Biochemical Testing and Thresholds for Diagnosing Diabetic Ketoacidosis in Children and Adolescents without Known Diabetes Mellitus: Systematic Review and Meta-Analysis

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication of Type 1 Diabetes Mellitus (T1DM). Although international guidelines propose biochemical criteria for diagnosis, inconsistencies in threshold values and their application in clinical practice persist, particularly for children with previously undiagnosed T1DM. We conducted this systematic review to evaluate what plasma glucose levels and other biochemical tests are indicative of DKA in children and adolescents presenting without known T1DM.

Methods: We conducted a systematic review in accordance with PRISMA guidelines (PROSPERO ID: CRD42024621961) and searched PubMed, CINAHL, Cochrane, and Scopus for studies reporting biochemical diagnostic criteria of DKA in children aged 0-19 years. The quality of included studies was assessed using the National Institutes of Health’s Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A proportional meta-analysis was conducted on Stata 17 to estimate the pooled incidence.

Results: We included 97 studies involving 159,585 participants. Most studies (n = 71, 73%) originated from high-income settings. No study directly compared different biochemical thresholds for diagnosing DKA. Across 77 studies, 12 distinct criteria were identified that used a combination of blood glucose, venous pH, bicarbonate, ketonemia, and ketonuria, while the remaining 20 studies used author-defined criteria. The International Society for Pediatric and Adolescent Diabetes (ISPAD) guideline was the most frequently reported, with a pooled DKA incidence of 39% (95% CI = 35%,44%, certainty of evidence: low). Heterogeneity across studies, as measured by different diagnostic criteria, was high (I² > 80%). Subgroup analysis showed a higher incidence of DKA (56%, 95% CI = 50%, 62%) in children aged 0-9 years.

Conclusion: This systematic review highlights significant global variation in the biochemical definitions used to diagnose and classify DKA in children and adolescents. Standardization of diagnostic criteria is essential to improve early detection and reduce DKA-related morbidity and mortality.

In 2024, an estimated 1.81 million individuals younger than 20 years were living with Type 1 Diabetes Mellitus (T1DM) worldwide [1]. A common, acute, and life-threatening condition that occurs mostly in people with T1DM is diabetic ketoacidosis. It is characterized by hyperglycemia leading to osmotic diuresis that results in dehydration, metabolic acidosis, and excessive ketone production. While mortality from DKA in high-income countries remains below 1%, it is significantly higher in Low- and Middle-Income Countries (LMICs), ranging from 3% to 13% [2-4]. Most new-onset type 1 diabetes patients present with DKA, with the frequency of DKA in this population ranging from 13% to 80% [5]. Accurate and timely diagnosis is therefore the cornerstone for preventing the morbidity and mortality associated with DKA. Yet, diagnosing DKA at first presentation can be challenging, especially in children with no known history of diabetes, where early symptoms can be non-specific and easily mistaken for other common pediatric illnesses.

The biochemical criteria for diagnosing DKA typically include evaluating venous pH, serum bicarbonate levels, hyperglycemia, ketonemia, and ketonuria [6]. Multiple biochemical parameters for DKA diagnosis are crucial, as various other acute medical conditions can present with overlapping symptoms and laboratory findings, potentially mimicking DKA [7]. For instance, sepsis, particularly in children, can lead to metabolic acidosis, dehydration, and altered mental status, making clinical differentiation challenging. Therefore, a comprehensive assessment of venous pH, serum bicarbonate, glucose, and ketone levels is essential to establish the diagnosis of DKA for timely therapeutic interventions accurately and to differentiate it from similar conditions.

While there is general agreement on defining acidosis in DKA (with acidosis characterized by a pH < 7.30 and accompanying changes in bicarbonate levels), specific cut-off values for other biochemical measurements used to diagnose DKA are not universally standardized [8]. Although the International Society for Pediatric and Adolescent Diabetes (ISPAD) criteria [9] for DKA is the most recent internationally accepted publication and is in line with the standards set in evidence-based reviews such as the National Institute for Clinical Excellence (NICE) guidelines [9] practices still vary across different centers. This variation is due, in part, to the absence of globally enforced, uniform criteria for DKA diagnosis. This warrants a systematic review of the literature to evaluate which threshold values and combination biochemical tests are indicative of DKA for children and adolescents presenting with symptoms of DKA but without known diabetes.

