Management of critically ill patients with type 2 diabetes: The need for personalised therapy

Table 1 Prevalence of diabetes in hospital population (chronological order)

Ref.	Year	R-D	UR-D	Total study patients	Location	Diabetes diagnosed by	Unrecognised diabetes diagnosed by
Umpierrez et al[14]	2002	495 (26%)	2231 (12%)	1886	Atlanta, United States	Admission history	Fasting blood glucose ≥ 7 mmol/LRandom blood glucose ≥ 11.1 mmol/L × 2
Wallymahmed et al[15]	2005	126 (11%)	131 (1%)	1129	Liverpool, United Kingdom	Admission historyHospital records	Random blood glucose ≥ 11.1 mmol/L
Wexler et al[17]	2008	136 (19%)	33 (5%)	695	Boston, United States	Admission historyHospital records	HbA1c > 6.5
Mazurek et al[18]	2010	342 (35%)	152 (16%)	971	New York, United States	Admission historyHospital recordsMedication review	HbA1c ≥ 6.5
Feldman-Billard et al[16]	2013	355 (17%)	1561 (7%)	2141	Multicentre (France)	Admission history	Fasting blood glucose ≥ 7 mmol/L

¹May include patients with stress hyperglycaemia/critical illness associated hyperglycaemia. R-D: Recognised diabetes; UR-D: Unrecognised diabetes.

Table 2 Prevalence of diabetes in the intensive care unit population (chronological order)

Ref.	Year	Study type	R-D	UR-D	Total study patients	Location	Recognised DM diagnosis	Unrecognised diabetes diagnosed by
Van den Berghe et al[36]	2001	Interv	204 (13%)	N/A	1548	Leuven, Belgium	Admission history	N/A
Finney et al[27]	2003	Observ	86 (16%)	N/A	523	London, United Kingdom	Unknown	N/A
Whitcomb et al[23]	2005	Observ	574 (21%)	3951 (15%)	2713	Baltimore, United States	Admission history	Hyperglycaemia without a history of DM
Van den Berghe et al[37]	2006	Interv	203 (17%)	N/A	1200	Leuven, Belgium	Admission history	N/A
Krinsely[24]	2006	Observ	1110 (21%)	N/A	5365	Stamford, United States	Hospital records (ICD-9 codes) for the first 2 yr then all available info	N/A
Egi et al[28]	2008	Observ	728 (15%)	N/A	4946	Multicentre (Australia)	Hospital records	N/A
Treggiari et al[25]	2008	Observ	1361 (13%)	N/A	10456	Seattle, United States	Hospital records	N/A
Arabi et al[39]	2008	Interv	208 (40%)	N/A	523	Riyadh, Saudi Arabia	Admission historyHospital records	N/A
Bronkhurst et al[38]	2008	Interv	163 (30%)	N/A	537	Multicentre (Germany)	Unknown	N/A
Del La Rosa et al[42]	2008	Interv	61 (12%)	N/A	504	Medellin, Colombia	Admission history	N/A
Finfer et al[41]	2009	Interv	1211 (20%)	N/A	6029	Multicentre (Australia, NZ, Canada)	Admission history	N/A
Preiser et al[40]	2009	Interv	203 (19%)	N/A	1078	Multicentre (Europe)	Admission history	N/A
Falciglia et al[26]	2009	Observ	77850 (30%)	N/A	259040	Multicentre (United States)	Hospital records (ICD-9 codes)	N/A
Stegenga et al[30]	2010	Observ	188 (23%)	N/A	830	Multicentre (Worldwide)	Admission history	N/A
Hermanides et al[29]	2010	Observ	699 (12%)	N/A	5961	Amsterdam, Netherlands	Hospital records (computerised system)	N/A
Krinsely et al[33]	2011	Observ	669 (21%)	N/A	3263	Multicentre (United States, Europe)	Hospital records (ICU clinical database)	N/A
Krinsley et al[32]	2013	Observ	12880 (29%)	N/A	44964	Multicentre (Worldwide)	Admission history	N/A
Plummer et al[34]	2014	Observ	220 (22%)	55 (6%)	1000	Adelaide, Australia	Admission historyPhone call to GPHbA1c ≥ 6.5	HbA1c ≥ 6.5 without a history of DM

¹May include patients with stress hyperglycaemia/critical illness associated hyperglycaemia. Interv: Interventional; Observ: Observational; R-D: Recognised diabetes; UR-D: Unrecognised diabetes; NZ: New Zealand; N/A: Not available.

