Hyperglycemia
New Recommendations,
Evolving Data, and
Practical Implications
for Implementation
Guest Editor: Etie S. Moghissi, MD, FACE
A Supplement to ACP Hospitalist
Release date: December 15, 2009
Expiration date: December 31, 2010
Estimated time to complete activity: 2.0 hours
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Target Audience
This activity has been designed to meet the educational needs of physicians, registered
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Authors
Etie S. Moghissi, MD, FACE (Guest Editor)
Treasurer, American Association of Clinical Endocrinologists
Associate Clinical Professor
Department of Medicine
University of California, Los Angeles
Marina del Rey, California
Name of Faculty
Marie E. McDonnell, MD
The following PIM planners and managers, Linda Graham, RN, BSN, BA, Jan Hixon,
RN, BSN, MA, Trace Hutchison, PharmD, Julia Kirkwood, RN, BSN, Samantha
Mattiucci, PharmD, and Jan Schultz, RN, MSN, CCMEP, hereby state that they or their
spouse/life partner do not have any financial relationships or relationships to products or
devices with any commercial interest related to the content of this activity of any amount
during the past 12 months.
Katherine V. Mann, PharmD, and the content collaborators at Global Directions in
Medicine, Inc., have no financial relationships to disclose.
On behalf of Global Directions in Medicine, Katherine V. Mann, PharmD, performed a
clinical review, identification of supporting references, and data check of content, and
Lynda Seminara performed editorial review of content for grammar, syntax, and spelling,
as well as stylized content in accordance with guidelines set forth by the American
Medical Association's Manual of Style. All authors received payment from Global
Directions in Medicine via an educational grant from Novo Nordisk Inc.
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The information presented in this activity is not meant to serve as a guideline for patient
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Cover photograph: Getty Images.
Table of Contents
Chapter 1: The Importance of Managing Hyperglycemia in Hospitalized Patients and the Evolution of Treatment Guidelines
Etie S. Moghissi, MD, FACE
Chapter 2: Reexamining the Evidence: In Which Hyperglycemic Inpatients Does Improving Glycemic Control Improve Outcomes?
Faramarz Ismail-Beigi, MD, PhD
Chapter 3: Treatment Options for Safely Achieving Glycemic Targets in the Hospital
Mary Korytkowski, MD
Chapter 4: Transitioning Patients Along the Continuum of CareIntravenous to Subcutaneous Insulin,
Inpatient to Outpatient Settings: Practical Considerations
Marie E. McDonnell, MD, and Marina Donahue, MS, NP, CDE
15
24
Chapter 1
previously undiagnosed diabetes who are identified and diagnosed when evaluated during hospitalization, and otherwise
healthy individuals in whom the hyperglycemia may be
induced by trauma or critical illness, known as stress hyperglycemia.7 In a study conducted in a community teaching hospital with a 38% prevalence of inpatient hyperglycemia, one
third of these patients were identified as having newly discovered hyperglycemia.8
A decade ago, the significance of acute hyperglycemia in
the inpatient setting was not fully appreciated; therefore,
managing hyperglycemia was not a priority, and sliding-scale
insulin was a common mode of therapy. To complicate matters, there were no published glycemic targets or treatment
guidelines for inpatients. The early studies in patients admitted with acute myocardial infarction, or for cardiac or other
surgery,911 brought attention to the importance of inpatient
hyperglycemia and created a need to examine the evidence
and develop practice guidelines. On the basis of impressive
findings from a European study12 of critically ill surgical
patients treated with intravenous insulin to a treatment goal of
80 to 110 mg/dL (4.4 to 6.1 mmol/L), which showed improvement in mortality and measures of serious morbidity, treatment
References
1. American Diabetes Association. Economic costs of diabetes in
the U.S. in 2007. Diabetes Care. 2008;31:596-615. [PMID:
18308683]
2. Centers for Disease Control and Prevention. Number (in thousands) of hospital discharges with diabetes as first-listed diagnosis, United States, 19802005. 2005. Accessed at
www.cdc.gov/diabetes/Statistics/dmfirst/fig1.htm on 5
November 2009.
3. Centers for Disease Control and Prevention. National Diabetes
Fact Sheet, 2007. Accessed at http://cdc.gov/diabetes/pubs/
pdf/ndfs_2007.pdf on 5 November 2009.
4. Moghissi ES, Korytkowski MT, DiNardo M; American
Association of Clinical Endocrinologists. American Association
of Clinical Endocrinologists and American Diabetes Association
consensus statement on inpatient glycemic control. Endocr
Pract. 2009;15:353-69. [PMID: 19454396]
5. Estrada CA, Young JA, Nifong LW, Chitwood WR Jr. Outcomes
and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann
Thorac Surg. 2003;75:1392-9. [PMID: 12735552]
6. Yendamuri S, Fulda GJ, Tinkoff GH. Admission hyperglycemia
as a prognostic indicator in trauma. J Trauma. 2003;55:33-8.
[PMID: 12855878]
7. Clement S, Braithwaite SS, Magee MF; American Diabetes
Association Diabetes in Hospitals Writing Committee.
Management of diabetes and hyperglycemia in hospitals.
Diabetes Care. 2004;27:553-91. [PMID: 14747243]
8. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM,
Kitabchi AE. Hyperglycemia: an independent marker of in-hospital
mortality in patients with undiagnosed diabetes. J Clin
Endocrinol Metab. 2002;87:978-82. [PMID: 11889147]
22. Pomposelli JJ, Baxter JK 3rd, Babineau TJ, Pomfret EA, Driscoll
DF, Forse RA, et al. Early postoperative glucose control predict
nosocomial infection rate in patients. JPEN J Parenter Enteral
Nutr. 1998;22:77-81. [PMID: 9527963]
23. McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J,
Marrie TJ. The relation between hyperglycemia and outcomes in
2,471 patients admitted to the hospital with communityacquired pneumonia. Diabetes Care. 2005;28:810-5. [PMID:
15793178]
24. Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL,
Wood DM, et al. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations
of chronic obstructive pulmonary disease. Thorax.
