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0.9% saline versus Plasma-Lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): a double-blind randomized controlled trial.
Williams, V, Jayashree, M, Nallasamy, K, Dayal, D, Rawat, A
Critical care (London, England). 2020;(1):1
Abstract
BACKGROUND Acute kidney injury (AKI) is an important complication encountered during the course of diabetic ketoacidosis (DKA). Plasma-Lyte with lower chloride concentration than saline has been shown to be associated with reduced incidence of AKI in adults with septic shock. No study has compared this in DKA. METHODS This double-blind, parallel-arm, investigator-initiated, randomized controlled trial compared 0.9% saline with Plasma-Lyte-A as initial fluid in pediatric DKA. The study was done in a tertiary care, teaching, and referral hospital in India in children (> 1 month-12 years) with DKA as defined by ISPAD. Children with cerebral edema or known chronic kidney/liver disease or who had received pre-referral fluids and/or insulin were excluded. Sixty-six children were randomized to receive either Plasma-Lyte (n = 34) or 0.9% saline (n = 32). MAIN OUTCOMES Primary outcome was incidence of new or progressive AKI, defined as a composite outcome of change in creatinine (defined by KDIGO), estimated creatinine clearance (defined by p-RIFLE), and NGAL levels. The secondary outcomes were resolution of AKI, time to resolution of DKA (pH > 7.3, bicarbonate> 15 mEq/L & normal sensorium), change in chloride, pH and bicarbonate levels, proportion of in-hospital all-cause mortality, need for renal replacement therapy (RRT), and length of ICU and hospital stay. RESULTS Baseline characteristics were similar in both groups. The incidence of new or progressive AKI was similar in both [Plasma-Lyte 13 (38.2%) versus 0.9% saline 15 (46.9%); adjusted OR 1.22; 95% CI 0.43-3.43, p = 0.70]. The median (IQR) time to resolution of DKA in Plasma-Lyte-A and 0.9% saline were 14.5 (12 to 20) and 16 (8 to 20) h respectively. Time to resolution of AKI was similar in both [Plasma-Lyte 22.1 versus 0.9% saline 18.8 h (adjusted HR 1.72; 95% CI 0.83-3.57; p = 0.14)]. Length of hospital stay was also similar in both [Plasma-Lyte 9 (8 to 12) versus 0.9% saline 10 (8.25 to 11) days; p = 0.39]. CONCLUSIONS The incidence of new or progressive AKI and resolution of AKI were similar in both groups. Plasma-Lyte-A was similar to 0.9% Saline in time to resolution of DKA, need for RRT, mortality, and lengths of PICU and hospital stay. TRIAL REGISTRATION Clinical trial registry of India, CTRI/2018/05/014042 (ctri.nic.in) (Retrospectively registered).
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Effect of Volume of Fluid Resuscitation on Metabolic Normalization in Children Presenting in Diabetic Ketoacidosis: A Randomized Controlled Trial.
Bakes, K, Haukoos, JS, Deakyne, SJ, Hopkins, E, Easter, J, McFann, K, Brent, A, Rewers, A
The Journal of emergency medicine. 2016;(4):551-9
Abstract
BACKGROUND The optimal rate of fluid administration in pediatric diabetic ketoacidosis (DKA) is unknown. OBJECTIVE Our aim was to determine whether the volume of fluid administration in children with DKA influences the rate of metabolic normalization. METHODS We performed a randomized controlled trial conducted in a tertiary pediatric emergency department from December 2007 until June 2010. The primary outcome was time to metabolic normalization; secondary outcomes were time to bicarbonate normalization, pH normalization, overall length of hospital treatment, and adverse outcomes. Children between 0 and 18 years of age were eligible if they had type 1 diabetes mellitus and DKA. Patients were randomized to receive intravenous (IV) fluid at low volume (10 mL/kg bolus + 1.25 × maintenance rate) or high volume (20 mL/kg bolus + 1.5 × maintenance rate) (n = 25 in each). RESULTS After adjusting for initial differences in bicarbonate levels, time to metabolic normalization was significantly faster in the higher-volume infusion group compared to the low-volume infusion group (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.0-3.9; p = 0.04). Higher-volume IV fluid infusion appeared to hasten, to a greater extent, normalization of pH (HR = 2.5; 95% CI 1.2-5.0; p = 0.01) than normalization of serum bicarbonate (HR = 1.2; 95% CI 0.6-2.3; p = 0.6). The length of hospital treatment HR (0.8; 95% CI 0.4-1.5; p = 0.5) and time to discharge HR (0.8; 95% CI 0.4-1.5; p = 0.5) did not differ between treatment groups. CONCLUSIONS Higher-volume fluid infusion in the treatment of pediatric DKA patients significantly shortened metabolic normalization time, but did not change overall length of hospital treatment. ClinicalTrials.gov ID NCT01701557.
