GLYCEMIC CONTROL IN NEUROCRITICAL CARE PATIENTS David Zygun MD MSc FRCPC Professor 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; R 2 =0.78; p<0.001) and cerebral perfusion pressure (R 2 =0.85; p<0.01), and increasing core temperature (R 2 =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)]