2006;61:284-9. [PMID: 16449265]
25. Noordzij PG, Boersma E, Schreiner F, Kertai MD, Feringa HH,
Dunkelgrun M, et al. Increased preoperative glucose levels are
associated with perioperative mortality in patients undergoing
noncardiac, nonvascular surgery. Eur J Endocrinol.
2007;156:137-42. [PMID: 17218737]
26. Kripalani S, Jackson AT, Schnipper JL, Coleman EA. Promoting
effective transitions of care at hospital discharge: a review of
key issues for hospitalists. J Hosp Med. 2007;2:314-23.
[PMID: 17935242]
27. Forster AJ, Murff HJ, Peterson JF, Gandhi TK, Bates DW. The
incidence and severity of adverse events affecting patients after
discharge from the hospital. Ann Intern Med. 2003;138:161-7.
[PMID: 12558354]
28. Donihi AC, Yang E, Mark SM, Sirio CA, Weber RJ. Scheduling
of pharmacist-provided medication education for hospitalized
patients. Hosp Pharm. 2008;43:121-126.
29. Lauster CD, Gibson JM, DiNella JV, DiNardo M, Korytkowski
MT, Donihi AC. Implementation of standardized instructions for
insulin at hospital discharge [Letter]. J Hosp Med. 2009;4:E412. [PMID: 19827044]
30. National Quality Measures. Surgical care improvement project:
percent of cardiac surgery patients with controlled 6 A.M. postoperative blood glucose. Accessed at www.qualitymeasures
.ahrq.gov/summary/summary.aspx?ss=1&doc_id=13233 on 5
November 2009.
31. Newton CA, Young S. Financial implications of glycemic control: results of an inpatient diabetes management program.
Endocr Pract. 2006;12 Suppl 3:43-8. [PMID: 16905516]
32. van den Berghe G, Wouters PJ, Kesteloot K, Hilleman DE.
Analysis of healthcare resource utilization with intensive insulin
therapy in critically ill patients. Crit Care Med. 2006;34:612-6.
[PMID: 16521256]
33. Olson L, Muchmore J, Lawrence CB. The benefits of inpatient
diabetes care: improving quality of care and the bottom line.
Endocr Pract. 2006;12 Suppl 3:35-42. [PMID: 16905515]
34. Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. Chest. 2006;129:644-50.
[PMID: 16537863]
35. Centers for Medicare & Medicaid Services Office of Public
Affairs. Eliminating serious, preventable, and costly medical
errors; never events [press release]. 18 May 2006.
Chapter 2
Trial
Patients,
n
VISEP14
Setting
Blood
glucose
achieved,
mg/dL
(mmol/L) *
C
Primary
outcome
End point
rate, %
C
ARR,
%
RRR,
%
Odds
ratio
(95% CI)
537
ICU
151
(8.4)
112
(6.2)
28-d
mortality
26.0
24.7
1.3
5.0
0.89||
(0.581.38)
Glucontrol29 1078
ICU
144
(8)
118
(6.6)
ICU
mortality
15.3
17.2
1.9
12
1.10||
(0.841.44)
De La
Rosa30
504
ICU
148
(8.2)
117
(6.5)
28-d
mortality
32.4
36.6
4.2||
13||
NR
NICESUGAR34
6104
ICU
145
(8.0)
115
(6.4)
3-mo
mortality
24.9
27.5
2.6
10.6
1.14**
(1.021.28)
DIGAMI-143
620
CCU
(AMI)
211
(11.7)
173
(9.6)
1-y
mortality
26.1
18.6
7.5
29**
NR
DIGAMI-244 1253
CCU
(AMI)
180
(10)
164
(9.1)
2-y
mortality
||
||
NR
240
CCU AMI
(GIK)
162
(9)
149
(8.3)
6-mo
mortality
6.1
7.9
1.8||
30||
NR
van den
Berghe5
1548
SICU
153
(8.5)
103
(5.7)
ICU
mortality
8.0
4.6
3.4
42
0.58**
(0.380.78)
van den
Berghe20
1200
MICU
153
(8.5)
111
(6.2)
Hospital
mortality
40.0
37.3
2.7
7.0
0.94||
(0.841.06)
Intraoperative38
399
Operating
room
157
(8.7)
114
(6.3)
Composite
46
44
4.3
1.0||
(0.81.2)
HI-545
Grp. 3: Grp. 1:
17.9
23.4;
grp. 2:
21.2
AMI = acute myocardial infarction; ARR = absolute risk reduction; C = Conventional; DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute
Myocardial Infarction; GIK = glucoseinsulinpotassium; HI-5 = Hyperglycemia: Intensive Insulin Infusion in Infarction; I = Intensive; ICU =
intensive care unit (mixed); MICU = medical intensive care unit(s); NICE-SUGAR = Normoglycemia in Intensive Care EvaluationSurvival Using
Glucose Algorithm Regulation; NR = not reported; RRR = relative risk reduction; SICU = surgical intensive care unit; VISEP = Efficacy of
Volume Substitution and Insulin Therapy in Severe Sepsis.
* Mean morning blood glucose concentrations, except for Glucontrol, which reported mean overall blood glucose concentrations.
||
** P<0.05.
Composite
of death, sternal infection, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure at 30 days.
10
Intensive
group, %*
Less intensive
group, %
Intensive/
less intensive
5.0
18.7
10.3
17.0
8.5
8.7
6.8
0.8
3.1
1.7
4.1
1.7
2.7
0.5
6.3
6.0
6.1
4.1
5.0
3.2
13.6
HI-5 = Hyperglycemia: Intensive Insulin Infusion in Infarction; NICE-SUGAR = Normoglycemia in Intensive Care EvaluationSurvival Using
Glucose Algorithm Regulation; VISEP = Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis.
