Inpatient Hyperglycemia

Management in Critically Ill

Patients
 Hyperglycemia & ICU Mortality
45

40

35

30

25

20
Retrospective study
15 n= 1826
10
patients 

0
80-99 100-119 120-139 140-159 160-179 180-199 200-249 250-299 > 300

Mean ICU glucose, mg/dL

Retrospective review of 1,826 consecutive intensive care unit patients at The Stamford Hospital in Stamford, Connecticut.
Krinsley JS. Mayo Clin Proc. 2003;78:1471–1478.
Effect of Hyperglycemia on Hospital Mortality

Prior history of Normoglycemia

35 Known diabetes
*
Mortality Rate (%)

30 New hyperglycemia
25
20
*
15
10 *
5
0
Total Non-ICU ICU

*P<.01 compared with normoglycemia and known diabetes.

Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978-982.

 Selected RCT of Intensive Glucose Management in
Critical Care Studies Showing No Benefit

*Blood glucose in mg/dL; †RRR=Relative risk reduction, intensive group vs conventional group; ‡Personal communication; Dr. Frank Brunkhorst; §P<.05;
¶Not significant (P>.05).

•1. Van den Berghe G et al. N Engl J Med. 2006;354(5):449-461; 2. Devos P et al. Intensive Care Med. 2007;33:S189; 3. Gandhi GY et al. Ann Intern Med.
2007;146(4):233-243; 4. Brunkhorst F et al. N Engl J Med. 2008;358(2):125-139; 5. De La Rosa G et al. Crit Care. 2008;12:R120; 6. The NICE-SUGAR Study
Investigators et al. N Engl J Med. 2009;360(13):1283-1297.
NICE SUGAR Study

• Comparing ICU patients on intensive control with a target BG of 81–108 mg/dl

to those on conventional control with a target of ≤180mg /dl.

• After 90-day follow-up, 829 patients (27.5%) in intensive arm & 751 (24.9%) in
the conventional arm had died (OR for intensive control: 1.14; 95% CI: 1.02–
1.28; p=0.02).

• This unfavorable outcome did not differ between surgical & non-surgical cases.

In this large, international, randomized trial, we found that intensive glucose control increased mortality
among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality
than did a target of 81 to 108 mg per deciliter

Nice Sugar, NEJM 2009;360:1283

 Kebutuhan Insulin Pada Pasien Rawat Inap

PASIEN RAWAT INAP

KRITIS TIDAK KRITIS

KEGAWAT DARURATAN KEGAWAT DARURATAN JUMLAH ASUPAN NUTRISI GLUKOSA DARAH

DIABETES NON-DIABETES SUKAR/TIDAK
Sepsis TERKENDALI :
Ketoasisosis Metabolik
Infark miokard akut Pemakaian steroid
Hipeosmolar Non Ketotik
Stroke Operasi dengan kendali GD
TERATUR TIDAK TERATUR buruk / harus puasa lebih
Ketidakstabilan dari 2x makan
hemodinamik
Stroke yang membutuhkan
Perencanaan operasi segera nutrisi parenteral total
dengan glukosa darah tinggi
Sub Kutan
Sub Kutan
dosis terbagi
dosis terbagi
Infus IV kontinyu/ tetap + dosis Infus IV kontinyu/
Infus IV kontinyu tetap
Sub Kutan koreksional Sub Kutan

Konsensus Insulin Perkeni 2019

 Inpatient Glycemic Targets

Individualized glycemic goal; depends on patient’s clinical condition

Critically ill Non-critically ill

Preferred route Intravenous Subcutaneous
Glucose target (mg/dl) 140-180 mg/dl Premeal <140 mg/dl
(ADA 2015) (Selected patients* 110 -140 mg/dl) Random <180 mg/dl

Glucose target (mg/dl) Premeal 110-140 mg/dl

(ESC 2012) Random 140-180 mg/dl

Not recommended Acceptable Recommended Not recommended

<110 110-140 140-180 >180
*centers with extensive experience and appropriate nursing support, cardiac surgical patients,
and patients with stable glycemic control without hypoglycemia

American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes Care. 2015 ; 38(1): S1-S93
Umpierrez GE, et al. an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012. 97:16–38.
 Intravenous Insulin in Hospitalized Patients

• IV insulin infusions were specifically designed for in-hospital use

• Evidence-based studies support the use of IV insulin for :

o Critically ill patients
o Coronary and surgical ICU patients

• Rapid Acting Analogs have been approved for IV use but offer no advantage over
human insulin in this setting since absorption is not dependent on monomer
formation when human insulin is given IV

Clement S et al. Diabetes Care. 2004;27:553-591.

