Clinical trial NCT02950753
Conditions: Hyperlactatemia
Keywords: Elevated Serum Lactate Serum lactate Ringer's Lactate Lactated Ringer's Hyperlactatemia
Sponsor: University Medical Center of Southern Nevada
Start date: 2017-01-04; Completion date: 2017-06-01
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Lactated Ringer's (LR) solution bolus is commonly administered in the emergency department setting to seriously ill patients. It is also common to obtain blood samples to determine serum lactate levels to aid in the assessment of the patient's degree of illness. This study endeavors to determine if serum lactate levels are affected by LR fluid administration in healthy adult individuals as compared to those who receive Normal Saline (NS). Healthy adult volunteers will be used as subjects so that the illness of hospital patients does not confound the results.

Detailed description:
Methods:

Approximately 30 subjects will be randomized to either the Lactated Ringer's group or the Placebo group. The study is powered to detect a difference of 0.3mmol/L between pre- and post-treatment lactate levels. All subjects are healthy volunteers over 18 years old. Healthy volunteers are defined as subjects with no acute symptoms who do not meet any of the exclusionary criteria below:

* Pregnancy or currently breast-feeding
* Prisoner status
* Those with any history of clinical conditions associated with fluid overload: congestive heart failure, renal, or hepatic failure
* Baseline serum lactate level \>2.2mmol
* Baseline creatinine \> 1.5 mg/dL

All volunteers will sign a written consent, approved by the Institutional Review Board (IRB). The consent form will discuss the risks and benefits of our study. The benefit of our study is to identify a possible confounder to our current interpretation of serum lactates. By clarifying whether Lactated Ringer's fluid can contribute to measured serum lactate level we hope to improve our care to septic patients and those patients with abnormal vital signs and elevated serum lactate levels in whom the diagnosis of sepsis is being considered. The risks of this study include the possible development of fluid overload state and pulmonary edema. We believe these sequelae would be very unlikely to occur since we are excluding anyone with a history of any clinical conditions associated with fluid overload.

The intended pool of our volunteer subjects will be from residents, attendings, hospital staff, and medical students in the hospital. Only healthy volunteers (as described previously) will be allowed to participate. Volunteer subjects from the hospital will be instructed to only participate after their work shifts or on their days off from work so as not to interfere with their job duties. The consent form will clearly specify that their participation in the study will not impact their academic status or employment. The subjects will also fill out a short data collection form that will have age, gender, known medical problems, medications, and allergies. The subjects will designate their weight in this consent form.

All subjects will receive an 18-gauge IV in one antecubital fossa. A second IV will be placed on the contralateral arm from which to draw serum studies.

The subjects randomized to the Lactated Ringer's arm will receive 30ml/kg Lactated Ringer's solution run wide open. Those randomized to the Placebo group will receive 30ml/kg of normal saline wide open. The precise fluid bolus quantity will be determined using a measure of the patient's weight in kilograms multiplied by 30, rounding the final figure to the nearest 100ml for simplicity. (E.g. 2077 ml would be rounded to 2100ml.) The pharmacist for the study will randomly assign each subject to a treatment group ensuring that there are an equal number of subjects in the Lactated Ringer's arm and in the Placebo arm. The pharmacist will obscure the fluid bag contents from the investigators to maintain the blinding. Only the pharmacist will know which treatment each subject received. The person administering the medications and those doing the analysis of the data will only know the study number of each patient, and will be blind to the pharmacist's randomization.

We have chosen a bolus of 30ml/kg Lactated Ringer's solution over one hour as the regimen for two reasons primarily. The first is that in a clinical scenario of sepsis or septic shock a 30ml/kg bolus is typical.\[2\] Therefore this protocol simulates what actually happens during the care of a septic patient. A second reason for the selection of a substantial quantity of LR given over a short time interval is to ensure detection of any change in serum lactate concentration secondary to this fluid bolus, if there is one to be found. A smaller quantity of LR over a shorter time span may result in a false negative result.

A serum lactate level will be drawn just prior to initiating treatment. Any subject found to have an abnormally high baseline serum lactate level (\>2.2 mmol/L) before treatment will be excluded from the study.

The lactate will then be measured five minutes after the conclusion of the intravenous fluid treatment. 5ml of blood will be wasted to clear the line prior to this blood draw. Lactate will be measured with a point-of-care meter (the iSTAT-1 analyzer). The before-treatment and after-treatment lactate levels will be compared to see if the Lactated Ringer's caused a significant rise (\>0.3 mmol/L) in the lactate level at any point during the data collection period.

