Transcript Special Treatment Populations: Renal Disease, Women

Journal Club Grand Rounds
Nilda Franco, MD
Richard Gerkin, MD
Kristin Manley, DO
Cheryl W. O’Malley, MD
Revamped Journal Club
• Teach critical appraisal: “JAMA User’s Guides”
• Review 2 important articles around a common
theme
– One retro “landmark”
– One recent
• Statistical Principle
• Review how to apply these studies to current
practice
November 2001
What we knew…
• Hyperglycemia in critically ill patients was common
• Hyperglycemia was associated with worse outcomes
• Physiologic rationale for improvements with glycemic
control.
• Outpatient control benefited type 1 and type 2 DM
• Diabetes and Insulin-Glucose infusion in Acute MI
(DIGAMI)
First DIGAMI: Insulin Therapy Improves
Outcomes in Patients with MI
•
•
•
•
•
•
IV insulin in AMI X 24 hours
Then subcutaneous for 3 months
Target glucose 126-180mg/dL
29% reduction in mortality- 1 year
28% reduction in mortality- 3.4 year
Which component (type of insulin) was responsible
for the reduction?
Intensive Insulin Therapy in
Critically Ill Patients
Known famously as the “Van Den Berghe”
trial
 Published in the New England Journal of
Medicine in November 2001

Hypothesis of the study:

Study was to determine whether
normalization of blood glucose levels with
intensive insulin therapy reduces mortality
and morbidity in critically ill patients.
Study design




Prospective, randomized controlled trial at one
university hospital in Belgium.
Involved adults admitted to the surgical ICU
between 2/2/2000 and 1/18/2001 who were
mechanically ventilated.
A total of 1548 patients were enrolled
On admission to the ICU patients were randomly
assigned to either intensive or conventional
insulin therapy
Study design continued….
Assignments to the treatment groups were
made with the use of sealed envelopes
 “Permuted block randomization” and
stratification according to the type of
illness were used to balance the two
groups

.
Van den Berghe G et al. N Engl J Med 2001;345:1359-1367
Study design continued….

Pts were given IV glucose 200-300gm over the first 24
hours followed by parental/enteral/combined feeding

Undiluted arterial blood was used obtain the whole blood
glucose on admission and Q4hours

The dose of the insulin was adjusted by a team of nurses
and a study physician that were not involved in the
clinical care of the patients.

The laboratory staff, electrophysiologist, and pathologist
involved in the patients care were unaware of the
treatment assignments of the patients.
Study design: Conventional Group

The group had a continuous infusion of
insulin mixed with normal saline and
administered via pump if the glucose level
exceeded 215 mg/dL.

Whole blood glucose levels were
maintained between 180-200 mg/dL
Study design: Intensive Treatment

In the group the insulin infusion was
started if the blood glucose level exceeded
110 mg/dL.

Whole blood glucose levels were
maintained between 80-110 mg/dL
What Data Was Collected?

Baseline demographics, information to calculate
APACHE scores, and Therapeutic Intervention
Scoring System scores, blood glucose levels.

Blood cultures were obtained if there was a
temperature of 38.5 degrees Celsius or above.

Weekly electromyographic screening for critical
illness polyneuropathy was performed if duration
of ICU stay was greater than 1 week
Outcome Measures of the Study










Death from any cause during ICU stay
Number of days in ICU, prolonged stay or need
for readmission
Ventilatory support
Renal replacement therapy
Inotropic/pressor support
Critical-illness polyneuropathy
C-reactive protein, WBC, body temperature
Bloodstream infection
Use of antibiotics for more than 10 days
Hyperbilirubinemia
Results of the Study

Intensive Insulin Group:
 Almost
all required insulin.
 AM glucose was 103 mg/dL on average.
 39 patients affected by hypoglycemia

Conventional Treatment Group:
 39%
required insulin therapy
 Average AM blood glucose was 153 mg/dL.
 The remainder of the group had average AM
glucose of 140 mg/dL.
Results…

The trial had interim analyses of the
overall mortality that were investigated at 3
month intervals. During the 4th interval it
was determined that the conventional
treatment was inferior and the study
should be terminated early.
Results on Mortality
35 patients in the intensive-treatment
group died during ICU stay as compared
to 63 patients in the conventional group.
 Apparent Risk reduction of 42
 Greatest reduction in deaths were those
due to multiple-organ failure and
associated sepsis

