1. Glycemic Control in Adult
Intensive Care Patients
Joshua Alderman
Adult-Gerontology Acute Care Nurse Practitioner Track
University of Connecticut
2. In adult medical/surgical
intensive care patients, what is
the effect of intensive vs.
conventional glycemic control
on mortality and the incidence
of hypoglycemic events?
3. Neuman Systems Theory
Provides a holistic and system-based approach to
nursing, and states there is constant energy exchange
with the environment
Examines how the patient-system responds to actual or
potential stressors; these responses can be used as a
guide as to how severe illness is
Primary, secondary, and tertiary nursing
prevention/intervention is utilized to retain, attain, and
maintain patient-system wellness
In acute care we focus on the secondary and tertiary
prevention/intervention
6. Prevalence of Hyperglycemia in ICU
Australian study from 2013 found approximately 80% of the
1,000 patient’s developed hyperglycemia at some point
within the first 48 hours in the ICU (Farrokhi et al., 2013)
Other studies have shown this percentage to be even higher
7. Major Causes of Hyperglycemia in the
ICU
Critical illness and Stress Hyperglycemia
Immobility
IV fluids containing dextrose and feedings
Drugs including: corticosteroids, catecholemines
(particularly epinephrine), beta blockers, octreotide
History of Diabetes mellitus, and related disorders such as
DKA and HHNK
8. Critical Illness and Hyperglycemia
Increased levels of counter-regulatory hormones and
cytokines cause insulin resistance
This resistance results in impaired cellular glucose uptake
as well as hepatic glycogenesis/gluconeogenesis leading to
hyperglycemia
These mechanisms are believed to be a way for the body to
provide more “fuel” for vital organs
11. Deleterious Effects of Hyperglycemia
These factors can lead to acute
complications including, but not
limited to:
Poor wound healing
Severe infections
Kidney injury
Critical illness polyneuropathy
Hypovolemia
Poor wound healing
12. Given these consequences, the question is
not whether to control glucose, but rather
what is the optimal level of glycemic
control during critical illness?
13. The Push for Intensive Glycemic Control
AKA Intensive Insulin Therapy (IIT)
In 2001, Van den Berghe G, et al. published their landmark
article “Intensive Insulin Therapy in Critically Ill Patients” in
the New England Journal of Medicine
The study asked, in surgical ICU patients, how does
intensive glycemic control (80-110 mg/dl) compare to
conventional glycemic control (180-200 mg/dl) in reducing
mortality?
14. The Push for Intensive Glycemic Control
12-month single center, non-blinded, randomized,
controlled trial with 1,548 mostly surgical ICU patients
The trial found ICU mortality to be 4.6% in the intensive
group vs. 8% in the conventional group (p < 0.04)
However, hypoglycemic events for the intensive group
were seen much more often than with the conventional
group (7% vs. 0.5%, respectively)
The trial concluded that intensive glucose therapy at or
below 110 mg/dl reduced morbidity and mortality in the
surgical intensive care unit
15. The Push for Intensive Glycemic Control
Quick Adoption of IIT throughout critical care
However, as research progressed, a number of new trials
began to show that intensive glycemic control may not be
as beneficial as once thought
16. Follow-up Lueven Trial
One of the major limitations of the Lueven Surgical Trial
was the lack of medical patients
In 2006, the Lueven investigators published a follow-up
RCT to their 2001 study focusing on 1,200 medical
patients
“Intensive insulin therapy significantly reduced
morbidity but not mortality among all patients in the
medical ICU.”
