Patients: Between January 2011 and March 2018, 134 episodes of DKA (120 patients) were admitted in the ICU. We did not include 32 episodes (29 patients) because of the absence of eligibility criteria, wrong coding diagnosis or missing data (Fig. 1). The remaining 102 episodes (91 patients) were included in the analysis. There were 50 (49.0%) males and 52 (51.0%) females, with a mean age of 46 years (29–58 years) (Table 1). Type 1 diabetes was the most frequent type of diabetes (n = 60 episodes, 58.8%) and inaugural DKA accounted for 17.6% (n = 18 episodes). Eight patients (8.8%) had recurrent episodes of DKA (2 episodes: 6 patients, 3 episodes: 1 patient, 4 episodes: 1 patient). Triggering factors were poor compliance to antidiabetic treatments and bacterial infection, for 50.0% and 19.6% of the episodes respectively. For 21 episodes (20.6%), no triggering factor was identified. At ICU admission, median pH and bicarbonate were 7.14 [7.05–7.24] and 6.0 mmol/L [3.5–10.4 mmol/L] respectively. On D2, ketoacidosis was corrected as attested by a median pH of 7.41 [7.38–7.43] and glycaemia 6.6 mmol/L [5.2–11.0 mmol/L].
Table 1
Demographic and clinical baseline characteristics of the patients.
Variables | All Cohort (n = 102) | Infected patients (n = 20) | Non-infected patients (n = 82) | p valuea |
Age, year, median [IQR] | 47 [29–58] | 56 [48–64] | 41 [28–57] | 0.003 |
Males, n (%) | 50 (49.0%) | 9 (45.0%) | 41 (50.0%) | |
Body mass index, kg/m2, median [IQR] | 23.65 [20.97–26.54] | 24.49 [20.89–30.25] | 23.63 [21.05–26.30] | |
Inaugural diabetes ketoacidosis, n (%) | 18 (17.6%) | 7 (35.0%) | 11 (13.4%) | 0.045 |
Type 1 diabetes mellitus, n (%) | 61 (59.8%) | 7 (35.0%) | 54 (65.9%) | 0.021 |
Type 2 diabetes mellitus, n (%) | 23 (22.5%) | 6 (30.0%) | 17 (20.7%) | ns |
Insulin-dependent diabetes mellitus, n (%) | 72 (70.6%) | 9 (45.0%) | 63 (76.8%) | 0.006 |
COMORBIDITIES |
Hypertension, n (%) Dyslipidemia, n (%) | 30 (29.4%) | 5 (25.0%) | 25 (30.5%) | |
19 (18.6%) | 4 (20.0%) | 15 (18.3%) | |
Ischemic heart disease, n (%) | 7 (6.9%) | 2 (10.0%) | 5 (6.2%) | |
Diabetic retinopathy, n (%) | 27 (26.7%) | 4 (20.0%) | 23 (28.4%) | |
Chronic kidney disease, n (%) | 24 (23.8%) | 5 (25.0%) | 19 (23.5%) | |
Smoking, n (%) | 43 (42.2%) | 5 (25.0%) | 38 (46.3%) | ns |
Alcohol, n (%) | 24 (23.5%) | 4 (20.0%) | 20 (24.4%) | |
MEDICATIONS |
Insulin, n (%) | 72 (70.6%) | 9 (45.0%) | 63 (76.8%) | 0.006 |
Metformin, n (%) | 23 (22.5%) | 6 (30.0%) | 17 (20.7%) | ns |
Sulfonylurea, n (%) | 8 (7.9%) | 3 (15.0%) | 5 (6.2%) | ns |
No antidiabetic, n (%) | 18 (17.6%) | 7 (35.0%) | 11 (13.4%) | 0.045 |
TRIGGERING FACTORS |
Poor compliance to antidiabetic treatment, n (%) | 51 (50.0%) | | | |
No triggering factors, n (%) | 21 (20.6%) | | | |
Infection, n (%) | 20 (19.6%) | | | |
Others, n (%) | 11 (10.8%) | | | |
CLINICAL AND BIOLOGICAL DATA |
pH, median [IQR] | 7.14 [7.05–7.24] | 7.15 [7.02–7.27] | 7.14 [7.05–7.22] | ns |
Bicarbonate, mmol/L, median [IQR] | 6.00 [3.50–10.40] | 8.00 [4.15–10.55] | 5.90 [3.30–10.30] | ns |
Glycemia, mmol/L, median [IQR] | 27.5 [26.1–30.6] | 27.5 [25.1–29.0] | 27.5 [26.1–30.9] | |
