Factors associated with mortality in children with diabetic ketoacidosis (DKA) in South India

Mortality in diabetic ketoacidosis (DKA) among children has been reported to be 0.3–3 % in developed countries. Based on the limited data from developing countries, the mortality reported is as high as 13.4 %. A prospective study was conducted to identify the factors leading to high mortality in children with DKA in South India. This was a study of 118 episodes of DKA among children, admitted in a pediatric tertiary care center at Chennai. Clinical presentation, laboratory parameters at admission, parameters during treatment, and complications were considered as risk factors. All children were followed up till discharge from hospital or death. Univariate and multivariate analyses for risk factors were undertaken. Altered sensorium and higher osmolality at admission, delayed diagnosis, cerebral edema, shock, renal failure, and sepsis were the major risk factors associated with mortality in multivariate analysis. Cerebral edema was encountered in 23.7 %, shock in 12.7 %, sepsis in 11 %, and renal failure in 9.3 %. The overall mortality rate was 11 %. Delayed diagnosis may be the root cause for high mortality in children with DKA in developing countries. There is an urgent need to create awareness among physicians, teachers, and parents to avoid a delay in diagnosis and decrease the mortality in children with DKA. Higher incidence of cerebral edema, shock, renal failure, and sepsis are unique problems identified in this study. There is a need for further studies on fluid management of shock, strategies for management of renal failure in DKA, and use of antibiotics in DKA in developing countries.     

Unusual renal involvement during diabetic ketoacidosis (DKA) in a newly diagnosed type I diabetic child

Summary A 10-year-old boy, in a precomatose state, was admitted to our Endocrine Unit for diabetic keatoacidosis. It took unusually long to reequilibrate the acidosis despite a bicarbonate drip. On the 4th day the patient suddenly complained of an acute abdominal pain associated with macrohematuria and oliguria; ankle edema was evident. No radio-opaque image was detected along the urinary tract. An intravenous pyelogram (IVP) showed an almost totally silent left kidney. Ten days later a control IVP showed complete normality of both kidneys. We postulated that the serious and protracted dehydration might have resulted in the formation of a blood clot along the renal tract and that the rehydration may have subsequently removed it.     

Cytokine response to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM)

It has been suggested that cytokine release during DKA may result in capillary perturbation and thus may contribute to the development of its acute clinical complications (i.e.cerebral or pulmonary edema). We studied in 38 newly diagnosed T1DM children with DKA, aged 7.68±3.07 years, plasma levels of cytokines IL-1β (interleukin-1β), IL-2, IL-6, IL-8, IL-10, TNF-α (tumour necrosis factor-α) and also WBC (white blood cell count), hs-CRP (high sensitivity C-reactive protein), GH (growth hormone) and cortisol, prior to, during and 120h after DKA management, with the aim to monitor their levels at different time-points and in different degrees of DKA severity. Prior to DKA management the levels of IL-6, IL-8, IL-10, WBC and cortisol were elevated, but were all reduced within 120 h after DKA management. Then the patients were divided into two groups: a. moderate/severe: pH≤7.2, b. mild DKA: pH>7.2. In the group with moderate/severe DKA (ph≤7.2), IL-10 levels were the highest of all cytokines, but were significantly decreased after 6h (91.76 vs 18.04 pg/mL, p=0.008), with no further change, while IL-6 levels were decreased at 120 h (28.32 vs 11.9 pg/mL, p=0.003). The above were not observed in the group with mild DKA. In conclusion, in the children with DKA of our study, in the group with moderate/severe DKA the IL-10 levels were prematurely reduced at 6 hours, while the IL-6 levels remained high and were reduced at 120 hours after the DKA management. These changes may be responsible for increased capillary perturbation, which could lead to the subsequent development of acute DKA complications.     