Table 3 Prevalence of undiagnosed diabetes in the hospital population (chronological order)

Ref.	Year	Diagnosis	UR-D	Total study patients	Location	Patient population
Norhammer et al[45]	2002	OGTT	51 (31%) at discharge36 (25%) at 3 mo	164 144	Multicentre (Sweden)	Post AMI, Hospital/ICU
George et al[47]	2005	Fasting blood glucose ≥ 7 mmol/L	13 (3%)	427	London, United Kingdom	Emergency Department
Wexler et al[17]	2008	HbA1c > 6.5	33 (5%)	695	Boston, United States	Hospital
Lankisch et al[46]	2008	OGTT	31 (32%) at discharge19 (31%) at 3 mo	96 62	Wuppertal, Germany	Post AMI, Hospital/ICU
Mazurek et al[18]	2010	HbA1c ≥ 6.5	152 (16%)	971	New York, United States	Hospital
Feldman-Billard et al[16]	2013	Fasting blood glucose≥ 7 mmol/L	156 (7%)	2141	Multicentre (France)	Hospital
Plummer et al[34]	2014	HbA1c ≥ 6.5	55 (6%)	1000	Adelaide, Australia	ICU
Hoang et al[44]	2014	HbA1c ≥ 6.5	14 (14%)	102	New Haven, United States	Medical ICU
Ochoa et al[43]	2014	HbA1c ≥ 6.5	8 (9%)	92	Abilene, United States	Hospital

UR-D: Unrecognised diabetes; OGTT: Oral Glucose Tolerance Test; AMI: Acute myocardial infarction.

Table 4 Observational studies (diabetes as a binary variable) and outcomes related to hyperglycaemia (chronological order)

Ref.	Year	Study pts	Study point	Patients without diabetes	Patients with diabetes	Overall message
Rady et al[35]	2005	7285	Glycaemia vs hospital mortality	Inc mortality with blood glucose > 8 mmol/L	Inc mortality with blood glucose > 11.1 mmol/L	Mortality inc in non diabetics (10%) compared to diabetics (6%), (P < 0.01)
Whitcomb et al[23]	2005	2713	Admission hyperglycaemia (> 11.1 mmol/L) vs in-hospital mortality	Admission hyperglycaemia associated with inc mortality in CICU, CTICU and NSICU	Admission hyperglycaemia not associated with mortality	Mortality inc in non diabetics (10%) compared to diabetics (5%), (P < 0.05)
Krinsely[24]	2006	5365	Pre ITT and post ITT vs hospital mortality	Dec mortality risk with mean blood glucose 3.9-6.7 mmol/LInc mortality risk with mean blood glucose > 7.8 mmol/LMortality drop 19% (pre-ITT) to 14% (post-ITT), P < 0.01	Dec mortality risk with mean blood glucose 3.9-5.5 mmol/LInc mortality risk with mean blood glucose > 10.0 mmol/LNo statistically significant change in mortality pre and post ITT	Non-diabetics: 4.5-fold inc in mortality from lowest mean blood glucose, 3.9-5.5 mmol/L (9%) to highest, > 10mmol/L (40%)Diabetics: 2-fold inc in mortality from lowest mean blood glucose, 3.9-5.5 mmol/L (13%) to highest, > 10mmol/L (26%)
Egi et al[28]	2008	4896	Glycaemia vs mortality	Inc risk of ICU mortality with hyperglycaemia - with non survivors spending more time with blood glucose > 8.0 mmol/L	No association with hyperglycaemia and ICU mortality Lower OR of death at all levels of hyperglycaemia	Diabetic patients: lower ICU mortality (P = 0.02)No difference in hospital mortality between groups (P = 0.3)
Falciglia et al[26]	2009	259040	Glycaemia vs mortality	5-fold inc in mortality from lowest mean blood glucose, 3.9-6.1 mmol/L (8%) to highest, > 16.7 mmol/L (41%)	2-fold inc in mortality from lowest mean blood glucose, 3.9-6.1 mmol/L (6%) to highest, > 16.7 mmol/L (11%)	Hyperglycaemia associated with inc mortality in diabetics and non diabeticsMortality greater for hyperglycemic non diabetics patients
Stegenga et al[30]	2010	830	DM vs outcomes of sepsis	Admission hyperglycaemia (> 11.1 mmol/L) associated with inc 28 and 90 d mortality (P < 0.03)	Admission hyperglycaemia had no effect on diabetic mortaltity	Diabetes did not influence mortality in sepsis
Krinsley et al[32]	2013	44964	Hyperglycaemia, hypoglycaemia, and glycemic variability vs mortality (and how DM effects this)	Inc mortality with higher mean blood glucose (≥ 7.8 mmol/L)Dec mortality with lower blood glucose (4.4-7.8 mmol/L)	Inc mortality with mean blood glucose between 4.4-6.1 mmol/LDec mortality when blood glucose were higher (6.2-10 mmol/L)	Hyperglycaemia, hypoglycaemia, and increased glycemic variability are independently associated with mortality in ICU patientsDiabetic status tempers these relations