Ketonemia, mmol/L, median [IQR] | 6.0 [5.1–6.9] | 5.00 [3.95–5.93] | 6.1 [5.3-7.0] | 0.007 |
SAPS II, median [IQR] | 29 [21–40] | 45 [35–58] | 26 [20–36] | < 0.001 |
TREATMENTS AND OUTCOMES | | | | |
Antibiotics treatments, n (%) | 45 (44.1%) | 20 (100.0%) | 25 (30.5%) | < 0.001 |
ICU length of stay, day, median [IQR] | 2 [1–4] | 7 [6–12] | 2 [1–3] | < 0.001 |
Hospital length of stay, day, median [IQR] | 9 [6–14] | 20 [12–24] | 8 [6–12] | < 0.001 |
Death, n (%) | 2 (2.0%) | 1 (5.0%) | 1 (1.2%) | |
aSignificant difference (p < 0.05) between infected and non-infected patients are reported in the “p value” column. IQR: interquartile range 25–75%, ICU: Intensive care unit, SAPS II: simplified acute physiology score II, |
Infections: Among the 102 (19.6%) episodes, 20 were classified “infected patients”. These patients were older and have more frequently inaugural DKA compared with non-infected patients (Table 1). On D0, ketonemia was significantly lower and gravity score [simplified acute physiology score II (SAPS II)] was significantly higher for infected patients. On D2, correction of DKA was similar in both groups. Antibiotics were administered to 45 patients: 20/20 (100%) for infected patients versus 25/82 (30.5%) for non-infected patients. Length of stay in ICU and hospital were higher for infected patients (7 vs 2 days, p < 0.001 and 8 vs 20 days, p < 0.001 respectively).
Sepsis markers at ICU admission:
Univariate analysis: On D0, temperature, fever rate and PCT level were significantly higher in infected patients compared with non-infected patients (36.9 [36.2–38.0] vs 36.4 [35.7–36.8]°C; 5 (25%) vs 3 (4%) episodes and 3.58 [1.87–11.24] vs 0.52 [0.19–1.38] ng/mL respectively). The other sepsis markers (hypothermia, WBC, neutrophil count, leukocytes abnormalities and NLCR) did not significantly differ between groups (Table 2).
Table 2
Association between sepsis markers and presence of infection at admission and day 2.
Variables | Admission | Day 2 |
Infected patients (n = 20) | Non-infected patients (n = 82) | p-valuea | Infected patients (n = 20) | Non-infected patients (n = 82) | p-valuea |
Temperature, °C, median [IQR] | 36.9 [36.2–38.0] | 36.4 [35.7–36.8] | 0.032 | 38.4 [37.1–39.0] | 37.0 [36.8–37.3] | < 0.001 |
Feverb, n (%) | 5 (25.0%) | 3 (3.6%) | 0.007 | 12 (60.0%) | 7 (8.5%) | < 0.001 |
Hypothermiac, n (%) | 4 (20.0%) | 26 (31.7%) | 0.410 | 0 (0.0%) | 1 (1.2%) | 1 |
WBC, G/L, median [IQR] | 16.85 [14.25–22.15] | 15.40 [12.30–22.50] | 0.606 | 13.05 [8.68–18.23] | 8.15 [6.68–10.20] | < 0.001 |
Leukocyte abnormalitiesd, n (%) | 18 (90.0%) | 62 (75.6%) | 0.232 | 11 (55.0%) | 14 (17.1%) | 0.001 |
Neutrophils count, G/L, median [IQR] | 13.30 [12.01–18.24] | 13.71 [9.69–20.88] | 0.673 | 10.79 [7.39–16.64] | 5.38 [3.60–7.62] | < 0.001 |
NLCR; median [IQR] | 14.04 [8.79–19.07] | 11.40 [5.78–19.27] | 0.359 | 11.54 [7.63–23.99] | 2.84 [1.56–4.96] | < 0.001 |
Procalcitonin, ng/mL, median [IQR] | 3.58 [1.87–11.24] | 0.52 [0.19–1.38] | < 0.001 | 7.43 [2.63–22.70] | 0.42 [0.14–1.42] | < 0.001 |