Aminoaciduria and metabolic dysregulation during diabetic ketoacidosis: Results from the diabetic kidney alarm (DKA) study

ObjectiveWe examined changes in the excretion of various amino acids and in glycolysis and ketogenesis-related metabolites, during and after diabetic ketoacidosis (DKA) diagnosis, in youth with known or new onset type 1 diabetes (T1D).MethodsUrine samples were collected from 40 youth with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, blood glucose 451 ± 163 mg/dL) at 3 time points: 0–8 h and 12–24 h after starting an insulin infusion, and 3 months after hospital discharge. Mixed-effects models evaluated the changes in amino acids and other metabolites in the urine.ResultsConcentrations of urine histidine, threonine, tryptophan, and leucine per creatinine were highest at 0–8 h (148.8 ± 23.5, 59.5 ± 12.3, 15.4 ± 1.4, and 24.5 ± 2.4% of urine creatinine, respectively), and significantly decreased over 3 months (p = 0.028, p = 0.027, p = 0.019, and p < 0.0001, respectively). Urine histidine, threonine, tryptophan, and leucine per urine creatinine decreased by 10.6 ± 19.2, 0.7 ± 0.9, 1.3 ± 0.9, and 0.5 ± 0.3-fold, respectively, between 0 and 8 h and 3 months.ConclusionsIn our study, DKA was associated with profound aminoaciduria, suggestive of proximal tubular dysfunction analogous to Fanconi syndrome.     

胰岛素泵和多次胰岛素皮下注射治疗对糖尿病酮症酸中毒和高渗昏迷的疗效比较

目的比较不同胰岛素给药方法对糖尿病酮症酸中毒（DKA）和糖尿病高渗性昏迷（DHC）的疗效。方法对DKA和DHC患者首先用静脉泵小剂量胰岛素持续输注,在生命体征平稳并能进半流食后分别用不同的胰岛素给药方式进行治疗：（1）持续皮下胰岛素输注（CSII）组;（2）常规4次皮下注射胰岛素（MSII）组。治疗目标为FBG≤7.0mmol/L、2hBG≤10mmol/L。结果两组每日胰岛素用量无统计学差异（P〉0.05）,但平均达标天数CSII组较MSII组明显缩短（P〈0.01）,CSII组血糖波动小,发生低血糖次数明显减少,且FBG及晚餐后2hBG控制亦明显优于MSII组（P〈0.01）。结论在治疗DKA和DHC时采用静脉泵连续小剂量胰岛素输注急救后,使用CSII较MSII能更快、更平稳、更有效地控制高血糖。     

Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA

OBJECTIVE: The aim of this study was to evaluate the incidence, pathogenesis, and prognosis of acute pancreatitis (AP) in diabetic ketoacidosis (DKA). DKA is associated with nonspecific increase in serum amylase levels. Autopsy studies, on the other hand, had previously raised the issue of pancreatic necrosis in patients with DKA. However, the incidence, pathogenesis and prognosis of AP in the setting of DKA has not been prospectively evaluated. METHODS: This is a prospective evaluation of 100 consecutive episodes of DKA during a period of 13 months starting in January 1998, in a university hospital in New York City. In addition to careful history, complete blood count, arterial blood gas estimation, and a comprehensive metabolic assay, serum amylase, lipase, and triglyceride levels were estimated on admission and 48 h later. All patients with abdominal pain or elevated serum levels of amylase or lipase (more than three times normal) or triglyceride levels >5.65 mmo/L (500 mg/dl) had a CT scan of the abdomen. The diagnosis of AP was confirmed when pancreatic enlargement or necrosis on contrast enhanced CT scan was seen. RESULTS: Eleven patients (11%) had AP. History of abdominal pain, not a feature on admission to include AP in the differential diagnosis, was elicited subsequently in eight patients. Abdominal pain was absent in two and one was comatose on admission. The etiology of AP was hypertriglyceridemia in four, alcohol in two, drug induced in one, and idiopathic in four patients. The hypertriglyceridemia was transient in four patients and resolved once the episode of DKA was corrected. Lipase elevation was noted in 29% and amylase elevation in 21% of all patients with DKA. Similar to increased amylase levels, serum lipase levels were also noted to be high in the absence of CT evidence of AP. CONCLUSIONS: DKA may mask coexisting AP, which occurs in at least 10-15% of cases. The pathogenesis of AP in DKA varies, but at least in some transient and profound hyperlipidemia is an identifiable factor. AP is more likely to be associated with a severe episode of DKA with marked acidosis and hyperglycemia. Ranson's prognostic criteria are not applicable to assess the severity of AP in DKA because they overestimate the severity. Severity index based on CT findings appears to better correlate with outcome. Elevation of serum lipase and amylase occur in DKA, and elevation of lipase levels appears to be less specific than amylase levels for the diagnosis of AP in the diagnosis of DKA. Although in this study AP in DKA appeared to be mild, a definite conclusion with regard to the severity should be based only on a much larger number of patients, as only 20% of patients with AP in general have serious disease.     