Inc: Increased; Dec: Decreased; CICU: Cardiac Intensive Care Unit; CTICU: Cardiothoracic Intensive Care Unit; NSICU: Neurosurgical Intensive Care Unit; ITT: Intensive insulin therapy.

Table 5 Interventional studies (diabetes as a binary variable) and outcomes related to hyperglycaemia (chronological order)

Ref.	Year	Study pts	Study point	Non diabetic patients	Diabetic patients	Overall message
1Van den Berghe et al[54]	2006	2748	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (insulin if blood glucose > 12 then target 10-11.1 mmol/L) on mortality	Reduced mortality and morbidity with ITT	No survival benefit with ITTHigher rates of hypoglycaemia	Hosp mortality 20% (40/200) of the DM patients in conventional arm Hosp mortality 22% (46/207) of the DM patients in the ITT arm
Arabi et al[39]	2008	523	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (blood glucose 10-11.1 mmol/L) on ICU mortality	Mortality: ITT (14%) vs CIT (14%) - no significant difference (P = 0.2)	Mortality: ITT (13%) vs CIT (20%) - no significant difference (P = 0.3)	No significant difference in ICU mortality between IIT and CIT (P = 0.3)
Brunkhorst et al[38]	2008	537	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (blood glucose 10-11.1 mmol/L) on mortality	28 d mortality: ITT 25% vs CIT 23% (P = 0.8)90 d mortality: ITT 40% vs CIT 32% (P = 0.2)	28 d mortality: ITT 25% vs CIT 32% (P = 0.3)90 d mortality: ITT 40% vs CIT 42% (P = 0.9)	No mortality benefit with ITT vs CITStopped early due to safety risk
Del La Rosa et al[42]	2008	504	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (blood glucose 10-11.1 mmol/L) on morbidity and mortality	ICU mortality ITT 37% vs CIT 32% (no significance)2In-hospital mortality: ITT 40% vs CIT 39% (no significance)2	Mortality: ITT (38%) vs CIT (31%) - no significant difference	No difference in ICU mortality, 28 d mortality or ICU infectionsIncreased hypoglycaemia in ITT
Finfer et al[41]	2009	6029	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (blood glucose < 10 mmol/L) on mortality	Mortality: ITT (27%) vs CIT (24%) - no significant difference	Mortality: ITT (32%) vs CIT (28%) - no significant difference	ITT arm - inc 90 d mortalityNo difference in those with and without DM (P = 0.60)
Preiser et al[40]	2009	1078	ITT (blood glucose 4.4-6.1 mmol/L) vs CIT (blood glucose 7.8-10 mmol/L) on mortality	ICU mortality ITT 17% vs CIT 15% (P = 0.4) 2Hospital mortality: ITT 23% vs CIT 19% (P = 0.1)2	Not described	Stopped early due to protocol violations

¹Contains pooled data from the 2001 (surgical) and 2006 (medical) study;

²Mortality of total patients (includes non-diabetic and diabetic patients). ITT: Intensive insulin therapy; CIT: Conventional insulin therapy; Inc: Increased; Dec: Decrease.