First to contradict 2001 study
17. Further Data Against IIT
In the years following, several other RCTs concluded
similar findings to the 2006 Lueven study
The VISEP and Glucontrol trials were both terminated
early due to safety concerns related to the high
incidence of hypoglycemic events
Both of these studies concluded mortality was not
significantly affected with IIT, and the risk of
hypoglycemia was significant
18. The NICE-SUGAR Trial
This trial put the nail in the coffin of the research
supporting IIT
In 2009, the “Normoglycemia in Intensive Care
Evaluation – Survival Using Glucose Algorithm
Regulation” was published
This was a large, multi-center, parallel-group, RCT with
6,104 patients in medical/surgical 42 ICUs with the
hypothesis that IIT would decrease 90-day mortality
19. The NICE-SUGAR Trial
Those expected to require 3 or more days in ICU were
randomly placed into an IIT group (81-108 mg/dl) or
conventional group (144-180 mg/dl)the two groups had
similar characteristics at baseline
A total of 829 patients (27.5%) in the intensive-control
group and 751 (24.9%) in the conventional-control group
died (p = 0.02); no effect on ICU LOS, Hospital LOS, or days
of mechanical ventilation
Severe hypoglycemia presented in 6.8% of the IIT vs. only
0.5% of the conventional group
20. Can computers help?
In 2014, Kalfon et al. published the Computerized
Glucose Control in Critically Ill Patients trial
Large, multi-center, RCT with 2,646 mixed ICU patients
Used computerized glucose control with computer-aided
clinical decision making tool
Found that IIT with computer-aided tech could not
significantly change 90-d mortality (32.3% IIT vs. 34.1%
conventional), and hypoglycemic risk was greater
21. Limitations Shared by the RCTs
Inability to blind ICU staff
Use of subjective inclusion criteria (expected ICU LOS >2 or
3 days)
Inability to keep patients in the target glucose ranges
22. “Diabetes Paradox”
Although the exact rationale remains unknown, it appears
the chronicity of higher glucose levels in diabetics actually
reduces the harm of hyperglycemia when critically ill
The benefit of IIT in the 2001 Lueven trial was seen to be
greatest in the non-diabetic population (mortality rate 4.8%
in IIT group vs. 8.4% in the conventional group)
23. Hypoglycemia and Mortality
Since the NICE-SUGAR trial, the Lueven Trial, NICE-
SUGAR, and CGAO-REA authors published post-hoc
analyses of their studies examining hypoglycemia and
it’s association with mortality
All three studies determined that hypoglycemia is
independently associated with increased mortality
In 2010, the Leuven investigators found that there is a
threefold increase in the risk of death associated with a
single severe hypoglycemic event (<40 mg/dl)
24. Hypoglycemia and Mortality
NICE-SUGAR investigators supported that moderate (41-70
mg/dl) and severe hypoglycemia (<40 mg/dl) are associated
with increased mortality (particularly in those with
distributive shock)
Mortality rate was 23.5% in those without hypoglycemic
event
Morality rates for moderate vs. severe hypoglycemic events
were 28.5% and 35.4%, respectively
25. Summary
IIT adult medical/surgical ICUs has the potential to
increase mortality
IIT is strongly associated with greater incidence of
severe hypoglycemia (BG <40 mg/dl)
Hypoglycemia is independently associated with
increased mortality and increased LOS
Due to glucose variability, it is difficult to keep
glucose within target ranges
26. Recommendations for Practice
Insulin therapy should be initiated when BG reaches >180
mg/dl
The target range for blood glucose should be 140-180 mg/dl
The best way to achieve target glucose levels and reduce
hypoglycemia is by reducing use of fluids with containing
dextrose and using insulin only when necessary
Enteral feeding is the method of choice over parenteral
How would Neuman’s System Theory be used in the
management of hyperglycemia?
27. 1. Check BG level and
monitor S/Sx
hyperglycemia
2. Diagnosis of
treatable
hyperglycemia
>180 mg/dl
3. BG Target
Range of 140-
180 mg/dl
4. Determining
best treatment
plan to reduce
hyperglycemia
5. Restriction of
IVF containing
dextrose and
short-acting insulin
therapy;
continuous enteral
feedings
6. Continuously evaluating BG
and assessing patient’s core and
lines of defense after treatment
28. Current Practice
Despite being recommended in several guidelines (e.g.
Surviving Sepsis), the best evidence on proper glycemic
control is not being practiced universally
Not all ICU protocols have been updated to reflect current
evidence
Practitioners do not always follow current guidelines or
their specific ICUs protocol
How can the APRN increase awareness of evidence and best
incorporate it into standard practice?
29. APRN Role in Implementing the
Evidence
LEADER
COLLABORATER
EDUCATER
CLINICIAN
ADVOCATE
31. Future Research
Glucose variability effects and control
More over, with the development and implementation of
better tech/glucose variability control, could intensive
glycemic control be viable?
Should diabetics be managed differently?
Certain populations should be examined further (e.g.
neurosurgical/trauma/on corticosteroids)
32. References
Arabi, Y. M., Dabbagh, O. C., Tamim, H. M., Al-Shimemeri, A. A., Memish, Z. A., Haddad, S. H., . . . Sakkijha, M. H. (2008).
Intensive versus conventional insulin therapy: A randomized controlled trial in medical and surgical critically ill patients*.
Critical Care Medicine, 36(12), 3190-3197.
Brunkhorst, F. M., Engel, C., Bloos, F., Meier-Hellmann, A., Ragaller, M., Weiler, N., . . . Reinhart, K. (2008). Intensive
Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis. New England Journal of Medicine N Engl J Med, 358(2), 125-
139.