Increased plasma pancreatic polypeptide (PP) in diabetic ketoacidosis; normalization following treatment

As both hypoglycaemia and hyperglycaemia may modify plasma levels pancreatic polypeptide (PP), we measured plasma PP by a homologous radioimmunoassay in seven diabetics who were admitted to the hospital in overt diabetic ketoacidosis (initial blood glucose 27.1-55.0 mmol/l). None had circulating PP-antibodies. All were treated with continuous infusion of insulin and fluids. Before starting treatment, plasma PP ranged from 2585-136 mmol/l (mean 629 pmol/l). Following treatment plasma PP decreased gradually in all patients. The following morning mean plasma PP was 242 pmol/l, 67 pmol/l when one ureamic patient was excluded. The normal value is less than 100 pmol/l. This study shows that plasma PP is clearly elevated in diabetic ketoacidosis and decreases following treatment.     

Determinants of plasma potassium levels in diabetic ketoacidosis

The classic proposal of intracellular K+ for extracellular H+ exchange as responsible for the hyperkalemia of diabetic ketoacidosis (DKA) has been questioned because experimentally induced organic anion acidosis fails to produce hyperkalemia. It has been suggested, instead, that the elevated serum [K+] of DKA might be the result of the compromised renal function, secondary to volume depletion, that usually accompanies DKA. However, several metabolic derangements other than volume depletion and acidosis, which are known to alter potassium metabolism, also develop in DKA. This study of 142 admissions for DKA examines the possible role of alterations in plasma pH, bicarbonate, glucose (G), osmolality, blood urea nitrogen (BUN) and plasma anion gap (AG) on the levels of [K+]p on admission. Significant (p less than 0.01) correlations of [K+]p with each of these parameters were found that could individually account for 8 to 15 percent of the observed variance in the plasma potassium levels; however, the effects of some or all of these parameters on the [K+]p could be independent and therefore physiologically additive. Since the parameters under study are themselves interrelated, having statistically significant correlations with each other, their possible independent role on [K+]p was evaluated by multiple regression analysis. Only plasma pH, glucose and AG emerged as having a definite independent effect on [K+]p, with no independent role found for bicarbonate, BUN and osmolality. The equation that best describes [K+]p on admission for DKA was: [K+]p = 25.4 - 3.02 pH + 0.001 G + 0.028 AG, (r = 0.515). These results indicate that the endogenous ketoacidemia and hyperglycemia observed in DKA, which result primarily from insulin deficit, are the main determinants of increased [K+]p. Since exogenous ketoacidemia and hyperglycemia in the otherwise normal experimental animal do not increase [K+]p, it is postulated that insulin deficit itself may be the major initiating cause of the hyperkalemia that develops in DKA. Renal dysfunction by enhancing hyperglycemia and reducing potassium excretion also contributes to hyperkalemia.     

Immediate plasma potassium levels in treating diabetic ketoacidosis

A patient presented with diabetic ketoacidosis and severe hypokalemia (less than 2.0 mmol/L [less than 2.0 mEq/L]). The availability of immediate plasma potassium levels using a blood gas analyzer (Radiometer) prevented the use of potentially hazardous therapy. Potassium levels should be determined immediately using this technology in all patients with ketoacidosis.     