Leuven Study: Intensive Insulin
Therapy in the Surgical ICU
100
Intensive treatment
Survival in ICU, %
96
92
Conventional treatment
88
Mortality
 42%,
P<.04
84
80
96
Intensive treatment
92
Conventional treatment
88
Mortality
 34%,
P<.01
84
80
0
0
In-Hospital Survival, %
100
20 40 60 80 100 120 140 160
Days After Admission
0
0
50
100
150
200
250
Days After Admission
Van den Berghe G, et al. N Engl J Med. 2001.
Risk Factors for Increased Mortality
APACHE II score of 9 or higher during the
first 24 hours
 Older in age
 Admission involving non-cardiac surgery
 Outside hospital referral
 In the conventional insulin group without a
prior history of diabetes or hyperglycemia

Intensive Insulin Therapy in Critically Ill Surgical
Patients: Morbidity and Mortality Benefits
Mortality
Sepsis
Dialysis
Blood
Transfusion Polyneuropathy
0
-10
-20
N = 1,548
-30
-40
Reduction
-50
(%)
34%
41%
46%
-60
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.
44%
50%
Van den Berghe Morbidity Data
30
% of Patients
25
20
15
10
5
0
Glucose 180-200
Glucose 80-110
Are the Results of the Study Valid?

Was the Assignment of the Patients to
Treatment Randomized?
 The
assignment to the two groups was
randomized using “permuted blocks.”
Were All Patients Who Entered the
Trial Properly Accounted for and
Attributed at Its Conclusion?

Patients were accounted for but the trial
was stopped early secondary to results
showing a better outcome with mortality in
the intensive insulin group.
Were Patients, Their Clinicians, and
Study Personnel “Blind” to Treatment?


Mostly-The clinicians involved could not be
completely blinded because the blood sugar
monitoring basically revealed the patient group.
To minimize the bias the physician and ICU
nurses involved in the insulin adjustment were
blinded to important outcome measures and did
not take part in clinical decisions.
Lab personnel, EMG physician, pathologist were
all blinded to the treatment groups of the
patients.
Were the Groups Similar at the
Start of the Trial?

Yes. Secondary to the randomization with
permuted blocks-the groups had no
significant difference between them at the
beginning of the trial.
Aside From the Experimental
Intervention, Were the Groups Treated
Equally?

The only differences in the treatments
between the two groups were the insulin
therapy and the antibiotics for the patients.
The patients in the intensive insulin group
required a shorter duration and less
frequency of use of the antibiotics since
there was an overall lower significant
outcome of sepsis.
What Were the Results?

How Large was the Treatment Effect?
 Is
significant with the risk reduction of death
being 42% (ARR = 8.0%-4.6% = 3.4%)
 Number needed to treat:

1/ARR = 1/0.034 = 29.4
How Precise Was the Estimate of
Treatment Effect?
Precision is the relative width of the
confidence interval
 For mortality, the risk reduction was 42%
(95% CI 22%-62%). This is slightly wide.

Were all Clinically Important
Outcomes Considered?

Yes
 Mortality
 Morbidity
(Table 4)
 Hypoglycemia
Are the Likely Treatment Benefits
Worth the Potential Harms and Costs?




