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In the United States the Most Common Endocrine Disorder Is Diabetes Peer Review

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Is diabetic ketoacidosis a good predictor of v-year metabolic command in children with newly diagnosed type i diabetes?

  • Stypułkowska Anetaone,
  • Majewska Barbara2,
  • Jarzębowska Małgorzata2,
  • Hoffmann Aleksandra2,
  • Buła Paulinaii &
  • Szypowska Agnieszkathree

BMC Endocrine Disorders volume 21, Article number:218 (2021) Cite this commodity

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Abstract

Groundwork

The study aimed to evaluate whether the presence of DKA at diabetes diagnosis was associated with poorer metabolic control during a v-year follow-upward.

Methods

The study included children treated due to newly diagnosed T1D complicated with DKA between 2010 and 2014 with a consummate 5-year follow-upwardly. In every example nosotros performed individual matching for historic period, gender and BMI with a person without DKA (nDKA) on recognition. We collected information regarding treatment modality, HbA1C, full daily insulin dose, basal insulin and BMI-SDS.

Results

85 children at the median age of seven.93 years had DKA at diabetes diagnosis. The median pH was seven.19.Continuous subcutaneous insulin infusion (CSII) was used in 87% of participants in each group. No differences in HbA1C level (7,iii%vs7,2%;p = .413) were noted after 5 years of disease duration. The severity of ketoacidosis exerted no significant effect on HbA1C. The method of insulin delivery at baseline was significantly associated with HbA1C levels subsequently 5 years of observation, βCSII = − 1.46,95%CI[− 2.01 to − 0.92],p < .001.

Conclusions

The presence of DKA at diabetes diagnosis is non associated with deteriorated long-term metabolic control in children using modernistic technologies. The early implementation of CSII into diabetes treatment may change the consequence of DKA and atomic number 82 to a long-term HbA1C improvement.

Peer Review reports

Background

Type ane diabetes (T1D) is one of the most common metabolic diseases in the pediatric population worldwide. The global increase in the incidence of type i diabetes among children still remains at the level of 3 to 5% annually [1, 2]. The alarming epidemiological situation may as well be observed in Poland with the trend toward younger age groups [iii]. In children aged 0–14 the disease frequency boosted approximately six-fold from 4.2 per 100,000 persons/yr in the early on 1970s to 24.3 per 100,000 persons/yr in 2013 with regular, sinusoidal fluctuations and a slight levelling-off over the past few years [3,4,v].

.The International Society for Pediatric and Adolescent Diabetes (ISPAD) stated that diabetic ketoacidosis (DKA) was the most common, but potentially preventable life-threatening complexity related to newly diagnosed T1D [6]. The incidence of this problem is all the same unacceptably high, especially in the youngest group (below 5 years) and has not changed over the last 20 years despite a sharp increase in T1D diagnoses and improvement in medical intendance [1, two, 7]. Overall, more than i-third of newly diagnosed children are affected by DKA [2, 7,eight,9]. A large global variation is observed in DKA prevalence, with the values varying from fourteen.7% (Denmark) to 79,eight% (Saudi arabia) depending on a geographic location, the socioeconomic factors of the country and the incidence of diabetes (the sensation is poorer in countries with a lower incidence) [two]. The socioeconomic inequalities play a crucial and of import role in the DKA charge per unit at diabetes diagnosis [2, 7,8,9]. The frequency of DKA in Poland was estimated to exist between 22 to 36% [one, x,11,12] and the incidence of coma due to DKA was around four.seven% of children [12]. DKA is the most common cause of diabetes-related death and has an associated mortality rate from 0.15 to 0.35% in developed countries and from 3.4 to 24% in developing countries [vii]. Cognitive edema is the leading crusade of DKA-related decease. It occurs in 0.three–1% people at illness onset [3]. Some authors suggested that when clinically cognitive edema was non observed mild encephalon injuries were present in at least 50% of children during DKA treatment [13]. Negative neurological complications were associated with persistent alterations in attention and retentiveness 6 months following a DKA episode. Moreover, DKA severity and younger age were the greatest chance factors for changes in the cerebral structure [fourteen]. Aye et al. reported that a unmarried episode of moderate or astringent DKA in young children at diabetes diagnosis contributed to lowering the cerebral office and altering brain growth [two, xv]. DKA was also correlated with a longer hospitalization and higher baseline insulin requirements [16]. Moreover, ketoacidosis at diabetes onset was associated with a poor residual β-prison cell office and, thereby, a shorter remission menstruation [1, three]. Data concerning long-term glycemic control depending on DKA presence on diabetes diagnosis are contradictory. The majority of authors supported the concept of metabolic tracking and reported a negative influence on metabolic command if diabetes was accompanied by DKA at onset [2, 3]. Numerous differences are observed worldwide in terms of the access to medical services, education level, approach to new insulin and diabetes technologies which could influence the observed data inhomogeneity. No reports concerning this field are available in Poland.

