© SUPPLEMENT TO JAPI • april 2011 • VOL.

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Inpatient Management of Diabetes Mellitus

Anil Bhoraskar

Abstract
Inpatient hyperglycemia is associated with increased morbidity and mortality. The length of hospital stay and cost of
care is higher for patients with diabetes than for others. Current evidence suggests that tight control of hyperglycemia in
critically ill hospitalized patients with diabetes or acute hyperglycemia has been shown to reduce the risk of morbidity
and mortality. In view of risk of severe hypoglycemia with near normal blood glucose target, latest consensus is to adopt
a less stringent target of 140–180 mg/dl. The development of insulin analogs with more physiologic time-action profiles,
improved insulin delivery systems, and standardized protocols for subcutaneous insulin administration and intravenous
insulin infusion have improved the safety and convenience of insulin therapy for treating inpatients.

Hyperglycemia in Hospitalized Inpatient hyperglycemia is associated with increased

morbidity and mortality. The length of hospital stay and cost of
Subjects care are greater for patients with diabetes than for those without

H yperglycemia is very common in the inpatient setting. It is it.4 In addition, it results in additional health care costs due to
seen in patients with and without diabetes.1 Patients with extended hospital stay, readmission, or complications associated
type 1 or type 2 diabetes mellitus are frequently admitted to with hyperglycemia. However, still inpatient hyperglycemia is
hospital, usually for the treatment of conditions other than the under-recognized, underreported, and suboptimally managed.1
diabetes. The prevalence of diabetes rises with increasing age, To improve outcomes, proactive assessment of inpatients’
as does the prevalence of other diseases; both factors increase glycemic status and aggressive treatment approaches are
the likelihood that an older person admitted to hospital will needed.5
have diabetes. Glycemic control is unstable in these patients
because of the stress of the illness or procedure, the concomitant Insulin Therapy for Inpatient
changes in dietary intake and physical activity, and the frequent
interruption of the patient’s usual antihyperglycemic regimen.2
Hyperglycemia: Evidence and
Conditions like trauma, hemorrhage, burns, hypoxia, infections, Controversy
sepsis, or shock, may induce both insulin resistance and Improving hyperglycemia management in hospitalized
relative insulin secretory defect.2 This leads to increased muscle patients provides an opportunity to reduce morbidity,
protein degradation, decreased peripheral glucose disposal, mortality, and health care costs. Insulin is the most preferred
lipolysis resulting in increased circulating nonesterified fatty glucose-lowering agent in this setting. Other antidiabetic drugs
acids, hyperlactatemia, and increased hepatic glucose output. are not suitable in managing hospital hyperglycemia due
Mechanisms of defects of insulin signaling and relative β-cell to difficulty in titrating their dose to meet fluctuating blood
suppression seen during acute illness are still under evaluation.3 glucose levels, associated co-morbid conditions like hepatic
and renal impairment, and most importantly the need for quick
Metabolic stress response achievement of target blood sugar levels.
 Stress hormones and peptides Insulin exerts its protective action on several tissues and
signaling pathways like the heart, the endothelium (vasodilatory
Intensive Glucose Management in Critical Care : Studies Showing
 Glucose Benefit
 Insulin Study Setting N Outcome Intervention ARR RRR
DIGAMI CCU 620 1-year IIP (D5W) + 7.5% 29%
Immune dysfunction  FFA  Reactive O2 species 19972 (AMI) mortality MDI : 126-196
 Ketones
 Lactate mg/dl
 Transcription factors
Furnary CTICU 2467 Sternal IIP : 150-200 1.2% 66%
 Secondary 1991* infections mg/dL
Infection dissemination
mediators Leuven SICU 1548 ICU mortality IIP: 80-110 3.4% 42%
Cellular injury/apoptosis 20013 mg/dL
Inflammation
Prolonged
Tissue damage
Krinsley ICU 1600 Hospital SC or IV 6.1% 29%
2004 mortality insulin, <140
hospital stay
Altered wound repair
Acidosis mg/dL
Disability
Thrombosis
Infarction/ischemia Leuven 2 MICU 1200 Hospital IIP : 80-110 2.7%† 7%†
Death 20064 mortality mg/dL
AMI, acute myocardial infarction; ARR, absolute risk reduction;
Fig. 1 : Consequences of uncontrolled hyperglycemia among CCU, coronary care unit; CTICU, cardiothoracic ICU; IIP, insulin
inpatients infusion protocol; IV, intravenous; MDI, multidose insulin; MICU,
medical ICU; RRR, relative risk reduction; SC, subcutaneous; SICU,
surgical ICU.
“Vaishali,” Agar Bazar , College Lane, Prabhadevi, Mumbai - 400028,
Fig 2 : Studies showing benefits of intensive glucose management in
India
critical care
30 © SUPPLEMENT TO JAPI • april 2011 • VOL. 59
Mimicking Nature
Basal/Bolus Rx with Rapid-acting and Long-acting
Analogs
Breakfast Lunch Dinner
Aspart, Aspart, Aspart,
Lispro Lispro Lispro
Plasma insulin
or or or
Glulisine Glulisine Glulisine
Detemir
or
Glargine
4:00 8:00 12:00 16:00 20:00 24:00 4:00
Time
Dr. Bhoraskar
Fig. 3 : Intensive insulin therapy using subcutaneous insulin
analogs
action, protection against vessel wall inflammatory processes),