According to this study results the treatment benefits do
outweigh the harm and costs
39 patients in the intensive insulin control group did have
hypoglycemic episodes
The study using whole arterial blood with the
measurement of the glucose likely was protective of
hypoglycemic events as usually whole blood glucose is
measured 15% lower than plasma glucose
The study also gave the patients 24 hours of IV glucose
at the start of the study which probably helped lower the
adverse outcome of severe hypoglycemia and death
Can the Results be Applied to My
Patient Care?
-Single European center
-Largely surgical patients
Examples of clinical trials and other studies demonstrating
better outcomes with improved glycemic control.
Setting
General medical
and surgical
Umpierrez; Pomposelli
Acute MI
Capes; Bolk
Cardiac surgery
Furnary & Zerr
Stroke
Williams; Bruno
*No diabetes
†Diabetes
BG Threshold
Outcomes
>189*; >230†
>220
↑ Mortality; ICU; LOS
↓ Infection rates
<100.8 vs 199.8
>109.8*; >124†
↑ Mortality
↑ Mortality; CHF shock
>150
↑ Mortality
↑ Sternal wound infection
>130
90-180
↑ Mortality (HR 1.87); LOS
60% ↑ Penumbra salvage
56 cm2 ↓ Infarct size
Even more conditions have better outcomes with
better glycemic control:
• Chemotherapy outcomes (remission, survival, and infection
rates) Weiser et al. Cancer 2004 Mar 15;100(6):1179-85
• Reduced rates of kidney transplant rejection Mathew et al,
Transplantation 2001 Oct 15;72(7):1321-4
• Better outcomes in a mixed med / surgical “real world” ICU
setting Krinsley JS. Mayo Clin Proc. 2004;79:992–1000.
• Better outcomes in community acquired pneumonia
The weight of evidence supports a goal of good
glycemic control for all inpatients!
American Association of Clinical Endocrinologists
Inpatient Consensus Conference - 2003
• Conference Conclusions:
– Improved glycemic control during hospitalization
results in improved clinical outcomes
– Diabetes management during hospitalization needs to
become a much greater priority
• Upper Limit Inpatient Glycemic Targets:
– ICU: 110 mg/dl (6.1 mmol/L)
– [Non-critical care
• Pre-prandial: 110 mg/dl (6.1 mM)
• Maximum: 180 mg/dL (10 mM)
AACE Position Statement on Inpatient Diabetes and Metabolic Control
Endocrine Practice 10 (1): 77-82, 2004
Targets established in Dec 2003
AACE/ACE
ADA
ICU
Non-ICU
Preprandial
Non-ICU
Maximal
110 mg/dL
100 mg/dL
110 mg/dL
90-130 mg/dL
180 mg/dL
180 mg/dL
•AACE Position Statement on Inpatient Diabetes and Metabolic Control
Endocrine Practice 10 (1): 77-82, 2004
•Garber AJ et al.; American College of Endocrinology Task Force on Inpatient
Diabetes Metabolic Control. Endocr Pract. 2004;10:77-82. American Diabetes
Association. Diabetes Care. 2005;28:S4-S36.
History of Inpatient Glucose Control: 2006
• ACE, AACE & ADA plus numerous cosponsoring organizations – “Call to Action
Consensus Conference”
– Addressing systemic implementation
barriers
– Inpatient hyperglycemia – a quality-ofcare measure
ACE/ADA Task Force on Inpatient Diabetes. Endocr Pract. 2006;12:458-468.
Joint Commission
Inpatient Diabetes Certification
• Specific staff education requirements
• Written blood glucose monitoring protocols
• Plans for treatment of hypoglycemia and
hyperglycemia
• Data collection of incidences of hypoglycemia
• Diabetes self-care education
• Identified program champion or team
http://www.jointcommission.org/certificationprograms/inpatient+diabetes; accessed May 20, 2010.
Intensive Insulin Therapy in the
Medical ICU
Greet Van den Berghe, M.D., Ph.D., and the Leuven Group
N Engl J Med, Volume 354;5:449-461, February 2, 2006
• RCT of insulin infusion to goal of 80-110 mg/dL vs
usual therapy (180-200 mg/dL).
• 1,200 patients randomized
• A priori outcome of interest: patients in MICU for
> 3 days
• Only 17% were diabetic
Conclusions: MICU study
• Intention to treat: Intensive insulin therapy significantly
reduced overall morbidity but not mortality.
– Morbidity Reduced (newly acquired kidney injury, ICU days,
hospital days and days on the vent.)
• Predefined population analysis (ICU > 3 d):
– In-house mortality reduced (ARR 9.5%-NNT10)
– ICU mortality reduced (ARR 7.2%-NNT 14) p=.05
• BUT, More deaths (18.8 vs 26.8%) in patients in ICU < 3
days
– -Once adjusted for patients with care limited or withdrawn in
the first 72 hours it was (37.8% vs 33.5%-p=.1)
• “More studies needed”
Glucontrol Study (abstract info)
• Mixed population of ICU patients (medical,
scheduled and trauma surgery)
