–12 yr, were infused with a mean volume crease (below the normal range) both in the speed of of 11 4.8 mL/kg of HES (130/0.42). Cardiovascular clot formation (MA value and angle) and in stability was maintained in all cases. There were no fibrinogen/fibrin polymerization (a special additional serious adverse drug reactions, such as anaphylaxis, test that measured clot stability). The authors sug- renal failure, or clotting disorder. In this study, only gested that this might explain the increase in blood patients with normal renal function and intact coagu- loss after pediatric cardiopulmonary bypass associ- lation symptoms were investigated, suggesting that ated with HES use.105,106 The authors also concluded although HES may be safe in patients with normal that from a hemostatic point of view, gelatin was renal and clotting function, further studies are still preferable to HES. These hemostatic concerns re- necessary before presuming safety in patients with garding HES have been further substantiated by a renal failure or those at increased risk of bleeding. One meta-analysis of children and adults receiving HES potential side effect of HES (130/0.42) noted in this during cardiac surgery, which showed increased study, however, was a decrease in the anion gap as blood loss in those patients receiving HES compared well as an increase in the chloride concentration. The with albumin.66 increase in chloride concentration occurs to maintain electroneutrality because the electroneutral HES re- Nonprotein Colloids: Gelatins places the negatively charged plasma proteins, Gelatins are polypeptides produced by degradation thereby decreasing the amount of unmeasured nega- of bovine collagen. There are currently 3 gelatin tive charges.99 This may be of clinical importance products available commercially (crosslinked [Gelo- when using anion gap and strong ion difference for fundiol®, Biotest Pharmazeutika, Vienna, Austria], acid base interpretation of metabolic disturbances urea crosslinked [Hemacel®, Aventis Pharma, Vienna, during pediatric surgery. A low anion gap caused by Austria], and succinylated gelatin [Gelofusine®, HES infusion could mask a high gap acidosis signify- B. Braun, Melsungen, Germany]). None are available ing acute renal failure or sepsis. In addition, the in the United States. Gelatin has not been available in Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 381
  8. 8. the United States since 1978 because of a high inci- differences regarding success in the treatment of shock dence of hypersensitivity reactions with the initial or acidosis between the 2 solutions. However, fatal formulations.107 The MWs of these gelatins are ap- neurological events were more frequent in the gelatin proximately 30 –35,000 Da and are lower than the group. In an adult study comparing the use of gelatin other colloids. It is this lower MW that is responsible or HES for blunt trauma resuscitation, Allison et al.115 for the gelatin’s decreased colloid oncotic effects com- suggested that gelatin was associated with a worse pared with the other colloid fluids. Furthermore, the posttrauma capillary leak than HES fluids. Their find- actual increase in blood volume is less than the ings might have implications regarding fluid resusci- infused volume of gelatin because of the rapid but tation in septic newborns with respect to the severity transient passage of gelatins into the interstitial space, of their capillary leak syndrome.116 However, data in rapid glomerular filtration, and gelatin’s susceptibility animals with regard to capillary leak and septic shock to enzymatic cleavage by proteases. Therefore, re- indicate that gelatin and HES actually maintain peated infusions are necessary to maintain adequate plasma volume more effectively than albumin.117 blood volume. The disadvantage of repeat infusions is balanced by the lack of a gelatin dose limitation. This Nonprotein Colloids: Dextrans lack of a dose limitation is distinct from the other Dextran is a water-soluble glucose polymer (poly- nonprotein colloids. There is no accumulation of gela- saccharide) synthesized by specific bacteria from su- tin in the body, and gelatins have few adverse effects. crose. The current formulations available are 10% Other advantages of gelatin include its cost (the least dextran 40 and 6% dextran 70. Dextran 40 is regarded expensive of the synthetic colloids) and its long shelf as a low-MW dextran of approximately 40,000 Da, life.108 Although initially it