Diabetic ketoacidosis (DKA) in type 1 diabetes mellitus (T1DM) temporally related to COVID-19 vaccination

SARS-CoV-2 pandemic has claimed millions of lives since its first identification in December 2019. Patients with diabetes are at a high risk of adverse outcomes after COVID-19 infection, whereas infection itself can be associated with severe hyperglycemia, including hyperglycemic emergencies. While the accelerated vaccine development and rollout have considerably decreased morbidity and mortality with reasonable safety, there are emerging reports of worsening of hyperglycemia in response to vaccination, with possible shared pathophysiology with COVID-19 infection-related hyperglycemia. We hereby report two young patients with type 1 diabetes (T1DM) who presented with severe diabetic ketoacidosis (DKA) after receiving second doses of COVISHIELD (ChAdOx1 nCoV-19) and COVAXIN (BBV152- inactivated whole virion) vaccines. Though a causal link cannot be established, post-vaccination immune response can potentially explain this transient worsening of hyperglycemia and hyperglycemic emergencies. We, hence report diabetic ketoacidosis (DKA) following COVID-19 vaccination in T1DM. We suggest that people with diabetes, particularly patients with T1DM with inadequate glycemic control should ideally be closely monitored for hyperglycemia and ketonemia for at least 2 weeks after receiving vaccination for COVID 19.     

Treatment of diabetic ketoacidosis (DKA) with 2 different regimens regarding fluid substitution and insulin dosage (0.025 vs. 0.1 units/kg/h)

Diabetic ketoacidosis (DKA) is still the most dangerous acute complication in type 1 diabetes. The aim of this study was to compare treatment of DKA with a regimen of a low insulin dose (0.025 units/kg/h) vs. a standard insulin dose (0.1 units/kg/h).We retrospectively analysed all cases of children and adolescents (age 0-18 years) with type 1 diabetes and DKA who needed treatment in the ICU in the time period of 1998-2005 in 2 pediatric diabetes centers. In a chart review of the first 48 h after onset of DKA the following parameters where evaluated: pH, blood glucose, sodium, potassium, and ketones in urine. Consciousness, neurological status and complications such as cerebral edema, hypoglycaemia or hypokalemia were also recorded.23 children were treated in center A (low insulin dose) whereas 41 where treated in center B (standard insulin dose). Mean age of the patients was 8.9 (range 1.58-17.7) and 13.5 years (1.25-17.7) respectively (p=0.134). Mean pH was 7.1 and HCO3 was 9.05 and 7.79 respectively (p=0.122). Initial blood glucose was 26 mmol/l (no difference between the 2 centres). Treatment with the standard insulin dose resulted in a slightly shorter duration of acidosis (8 h in center A, 6.5 h in center B) and a significantly faster normalization of blood glucose (18 h in A, vs. 10.5 h in B) (p<0.005). During the first day we found similar and very low rates of hypoglycaemia. In center B one case of suspected cerebral edema and cerebral infarction occurred.Low dose insulin substitution is as safe as the recommended standard dose in respect to the occurrence of acute complications. Acidosis is broken slightly earlier with the standard dose. Implications of this earlier normalisation of pH remain unclear.     