• N = ~3500, multicenter, Europe
• Target glucose:
– 80 – 110 mg/dl vs. 140 – 180 mg/dl
• Endpoint: in-hospital and 28 day mortality
• Start: October 2004
VISEP
Brunkhorst et al, N Engl J Med 358:125-39, 2008
VISEP Trial
Study Aim: 600 subjects with sepsis randomized to conventional
or intensive insulin therapy
Methods:
• Conventional Therapy: CII started at BG > 200 mg/dl and
adjusted to maintain a BG 180 - 200 mg/dl.
• Intensive Therapy group: CII started at BG > 110 mg/dl and
adjusted to maintain BG 80 -110 mg/dl (Leuven’s protocol)
Primary Outcomes:
• Mortality (28 days) and morbidity (sequential organ failure
dysfunction, SOFA)
• Safety end-point: hypoglycemia (BG<40 mg/dl)
VISEP Trial
IIT
(n = 247)
CIT
(n = 290)
P
- 28 days
24.7%
26%
0.74
- 90 days
39.7%
35.4%
0.31
Patients with
hypoglycemia < 40, %
17.0 %
4.1 %
< 0.0001
SOFA Score
7.7
7.3-8.3
7.8
7.3-8.3
0.16
Mortality rate, %
Data from 488 patients:
IIT [goal: 80 – 110 mg/dL]: mean BG 112 mg/dl
CIT [goal: 180 – 200 mg/dL]: mean BG 151 mg/dl
Brunkhorst et al, N Engl J Med 358:125-39, 2008
Infusion Protocols –
Variable Hypoglycemia Rates
Study
Population
Target
Percent of
Glucose
patients with
(upper
severe
limit)
hypoglycemia
mg / dl
Leuven 1 (a)
Surgical
110
7.2%
Leuven 2 (b)
Medical
110
19%
Glucontrol (c) Medical and Surgical
110
8.6%
VISEP (d)
Medical
110
17%
Yale (e)
Surgical
120
0
Yale (e)
Medical
120
1.7%
Krinsley (f) Medical and Surgical
140
2.2%
Glucommander (g) Medical and Surgical 120 – 140
2.6%
(a) vdB 1 (b) vdb 2 (c) Devos (d) Brunkhorst (e) Goldberg – Diabetes
Spectrum (f) Krinsley (g) Davidson
Wiener, R. S. et al. JAMA 2008;300:933-944.
Association of Tight Glucose Control vs Usual Care With
Outcomes Among Critically Ill Adults
Subgroup
# studies
RR
Hospital Mortality
Very tight (<110)
Moderately tight (<150)
Overall
14
13
27
0.90 (0.77-1.08)
0.99 (0.83-1.18)
0.93 (0.85-1.03)
Septicemia
Very tight (<110)
Moderately tight(<150)
Overall
4
5
9
0.80 (0.57-1.11)
0.64(0.41-1)
0.76 (0.59-.97)
New need for Dialysis
Very tight (<110)
Moderately tight(<150)
Overall
4
5
9
0.95(.7-1.29)
0.98(0.59-1.61)
0.96 (0.76-1.20)
Wiener, R. S. et al. JAMA 2008;300:933-944.
Meta-Analysis results
Subgroup
# studies
RR
11
4
15
5.23(4.12-6.54)
4.37(2.19-5.72)
5.13 (4.09-5.42)
Severe Hypoglycemia
Very tight
Moderately tight
Overall
Percent of patients with >1 BG
Less than 40
13.7% of patients VS 2.5%
NNH=8.9
Bringing it home: What’s been happening at Good
Sam?
•
•
•
•
•
•
•
IV order set
Early 2004- multidisciplinary group
May 2004- subcut order set
Oct 2005- larger scale data collection
2006- revisions in protocol and data analysis
June 2007- new tube feed order set
Dec 2007- IV order set standardized and data
collection
• Jan 2008-System-wide initiative targeting glycemic
control (70-140 mg/dL)
in the ICU
BGSMC: Second Floor ICUs a “win- win”
% in range
% <70
66.44
68
3.5
3.24
66
65.81
64
3
60.5
62
2.67
2.64
2.5
57.47
59.35
% in range
59.34
56
54
2.86
2.75
2.5
60
58
2.93
% <70
1.83
2
57.09
55.63
54.54
1.5
52
1.29
50
Mar-08 Apr-08 May-08 Jun-08
Jul-08
Aug-08
Sep-08
Oct-08 Nov-08 Dec-08
1
Mar-08 Apr-08 May-08 Jun-08
Jul-08
Aug-08 Sep-08
Oct-08 Nov-08 Dec-08
How low do we need to go?
“Tight/intensive” vs “Moderate/good”
Waiting for NICE SUGAR…
Original Article
Intensive versus Conventional Glucose Control in
Critically Ill Patients
The NICE-SUGAR Study Investigators
N Engl J Med
Volume 360(13):1283-1297
March 26, 2009
Hypothesis of the Study
That intensive glucose control reduces
mortality at 90 days
Assessment, Randomization, and Follow-up of the Study Patients
The NICE-SUGAR Study Investigators. N Engl J Med
2009;360:1283-1297
Baseline characteristics
The NICE-SUGAR Study Investigators. N Engl J Med
2009;360:1283-1297
Methods
• RCT involving medical and surgical ICUs of 42
hospitals in New Zealand, Australia and North
America
• Eligible patients were those expected to
require treatment in the ICU on 3 or more
consecutive days
• Control of blood sugar was achieved with IV
infusion of insulin in saline
Methods
• The trial intervention was discontinued once a
patient was eating or discharged from the ICU
but it was resumed if the patient was
readmitted to the ICU within 90 days.
• It was discontinued permanently at the time
of death or 90 days after randomization,
whichever occurred first.
Methods
• Blood samples for glucose measurement were
obtained by arterial catheters whenever
possible, the use of capillary samples was
