Thursday, April 11, 2013

Cold Lysis: Alteplase in the Hypothermic Patient

Let us say that you have a patient who presents with cardiac arrest with a rhythm of pulseless electrical activity. After going through a mental checklist of the 6Hs and 6Ts, you are highly suspicious that the patient has experienced a pulmonary embolism, and the decision is made to administer alteplase. You are informed that the rectal temperature of the patient is 32°C. 

An interesting question can be posed from this situation. What bearing do the effects of hypothermia have on the pharmacokinetic and pharmacodynamic properties of alteplase? In other words, will alteplase work in the setting of hypothermia? 

One small in vitro study demonstrated that in the setting of mild hypothermia, the lysing ability of alteplase decreased by 2 to 4% in a dose-dependent fashion when added to suspensions of clots derived from rabbits. The investigators of this study estimated that alteplase-induced lysis decreases linearly by 0.5% per 1°C decrease in temperature. In addition, the results of another in vitro study showed that the time of induced fibrinolytic activity of alteplase decreased by 25% at 37.5°C compared to 32.5°C. The results of these two studies have been simulated in this in vitro human model, in which the investigators derived a series of mathematical formulas to determine the dependence of temperature on the lysing activity of alteplase. 

How does this translate to clinical outcomes? Several studies have evaluated the effects of temperature at presentation in patients who have been treated with alteplase for acute ischemic stroke (AIS), a number of which are reviewed below:

The mixed results of these studies makes it somewhat difficult to determine the impact of temperature on clinical outcomes in patients treated with alteplase. In addition, the studies described here are all related to the outcomes of patients who have experienced AIS, which may not necessarily be applicable to the case of the patient in cardiac arrest as I have portrayed above.

Nonetheless, it is still a curious question to consider, and hopefully, more studies will be conducted in the future to determine the effects of hypothermia on the neurological outcomes in surviving patients who receive alteplase in the setting of cardiac arrest. 

1. Lees JS, Mishra NK, Saini M, et al. Low body temperature does not compromise the treatment effect of alteplase. Stroke 2011; 42:2618-2621.
2. Naess H, Idicula T, Lagallo N, et al. Inverse relationship of baseline body temperature and outcome between ischemic stroke patients treated and not treated with thrombolysis: the Bergen stroke study. Acta Neurol Scand 2010; 122:414-417. 
3. Blanco M, Campos F, Rodriguez-Yanez M, et al. Neuroprotection or increased brain damage mediated by temperature in stroke is time dependent. PLoS One 2012; 7:e30700. [Epub 2012 February 17]