Table 6 Observational studies that have recorded chronic glycaemia as a dynamic variable (chronological order)

Ref.	Year	Study pts	Study point	Non diabetic patients	Diabetic patients	Overall message
Egi et al[55]	2011	415	Does preexisting hyperglycaemia modulate the association between glycemia and outcome in ICU patients with DM	N/A	Patients with elevated preadmission HbA1c levels (> 7%) showed a mortality benefit when mean ICU glucose concentrations were > 10 mmol/L	Relationship between HbA1c and mortality changed according to the levels of time-weighted average of blood glucose concentrations
Plummer et al[34]	2014	1000	Prevalence of CIAH and recognized/unrecognized DM in ICU and to evaluate the premorbid glycaemia on the association between acute hyperglycaemia and mortality	50% had CIAHRisk of death inc by 20% for each increase in acute glycaemia of 1 mmol/L	Well controlled DM (HbA1c < 6%) and adequately controlled (DM 6%-7%) - risk of death as per non diabetic patientHbA1c ≥ 7% (insufficiently controlled DM) had no significance between mortality and acute glycaemia	22% had recognised DM6% had unrecognised diabetes
Hoang et al[44]	2014	299	Prevalance of unrecognized DM amongst those with CIAH and the association between baseline glycaemia and mortality	102 (34%) had no history of DM14/102 (14%) had unrecognized DM (diagnosed with HbA1c ≥ 6.5)	197 (66%) had a history of DM	Lower HbA1c had inc mortality (in this population of CIAH patients) despite lower median glucose values and less glucose variabilityMortality in HbA1c < 6.5 (19%) vs HbA1c ≥ 6.5 (12%), P = 0.04

Inc: Increased; Dec: Decreased; N/A: Not available.

Table 7 Observational studies and outcomes related to hypoglycaemia (chronological order)

Ref.	Year	Study pts	Study point	Non diabetic patients	Diabetic patients	Overall message
Krinsley and Grover[60]	2007	408	Risk factors for developing hypoglycaemia in ICU and outcomes	Severe hypoglycaemia associated with septic shock. Renal insufficiency, mechanical ventilation, illness severity and use of ITT	Associated with inc risk of severe hypoglycaemia (P < 0.01)DM had no association with mortality	Mortality in severe hypoglycaemia cohort 56% vs control cohort 40%, P < 0.01
Egi et al[61]	2010	4946	Hypoglycaemia vs risk of death in critically ill patients	Mild or moderate hypoglycaemia was associated with mortality in critically ill patientsMortality increases as severity of hypoglycaemia increases	Diabetic patients more likely to suffer from insulin-associated hypoglycaemia	22% of total patients had one episode of hypoglycaemiaHospital mortality: hypoglycaemic cohort 37% vs control cohort 20%, P < 0.01
Krinsely et al[33]	2011	62401	Mild hypoglycaemia (blood glucose level < 3.9 mmol/L) vs risk of mortality in critically ill patients.	Mild hypoglycaemia was associated with a significantly increased risk of mortality	The association between hypoglycaemia and mortality was independent of diabetic status	Inc severity of hypoglycaemia was associated with inc risk of mortalityHypoglycemic patients had higher mortality regardless of diagnostic category and ICU LOS
Krinsley et al[32]	2013	44964	Hyperglycaemia, hypoglycaemia, and glycemic variability vs mortality (and how DM effects this)	Inc mortality with higher mean blood glucose (≥ 7.8 mmol/L)Dec mortality with lower blood glucose (4.4-7.8 mmol/L)	Inc mortality with mean blood glucose between 4.4-6.1 mmol/LDec mortality when blood glucose were higher (6.2-10 mmol/L)	Hyperglycaemia, hypoglycaemia, and increased glycemic variability are independently associated with mortality in ICU patientsDiabetic status tempers these relations

¹Contains partial data from one prospective RCT (Glucontrol trial) and complete data from two observational cohorts (United States and The Netherlands). Inc: Increased; Dec: Decrease; LOS: Length of stay.