immune system, the inflammatory pathway, the coagulation
pathway, etc. Protection may be conferred by insulin in part by
metabolic controls as well as other direct or indirect nonmetabolic
effects of insulin like nitric oxide–mediated improvement of
endothelial function; regulation of nuclear factor-κB; inhibition
of the production of harmful reactive oxygen species; regulation
of the transcription of proinflammatory genes, adhesion
molecules, and chemokines; and suppression of early growth
response gene-1, plasminogen activator inhibitor 1, and matrix
metalloproteinases.6
van den Berghe and colleagues7 conducted a landmark study
to evaluate the benefits of intensive insulin therapy in critically
ill patients. It was a prospective, randomized, controlled study
involving adults admitted to surgical intensive care unit who
were receiving mechanical ventilation. On admission, 1548
patients were randomly assigned to receive intensive insulin
therapy (maintenance of blood glucose at a level between 80
and 110 mg per deciliter) or conventional treatment (infusion
of insulin only if the blood glucose level exceeded 215 mg per
deciliter) and maintenance of glucose at a level between 180 and
200 mg per deciliter. Intensive insulin therapy reduced mortality
during intensive care from 8.0% with conventional treatment
to 4.6% (P < 0.04, with adjustment for sequential analyses). The
benefit of intensive insulin therapy was attributable to its effect
on mortality among patients who remained in the intensive care
unit for more than 5 days (20.2% with conventional treatment,
vs. 10.6% with intensive insulin therapy; P = 0.005). Intensive
insulin therapy also reduced overall in-hospital mortality by
34%, bloodstream infections by 46%, acute renal failure requiring
dialysis or hemofiltration by 41%, the median number of red-cell
transfusions by 50%, and critical-illness polyneuropathy by
44%, and patients receiving intensive therapy were less likely
to require prolonged mechanical ventilation and intensive care.
Following this, several studies have published supporting as
well as refuting the results of this study.
Subsequent to the initial van den Berghe study, some
multicenter trials including the latest NICE SUGAR study8 have
shown an increased frequency of hypoglycemia and have failed
to consistently demonstrate improved outcomes with intensive
insulin therapy. In the NICE SUGAR study, 6104 critically ill
patients were randomized to undergo either intensive glucose
control, with a target blood glucose range of 81–108 mg per
deciliter, or conventional glucose control, with a target of 180
mg or less per deciliter. The primary end point was death from
any cause within 90 days after randomization. A total of 829
patients (27.5%) in the intensive-control group and 751 (24.9%)
in the conventional-control group died. Severe hypoglycemia
(blood glucose level ≤40 mg per deciliter) was reported in 6.8% in
the intensive control group and 0.5% in the conventional-control
group (P < 0.001). This study concluded that 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.
Hospitals and expert panels are in the process of examining the
combined evidence and considering modifying treatment goals.
8:00
Current strategy is continued focus on avoiding hyperglycemia
with less aggressive glycemic targets in the critically ill and
rational subcutaneous insulin in the noncritically ill, avoiding a
return to the non-physiological sliding-scale insulin.9 The latest
consensus statement from AACE/ADA on inpatient management
of hyperglycemia10 is a welcome step in this regard.
Current Consensus on Inpatient Blood
Glucose Management
Evidence from several cohort studies and randomized
controlled trials showing improved hospital outcomes with
intensive treatment of hyperglycemia led the American College
of Endocrinology (ACE) and the American Association of
Clinical Endocrinologists (AACE), in collaboration with the
American Diabetes Association (ADA) and other medical
organizations, to develop recommendations for treatment of
inpatient hyperglycemia in 2004. The latest consensus statement
from AACE/ADA on inpatient management of hyperglycemia
released in 2009 addresses several controversial questions on
this topic.
After reviewing conflicting evidence AACE/ADA consensus
continues to emphasize the importance of glycemic control in
hospitalized patients with critical and noncritical illness while
aiming at targets that are less stringent than 80–110 mg/dL.
AACE/ADA consensus recommends initiating insulin therapy
at a threshold of no greater than 180 mg/dL. Once insulin
therapy has been started, a glucose range of 140–180 mg/
dL is recommended for the majority of critically ill patients.
Intravenous insulin infusions are the preferred method for
achieving and maintaining glycemic control in critically ill
patients. For the majority of noncritically ill patients treated with
insulin, the premeal BG target should generally be <140 mg/dL
in conjunction with random BG values <180 mg/dL, provided
these targets can be safely achieved.10
Insulin Regimens in Hospital Setting
To achieve glycemic control, individual physicians often
implement a variety of insulin strategies. Some strategies can
lead to confusion among the health care staff, others to the use