Common Indications for IV Insulin in Hospital
• Diabetic ketoacidosis and nonketotic hyperosmolar state
• Preoperative, intraoperative, and postoperative care
• Organ transplantation
• Myocardial infarction or cardiogenic shock
• Stroke
• Critically ill surgical patients on mechanical ventilation
• Hyperglycemia during high-dose glucocorticoid therapy
• NPO status in type 1 diabetes
• Dose-finding strategy prior to initiation of subcutaneous insulin therapy (type 1 or
type 2 diabetes)

NPO = nothing by mouth.

Clement S et al. Diabetes Care. 2004;27:553-591 .

Hiperglikemia di Unit Rawat Intensif

Penatalaksanaan Hiperglikemia di Ruang Rawat Intensif, 2018

Protokol Insulin Infus Modifikasi Texas untuk pasien dewasa di ICU

Algoritme ini Tidak untuk pasien DM tipe 1, KAD, SHH

1. Mulai insulin iv saat glukosa di atas target. Insulin iv dihentikan saat:
- Pasien sudah stabil
- Asupan nutrisi mulai adekuat
- Tidak ada riwayat diabetes dan mendapatkan insulin <1 unit/jam
2. Dosis bolus inisial iv dan kecepatan infus insulin inisial: Nilai glukosa/100, kemudian dibulatkan ke 0,5 unit
yang terdekat untuk bolus iv dan kecepatan infus
Contoh:
Nilai glukosa awal 326 mg/dL; 326/100 = 3,26 dibulatkan menjadi 3,5; bolus iv 3,5 unit + mulai infus insulin
3,5 unit/jam
3. Sesuaikan dosis insulin iv dengan algoritma

Penatalaksanaan Hiperglikemia di Ruang Rawat Intensif, 2018

 Protokol Modifikasi Texas
Algoritme 1 Algoritme 2 Algoritme 3 Algoritme 4
GD Unit/jam GD Unit/jam GD Unit/jam GD Unit/jam
Jika GD<70 = hipoglikemia, lihat protokol hipoglikemia
<100 Off <100 Off <100 Off <100 Off

100-119 0,2 100-119 0,5 100-119 1 100-119 1,5

120-149 0,5 120-149 1 120-149 2 120-149 3

150-179 1 150-179 1,5 150-179 3 150-179 5

180-209 1,5 180-209 2 180-209 4 180-209 7

210-239 2 210-239 3 210-239 5 210-239 9

240-269 2 240-269 4 240-269 6 240-269 12

270-299 3 270-299 5 270-299 8 270-299 16

300-329 3 300-329 6 300-329 10 300-329 20

330-359 4 330-359 7 330-359 12 330-359 24

>360 4 >360 8 >360 14 >360 28

Penyesuaian algoritme untuk mencapai target setiap 6 jam

Pindah dari satu algoritme satu ke algoritme lainnya:

- Naik ke algoritme selanjutnya: ketika nilai glukosa masih di luar target setelah titrasi insulin
- Turun ke algoritme sebelumnya: ketika nilai glukosa <70 mg/dL sebanyak 2 kali atau penurunan glukosa > 100 mg/dL dalam 1
jam
Penatalaksanaan Hiperglikemia di Ruang Rawat Intensif, 2018
 Protokol Insulin IV Kontinyu

Dosis awal 0,5-1 U/jam

Sasaran glukosa darah

< 100 mg/dL atau

klinis didapatkan 100-<140 mg/dL 140-180mg/dL >180mg/dL
hipoglikemia

Stop insulin Dosis diturunkan

sampai 50% dari Penurunan Penurunan
IV kontinyu
dosis terakhir glukosa darah glukosa darah <
> 60 mg/dL 60 mg/dL

