GLYCEMIC CONTROL IN

NEUROCRITICAL CARE PATIENTS

David Zygun MD MSc FRCPCProfessor and Director

Division of Critical Care Medicine

University of Alberta

Zone Clinical Department Head

Critical Care Medicine, Edmonton Zone

Outline

• Association of glycemic abnormalities and outcome in

neurocritical care

• Mechanisms of glycemic induced neuronal injury

• Effects of tight glycemic control in neurocritical care

When I was a resident…

Episodes of hyperglycemia (>11.1 mmol/l or 200 mg/dl) during the

first 10 days occurred in 65% of patients (5.4% of all glucose

measurements).

Hyperglycemia and Outcome

• TBI• a serum glucose level greater than 200 mg/dl (11.1 mmol/liter)

postoperatively is associated with a significantly worse outcome(p <0.01) J Neurosurg 1991, 75:545-51.

• ninety percent of the patients with blood glucose levels of 9.6 mmol/L (171.4 mg/100 mL) at admission died within the first month; in the patients with lower glucose levels the mortality was 15%

Surg Neurol 1995, 44:373-7

• a glucose level greater than 200 mg/dl was associated with a worse outcome. Multivariate analysis showed that postoperative glucose levels were an independent predictor of outcome

Neurosurgery 2000, 46:335-42

• associated with increased mortality irrespective of injury severity OR = 1.034; 95% CI 1.021-1.047, P < 0.001

Neurocrit Care 2009, 11:151-7

• Using multivariable regression, a single episode of hyperglycemia was associated with 3.6-fold increased risk of hospital mortality (95%CI: 1.2-11.2, P = 0.02) Neurocrit Care 2009, 11:311-6

Figure 2. Pooled analyses on poor outcome associated with admission hyperglycemia in

patients with aneurysmal SAH. Included studies were subdivided according to the cutoff

value used in each individual study to define hyperglycemia into studies with a defin...

Kruyt N D et al. Stroke 2009;40:e424-e430

Copyright © American Heart Association

Hyperglycemia and Outcome

ICH

• The risk of poor outcome (mRS 4-6) in those with

increasing serum glucose levels was over two-fold relative to those

who had declining serum glucose levels (RR = 2.64, 95%

confidence interval [CI]: 1.03, 6.75). The RRs were 2.59 (95% CI:

1.27, 5.30) for hematoma expansion >33%; and 1.25 (95% CI:

0.73, 2.13) for relative edema expansion >40%

Neurocrit Care 2011, 15:428-35

• On multivariate logistic regression analysis, admission plasma

glucose level>150 mg/dl (OR 37.5, CI 1.4-992.7, p=0.03) and IVH

volume>20 ml (OR 64.6, CI 1.3-3173.5, p=0.04) were independent

factors associated with early death

J Neurol Sci 2007, 255:90-4

Hyperglycemia and Brain pH

• Generalized estimating equation model predicted that for each 1 mmol/L increase in blood glucose, pH(b) changed by -0.011 mmol/L (95% confidence interval, -0.016 to -0.005 mmol/L; P < 0.001)

• 21 episodes of hyperglycemia (>or=11.1 mmol/L) treated with intravenous insulin were identified.

• Insulin therapy significantly reduced blood glucose concentration from a median (interquartile range) of 11.9 mmol/L (range, 11.4-13.6 mmol/L) to 8.8 mmol/L (range, 7.3-9.6 mmol/L; P < 0.001).

• Baseline pH(b) was not significantly different from pH(b) associated with the subsequent glucose reading of less than 11.1 mmol/L (P = 0.29)

Intensive Insulin Therapy

• Intensive insulin therapy was associated with increased

incidence of microdialysis markers of cellular distress,

namely:

• elevated glutamate (38+/-37% vs. 10+/-17%, p<.01)

• elevated lactate/pyruvate ratio (38+/-37% vs. 19+/-26%, p<.03)

• low glucose (26+/-17% vs. 11+/-15%, p<.05

Crit Care Med. 2006 Mar;34(3):850-6

Treatment Thresholds

• Intensive insulin therapy

• most often 80-110 mg/dl (4.4-6.1 mmol/L), but did vary slightly

across RCTs, ranging from 70- 150 mg/dl (3.9-8.3 mmol/L).

• Conventional treatment

• In the most extreme case, insulin therapy was only initiated when

glucose levels exceeded 300 mg/dl (16.7 mmol/L),

• At the opposite extreme, one study had a “conventional” glucose

target of 110-144 mg/dl (6.1-8.0 mmol/L)

• In most cases, insulin was only initiated in control patients when

glucose levels exceeded 180-200 mg/dl

• Duration of Treatment

• as short as 24 hours to as long as the entire ICU admission

Mortality

Neurological Outcome

Spreading Depression

• Pathological waves of spreading mass neuronal

depolarisation arise repeatedly in injured, but potentially

salvageable, grey matter in 50-60% of patients after

traumatic brain injury Lancet Neurol. 2011 Dec;10(12):1058-64

• The probability of a depolarization

occurring increased significantly as a

function of declining mean arterial

pressure (MAP; R2=0.78; p<0.001)

and cerebral perfusion pressure

(R2=0.85; p<0.01), and increasing core

temperature (R2=0.44; p<0.05).

J Neurotrauma. 2009 November; 26(11): 1857–1866

Scatter diagram comparing total number of fluorescence transients with mean plasma

glucose (at and for 4 hours) after MCAO in 8 cats.

Strong A J et al. Stroke 2000;31:214-222

Copyright © American Heart Association

What now?

Conclusions

• The optimal glucose target for neurocritical care patients

is likely to fall between 80 (4.4 mmol/L) and 180 mg/dl

(10.0 mmol/L)

• Given that RCTs suggest a relatively high incidence of

hypoglycemia when clinicians attempt to maintain glucose

levels between 80 and 110 mg/dl (4.4-6.1 mmol/L), we

consider a more conservative approach to be most

appropriate [e.g. 110-180 mg/dl (6.1-10.0 mmol/l)]