was thought that gelatins whereas dextran 70 is a high-MW dextran of approxi- did not have any negative hemostatic effects, gelatins mately 70,000 Da. This leads to a differential excretion have been shown to negatively affect TEG values and of these 2 products by the kidneys, because the renal should be used with caution in patients with bleeding threshold for these dextrans is approximately 55,000 tendencies such as von Willebrand disease.68,105,109 Da. The result of this differential excretion is that The data supporting the use of gelatin in children dextran 70 remains in the intravascular space for 5– 6 are limited. A randomized, prospective, double-blind h, whereas dextran 40 remains intravascular for 3– 4 h. study focused on children with dengue shock syn- Although these dextrans have excellent colloid on- drome, which is distinguished by hypovolemia sec- cotic powers, they probably should not be used be- ondary to increased vascular permeability. In these cause of their negative coagulation effects and high children, initial resuscitation was achieved with 1 of 4 anaphylactic potential. Their negative coagulation ef- fluid regimens (20 mL/kg of dextran, gelatin, LR, or fects are well documented and lead to an increased normal saline). All of the children survived, and there bleeding tendency.68 Dextran not only induces a dose- was no clear advantage of any of the 4 fluids. However, dependent von Willebrand–type syndrome but also the LR group was associated with longer recovery times. enhances fibrinolysis. This fibrinolytic phenomenon is The authors suggested that the most significant factor worse with the high-MW dextrans. Furthermore, dex- determining clinical response was the pulse pressure tran use has been associated with acute renal failure in at presentation and that colloids, which restore the patients with acute ischemic strokes.118 The anaphylactic/ intravascular volume efficiently, might be the better anaphylactoid reactions are the result of dextran reac- choice of fluids.110 In a multicenter study, the North- tive antibodies, which trigger the release of vasoactive ern Neonatal Nursing Initiative Trial Group compared mediators. The current suggestion is to limit the use of early mortality and morbidity in preterm infants after dextrans to 1500 mL in an adult or 20 mL/kg in a child administration of FFP, gelatin, and glucose. They were per day. It has also been suggested that patients unable to show evidence of any adverse short-term should be pretreated with a hapten inhibition prior to outcomes related to gelatin use,111 and developmental the infusion of a dextran to decrease the incidence of outcome after 2 yr was similar in all 3 groups.112 allergic reactions.119 However, there was no attempt to evaluate the effi- cacy of gelatin as an intravascular volume expander in neonates in this study. HYPERTONIC SALINE Adverse events have been associated with the use Hypertonic saline solutions have been used in the of gelatins in infants and older children. In a Cochrane treatment of refractory hypovolemic shock because of review of early volume expansion in preterm infants their ability to rapidly mobilize fluid into the intravas- (including 7 randomized controlled trials), it was cular space and thus expand the plasma volume. They noted that the use of gelatin or no treatment was have been shown to improve organ blood flow and associated with an increased risk of developing necro- microcirculation and may even have positive inotropic tizing enterocolitis, when compared with patients effects. These solutions are only given in small receiving FFP.113 In a randomized study of children amounts (4 mL/kg) because of their hypertonicity, but with malaria comparing volume expansion with albu- are able to improve preload and thereby cardiac min or gelatin, Akech et al.114 reported no significant output.120,121 382 Perioperative Fluid Management in Pediatric Patients ANESTHESIA & ANALGESIA
