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Ann Thorac Surg 2000;69:312-313
© 2000 The Society of Thoracic Surgeons
a Research Department, Kokura Memorial Hospital, 1-1 Kifunecho, Kokura-Kitaku, Kitakyushu-shi 802, Japan
b II Department of Physiology, University of the Ryukius School of Medicine, Okinawa, Japan
To the Editor
We read with great interest the excellent articles titled: "Nitric oxide mediates neurologic injury after hypothermic circulatory arrest" [1] and "Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest" [2] both by E. Tseng and colleagues. The researchers are to be congratulated for having identified the mechanism of central nervous system injury associated with deep hypothermic circulatory arrest after alpha-stat blood gas management: excitotoxicity caused by increased N-methyl D-aspartate (NMDA) receptor activation and subsequent increased generation of nitric oxide. Would the same occur with pH-stat management of hypothermic perfusion?
To reconcile the findings described by these investigators with the reported clinical superiority of pH-stat management over alpha-stat blood gas management for deep hypothermic circulatory arrest [3] in infants in terms of neurologic outcome, it would be logical to assume that pH-stat management during hypothermic perfusion somehow resulted in lesser excitotoxicity and reduced generation of nitric oxide than alpha-stat strategies. Some theoretical considerations are offered to link these facts.
Hypothermia per se results in a shift of the oxyhemoglobin dissociation curve to the left, which is aggravated by the alkalosis induced by alpha-stat management, thus impairing oxygen delivery at the tissue level to the point of developing tissular hypoxia that is known to induce NMDA activation [4].
Although not statistically significant, according to the second paper glutamate concentrations increased during hypothermic perfusion before the induction of circulatory arrest, which may be already suggesting the development of a hypoxic metabolic state secondary to inadequate oxygen delivery starting to produce excitotoxicity. Normal oxygen delivery during hypothermia can be restored by inducing acidosis, that is, pH-stat management.
The described abnormal glucose utilization during hypothermic perfusion [5] likely to be secondary to the tisuue hypoxic state from inadequate oxygen delivery, is analogous to glucose deprivation. Glucose deprivation is known to cause neuronal injury by causing excesssive NMDA receptor activation [6].
The alkalosis resulting from alpha-stat management impairs the Ca2+ extrusion pump, and increases NMDA currents [7–9], thus promoting intracellular Ca2+ overloading. Extracellular alkalinity has been found to exacerbate excitotoxic neuronal injury by sensitizing neurons to ischemic injury and to potentiate reperfusion injury [8, 9], which is the scenario with deep hypothermic circulatory arrest using the alpha-stat strategy. On the other hand mild acidosis decreases Ca2+ influx, glutamate neurotoxicity, and oxygen–glucose deprivation-neuronal injury in cortical cultures, as well as hippocampal neurons by reducing NMDA receptor activation [4, 6, 9, 10].
Thus, the mild acidosis obtained by pH-stat management may explain the superiority of the neurologic outcome over alpha-stat management reported by du Plessis and colleagues [3].
Although excellent inhibition of nitric oxide generation was obtained with 17477 AR, if part of that nitric oxide-generating cause lies in the pH management during hypothermic perfusion besides the nitric oxide generated obligatorily during the circulatory arrest period, perhaps the combination of 17477 AR and pH-stat management might be more effective in curtailing the amount of nitric oxide generated during deep hypothermic circulatory arrest.
In spite of the fact that alpha-stat management has been considered as the golden standard strategy based on the argument of avoiding the so-called "luxury perfusion" of pH-stat strategies and the consequent increased chances (?) of microembolization, pH-stat management is more physiologic in terms of metabolism and is the way nature has adapted to temperature changes through the evolutionary scale, as observed in hibernating mammals and poikilothermic animals [10].
We believe the neurologic injury coincidental to hypothermic perfusion arrest is the resultant of the algebraic sum of both factors, positive metabolic (decrease of oxygen consumption influenced by the pH) and negative microembolization. The relative role of each one being variable for each individual depending on factors such as duration of the hypothermic perfusion arrest period, the rate of cooling and rewarming, the hemodynamic status before and after cardiopulmonary bypass, the type of oxygenator, the lack of pulsatility, the pore size of cardiopulmonary bypass circuit filters, among others.
These researchers possess the know how to end definitively the long debated issue of whether alpha-stat or pH-stat management during hypothermic perfussion is better. They are encouraged to repeat the phenomenal amount of work using pH-stat instead of alpha-stat strategies. A group of animals in each of the management strategies subjected to deep hypothermia for 2 hours, but no circulatory arrest, should be added to evaluate the relative contribution of hypothermia per se and the pH management to that excitotoxicity, in order to develop the most effective protective strategy with the least side effects, which should allow to decrease the dosage of NO inhibitors to the minimum necessary.
References
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