The study design described previously lends itself to a brief investigation into an important clinical phenomenon during fluid resuscitation that will be investigated as a secondary outcome to this study. One consideration for the use of the Lactated Ringer's solution clinically is the incidence of hyperchloremic metabolic acidosis with the use of normal saline during fluid resuscitation.\[8\] Using our point-of-care meter (the iSTAT 1 analyzer) we will measure not only serum lactate but also a complete metabolic panel prior to and subsequent to the delivery of the 30 ml/kg fluid administration. We will subsequently analyze changes in serum sodium, chloride, potassium, and bicarbonate in each of the treatment groups, assessing for the degree of derangement that occurs in those electrolytes, and specifically evaluating for any trend toward hyperchloremic metabolic acidosis in the normal saline group.

While patients are in the process of receiving IV fluids, they will be kept on continuous cardiac and oxygenation monitoring. We believe it is highly unlikely that any subject will need any medical care during this study. However, let it be noted that there will be an attending and/or resident physician present at all times while patients are receiving treatment. Should any subject develop adverse effects as a result of our study, the physician will assess the patient and offer to register them in the emergency department. Any Serious Adverse Event (SAE) will be reported to the IRB within 5 days.

In order to protect the privacy of the research subjects and to maintain the confidentiality of the data, all data will be handled only by research assistants or investigators and will be stored in secure cabinets and on password protected computer files in the locked research offices. All research assistants and investigators are HIPAA-trained and credentialed by UMC IRB.

We have chosen a goal sample size of 30 based on the following calculation. A sample size of 25 achieves 80% power to detect a mean of paired differences of 0.3 with a known standard deviation of differences of 0.5 and with a significance level (alpha) or 0.05 using a one-sided paired t-test. To allow for patient drop out or equipment failure, we will aim to enroll 30 patients.

Arms: arm 1: Intravenous bolus of Lactated Ringer solution (30ml/kg) via 18ga IV catheter at wide open. arm 2: Intravenous bolus of Normal Saline (30ml/kg) via 18ga IV catheter at wide open.
Interventions: intervention 1: Lactated Ringer Solution intervention 2: Normal Saline
Intervention descriptions: intervention 1: Fluid bolus of Lactated Ringer solution (30ml/kg). intervention 2: Fluid bolus or Normal Saline (30ml/kg).

Protocol documents:
Prot_SAP_000.pdf: 
 
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Official Title:  “Does Intravenous Lactated Ringer’s Solution Raise 
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Serum Lactate?” 
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NCT number:  NCT02950753 
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Date approved by IRB:  Nov 17, 2016 
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Introduction 
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Since “early goal-directed therapy,” early recognition of septic shock using the serum 
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lactate has become standard of care [1-4].  Indeed, the central place of lactate in sepsis 
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care has been promoted by the Surviving Sepsis campaign, and it is now backed by 
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financial incentives for hospitals with its adoption as a CMS Core Measure [5]. 
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In this context, it is important to elucidate all possible causes of hyperlactatemia. 
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Previous studies have shown that serum lactate increases in all shock states, not just 
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septic shock [6].  Furthermore, lactate has also been shown to increase from albuterol [7], 
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anti-retroviral medications, metformin, propofol, and alcohols [8]. 
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According to Surviving Sepsis Guidelines, patients diagnosed with septic shock should 
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receive 30 mL/kg of crystalloid solution within three hours [9].  One commonly used 
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crystalloid, Lactated Ringer’s solution (LR), contains 28 mmol/L of racemic lactate in the 
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form of sodium lactate. While lactate is rapidly metabolized by the liver and kidney, 
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aggressive fluid resuscitation with LR may transiently raise serum lactate, potentially 
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confounding the interpretation of this test. 
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There has only been one trial looking at the question of whether administration of LR 
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raises serum lactate. That study did not show a difference in lactate levels in those 
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receiving LR versus those receiving alternative crystalloid solutions. However, that study 
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used only 1 liter of LR delivered over one hour [10].  As mentioned above, patients in 
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septic shock are mandated to receive 30 mL/kg of crystalloid solution, and the fluids are 
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typically given at a rate faster than 1 liter per hour.  Therefore, when LR is given at a 
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volume and rate more similar to what is done for septic shock patients, LR may have an 
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effect on serum lactate level that was not identified in the previous study.  
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Thus, we propose a double-blind, randomized controlled trial to investigate whether the 
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administration of intravenous LR at 30 mL/kg increases levels of serum lactate. As our 
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study compares the effect of NS and LR, it lends itself easily to secondarily investigating 
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changes in sodium (Na), chloride (Cl), and pH in the NS group compared to the LR 
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group. 
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Materials and Methods 
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Study Design and Setting 
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This will be a double-blind, randomized controlled trial performed on a group of healthy 
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volunteers, made up primarily of family, friends, and colleagues of the investigators.   
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All subjects will be healthy volunteers aged 18 years or older. Healthy volunteers are 
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defined as subjects with no acute symptoms who meet none of the following exclusion 
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criteria: pregnant, breast-feeding, prisoners, history of conditions associated with fluid 
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overload (congestive heart, renal, or hepatic failure), baseline serum lactate level >2.2 
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mmol, and baseline creatinine >1.5 mg/dL. 
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All volunteers will fill out a short data collection form assessing their age, weight, 
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gender, and medical history. All volunteers will signed a written consent, approved by the 
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IRB. 
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A random-number generator will be used to assign each subject to either LR or NS. After 
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assignment, a pharmacist with no role in data collection prepared the fluids in a locked 
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room.  The pharmacist will use an opaque black bag to obscure the fluids. The subjects 
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will then receive 30 mL/kg rounded to the nearest 100 mL of the solution to which they 
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were randomized.  
 