  9. 9. The greatest concern with hypertonic saline solu- still a dearth of evidence supporting any particular tions is their short duration of action. There has been method of volume expansion in the pediatric popula- an interest in combining these solutions with colloid tion.136 The International Guidelines 2000 Conference solutions, such as HES and dextran, to prolong their for Neonatal Resuscitation recommended that emer- positive intravascular effects. These combinations gency volume expansion should be accomplished seem to have a beneficial effect and may lead to an with either isotonic crystalloid solution or O-negative improved survival rate in adult patients after trauma RBCs.137 A more recent clinical practice guideline compared with the hypertonic saline alone.122 However, from the Dutch Pediatric Society concluded that be- these results have been questioned in a meta-analysis in cause of the limited number and quality of available which patients receiving hypertonic solutions were not pediatric research studies, recommendations for vol- shown to have any better outcomes than the patients ume expansion should be made based on the solu- receiving crystalloids.123 tion’s side effects, mechanisms of action, and cost. Hypertonic saline solutions have, however, been Thus, isotonic saline was recommended as safe, effec- shown to be beneficial in the treatment of TBI by tive, and 100 times less expensive than albumin.63 reducing cerebral edema and subsequently decreasing In the most recent Cochrane database review of high intracranial pressure.124 –126 Because the blood- colloids versus crystalloids for fluid resuscitation in brain barrier has a low permeability for sodium, it is critically ill adult patients (2007), the authors con- thought that the hypertonic saline creates an osmotic cluded that there is no evidence to support the use of gradient to decrease cerebral edema and has a reflec- colloids over crystalloids in the resuscitation of pa- tion coefficient even better than mannitol. Hypertonic tients with burns, trauma, or after surgery, because saline may improve brain cell function by reestablish- they are significantly more expensive and not associ- ing electrochemical gradients that restore normal rest- ated with improved survival.138 In a letter to the ing membrane potential, as well as modulating the editor, Drs. Jacob and Chappell suggested that pa- inflammatory response, thereby helping to maintain tients who do not have substantial blood losses should the integrity of the blood-brain barrier and prevent not generally require the substitution of colloid for brain cell death.127–130 In 2 separate studies of children crystalloids in their fluid management. Rather, pa- with TBI, hypertonic saline was shown to increase tients with continuing urinary output and insensible cerebral perfusion pressure in the 3 days after head losses, representing colloid-free losses, primarily trauma, when compared with LR.131,132 require crystalloid fluid replacement.139 A further In pediatric burn patients, there seems to be evidence meta-analysis analyzing the different colloid solutions in favor of a combined hypertonic/hyperosmotic solu- available for fluid resuscitation concluded that when tion. In an experimental animal study involving measuring mortality, blood administration, and the burned pigs, small volumes of hypertonic saline com- incidence of allergic reactions, there was no evidence bined with 6% dextran 70 improved heart contractil- to suggest that one colloid solution is more effective or ity, reduced cardiac myocyte damage, and reduced safer than another.140 total fluid volume compared with LR alone.133 In a There is a tremendous need for well-controlled study of burned patients, Murphy et al.134 noted that a studies in all pediatric patients that adequately assess combination of hypertonic saline/dextran 70 solution the various types of fluid regimens with clearly de- had no deleterious hemodynamic or metabolic side fined end points. Unitil such studies exist, we continue effects compared with standard LR resuscitation. to extrapolate from adult studies and use a combina- There are a number of potential concerns regarding tion of crystalloid and colloids to achieve the desired the use of hypertonic saline. There is the theoretical outcomes. possibility of the development of osmotic demyelina- tion syndrome, rebound increases in intracranial pres- Postoperative Hyponatremia sure, and acute renal failure from an increase in serum In 1983, a study of children undergoing scoliosis osmolarity.135 However, in a retrospective chart re- surgery demonstrated that hyponatremia developed view by Peterson et al.,125 no children developed renal when hypotonic IV fluids were used postoperatively.141 failure after the use of hypertonic saline. Hyperkale- In 1986, a report was published of 15 previously healthy mia and a nonanion gap metabolic acidosis were women who developed severe postoperative hyponatre- common electrolyte abnormalities associated with its