The major objective of our written report was to assess whether long-term glycemic control in children and adolescents with T1D who had DKA at diabetes onset was poorer than in people with T1D without DKA during a 5-yr observation flow.

Methods

The written report population included people treated in the Department of Pediatric Diabetology and Pediatrics, Pediatric Pedagogy Clinical Infirmary of the Medical Academy of Warsaw due to newly diagnosed type ane diabetes complicated past DKA betwixt 2010 and 2014. The inclusion criteria were: newly recognized diabetes blazon 1 with DKA at the onset of the disease and a complete follow-up for 5 consecutive years. No restrictions on participation were imposed as regards the type of insulin therapy. Participants treated both with continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) were recruited. Handling with insulin pumps providing continuous subcutaneous insulin infusion has been available to children with diabetes mellitus in Poland since 2008. The service is covered by the National Health Fund (Narodowy Fundusz Zdrowia, NFZ) from the catalogue of public-funded services nether separately commissioned healthcare services. The patients had the admission to two types of insulin pump brands: Medtronic (MiniMed) and Roche - Accu Check. A tender for insulin pumps is conducted annually past the infirmary and the admission to the devices depends on its results. Nearly participants had CSII implemented at diabetes diagnosis. Personal continuous glucose monitoring devices have been widely available in Poland since 2018 (70% of the price of the devices was paid by the national health insurance organisation covered past public funds). Closed loop pumps were non bachelor for any study participants.

We excluded participants diagnosed and initially treated in some other Pediatric Department who were finally transferred to our Department and those with an incomplete follow-upwardly. Subsequently, individual 1:1 matching was performed: every participant with DKA was matched with a newly diagnosed type 1 diabetes person without DKA. The participants were matched for age, gender and Body Mass Index (BMI) to minimize the influence of residual misreckoning. Moreover, no differences were revealed in wellness insurance condition. Smooth citizens have equal and unpaid admission to healthcare services provided by the national health insurance system covered by public funds and managed by NFZ. DKA was defined as pH below 7.3 with concomitant hyperglycemia exceeding 200 mg/dL (11 mmol/L) and ketonemia or ketonuria [6]. The autoimmune origin of diabetes was confirmed with typical autoantibody testing and C-peptide level measurement. The onset was defined as the first two weeks later T1D manifestation. The obligatory part of the kickoff hospitalization was a ii-week intensive educational course with a diabetic educator.

Data were collected at diagnosis and prospectively, during routine clinical visits for 5 years following the diagnosis. During the observation period the participants were under the abiding care of the Outpatient Clinic (every 3 months) and had permanent admission to medical assistance. Data concerning HbA1C, insulin requirements (the total daily dose of insulin (TDD), basal rate) and Body Mass Alphabetize standard deviation score (BMI-SDS) were nerveless during every clinical visit. BMI-SDS was calculated using the World Health Organisation (WHO) child growth standards. The once-yearly assessment of metabolic command was selected and analyzed in every participant. We took into consideration the visit according to the engagement of diagnosis, and the dates which were the closest to the appointment of diagnosis + 1 year, + 2 years (etc.).