* Values denote the percentage of patients experiencing 1 severe hypoglycemic events (blood glucose level 40 mg/dL [2.2 mmol/L]).
Studies on glycemic
management during
surgical procedures
In a randomized, double-blind, placebo-controlled study
of 82 adults, intraoperative glucoseinsulinpotassium infusion during coronary bypass surgery did not reduce myocardial
damage or improve intraoperative cardiac performance in
patients without contractile dysfunction.37 In another study,
399 patients undergoing cardiac surgical procedures were
assigned to the insulin infusion group or the conventional
group;38 after surgery, both groups underwent insulin infusion.
Results showed no significant reduction in the primary outcome (composite end point of death, sternal infection, prolonged ventilation, arrhythmias, stroke, and renal failure
within 30 days after surgery) or the secondary outcome
(length of stay in the ICU and hospital). High-dose insulin
(5 mU/kg body weight per minute) and dextrose infusion in
patients who had elective coronary bypass surgery resulted in
significantly lower levels of interleukin-6, interleukin-8, and
tumor necrosis factor- in the early postoperative period.39
However, the study did not examine the potential effect of
these reductions on clinical outcomes.
Glycemic control in
patients with acute
myocardial infarction
An association between hyperglycemia and adverse outcomes after acute myocardial infarction (AMI) has been documented.18,40 For example, a study of 16,971 patients with
AMI41 showed a direct correlation between hyperglycemia and
in-hospital mortality. Nevertheless, it is not known whether
hyperglycemia is mediator of post-AMI complications or
merely a marker of the patients underlying health status.
The American Heart Association recently published a scientific statement on this topic.42
In the Diabetes and Insulin-Glucose Infusion in Acute
Myocardial Infarction (DIGAMI) study, 620 diabetic
patients with AMI were assigned to receive intensive or
conventional blood glucose management, both in the hospital and after discharge.43 Mortality rates were 19% for the
intensive group and 26% for the conventional group. The
multicenter DIGAMI-2 study assessed whether the
observed risk reduction was attributable to the inpatient or
outpatient components of the therapeutic intervention.44 A
total of 1253 diabetic patients with AMI were randomly
assigned to 1 of 3 treatment strategies: insulin infusion followed by aggressive outpatient therapy, insulin infusion
alone, or conventional diabetes care. At 2 years, mortality
rates did not differ among the groups. In the Hyperglycemia
Intensive Insulin Infusion in Infarction (HI-5) study, 240
diabetic participants with AMI were randomly assigned to
receive insulin infusion for at least 24 hours (blood glucose
goal <180 mg/dL [10.0 mmol/L]) or conventional diabetes
management.45 Mortality rates were not different in the
hospital, at 3 months, or at 6 months. Other studies of glucoseinsulinpotassium infusions have also had conflicting
results.46 The largest study, Clinical Trial of Reviparin and
Metabolic ModulationEstudios Cardiolgicos Latin
America (CREATE-ECLA), randomly assigned 20,201
patients in 470 centers worldwide; it found no mortality
benefit with glucoseinsulinpotassium treatment.47
Spontaneous, noniatrogenic hypoglycemia is associated
with poor outcomes.4850 A J-shaped distribution between
average glucose and mortality was observed, with hypoglycemia being associated with adverse outcomes. Similarly,
2 earlier investigations49,50 suggested that hypoglycemia (unrelated to diabetes) during AMI portended a poorer prognosis.
Further, in a study of 7924 patients with AMI at 40 U.S. hospitals, hypoglycemia was a predictor of higher mortality among
patients who were not treated with insulin.48
Glycemic control in
neurosurgical ICUs and
after burns or trauma
Several retrospective studies have examined the relationship between glycemia and clinical outcomes in patients with
extensive burns, body trauma, or traumatic brain injury and
those who have just had surgery for cerebral aneurysms.5161
Pasternak and colleagues61 reviewed the records of 1000
patients who had undergone aneurysm clipping for subarachnoid hemorrhage. Three months after surgery, patients whose
blood glucose level was 129 mg/dL (7.1 mmol/L) or greater
were more likely to have impaired cognition, and those with a
level greater than 152 mg/dL (8.4 mmol/L) had more deficits
in gross neurologic function according to the National
Institutes of Health Stroke Scale. Sung and colleagues62
reported that nondiabetic patients with severe blunt injury
and hyperglycemia on admission had higher rates of infection,
longer hospital stays, and a 2.2-fold higher rate of mortality
after adjustment for age and Injury Severity Score. Although
mortality benefits have not been observed in similar studies,6365 decreased rates of infection have been associated
with lower blood glucose levels.65
The effect of tight glycemic control on outcomes was
determined in a randomized, controlled trial of 97 patients
with severe traumatic brain injury.66 The rate of hypoglycemia
was approximately 2-fold higher for the intensive group.
Although the ICU stay was shorter for the intensive group
(7.3 vs. 10.0 days), no differences were found in the rate of
infection during ICU stay, the mortality rate at 6 months, or
the neurologic outcomes measured by using the Glasgow
Outcome Scale. In a randomized, controlled trial of 78
patients who had just had surgery for subarachnoid hemorrhage, the rate of infection was lower for the intensive
group.67 However, the incidence of postoperative vasospasm
and the overall mortality rate at 6 months did not change significantly. The power of these smaller studies may not have
been sufficient to demonstrate benefit.
