Subcutaneous rapid‐acting insulin analogues for diabetic ketoacidosis

Carlos A Andrade‐Castellanos; Luis Enrique Colunga‐Lozano; Netzahualpilli Delgado‐Figueroa; Daniel A Gonzalez‐Padilla

doi:10.1002/14651858.CD011281.pub2

Subkutane schnell wirkende Insulinanaloga gegen diabetische Ketoazidose

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Referencias

References to studies included in this review

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estudios excluidos
estudios a la espera de valoración
otras referencias

Della Manna T, Steinmetz L, Campos PR, Farhat SC, Schvartsman C, Kuperman H, et al. Subcutaneous use of a fast‐acting insulin analog: an alternative treatment for pediatric patients with diabetic ketoacidosis. Diabetes Care 2005;28(8):1856‐61.

Ersöz HO, Ukinc K, Köse M, Erem C, Gunduz A, Hacihasanoglu AB, et al. Subcutaneous lispro and intravenous regular insulin treatments are equally effective and safe for the treatment of mild and moderate diabetic ketoacidosis in adult patients. International Journal of Clinical Practice 2006;60(4):429‐33.

Karoli R, Fatima J, Salman T, Sandhu S, Shankar R. Managing diabetic ketoacidosis in non‐intensive care unit setting: Role of insulin analogs. Indian Journal of Pharmacology 2011;43(4):398‐401.

Umpierrez GE, Latif K, Stoever J, Cuervo R, Park L, Freire AX, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. American Journal of Medicine 2004;117(5):291‐6.

Umpierrez GE, Cuervo R, Karabell A, Latif K, Freire AX, Kitabchi AE. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care 2004;27(8):1873‐8.

References to studies excluded from this review

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estudios a la espera de valoración
otras referencias

Adesina OF, Kolawole BA, Ikem RT, Adebayo OJ, Soyoye DO. Comparison of lispro insulin and regular insulin in the management of hyperglycaemic emergencies. African Journal of Medicine and Medical Sciences 2011;40:59‐66.

Armor B, Harrison D, Lawler F. Assessment of the clinical outcome of a symptom‐based outpatient hyperglycemia protocol. Diabetes Therapy 2011;2:67‐80.

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NCT00467246. Sub‐cutaneous insulin in hyperglycaemic emergencies. https://www.clinicaltrials.gov/ct2/show/NCT00467246 (last accessed 4 December 2015).

NCT01365793. Randomized control trial of fluid therapy for pediatric diabetic ketoacidosis. https://www.clinicaltrials.gov/ct2/show/NCT01365793 (last accessed 4 December 2015).

NCT02006342. Effectiveness of subcutaneous glargine on the time to closure of the anion gap in patients presenting to the emergency department with diabetic keto‐acidosis (GT‐COG). https://www.clinicaltrials.gov/ct2/show/NCT02006342 (accessed 4 December 2015).

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Vincent M, Nobécourt E. Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies. Diabetes & Metabolism 2013;39(4):299‐305.

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References to studies awaiting assessment

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otras referencias

El Ebrashy I, El Hefnawy MHMF, Basyouni A, Mahfouz H. Subcutaneous use of rapid insulin analog: an alternative treatment for patients with mild to moderate diabetic ketoacidosis. Pediatric Diabetes 2010;11(Suppl 14):32 (O/6/FRI/01).

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NCT00920725. Subcutaneous aspart insulin to treat diabetic ketoacidosis (DKA) and beta‐hydroxybutyrate testing in DKA. https://www.clinicaltrials.gov/ct2/show/NCT00920725 (last accessed 4 December 20015).

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Howey DC, Bowsher RR, Brunelle RL, Rowe HM, Santa PF, Downing‐Shelton J, et al. [Lys(B28), Pro(B29)]‐human insulin: effect of injection time on postprandial glycemia. Clinical Pharmacology and Therapeutics 1995;58(4):459‐69.

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Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49(6):999‐1005.

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic and meta‐analyses of studies that evaluate interventions: explanation and elaboration. PLoS Medicine 2009;6(7):1‐28. [DOI: 10.1371/journal.pmed.1000100]

Luzi L, Barrett EJ, Groop LC, Ferrannini E, DeFronzo RA. Metabolic effects of low‐dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes 1988;37(11):1470‐7.

Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus younger adults. Journal of the American Geriatrics Society 1992;40(11):1100‐4.

Mathiesen ER, Kinsley B, Amiel SA, Heller S, McCance D, Duran S, et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 2007;30(4):771‐6.

Mazer M, Chen E. Is subcutaneous administration of rapid‐acting insulin as effective as intravenous insulin for treating diabetic ketoacidosis?. Annals of Emergency Medicine 2009;53(2):259‐63.

Meader N, King K, Llewellyn A, Norman G, Brown J, Rodgers M, et al. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation. Systematic Reviews 2014;3:82.

Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification. Diabetes Care 2004;27(7):1541‐6.

Nyenwe EA, Kitabchi AE. Evidence‐based management of hyperglycemic emergencies in diabetes mellitus. Diabetes Research and Clinical Practice 2011;94(3):340‐51.

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The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta‐analyses. BMJ 2011;342:d549.

Roach P. New insulin analogues and routes of delivery: pharmacodynamic and clinical considerations. Clinical Pharmacokinetics 2008;47(9):595‐610.

Savage MW, Dhatariya KK, Kilvert A, Rayman G, Rees JA, Courtney CH, et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabetic Medicine 2011;28(5):508‐15.

Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD003287]

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Warner DP, Mckinney PA, Law GR, Bodansky HJ. Mortality and diabetes from a population based study in Yorkshire. Archives of Disease in Childhood 1998;78:435‐8.

Alberti KM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine 1998;15:539‐53.

Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ 2008;336(7644):601‐5.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Della Manna 2005

Methods	Parallel randomised controlled trial Randomisation ratio: 1:1 Superiority design
Participants	Inclusion criteria: DKA, blood glucose > 300 mg/dL, pH < 7.3, and/or bicarbonate < 15 mmol/L, and > ++ ketonuria Exclusion criteria: surgery, use of glucocorticoid or immunosuppressive agents Diagnostic criteria: ADA criteria for DKA Causes of DKA (n) ‐ (subcutaneous insulin/intravenous insulin): Excessive food intake: 13/13 Infection: 8/4 Missed injection: 10/5 New onset diabetes: 6/5 Unidentified: 1/4
Interventions	Number of study centres: 1 Treatment before study: not stated Group 1: s.c. insulin lispro. 0.15 IU/kg every 2 h until blood glucose < 250 mg/dL, then every 4 h for the next 24 h (n = 30) Group 2: i.v. regular insulin. 0.1 IU/kg/h, continuous infusion until blood glucose < 250 mg/dL, and then 0.15 IU/kg subcutaneously every 4 h for 24 h (n = 30)
Outcomes	Composite outcome measures reported: no
Study details	Run‐in period: no Study terminated before regular end (for benefit/because of adverse events): no
Publication details	Language of publication: English Non‐commercial funding: Fundacao de Amparo à Pesquisa do Estado de Sao Paulo grant (FAPESP 00/09682‐7) Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "... to compare the efficacy of a subcutaneous fast‐acting analog (lispro) with continuous intravenous regular insulin (CIRI) in the treatment of pediatric DKA"
Notes	Study authors randomised episodes of DKA, not participants
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "Of the 60 DKA episodes, 30 were randomised to treatment with a subcutaneous fast‐acting insulin analog (lispro) and the other 30 were randomised to treatment with CIRI" Comment: no detailed information
Allocation concealment (selection bias)	Unclear risk	Comment: no detailed information
Blinding of participants and personnel (performance bias) Time to resolution of diabetic ketoacidosis	High risk	Comment: participants and personnel were probably unblinded
Blinding of participants and personnel (performance bias) All‐cause mortality	Low risk	Comment: study personnel/participants probably not blinded, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of participants and personnel (performance bias) Hypoglycaemic episodes	Unclear risk	Comment: study personnel/participants probably not blinded
Blinding of participants and personnel (performance bias) Morbidity	Low risk	Comment: study personnel/participants probably not blinded, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) Time to resolution of diabetic ketoacidosis	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) All‐cause mortality	Low risk	Comment: no detailed information, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) Morbidity	Low risk	Comment: no detailed information, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) Hypoglycaemic episodes	Unclear risk	Comment: no detailed information
Incomplete outcome data (attrition bias) Time to resolution of diabetic ketoacidosis	Low risk	Comment: reasons for dropouts explained
Incomplete outcome data (attrition bias) All‐cause mortality	Unclear risk	Comment: DKA occurrences randomised, not participants (unclear which participants had only 1 DKA)
Incomplete outcome data (attrition bias) Hypoglycaemic episodes	Unclear risk	Comment: DKA occurrences randomised, not participants (unclear which participants had only 1 DKA)
Incomplete outcome data (attrition bias) Morbidity	Unclear risk	Comment: DKA occurrences randomised, not participants (unclear which participants had only 1 DKA)
Selective reporting (reporting bias)	Unclear risk	Comment: possible outcome reporting bias for time to resolution of DKA (see Appendix 6)
Other bias	Low risk	Comment: none detected