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An investigator will place an 18 gauge IV in one upper extremity, and an initial serum 
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lactate and electrolyte panel will be drawn, measured using the i-STAT 1 analyzer 
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(Abbott Point of Care, Princeton, NJ). Fluids will be administered as a rapid bolus via 
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pressure bag. Post-treatment blood will be drawn from the contralateral upper extremity 
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five minutes after the conclusion of the IV fluid administration.      
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Outcomes 
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The primary outcome will be the difference in change in serum lactate levels between the 
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LR and NS groups. Secondarily, we will compare the change in lactate within each group 
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(before and after treatment), and we will compare the change in pH, creatinine, 
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bicarbonate, Na, and Cl levels between NS and LR groups.    
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Data Analysis 
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We powered the study as follows. A sample size of 30 achieves 80% power to detect a 
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difference of 0.5 mmol/L in the mean change in lactate between the NS and LR groups 
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assuming a standard deviation of differences of 0.5 and an alpha of 0.05.  We chose the 
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value of 0.5 mmol/L by clinical gestalt based on what we consider a clinically significant 
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difference in lactate levels. Before and after treatment lactate levels will be compared 
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within each group using paired t-tests. We will compare the change in mean lactate and 
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the change in other variables (pH, creatinine, bicarbonate, Na, and Cl) between the LR 
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and NS groups using two-tailed t-tests.   
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References 
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1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of 
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severe sepsis and septic shock. N Engl J Med. 2001; 345 (19): 1368–77. 
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2. Process Investigators, Yealy DM, Kellum JA, et al, A randomized trial of protocol-
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based care for early septic shock. N Engl J Med. 2014;370:1683–1693. 
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3. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation 
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for septic shock. N Engl J Med. 2015;372:1301–1311. 
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4. ARISE Investigators, Anzics Clinical Trials Group, Peake SL, et al. Goal-directed 
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resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496–1506. 
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5. Centers for Medicare & Medicaid Services. CMS specifications manual version 5.2a. 
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Available at:  
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 https://www.qualitynet.org/dcs/ContentServer?c=Page&pagename=QnetPublic%2FPage
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%2FQnetTier3&cid=1228775749207.  Accessed August 22, 2017 
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6. Cecconi M., De Backer D., Antonelli M, et al. Consensus on circulatory shock and 
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hemodynamic monitoring. Task force of the European Society of Intensive Care 
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Medicine. Intensive Care Med. 2014; 40:1795–815. 
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7. Zitek T, Cleveland N, Rahbar A, et al. Effect of Nebulized Albuterol on Serum Lactate 
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and Potassium in Healthy Subjects. Acad Emerg Med. 2016; 23(6):718-21. 
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8. Kraut, JA. Madias NE.  Lactic Acidosis.  N Engl J Med.  2014;371:2309-19.   
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9. Dellinger R, Levy M, Rhodes A, et al. Surviving Sepsis Campaign: international 
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guidelines for the management of severe sepsis and septic shock 2012. Crit Care Med. 
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2013; 41: 580–637.  
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10. Didwania A, Miller J, Kassel D, et al. Effect of intravenous lactated Ringer's solution 
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infusion on the circulating lactate concentration: Part 3. Results of a prospective, 
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randomized, double-blind, placebo-controlled trial. Crit Care Med. 1997; 25(11):1851-4. 
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