The methods used in this systematic review followed the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42024621961).

The review included prospective or retrospective cohort, case-control, and cross-sectional studies that recorded the biochemical diagnostic features of patients with DKA, with a sample size of 10 or more patients. We included studies that used clinical definitions to diagnose DKA, provided by ISPAD, American Diabetes Association (ADA), or author-defined criteria. The population defined for this review consisted of children and adolescents between the ages of 0 and 19 years with no previous history of diagnosed DKA at any point during their clinical evaluation.

The review excluded case series, case reports, opinions, editorials, conference abstracts, reviews, and systematic reviews. We excluded studies with mixed diabetes patient data with another group of patients and those evaluating signs and symptoms with conditions similar in diagnosis to DKA, such as COVID-19, chronic renal failure, thalassemia, cystic fibrosis, acute kidney injury, and hyperosmolar hyperglycemic state. We also excluded studies that included participants having syndromic diabetes, neonatal diabetes, and corticosteroid-induced diabetes, maturity-onset diabetes of the young, and gestational diabetes. The detailed eligibility criteria for this review are outlined in Box 1.

Inclusion criteria

• Low-, middle-, or high-income country.
• Children and adolescents aged 0 months to 19 years presenting with symptoms and signs suggestive of DKA and previously undiagnosed T1DM.
• Types of interventions: studies with index test as a possible criteria or likely combination that inform the decision, including glycaemic level, venous pH, bicarbonate level, ketonuria and ketonaemia.
• Comparison group: Criteria for DKA diagnosis (consensus from NICE/ISPAD guidelines)
• Blood glucose > 11 mmol/L [≈200 mg/dl]).
• Venous pH < 7.3 or serum bicarbonate < 18 mmol/L, and
• Confirmed ketosis (based on blood or urine testing).

Exclusion criteria

• Studies with mixed diabetes patient data with another group of patients, and those including only highly selected groups, such as neonates or children being treated with high-dose corticosteroids or receiving chemotherapy.
• Studies evaluating signs and symptoms with conditions similar in diagnosis to DKA, such as COVID-19, chronic renal failure, thalassemia, cystic fibrosis, acute kidney injury, and hyperosmolar hyperglycemic state.
• Studies that included participants having syndromic diabetes, neonatal diabetes, corticosteroid-induced diabetes, maturity-onset diabetes of the young, and gestational diabetes.
• Study designs: case reports, case series, cohort studies, opinions, editorials, commentaries, letters, conference abstracts, reviews or systematic reviews, and studies with external comparison groups (i.e. historical cohort etc.). Box 1.  Inclusion and exclusion criteria

The following outcomes are included in our review:

1. Incidence of DKA
2. Incidence of DKA according to the severity of DKA
3. Prognostic outcomes in new-onset DKA cases: Length of hospital or ICU stay, or hospitalization rates in patients diagnosed with DKA.

Search strategy

We conducted a systematic search across four databases: PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, and Scopus. The search strategy had both free text and Medical Subject Headings terms related to DKA (e.g., ketoacidosis, diabetic acidosis), biochemical criteria (e.g., blood glucose, bicarbonate, venous pH) and paediatric populations (e.g., child* and adolescent*) (Appendix 1). We limited the search to English-language articles and included all eligible studies published up to September 2024. The bibliographies of all included studies and existing systematic reviews were hand-searched.

Study selection

After deleting duplicates, all retrieved articles were imported into Covidence, where two reviewers independently screened each title and abstract. All studies meeting the eligibility criteria were considered for full-text screening, and any conflicts were resolved by a third reviewer. A similar process was followed for the full-text screening. The reasons for excluding studies at the full-text screening stage were recorded. The PRISMA flow chart was used to report on the selection of the studies.