Ersöz 2006

Methods	Parallel randomised controlled trial Randomisation ratio: 1:1 Superiority design
Participants	Inclusion criteria: DKA (mild or moderate only), serum blood glucose > 250 mg/dL, arterial pH < 7.3, bicarbonate < 15 mmol/L, beta‐hydroxybutyrate > 1.6 mmol/L, ketonuria Exclusion criteria: plasma glucose > 600 mg/dL, pH < 7.0, bicarbonate < 10 mmol/L, persistent hypotension, hypothermia, severe concomitant illness Diagnostic criteria: ADA criteria for DKA Causes of DKA: new onset diabetes (3 subcutaneous insulin lispro/2 intravenous regular insulin)
Interventions	Number of study centres: 1 Treatment before study: not stated
Outcomes	Composite outcome measures reported: no
Study details	Run‐in period: no Study terminated before regular end (for benefit/because of adverse events): no
Publication details	Language of publication: English Commercial funding/non‐commercial funding/other funding: no Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "... to evaluate the efficacy and safety of hourly SC insulin lispro administration in the treatment of DKA in comparison with standard IV regular insulin treatment"
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "The patients were randomly assigned into two groups" Comment: no detailed information
Allocation concealment (selection bias)	Unclear risk	Comment: no detailed information
Blinding of participants and personnel (performance bias) Time to resolution of diabetic ketoacidosis	High risk	Comment: participants and personnel were probably not blinded
Blinding of participants and personnel (performance bias) All‐cause mortality	Low risk	Comment: study personnel/participants probably not blinded, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of participants and personnel (performance bias) Hypoglycaemic episodes	Unclear risk	Comment: study personnel/participants probably not blinded, outcome measurement not defined
Blinding of outcome assessment (detection bias) Time to resolution of diabetic ketoacidosis	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) All‐cause mortality	Low risk	Comment: no detailed information, but outcome measurement unlikely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) Hypoglycaemic episodes	Low risk	Comment: no detailed information, but outcome measurement unlikely to be influenced by the lack of blinding
Incomplete outcome data (attrition bias) Time to resolution of diabetic ketoacidosis	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) All‐cause mortality	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Hypoglycaemic episodes	Low risk	Comment: all randomised participants completed the study
Selective reporting (reporting bias)	Unclear risk	Comment: possible outcome reporting bias for time to resolution of DKA (see Appendix 6)
Other bias	Low risk	Comment: none detected

Karoli 2011

Methods	Parallel randomised controlled trial Randomisation ratio: 1:1 Superiority design
Participants	Inclusion criteria: DKA (mild or moderate only, ADA criteria) Exclusion criteria: severe DKA and those requiring ICU admission, loss of consciousness, acute myocardial ischaemia, congestive heart failure, end‐stage renal disease, anasarca, pregnancy, serious comorbidities, persistent hypotension Diagnostic criteria: ADA criteria for DKA Causes of DKA (% regular intravenous insulin/subcutaneous insulin lispro) Infection: 56/52 Poor compliance: 32/40 New onset diabetes: 12/8
Interventions	Number of study centres: 1 Treatment before study: not stated Titration period: no
Outcomes	Composite outcome measures reported: no
Study details	Run‐in period: no Study terminated before regular end (for benefit/because of adverse events): no
Publication details	Language of publication: English Commercial funding/non‐commercial funding/other funding: none Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "... to compare the efficacy of insulin lispro subcutaneous 2 hourly in patients of mild to moderate DKA with standard intravenous regular insulin"
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "The study patients were randomised in emergency department following a computer generated randomisation table in two groups"
Allocation concealment (selection bias)	Unclear risk	Comment: no detailed information
Blinding of participants and personnel (performance bias) Time to resolution of diabetic ketoacidosis	High risk	Quote from publication: "In this prospective, randomised and open trial ..." Comment: participants and personnel were unblinded (open trial)
Blinding of participants and personnel (performance bias) All‐cause mortality	Low risk	Quote from publication: "In this prospective, randomised and open trial ..." Comment: participants and study personnel not blinded, but outcome measurement not likely to be influenced by the lack of blinding
Blinding of participants and personnel (performance bias) Hypoglycaemic episodes	Unclear risk	Quote from publication: "In this prospective, randomised and open trial ..." Comment: participants and personnel were unblinded (open trial)
Blinding of participants and personnel (performance bias) Morbidity	Unclear risk	Quote from publication: "In this prospective, randomised and open trial ..." Comment: participants and personnel were unblinded (open trial)
Blinding of participants and personnel (performance bias) Socioeconomic effects	Unclear risk	Quote from publication: "In this prospective, randomised and open trial ..." Comment: participants and personnel were unblinded (open trial)
Blinding of outcome assessment (detection bias) Time to resolution of diabetic ketoacidosis	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) All‐cause mortality	Low risk	Comment: no detailed information, outcome not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) Morbidity	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) Hypoglycaemic episodes	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) Socioeconomic effects	Unclear risk	Comment: no detailed information
Incomplete outcome data (attrition bias) Time to resolution of diabetic ketoacidosis	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) All‐cause mortality	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Hypoglycaemic episodes	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Morbidity	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Socioeconomic effects	Low risk	Comment: all randomised participants completed the study
Selective reporting (reporting bias)	Low risk	Comment: none detected
Other bias	Low risk	Comment: none detected

