Insulin Therapy in the ICU: Hyperglycemic Protocols Bradley J. Phillips, M.D. Critical Care Medicine Boston Medical Center Boston University School of Medicine TRAUMA-ICU NURSING EDUCATIONAL SERIES
Dec 29, 2015
Insulin Therapy in the ICU: Hyperglycemic Protocols
Bradley J. Phillips, M.D.
Critical Care Medicine
Boston Medical Center
Boston University School of Medicine
TRAUMA-ICU NURSING EDUCATIONAL SERIES
Insulin in the ICU…Hypergylcemia associated with insulin resistance
is common in ICU patients, even those who have not previously had diabetes.
• Reports of pronounced-hyperglycemia leading to multiple complications– a lack of clinical trials to support
• High serum levels of insulin-like growth factor-binding protein 1 increases the risk of death– reflects an impaired response of the hepatocyte to insulin
NEJM 2001
Landmark Paper
• Van Den Berghe et al. Intensive Insulin Therapy in Critically Ill Patients. NEJM 2001;345 (19): 1359-67.
– Prospective, Randomized, Controlled study
– 1,548 Adults admitted to a SURGICAL-ICU receiving Mechanical Ventilation
– 2 Groups Assigned• Intensive-Insulin: Blood Glucose 80 – 110• Conventional: Insulin therapy only if Blood Glucose > 215 with a
maintenance between 180 – 200
NEJM 2001: Hypothesis
Hyperglycemia or relative insulin deficiency
(or both) during critical illness may
directly or indirectly confer a predisposition
to complications, such as
severe infections,
polyneuropathy,
multiple-organ failure, and death.
NEJM 2001: Purpose
To determine
whether normalization of blood glucose levels
with intensive insulin therapy
reduces mortality and morbidity
among critically ill patients.
Some of the Logistics (1)
• Conventional Group– IV Insulin was started if the Blood Glucose exceeded 215
– Infusion was adjusted to maintain level between 180-200
• Intensive-Insulin Group– Started if Blood Glucose exceeded 110
– Infusion was adjusted to maintain level between 80 – 110
– Maximal rate of insulin was set at 50 IU per hr.
– Dose adjustment was via strict algorithm followed by ICU-nurses and assisted by a single study-physician that was NOT involved in the clinical mgmt of the patient
Some of the Logistics (2)
• On admission, all patients were fed continuously with IV Glucose (200 – 300 g/24 hrs).
• The next day, TPN, Combined Enteral-Parenteral, or Total Enteral Feeding was instituted according to a standardized schedule– 20-30 nonprotein kilocalories/kg/24 hrs– AND a balanced formula
• 0.13-0.26 g/N2/kg/24 hrs• 20-40 % of nonprotein calories via lipid solution
• Total Enteral Feeding was attempted as early as possible
Some of the Logistics (3)
• Original Plan was to enroll 2,500 patients in order to detect an absolute difference in mortality of 5%
• Interim analysis (conducted every 3 months) of overall mortality required the study be terminated early
• Sponsors were not involved in the study design, data collection, analysis, interpretation of the data, or preparation of the manuscript…
Demographics
• ½ of the pts were CT Surgery
•Note:
• the AGE
• the Hx of Cancer
• Hx of Diabetes
• % of pts above 200…
Method – Serious Study
• All patients admitted to the SICU from February 2, 2000 through January 18, 2001 were considered for enrollment – after consent was obtained
• Only 14 pts were excluded– 5 because of participation in other studies– 9 pts were moribund or DNR
A Few Points (1)
• 98% of the pts in the Intensive-Insulin Group required therapy– Mean Morning Blood Glucose Level: 103 +/- 19 mg/dl
• 39% of the pts in the Conventional Group required therapy– Treated group: Mean Morning Blood Glucose Level:
173 +/- 33 mg/dl– Untreated group: Mean Morning Blood Glucose Level:
140 +/- 25 mg/dl.
Results (1)
Results (2)
Mortality in Perspective (1)
• 35 pts in the Intensive Group Died (4.6 %)• 63 pts in the Conventional Group Died (8.0 %)
– Apparent Risk Reduction of 42 %– Unbiased Risk Reduction of 32 %
• Due to having to adjust for repeated interim analysis
• Intensive therapy also reduced the in-hospital mortality – mostly in those pts with multiple-organ failure secondary to a septic focus, regardless if there was a history of diabetes or hyperglycemia.
Results were similar in patients who had undergone CT Surgery versus other types of surgery
Results (4)
Mortality in Perspective (2)
• Since the introduction of Mechanical Ventilation, few direct interventions have actually improved ICU Survival.
Treatment of sepsis with Activated Protein C
results in a 20 % relative reduction
in mortality at 28 days…
glycemic control reduces R.R. of mortality by 42 %.
A Few Points (2)
• Hypoglycemia (Blood Glucose < 40 mg/dl)
– 39 pts in the Intensive Group • 2 of the 39 pts had associated sweating and agitation
– 6 pts in the Conventional Group
There were no instances of hemodynamic deterioration or convulsions !