The follow-upward period was set for 5 years and only data from those who completed the follow-upwardly were investigated. The comparison of HbA1C betwixt DKA and nDKA groups after 5 years of treatment constituted the chief outcome. The secondary outcomes included the comparisons of the following parameters between groups: TDD, basal charge per unit and BMI-SDS. The analysis was besides performed in subgroups with unlike degrees of acidosis defined according to the ISPAD [6] criteria: mild, moderate, severe (pH < 7.3; < 7.2; < 7.1; respectively). Good metabolic control was divers equally HbA1C ≤ six.5% according to the ISPAD target of handling [17].

Laboratory piece of work-upwards

At diabetes diagnosis standard laboratory methods were used to measure glucose and blood gases in the clinical laboratory of the Pediatric Teaching Clinical Hospital of the Medical University of Warsaw. HbA1C levels were measured at baseline and at each visit in the Outpatient Clinic with high-performance liquid chromatography (D-x Hemoglobin Testing System, Bio-Rad Laboratories, The states) with a nondiabetic range of four.1–half-dozen.four% (21–46 mmol/mol).

The Children's Memorial Health Institute Laboratory performed autoantibody testing to glutamic acid decarboxylase (GADA), islet prison cell antibodies (ICA, against cytoplasmic proteins in the beta cell) and insulinoma-associated-2 autoantibodies (IA-2A). Fasting C-peptide concentrations were analyzed using radioimmunoassay, with an assay detection limit of 0.1 nmol/Fifty.

Statistical analysis

GraphPad Prism Software Version viii.four.ii was used for all analyses. Nominal variables were presented every bit northward (% of grouping), continuous variables every bit medians (Q1;Q3) due to the lack of normal distribution. Data normality was verified based on the Shapiro-Wilk test. Spearman's rank correlation tests were conducted to examine the correlations between baseline pH and HbA1C Univariate linear regression analysis was conducted to investigate the influence of CSII/MDI on the 5th year HbA1C. Model β coefficient with 95% confidence intervals (CI) was estimated.

Group comparison for nominal variables was conducted with the Fisher's exact test or the χ2 test, every bit appropriate. The Wilcoxon signed rank test was used for the paired comparisons of clustered data. Continuous variables were compared with the Kruskal-Wallis and the Mann–Whitney U exam. All tests were two-tailed, and the differences were considered significant at the level of p value of ≤0.05.

Results

A total of 127 potentially eligible participants were recruited. 42 participants were excluded due to missing data, an incomplete follow-upwardly period or transfer from pediatric to adult medical care. As a result, 85 individuals met the study inclusion criteria and were analyzed. DKA participants were matched 1:1 to 85 participants without DKA at diagnosis. The baseline characteristics of the study groups are presented in Table 1. The year of diagnosis with number of cases per year in each group are shown in Table two.

Table one Characteristic of study groups

Full size table

Tabular array two The dates of diagnosis and the number of cases per year in each group

Full size table

85 children at the median age of seven.93 years had DKA at diabetes diagnosis with the median pH of 7.19. Severe DKA occurred in 20 participants (24%), moderate in 23 (27%) and mild in around half of DKA group (49%). HbA1C at onset of diabetes was statistically higher in DKA children (p = < .001) with the maximum values reported in those with severe DKA (122 mmol/mol; 13.25%). Insulin pump therapy was implemented in the majority of participants during the first hospitalization, within 2 weeks later on the stabilization of the general condition. The same insulin therapy epitome was introduced, equally 87% (due north = 74) of the participants in each group used CSII. During the follow-upward period ane person from nDKA group inverse insulin therapy from CSII to MDI later 1 year. Children in DKA group had higher TDD (p = .005) and basal insulin (p < .001) compared to nDKA participants. A moderate positive correlation was revealed betwixt initial HbA1C and basal insulin requirement (r = 0.33; p < .001).

