应激性血糖升高对重症监护病房患者28 d全因死亡风险的预测价值

doi:10.19723/j.issn.1671-167X.2023.03.009

摘要/Abstract

摘要：

目的: 探究应激性血糖升高与重症监护病房(intensive care unit, ICU) 患者28 d全因死亡风险之间的关系, 并比较不同应激性血糖升高指标的预测效能。方法: 以重症医学(Medical Information Mart for Intensive Care Ⅳ, MIMIC-Ⅳ) 数据库中符合纳入、排除标准的ICU患者为研究对象，将应激性血糖升高指标按照百分位数分为Q1(0~25%)、Q2(>25%~75%)、Q3(>75%~100%)组，以是否发生ICU内死亡及在ICU内接受治疗的时间为结局变量，以人口学特征、实验室指标、合并症等为协变量，利用Cox回归及限制性立方样条探究应激性血糖升高和ICU患者28 d全因死亡风险之间的关联; 采用受试者工作特征(receiver operation characteristic, ROC)曲线下面积(area under curve, AUC)评价不同应激性血糖升高指标的预测效能，应激性血糖升高指标包括应激性血糖升高比值(stress hyperglycemia ratio, SHR) 1、SHR2、血糖间隙(glucose gap, GG); 进一步将应激性血糖升高指标纳入牛津急性疾病严重程度评分(Oxford acute severity of illness score, OASIS)，探究其改善评分的预测效能，即采用AUC评估评分区分度，AUC越大表明评分区分度越好，采用Brier score评价评分校准度，Brier score越小，表明评分校准度越好。结果: 共纳入5 249例ICU患者，其中发生ICU内死亡的患者占7.56%。调整混杂因素后的Cox回归分析结果表明，SHR1、SHR2和GG的最高组Q3与最低组Q1相比，ICU患者28 d全因死亡HR(95%CI)分别为1.545(1.077~2.217)、1.602(1.142~2.249)和1.442(1.001~2.061)，且随着应激性血糖升高指标的增加，ICU患者死亡风险也逐渐增加(P_trend < 0.05)。限制性立方样条分析表明，SHR和28 d全因死亡风险之间呈线性关系(P>0.05)。SHR2和GG的AUC显著高于SHR1: AUC_SHR2=0.691(95%CI: 0.661~0.720)，AUC_GG=0.685(95%CI: 0.655~0.714)，AUC_SHR1=0.680(95%CI: 0.650~0.709)，P < 0.05。将SHR2纳入OASIS评分中，能显著提高评分的区分度和校准度：AUC_OASIS=0.820(95%CI: 0.791~0.848)，AUC_OASIS+SHR2=0.832(95%CI: 0.804~0.859)，P < 0.05; Brier score_OASIS=0.071，Brier score_OASIS+SHR2= 0.069。结论: 应激性血糖升高与ICU患者28 d全因死亡风险密切相关，可为重症监护患者的临床管理和决策提供参考。

关键词: 应激性血糖升高, 重症监护病房, 死亡风险, Cox回归, 限制性立方样条

Abstract:

Objective: To investigate the relationship between stress glucose elevation and the risk of 28 d all-cause mortality in intensive care unit (ICU) patients, and to compare the predictive efficacy of different stress glucose elevation indicators. Methods: ICU patients who met the inclusion and exclusion criteria in the Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database were used as the study subjects, and the stress glucose elevation indicators were divided into Q1 (0-25%), Q2 (>25%- 75%), and Q3 (>75%-100%) groups, with whether death occurred in the ICU and the duration of treatment in the ICU as outcome variables, and demographic characteristics, laboratory indicators, and comorbidities as covariates, Cox regression and restricted cubic splines were used to explore the association between stress glucose elevation and the risk of 28 d all-cause death in ICU patients; and subject work characteristics [receiver operating characteristic (ROC) and the area under curve (AUC)] were used to evaluate the predictive efficacy of different stress glucose elevation indicators, The stress hyperglycemia indexes included: stress hyperglycemia ratio (SHR1, SHR2), glucose gap (GG); and the stress hyperglycemia index was further incorporated into the Oxford acute severity of illness score (OASIS) to investigate the predictive efficacy of the improved scores: the AUC was used to assess the score discrimination, and the larger the AUC indicated, the better score discrimination. The Brier score was used to evaluate the calibration of the score, and a smaller Brier score indicated a better calibration of the score. Results: A total of 5 249 ICU patients were included, of whom 7.56% occurred in ICU death. Cox regression analysis after adjusting for confounders showed that the HR (95%CI) for 28 d all-cause mortality in the ICU patients was 1.545 (1.077-2.217), 1.602 (1.142-2.249) and 1.442 (1.001-2.061) for the highest group Q3 compared with the lowest group Q1 for SHR1, SHR2 and GG, respectively, and The risk of death in the ICU patients increased progressively with increasing indicators of stressful blood glucose elevation (P_trend < 0.05). Restricted cubic spline analysis showed a linear relationship between SHR and the 28 d all-cause mortality risk (P>0.05). the AUC of SHR2 and GG was significantly higher than that of SHR1: AUC_SHR2=0.691 (95%CI: 0.661-0.720), AUC_GG=0.685 (95%CI: 0.655-0.714), and AUC_SHR1=0.680 (95%CI: 0.650-0.709), P < 0.05. The inclusion of SHR2 in the OASIS scores significantly improved the discrimination and calibration of the scores: AUC_OASIS=0.820 (95%CI: 0.791-0.848), AUC_OASIS+SHR2=0.832 (95%CI: 0.804-0.859), P < 0.05; Brier score_OASIS=0.071, Brier score_OASIS+SHR2=0.069. Conclusion: Stressful glucose elevation is strongly associated with 28 d all-cause mortality risk in ICU patients and may inform clinical management and decision making in intensive care patients.

Key words: Stress-induced hyperglycemia, Intensive care unit, Risk of death, Cox regression, Restricted cubic splines

中图分类号:

R193.3

汪雨欣,邓宇含,谭银亮,刘宝花. 应激性血糖升高对重症监护病房患者28 d全因死亡风险的预测价值[J]. 北京大学学报（医学版）, 2023, 55(3): 442-449.

Yu-xin WANG,Yu-han DENG,Yin-liang TAN,Bao-hua LIU. Predictive value of stress-induced hyperglycemia on 28 d risk of all-cause death in intensive care patients[J]. Journal of Peking University (Health Sciences), 2023, 55(3): 442-449.

图/表 8

图1

表1

5 249例ICU患者的基本特征"