Curkendall, S., Natoli, J., Alexander, C., Nathanson, B., Haidar, T., & Dubois, R. (2009). Economic and Clinical Impact of
Inpatient Diabetic Hypoglycemia. Endocrine Practice, 15(4), 302-312.
Farrokhi, F., Smiley, D., & Umpierrez, G. E. (2011). Glycemic control in non-diabetic critically ill patients. Best Practice &
Research Clinical Endocrinology & Metabolism, 25(5), 813-824.
Finfer, S., et al. (2009). Intensive versus conventional glucose control in critically ill patients. The New England Journal of
Medicine, 360 (13), 1283-1297.
Finfer, S., et al. (2012). Hypoglycemia and Risk of Death in Critically Ill Patients. (2012). New England Journal of Medicine N
Engl J Med, 367(12), 1108-1118.
Inzucchi, S., & Honiden, S. (2015). Metabolic Management during Critical Illness: Glycemic Control in the ICU. Seminars in
Respiratory and Critical Care Medicine Semin Respir Crit Care Med, 36(06), 859-869.
33. References
Kalfon, P., Giraudeau, B., Ichai, C., Guerrini, A., Brechot, N., Cinotti, R., . . . Riou, B. (2014). Tight computerized versus
conventional glucose control in the ICU: A randomized controlled trial. Intensive Care Med Intensive Care Medicine, 40(2),
171-181.
Krinsley, J. S. (2015). Glycemic control in the critically ill: What have we learned since NICE-SUGAR? Hospital Practice,
43(3), 191-197.
Krinsley, J., Schultz, M. J., Spronk, P. E., Houckgeest, F. V., Sluijs, J. P., Mélot, C., & Preiser, J. (2011). Mild hypoglycemia
is strongly associated with increased intensive care unit length of stay. Ann Intensive Care Annals of Intensive Care, 1(1),
49.
Krinsley, J. S., & Grover, A. (2007). Severe hypoglycemia in critically ill patients: Risk factors and outcomes*. Critical Care
Medicine, 35(10), 2262-2267.
Meyfroidt, G., Keenan, D. M., Wang, X., Wouters, P. J., Veldhuis, J. D., & Berghe, G. V. (2010). Dynamic characteristics of
blood glucose time series during the course of critical illness: Effects of intensive insulin therapy and relative association
with mortality*. Critical Care Medicine, 38(4), 1021-1029.
Preiser, J., Devos, P., Ruiz-Santana, S., Mélot, C., Annane, D., Groeneveld, J., . . . Chioléro, R. (2009). A prospective
randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units:
The Glucontrol study. Intensive Care Med Intensive Care Medicine, 35(10), 1738-1748.
34. References
Rosa, G. D., Donado, J. H., Restrepo, A. H., Quintero, A. M., Gonzalez, L. G., Saldarriaga, N. E., . . .
Cadavid, C. A. (2008). Strict glycemic control in patients hospitalized in a mixed medical and surgical
intensive care unit: A randomized clinical trial. Critical Care Crit Care, 12(5).
Systems Theory. (2015). Retrieved March 04, 2016, from http://nursing-theory.org/theories-and-
models/neuman-systems-model.php
Van de Berghe, G., et al. (2001). Intensive Insulin Therapy in Critically Ill Patients. New England Journal of
Medicine N Engl J Med, 346(20), 1586-1588.
Van de Berghe, G., et al. (2006). Intensive Insulin Therapy in the Medical ICU. (2006). New England Journal
of Medicine N Engl J Med, 354(19), 2069-2071.
Hinweis der Redaktion
Found myself asking what is best range for glucose control. Different providers have opinions and still remains controverisal, and practice not always based on best evidence. Some protocols are still based on older evidence.
The patient-system has a central core with a lines of defense that are broken down when stressors overwhelm the system
It is the responsibility of the Acute Care APRN to shift the patient back to system wellness and primary prevention, and help reestablish the patient’s “lines of defense”
Teriary prevention = maintainence and shift back toward primary prevention
As a way to implement into practice
Australian study: random glucose >200, fasting glucose >126
Glycemic control in non-diabetic patients (Farrokhi et al)
Immobility = no exercise induced uptake of glucose
1. Counter reg hormones (including cortisol, glucagon, and catecholamines) and cytokines (including TNF, IL-1, and IL-6) cause insulin resistance
2. Also there can be impairment of glucose metabolism causing glucose varibility and hypoglycemia
IMPRAIRED IMMUNE: increased production of anti-inflammatory agent IL-10 as well as impairment of neutrophil function lead to decreased bactericidal activity, opsonic activity (i.e. foreign cells marking phagocytosis), and overall natural immune functioning
INFLAMMATION/COAGULPATHY: Hyperglycemia promotes production if pro-inflammatory cytokines such as TNF, IL-1, IL-6, and IL-8. Also, increased leukocyte adhesion molecules produces a procoagulant state.