mia, which resulted in neurologic devastation or use. However, both are easily managed and are not death.142 Six years later, similar catastrophic results clinically relevant if the serum sodium is kept below were reported in hospitalized children, many of 155 mmol/L. whom were recovering from surgery. The hyponatre- mia (mean 115 mmol/L) was primarily caused by extrarenal loss of electrolytes, in the presence of in- CONTROVERSIES creased antidiuretic hormone (ADH) activity, fol- Crystalloid Versus Colloids lowed by the administration of hypotonic fluids.143 Despite the recognition and focus on the impor- Hyponatremia produces osmotic movement of free tance of both colloid and crystalloid solutions, there is water across cell membranes from the extracellular to Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 383
  10. 10. Table 3. Clinical Settings Associated with Increased Antidiuretic Hormone Production Hemodynamic stimuli Nonhemodynamic stimuli Hypovolemia Vomiting, diarrhea, diuretics, CNS disturbances Meningitis, encephalitis, stroke brain abscess, head diuretics, renal salt wasting, injury, hypoxic brain injury hypoaldosteronism Pulmonary diseases Pneumonia, asthma, tuberculosis, empyema, chronic obstructive pulmonary disease, bronchiolitis, acute respiratory failure Hypervolemia Nephrosis, cirrhosis, Cancers Lung, brain, CNS, head, neck, breast, congestive heart failure, gastrointestinal tract, genitourinary tract, hypoalbuminemia leukemia, lymphoma, thymoma, and melanoma Hypotension Medications Cyclophosphamide, vincristine, morphine, selective serotonin reuptake inhibitors, carbamazepime Other Nausea, emesis, pain, stress, postoperative state, cortisol deficiency CNS central nervous system. the intracellular compartments, and the brain is the Another factor that may contribute to a poor out- most seriously affected organ. Estrogens seem to im- come in children with hyponatremia is the lack of pair the ability of the brain to adapt to hyponatremia. timely treatment resulting from a low index of suspi- In a review of the adult literature, Arieff144 reported cion. The early symptoms of lethargy, headache, nau- that women are much more likely to experience per- sea, and vomiting are common occurrences in many manent neurologic sequelae or even death secondary disease states and are often seen in the postoperative to hyponatremia. Additionally, menstruant women period. In children, a respiratory arrest may be the seem to be at an even greater risk. Ayus et al.145 event that triggers identification and subsequent treat- reviewed 65 cases of postoperative hyponatremia in ment of the electrolyte imbalance. In a series of 16 adults and found that of the 40 women and 25 men, hospitalized children with symptomatic hyponatre- there were 34 cases of permanent brain damage: 33 of mia, all had a respiratory arrest after a mean of 37 h these were women (97%) and 25 were menstruant. The from the start of IV fluid administration, although brain Na-K ATPase system, which helps the brain other milder symptoms were present earlier.134 Unfor- adapt to lower serum concentrations of sodium, is tunately, in this series, 10 patients died, 5 survived in impaired by vasopressin plus estrogen but is stimu- a vegetative state, and 1 survived with neurologic defi- lated by testosterone.144 Female rats given vasopressin cits. The single patient who survived with moderate plus estrogen have greatly reduced cerebral perfusion deficits was treated within 10 min of the respiratory compared with male rats.146 arrest; therapy was delayed or absent in the others. Postmenarchal girls may be at a higher risk of The ubiquity of increased ADH, the propensity of the complications than their male counterparts because of medical community to prescribe hypotonic IV fluids to these gender differences. In prepubescent children, children, and the lack of routine electrolyte monitoring there are no gender differentials. Rather, all children, create the potential for frequent occurrences of hypona- regardless of gender, are more prone to cerebral tremia. ADH release is associated with many clinical edema than adults. This results from differences in the scenarios, resulting from both hemodynamic and nonhe- ratio of intracranial capacity to brain size, cerebrospi- modynamic stimuli (Table 3).150 The pediatric surgical nal fluid volume, and brain water and electrolyte patient is certainly at risk for increased ADH, given content. The brain of a child grows rapidly, achieving