Changes in plasma leptin during the treatment of diabetic ketoacidosis

To test the hypothesis that insulin regulates leptin, we measured the plasma leptin concentration before and during treatment of diabetic ketoacidosis (DKA), a condition characterized by extreme insulin deficiency. The study included 17 patients with type 1 diabetes (7 males and 10 females), aged 10+/-1 yr (mean +/- SE), with a body mass index of 17.6+/-1.9 kg/m2. Patients were treated with continuous insulin infusion and fluid and electrolyte replacement. Plasma leptin was measured every 6 h in the first 24 h, during which patients received a total insulin dose of 0.6-2.0 U/kg. Plasma leptin concentrations were also measured in a control group of 29 stable type 1 diabetic children (12 males and 17 females) and 25 healthy children (11 males and 14 females), aged 11+/-1 yr, with a body mass index of 18.5+/-1.1 kg/m2. Before treatment, plasma leptin concentrations were significantly lower in patients with DKA than those in diabetic and healthy controls (4.9+/-1.2 vs. 9.0+/-1.8 and 11.2+/-2.1 ng/mL, respectively; P < 0.05). In the DKA patients, plasma leptin increased to 6.4+/-1.5, 7.5+/-1.9, 9.1+/-2.7, and 8.9+/-2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P = 0.001). Thus, leptin levels increased by 38+/-10% and 92+/-38% within 6 and 24 h of starting treatment. There was no difference in the change in plasma leptin by 24 h between subjects who could eat (n = 7) and those who could not (n = 10). The plasma leptin increase was paralleled by a rise in insulin level and a decline in glucose and cortisol levels at 6 and 24 h. In conclusion, DKA was associated with decreased plasma leptin concentrations. Treatment resulted in a significant increase in plasma leptin, which may be due to the effect of insulin on leptin production. Our data lend support to the hypothesis that insulin is the link between caloric intake and plasma leptin.     

The influence of ketoacids on plasma creatinine assays in diabetic ketoacidosis

OBJECTIVE: Analysis of the interference of ketoacids on various routine plasma creatinine assays during a clinical episode of diabetic ketoacidosis (DKA). DESIGN: Observational study. Blood samples were drawn before, during and after standard in-hospital treatment. Plasma creatinine was measured with two dissimilar enzymatic assays (creatininase PAP + and creatinine iminohydrolase Serapak), a kinetic alkaline picrate method (Jaffé) and a high-performance liquid chromatography (HPLC) procedure. Acetoacetate and beta-hydroxybutyrate were analysed by enzymatic methods. SETTING: Department of Medicine, University Hospital. SUBJECTS: Nine patients who experienced 10 episodes of DKA. MAIN OUTCOME MEASURES: Agreement of the routine plasma creatinine assays with HPLC and analysis of possible interferents. RESULTS: At presentation, the Jaffé assay gave falsely high values of plasma creatinine (median 99 micromol L(-1)), in contrast to the PAP+ (median 60.5 micromol L(-1)) and HPLC assays (median 67.5 micromol L(-1)). This positive error decreased during treatment. This was due to a decrease in acetoacetate, as the positive error by the Jaffé method correlated with the acetoacetate concentration (r = 0.79, P < 0.0001). In the multiple regression analysis, beta-hydroxybutyrate caused no additional interference by the Jaffé assay, confirmed by in vitro experiments. Analysis of agreement showed that the difference between PAP+ and HPLC creatinine was -4.6 +/- 3.0 micromol L(-1) (mean +/- SD), and 2.0 +/- 5.3 micromol L(-1) between Serapak and HPLC. This was statistically significant, but clinically negligible. CONCLUSION: Acetoacetate caused severe interference of the alkaline picrate (Jaffé) assay, which might influence therapeutic decisions at the start of diabetic ketoacidosis. Enzymatic assays lack this interference.     

Alkalemia in diabetic ketoacidosis

A patient with a history of diabetes mellitus and congestive heart failure was taking furosemide and metolazone as diuretics. Diabetic ketoacidosis developed, and the patient became lethargic and confused. Initial biochemical determinations showed an alkalemic pH, serum and urine ketones with an anion gap, and hyperventilation. The hyperventilation was appropriate for the degree of ketoacidosis but it was grossly inappropriate for the alkalemia. This could be explained by a direct effect of ketones on the respiratory center or a sudden increase in hydrogen ion concentration superimposed on previously chronic alkalemic pH due to the potent combination of furosemide and metolazone.     