Umpierrez 2004b

Methods	Parallel randomised controlled trial Randomisation ratio: 1:1:1 Superiority design
Participants	Inclusion criteria: "Uncomplicated DKA" defined by a plasma glucose level > 250 mg/dL, serum bicarbonate level < 15 mEq/L, venous pH < 7.3, serum ketone level at a dilution of greater than or equal to 1:4 by nitroprusside reaction, or serum beta‐hydroxybutyrate level > 3.0 mmol/L Exclusion criteria: persistent hypotension after the administration of 1 liter of normal saline (systolic blood pressure < 80 mmHg), acute myocardial ischaemia, end‐stage renal or hepatic failure, anasarca, dementia, or pregnancy Diagnostic criteria: ADA criteria for DKA Causes of DKA (%): poor compliance: 53 (s.c. insulin aspart, every hour)/60 (s.c. insulin aspart, every 2 hours)/60 (i.v. regular insulin); new onset diabetes: 20 (s.c. insulin aspart, every hour)/20 (s.c. insulin aspart, every 2 hours)/13 (i.v. regular insulin)
Interventions	Number of study centres: 1 Treatment before study: not stated Titration period: no
Outcomes	Composite outcome measures reported: no
Study details	Run‐in period: no Study terminated before regular end (for benefit/because of adverse events): no
Publication details	Language of publication: English Commercial funding: unrestricted grant from Novo Nordisk; non‐commercial funding: United States Public Health Services/National Institutes of Health grant (RR00211; General Clinical Research Center) Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "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)"
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "Patients were randomly assigned in the emergency department to receive SC aspart insulin every hour (SC‐1h, n15) or every 2 h (SC‐2h, n15), or to receive IV regular insulin (n15)" Comment: insufficient information about the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: no detailed information
Blinding of participants and personnel (performance bias) Time to resolution of diabetic ketoacidosis	High risk	Quote from publication: "In this prospective, randomised, open trial ..." Comment: participants and personnel were unblinded
Blinding of participants and personnel (performance bias) All‐cause mortality	Low risk	Quote from publication: "In this prospective, randomised, open trial ..." Comment: outcome measurement not likely to be influenced by the lack of blinding
Blinding of participants and personnel (performance bias) Hypoglycaemic episodes	Unclear risk	Quote from publication: "In this prospective, randomised, open trial ..." Comment: unclear whether outcome was influenced by lack of blinding
Blinding of participants and personnel (performance bias) Socioeconomic effects	Unclear risk	Quote from publication: "In this prospective, randomised, open trial ..." Comment: unclear whether outcome was influenced by lack of blinding
Blinding of outcome assessment (detection bias) Time to resolution of diabetic ketoacidosis	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) All‐cause mortality	Low risk	Comment: outcome measurement not likely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) Hypoglycaemic episodes	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) Socioeconomic effects	Unclear risk	Comment: no detailed information
Incomplete outcome data (attrition bias) Time to resolution of diabetic ketoacidosis	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) All‐cause mortality	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Hypoglycaemic episodes	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Socioeconomic effects	Unclear risk	Comment: all randomised participants completed the study
Selective reporting (reporting bias)	Low risk	Comment: none detected
Other bias	Unclear risk	Comment: possible sponsor bias (unrestrictive grant from Novo Nordisk)