the pain, stress, narcotics, hypovolemia, and/or hem- adult size by age 6 yr, whereas the skull continues to orrhage associated with the postoperative period. grow until age 16 yr. The volume of cerebral spinal Moreover, recent surveys demonstrate that it is com- fluid buffers brain expansion, but this is relatively mon practice to administer hypotonic fluids post- smaller in children than adults. The brain intracellular operatively in children.151–153 Additionally, routine concentration of sodium is about 27% higher in chil- electrolyte monitoring is often not performed unless dren than adults.143 Early in hyponatremia, the brain clinically indicated. Therefore, the true incidence of responds by transporting intracellular sodium to the hyponatremia in these patients is not known but may extracellular environment using the Na -K ATPase be much higher than suspected. In a meta-analysis mechanism.147 This enzyme activity is decreased in comparing hypotonic versus isotonic fluids in all prepubertal animal models.148 Newborn puppies with hospitalized children, the odds of developing hypona- hyponatremia are unable to extrude cations from brain tremia after the administration of hypotonic solutions cells.149 The inability of the pediatric brain to adapt to was 17 times greater than with isotonic fluids.154 excess free water, along with the high brain-to-skull For several years, the general pediatric community ratio, help to explain the relatively rapid cerebral edema has been intensely debating the wisdom of continuing seen with hyponatremia in pediatric patients. routine hypotonic maintenance IV fluid therapy in 384 Perioperative Fluid Management in Pediatric Patients ANESTHESIA & ANALGESIA
  11. 11. desalination. and may be the etiology of the slight hyponatremia reported in some children receiving isotonic fluids.141,165–168 Although the potential for significant hyponatremia is lower with isotonic fluids than with hypotonic fluids, large volumes of any IV solution, which may collect in the extracellular space, can increase the risk for low serum sodium. Second, there is a concern that patients who are given isotonic fluids may develop hypernatremia.158 In a retrospective study of postoperative surgical ICU patients, 11 of 29 patients who received isotonic fluids had at least 1 measurement of sodium larger than 145 mmol/L, compared with 0 of 116 who received hypo- Figure 3. The desalination process. Hatching represents tonic fluids; no values were considered dangerously isotonic saline in the extracellular fluid. The rectangle on the increased.165 The authors also found that 15 of 116 left represents the preoperative setting with a normal serum patients receiving hypotonic fluids had moderate or sodium. The rectangle on the right represents the postop- severe hyponatremia in addition to 1 of 29 patients in erative state. The extracellular space is expanded by isotonic solutions, but the loss of hypertonic urine and retention of the isotonic fluid group. In a study of 12 posterior free water caused by antidiuretic hormone creates a net spine fusion patients randomized to isotonic or hypo- increase in hypotonic fluids. This process leads to post- tonic fluids at a rate of 1.5 mL kg 1 h 1, 4 of 7 operative hyponatremia. (Reproduced from Steele et al.164 patients in the hypotonic group had a sodium 130 with permission.) mEq/mL postoperatively.166 The control group did not exhibit hypernatremia; rather, there was a small hospitalized children. Proponents of maintaining the decrease in serum sodium. Hypernatremia was also hypotonic requirements outlined by Holliday and Segar not observed in 122 primarily postoperative surgical argue that extracellular deficits should be replaced first ICU patients randomized to receive either hypotonic with isotonic fluids, followed by only the amount of or isotonic fluids.167 At 24 h, the incidence of hypona- fluid and electrolytes required to replace insensible tremia was 20.6% in the hypotonic fluid group com- losses and urine output.155–159 Recognizing that in- pared with 5.1% in the isotonic fluid group. This creased ADH levels may affect urine output, decreased finding was replicated by Yung and Keley168 in their volumes are recommended. On the other hand, those study of both medical and surgical ICU patients who who favor using isotonic fluids recognize the potential were randomized to 0.9% saline or 4% dextrose with for iatrogenic hyponatremia and wish to minimize this 0.18% saline. Hypotonic