Data extraction and management

Two investigators independently extracted the data into a pre-piloted extraction form developed on Covidence, and a senior investigator cross-checked this. The extracted variables included the study information (study design, country of study, income status of the country according to the new World Bank country classifications, study period, sample size), DKA diagnostic criteria and their cut-off values, DKA severity criteria, incidence of DKA, age-wise incidence of DKA, and incidence of mild, moderate, and severe DKA, and prognostic outcomes (pediatric intensive care unit, or hospital length of stay). We adopted the normal laboratory reference ranges reported in each individual study as the standard for that respective study. Two reviewers assessed each paper independently and resolved any disagreements via discussion with a third reviewer.

Quality assessment

We appraised the risk of bias through the National Institutes of Health Quality Assessment Tool, using the 14-point Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [11]. The tool evaluates the integrity of the following characteristics: research question, study population, recruitment of groups and uniform eligibility criteria, sample size justification, assessment of exposure, time frame, varying levels of the exposure of interest, exposure measures and assessment, repeated exposure assessment, outcome measures, blinding, follow-up rate, and statistical analyses. Each study was assessed independently twice to ensure reliability and thoroughness. Any differences in the assessments were resolved through discussion, with input from a third reviewer when necessary to achieve consensus.

Statistical analysis

A random effects meta-analysis of proportions was performed to estimate the pooled incidence of DKA. Dichotomous data reported as percentages were included in the proportional meta-analysis. The Wilson-Score method was used to calculate accurate confidence intervals (CIs) for proportions. The Freeman-Tukey transformation was used to calculate the weighted pooled incidence estimate with a 95% CI. The pooled incidence of DKA was estimated based on the criteria used for diagnosing DKA and its severity.

If incidence estimates and 95% CI were not reported but enough data were available, estimates for the incidence proportion were calculated. We converted any data reported as medians, Interquartile Ranges (IQRs), or CIs to means and Standard Deviations (SDs) using Hozo’s method [12]. Between-study heterogeneity was assessed using the I2 statistic. Stratified analyses were carried out based on patient population (hospital- or community-based), and age groups (1-09 years and 10-19 years). p < 0.05 (2-sided) was considered statistically significant. All analyses was conducted using Stata (Stata Corp) version 17 [13].

Forest plots were created for all the outcomes. The results of trials that provided data unsuitable for inclusion in pooled analyses were described in the textual content of this review.

Assessment of heterogeneity

We assessed overall heterogeneity among studies using I2 statistics and by visually inspecting forest plots to detect non-overlapping CIs. Heterogeneity among effect sizes was considered significant if I2 was greater than 50% and if the p-value was < 0.05.

Subgroup analysis

We performed pre-planned subgroup analysis based on the age group of children (0-9 and 10-19 years) due to the difference in metabolic needs of children and adolescents.

Study characteristics

Our search identified a total of 3,252 studies, of which 648 were removed as duplicates. The remaining 2,604 studies underwent full-text assessment, and 262 studies were selected after screening. A total of 97 studies meeting the inclusion criteria were ultimately included in this systematic review, as illustrated in figure 1.

Figure 1: PRISMA flow diagram for study selection.

We aimed to identify studies that directly compared the incidence of DKA based on different diagnostic criteria or varying thresholds of biochemical tests. However, no such comparative studies were found. As a result, this systematic review reports the proportion of DKA cases per individual criterion rather than providing a direct comparison between different diagnostic approaches.

Participant’s characteristics

We included 97 studies (Supplementary File Appendix 2), encompassing a total of 159,585 children and adolescents. Sample sizes ranged from 23 to 41,189 participants. The time span of the studies was from 1996 to 2024. The majority were conducted in high-income countries (n = 71, 73%), followed by upper-middle income (n = 19, 20%), lower-middle income (n = 4, 4%), and low-income countries (n = 2, 2%), with one study not reporting its country. Most studies were conducted in a hospital-based setting (n=83), while 14 studies included population-based samples. Detailed study characteristics are shown in supplementary table 1.

Quality assessment of studies

Quality assessment of the studies included in our review revealed a mean score of 8.8. Details of quality assessment can be found in supplementary table 2.