OXIDANT STRESS on tissue, and results in mitochondrial injury, which causes impaired cellular functioning. This has also been found to be associated with multiorgan dysfunction.
ARF: Hyperglycaemia is most probably a contributing factor in the development of ischaemic acute renal failure (ARF) in many patients. Both clinical and experimental data suggest that hyperglycaemia increases the risk of ARF
Polyneuropahty: diffuse, symmetric, flaccid muscle weakness, including respiratory muscular difficulty
Also, particularly severe hyperglycemia assoicated with increased mortality as well
Known as the Leuven Surgical Trial
The day this came out along with the River’s article has been called the “one of the darkest days in the history of critical care”
Notes:
The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus
In septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemo- filtration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness poly- neuropathy by 44 percent, and patients receiving in- tensive therapy were less likely to require prolonged mechanical ventilation and intensive care.
INCREASE IN 90-d MORTALUTY BY 2.6% with IIT - POWER OF 90% ability to identify differences in mortality
Separated into 6 groups operative v. nonoperative, with and without DM, with or without trauma, with/without severe sepsis, and with/withour corticosteroid therpay within 72 hours, and APCHE II score above 25 or less than 25 DIVIDED and then placed in IIT or control
Inclusion:
-expected 3 or more days
-med/surg icu patient
WIth the parameters of insulin therpay in this study, 97.2% of IIT vs. 69% of convetional group received insulin
Average age: 60.4 IIT v. 59.9 conventional
Average BMI about 28 for both groups
Average daily feeding 880 calories a day between two groups through enteral feeding (approx. 70%) or parental (18% conventional and 10% IIT)
Comorbidities: respiratory dysfunction/failure (about 40/50%, repsitively), DM (about 20% in each group), severe sepsis (about 20% each group)
INCREASE IN 90-d MORTALUTY (BY LOGISITIC REGRESSION) BY 2.6% with IIT - POWER OF 90% ability to identify differences in mortality - NUMBER NEEDED TO HARM = 38 patients
Separated into 6 groups operative v. nonoperative, with and without DM, with or without trauma, with/without severe sepsis, and with/withour corticosteroid therpay within 72 hours, and APCHE II score above 25 or less than 25 DIVIDED and then placed in IIT or control
Inclusion:
-expected 3 or more days
-med/surg icu patient
WIth the parameters of insulin therpay in this study, 97.2% of IIT vs. 69% of convetional group received insulin
Average age: 60.4 IIT v. 59.9 conventional
Average BMI about 28 for both groups
Average daily feeding 880 calories a day between two groups through enteral feeding (approx. 70%) or parental (18% conventional and 10% IIT)
Comorbidities: respiratory dysfunction/failure (about 40/50%, repsitively), DM (about 20% in each group), severe sepsis (about 20% each group)
Include some notes on computer system used
However, I believe this use of computers is the future of research in this field
Will talk more about this soon
Time in Range
Lueven Surg: 53.1%
Lueven Med: 35.5%
Glucontrol: 45.4%
VISEP: 42.8%
NICE: 31%
GLUCOSE VARIBAILITY!!!
*All RCTs evaluated for quality based on sample size, patient population, risk of bias, consistency with other trials, directness in assessing outcomes and applicability to practice
What has been larned since nice
USED COX REGRESSION
In addition, mild hypoglycemia has been strongly associated with greater ICU LOS. Mean 1.8 w/o hypoglycemia vs. 3.0 (krinsley retrosepcitve investigation)
Severe hypoglycemia aslo depletes astrocyte glycogen stores, and if prolonged, will cause permanent brain damage
THEREFORE….