11
Glucose control in
hospitalized medical and
surgical patients
in non-ICU settings
As mentioned earlier, no randomized, controlled trials
have been conducted among these patients, a major shortcoming. In the studies discussed in this section, it is not known
whether the elevated blood glucose is a marker of underlying
disease severity or an independent risk factor for disease progression. Many observational studies indicate a strong association between hyperglycemia and poor clinical outcomes in
various hospital (non-ICU) settings.12,18,7178 The presence of
hyperglycemia in patients with and those without diabetes has
been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.12,71,72,78,79 Among
1886 patients admitted to a community hospital, the mortality
rate on the general floors was significantly higher for patients
with newly diagnosed hyperglycemia than for those with
known diabetes.71 In a multicenter cohort study of 2471
patients, those with admission glucose levels greater than
198 mg/dL (11.0 mmol/L) had a greater risk for death and
complications than those with glucose levels less than
198 mg/dL (11.0 mmol/L).78 Among 348 patients with chronic obstructive pulmonary disease and respiratory tract infection, the relative risk for death was 2.10 for those with a blood
glucose level of 126 to 160 mg/dL (7.0 to 8.9 mmol/L) and
3.42 for those with a level greater than 160 mg/dL (8.9
mmol/L) compared with patients whose level was less than
108 mg/dL (6.0 mmol/L).79 Furthermore, each 18 mg/dL
(1.0 mmol/L) increase in blood glucose was associated with a
15% increase in the risk for death or a length of stay exceeding 9 days. Similarly, general surgery patients with hyperglycemia also have a higher risk for adverse outcomes.72,80
Commentary
Available evidence suggests that very tight glycemic control (target blood glucose of 80 to 110 mg/dL [4.4 to 6.1
mmol/L]), as reported in the first Leuven trial5 in surgical
ICU patients, may have benefits, including decreased mortality, reduction of wound infections, and reduction in septicemia
in postcardiac surgery patients.5 Most subsequent studies in
surgical, medical, and mixed ICUs have not replicated those
findings, especially the reduction in mortality.14,20,34,81 The
reasons for this discrepancy are not entirely clear. The originally reported positive results might have been attributable to
patient selection (mostly patients who had undergone coronary artery bypass grafting) or to chance alone. Alternatively,
12
the results may reflect the patients high degree of caloric support in the form of glucose infusion and parenteral nutrition,
which would be expected to cause hyperglycemia. As noted
earlier, attempts to tightly control glycemia can lead to high
rates of hypoglycemia, a complication that has been identified
as an independent risk factor for death.
However, the conclusion from the present analysis should
not be that judicious control of glycemia is not warranted in
critically ill patients or in hospital settings in general. Reasons
for judicious control of glycemia in hospital settings include
the following. First, many observational studies in a variety of
settings clearly show that hyperglycemia is associated with
poor outcomes. Second, whereas most experts would agree
that the reported rates of hypoglycemia for intensively managed patients are unacceptably high, hypoglycemic events
could probably be minimized with improvement in, standardization of, and careful implementation of protocols. Additional
tools that help translate protocols into practice are urgently
needed. More important, relaxation of the target range of 80
to 110 mg/dL (4.4 to 6.1 mmol/L) for intensive control of
glycemia to a higher range would be expected to result in
lower rates of hypoglycemia. Third, the achieved difference
in blood glucose levels between the intensive and standard
glycemia treatment groups (approximately 45 mg/dL
[2.5 mmol/L] in most studies) may not have been large
enough to allow investigators to discern a statistically significant difference between the groups. The determination of
an appropriate and effective target range is an important
topic for future research.
References
1. Malmberg K. Prospective randomised study of intensive insulin
treatment on long term survival after acute myocardial infarction
in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus,
Insulin Glucose Infusion in Acute Myocardial Infarction) Study
Group. BMJ. 1997;314:1512-5. [PMID: 9169397]
2. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous
intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical
procedures. Ann Thorac Surg. 1999;67:352-60; discussion
360-2. [PMID: 10197653]
3. Malmberg K, Norhammar A, Wedel H, Rydn L. Glycometabolic
state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute
myocardial infarction: long-term results from the Diabetes and
Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation. 1999;99:2626-32. [PMID: 10338454]
4. Latham R, Lancaster AD, Covington JF, Pirolo JS, Thomas CS.
The association of diabetes and glucose control with surgicalsite infections among cardiothoracic surgery patients. Infect
Control Hosp Epidemiol. 2001;22:607-12. [PMID: 11776345]
5. van den Berghe G, Wouters P, Weekers F, Verwaest C,
Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the
critically ill patients. N Engl J Med. 2001;345:1359-67. [PMID:
11794168]
13
14
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
15
Chapter 3
Intravenous insulin
infusion protocols
Validated intravenous (IV) insulin infusion protocols that
are efficacious in achieving and maintaining desired glycemic
targets with a low risk for hypoglycemia are preferred for critically ill patients.1 IV insulin decreases blood glucose levels in
a reasonable time period (6 to 10 hours), permits rapid titration of dose for anticipated (for example, initiation or discontinuation of vasopressors) or unanticipated (for example, acute
deteriorations in clinical status) changes in a patients clinical
16
Obstacles to
implementation of an IV
insulin infusion protocol
Identified obstacles to the success of an IV insulin infusion protocol include fear of hypoglycemia and related adverse
events, difficulty in abandoning practices that may have had
variable success, increases in nurse workload, and the requirement for increases in the numbers of glucose meters and
materials needed to achieve glycemic targets.6 The relaxation
of glycemic targets from 80 to 110 mg/dL (4.4 to 6.1 mmol/L)
to 140 to 180 mg/dL (7.8 to 10.0 mmol/L) in critical care
areas may lead to improved blood glucose control because the
higher target reduces the risk for hypoglycemia.20 Nurse workload has been addressed in some institutions by training
patient care technicians to obtain samples for blood glucose
measurements and to enter data into bedside or electronic
flow sheets.
Elements of a safe IV
insulin infusion protocol
Protocols with demonstrated safety and efficacy consider
certain essential elements, including current and previous
blood glucose levels and the current rate of insulin infusion.