Criteria for Diagnosis of DKA

Across the total 97 studies, 77 studies reported DKA diagnostic criteria that were grouped into 12 categories and pooled for meta-analysis (Supplementary figure 1). The remaining 20 studies used unique author-defined criteria and were analyzed descriptively (Supplementary table 3). The most frequently reported diagnostic criteria were based on ISPAD guidelines, used in 41 studies with a pooled proportion of 39% (95% CI: 35%-44%). The criterion of pH < 7.3 was used in 8 studies, with a pooled incidence of 29% (95% CI: 22%-36%). Other frequently used criteria included the European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE) consensus statement (hyperglycemia with a venous pH < 7.3 and/or bicarbonate < 15 mmol/L), pH < 7.3 or Serum Bicarbonate < 15 mmol/L and ADA (elevated ketones and metabolic acidosis in addition to hyperglycemia) with pooled incidence ranging from 28% to 45%. The highest pooled DKA incidence was observed in two studies using the criterion of hyperglycemia > 11 mmol/L, pH < 7.3 or serum bicarbonate < 15 mmol/L, with both ketonemia and ketonuria (48%, 95% CI: 46%-51%). Details of other criteria are provided in table 1.

Biochemical criteria for severity of DKA

Biochemical Criteria for Mild DKA: The biochemical criteria for mild DKA diagnosis ranged from 7.0 to 7.3 for pH and 10 to 15 mmol/L for bicarbonate levels. The most frequently reported criterion was pH < 7.3 or bicarbonate < 15 mmol/L, used in 16 studies, with an overall incidence ratio of 43% (95% CI: 34%-52%). Other commonly reported definitions included pH 7.2-7.3 or bicarbonate 10-15 mmol/L, reported in 5 studies (35%, 95% CI: 29%-41%). Moreover, for pH < 7.3, five studies showed an effect size of 43% (95% CI: 26%-60%). The highest incidence ratio of 58% (95% CI: 39%-75%) was reported for the criterion of pH > 7.1 to < 7.3, based on 3 studies. Full details are provided in supplementary figure 2 and table 4. Biochemical criteria for moderate DKA: The biochemical criteria for moderate DKA ranged from pH 7.0 to 7.25 and bicarbonate levels from 5 to 10 mmol/L. The most frequently reported definition was pH < 7.2 or bicarbonate < 10 mmol/L, identified in 15 studies, with a pooled proportion of 29% (95% CI: 25%-33%). Other frequently used criteria included pH 7.1-7.2, reported in 7 studies (37%, 95% CI: 26%-48%), and pH < 7.2, reported in 5 studies (35%, 95% CI: 19%-54%). The highest pooled proportion was 73% (95% CI: 57%-85%), observed in a single study applying the criterion of pH 7.1-< 7.2 or bicarbonate 10-14 mmol/L. Full details are presented in supplementary figure 3 and table 5.

Biochemical criteria for severe DKA: Criteria for severe DKA included a pH threshold below 7.1 and a bicarbonate level below 5 to 10 mmol/L. The most frequently reported definition was pH < 7.1 or bicarbonate < 5 mmol/L, reported in 34 studies, with a pooled proportion of 29% (95% CI: 26%-32%). Additionally, 30 studies reported severe DKA as pH < 7.1 alone, yielding a pooled proportion of 25% (95% CI: 22%-28%). A similar criterion, using a threshold of < 7.1 for pH but bicarbonate < 10 mmol/L, was identified in two studies, with the highest pooled proportion of 43% (95% CI: 35%-51%). Full details are presented in supplementary figure 4 and table 6.

Prognostic outcomes

Hospitalisation: Five studies reported on hospitalisation duration or rates (Table 2). Abdul-Rasoul (2010) observed a mean hospital stay of 8.4 days (SD: 3.2), while Peng (2021) reported a mean duration of 9.0 days (SD: 2.97) [14,15]. Klingensmith (2013) reported that 252 of 277 children with DKA (91%) were hospitalised, with a mean stay of 3.0 days (SD: 1.48) [16]. Levy-Marchal (2001) found that 394 of 440 children with DKA (89.5%) were admitted for initial treatment, which was initiated on the day of diagnosis for 91% of the cases [17]. AlShaikh (2019) reported severity-specific hospital stays, with medians of 4.0 days for mild DKA, 4.5 days for moderate DKA, and 5.0 days for severe DKA (all with IQR 3.0) [18]. Figure 2 shows the forest plot of the length of hospital stay for the two studies.