Important to assess for patient’s at increased risk for hypoglcyemia and monitor for s/sx (tachy, AMS, palpiations, anxiety, diaphoresis)
-Interruption of nutrition
-Sepsis (imparied glucose metabolism and masked hypoglycemia/delayed recog from capillary in low-perfusion state)
-Female sex
-Hx DM
***Something to note with these studies is that a causal relationship between cannot be confirmed, but given we cannot have a RCT on hypoglycemia and mortality, this is the best evidence we have right now
The optimal target glucose range remains controversial
Nutrition also matters. Luven trials used PRN parental nutition while NICE-SUGAR used continuous enteral feeding. The PRN feedings may have contributed to increased glucose variability and risk of hypoglycemic events
BG checks should be done q4-6 on SSI or hourly if on infusion
ENTERAL FEEDING WAS PREDOMINANT THERAPY USED IN NICE-SUGAR, SO RECOMMENDATION PRIMARILY BASED ON THIS
PARENTAL NUTRITON ALSO WITH LIVER AND GALLBLADDER PROBLEMS (cholelitiasis) and INFECTION ISSUES
*****Talk about clinical situation where patient was left in mid 200s for two days
LEAD:
Work with education dept and CNL to review protocol, and update accordingly to reflect current best evidence to lead practice change in your institiution
If it is already part of the protocol, patient charts should be reviewed to establish the degree the unit is implementing the practice
Speak with hospital leadership/physians and present the evidence, have them understand the practice change, support it, and commit to moving toward the change in the institiution
Start a campaign for proper glycemic control (send emails, make flyers, posters and post them with approval)
work with naysayers to understand why they are resistant to the change (they may have good reasons for resistance that may not be obvious to you)
It is not enough to present the change just once, repetition is key with practice change
COLLABORATE:
- Absolutely necessity that we collaborate and are on the same page
Work with other clinicians to collaborate to properly monitor BG, and treat quickly.
Collaborate with other supporters to implement practice
EDUCATE:
Hospital clinicians (APRNs/PAs, Physicians, Nurses, PCTs) need to be trained and made aware of proper glycemic control and management.
As APRN can hold lectures on the topic to play activate role in educating/training of other clinicans
ClINICIAN:
Be vigilant for patient’s with BG >180 not being treated (do not let patient sutatuations like the previously described happen in your practice)
Try to elimate any unessary glucose sources and provide adequate continuous nutrition to provide steady glucose
ADVOCATE:
Other clinicians may be resistant to these recommendations, advocate the patient’s and do not be afraid to speak up
Others may just not be familiar with these recommendations, so speaking up for patient’s who cannot do so is necessary
If they are aware, it is still best to present the evidence and explain why you are advocating for the patient
LASTLY, THIS IS A TEAM EFFORT. I WILL NOT BE THE ONLY PROVIDER CARING FOR THESE PATIENTS. PRACTICE NEEDS TO BE CONSISTENT TO ACHIEVE THE BEST OUTCOMES
ECONOMIC
-decreased patient care expenses (nursing, radiology, pharmacy and laboratory), ancillary servives (e.g. nutrition)
-Study from Curkendall et al. estimated a severe hypoglycemic event in the hospital is assoicated with an average of $98k in total charges, while patient’s without hypoglycemia had an average of $54k in total charges
Curkendall SM, et al. Endocr Pract. 2009;15:302-312.
PATIENT/FAMILY
-Clear how this benefits patient and families
-Reduction in hyperglycemic compilations and mortality/LOS from hypoglycemic events
-Reduced ICU LOS, and fewer complications r/t to ICU stay (delirium, infection, etc.)
-This change will help restore the patient-system wellness and aid in reestablishing the lines of defense (Neuman theory)
-Extends to families; greater survival of loved ones, less stress on them if patient’s complications are reduced and are able to recover
COMMUNITY
-Less tax burden on individuals in community due to lower costs associated with proper glycemic control; shortened hospital and ICU LOS results in less cost for those with governement supported insurance policies
ENVIRONMENT
-Less use of resources dedicated to those being taken care of in ICU
GLUCOSE VARI: POTENTIALLY MORE IMPORTANT IN OUTCOMES THAN MEAN GLUCOSE ACHIEVED; MECHANISM = FLCUATIONS INCREASE APOPTOSIS AND OXIDATIVE STRESS
TECH: Integrate personalized glucose regimens and advanced computer-assisted clinical decision making tools into trials to establish how to reduce glucose variability and maintain target levels
Talk about how furture of technology will pave way for new research (ie continuous glucose monitoring) and more accurate dosing of insulin customized for patient
BETTER CONTROL = Thought here is, would using continuous BG monitoring and improved computer aided decision making ptoentially reduce risk of hypoglcyemia and prove well-controlled intensive control is feasible.
Neurosurgical patients have been shown to have increased mortality/morbidity with glucose levels 150-170 (particularly in those with cerebral hemorrhage and ischemia); but conversely BG less than 80 can be detrimental
NICE-SUGAR SHOWED IIT MAY BE BETTER IN TRAUMA PATIENT and THOSE ON CORTICOSTEROIDS