Adjustments are made according to the rate of change or stability from the previous reading. This helps minimize the risk
for hypoglycemia or undesired reductions in blood glucose levels. Several hospitals have created Web sites and computer
algorithms that guide these changes in infusion rates and have
reported improved glycemic outcomes compared with paperbased protocols.11,21,22
Another element of a safe and effective IV insulin infusion protocol is the frequency of blood glucose monitoring.23
With initiation of any protocol in a critically ill patient, hourly
monitoring with adjustments in insulin infusion rates is essential. Once the blood glucose levels and infusion rate have
been stable for 2 to 4 hours, the frequency of blood glucose
monitoring can be decreased to every 2 hours. With prolonged
stability, many protocols allow monitoring every 4 hours if the
patients clinical status does not change. Any change in nutrition, glucocorticoid therapy, or vasopressor therapy requires a
return to more frequent glucose monitoring.
The sampling site and device used for obtaining point-ofcare blood glucose measurements have been identified as a
source of potential error and risk in hospitalized patients.24 In
the initial Leuven study, all blood glucose samples were
obtained from an arterial line and measured in the critical
care laboratory.3 Subsequent studies have reported variability
in sites for blood sampling and monitoring devices.20,23 This
can result in lower levels of accuracy and reproducibility of
blood glucose measurements, with associated errors in adjustments of insulin infusions. There is a need to standardize not
only the insulin infusion protocols used but also the source of
sampling for blood glucose measurements and the device used
to obtain the results. Many hospitals have interfaced blood
Transition from IV to
SC insulin
IV insulin infusions usually are continued for the duration
of mechanical ventilation, volume resuscitation, and vasopressor and nutrition support. As patients improve and are transferred from a critical care unit, they are also transitioned from
IV to SC insulin to avoid deteriorations in glycemic control.26,27 Although some institutions have had success with IV
insulin infusion protocols outside the critical care units10,28,
all patients treated with IV insulin will eventually require transition to SC insulin before discharge. Deployment of IV
insulin infusion protocols outside of intensive care units must
be done with extreme caution given increased nurse-to-patient
ratios, decreased resources for blood glucose monitoring, and
the associated increased risk for hypoglycemia. Upon conversion, the dose of SC insulin is determined from the recent
history of IV insulin requirements immediately prior at the
time of transition, with consideration of nutritional status, use
of concurrent medications (such as corticosteroid therapy),
and history of diabetes. In a study of patients in a surgical
intensive care unit, an SC insulin dose calculated as 80%
(compared with 40% or 60%) of the insulin requirement in
the preceding 24 hours was more effective at maintaining
glycemic targets of 80 to 150 mg/dL (4.4 to 8.3 mmol/L) in
the next 24 hours.26,29 A study of patients in a medical intensive care unit compared different strategies of transitioning
from IV to SC insulin.27 Patients who received scheduled
basal and short- or rapid-acting insulin calculated as approximately 66% of the previous 24-hour insulin requirement had
more blood glucose values in the goal range of 80 to 180
mg/dL (4.4 to 10.0 mmol/L) than those who received slidingscale insulin alone or in combination with basal insulin.27 The
frequency of moderate or severe hypoglycemia with the more
intensive strategies did not differ in either of these studies.
What is important at the time of transition is that the
SC insulin be administered 1 to 2 hours before discontinuation of the insulin infusion. This allows sufficient time for
the SC insulin to be absorbed and active, reducing the risk
for clinically significant hyperglycemia during the transition
period.5 For practical considerations and case studies on
this topic, see the chapter in this supplement by
McDonnell and Donahue (page 24).
SC insulin therapy
Scheduled SC insulin that includes an intermediate or
long-acting insulin preparation (basal insulin) in combination
with short- or rapid-acting insulin (bolus) is the preferred
method of glycemic management for most patients with a history of diabetes or new-onset hyperglycemia in noncritical
care hospital settings (Table 1). A correction insulin scale,
rather than a reactive sliding-scale insulin, can be added to
scheduled insulin therapy to allow for the administration of
supplemental doses of short- or rapid-acting insulin when
blood glucose level exceeds the glycemic target.3033
In general, any patient who uses scheduled insulin therapy at home will require scheduled insulin therapy in the hospital, although dose adjustments may be required.
Unfortunately, sliding-scale insulin, which is reactive and not
a proactive physiologic approach, remains the treatment of
choice for clinicians at many institutions. The practice of discontinuing oral diabetes medications or insulin therapy and
starting sliding-scale insulin as the only glycemic management
strategy results in undesirable levels of both hypoglycemia and
hyperglycemia and places the patient at increased risk at transitions if medication reconciliation is not done appropriately.34,35 Sliding-scale insulin has been abandoned altogether by
some institutions,36 where use of correction insulin in conjunction with scheduled SC insulin to regulate blood glucose
excursions that are outside the desired range is
deployed.32,33,3739
In some situations, the use of correction insulin alone
may be acceptable. Patients with no history of diabetes, those
with previously well-controlled type 2 diabetes who are admitted with elevated blood glucose levels, or those who begin a
therapy known to be associated with hyperglycemia in many
patients (corticosteroids, enteral or parenteral nutrition) can
have blood glucose monitoring performed with insulin administration in accordance with a correction scale to determine
the need for scheduled insulin therapy.38,40,41 Although a small
percentage of patients who become hyperglycemic with these
therapies can achieve glycemic control with correction insulin
alone, most will require scheduled insulin therapy with longor intermediate-acting insulin in combination with short- or
rapid-acting analogues.33,38,39 For patients who do not become
hyperglycemic, blood glucose monitoring can be discontinued
17
Onset
Peak
Duration
515 min
12 h
46 h
3060 min
24 h
24 h
2h
23 h
410 h
Relatively flat
Relatively flat
610 h
1218 h
Up to 24 h
Up to 24 h
18
Continuous SC insulin
infusion pumps
The number of outpatients who use continuous SC
insulin infusion (CSII) pumps for glycemic management is
growing, thereby increasing the likelihood that these patients
will be encountered in the hospital.49 Patients who use CSII
pumps in the outpatient setting are candidates for diabetes
self-management when they are hospitalized if they have the
mental and physical capacity to do so.30,50 However, many
nurses and physicians are uncomfortable allowing patients to
use a technology with which they have limited familiarity.51 As
a result, treatment of these patients when they are admitted
to the hospital varies.34
Some hospitals have established protocols to guide inpatient
insulin pump therapy and provide support for patients who have
the desire and ability to self-manage while hospitalized.52,53 In a
hospital with an established CSII protocol, mean glucose values
were similar for patients who continued and those who discontinued pump therapy. However, the frequency of hypoglycemia
(blood glucose level < 70 mg/dL [3.9 mmol/L]) was significantly
lower among those who continued CSII.52
The ability of a hospitalized patient to self-manage diabetes
care is a key component of the safety and efficacy of a CSII
pump protocol because it is not reasonable to assume that
Insulin pens
Several institutions have transitioned from vials to patientspecific insulin pen devices as a way to reduce the risk for errors
and needle-stick injuries. Pen devices with safety autocovers have
the potential to reduce the risk for needle-stick injuries. The presence of a window on the pen device, allowing direct visualization
of the number of units being administered, has the potential to
reduce dosing errors. Certain factors favor this practice and others
warrant caution. A favorable aspect of this practice is the
increased use of insulin pens in the outpatient setting. The availability of pen devices in the hospital can facilitate patient education for insulin administration using these devices, decreasing the
need for separate education at the time of hospital discharge.