Figure 2: Hospital stay in newly diagnosed DKA patients.

ICU Admission: ICU data were available in two studies. Klingensmith, et al. [16] reported ICU admission for 146 of 252 hospitalised DKA children (58%). Habib HS, et al. [19], found that 131 of 172 children with DKA (76%) were admitted to the ICU.

Subgroup analysis

Subgroup analysis showed that among children aged 0-9 years, the pooled incidence of DKA was 56% (95% CI: 50%-62%), whereas in adolescents aged 10-19 years, the incidence was 39% (95% CI: 34%-43%). (Supplementary figures 5a,5b). The full GRADE assessment is provided in supplementary tables 7-11.

This systematic review identified substantial heterogeneity in diagnostic criteria used to define DKA in children and adolescents without known diabetes. While the ISPAD guideline, which defines DKA as hyperglycemia, pH <7.3 or bicarbonate < 15 mmol/L, and ketonemia or ketonuria, was the most frequently used criterion, the pooled incidence indicated high heterogeneity. The heterogeneity observed across diagnostic criteria has important implications for clinical care. Variation in cut-offs may delay diagnosis or contribute to misclassification, affecting outcomes such as timely insulin initiation and ICU admission [20,21]. Additionally, our findings highlight that despite the existence of international guidelines, many studies used divergent or author-defined definitions, with at least seven distinct combinations identified across 24 studies, and 20 studies that were excluded from meta-analysis due to non-combinable definitions. This inconsistency poses important consequences for comparability across studies and in meta-epidemiological research.

Notably, studies that employed broader or less stringent diagnostic criteria, such as the combination of hyperglycemia, pH < 7.3 or bicarbonate < 15 mmol/L, and both ketonemia and ketonuria, showed the highest pooled proportion of 48%, which suggests that inclusion of multiple ketone measures may increase sensitivity. This variability extended to biochemical thresholds used to categorize DKA severity, particularly in distinguishing between mild and moderate presentations. In contrast, more stringent biochemical cutoffs, particularly those used for moderate and severe DKA (e.g., pH < 7.1), were associated with lower pooled proportions, which reflects their selectivity in identifying more advanced disease. This highlights a critical point: stricter thresholds may better identify clinical severity, but will classify fewer children as meeting criteria, potentially underestimating DKA prevalence in surveillance contexts. However, since most included studies in our review using more stringent DKA definitions were from high-income countries, where better healthcare access and earlier recognition may lead to fewer presentations with moderate or severe DKA. Prior research has shown that children in high-income settings are more likely to be diagnosed earlier in the disease course and thus contribute to the lower pooled proportions observed for more stringent thresholds. This suggests that both the diagnostic criteria and the health system context are important to consider when interpreting DKA prevalence across settings [3,5].

Consistent with previous evidence, our review found a higher incidence of DKA in younger children compared with adolescents [5]. This is often linked to delayed recognition as infants and toddlers may exhibit nonspecific symptoms (e.g. lethargy, vomiting, dehydration) that parents and clinicians initially attribute to common infections, allowing T1DM to progress undetected to full ketoacidosis [22]. Physiological factors may also play a role: young children have lower glycogen reserves and higher metabolic rates so that insulin deficiency can induce ketoacidosis more rapidly. The increased prevalence of DKA in younger children also correlates with their reduced functional β-cell mass, higher rates of hyperglycemia, and the development of autoantibodies at disease onset [20]. This underscores the critical need for heightened vigilance in recognizing early signs of DKA, including lethargy, vomiting, and polyuria, to prevent delayed diagnosis and complications in this vulnerable age group.