fluids were associated with a risk, albeit at the expense of a precise replacement of decrease in serum sodium, with surgical patients exact sodium and free water requirements.160 –163 In experiencing the greatest decrease; no patient was postsurgical patients, the concern over ADH release found to have hypernatremia. causing decreased urine output is confounded by the This debate regarding hypotonic fluids became the possibility of volume depletion caused by blood loss or focus of a national inquiry in Great Britain after the other fluid shifts. The natural inclination when faced deaths of 4 children who became profoundly hy- with decreased urine output in this scenario is typically ponatremic after receiving hypotonic fluids while hos- to give more volume, not less. The risk of hyponatremia, pitalized. In 2007, The National Patient Safety Agency when faced with oliguria, could be lessened with iso- of the United Kingdom issued an alert recommending tonic fluids regardless of the volume status. the removal of 4% dextrose with 0.18% saline from There are at least 2 potential problems when using general use in children.169 The preferred fluids for only isotonic fluids to avoid hyponatremia. The first of maintenance therapy are either 0.45% saline with these, described only in the adult population, is the dextrose or isotonic fluids. Additionally, they recom- phenomenon of desalination. In a study of 22 young mended measuring plasma sodium, potassium, and women having gynecologic surgery with minimal urea and/or creatinine at baseline and at least once blood loss, it was described that plasma sodium daily in any child who receives IV fluids. concentrations decreased an average of 4.2 mmol/L In most countries, there is neither consensus nor after the administration of large volumes of isotonic mandate about the composition of maintenance fluids fluids.164 The large volume of fluid administered in children despite the continuing controversy in the resulted in hypertonic urine, likely secondary to ADH literature. An editorial in a specialty anesthesia journal release both intraoperatively and postoperatively. Re- highlighted the issue and proposed the creation of a searchers proposed that when the extracellular space new IV solution with a fraction of the glucose and a expands with isotonic fluids, the urinary excretion of a higher concentration of sodium in comparison to hypertonic solution leaves excess electrolyte-free wa- currently available solutions.29 No such commercial ter leading to hyponatremia and subsequent intracel- solution is available in the United States. A review of lular swelling (Fig. 3). This process is known as the presently marketed IV solutions demonstrates that Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 385
  12. 12. Table 4. Composition of Frequently Used IV Fluids in the United States Glucose Na K Cl HCO3 Ca2 Fluid (g/100 mL) (mEq/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L) mOsm/L Tonicitya Lactated Ringer’s 130 4 109 28 3 273 Hypotonic (slightly) Normal saline (NS) 154 154 308 Isotonic D5W 5 252 Hypotonic D10W 10 505 Hypotonic D5 1⁄4 NS 5 34 34 329 Hypotonic D5 1⁄2 NS 5 77 77 154 Hypotonic a With respect to intravascular fluid composition. Adapted from Kuster JW, Rau RE, eds., John Hopkins: the Harriet Lane handbook, 2008, 18th ed., Elsevier Mosby. most are hypotonic (Table 4).170 A 2007 edition of a hyponatremia. At the very least, we should change pediatric textbook has acknowledged the potential for our practice of using D5 0.2 normal saline and educate hyponatremia in the postoperative period and advises others (surgeons and pediatricians) who are respon- this generation of pediatricians to expect the adminis- sible for the care of the postoperative pediatric surgi- tration of isotonic fluids intraoperatively and also cal patient. immediately postoperatively, albeit at two-thirds of the calculated maintenance rate in the recovery room. REFERENCES It further suggests that subsequent maintenance fluids 1. Blackfan KD, Maxcy KF. Intraperitoneal injection of saline. should contain 0.45% saline in the absence of a specific Am J Dis Child 1918;15:19 –28 2. Karelitz S, Schick B. Treatment of toxicosis with the aid of a indication for 0.25% saline. Most importantly, this text continuous intravenous drip of dextrose solution. 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Ann Thorac Surg 1997;63:78 – 82 Vol. 110, No. 2, February 2010 © 2010 International Anesthesia Research Society 387