discouraged
• Blood glucose levels were measured with the
use of point of care or arterial blood gas
analyzer or laboratory analyzer in routine use
at each center.
Calorie Administration, and Corticosteroid Treatment, According
to Treatment Group
• Calorie administration: 891 in intensive
control group and 872 in conventional control
group (mostly by enteral route, but also by
parenteral route and as IV glucose)
• 34.6% in intensive control group and 31.7% in
the conventional control group received
corticosteroids – main indication was septic
shock
NICE-SUGAR Study: Design
6104 ICUa patients
Conventional
IV insulin if BG >180 mg/dL
Target: 140-180 mg/dL
Intensive
IV insulin if BG >108 mg/dL
Target: 81-108 mg/dL
69% insulin
BG = 144 mg/dL
97% insulin
BG = 115 mg/dL
Primary Outcome:
90-day mortality
aOne
third were surgical patients and two thirds were medical patients; 20% had diabetes.
NICE-SUGAR Study Investigators, et al. N Engl J Med. 2009.
NICE-SUGAR
• Intensive control vs conventional control
• Mortality 27.5% vs 24.9%; P = 0.02
• ARR=27.5%-24.9%= 2.6% NNH = 38
• Severe hypoglycemia (BG ≤40 mg/dl) 6.8% vs
0.5%; P<0.001
• No significant difference between the two
treatment groups in the median number of
days in the ICU or hospital
The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360:1283-1297.
Conclusion
• “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”
Are the test results of the study valid?
• Was the assignment to patients randomized?
Yes, 6104 patients underwent randomization,
3054 were assigned to undergo intensive
control and 3050 to undergo conventional
control. Data with regard to primary outcome
was available for 3010 and 3012 respectively.
• Were all patients who entered the trial properly
accounted for and attributed at its conclusion?
Yes all the patients were accounted for. Study
treatment was discontinued prematurely on
304/3054 in the intensive control group and
225/3050 in the conventional control group. Patients
were withdrawn because of patients request or
surrogate request, physicians request, were switched
to palliative care, had other reason, or were
withdrawn because of serious adverse event.
• Was follow up complete?
– At the completion of the trial data on vital status
90 days after randomization were unavailable for
82 of the 6104 patients (1.4%), 44 in the intensive
control group and 38 in the conventional control
group.
– For 74 of those 82 patients the vital status data
were missing because consent had been withheld
or withdrawn
• Were patients analyzed in groups to which
they were randomized?
Yes, they were analyzed in either the intensive
glucose control group or the conventional
glucose control group.
• Were the groups similar at the start of the
trial?
Yes. According to Table 1, the groups were
similar in the measured baseline
characteristics.
• Aside from experimental intervention, were
the groups treated equally?
– Yes, they were both in the same environment;
they were allowed to eat the same diet (by enteral
route, parenteral rout and IV glucose) for a total of
891 calories for the intensive glucose control
group and 871 calories for the conventional
glucose control group.
– Both groups also received corticosteroid
treatment.
• Blood sample for glucose measurement was
obtained by means of arterial catheters in
both groups whenever possible.
• The use of capillary sample was discouraged.
• Blood glucose level was measured via the use
of point of care or arterial blood gas analyzers
in both groups
What were the results?
• How large was the treatment effect?
90 days after randomization 27.5% in the
intensive control group had died as compared
to 24.9% in the conventional control group,
therefore intensive glucose control increased
mortality among adults in the ICU. The
absolute difference in mortality was 2.6%.
The odds ratio was 1.14
• How precise was the estimate of the
treatment?
– Precision is defined by the tightness of the
confidence interval of the treatment effect.
– For the odds ratio of 1.14, the 95% CI was 1.02 to
1.28. This odds ratio is significant because it does
not include 1.00.
– It is somewhat precise, because it says the “true”
odds ratio is likely from 1.02 to 1.28.
NNT
What is your number?
Absolute Risk (AR)
The incidence of disease in a group
(either the exposed or nonexposed
group)
 Absolute Risk Reduction (ARR) is
the disease incidence that can be
attributed to an exposure