Hyperkalemia in diabetic ketoacidosis

Patients with diabetic ketoacidosis tend to have somewhat elevated serum K+ concentrations despite decreased body K+ content. The hyperkalemia was previously attributed mainly to acidemia. However, recent studies have suggested that "organic acidemias" (such as that produced by infusing beta-hydroxybutyric acid) may not cause hyperkalemia. To learn which, if any, routinely measured biochemical indices might correlate with the finding of hyperkalemia in diabetic ketoacidosis, we analyzed the initial pre-treatment values in 131 episodes in 91 patients. Serum K+ correlated independently and significantly (p less than 0.001) with blood pH (r = -0.39), serum urea N (r = 0.38) and the anion gap (r = 0.41). The mean serum K+ among the men was 5.55 mmol/l, significantly higher than among the women, 5.09 mmol/l (p less than 0.005). Twelve of the 16 patients with serum K+ greater than or equal to 6.5 mmol/l were men, as were all eight patients with serum K+ greater than or equal to 7.0 mmol/l. Those differences paralleled a significantly higher mean serum urea N concentration among the men (15.1 mmol/l) than the women (11.2 mmol/l, p less than 0.01). The greater tendency to hyperkalemia among the men in this series may have been due partly to their greater renal dysfunction during the acute illness. However, other factors that were not assessed, such as cell K+ release associated with protein catabolism, and insulin deficiency per se, may also have affected serum K+ in these patients.     

Recurrent diabetic ketoacidosis

This report presents and analyzes certain clinical and laboratory findings in 17 patients who were hospitalized repeatedly for diabetic ketoacidosis on a municipal hospital medical service during the early 1970s and the early 1980s. The 17 patients had a total of 92 hospitalizations for ketoacidosis during the survey periods. During the 1970s, most of the frequent recurrences occurred in young women, as has often been noted by others. In recent years, however, the number of patients with frequent recurrences hospitalized at Bronx Municipal Hospital Center has declined, and most of the patients have been young men. There is no obvious explanation for the latter trend. The laboratory findings were analyzed in order to learn whether they were similar in each patient during his or her recurrent admissions. In a few patients, blood pH, hemoglobin concentration, serum glucose level, anion gap, and osmolarity tended to be similar during their repeated hospitalizations. In the majority of the patients, however, there was significant variation in most of these laboratory indexes, except for the serum osmolarities and blood hemoglobin concentrations. The similarity of the serum osmolarities and hemoglobin concentrations in sequential episodes in most of the patients suggested that a certain severity of dehydration may have been the main factor that led them to seek hospitalization.     

Recurrent diabetic ketoacidosis

In a study over 15 years, 740 episodes of diabetic ketoacidosis occurred in 505 patients. A total of 113 patients had more than one episode. The majority (90%) of recurrences were within 4 years of the initial episode. Taking a definition of recurrent ketoacidosis as three or more episodes within 4 years, 39 patients were identified. Two subgroups appeared prone to such frequent recurrences, namely girls less than 20 years of age and women more than 59 years of age. A variety of causes of recurrent episodes was noted in the young patients but in the older patients other chronic illnesses complicated the diabetes. The need for good domiciliary supervision of elderly chronic sick patients who require insulin is emphasized.     

Euglycemic diabetic ketoacidosis

Euglycemic DKA (eu-DKA) is a life-threatening emergency. It may occur in patients with both type 1 and type 2 DM, and characterized by milder degrees of hyperglycemia with blood glucose level < 200 mg/dl, which can result in delayed diagnosis and treatment with potential for adverse metabolic consequences.Following the wide introduction of the sodium glucose transporter 2 inhibitors (SGLT2i) in therapeutic practice for DM type 2 treatment the amount of eu-DKA increased and therefore, interest to this entity rose. Other causes associated with eu-DKA include pregnancy, decreased caloric intake, heavy alcohol use, insulin use prior to hospital admission, cocaine abuse, pancreatitis, sepsis, chronic liver disease and liver cirrhosis.Patients with eu-DKA as well as with DKA need immediate referral for emergency evaluation and treatment.The treatment includes rapid correction of dehydration, correction electrolyte abnormalities, and use of insulin drip until the anion gap, and bicarbonate levels normalize. Increased glucose administration using higher percentages of dextrose (10 or 20%) are required to facilitate the concomitant administration of the relatively large amounts of insulin that are needed to correct the severe acidosis in these patients.