of nonphysiologic sliding-scale insulin protocols that result in
poor glycemic control, widely fluctuating blood glucose values,
and errors in insulin administration.
The basal-prandial-correction subcutaneous insulin therapy
may be appropriate for most hospitalized patients who are
eating.11 It is simple and can be standardized to excellence by
the development of institutional order sets or computerized
order entry templates. Basal insulin therapy is prescribed as
© SUPPLEMENT TO JAPI • april 2011 • VOL. 59 31
intermediate-acting insulin neutral protamine hagedorn (NPH)
or long-acting insulin analog like insulin detemir. Insulin
detemir, in addition to a 24-hr action profile, is associated with
less intra- and inter-subject pharmacokinetic variability, which
will further reduce the risk of hypoglycemia.12 Prandial insulin
therapy is delivered with meals to prevent excessive glycemic
excursions from occurring after ingestion of meals and is
prescribed as short human insulin or rapid-acting insulin analog
like insulin aspart. Correction-dose insulin therapy is ordered as
small doses of short human insulin or rapid-acting insulin analog
like insulin aspart delivered to correct hyperglycemia and is
prescribed with appropriate timing so as to avoid stacking with
previously administered doses of short acting human insulin or
rapid-acting insulin analog. Rapid acting analogs like insulin
aspart are quickly absorbed; provide better post meal blood
glucose control with less risk of hypoglycemia.13 In addition, the
flexibility in meal timing and meal size could be very useful in
hospital setting wherein meal time and meal size are uncertain.
Subcutaneous insulin therapy with insulin detemir plus insulin
aspart is an attractive option for managing hospitalized patients
who are eating.
Intravenous insulin infusions are the preferred method
for achieving and maintaining glycemic control in critically
ill patients. Validated IV insulin infusion protocols with
demonstrated safety and efficacy, and with low rates of
occurrence of hypoglycemia, are recommended by AACE/ADA
consensus. With IV insulin therapy, frequent glucose monitoring
is essential to minimize the occurrence of hypoglycemia and
to achieve optimal glucose control. Regular human insulin is
commonly used for IV infusion. A recent observational study
with approximately 3000 subjects has shown that rapid acting
insulin analog insulin aspart can be given intravenously for
managing inpatient hyperglycemia.14-15
Summary
Current evidence suggests that stringent control of
hyperglycemia in critically ill hospitalized patients with diabetes
or acute hyperglycemia has been shown to reduce the risk of
morbidity and mortality. In view of risk of severe hypoglycemia
with near normal blood glucose target, latest consensus is to
adopt a less stringent target of 140–180 mg/dl. The development
of insulin analogs with more physiologic time-action profiles,
improved insulin delivery systems, and standardized protocols
for subcutaneous insulin administration and intravenous insulin
infusion have improved the safety and convenience of insulin
therapy for treating inpatients.
References
1. Juneja R. Hyperglycemia management in the hospital: about glucose
targets and process improvements. Postgrad Med 2008;120:38-50.
2. Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia.
Lancet 2009;373:1798-807.
3. Le Roith D. Molecular mechanisms by which metabolic control
may improve outcomes. Endocr Pract 2004;10Suppl2:57–62.
4. Moghissi ES. Insulin strategies for managing inpatient and
outpatient hyperglycemia and diabetes. Mt Sinai J Med 2008;75:558-
66.
5. Hirsch IB, Paauw DS, Brunzell J. Inpatient management of adults
with diabetes. Diabetes Care 1995;18:870.
6. Hirsch IB: Effect of insulin therapy on nonglycemic variables during
acute illness. Endocr Pract 2004;10 Suppl 2:63–70.
7. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin
therapy in the critically ill patients. N Engl J Med 2001;345:1359-67.
8. NICE-SUGAR Study Investigators. Intensive versus conventional
glucose control in critically ill patients. N Engl J Med 2009;360:1283-
97.
9. Yalla NM, Reynolds LR. Inpatient glycemic control: an evolving
paradigm. Postgrad Med 2009;121:26-32.
10. Moghissi ES, Korytkowski MT, DiNardo M et al. American
Association of Clinical Endocrinologists and American Diabetes
Association consensus statement on inpatient glycemic control.
Endocr Pract 2009;15:353-69.
11. Braithwaite SS, Robertson B, Mehrotra HP, McElveen LM,
Thompson CL. Managing hyperglycemia in hospitalized patients.
Clin Cornerstone 2007;8:44-54.
12. King AB. Insulin detemir: a better basal insulin for the management
of diabetes? Expert Rev. Endocrinol Metab 2009;4:15-23.
13. Reynolds NA, Wagstaff AJ. Insulin aspart: a review of its use in the
management of type 1 or 2 diabetes mellitus. Drugs 2004;64:1957-74.
14. Udwadia F, Bhattacharya A, Seshaiah V et al. Management of
in-patient hyperglycemia: safety of intensive intravenous insulin
aspart. Abstract number P-1462, 20th World Diabetes Congress,
International Diabetes Federation, 2009.
15. Udwadia F, Bhattacharya A, Seshaiah V et al. Intravenous use
of insulin aspart: observational data from a large population of
hospitalised patients. Diabetes 2009;58 Supp1:A530-A531.