Nurses who learn to appropriately use the pens can educate
patients on using them at home. The insulin volume in pens is
less than that in vials, which may yield cost advantages for
patients with short hospital stays or low insulin requirements.54,55
Areas that warrant caution for introducing insulin pens for
hospital use relate to the portability of these devices, which
make them easy to use in more than one patient. This practice,
along with using these devices to draw up an insulin dose with
a syringe, has been observed, presenting the need to test
patients for associated infections.56 Because many nurses are
unfamiliar with these devices, education and surveillance of
nursing personnel are mandated, with demonstration of competency before the pens can be introduced for hospital use.
Suggestions for safe introduction of these devices include
oversight by a multidisciplinary committee, the introduction of
one device at a time, initial and follow-up nurse education,
the availability of nursing personnel knowledgeable in diabetes
management, and a requirement for initial and periodic testing of proficiency and competency.
Mechanism of action
Side effects
Agents
Sulfonylureas
Short-acting insulin
secretagogues
Biguanides
Hypoglycemia
Decrease gluconeogenesis
Increase insulin sensitivity
Reduce insulin resistance
Nausea; diarrhea,
lactic acidosis (rarely)
Edema; congestive heart
failure; increased abnormalities
on liver function tests
Bloating; abdominal discomfort,
diarrhea
Upper respiratory tract infection,
nausea
Metformin
Thiazolidinediones
-Glucosidase
inhibitors
Dipeptidyl
peptidase-4
inhibitors
Decrease rate of
carbohydrate absorption
Prolong action of
glucagon-like peptide-1
Increase insulin release
Decrease glucagon
19
Rosiglitazone, pioglitazone
Acarbose, miglitol
Sitagliptin
20
Summary
The glycemic targets outlined in the AACE/ADA consensus
statement are achievable with a rational approach to insulin
therapy in critical care and noncritical care areas of hospitals.
Intravenous insulin infusion protocols with demonstrated safety
and efficacy offer advantages to achieve these goals in critical
care areas. Transition to SC insulin is recommended with discontinuation of these infusion protocols to avoid rebound hyperglycemia. Outside critical care areas, scheduled SC insulin with
a basal and prandial or nutritional (that is, bolus) component is
effective for achieving glycemic control. Correction insulin can
be used in combination with basalbolus insulin to treat
glycemic excursions above the desired range. Staff education,
the development of point-of-care meters that provide reliable
and reproducible blood glucose measurements, appropriate
administration of insulin, and careful implementation of standardized protocols are essential elements of a successful inpatient glycemic management program.
References
1. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman
R, Hirsch IB, et al; American Association of Clinical
Endocrinologists. American Association of Clinical
Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care.
2009;32:1119-31. [PMID: 19429873]
21
22
23
24
Chapter 4
Calculating the
subcutaneous insulin
transition dose
The ultimate insulin regimen should address the 3 components of insulin requirement: basal (what is required in the
fasting state to maintain normal metabolism), nutritional
(what is required for peripheral glucose disposal), and correctional (what is required for unexpected glucose elevations).
For patients who are not receiving significant calories, the
infusion rate represents the basal insulin requirement. Some
published strategies that are used to find the basal dose
involve estimating a 24-hour insulin requirement and distributing it into basal and nutritional insulin to maintain glucose
in the optimal range.8 However, with heightened concerns
about the risk for hypoglycemia during acute illness, and
recent support for more moderate glycemic control in the hospital, strategies that consider the most recent insulin requirements may be better tailored to the recovering patient. Studies
in inpatient critical care areas have determined successful
dose-finding strategies by extrapolating 24-hour doses from
insulin infusion rates over the past 6 hours.
In a study conducted in the surgical intensive care unit,9 the
24-hour insulin requirement was calculated by taking the total
amount of insulin infused within the past 6 hours and multiplying by 4. Of note, the insulin was infused while the patient was
not receiving significant calories, so the infusion rate represented
the fasting insulin requirement. In this study, a safe and effective basal insulin dose for the subsequent 24 hours was calculated as 80% of this estimated requirement. Other percentages were
compared to 80% (such as 40% and 60%), but 80% resulted in
more glucose values of 80 to 150 mg/dL (4.4 to 8.33 mmol/L)
without more hypoglycemia. The extrapolated basal dose can be
given in 1 long-acting insulin dose (for example, detemir or
glargine) or split in half and given in 2 moderate-acting insulin
doses 12 hours apart (for example, neutral protamine Hagedorn
insulin). Insulins that are short- (regular) or rapid-acting (aspart,
glulisine, or lispro) can be added as needed depending on nutritional status and glucose levels. The total daily nutritional insulin
requirement approximates the total basal requirement10 and can
be divided into doses according to the nutritional plan.