Absolute Risk (AR)

AR = Incidence in each group

ARR = Incidence in exposed group –
Incidence in unexposed group
Smoking Example
Exposure
Disease
CHD
No CHD
Smoker
50
450
500
Nonsmoker
35
465
500
ARR = 50/500 – 35/500 = 15/500 = 0.03
Number Needed to Treat
(NNT)
The number of patients that need
to be treated to prevent one
additional case of the disease
 NNT = 1/ARR

Smoking Example
Exposure
Disease
CHD
No CHD
Smoker
50
450
500
Nonsmoker
35
465
500
NNT = 1/ARR =
1
=
1
= 33.3
50/500 – 35/500
15/500
Toxic Example
Exposure
Outcome
Live
Die
Tx
900
100
1000
Control
910
90
1000
ARR = 100/1000 – 90/1000 = 10/1000
Number Needed to Treat
(NNH)
The number of patients that need
to be treated to cause one
additional bad outcome
 NNH = 1/ARR

Toxic Example
Exposure
Outcome
Live
Die
Tx
900
100
1000
Control
910
90
1000
NNH = 1/ARR =
1
=
1
= 100
100/1000 – 90/1000 10/1000
NNT
What is a good number?
How serious is the outcome?
 How expensive is the treatment
 How serious are side effects of the
treatment?

