Clinical trial NCT03054922
Conditions: Anesthesia
Sponsor: Nationwide Children's Hospital
Start date: 2017-02-23; Completion date: 2018-09-30
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
During major surgical procedures, intravascular volume is maintained with the administration of isotonic fluids such as Lactated Ringers (LR), Normal Saline (NS) or Normosol-R. All three of these fluids are in common clinical use for this purpose. As large volumes of NS may result in a dilutional acidosis and an increasing base deficit, it may cloud clinical decision making when resuscitative efforts are guided by acid-base status on routine arterial blood gas analysis. This is a prospective, randomized study to evaluate changes in acid-base and electrolyte (sodium, potassium, calcium) status with the use of various isotonic fluids for intraoperative resuscitation.

Detailed description:

Arms: arm 1: 0.9% Sodium Chloride arm 2: Each 100 mL of Lactated Ringer's Injection USP contains:

Sodium Chloride USP 0.6 g; Sodium Lactate USP 0.31 g; Potassium Chloride USP 0.03 g; Calcium Chloride Dihydrate USP 0.02 g; Water for Injection USP qs arm 3: Each 100 mL of Normosol-R contains sodium chloride, 526 mg; sodium acetate, 222 mg; sodium gluconate, 502 mg; potassium chloride, 37 mg; magnesium chloride hexahydrate, 30 mg.
Interventions: intervention 1: Normal Saline intervention 2: Lactated Ringer intervention 3: Normosol-R Inj
Intervention descriptions: intervention 1: IV infusion of 0.9% NaCl throughout surgery. intervention 2: IV infusion of lactated ringer throughout surgery. intervention 3: IV infusion of Normosol throughout surgery.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Impact of intraoperative fluid management on electrolyte and acid-base 
variables 
 
 
 
NCT03054922 
 
 
 
February 17, 2017 


Title: Impact of intraoperative fluid management on electrolyte and acid-base 
variables 
 
Investigators: David P. Martin, Renata Miketic, Ajay D’Mello, Joseph D. Tobias 
 
Describe the background and rationale for this project. Reference to 
peer reviewed literature is desirable: During major surgical procedures, 
intravascular volume is maintained with the administration of isotonic fluids such 
as Lactated Ringers (LR), Normal Saline (NS) or Normosol-R. All three of these 
fluids are in common clinical use for this purpose. While all of these fluids have 
sodium concentrations that are close to physiologic levels, they contain varying 
amounts 
of 
chloride 
and 
different 
buffers 
(none 
in 
normal 
saline, 
acetate/gluconate in Normosol, and lactate in LR). Prospective trials have failed 
to show any significant differences in clinical outcomes among these 3 isotonic 
fluids, although there may be subtle differences in biochemical and electrolyte 
parameters (sodium and acid-base status). During the intraoperative care of 
patients undergoing major surgical procedures, acid-base status may be followed 
as an indirect measure of intravascular resuscitation and tissue perfusion. 
Inadequate resuscitation may result in a rising lactic acid, which will be reflected 
as an increasing base excess. However, an increasing base deficit may also  
occur merely due to the administration of a large volume of normal saline which 
results in a dilutional acidosis. This dilutional acidosis is not seen when LR or 
Normosol are used for intraoperative resuscitation. The difference is not easily 
discernible on standard arterial blood gas analysis and may require additional 
testing such as measurement of a serum lactate value. 
 
1. Awad S, Allison SP, Lobo DN: The history of 0.9% saline. Clin Nutr 2008; 
27:179–188. 
2. Scheingraber S, Rehm M, Sehmisch C, et al: Rapid saline infusion 
produces hyperchloremic acidosis in patients undergoing gynecologic 
surgery. Anesthesiology 1999; 90:1265–1270. 
3. Chowdhury AH, Cox EF, Francis ST, et al: A randomized, controlled, 
double-blind crossover study on the effects of 2-L infusions of 0.9% saline 
and Plasmalyte® 148 on renal blood flow velocity and renal cortical tissue 
perfusion in healthy volunteers. Ann Surg 2012; 256:18–24. 
4. Williams EL, Hildebrand KL, McCormick SA, et al: The effect of intravenous 
lactated Ringer’s solution versus 0.9% sodium chloride solution on serum 
osmolality in human volunteers. Anesth Analg 1999;88:999–1003. 
5. Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al: Meta-analysis of 
high- versus low-chloride content in perioperative and critical care fluid 
resuscitation. Br J Surg 2015;102:24–36. 
6. Yunos NM, Kim IB, Bellomo R, et al: The biochemical effects of restricting 
chloride-rich fluids in intensive care. Crit Care Med 2011;39:2419–2424. 


7. Neyra JA, Canepa-Escaro F, Li X, et al; Acute Kidney Injury in Critical 
Illness Study Group: Association of hyperchloremia with hospital mortality 
in critically ill septic patients. Crit Care Med 2015; 43:1938–1944. 
8. Rocktaeschel J, Morimatsu H, Uchino S, et al: Unmeasured anions in 
critically ill patients: Can they predict mortality? Crit Care Med 
2003;31:2131–2136. 
 