Umpierrez 2004a

Methods	Parallel randomised controlled trial Randomisation ratio: 1:1 Superiority design
Participants	Inclusion criteria: plasma glucose level > 250 mg/dL, serum bicarbonate level < 15 mEq/L, venous pH < 7.3, serum ketone level, beta‐hydroxybutyrate > 3 mmol/L Exclusion criteria: persistent hypotension after the administration of 1 liter of normal saline (systolic blood pressure < 80 mmHg), acute myocardial ischaemia, heart failure, end‐stage renal disease, anasarca, dementia, or pregnancy Diagnostic criteria: ADA criteria for DKA Causes of DKA (%): poor compliance: 60 (subcutaneous insulin lispro)/70 (intravenous regular insulin)
Interventions	Number of study centres: 1 Treatment before study: not stated Titration period: no
Outcomes	Composite outcome measures reported: no
Study details	Run‐in period: no Study terminated before regular end (for benefit/because of adverse events): no
Publication details	Language of publication: English Commercial funding: unrestricted grant from Eli Lilly; non‐commercial funding: United States Public Health Services grant (RR00211) Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "To compare the efficacy and safety of subcutaneous insulin lispro with that of low‐dose continuous intravenous regular insulin in the treatment of patients with uncomplicated diabetic ketoacidosis"
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "Patients were assigned in the emergency department to receive subcutaneous insulin lispro or intravenous regular insulin following a computer‐generated randomisation table"
Allocation concealment (selection bias)	Unclear risk	Comment: no detailed information
Blinding of participants and personnel (performance bias) Time to resolution of diabetic ketoacidosis	High risk	Quote from publication: "open trial" Comment: participants and personnel were unblinded (open trial)
Blinding of participants and personnel (performance bias) All‐cause mortality	Low risk	Comment: study personnel not blinded, but outcome measurement not likely to be influenced by the lack of blinding of outcome assessment
Blinding of participants and personnel (performance bias) Hypoglycaemic episodes	Unclear risk	Comment: unclear whether outcome was influenced by lack of blinding
Blinding of participants and personnel (performance bias) Socioeconomic effects	Unclear risk	Quote from publication: "open trial" Comment: participants and personnel were unblinded (open trial)
Blinding of outcome assessment (detection bias) Time to resolution of diabetic ketoacidosis	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) All‐cause mortality	Low risk	Comment: no information on blinding of outcome assessment, but outcome measurement not likely to be influenced
Blinding of outcome assessment (detection bias) Hypoglycaemic episodes	Unclear risk	Comment: no detailed information
Blinding of outcome assessment (detection bias) Socioeconomic effects	Unclear risk	Comment: no detailed information
Incomplete outcome data (attrition bias) Time to resolution of diabetic ketoacidosis	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) All‐cause mortality	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Hypoglycaemic episodes	Low risk	Comment: all randomised participants completed the study
Incomplete outcome data (attrition bias) Socioeconomic effects	Low risk	Comment: all randomised participants completed the study
Selective reporting (reporting bias)	Low risk	Comment: none detected
Other bias	Unclear risk	Comment: possible sponsor bias (unrestrictive grant from Eli Lilly)

Note: where the judgement is 'unclear risk' and the description is blank, the trial did not report that particular outcome

ADA: American Diabetes Association; DKA: diabetic ketoacidosis; ICU: intensive care unit; i.v.: intravenous; s.c.: subcutaneous

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios a la espera de clasificación

Study	Reason for exclusion
Adesina 2011	Intervention not relevant (insulin therapy was by the intramuscular route)
Armor 2011	Not an RCT (case series)
Attia 1998	Not aimed at treating DKA (well‐controlled insulin‐dependent diabetes mellitus)
Fisher 1977	Intervention not relevant (regular insulin by various routes)
Hsia 2011	Intervention not relevant (s.c. administration of long‐acting insulins)
Kadowaki 2010	Not aimed at treating DKA
Liu 2006	Intervention not relevant (s.c. and i.v. infusion of regular insulin)
NCT00467246	Intervention not relevant (insulin levemir)
NCT01365793	Intervention not relevant (fluid therapy)
NCT02006342	Intervention not relevant (s.c. insulin glargine)
Philotheou 2011	Not aimed at treating DKA
Savoldelli 2010	Not an RCT (review article)
Umpierrez 2009	Intervention not relevant (i.v. regular or i.v. glulisine insulin)
Vincent 2013	Not an RCT (review article)
Weinzimer 2008	Not aimed at treating DKA
Yanai 2011	Not an RCT (case report)

DKA: diabetic ketoacidosis; i.v.: intravenous; RCT: randomised controlled trial: s.c.: subcutaneous

Characteristics of studies awaiting assessment [ordered by study ID]

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estudios incluidos
estudios excluidos

El Ebrashy 2010

Methods	Randomised controlled trial
Participants	80 people with DKA
Interventions	Group 1: regular insulin infusion (n = 20) Group 2: s.c. rapid‐acting insulin analogue aspart every 2 hours (n = 20) Group 3: s.c. rapid‐acting insulin analogue aspart every hour (n = 20) Group 4: rapid‐acting insulin analogue by subcutaneous insulin pump (n = 20)
Outcomes	Time to resolution of DKA
Study details	Intervention model: factorial design Masking: not stated Primary purpose: treatment
Publication details	Conference abstract
Stated aim of study	To look for technical simplification and economic efficiency in the treatment of DKA with s.c. use of rapid‐acting insulin analogue and to compare its use with regular i.v. insulin treatment
Notes	No outcome data reported in abstract (authors contacted by email; no reply received)

NCT00920725

Methods	Randomised controlled trial
Participants	Adults with DKA
Interventions	Group 1: s.c. insulin aspart every 2 hours Group 2: i.v. regular insulin Group 3: i.v. insulin aspart (NovoLog)
Outcomes	Hours to resolution of ketoacidosis as defined as beta‐hydroxybutyrate < 0.6 Hours to achieve blood glucose less than 200 mg/dL
Study details	Intervention model: parallel assignment Masking: open label Primary purpose: treatment
Publication details	Study start date: January 2005 Study completion date: December 2007 Primary completion date: July 2007 (final data collection date for primary outcome measure) Study not yet published (authors contacted by email; no reply received yet)
Stated aim of study	To determine whether insulin administered by a subcutaneous injection is effective in the treatment of a diabetic crisis and to determine whether it is useful to monitor beta‐hydroxybutyrate during treatment of a diabetic crisis
Notes	Responsible party: David Baldwin, MD. Rush University Medical Center Chicago, Illinois, United States, 60612 Registered in ClinicalTrials.gov. Study completed, no results published