Variables	Total (n=5 249)	Survival (n=4 852)	Death (n=397)	P value
Demographic characteristics
Insurance, n(%)				< 0.001
Medicaid	302 (5.8)	289 (6.0)	13 (3.3)
Medicare	2 289 (43.6)	2 074 (42.7)	215 (54.2)
Other	2 658 (50.6)	2 489 (51.3)	169 (42.6)
Marital status, n(%)				< 0.001
Divorced	407 (7.8)	378 (7.8)	29 (7.3)
Married	2 788 (53.1)	2 594 (53.5)	194 (48.9)
Single	1 372 (26.1)	1 280 (26.4)	92 (23.2)
Widowed	682 (13.0)	600 (12.4)	82 (20.7)
Length of stay/d, M(P₂₅, P₇₅)	2.24 (1.28, 4.58)	2.17 (1.26, 4.23)	4.25 (2.12, 9.16)	< 0.001
Male, n(%)	3 088 (58.8)	2 895 (59.7)	193 (48.6)	< 0.001
Age/year, M(P₂₅, P₇₅)	68.00 (56.00, 78.00)	67.00 (56.00, 77.00)	76.00 (62.00, 84.00)	< 0.001
Complications
Myocardial infarction, n(%)	1 410 (26.9)	1 292 (26.6)	118 (29.7)	0.201
Congestive heart failure, n(%)	1 506 (28.7)	1 344 (27.7)	162 (40.8)	< 0.001
Peripheral vascular disease, n(%)	651 (12.4)	595 (12.3)	56 (14.1)	0.321
Cerebrovascular disease, n(%)	1 999 (38.1)	1 769 (36.5)	230 (57.9)	< 0.001
Dementia, n(%)	176 (3.4)	152 (3.1)	24 (6.0)	0.003
Chronic pulmonary disease, n(%)	1 042 (19.9)	953 (19.6)	89 (22.4)	0.205
Rheumatic disease, n(%)	143 (2.7)	130 (2.7)	13 (3.3)	0.589
Peptic ulcer, n(%)	63 (1.2)	56 (1.2)	7 (1.8)	0.406
Mild liver disease, n(%)	291 (5.5)	238 (4.9)	53 (13.4)	< 0.001
Severe liver disease, n(%)	71 (1.4)	52 (1.1)	19 (4.8)	< 0.001
Diabetes with chronic complication, n(%)	550 (10.5)	507 (10.4)	43 (10.8)	0.878
Diabetes without chronic complication, n(%)	1 561 (29.7)	1 439 (29.7)	122 (30.7)	0.695
Paraplegia, n(%)	975 (18.6)	843 (17.4)	132 (33.2)	< 0.001
Renal disease, n(%)	896 (17.1)	791 (16.3)	105 (26.4)	< 0.001
Charlson comorbidity index, ±s	5.47±2.48	5.36±2.44	6.91±2.51	< 0.001
Vital signs，M(P₂₅, P₇₅)
Heart rate/(beats/min)	79.97 (71.74, 89.58)	79.77 (71.72, 89.11)	83.61 (72.40, 95.48)	< 0.001
Respiratory rate/(times/min)	18.20 (16.58, 20.23)	18.08 (16.51, 20.04)	19.90 (17.81, 22.57)	< 0.001
Temperature/℃	36.81 (36.62, 37.04)	36.81 (36.62, 37.02)	36.87 (36.62, 37.25)	< 0.001
Oxygen saturation/%	96.83 (95.60, 97.97)	96.80 (95.60, 97.93)	97.36 (95.61, 98.59)	0.001
Weight/kg	84.13 (70.71, 100.08)	84.50 (71.19, 100.37)	80.00 (65.80, 96.00)	< 0.001
Lab indexes, M(P₂₅, P₇₅)
White blood cell count/(×10⁹/L)	10.80 (8.27, 13.67)	10.60 (8.18, 13.48)	12.80 (10.25, 16.25)	< 0.001
Chloride/(mmol/L)	104.60 (101.67, 107.00)	104.50 (101.75, 107.00)	105.00 (100.05, 108.00)	0.157
Creatinine/(mg/dL)	0.93 (0.75, 1.20)	0.90 (0.75, 1.20)	1.23 (0.87, 1.98)	< 0.001
AG/(mg/dL)	7.29 (6.39, 8.89)	7.22 (6.34, 8.72)	8.37 (7.02, 10.69)	< 0.001
Sodium/(mmol/L)	138.20 (136.20, 140.50)	138.02 (136.17, 140.28)	139.40 (136.67, 142.11)	< 0.001
Hemoglobin/(g/dL)	11.54 (10.06, 12.90)	11.59 (10.11, 12.96)	11.00 (9.45, 12.55)	< 0.001
Blood urea nitrogen/(mg/dL)	16.67 (12.50, 23.50)	16.00 (12.25, 22.50)	25.00 (16.00, 41.40)	< 0.001
Anion gap/(mEq/L)	14.00 (12.00, 16.00)	13.67 (12.00, 15.67)	16.00 (14.00, 18.31)	< 0.001
Potassium/(mEq/L)	4.14 (3.87, 4.42)	4.13 (3.88, 4.40)	4.17 (3.85, 4.56)	0.073
Blood platelet count/(×10⁹/L)	193.71 (152.56, 244.50)	193.00 (152.84, 243.66)	202.00 (150.67, 252.00)	0.547
Thrombin time/s	13.27 (12.05, 14.70)	13.20 (12.00, 14.60)	13.75 (12.35, 16.10)	< 0.001
Prothrombin time/s	30.65 (27.30, 38.70)	30.56 (27.30, 38.28)	31.70 (28.40, 47.65)	< 0.001
International normalized ratio	1.20 (1.10, 1.30)	1.20 (1.10, 1.30)	1.25 (1.10, 1.50)	< 0.001
Bicarbonate/(mEq/L)	23.50 (21.60, 25.40)	23.67 (22.00, 25.50)	21.80 (19.00, 24.00)	< 0.001
Haematocrit/%	34.70 (30.90, 38.80)	34.80 (31.07, 38.80)	33.88 (29.05, 38.40)	0.004
Red blood cell distribution width/%	13.76 (13.10, 14.70)	13.70 (13.10, 14.65)	14.40 (13.60, 15.80)	< 0.001
Calcium/(mg/dL)	8.65 (8.20, 9.00)	8.65 (8.24, 9.00)	8.53 (8.10, 9.00)	0.003
HbA1c/%	5.90 (5.50, 6.80)	5.86 (5.50, 6.80)	5.90 (5.50, 6.70)	0.798
Scores, M(P₂₅, P₇₅)
GCS	13.00 (10.00, 14.00)	14.00 (11.00, 14.00)	8.00 (6.00, 11.00)	< 0.001
SIH-related index
SHR1, M(P₂₅, P₇₅)	1.04 (0.90, 1.20)	1.03 (0.90, 1.18)	1.19 (1.01, 1.42)	< 0.001
GG, M(P₂₅, P₇₅)	0.28 (-0.71, 1.31)	0.20 (-0.75, 1.22)	1.31 (0.11, 2.87)	< 0.001
SHR2, M(P₂₅, P₇₅)	1.20 (1.06, 1.37)	1.19 (1.05, 1.35)	1.39 (1.19, 1.64)	< 0.001
SHR1 tertile, n(%)				< 0.001
Q1(≤0.90)	1 288 (24.5)	1 241 (25.6)	47 (11.8)
Q2(>0.90, ≤1.20)	2 681 (51.1)	2 523 (52.0)	158 (39.8)
Q3(>1.20)	1 280 (24.4)	1 088 (22.4)	192 (48.4)
SHR2 tertile, n(%)				< 0.001
Q1(≤1.06)	1 342 (25.6)	1 289 (26.6)	53 (13.4)
Q2(>1.06, ≤1.37)	2 594 (49.4)	2 456 (50.6)	138 (34.8)
Q3(>1.37)	1 313 (25.0)	1 107 (22.8)	206 (51.9)
GG tertile, n(%)				< 0.001
Q1(≤－0.71)	1 320 (25.1)	1 270 (26.2)	50 (12.6)
Q2(>-0.71, ≤1.32)	2 631 (50.1)	2 482 (51.2)	149 (37.5)
Q3(>1.32)	1 298 (24.7)	1 100 (22.7)	198 (49.9)