How will your study be funded (i.e., will you use departmental funds, 
submit a grant application, etc.): No funding is required. 
 
Provide a potential start date for your study to be included in the IRB 
application: December 2016 
 
Describe the significance of the proposed research: As large volumes of 
NS may result in a dilutional acidosis and an increasing base deficit, it may cloud 
clinical decision making when resuscitative efforts are guided by acid-base status 
on routine arterial blood gas analysis. The current study will evaluate changes in 
acid-base and electrolyte (sodium, potassium, calcium) status and lactate values. 
with the use of various isotonic fluids for intraoperative resuscitation. We 
hypothesize that the use a fluid containing a buffer (LR or Normosol) will 
mitigate acid-base changes during intraoperative care and allow for the use of 
the base deficit as a surrogate measure of intravascular resuscitation. 
 
State the primary and secondary objectives of the study: 
1. The primary objective is to determine differences in acid-base status 
based on the fluid used for intraoperative status. 
2. The second objectives are to determine the following based on the 
isotonic fluid used for intraoperative resuscitation: 
a. Differences in electrolyte values (sodium, potassium and ionized 
calcium) and lactate values 
b. Differences in intraoperative fluid requirements as judged by heart 
rate and blood pressure 
c. Differences in intraoperative urine output 
 
If this research is hypothesis driven, succinctly state the hypothesis: 
The intraoperative administration of NS will result in an increase in the base 
deficit when compared to LR or Normosol-R resuscitation. 
 
Outline the major steps and methodologies in the clinical protocol.      
If necessary, include a description of any procedures being performed 
already for diagnostic or treatment purposes. 
Inclusion would be: 
10-21 years of age 


Major surgical procedure requiring arterial access 
 
Exclusion criteria: 
Comorbid disease process that contraindicates the use of any of the 3 crystalloid 
solutions. 
The only variable that will be altered for the purpose of the study is the 
fluid used for intraoperative resuscitation. Although all 3 fluids are commonly 
used, the choice is based on the discretion of the attending anesthesiologist. For 
the purpose of this study, randomization will occur so that intraoperative fluid 
resuscitation/administration will include one of 3 isotonic fluids: NS, LR or 
Normosol-R. 
The anesthetic technique will follow our routine standardized anesthetic 
for posterior spinal fusion. Premedication will include oral or intravenous 
midazolam following by anesthetic induction to including either inhalational or 
intravenous induction. As per our usual routine, two peripheral intravenous 
cannuals and an arterial cannula will be placed. Maintenance anesthesia will 
include desflurane (inspired concentration adjusted to maintain the bispectral 
index at 50-60) and a sufentanil or remifentanil (infusion up to 0.3 µg/kg/hour 
for sufentanil or 0.3 µg/kg/hour) to maintain the mean arterial pressure at 50-65 
mmHg. Additional opioids such as morphine, hydromorphone or methadone may 
be administered according to the clinical plan per the attending anesthesiologist. 
Labetolol (0.1-0.15 mg/kg/dose) will be administered as needed to control the 
MAP if the sufentanil infusion is not effective. Fluid will be administered as 
clinically indicated based on clinical parameters including heart rate, blood 
pressure, and urine output. As clinically indicated, arterial blood gas and 
electrolytes will be analyzed using the point-of-care monitoring (I-stat). At this 
time, we will also run for lactate values. This is generally obtained 2-4 times 
during these cases. We will be recording the pre and post Cobb Angle, levels 
fused of spine, region of spinal fusion, and instrumentation. 
 
Identify the variables to be measured and how they will be statistically 
evaluated: The primary outcome variable is base deficit. Secondary outcomes 
include electrolyte values, lactate values, intraoperative fluid requirements, and 
intraoperative urine output. The primary hypothesis of the study will be 
evaluated using measurements obtained after administration of fluid (NS, LR, or 
Normosol, according to randomized assignment) during each procedure. 
Specifically, the incidence of base deficit in excess of -2 mEq/L will be compared 
between NS and LR and between NS and Normosol using tests of proportions. In 
a pilot study enrolling 48 patients, we found that the incidence of base deficit in 
excess of -2 mEq/L was 15%. The study will be powered to detect an increase in 
incidence from 15% to 40% between NS and either LR or Normosol, with the 
overall Type I error set at 0.05 and the significance level of individual tests (NS 
vs. LR; NS vs. Normosol) adjusted for multiple comparisons using the Bonferroni 
correction. To attain 80% power for detecting this expected difference, two- 


tailed tests of independent proportions will require 60 patients in each group. 
Therefore, we propose enrolling a total of 180 patients in the study, randomized 
equally among the 3 groups. For comparison, the proposed sample size will have 
>99% power to detect a -2 mEq/L difference in base deficit after fluid 
administration between NS and either LR or Normosol, using ANOVA with a 
Bonferroni correction for multiple comparisons, and assuming a standard 
deviation of 2.2 mEq/L based on our pilot data. Continuous data on the primary 
and secondary outcomes will be evaluated further using mixed effects linear 
models, to account for repeated measures (including any measures taken prior  
to 
fluid 
administration) 
and 
potential 
time-varying 
and 
time-invariant 
confounding characteristics.