aSignificant difference (p < 0.05) between infected and non-infected patients are reported in the “p-value” column. bFever: Temperature > 38 °C. cHypothermia: Temperature < 36 °C. dLeukocyte abnormalities: white blood cell count > 12000/mm3 or < 4000/mm3. IQR: interquartile range 25–75%, WBC: white blood cell count, NLCR: neutrophils-to-lymphocytes count ratio. |
Multivariate analysis: Adjustment for age, type of diabetes, insulin treatment, ketonemia and SAPS II (significant variables during the univariate analysis) revealed that PCT [OR = 1.27, 95% confidence interval (IC95) [1.04–1.63] (p = 0.029) for each point of increase of PCT] and presence of fever [OR = 27.86, IC95 [1.97-887.92] (p = 0.023)] were independently associated with infection.
ROC curves: The area under the curve (AUC) for PCT was 0.87 (IC95 [0.79–0.94]) (Fig. 2A). The optimal threshold was obtained at 1.44 ng/mL leading to a sensibility (Se) of 0.90 (IC95 [0.75-1.00]) and specificity (Sp) of 0.76 (IC95 [0.66–0.84]). The AUC for temperature was 0.66 (IC95 [0.50–0.81]) with an optimal threshold of 36.8ºC (Se: 0.65 IC95 [0.45–0.85] ; Sp: 0.65 IC95 [0.56–0.75]) (Fig. 2B).
Performance of PCT and fever (> 38.0 °C) for the diagnosis of infection (Fig. 3): Association of a high PCT level (PCT > 1.44 ng/mL) with or without presence of fever for the diagnosis of infection was then investigated. All patients with PCT level of more than 1.44 ng/mL (defined using ROC curves, see above) and fever were infected patients. The presence of one of these 2 markers was associated with 46% of infected patients. No afebrile patient with PCT level less than 1.44 ng/mL was infected.
Sepsis markers at D2:
Univariate analysis: On D2, more differences appeared between the two groups. Indeed, temperature, fever rate, WBC, neutrophil count, leukocytes abnormalities, NLCR and PCT were significantly higher in infected patients (Table 2). Both groups were also different when looking at any episode of fever during the first 2 days of hospitalization (infected patients: 60.0% vs non-infected patients: 9.1%, OR = 14.3 IC95% [4.0–58.0], p < 0.001). In infected patients, between D0 and D2, NLCR and PCT did not change significantly (p = 0.968 and p = 0.283 respectively). Whereas in non-infected patients, NLCR (D0: 13.42 vs D2: 5.37, p < 0.001) and PCT (D0: 0.51 ng/mL vs D2: 0.39 ng/mL, p = 0.005) significantly decreased [see Table S1 and S2 in the Additional file 1].
Multivariate analysis: Adjustment for age, type of diabetes, insulin treatment and ketonemia and SAPS II during the multivariate analysis revealed that only PCT was independently different between both groups [OR = 4.45, IC95 [1.73–39.53] (p = 0.030) for each point of increase of PCT]. Presence of fever and WBC were not different.
ROC curves: The AUC for PCT was 0.91 (IC95 [0.84–0.99] with an optimal threshold at 2.78 ng/mL leading to a Se of 0.74 (IC95 [0.53–0.89] and a Sp of 0.96 (IC95 [0.89-1.00]) [see Figure S1 in the Additional file 1]. The AUC for temperature, WBC, neutrophil count and NLCR were 0.79, 0.78, 0.84 and 0.87 respectively [see Figure S2 in the Additional file 1].