Table 8 Observational and interventional studies and outcomes related to glycaemic variability (chronological order)

Ref.	Year	Study pts	Study point	Non diabetic patients	Diabetic patients	Overall message
Egi et al[65]	2006	7049	GV (measured by SD and %CV) vs mortality (hospital and ICU)	Both mean and GV of blood glucose were significantly and independently associated with ICU and hospital mortalityGV was a stronger predictor of ICU mortality than mean glucose concentration	Inc mortality when comparing highest and lowest glucose SDNo other significant relation with blood glucose (SD and mean) and ICU/hospital mortality Logistic regression: DM associated with decrease OR for ICU mortality	The mean ± SD of blood glucose: Survivors 1.7 ± 1.3 mmol/L vs Non survivors 2.3 ± 1.6 mmol/L (P < 0.001)Post logistic regression analysis, both mean and SD of blood glucose were significantly associated with ICU and hospital
Ali et al[66]	2008	1246	GV vs hospital mortality in septic ICU patients	GV is independently associated with hospital mortality in sepsis	Mortality rise remained even after adjusting for a diagnosis of diabetes	Higher observed mortality with increasing levels of variabilityHigher odds of hospital mortality with lower mean blood glucose + high GV or higher mean blood glucose + lower GV
Krinsely[67]	2008	3252	GV vs mortality in ICU patients	Inc GV conferred a strong independent risk of mortality	Multivariable regression analysis demonstrated that diabetes had an independent positive correlation to SD	Amount of GV had a significant effect on mortality - e.g., patients with mean blood glucose 3.9-5.5 mmol/L mortality: Lowest GV 6% while high GV 30%
Krinsely[68]	2009	4084	Impact of DM or its absence on GV as a risk factor for mortality	Low GV was associated with increased survivalHigh GV was associated with increased mortality	Higher measures of GVNo association between GV and mortality among diabetics	Attempts to minimize GV may have a significant beneficial impact on outcomes of critically ill patients without diabetes
Lundelin et al[69]	2010	42	Glycemic dynamics (measured via non-lineal dynamics) vs mortality in ICU patients	Loss of complexity (therefore higher variability) in glycaemia time series is associated with higher mortality	This association persisted in diabeticsNo difference in DFA (detrended fluctuation analysis a measure of complexity) between DM and nondiabetics	In critically ill patients, there is a difference in the complexity of the glycaemic profile between survivors and nonsurvivorsLoss of complexity correlates with higher mortality
1Meyfroidt et al[71]	2010	2 748	Blood glucose signal characteristics vs hospital mortality,	GV was independently associated with hospital mortality	Increased mortality was seen in both diabetics and non diabetic patients.	Increased glucose amplitude variation was associated with mortality, irrespective of blood glucose level
Hoang et al[44]	2014	299	Prevalance of unrecognized DM amongst those with CIAH and the association between baseline glycaemia and mortality	102 (34%) had no history of DM14/102 (14%) had unrecognized DM (diagnosed with HbA1c ≥ 6.5)	197 (66%) had a history of DM	Lower HbA1c had inc mortality (in this population of CIAH patients) despite lower median glucose values and less glucose variabilityMortality in HbA1c < 6.5 (19%) vs HbA1c ≥ 6.5 (12%), P = 0.04
Donati et al[70]	2014	2 782	GV and mean BGLs vs mortality and intensive care unit-acquired infections	High GV is associated with higher risk of ICU acquired infection and mortality	Diabetic patients had higher mean BGL and GVNo change in mortality or infections	Mean BGL was not associated with infections and mortality

¹Interventional study data - pooled from the Leuven trials. GV: Glycaemic variability; SD: Standard deviation; %CV: Coefficient of variation; Inc: Increased; Dec: Decreased; OR: Odds rat.