Penurunan glukosa Penurunan glukosa Turunkan Naikan dosis

darah > 60 mg/dL darah < 60 mg/dL dosis 25% dari 25% dari
dosis terakhir dosis terakhir
Dosis diturunkan
Lanjutkan dosis
sampai 25% dari
sebelumnya
dosis terakhir

PERKENI. Terapi Insulin pada Pasien Rawat Inap dengan Hiperglikemia. 2019
Study of Continuous Insulin Infusion Protocols in the Medical
Intensive Care Unit by using Glulisine
Multicenter randomized trial of 153 ICU patients randomized to CII using the Glucommander (n=77) or a standard
paper protocol (n=76). Both protocols used glulisine insulin and targeted blood glucose (BG) between 80 mg/dL and 120 mg/dL.

• Both treatment
algorithms resulted in
significant improvement
in glycemic control in
critically ill patients in
the medical ICU.

Standard (n) 77 77 55 35 24 14 13 10 7 7 3
Glucommander (n) 76 76 50 37 31 32 18 17 15 11 8

Time on Infusion (Days)

Newton CA, et al. Journal of Hospital Medicine. 2010;5(8):432–7.

 Study of Glucose Control using Glulisine in
the Coronary Care Unit

Glucose levels over the course of

the trial were significantly lower in the insulin arm.

DESIGN AND METHODS P-values standard therapy

1 NS
Insulin arm
2 <0.05
Total 287 participants with an
3 <0.005

Glucose (mmol/L)
acute STEMI and a capillary 4 <0.0005
glucose ≥ 8.0 mmol/L were
randomized to insulin arm
(insulin glulisine infusion in the
CCU, and insulin glargine once-
daily in ward) versus standard
therapy arm (physicians free to
add insulin therapy to treat
high glucose level) for 30 days

Time
Nerenbergh et al., Diabetes Care 35:19–24, 2012
Pathogenesis of diabetic ketoacidosis and
hyperosmolar hyperglycemic syndrome

French EK, Donihi AC, Korytkowski MT. Bmj. 2019;:l1114.

 Laboratory diagnostic criteria for KAD
and HHS on presentation
DKA
Metabolic HHS
indicators Mild DKA Moderate Severe

Serum glucose >250mg/dl >250mg/dl >250mg/dl >600mg/dl

Arterial pH 7.25-7.30 7.00 to <7.24 <7.00 >7.30
Urine ketone Positive Positive Positive Small
Serum ketone Positive Positive Positive Small
Serum Osmolality† Variable Variable Variable >320 mOsm/kg

Anion gap‡ >10 >12 >12 Variable

Mental status Alert Alert / drowsy Stupor / coma Stupor / coma
†
Effective serum osmolality: 2 [measured Na (mEq/l)] + glucose (mg/dl)/18
‡
Anion gap: (Na+) - [(Cl- + HCO3- (mEq/l)]
DKA: diabetic keto acidosis; HHS: hyperglycemic hyperosmoler state