DKA: diabetic ketoacidosis; i.v.: intravenous; s.c.: subcutaneous

Data and analyses

Open in table viewer

Comparison 1. Insulin lispro versus regular insulin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to resolution of diabetic ketoacidosis Show forest plot	2	90	Std. Mean Difference (IV, Random, 95% CI)	0.13 [‐0.64, 0.90]
Open in figure viewer Analysis 1.1 Comparison 1 Insulin lispro versus regular insulin, Outcome 1 Time to resolution of diabetic ketoacidosis.
2 All‐cause mortality Show forest plot	4	156	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
Open in figure viewer Analysis 1.2 Comparison 1 Insulin lispro versus regular insulin, Outcome 2 All‐cause mortality.
3 Hypoglycaemic episodes Show forest plot	4	156	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.23, 1.52]
Open in figure viewer Analysis 1.3 Comparison 1 Insulin lispro versus regular insulin, Outcome 3 Hypoglycaemic episodes.
3.1 Adults	3	110	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.11, 3.94]
3.2 Children	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.18, 1.72]
4 Length of hospital stay Show forest plot	2	90	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.97, 0.22]
Open in figure viewer Analysis 1.4 Comparison 1 Insulin lispro versus regular insulin, Outcome 4 Length of hospital stay.

Open in table viewer

Comparison 2. Insulin aspart versus regular insulin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to resolution of diabetic ketoacidosis Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.1 Comparison 2 Insulin aspart versus regular insulin, Outcome 1 Time to resolution of diabetic ketoacidosis.
2 All‐cause mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.2 Comparison 2 Insulin aspart versus regular insulin, Outcome 2 All‐cause mortality.
3 Hypoglycaemic episodes Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.3 Comparison 2 Insulin aspart versus regular insulin, Outcome 3 Hypoglycaemic episodes.
4 Length of hospital stay Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.4 Comparison 2 Insulin aspart versus regular insulin, Outcome 4 Length of hospital stay.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials (blank cells indicate that the particular outcome was not measured in some trials).

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial (blank cells indicate that the trial did not measure that particular outcome).

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Analysis 1.1

Comparison 1 Insulin lispro versus regular insulin, Outcome 1 Time to resolution of diabetic ketoacidosis.

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Analysis 1.2

Comparison 1 Insulin lispro versus regular insulin, Outcome 2 All‐cause mortality.

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Analysis 1.3

Comparison 1 Insulin lispro versus regular insulin, Outcome 3 Hypoglycaemic episodes.

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Analysis 1.4

Comparison 1 Insulin lispro versus regular insulin, Outcome 4 Length of hospital stay.

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Analysis 2.1

Comparison 2 Insulin aspart versus regular insulin, Outcome 1 Time to resolution of diabetic ketoacidosis.

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Analysis 2.2

Comparison 2 Insulin aspart versus regular insulin, Outcome 2 All‐cause mortality.

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Analysis 2.3

Comparison 2 Insulin aspart versus regular insulin, Outcome 3 Hypoglycaemic episodes.

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Analysis 2.4

Comparison 2 Insulin aspart versus regular insulin, Outcome 4 Length of hospital stay.

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Summary of findings for the main comparison. Subcutaneous insulin lispro versus intravenous regular insulin for diabetic ketoacidosis

