In the era of recanalization therapies, the factors responsible for the onset-to-treatment (OTT) time vs. outcome relationship need further investigations in acute stroke patients. Treating the factors that shorten the therapeutic time window for excellent outcome in fact may correspond to slow down the penumbra’s evolution. Baseline post-stroke hyperglycemia could be one of these factors. To date, most studies showed that higher admission glucose levels (AGL) were associated with less favorable outcome in thrombolysis [
1], but could AGL’s impact on outcome vary by OTT time?
This possibility arises from an association between hyperglycemia and an accelerated infarct growth in experimental and imaging studies as reviewed in Piironen et al. [
2]. Moreover, in these studies, there is accumulating evidence indicating that the glucose toxicity threshold was low (between 6 and 8 mmol/l) [
3]. To our knowledge, the interaction between OTT time and AGL has never been formally tested.
The proportion of patients with excellent outcome after thrombolysis sharply decreases when a threshold volume of infarction is reached, corresponding to a certain amount of penumbra volume being transformed. Parsons et al. reported that 48% of patients with diffusion-weighted imaging (DWI) lesions < 18 ml at admission had excellent outcome at 3 months, compared to only 15% with DWI lesions > 18 ml [
4], with similar results reported by others [
5‐
7]. Our hypothesis is that the true effect of OTT time on infarct volume may actually be changed by a penumbra-modifying factor, such as AGL (Fig.
1). More precisely and theoretically (Fig.
1), if a factor
F (i.e., a penumbra-modifying factor, such as AGL) increases the rate of infarct growth, the infarct volume threshold for excellent outcome will be reached at an earlier time (T1) for higher values of
F. Conversely, lower values of F can extend this cut-off point to a later time (T2). Prior to T1, the rate of excellent outcome will be high for any value of
F, and
F will not statistically predict outcome. We called this period (before T1) the “silver hours”, by analogy with the golden hour [
8]. During the subsequent “critical period” (T1–T2), the rate of excellent outcome will decrease faster for higher values of
F, which will ultimately predict outcome. Beyond T2 or in the absence of recanalization, the rate of excellent outcome will continue to decrease even for low values of
F, which will lose its predictive value. In other words, a “silver effect” predicts a significant interaction between OTT time and
F, with the predictive value of
F for excellent outcome being low during the silver hours, high during the critical T1–T2 period, and low again beyond T2. A “silver effect” also implies that the OTT time ×
F interaction should be significant in patients with successful thrombolysis but not in those with persistent occlusion. In this latter, time goes on beyond T2 and, whatever the level of
F, patients are more likely to have a poor outcome as the infarct volume will grow up to the critical threshold.
We investigated this issue in our prospective registry of patients treated by intravenous thrombolysis. We hypothesized that AGL at admission could constitute a hypothetical factor F and tested the interaction between AGL and OTT time on outcome.