Case example 1
A 48-year-old woman is ready to eat 36 hours after coronary artery bypass graft surgery. Between 1 a.m. and 7 a.m.,
she was receiving an average of 2 units of intravenous regular
insulin per hour, with a glucose level of 130 to 150 mg/dL
(7.2 to 8.3 mmol/L). She was given a small amount of juice at
7 a.m., and her glucose level increased to 195 mg/dL, prompting an increase in the infusion rate to 3 U/h. Using the fasting
overnight rate of 2 U/h, the total basal insulin requirement is
calculated as (2 24 [80%] = 42 [0.8] = 34 units). The 34
units is given as detemir or glargine insulin 2 hours before discontinuation of the insulin infusion: 1.5 (hourly rate) 20
(equivalent to taking 80% of 1.5 24 hours) = 30 U. Because
the patient is expected to eat at the next mealtime, nutritional
25
Case example 2
A 72-year-old man with type 2 diabetes is ready to leave
the intensive care unit after recovery from urosepsis. He is no
longer receiving vasopressors, is breathing on his own, and is
receiving continuous enteral feedings. Glucose values have
ranged from 120 to 160 mg/dL (6.7 to 8.9 mmol/L) for the
previous 6 hours, with an average intravenous insulin infusion
rate of 3 U/h during this time. The total daily insulin requirement is calculated as (3 U/h 24) (80%) = 72 (0.8) = 58 U of
insulin per day. The 58 U is distributed approximately as 29 U
(50%) of basal insulin given as a 1-time dose of basal insulin,
and 29 U (50%) of nutritional insulin, split into 4 doses per
day given every 6 hours. Because nutritional insulin is easily
titrated more than once daily, the initial dose is given as 6 U
and is administered along with supplemental correction
insulin as needed every 6 hours. The basal insulin is administered at the same time as the short-acting insulin dose, and
the insulin infusion is discontinued 1 hour later.
Key to success:
Writing the orders
As noted in these case examples, to prevent the recurrence of hyperglycemia, the insulin infusion and the subcutaneous insulin must overlap because the duration of
insulin effect when given intravenously is less than 1 hour.
Because of the time required for subcutaneous basal insulin
to reach adequate levels in the bloodstream, an insulin infusion should be discontinued 2 hours after a basal dose is
given, or 1 hour after the administration of a rapid- or shortacting insulin. Start by writing 1-time orders for the transition itself. For example, for the patient administered only
basal insulin at transition, you would note detemir insulin
26
Stress-induced
hyperglycemia:
management and
future risk
Hyperglycemia newly recognized in the hospital is common.11 Several studies have shown this group to be a higher-risk population, with greater mortality rates and more
complicated hospitalizations. In an important retrospective
analysis of hospital admissions in an academic urban hospital, hyperglycemia (glucose level >200 mg/dL [11.1 mmol/L])
was present in 38% of patients at some point during the
hospitalization, yet a third of these patients had no history
of diabetes before admission. This newly discovered hyperglycemia was associated with a higher in-hospital mortality
rate (16%) compared with patients with documented diabetes (3%) and normoglycemia (1.7%). This stress-induced
hyperglycemia was also found to be a marker for more complicated inpatient stays.
This risk for postdischarge abnormal glucose metabolism
after hyperglycemia in the hospital has been found to be as
high as 65% among patients who have had myocardial infarction.12 Because hyperglycemia may be transient and situational, diabetes cannot be diagnosed in the hospital by using commonly accepted criteria.13 Therefore, obtaining a reliable
hemoglobin A1c (HbA1c) level as part of the evaluation of
Unknown diabetes
Known diabetes
HbA1c <6.5%*
HbA1c 6.5%7%*
and insulin
requirement
<0.4 U/kg per d
HbA1c 6.5%7%*
and insulin
requirement
0.4 U/kg per d
HbA1c >7%*
Follow-up
Communicate recommendation
to outpatient providers;
address need for referral
to multidisciplinary care for
diabetes treatment or prevention
Assess for hypoglycemia risk;
Communicate recommendation
continue prehospital regimen
to outpatient providers;
unless new safety concerns arise
address need for referral
to multidisciplinary care for
diabetes treatment or prevention
Assess for hypoglycemia risk;
Communicate recommendation
continue prehospital regimen
to outpatient providers;
unless new safety concerns arise
address need for referral
to multidisciplinary care for
diabetes treatment or prevention
Consider transient effect of
Communicate recommendation
subacute illness before
to outpatient providers;
hospitalization on HbA1c;
address need for referral
consider advising augmentation
to multidisciplinary care for
of outpatient regimen to target <7% diabetes treatment or prevention
* HbA1c = hemoglobin A1c. The HbA1c is inaccurate after blood transfusion and in patients with severe anemia, or in those with high or low red
blood cell turnover states.