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[A comparison of two systems for hydration of children with diabetic ketoacidosis. a randomized controlled trial].
Ferreira, JP, Penazzi, M, Taborda, M, Funes, S, Villareal, M
Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina). 2015;(2):93-9
Abstract
BACKGROUND Treatment of diabetic ketoacidosis (DKA) requires hourly controls of blood glucose, which define changes in the intravenous glucose and insulin administration. Every change requires preparing a new solution, wasting time and allowing errors. The two bag system (same electrolytes composition, but one with and the other without glucose) allows immediate changes in glucose administration rate, just by changing the solutions drip. OBJECTIVE To compare the time needed to reach stabilization of patients with DKA using two different hydration systems: the traditional one (1 glucose/electrolyte solution) vs. the alternative one (2 glucose/electrolyte solutions -"two bag system"-). METHODS Randomized controlled trial, including children aged 1 to 18 years, hospitalized for DKA (glycemia >200 mg/dl, pH <7.3, bicarbonate <15 mmol/L, glycosuria and ketonuria). After initial emergency re-hydration, patients were randomized to one of the 2 hydration systems (traditional or alternative), using it until patient stabilization (glycemia ≤250 mg/dl, pH ≥ 7.3, bicarbonate ≥ 15 mmol/L); the time required to reach stabilization was the outcome variable. RESULTS After enrolling 12 of the 32 planned subjects (6 in each group) Data Monitoring Committee performed a scheduled interim analysis, finding that the time required to reach stabilization was significantly shorter using the alternative system (9.8±1.16 hs vs. 13.3±2.8 hs; p=0.018). Because of the magnitude of this finding, the Ethics Committee decided to terminate the study.
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Low-dose vs standard-dose insulin in pediatric diabetic ketoacidosis: a randomized clinical trial.
Nallasamy, K, Jayashree, M, Singhi, S, Bansal, A
JAMA pediatrics. 2014;(11):999-1005
Abstract
IMPORTANCE The standard recommended dose (0.1 U/kg per hour) of insulin in diabetic ketoacidosis (DKA) guidelines is not backed by strong clinical evidence. Physiologic dose-effect studies have found that even lower doses could adequately normalize ketonemia and acidosis. Lowering the insulin dose may be advantageous in the initial hours of therapy when a gradual decrease in glucose, electrolytes, and resultant osmolality is desired. OBJECTIVE To compare the efficacy and safety of low-dose insulin against the standard dose in children with DKA. DESIGN, SETTING, AND PARTICIPANTS This was a prospective, open-label randomized clinical trial conducted in the pediatric emergency department and intensive care unit of a tertiary care teaching hospital in northern India from November 1, 2011, through December 31, 2012. A total of 50 consecutive children 12 years or younger with a diagnosis of DKA were randomized to low-dose (n = 25) and standard-dose (n = 25) groups. INTERVENTIONS Low-dose (0.05 U/kg per hour) vs standard-dose (0.1 U/kg per hour) insulin infusion. MAIN OUTCOMES AND MEASURES The primary outcome was the rate of decrease in blood glucose until a level of 250 mg/dL or less is reached (to convert to millimoles per liter, multiply by 0.0555). The secondary outcomes included time to resolution of acidosis, episodes of treatment failures, and incidences of hypokalemia and hypoglycemia. RESULTS The mean (SD) rate of blood glucose decrease until a level of 250 mg/dL or less is reached (45.1 [17.6] vs 52.2 [23.4] mg/dL/h) and the mean (SD) time taken to achieve this target (6.0 [3.3] vs 6.2 [2.2] hours) were similar in the low- and standard-dose groups, respectively. Mean (SD) length of time to achieve resolution of acidosis (low vs standard dose: 16.5 [7.2] vs 17.2 [7.7] hours; P = .73) and rate of resolution of acidosis were also similar in the groups. Hypokalemia was seen in 12 children (48%) receiving the standard dose vs 5 (20%) of those receiving the low dose (P = .07); the tendency was more pronounced in malnourished children (7 [88%] vs 2 [28%]). Five children (20%) and 1 child (4%) receiving standard- and low-dose infusion (P = .17), respectively, developed hypoglycemia. Treatment failure was rare and comparable. One child in the standard-dose group developed cerebral edema, and no deaths occurred during the study period. CONCLUSIONS AND RELEVANCE Low dose is noninferior to standard dose with respect to rate of blood glucose decrease and resolution of acidosis. We advocate a superiority trial with a larger sample size before 0.05 U/kg per hour replaces 0.1 U/kg per hour in the practice recommendations. TRIAL REGISTRATION ctri.nic.in Identifier: CTRI/2012/04/002548.