表1

图2

表2

图3

表3

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图5

参考文献 24

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Variables	Model 1			Model 2			Model 3
Variables	HR(95%CI)	P	P_trend	HR(95%CI)	P	P_trend	HR(95%CI)	P	P_trend
SHR1	3.692(2.793, 4.881)	< 0.001		4.250(3.127, 5.776)	< 0.001		2.037(1.427, 2.908)	< 0.001
SHR1 tertile			< 0.001			< 0.001			< 0.001
Q1(≤0.90)	Reference			Reference			Reference
Q2(>0.90, ≤1.20)	1.421 (1.013, 1.992)	0.042		1.254 (0.889, 1.768)	0.198		1.068 (0.753, 1.516)	0.712
Q3(>1.20)	2.663 (1.907, 3.710)	< 0.001		2.548 (1.816, 3.576)	< 0.001		1.545 (1.077, 2.217)	0.018
SHR2	3.580 (2.767, 4.632)			4.098 (3.084, 5.445)	< 0.001		2.059 (1.488, 2.850)
SHR2 tertile			< 0.001			< 0.001			< 0.001
Q1(≤1.06)	Reference			Reference			Reference
Q2(>1.06, ≤1.37)	1.188 (0.856, 1.648)	0.302		1.163 (0.836, 1.619)	0.206		1.057 (0.754, 1.482)	0.747
Q3(>1.37)	2.558 (1.869, 3.502)	< 0.001		2.615 (1.902, 3.596)	< 0.001		1.602 (1.142, 2.249)	0.006
GG	1.215 (1.164, 1.269)	< 0.001		1.229 (1.172, 1.289)	< 0.001		1.110 (1.055, 1.168)	< 0.001
GG tertile			< 0.001			< 0.001			< 0.001
Q1(≤-0.71)	Reference			Reference			Reference
Q2(>-0.71, ≤1.32)	1.407 (1.005, 1.971)	0.047		1.215 (0.860, 1.718)	0.270		1.014 (0.711, 1.445)	0.940
Q3(>1.32)	2.739 (1.972, 3.805)	< 0.001		2.519 (1.802, 3.522)	< 0.001		1.442 (1.001, 2.061)	0.044

Variables	AUC(95%CI)	P^a	P^b	P^c	P^d
Hba1c	0.504 (0.475-0.532)
AG	0.650 (0.618-0.675)	< 0.001
SHR1	0.680 (0.650-0.709)	< 0.001	0.015
SHR2	0.691 (0.661-0.720)	< 0.001	< 0.001	0.007
GG	0.685 (0.655-0.714)	< 0.001	0.005	0.018	0.111

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