A rapid and sharp reject in HbA1C value was observed after the first yr following the diagnosis of diabetes. And then, it remained stable at a like level for the next four years in both groups (Fig. ane). After five years of the affliction HbA1C level was similar regardless of the group (p = .413). The 5th year HbA1c was non correlated with baseline HbA1C (r = 0.055; p = .478) and baseline pH (r = 0.066; p = .396). Nevertheless, a correlation was noted between the 5th year HbA1C and historic period at diagnosis (r = 0.204; 95%CI 0.06–0.34; p = .004). A univariate linear regression model showed that the method of insulin delivery at baseline (CSII or MDI) was significantly associated with the 5th year HbA1C, βCSII = − 1.46, 95%CI [− ii.01 to − 0.92], p < .001.

Fig. 1
figure 1

HbA1C modify during observation period in both groups. Abbreviations: DKA, diabetic ketoacidosis group; nDKA, not- diabetic ketoacidosis grouping; HbA1C, glycated hemoglobin

Full size image

The 5th year HbA1C was the highest amid children with moderate acidosis (62 mmol/mol; 7.fourscore%) in comparing with mild (54 mmol/mol; 7.10%) and severe (55 mmol/mol; 7.20%), but without statistical significance (p = .085) (Fig. 2).

Fig. 2
figure 2

HbA1C change during observation period in DKA group. The presentation in subgroups with different degrees of acidosis (pH). Abbreviations: HbA1C, glycated hemoglobin; DKA, diabetic ketoacidosis group

Full size epitome

The number of participants who achieved proficient metabolic control (HbA1C ≤ 6.v%) was 10% greater in nDKA compared to DKA group after the first yr of the disease (38% vs 28%, respectively; p = .253). After v years of follow-up it remained at a similar level (18% vs 22%, respectively; p = .566). A similar analysis was performed in terms of poor metabolic control (HbA1C ≥ eight%). A similar rate of participants in both groups achieved the elevated HbA1C level after the offset year of the disease (nDKA xvi.v% vs DKA 12.nine%, respectively; p = .666) and subsequently five years of follow-up (nDKA 24.vii% vs 30.6%, respectively; p = .493).

Total daily insulin requirements were similar in both groups after the follow-up menstruum (p = .629). Basal insulin requirements at diagnosis and after the beginning year of the disease were greater in those who had acidosis at the onset of diabetes. No changes concerning insulin requirements were observed in relation to DKA severity. An interesting trend was observed in relation to BMI z-score. Children who had acidosis at diagnosis featured lower torso weight at the beginning and rapid growth afterwards. Their body weight increased to a higher extent than in nDKA group individuals over the side by side 4 years. However, the observed differences were not statistically significant. Furthermore, no significant differences were noted in terms of metabolic control (HbA1C, insulin requirements, trunk weight) v years after T1D diagnosis between age groups and genders in DKA and nDKA groups. The chief outcomes were presented in Table iii.

Table 3 Comparison between groups during follow-up

Full size table

Discussion

To the all-time of our knowledge, it is the get-go study in Poland investigating whether DKA at diabetes diagnosis is associated with long-term metabolic consequences. Our inquiry was designed in a unique fashion with private matching to eliminate confounding and focus merely on the bear on of DKA on metabolic control. The results showed that DKA at diabetes onset was not associated with poorer HbA1C, greater insulin requirements and higher torso weight for 5 years of the affliction. HbA1C was similar in DKA and nDKA groups throughout the 5-year follow-up.