Kitabchi AE, Umpierrez GE, Miles JM, et al, Diabetes Care 32:1335-1343, 2009
 Treatment of hyperglycemic crisis
Intravenous fluids
1000–2000 ml 0.9% NaCl over 1–2 h for prompt recovery of hypotension and/or hypoperfusion. Switch to 0.9% saline or 0.45% saline at
250–500 ml/h depending upon serum sodium concentration. When plasma glucose level ~11.1 mmol, change to dextrose in 5% saline.
Insulin
Regular human insulin intravenous bolus of 0.1 U/kg followed by continuous insulin infusion at 0.1 U/kg/h. When glucose level ≤13.9
mmol/l, reduce insulin rate to 0.05 U/kg/h. Thereafter, adjust rate to maintain glucose level ~11.1 mmol/l. Subcutaneous rapid-acting
insulin analogues might be an alternative to intravenous insulin in patients with mild-to-moderate DKA.
Potassium
Serum potassium level >5.0 mmol/l (no supplement is required); 4–5 mmol/l (add 20 mmol potassium chloride to replacement fluid); 3–4
mmol/l (add 40 mmol to replacement fluid); <3 mmol/l (add 10–20 mmol/h per hour until serum potassium level >3 mmol/l, then add 40
mmol to replacement fluid).
Bicarbonate
Not routinely recommended. If pH <6.9, consider 50 mmol/l in 500 ml of 0.45% saline over 1 h until pH increases to ≥7.0. Do not give
bicarbonate if pH ≥7.0.
Laboratory evaluation
Initial evaluation should include blood count; plasma glucose; serum electrolytes, urea nitrogen, creatinine, serum or urine ketone bodies,
osmolality; venous or arterial pH; and urinalysis. During therapy, measure capillary glucose every 1–2 h. Measure serum electrolytes, blood
glucose, urea nitrogen, creatinine and venous pH every 4 h.
Transition to subcutaneous insulin
Continue insulin infusion until resolution of ketoacidosis. To prevent recurrence of ketoacidosis or rebound hyperglycaemia, continue
intravenous insulin for 2–4 h after subcutaneous insulin is given. For patients treated with insulin before admission, restart previous insulin
regimen and adjust dosage as needed. For patients with newly diagnosed diabetes mellitus, start total daily insulin dose at 0.6 U/kg/day.
Consider multi-dose insulin given as basal and prandial regimen.
Umpierrez G and Korytkowski M. Nature Rev 2016; 12: 222-232
Protocol for management of adult patients with
DKA and HHS recommended by the ADA

Umpierrez G and Korytkowski M. Nature Rev 2016; 12: 222-232

 Penatalaksanaan Ketoasidosis Diabetik dan Sindroma
Hiperosmolar Hiperglikemia
Jam Ke- Infus NaCI 0,9% Infus II (Insulin) Infus III (Koreksi K+) Infus IV (Koreksi
Bikarbonat HCO3))
0 } 2 kolf, ½ jam
1 kolf, ½ jam
1 } 2 kolf Pada jam ke-2 Bolus 180 50 mEq/6 jam (dalam infus)
Bila pH:
2 mU/kgBB dilanjutkan dengan Bila kadar K :
} 1 kolf
insulin IV kontinyu 90
• <7 : 100 mEq HCO3
3
} 1 kolf • <3 : 75 • 7 → 7,1 : 50 mEq HCO3
mU/jam/kgBB dalam NaCL
4 • 3 → 4,5 : 50 • >7,1 : 0
} ½ kolf 0,9%.
5 • 4,5 → 6 : 25
Bila GD < 200 mg/dL pada • >6 : 0 Analisa gas darah diperiksa
Bila GD < 200 mg/dL, ganti Dextrose 5%.
KAD atau GD < 300 mg/dL ulang tiap 6 jam sampai
Bila kadar Na > 145 mEq, infus NaCI 0,9% pada S, kecepatan insulin IV Kalium diperiksa ulang tiap stabil selama 24 jam.
diganti dengan NaCI 0,45 %. kontinyu dikurangi 6 jam sampai stabil selama
45mU/jam/kgBB. 24 jam
Pada pasien dengan gagal jantung dan gagal
ginjal direkomendasikan pemasangan CVC Bila GD stabil 200 → 300
(Central Venous Catheter) untuk memonitor mg/dLselama 12 jam dan
pemberian cairan. pasien dapat makan, dapat
dimulai pemberian insulin IV
Penanganan penyakit pencetus juga kontinyu 1 → 2 IU/jam disertai
merupakan prioritas yang harus segera dengan insulin koreksional
dilakukan (misalnya pemberian antibiotic yang ( sesuai Tabel IV,3,Bab IV).
adekuat pada kasus infeksi).

PERKENI. Petunjuk Praktis Terapi Insulin Pada Pasien Diabetes Melitus. 2019
 Can rapid acting analog insulins be
administered intravenously?