 What
is the NNH for a side effect?
Now What?
BGSMC Response to NICE SUGAR
Blood Glucose Values
Blood Glucose Targets for Mixed ICU Patients
200
180
160
140
120
100
80
60
40
NICE Sugar:
TIGHT
NICE Sugar:
GOOD
Banner targets Banner targets
Banner
2008
2009
revised targets
2009
Percentage of patients w ith a BG <40
8.00%
7.00%
6.00%
5.00%
4.00%
3.00%
2.00%
1.00%
0.00%
NICE Sugar: TIGHT
NICE Sugar: GOOD
BGSMC w ith 2008
targets
Glycemic Control in the
NICE-SUGAR & Leuven 1 Studies
NICE-SUGAR
LEUVEN I
Glycemic
Target
Mean (SD)
% Values in
Target
81-108
80-110
118 (25)
103 (19)
25
53
Control
Target
Control
Results
% Overlap
Results
Mean (SD)
Within 2 SD of
interventional
mean
NICE-SUGAR
140-180
145 (26)
80
LEUVEN I
180-210
153 (33)
30
RCT Glycemic Control Targets in Critically Ill
Patients
Intensive Target Range:
Mean achieved
103
Van den Berghe 1
112
VISEP
118
Glucontrol
118
BG <40
“Conventional” Target Range:
Mean= yellow bar
70 100
NICE SUGAR
130 140 160 180 200 250 299 400
Intensive Insulin Therapy & Mortality in ICU Patients:
Meta-analysis of 26 Articles
ICU
Mixed
Medical
Surgical
All
no. deaths/total n
IIT
Control
1351/5051
1301/5089
253/724
270/736
77/1037
110/935
1681/6812
1681/6760
Risk ratio
(95% CI)
0.99 (0.87-1.12)
1.00 (0.78-1.28)
0.63 (0.44-0.91)
0.93 (0.83-1.04)
Griesdale DE, et al. CMAJ. 2009.
Intensive Insulin Therapy and Mortality in
Critically Ill Patients: A Meta-analysis
No. Events/Total No. Patients
Hypoglycemic Events
Study
IIT
Control Risk ratio (95% CI) Favors IIT
Van den Berghe et al
Henderson et al
Bland et al
Van den Berghe et al
Mitchell et al
Azevedo et al
De La Rosa et al
Devos et al
Oksanen et al
Brunkhorst et al
Iapichino et al
Arabi et al
Mackenzie et al
NICE-SUGAR
Overall
39/765
7/32
1/5
111/595
5/35
27/168
21/254
54/550
7/39
42/247
8/45
76/266
50/121
206/3016
654/6138
6/783
1/35
1/5
19/605
0/35
6/169
2/250
15/551
1/51
12/290
3/45
8/257
9/119
15/3014
98/6209
6.65 (2.83-15.62)
7.66 (1.00-58.86)
1.00 (0.08-11.93)
5.94 (3.70-9.54)
11.00 (0.63-191.69)
4.53 (1.92-10.68)
10.33 (2.45-43.61)
3.61(2.06-6.31)
9.15 (1.17-71.35)
4.11(2.2-7.63)
2.67 (0.76-9.41)
9.18 (4.52-18.63)
5.46 (2.82-10.60)
13.72 (8.15-23.12)
5.99 (4.47-8.03)
0.1
Favors Control
1
Risk Ratio (95% CI)
Griesdale DE, et al. CMAJ. 2009.
10
Intensive Insulin Therapy & Mortality in ICU Patients:
Meta-analysis of 26 Articles
• IIT had no effect on overall risk of death
• IIT may benefit patients in SICU
• 6-fold increased risk of severe hypoglycemia among IIT
patients compared with controls
• Risk for hypoglycemic events did not differ by type of ICU
or by intensity of insulin therapy
Griesdale DE, et al. CMAJ. 2009.
History of Inpatient Glucose Control: 2009
Updated AACE/ADA Consensus Statement
– Identifies reasonable, achievable, and safe
glycemic targets
– Describes protocols, procedures, and system
improvements
Moghissi ES et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15:353-369.
http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.
Updated AACE/ADA Consensus Statement:
2009
118
<40
70 100
NICE Sugar
130 140 160 180 200 250 299 400
2009 AACE/ADA
goals
–Identifies reasonable, achievable, and safe glycemic targets
–Describes protocols, procedures, and system improvements
Moghissi ES et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15:353-369.
http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.
AACE/ADA Target Glucose Level
in ICU Patients- revised after NICE SUGAR
• ICU setting:
– Starting threshold of no higher than 180 mg/dL
– Once IV insulin is started, the glucose level should be maintained
between 140 and 180 mg/dL
– Lower glucose targets (110-140 mg/dL) may be appropriate in selected
patients
– Targets <110 mg/dL or >180 mg/dL are not recommended
Not recommended
<110
Acceptable
110-140
Recommended Not recommended
140-180
>180
Moghissi ES, et al. Endocr Pract. 2009.
Recommendations for Managing Inpatient
Hyperglycemia
Antihyperglycemic Therapy
Insulin
Recommended
IV Insulin
Critically ill ICU patients
Oral Agents
Not Generally
Recommended
SC Insulin
Non-critically ill patients
Clement S, et al. Diabetes Care. 2004; Moghissi ES, et al. Endocr Pract. 2009.
Will the results help me to care for my
patients?
 Choose a glycemic target that can be reached
safely:
– e.g., 140 mg/dL
 Avoid excessive severe hypoglycemia
 Use appropriate data monitoring tools
– Glycemic values
– Clinical and financial outcomes
 Minimize glycemic variability
Krinsley JS, et al. Crit Care. 2008.
Thank you
• Nilda Franco
• Kristin Manley
• Richard Gerkin
• Jonathan Frunzi
• Carl Houghton
• Peter McKellar
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