Insulin Therapy in the ICU:

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Insulin Therapy in the ICU
TRAUMA-ICU NURSING EDUCATIONAL SERIES

• Hyperglycemic Protocols
• Bradley J. Phillips, M.D.
• Critical Care Medicine
• Boston Medical Center
• Boston University School of Medicine

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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
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Landmark Paper

• Van Den Berghe et al. Intensive Insulin Therapy
  in Critically Ill Patients. NEJM 2001345 (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 gt 215 with a maintenance between 180 200

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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.

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NEJM 2001 Purpose

• To determine
• whether normalization of blood glucose levels
• with intensive insulin therapy
• reduces mortality and morbidity
• among critically ill patients.

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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

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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

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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

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Demographics

• ½ of the pts were CT Surgery
• Note
• the AGE
• the Hx of Cancer
• Hx of Diabetes
• of pts above 200

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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

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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.

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Results (1)
13
Results (2)
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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

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Results (4)
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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
  .

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A Few Points (2)

• Hypoglycemia (Blood Glucose lt 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 !

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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

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Morbidity (2)

• Variable Conventional Intensive p Val.
• Cr gt 2.5 12.3 9.0 0.04
• Plasma Urea N2 gt 54 11.2 7.7 0.02
• Dialysis or CVVH 8.2 4.8 0.007
• Bilirubin gt 2 26.7 22.4 0.04
• Septicemia 7.8 4.2 0.003
• Tx with Abx gt 10 days 17.1 11.2 lt 0.001
• EMG-Polyneuropathy 51.9 28.7 lt 0.001
• Transfusions per Pt 2 1 lt 0.001

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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 ?

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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.

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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

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• Blood Sugars Insulin Management in the ICU
• Tisha K Fujii, DO, Bradley J. Phillips, MD
• Traditional Thinking Blood Sugar less than 200
  is adequateafter 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
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• 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.

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• Blood Sugars in the ICU (in-press)
• A Tight Sliding Scale is also a component of
  Therapy
• Accucheck Treatment
• 70 or below Give 1/3 amp D50. Recheck in 1 hr.
• 71 - 80 Recheck in 1 hr.
• 81 - 120 No direct treatment
• 121 - 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
  Drip
• 351 - 400 12 units, recheck in 1 hr..? Insulin
  Drip
• 401 or greater 15 units, recheck in 1 hr.,
  notify MD.

ISPUB.COM
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BMC Version Insulin Protocol

• Currently in development
• Critical Care Medicine
• ICU Staff
• Pharm. D.s
• Committee and more committees

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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.

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Questions Comments

• Thank you.

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Insulin Therapy in the ICU

• Hyperglycemic Protocols
• Bradley J. Phillips, M.D.
• Critical Care Medicine
• Boston Medical Center
• Boston University School of Medicine