Subcutaneous insulin lispro versus intravenous regular insulin for diabetic ketoacidosis
Patient: participants with diabetic ketoacidosis Settings: emergency department and critical care unit Intervention: subcutaneous insulin lispro versus intravenous regular insulin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous regular insulin	Subcutaneous insulin lispro
All‐cause mortality (N) Mean hospital stay: 2‐7 days	See comment	See comment	Not estimable	156 (4)	⊕⊕⊕⊝ moderate^a	No deaths reported
Hypoglycaemic episodes (N) Mean hospital stay: 2‐7 days	118 per 1000	70 per 1000 (27 to 180)	RR 0.59 (0.23 to 1.52)	156 (4)	⊕⊕⊝⊝ low^b	Comparable risk ratios for adults (4 trials) and children (1 trial)
Morbidity (N) Mean hospital stay: 2‐7 days	See comment	See comment	Not estimable	96 (2)	See comment	No cases of cerebral oedema, venous thrombosis, adult respiratory distress syndrome, hyperchloraemic acidosis
Adverse events other than hypoglycaemic episodes	See comment	See comment	Not estimable	See comment	See comment	Not investigated
Time to resolution of diabetic ketoacidosis (h) Mean hospital stay: 2‐4 days	The mean time to resolution of diabetic ketoacidosis across the intravenous regular insulin groups was 11 h	The mean time to resolution of diabetic ketoacidosis in the subcutaneous insulin lispro groups was 0.2 h higher (1.7 h lower to 2.1 h higher)	‐	90 (2)	⊕⊝⊝⊝ very low^c	Metabolic acidosis and ketosis took longer to resolve in the subcutaneous insulin lispro group in 1 trial (60 children); no exact data published
Patient satisfaction	See comment	See comment	Not estimable	See comment	See comment	Not investigated
Socioeconomic effects: length of hospital stay (days) Mean hospital stay: 4‐7 days	The mean length of hospital stay in the intravenous regular insulin groups ranged between 4 and 6.6 days	The mean length of hospital stay in the subcutaneous insulin lispro groups was 0.4 days shorter (1 day shorter to 0.2 days longer)	‐	90 (2)	⊕⊕⊝⊝ low^d	US setting: treatment of diabetic ketoacidosis in a non–intensive care setting (step‐down unit or general medicine ward) was associated with a 39% lower hospitalisation charge than was treatment with intravenous regular insulin in the intensive care unit (USD 8801 (SD USD 5549) vs USD 14,429 (SD USD 5243); the average hospitalisation charges per day were USD 3981 (SD USD 1067) for participants treated in an intensive care unit compared with USD 2682 (SD USD 636) for those treated in a non–intensive care setting
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; h: hours; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
*Assumed risk was derived from the event rates in the comparator groups. ^aDowngraded by one level because of imprecision (see Appendix 12). ^bDowngraded by two levels because of risk of performance bias and serious imprecision (see Appendix 12). ^cDowngraded by three levels because of risk of performance bias, serious risk of inconsistency, and serious risk of imprecision (see Appendix 12). ^dDowngraded by two levels because of serious risk of imprecision (see Appendix 12).

Summary of findings for the main comparison. Subcutaneous insulin lispro versus intravenous regular insulin for diabetic ketoacidosis

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Summary of findings 2. Subcutaneous insulin aspart versus intravenous regular insulin for diabetic ketoacidosis

Subcutaneous insulin aspart versus intravenous regular insulin for diabetic ketoacidosis
Patient: participants with diabetic ketoacidosis Settings: general medicine ward and intensive care unit Intervention: subcutaneous insulin aspart versus intravenous regular insulin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous regular insulin	Subcutaneous insulin aspart
All‐cause mortality (N) Mean hospital stay: 3‐5 days	See comment	See comment	Not estimable	45 (1)	⊕⊕⊝⊝ low^a	No deaths reported
Hypoglycaemic episodes (N) Mean hospital stay: 3‐5 days	67 per 1000	67 per 1000 (5 to 970)	RR 1.00 (0.07 to 14.55)	30 (1)	⊕⊕⊝⊝ low^b	‐
Morbidity	See comment	See comment	Not estimable	See comment	See comment	Not investigated
Adverse events other than hypoglycaemic episodes	See comment	See comment	Not estimable	See comment	See comment	Not investigated
Time to resolution of diabetic ketoacidosis (h) Mean hospital stay: 3‐5 days	The mean time to resolution of diabetic ketoacidosis across the intravenous regular insulin groups was 11 h	The mean time to resolution of diabetic ketoacidosis in the subcutaneous insulin aspart group was 1 h lower (3.2 h lower to 1.2 h higher)	‐	30 (1)	⊕⊝⊝⊝ very low^c	‐
Patient satisfaction	See comment	See comment	Not estimable	See comment	See comment	Not investigated
Socioeconomic effects: length of hospital stay (days) Mean hospital stay: 3‐5 days	The mean length of hospital stay in the intravenous regular insulin group was 4.5 days	The mean length of hospital stay in the subcutaneous insulin aspart group was 1.1 days shorter (3.3 days shorter to 1.1 days longer)	‐	30 (1)	⊕⊕⊝⊝ low^d	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; h: hours; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
*Assumed risk was derived from the event rates in the comparator groups ^aDowngraded by two levels because of serious imprecision (see Appendix 12) ^bDowngraded by two levels because of risk of performance bias and imprecision (see Appendix 12) ^cDowngraded by three levels because of risk of performance bias and serious risk of imprecision (see Appendix 12) ^dDowngraded by two levels because of serious risk of imprecision (see Appendix 12)

Summary of findings 2. Subcutaneous insulin aspart versus intravenous regular insulin for diabetic ketoacidosis

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Table 1. Overview of study populations