Metformin (Diabetes Prevention Program trial36), thiazolidinedione (Diabetes REduction Assessment with ramipril and rosiglitazone Medication
trial37), and acarbose.38
27
28
Insulin therapy:
hospital to home
Insulin therapy, although always indicated for the hyperglycemic hospitalized patient, does not always follow a
patient home. Insulin is the safest practice for individuals
with changing insulin needs related to illness because it can
be titrated easily and has predictable action profiles. However,
for many patients receiving insulin in the hospital, the discharge diabetes regimen may be a combination of noninsulin
medications. If there is a reliable HbA1c measurement,
providers can opt to modify regimens to meet an HbA1c goal
(<7% in most patients), while considering any new contraindications to some agents (for example, renal insufficiency with
metformin therapy or congestive heart failure with thiazolidinediones). Recommendations for noninsulin agents after
discharge may be a relief for patients who have concerns
about continuing insulin therapy, yet the opportunity to identify those who would benefit from insulin therapy should not be
missed in the hospital. Patients requiring more than 0.4 U/kg
of insulin per day in the setting of an above-goal HbA1c, and
particularly if the HbA1c is greater than 10%, should be evaluated for insulin therapy after discharge. Use of 2 or more fully
titrated oral agents and an HbA1c value greater than 8.5%
should also prompt consideration of insulin therapy. A diabetes educator is optimally used to guide these patients
toward not only acceptance of insulin therapy but also the
practical design of a feasible insulin program. If a trained diabetes educator is not available, the patients nurse can assume
the role of educator to address several issues known to present
barriers to successful insulin therapy,2729 including fear of
pain, weight gain, inconvenience, complexity, time concerns,
cost, and sense of failure. Accurate medication reconciliation
is paramount to ensure that patients who begin receiving
insulin while hospitalized do not also inadvertently resume all
Outpatient follow-up
Outpatient follow-up after hospitalization-related hyperglycemia, ideally within a multidisciplinary approach to diabetes care, has led to successful prevention of diabetes-related
complications if abnormal glucose tolerance persists.3032 For
a successful transition from inpatient to outpatient care, the
inpatient providers should create a transparent link between
the inpatient plan and care at home. This includes direct
communication at the time of discharge with an outpatient
provider about the recommended treatment plan. Examples
include sending the primary care physician a copy of the discharge summary with a specific section dedicated to outpatient diabetes recommendation (either electronically or by
fax); calling the outpatient provider directly to discuss recommendations and concerns related to the patients success; and
contacting a certified diabetes educator to review concerns
identified in the hospital (such as problems with numeracy)
that can be targeted in a follow-up visit. Diabetes-targeted follow-up from the hospital for patients with hyperglycemia during illness should occur within 1 month after discharge.2
A major goal of rapid outpatient follow-up after hospitalization is to reevaluate the discharge regimen. Patients newly
receiving insulin therapy require more attentive follow-up.
Telephone conversations with the patient after discharge may
Summary
Because any single patient can enter the hospital through
different points (for example, emergency department, planned
admission for surgery) and then transition through many levels
(such as intensive care unit or regular medical floor) or points
of care (for example, diagnostic procedures, surgery), as well as
have a changing status (for example, requiring medications
such as steroids or pressors; enteral or parenteral nutrition),
the management of patients with hyperglycemia throughout
their continuum of care can be challenging. In addition, the
complexity of management increases because of the many
causes of hyperglycemia: documented diabetes, newly discovered diabetes, or transient stress hyperglycemia. Thus, it is
important to identify the points of transition and safely and
effectively manage glucose levels throughout the points of care.
One can easily see that multidisciplinary education and awareness are critical. The inpatient setting is also an opportunity to
29
References
1. Malmberg K, Rydn L, Efendic S, Herlitz J, Nicol P,
Waldenstrm A, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic
patients with acute myocardial infarction (DIGAMI study):
effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:5765. [PMID: 7797776]
2. Moghissi ES, Korytkowski MT, DiNardo M; American
Association of Clinical Endocrinologists. American Association
of Clinical Endocrinologists and American Diabetes Association
consensus statement on inpatient glycemic control. Endocr
Pract. 2009;15:353-69. [PMID: 19454396]
3. Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y,
Havranek EP, et al. Admission glucose and mortality in elderly
patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes.
Circulation. 2005;111:3078-86. [PMID: 15939812]
4. Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and
continuous intravenous insulin infusions on outcomes of cardiac
surgical procedures: the Portland Diabetic Project. Endocr
Pract. 2004;10 Suppl 2:21-33. [PMID: 15251637]
5. Schmeltz LR, DeSantis AJ, Thiyagarajan V, Schmidt K, OSheaMahler E, Johnson D, et al. Reduction of surgical mortality and
morbidity in diabetic patients undergoing cardiac surgery with a
combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care. 2007;30:823-8. [PMID:
17229943]
6. Sturis J, Polonsky KS, Mosekilde E, Van Cauter E. Computer
model for mechanisms underlying ultradian oscillations of
insulin and glucose. Am J Physiol. 1991;260:E801-9. [PMID:
2035636]
7. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN.
Hyperglycemic crises in adult patients with diabetes. Diabetes
Care. 2009;32:1335-43. [PMID: 19564476]
8. Mao CS, Riegelhuth ME, Van Gundy D, Cortez C, Melendez S,
Ipp E. An overnight insulin infusion algorithm provides morning
normoglycemia and can be used to predict insulin requirements
in noninsulin-dependent diabetes mellitus. J Clin Endocrinol
Metab. 1997;82:2466-70. [PMID: 9253319]
9. Schmeltz LR, DeSantis AJ, Schmidt K, OShea-Mahler E, Rhee
C, Brandt S, et al. Conversion of intravenous insulin infusions to
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10. Clement S, Braithwaite SS, Magee MF; American Diabetes
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11. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM,
Kitabchi AE. Hyperglycemia: an independent marker of in-hospital
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30
25. Forster AJ, Murff HJ, Peterson JF, Gandhi TK, Bates DW. The
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26. Lauster CD, Gibson JM, DiNella JV, DiNardo M, Korytkowski
MT, Donihi AC. Implementation of standardized instructions for
insulin at hospital discharge [Letter]. J Hosp Med. 2009;4:E412. [PMID: 19827044]
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Diabetes Care. 2005;28:2673-9. [PMID: 16249538]
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35. Garber AJ, Handelsman Y, Einhorn D, Bergman DA,
Bloomgarden ZT, Fonseca V, et al. Diagnosis and management
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risks of diabetes begin? A consensus statement from the
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37. DREAM (Diabetes REduction Assessment with ramipril and
rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096-105. [PMID: 16997664]
38. Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A,
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31
Should you have questions regarding obtaining CME/CE credit, please contact:
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