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Published on: May 28, 2019
Depletion of lactate by dichloroacetate reduces cardiac efficiency after hemorrhagic shock
R W Barbee1, J A Kline, J A Watts
1Emergency Medicine Research, Carolinas Medical Center, Charlotte, North Carolina 28232-2861, USA.
Insights
Dichloroacetate (DCA) did not improve cardiovascular function after hemorrhagic shock in dogs. DCA treatment reduced lactate levels but also decreased stroke volume and myocardial efficiency, suggesting impaired cardiac function during resuscitation.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Shock Pathophysiology
Background:
- Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex, previously shown to improve cardiovascular function after hemorrhagic shock in rodents.
- The precise mechanism by which DCA influences cardiovascular function during hemorrhagic shock requires further investigation in larger animal models.
Purpose of the Study:
- To investigate the effects of dichloroacetate (DCA) on cardiovascular function and myocardial substrate utilization during resuscitation from hemorrhagic shock in a large animal model.
- To elucidate the underlying mechanisms of DCA's action on cardiac performance in the context of severe blood loss and resuscitation.
Main Methods:
- Mongrel hounds underwent induced hemorrhagic shock, reaching a mean arterial pressure of 35 mm Hg for 90 minutes.
- Animals were randomized to receive DCA or saline during resuscitation, with hemodynamic parameters, myocardial contractility, and substrate utilization monitored.
- Two-thirds of shed blood volume was returned immediately post-intervention.
Main Results:
- DCA treatment significantly reduced arterial lactate levels post-resuscitation compared to controls.
- Despite reduced lactate, DCA was associated with decreased stroke volume index and myocardial efficiency.
- Myocardial lactate consumption was reduced in the DCA group, despite increased pyruvate dehydrogenase activity, indicating impaired lactate utilization.
Conclusions:
- Dichloroacetate (DCA) administration during resuscitation from hemorrhagic shock in canines did not improve, and potentially worsened, cardiac function.
- The impaired myocardial function may be due to a reduced supply of lactate to the myocardium, limiting its oxidation despite increased enzyme activity.
- These findings suggest that DCA's beneficial effects observed in rodents may not translate to larger animals, potentially due to altered substrate metabolism during shock resuscitation.
Abstract:
We have demonstrated previously that dichloroacetate (DCA) treatment in rodents ameliorates, via activation of the pyruvate dehydrogenase complex, the cardiovascular depression observed after hemorrhagic shock. To explore the mechanism of this effect, we administered DCA in a large animal model of hemorrhagic shock. Mongrel hounds were anesthetized with 1.5% isoflurane and were measured for hemodynamics, myocardial contractility, and myocardial substrate utilization. They were hemorrhaged to a mean arterial pressure of 35 mm Hg for 90 min or until arterial lactate levels reached 7.0 mM (1137 +/- 47 mL or 49 +/- 2% total blood volume). Animals were chosen at random to receive DCA dissolved in water or an equal volume of saline at the onset of resuscitation. Two-thirds of the shed blood volume was returned immediately after giving an equivalent volume of saline. Two hours after the onset of resuscitation, mean arterial pressure was not different between DCA and control groups (79 +/- 3 vs. 82 +/- 3 mm Hg, respectively). Arterial lactate levels were significantly reduced by DCA (0.5 +/- 0.06 vs. 2.0 +/- 0.2 mM). However, DCA treatment was associated with a decreased stroke volume index (0.56 +/- 0.06 vs. 0.82 +/- 0.08 mL/kg/beat) and a decreased myocardial efficiency (19 vs. 41 L x mm Hg/mL/100 g tissue). During resuscitation by DCA, myocardial lactate consumption was reduced (21.4 +/- 3.7 vs. 70.7 +/- 16.3 micromole/min/100 g tissue) despite a three-fold increase in myocardial pyruvate dehydrogenase activity, while free fatty acid levels actually began to rise. Although increased lactate oxidation should be beneficial during resuscitation, we propose that DCA treatment led to a deprivation of myocardial lactate supply, which reduced net myocardial lactate oxidation, thus compromising myocardial function during resuscitation from hemorrhagic shock.