	Intervention(s) and comparator(s)	Sample size^a	Screened/eligible [N]	Randomised [N]	Analysed [N]	Finishing trial [N]	Randomised finishing trial [%]	Follow‐up time^b
Umpierrez 2004a	I: s.c. insulin lispro	Arbitrary estimation of a difference between groups of ≥ 5 hours to determine ketoacidosis as being clinically important; a sample size of 20 participants was needed in each group to provide a power of 0.93, given an alpha level of 0.05, a SD of 4, and a 1:1 inclusion ratio	‐	20	20	20	100	Mean hospital stay: 4 days
	C: i.v. regular insulin		‐	20	20	20	100
	total:			40	40	40	100
Umpierrez 2004b	I1: s.c. insulin aspart, every hour	Arbitrary estimation of a difference between groups of ≥ 4 hours to determine ketoacidosis as being clinically significant. A sample size of 15 participants was needed in each group to provide a power of 0.81, given an alpha error of 0.05 and a SD of 3	‐	15	15	15	100	Mean hospital stay: 3.4 days
	I2: s.c. insulin aspart, every 2 h			15	15	15	100	Mean hospital stay: 3.9 days
	C: i.v. regular insulin			15	15	15	100	Mean hospital stay: 4.5 days
	total:			45	45	45	100
Della Manna 2005	I: s.c. insulin lispro	‐	‐	25	25	25	100	Mean hospital stay: 2‐3 days
	C: i.v. regular insulin	‐	‐	21	21	21	100
	total:			46	46	46	100
Ersöz 2006	I: s.c. insulin lispro	‐	‐	10	10	10	100	‐
	C: i.v. regular insulin	‐	‐	10	10	10	100
		total:		20	20	20	100
Karoli 2011	I: s.c. insulin lispro	‐	‐	25	25	25	100	Mean hospital stay: 6 days
	C: i.v. regular insulin	‐	‐	25	25	25	100	Mean hospital stay: 6.6 days
			total:	50	50	50	100
*Grand total*	*All interventions*			*110*		*110*
	*All comparators*			91		91
	*All interventions and comparators*			*201*		*201*
^aAccording to power calculation in study publication or report ^bDuration of intervention and/or follow‐up under randomised conditions until end of study ‐ denotes not reported C: comparator; I: intervention; i.v.: intravenous; s.c.: subcutaneous; SD: standard deviation

Table 1. Overview of study populations

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Comparison 1. Insulin lispro versus regular insulin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to resolution of diabetic ketoacidosis Show forest plot	2	90	Std. Mean Difference (IV, Random, 95% CI)	0.13 [‐0.64, 0.90]

2 All‐cause mortality Show forest plot	4	156	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

3 Hypoglycaemic episodes Show forest plot	4	156	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.23, 1.52]

3.1 Adults	3	110	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.11, 3.94]
3.2 Children	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.18, 1.72]
4 Length of hospital stay Show forest plot	2	90	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.97, 0.22]

Comparison 1. Insulin lispro versus regular insulin

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Comparison 2. Insulin aspart versus regular insulin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to resolution of diabetic ketoacidosis Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2 All‐cause mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Hypoglycaemic episodes Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Length of hospital stay Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Insulin aspart versus regular insulin

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Referencias

References to studies included in this review

Della Manna 2005 {published data only}

Ersöz 2006 {published data only}

Karoli 2011 {published data only}

Umpierrez 2004a {published data only}

Umpierrez 2004b {published data only}

References to studies excluded from this review

Adesina 2011 {published data only}

Armor 2011 {published data only}

Attia 1998 {published data only}

Fisher 1977 {published data only}

Hsia 2011 {published data only}

Kadowaki 2010 {published data only}

Liu 2006 {published data only}

NCT00467246 {unpublished data only}

NCT01365793 {unpublished data only}

NCT02006342 {unpublished data only}

Philotheou 2011 {published data only}

Savoldelli 2010 {published data only}

Umpierrez 2009 {published data only}

Vincent 2013 {published data only}

Weinzimer 2008 {published data only}

Yanai 2011 {published data only}

References to studies awaiting assessment

El Ebrashy 2010 {published and unpublished data}

NCT00920725 {unpublished data only}

Additional references

ADA 1999

ADA 2004

ADA 2008

Alberti 1973

Anderson 2004

Basu 1993

Beller 2013

Dave 2004

Faich 1983

Hemkens 2009

Higgins 2002

Higgins 2003

Higgins 2009

Higgins 2011a

Higgins 2011b

Home 2000

Home 2012

Howey 1995

Hróbjartsson 2013

Johnson 1980

Kim 2007

Kirkham 2010

Kitabchi 2001

Kitabchi 2009

Kurtzhals 2000

Liberati 2009

Luzi 1988

Malone 1992

Mathiesen 2007

Mazer 2009

Meader 2014

Muir 2004

Nyenwe 2011

Rayman 2007

RevMan 2014 [Computer program]

Riley 2011

Roach 2008

Savage 2011

Siebenhofer 2006

Sterne 2011

Warner 1998

WHO 1998

Wood 2008

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Data and analyses

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