To our knowledge, this is the first systematic review to synthesize the biochemical diagnostic criteria and severity definitions used across DKA studies in pediatric populations without known diabetes. Previous reviews have primarily focused on DKA management, treatment outcomes, or its frequency in known T1DM [5,23]. Unlike these reviews, our review is the first to quantify the heterogeneity in diagnostic definitions and to uniquely highlight that the fragmentation in these criteria might result in challenges around comparing study findings or establishing universal benchmarks. While the ISPAD, ADA, and ESPE guidelines provide similar core components, including hyperglycemia, acidosis, and ketosis, our findings reveal that even among studies citing these sources, the biochemical components and their threshold values varied. This limits the comparability of data, especially in meta-analyses aiming to estimate burden or risk factors.

A key strength of this review is its comprehensive scope, including 97 studies across diverse regions and healthcare settings. However, our findings must be interpreted with some caution. No study directly compared different diagnostic criteria in the same population. This gap means that some of our comparisons rely on indirect inference across different reports, rather than on definitive trial or cohort evidence. Moreover, the majority of studies included in our analysis were cross-sectional in design, limiting the overall quality of evidence as assessed by the GRADE framework, which ranged from very low to low. The reliance on author-reported criteria may introduce misclassification bias, particularly in studies that did not clearly define ketone thresholds. Lastly, while we pooled proportions for common criteria, data heterogeneity limited our ability to meta-analyze prognostic outcomes in a standardized way.

Implications for practice and research

This systematic review will help inform future efforts to revise existing evidence-based guidelines for diagnosing DKA based on biochemical testing. The findings of this review suggest that inconsistent definitions of DKA may contribute to variability in clinical recognition, severity classification, and reporting. This has important implications for clinical practice, as differing thresholds may lead to inconsistencies in triage decisions or treatment strategies. Standardized definitions of severity levels are particularly needed to stratify risk, guide triage decisions, and inform appropriate resource allocation, such as determining which patients require hospitalization or intensive care.

The heterogeneity observed across DKA diagnostic thresholds highlights a critical gap in the evidence base regarding current definitions. The findings also imply that widely used severity cutoffs (e.g., pH or bicarbonate levels) may not have been consistently validated against important clinical outcomes. This underscores a need for more robust study designs to inform the diagnostic standard in pediatric DKA. Specifically, comparative diagnostic accuracy studies and randomized or crossover trials applying multiple definitions to the same patient population are warranted. These would help clarify how various diagnostic thresholds affect DKA incidence estimates and severity classification. Research should also evaluate the sensitivity, specificity, and predictive value of individual and combined biochemical markers, such as blood glucose, serum ketones, and bicarbonate levels, across different age groups and settings. Further, current severity markers (e.g., pH and bicarbonate cutoffs) should be validated against clinical outcomes to determine whether existing thresholds are prognostically optimal.

This systematic review highlights significant global variation in the biochemical definitions used to diagnose and classify DKA in children and adolescents. Inconsistent use of pH and bicarbonate thresholds, as well as differing definitions of DKA severity, complicates epidemiologic surveillance and clinical decision-making. Efforts to standardize DKA diagnostic criteria globally, especially in research and reporting, are urgently needed to ensure accurate burden estimation, improve early recognition, and guide appropriate resource allocation.

This work was funded by a grant (2024/1486209-1) from the World Health Organization (WHO) to the Centre of Excellence in Women and Child Health, Aga Khan University (AKU). Employees of WHO were responsible for determining the research question, the population, interventions, comparators, and outcomes of interest for the systematic review. WHO was not involved in the implementation of the systematic review, nor directly involved in the development of the study manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the publication. Any views or opinions presented are solely those of the authors and do not necessarily represent those of the World Health Organization, unless otherwise specifically stated.

SS and SA conceived the study and initiated the study design. RA led the conduct of searches. RA, AI and HI screened relevant papers. RA and HI conducted the data extraction. Data analysis was conducted by RA. The manuscript was drafted by FM and RA. All authors contributed equally to the revisions and approved the manuscript.

The authors thank Dr Midrar Ullah and Dr Muhammad Yousuf Ali for their guidance while developing the search strategy, Nuhu Omeiza Yaqub Jr and Bianca Hemmingsen for their technical guidance throughout the study, and Dr Erfa Taher for her support during manuscript revision.

The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests.

The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the views, decisions or policies of the World Health Organization.

The article contains additional information as an online supplementary document.

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