Hyperglycemia Associated with Decreased Recanalization After IV t-PA in Acute Stroke
By Dana Leifer, MD, Associate Professor, Neurology, Weill Medical College of Cornell University. Dr. Leifer reports no consultant, stockholder, speaker's bureau, research, or other financial relationship related to this field of study.
Synopsis: Recanalization after treatment with intravenous tissue plasminogen activator (t-PA) is more likely in acute stroke patients whose admission serum glucose is less than 158 mg/dL.
Source: Ribo M, et al. Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients. Stroke. 2005;36:1705-1709.
The wide range of outcomes directly associated with intravenous (IV) thrombolytic treatment of stroke with tissue plasminogen activator (t-PA) is probably unique among pharmacologic therapies. It can produce dramatic resolution of severe neurologic deficits, but it can also cause intracerebral hemorrhage with catastrophic worsening. Multiple studies have attempted to develop criteria that use clinical characteristics and imaging studies to define the relative risks and benefits associated with IV thrombolytic therapy in individual patients, and to decrease the chance of a poor outcome.
A growing body of evidence suggests that hyperglycemia is associated with poor outcome in acute stroke patients and, in particular, decreases the chance of successful treatment with intravenous t-PA. Recently, Ribo and colleagues studied 139 consecutive patients who were treated with t-PA and had middle cerebral artery (MCA) occlusions documented on transcranial Doppler (TCD). Continuous TCD monitoring was performed for 2 hours after the start of t-PA administration. Recanalization was documented in 32% of the patients. Patients with complete recanalization had a lower average serum glucose (127 vs 146 mg/dL; P = 0.039) than those without it, but hemoglobin A1c levels were identical at 6.3% in the 2 groups. Distal (rather than proximal) MCA occlusion and relatively lower platelet counts (192 vs 229 x 106/L) also independently predicted recanalization after correction for etiology, age, and risk factors. Cardioembolic occlusions were more common in the group with recanalization (38% vs 22%), but this difference was not significant.
Statistical analysis demonstrated that the most predictive cut point was at 158 mg/dL. Thirty-six percent of those with a lower glucose recanalized, but only 16% of patients with a higher glucose recanalized (P = 0.035). Moreover, outcome was better in the group with lower glucose, which had an average NIHSS of 7 at 48 hours compared to 14.5 in the group with glucose over 158 mg/dL (P = 0.04).
It should be noted that continuous TCD monitoring can improve the rate of recanalization with IV t-PA (N Engl J Med. 2004;351:2170-2178.) and may, therefore, have influenced the results of this study. It is possible that the effects of hyperglycemia might be dependent on the concomitant TCD monitoring, but this possibility seems unlikely in light of other evidence that hyperglycemia worsens outcome in stroke patients in general, and after IV t-PA treatment in particular.
A recent study by Hachinski and colleagues prospectively studied 219 consecutive patients treated with intravenous t-PA at 2 academic medical centers and 33 affiliated hospitals (Neurology. 2005;65:1169-1743). Twenty-eight percent of the patients made a rapid, major neurologic improvement at 24 hours, with an improvement of 8 or more points on the NIH stroke scale (NIHSS) or an NIHSS of 0 or 1. Statistical analysis demonstrated that admission glucose level < 8.0 mmol (< 144 mg/dL) on admission, as well as absence of cortical involvement on CT scan 24 hours after t-PA and female sex were independently associated with major neurologic improvement after correction for age, diabetes, and NIHSS. There were no significant differences in age, vascular risk factors, previous medications including aspirin, admission NIHSS score, and t-PA dose between patients with major improvement compared to those without it. This study also found that early improvement was correlated with good recovery at 3 months.
Other studies have shown that hyperglycemia is associated with poor outcome in acute stroke patients who have not received t-PA (Stroke. 2001;32:2426-2432). At present, there is no direct evidence that aggressive treatment of hyperglycemia improves outcome in clinical stroke, but tight control of glucose in critically ill patients with a variety of different underlying diseases is beneficial (N Engl J Med. 2001;345:1359-1367). In addition, intravenous glucose/potassium/insulin therapy has been shown to be safe in acute stroke, and an efficacy trial is now in progress (Stroke. 2004;35:122-126).
The explanation for the deleterious effects of hyperglycemia in stroke is not certain but, as Ribo et al explain, elevated glucose levels appear to inhibit fibrinolysis and to elevate levels of plasminogen activator inhibitor-1 (Arterioscler Thromb. 1993;13:1822-1828). In addition, glycosylation of annexin II interferes with formation of the fibrinolytic complex between plasminogen, t-PA and annexin II (Diabetes. 50;2001:1666-1674). Interestingly, annexin II has a short half-life compared to hemoglobin. So, relatively short-term hyperglycemia could lead to alteration in the glycosylation of annexin II or other proteins involved in fibrinolysis. This could explain why Ribo et al found that admission glucose levels, but not chronic hyperglycemia, as measured by hemoglobin A1c, decreased the rate of recanalization.
In this background, although the mechanism for the effects of hyperglycemia remains uncertain, the provocative results of the work of Ribo et al suggest that glucose levels should be monitored carefully, and that aggressive treatment of hyperglycemia should be considered in patients receiving thrombolytic treatment for acute stroke. Further studies of hyperglycemia and stroke are required to define the optimum parameters for glucose control in stroke patients and to understand the mechanisms underlying the association of hyperglycemia and poor outcome in cerebral ischemia.
Recanalization after treatment with intravenous tissue plasminogen activator (t-PA) is more likely in acute stroke patients whose admission serum glucose is less than 158 mg/dL.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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