Morbidity (1)
Intensive therapy reduced the duration of ICU stay
but not overall-hospital stay
• Intensive therapy reduced episodes of septicemia by 46 %
• Fewer pts in the Intensive Group required prolonged ventilatory support and renal replacement therapy – yet the number of patients that required inotropic or vasopressor support were the same between groups
Morbidity (2)
Variable Conventional Intensive p Val.Cr > 2.5 12.3 % 9.0 % 0.04Plasma Urea N2 > 54 11.2 % 7.7 % 0.02Dialysis or CVVH 8.2 % 4.8 % 0.007
Bilirubin > 2 26.7 % 22.4 % 0.04
Septicemia 7.8 % 4.2 % 0.003Tx with Abx > 10 days 17.1% 11.2% < 0.001
EMG-Polyneuropathy 51.9 % 28.7 % < 0.001
# Transfusions per Pt 2 1 < 0.001
Some Critique
• European Study (Belgium)• Not Blinded
– Team of ICU Nurses and a Specific Study Physician following Pre-designed Protocol
• Nutritional Protocol is not described or reported
• Insulin Protocol is not described or reported
– Independent of Clinical Decision-making Process
• SICU-specific patient population• Are the results “too good”… ?
NEJM 2001: Conclusions
the use of exogenous insulin
to maintain
blood glucose at a level
less than 110 mg/dl
reduces morbidity and morality
among critically ill patients in the Surgical ICU,
regardless of whether there is a
history of diabetes or hyperglycemia.
So, where are we going ?
“we need to re-adjust our thinking…”
“there is a set-point (similar to a thermostat)
that we must adjust clinically in order to apply this
information at the bedside…”
“no longer can we accept Blood Sugars
outside of the normal physiologic range”
Blood Sugars: Insulin Management in the ICU
Tisha K Fujii, DO, Bradley J. Phillips, MD
• Traditional Thinking: Blood Sugar less than 200 is adequate…after all, the kidney dumps sugar above 180.
• 2002 Thinking: The human system is designed to function with a Glucose between 80 and 120. It is a matter of will that we, as healthcare workers, force it to do otherwise.
The following is a suggested protocol to allow appropriate “blood sugar control” in the intensive care unit. We have employed its
use successfully in a variety of units (i.e. trauma, surgical, medical) and
believe that focusing specific attention at undue hyperglycemia is well-worth the
effort required.
ISPUB.COM
Blood Sugars in the ICU (in-press)
• If Glucose is 121 - 150: Give 2 unit bolus injection and start drip at 1 u/hr.• If Glucose is 151 - 175: Give 3 unit bolus injection and start drip at 1 u/hr.• If Glucose is 176 - 200: Give 4 unit bolus injection and start drip at 2 u/hr.• If Glucose is 201 - 250: Give 6 unit bolus injection and start drip at 2 u/hr.• If Glucose is 251 - 300: Give 8 unit bolus injection and start drip at 3 u/hr.• If Glucose is 301 - 350: Give 10 unit bolus injection and start drip at 3 u/hr.• If Glucose is 351 - 400: Give 12 unit bolus injection and start drip at 4 u/hr.• If Glucose is above 401: Give 15 unit bolus injection and start drip at 4 u/hr.
• Accuchecks q 1 hr. until Glucose is “steady-state” between 80 - 150, then q 2hrs ATC. Adjust Drip Rate as Necessary to fit Target Parameters.
• Remember, the real goal is 80 - 120, but for practical reasons we accept the range of 80 - 150.
* Hourly adjustments are usually in increments of 1-2 units (most patients seem to reach a “steady-state” in the range of 3-5 units/hr.). We have had multiple patients intermittently require rates of 8-12 units per hour.
Blood Sugars in the ICU (in-press)
A Tight Sliding Scale is also a component of Therapy:
Accucheck Treatment70 or below Give 1/3 amp D50. Recheck in 1 hr.71 - 80 Recheck in 1 hr.81 - 120 No direct treatment121 - 150 2 units and recheck in 1 hr.151 - 175 3 units and recheck in 1 hr.176 - 200 4 units and recheck in 1 hr.201 - 250 6 units and recheck in 1 hr.251 - 300 8 units and recheck in 1 hr.301 - 350 10 units, recheck in 1 hr..? Insulin Drip351 - 400 12 units, recheck in 1 hr..? Insulin Drip401 or greater 15 units, recheck in 1 hr., & notify MD.
ISPUB.COM
BMC Version: Insulin Protocol
Currently in development
• Critical Care Medicine
• ICU Staff
• Pharm. D.’s
• Committee and more committees…
WHY ??
NEJM 2001: Hypothesis
Hyperglycemia or relative insulin deficiency
(or both) during critical illness may
directly or indirectly confer a predisposition
to complications, such as
severe infections,
polyneuropathy,
multiple-organ failure, and death.
Questions & Comments
Thank you….
Insulin Therapy in the ICU:
Hyperglycemic Protocols
Bradley J. Phillips, M.D.
Critical Care Medicine
Boston Medical Center
Boston University School of Medicine