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Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?
Kitabchi, AE, Murphy, MB, Spencer, J, Matteri, R, Karas, J
Diabetes care. 2008;(11):2081-5
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Abstract
OBJECTIVE The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose. RESEARCH DESIGN AND METHODS This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit x kg(-1) x h(-1) i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit . kg body weight(-1) x h(-1) without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 x kg(-1) x h(-1) without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA. RESULTS The load group reached a peak in free insulin value (460 microU/ml) within 5 min and plateaued at 88 microU/ml in 60 min. The twice no load group reached a peak (200 microU/ml) at 45 min. The no load group reached a peak (60 microU/ml) in 60-120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose or=7.3, and HCO(3)(-) >or=15 mEq/l did not differ significantly among the three groups. CONCLUSIONS A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit x kg body weight(-1) x h(-1) (about 10 units/h in a 70-kg patient) is given.
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A morning dose of insulin glargine prevents nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion with insulin lispro.
Johansson, UB, Wredling, R, Adamson, U, Lins, PE
Diabetes & metabolism. 2007;(6):469-71
Abstract
AIM: The aim of this crossover trial was to evaluate the potential of partial substitution of basal insulin with glargine, administered once daily in the morning, to protect against nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion (CSII). METHODS Seven patients with type 1 diabetes received 4 weeks of treatment with insulin lispro, administered by CSII, and 4 weeks of treatment with CSII and a partial basal replacement dose of insulin glargine administered in the morning. On day 28 of each treatment phase, patients were admitted to the research unit where dinner was served and their usual dinner insulin bolus dose given, after which CSII was discontinued at 7 pm. Plasma (p) beta-hydroxybutyrate and p glucose were measured every hour for 12 h thereafter. RESULTS Plasma beta-hydroxybutyrate at 7 pm was 0.16+/-0.05 and 0.13+/-0.07 mmol/l with and without glargine, respectively, and increased to 0.17+/-0.10 and 0.60+/-0.3 mmol/l within 6 h (P=0.02). Plasma glucose increased without glargine, from 8.6+/-2.9 to 21.1+/-3.0 mmol/l (P=0.003), but did not rise significantly following glargine (13.6+/-4.7 vs. 12.6+/-5.6 mmol/l; P=0.65). CONCLUSIONS Partial replacement with a morning dose of insulin glargine protects against the development of ketosis for as much as 12 h after postprandial interruption of CSII. This treatment strategy could, therefore, be useful for patients who are prone to ketosis but, for other reasons, are deemed suitable for CSII.
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Subcutaneous lispro and intravenous regular insulin treatments are equally effective and safe for the treatment of mild and moderate diabetic ketoacidosis in adult patients.
Ersöz, HO, Ukinc, K, Köse, M, Erem, C, Gunduz, A, Hacihasanoglu, AB, Karti, SS
International journal of clinical practice. 2006;(4):429-33
Abstract
In this prospective, randomised, open trial, we wanted to evaluate the efficacy and safety of hourly subcutaneous (SC) insulin lispro administration in the treatment of diabetic ketoacidosis (DKA) in comparison with intravenous (IV) regular insulin treatment. Twenty patients were enrolled in the study. The patients were randomly assigned into two groups. Following a bolus injection of 0.15 U/kg IV regular insulin, group L received half of this dose as hourly SC insulin lispro while group R was treated conventionally with IV regular insulin infusion. At the end of treatment period, time that needed for normalisation of serum glucose, beta-hydroxybutyrate, blood pH and urine ketone levels were not different in groups L and R. There was no mortality or serious side effects in both groups. In this study, we revealed that treatment of mild and moderate DKA with SC insulin lispro is equally effective and safe in comparison with IV regular insulin.