The findings of our enquiry are consequent with a study conducted past Khanolkar et al. [xviii] The authors analyzed associations between DKA presence at diagnosis and glycemic command during the first year mail service-diagnosis in 341 children and constitute that DKA was not correlated with deteriorated metabolic command [18]. Piccini et al. conducted a written report based on the Sugariness registry to investigate if the presence of DKA or HbA1C level at diabetes onset was a better predictor of long-term metabolic control and ended that the third year HbA1C was more closely related to baseline HbA1C than to DKA presence at onset [12]. The authors concluded that children who experienced DKA at diagnosis might achieve good metabolic control, just those with high primary HbA1C connected to have poor metabolic control [12]. The present study showed no correlation between the 5th yr HbA1C and HbA1C or pH at diabetes diagnosis. Data concerning the influence of DKA on long-term metabolic control are conflicting, just most of them relate to poor long-term prognosis if acidosis was present at diagnosis. The unfavorable impact of initial DKA was reported in a study by Shalitin et al. conducted after the first yr post-diagnosis. The mean daily insulin dose (0.74 ± 0.26 vs 0.69 ± 0.27 units/kg/d, p = .049) and HbA1C level (7.85 ± 1.13% vs 7.49 ± 0.94%, p = .01) were significantly higher in participants with DKA at diagnosis [19]. Our study showed that only basal insulin dose was significantly higher in DKA grouping after the first year of follow-up. Analogous negative effects of DKA were demonstrated in a accomplice study based on data retrieved from DanDiabKids, a Danish national diabetes registry of children with newly diagnosed type ane diabetes. It comprised 2964 children with a long-term follow-upwardly (5.viii years on average) [20]. They found moderate and severe DKA to be associated with increased HbA1C (0.24; 95% CI 0.xi,0.36; p = .0003) and insulin dose-adjusted HbA1C during the observation period [20]. Interestingly, they noted that CSII therapy in comparing to MDI changed the upshot of DKA at onset and led to the long-term improvement in HbA1C. The CSII therapy was implemented in around 40% of participants in the described written report group [20].

.A factor which could influence the study results is a low number of children using multiple daily injections in both groups. Nosotros would like to highlight the fact that we recruited a unique population, as around ninety% of the participants (the same number in both groups) were treated with CSII. The therapy was implemented merely afterwards diabetes diagnosis, during the first month, which probably affected the results nosotros accomplished. We noted that the method of insulin delivery at baseline (CSII or MDI) was significantly associated with the 5th-year HbA1C.

In the population-based cohort study conducted in 446 diabetes centers the information from 9814 patients using pump therapy were nerveless and matched with the aforementioned number of patients using injection therapy. Pump therapy, compared to injection therapy, was associated with lower rates of severe hypoglycemia and diabetic ketoacidosis. Glycated hemoglobin levels and total daily insulin doses were lower with pump therapy than with injection therapy. There was no pregnant departure in trunk mass index betwixt both treatment regimens [21]. A study conducted by Piechowiak et al. in our Pediatric Diabetology Department evaluated factors influencing diabetes command over 3 years following diabetes diagnosis [22]. The researchers reported that children who were started on CSII at T1D onset achieved long-term optimal glycemic control [22]. A study based on Diabetes-Patienten-Verlaufsdokumentation (DPV) registry provided evidence for improved clinical outcomes associated with the early on initiation (inside the first half dozen months) versus later implementation of insulin pump therapy in children with blazon 1 diabetes [23]. Seemingly, the early implementation of CSII might mitigate the negative consequences and all the burden of DKA at diabetes onset. Nevertheless, because of a great disproportion betwixt groups we should be cautious in drawing far-reaching conclusions.

Interestingly, Piccini et al. establish a positive implication betwixt initial DKA and further metabolic control. DKA presence at diabetes diagnosis might frighten families and stimulate them to attach to the diabetes regimen more strictly. Such an exception was reported in Northern Europe (Poland was included): after the 3rd year of the disease HbA1C was even meliorate in children who experienced DKA with a coma compared to children with DKA without a coma and with no DKA [12]. The findings might reverberate the low coma charge per unit related to DKA, a more intensive insulin treatment and loftier social sensation of the disease in those countries. It could also back up and explain our results.