Analogues vs Regular Insulin

68 Subjects with DKA

IV Insulin Glulisine (n=34) IV Regular insulin (n=34)

0.1 U/kg/hr until BD <250 mg/dl 0.1 U/kg/hr until BD <250 mg/dl
then 0.05 u/kg/hr until resolution then 0.05 u/kg/hr until resolution
of DKA of DKA

Transition to SC Transition to SC
Total daily dose 0.6 U/kg/day Total daily dose 0.6 U/kg/day

Given 1/2 as glargine OD, and 1/2 Given 2/3 as NPH, and 1/3 as
as glulisine before meals regular insulin twice daily

Umpierrez GE et al. Diabetes Care. 2009;32:1164–1169

 Analogues vs Regular Insulin
The rate of decline of blood glucose concentration; duration of treatment; amount of insulin;
and changes in acid base parameters were not significantly different between patients treated
with regular insulin (black circle) and glulisine (white circle).

Umpierrez GE et al. Diabetes Care. 2009;32:1164–1169

Glargine-Glulisine was associated with a lower rate of
hypoglycemia than NPH / regular insulin

Analogues vs Regular Insulin

Subcutaneous insulin therapy Glargine / NPH /
glulisine regular
Patients with BG <70 mg/dl (%) 5 (15) 14 (41) *
Episodes of BG <70 mg/dl 8 26 †
Patients with BG <40 mg/dl, n (%) 1 (3) 2 (6)
Episodes of BG <40 mg/dl 1 2
* P=0.03, † P=0.019

A transition to SC glargine and glulisine after resolution of DKA resulted in similar

glycemic control but in a lower rate of hypoglycemia than with NPH and regular
insulin

Umpierrez GE et al. Diabetes Care. 2009;32:1164–1169

 Conversion to subcutaneous insulin
WHEN. ??

1. Stable blood glucoses which are less than 180 mg/dL (7.7–10
mmol/L) for at least 4–6 h consecutively
2. Normal anion gap and resolution of acidosis in DKA
3. Table clinical status; hemodynamic stability
4. Not on vasopressors
5. Stable nutrition plan or patient is eating
6. Stable IV drip rates (low variability)
• Because of short half-life of IV insulin, SC basal insulin should be administered at least 1-2 hours prior to
discontinuing the drip

Evans Kreider, K, F. Lien, Lilian. Curr Diab Rep (2015) 15: 23

 Transition to subcutaneous insulin
• Criteria for resolution of ketoacidosis include:
• blood glucose <200 mg/dl
• two of the following criteria: a serum bicarbonate level ≥ 15 mEq/l, a venous pH > 7.3, and a
calculated anion gap ≤12 mEq/l.
• Resolution of HHS is associated with normal osmolality and regain of normal mental status.
• If the patient is to remain fasting/nothing by mouth, it is preferable to continue the intravenous insulin
infusion and fluid replacement.
• Patients with known diabetes may be given insulin at the dosage they were receiving before the onset
of DKA so long as it was controlling glucose properly
• In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.5– 0.8
units/kg/day

Kitabchi AE, Umpierrez GE, Miles JM, et al, Diabetes Care 32:1335-1343, 2009
 Bode: Transition From IV Insulin Infusion
to SC Insulin Therapy
Example: Patient has received an average of 2 U/h IV during previous 6 h. Recommended
doses are as follows: SC TDD is 80% of 24-h insulin requirement:

2 Unit/h x 24 h = 80% x 48 Units =

48 Units 38 Units

Basal dose is 50% of SC TDD:

◦ 50% of 38 Units = 19 Units of long-acting insulin

Bolus total dose is 50% of SC TDD:

◦ 50% of 38 Units = 19 Units. Give as ~6 Units with each meal

Correction dose is actual BG minus target BG divided by the CF, and CF is

equal to 1700 divided by TDD: CF = 1700 ÷ 38 = ~40 mg/dL
Correction dose = (BG - 100) ÷ 40

BG, blood glucose; CF, correction factor; IV, intravenous; SC, subcutaneous; TDD, total daily dose.
Bode BW, et al. Endocr Pract. 2004;10(suppl 2):71-80.
 Key messages
• Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state
(HHS) are the two most serious acute metabolic complications of
diabetes.
• Insulins glulisine can be used for IV infusion
• Transisition to SC insulin when : Stable blood glucoses which are less
than 180 mg/dL (7.7–10 mmol/L) for at least 4–6 h consecutively,
Normal anion gap and resolution of acidosis in DKA, hemodynamic
stability, and when patient is able to eat