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A prospective study of the "two-bag system'' in diabetic ketoacidosis management.
Poirier, MP, Greer, D, Satin-Smith, M
Clinical pediatrics. 2004;(9):809-13
Abstract
The "two-bag'' system, an adaptation of the euglycemic clamp technique, consists of simultaneous administration of 2 intravenous (IV) fluid bags of differing dextrose concentrations. Individualized therapy is dictated by adjustment of the infusion rate of each bag. We sought to assess the benefits of the two-bag system in the initial acute emergency department management of children in diabetic ketoacidosis (DKA). Thirty-three children presenting to an urban pediatric emergency department in DKA were randomized into 2 groups: patients managed with the two-bag system and patients managed with the traditional "one-bag'' system. Other aspects of the management were standardized. Outcome measures included rate of decline in serum glucose, rate of bicarbonate correction, time on IV insulin therapy, and response time for IV fluid changes. Study period was defined as time on IV insulin therapy. There were no differences between the 2 groups in demographic parameters, initial baseline metabolic parameters, or total time on IV insulin therapy. There were no differences between the groups in average rates of serum glucose decline: two-bag 33.1 mg/dL/hr (s.e. 5.57, 95% CI 22.2, 44), one-bag 30.2 mg/dL/hr (s.e. 5.72, 95% CI 19, 41.4); average rate of serum bicarbonate correction: two-bag 1.19 mEq/L/hr, one-bag 1.27 mEq/L/hr; or the average number of IV fluid bags used: two-bag 4.1 bags, one-bag 3.2 bags. However, there was a difference between the groups in regard to elapsed total time to make changes in the IV fluids: two-bag 1 minute, one-bag 42 minutes, (p < 0.001). The "two-bag'' system enables a faster response time in making IV fluid therapy changes. This efficiency makes this system ideal for use in the emergency department.
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Treatment of diabetic ketoacidosis with subcutaneous insulin aspart.
Umpierrez, GE, Cuervo, R, Karabell, A, Latif, K, Freire, AX, Kitabchi, AE
Diabetes care. 2004;(8):1873-8
Abstract
OBJECTIVE In this prospective, randomized, open trial, we compared the efficacy and safety of aspart insulin given subcutaneously at different time intervals to a standard low-dose intravenous (IV) infusion protocol of regular insulin in patients with uncomplicated diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS A total of 45 consecutive patients admitted with DKA were randomly assigned to receive subcutaneous (SC) aspart insulin every hour (SC-1h, n = 15) or every 2 h (SC-2h, n = 15) or to receive IV infusion of regular insulin (n = 15). Response to medical therapy was evaluated by assessing the duration of treatment until resolution of hyperglycemia and ketoacidosis. Additional end points included total length of hospitalization, amount of insulin administration until resolution of hyperglycemia and ketoacidosis, and number of hypoglycemic events. RESULTS Admission biochemical parameters in patients treated with SC-1h (glucose: 44 +/- 21 mmol/l [means +/- SD], bicarbonate: 7.1 +/- 3 mmol/l, pH: 7.14 +/- 0.09) were similar to those treated with SC-2h (glucose: 42 +/- 21 mmol/l, bicarbonate: 7.6 +/- 4 mmol/l, pH: 7.15 +/- 0.12) and IV regular insulin (glucose: 40 +/- 13 mmol/l, bicarbonate 7.1 +/- 4 mmol/l, pH: 7.11 +/- 0.17). There were no statistical differences in the mean duration of treatment until correction of hyperglycemia (6.9 +/- 4, 6.1 +/- 4, and 7.1 +/- 5 h) or until resolution of ketoacidosis (10 +/- 3, 10.7 +/- 3, and 11 +/- 3 h) among patients treated with SC-1h and SC-2h or with IV insulin, respectively (NS). There was no mortality and no differences in the length of hospital stay, total amount of insulin administration until resolution of hyperglycemia or ketoacidosis, or the number of hypoglycemic events among treatment groups. CONCLUSIONS Our results indicate that the use of subcutaneous insulin aspart every 1 or 2 h represents a safe and effective alternative to the use of intravenous regular insulin in the management of patients with uncomplicated DKA.