Moreover, similarly to some authors, we noted that participants who presented with DKA had a tendency to higher BMI-SDS after an initial lower rate [12]. Nosotros established no statistically pregnant differences betwixt groups concerning BMI-SDS. Weight 'differences' at baseline are not surprising and probably reflect differences in disease severity (and the degree of weight lost in the preceding months). In order to avoid confusion, we matched participants from DKA group based on their weight taken at discharge, when the clinical status was stable, without acidosis and dehydration. Previously conducted research revealed a difference after the tertiary twelvemonth favoring patients with T1D without DKA on recognition [12].

Race, ethnicity, socioeconomic status, and family structure are circuitous, interrelated variables that influence diabetes control. We recruited a homogenous population of children according to the race – all participants were Caucasian. The limitation of our study is associated with the lack of socioeconomic factor analysis. Numerous written report results unequivocally demonstrate that some factors negatively impact diabetes metabolic control in children. Depression socioeconomic status, lower levels of maternal instruction and maternal decease are associated with poor metabolic command [24]. Interesting results were constitute in Danish children where a universal admission to health intendance is provided. Inequality in glycemic control was noted to be related to maternal educational level among children with type one diabetes, i.east. lower maternal educational level was associated with poorer glycemic control [25].

STRENGHTS and limitations

  • The strength of our report is related to the unique population consisting of children with T1D treated mostly using CSII in around 90% of each group. Insulin pump therapy was implemented at diabetes onset which was rare at that time. Moreover, the report population was precisely matched (1:ane) to eliminate misreckoning factors and focus merely on the impact of DKA on the metabolic control with long-term follow-upward.

  • The limitation of this written report is associated with the lack of socioeconomic factors and a low number of children using multiple daily injections in both groups.

Conclusions

  • The presence of DKA at diabetes diagnosis was non associated with poor long-term metabolic command in T1D children using modern technologies after T1D onset. CSII therapy introduced at diabetes onset might prevent HbA1C deterioration during the follow-up menstruum in children with DKA at diabetes diagnosis. Farther studies are needed to evaluate the benefits of the early implementation of CSII to the long-term metabolic control in children with T1D complicated by DKA on recognition.

Availability of information and materials

Data available upon request. Delight contact Emilia Kowalczyk, emilia.kowalczyk@uckwum.pl.

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Funding

This inquiry did not receive whatsoever specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Writer information

Affiliations

  1. Department of Pediatric Diabetology and Pediatrics, Pediatric Teaching Clinical Hospital of the Medical University of Warsaw, Żwirki i Wigury 63A, 02-091, Warsaw, Poland

    Kowalczyk Emilia & Stypułkowska Aneta

  2. Students' Scientific Association, Medical University of Warsaw, Warsaw, Poland

    Majewska Barbara, Jarzębowska Małgorzata, Hoffmann Aleksandra & Buła Paulina

  3. Section of Pediatrics, Medical University of Warsaw, Warsaw, Poland

    Szypowska Agnieszka

Contributions

EK developed the first draft of the manuscript, information analysis and interpretation, final approval of article; Equally collected data and coordinated the data collection process, last approval of article; BM collected information, information analysis and interpretation, final approval of commodity; MJ nerveless data, data analysis and estimation, final approval of article; AH MJ nerveless information, data analysis and estimation, final blessing of article; PB collected information, Data analysis and estimation, final blessing of article; ASz conceptualized the written report and approved the final typhoon of the manuscript.

Corresponding author

Correspondence to Kowalczyk Emilia.

Ethics declarations

Ethics approval and consent to participate

The trial was approved past the Ethics Committee of the Medical Academy of Warsaw (KB/91/2011). Written informed consent was obtained from the legal caregivers of all participants.

Consent for publication

Not applicable.

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None.

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Emilia, K., Aneta, S., Barbara, K. et al. Is diabetic ketoacidosis a good predictor of 5-year metabolic control in children with newly diagnosed type 1 diabetes?. BMC Endocr Disord 21, 218 (2021). https://doi.org/10.1186/s12902-021-00882-8

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  • DOI : https://doi.org/ten.1186/s12902-021-00882-8

Keywords

  • In-patient diabetes
  • Children and adolescents
  • Other complications
  • Devices
  • Self-management

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