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Letter to the Editor effects of nitric oxide synthesis inhibition in an ovine mc of hyperdynamic endotoxaemia.' The hyperdynamic pet became obvious at approximately 12 h after the start of endotoxin infusion. Administration o f the NO syntt inhibitor N"-nitro-L-arginine methyl ester L-NAME , 24 h continuous endotoxin infusion normalised the rai:. cardiac output, the decreased systemic vascular resistanc-' and the increased pulmonary shunt tiaction. Thus P, synthesis inhibition in a model of hyperdynamic sep completely reversed the alterations i n hyperdynan, endotoxaetnia. J MEYER I 1 I> TRABER
Burns Institute Shriners Hospitals [or Crippled Children Galveston Unit Texas Avenue Galveston TX 77550-2788 USA Wright EC, Ress DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Ctrrt/io\vr.rc R e s 1992;26:48-57. Muldoon SM, Hart JL, Bowen KA. et trl. Attenuation of endothelium-mediated vasodilation by halothane. A I I C . S ~ / I C . S ~ / J / ~ J , ~ ! . IY88;68:3 1-7. Stone DJ, Johns RA. Endotheliutii-deprndctit eflects of halothane, enflurane. and isoflurane on isolated rat aortic vascular rings. Anesthrsiolog~I989;71: 126-37. Moncada S, Palmer RM. Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. fhtrnntrcml Re\. 1 YY I; 43: 10942. Kilbourn RG, Belloni P. Endothelial cell production of nitrogen oxides in rewonse to interferon ganiina in combination with tumor necrosis facior, interleukin- I , Gr endotoxin. J Ntul Ccrricer lnst 199082:772-6. Tuchschmidt J, Oblitas D, Fried JC. Oxygen consumption in sepsis and septic shock. Crit Ctrrr Mrtl 199 I;19:664-7 I . Meyer J. Traber LD, Nelson S, et trl. Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of nitric oxide synthesis. J Appl fhysiol ( i n press).
Downloaded from by guest on June 5, 2016
Nitric oxide and endotoxin shock Sir, - In their recent study reported in this journal, Wright, Rees. and Moncada investigated the role of nitric oxide in endotoxic shock under halothane anaesthesia.' The use of a nitric oxide donator combined with a nitric oxide synthase inhibitor is a very interesting approach and may offer new therapeutic strategies in the future. We agree with the authors' conclusion that the use of a vasoconstrictor or inhibition of a vasodilator may be deleterious in situations with a low cardiac output. However, the other conclusions drawn from this study are questionable for the following reasons. First, the administration of halothane alters the endothelium mediated vasodilatation in vitro, probably by affecting the nitric oxide pathway.' ' Second, the induction of the non-constitutive form of NO synthase requires protein synthesis.' This explains the time lag between activation and NO release observed in several studies.' Wright and colleagues observed their animals for only 3 h. Thus it is possible that the time point of maximum activity of the inducible NO synthase was not covered by their experimental protocol. The authors selectively inhibited the inducible form by dexamethasone in one of their experiments. However, dexamethasone did not influence the changes in regional blood flow after endotoxin administration despite maintenance of mean arterial pressure. Third, the authors did not report any fluid administration to their animals. Endotoxin administration is known to cause a relative hypovolaemia that requires fluid support for maintenance of haemodynamic stability.' It would have been helpful if the authors could have described their fluid resuscitation, which without any doubt may have influenced cardiovascular performance. Fourth, the data describing regional blood flow indicate that their model of endotoxin shock is a hypodynamic model. In contrast, clinical sepsis is very often characterised by a hyperdynamic state with an increased cardiac output and a decreased systemic vascular resistance.' We investigated the
Letter to the Editor effects of nitric oxide synthesis inhibition in an ovine mc of hyperdynamic endotoxaemia.' The hyperdynamic pet became obvious at approximately 12 h after the start of endotoxin infusion. Administration o f the NO syntt inhibitor N"-nitro-L-arginine methyl ester L-NAME , 24 h continuous endotoxin infusion normalised the rai:. cardiac output, the decreased systemic vascular resistanc-' and the increased pulmonary shunt tiaction. Thus P, synthesis inhibition in a model of hyperdynamic sep completely reversed the alterations i n hyperdynan, endotoxaetnia. J MEYER I 1 I> TRABER
Burns Institute Shriners Hospitals [or Crippled Children Galveston Unit Texas Avenue Galveston TX 77550-2788 USA Wright EC, Ress DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Ctrrt/io\vr.rc R e s 1992;26:48-57. Muldoon SM, Hart JL, Bowen KA. et trl. Attenuation of endothelium-mediated vasodilation by halothane. A I I C . S ~ / I C . S ~ / J / ~ J , ~ ! . IY88;68:3 1-7. Stone DJ, Johns RA. Endotheliutii-deprndctit eflects of halothane, enflurane. and isoflurane on isolated rat aortic vascular rings. Anesthrsiolog~I989;71: 126-37. Moncada S, Palmer RM. Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. fhtrnntrcml Re\. 1 YY I; 43: 10942. Kilbourn RG, Belloni P. Endothelial cell production of nitrogen oxides in rewonse to interferon ganiina in combination with tumor necrosis facior, interleukin- I , Gr endotoxin. J Ntul Ccrricer lnst 199082:772-6. Tuchschmidt J, Oblitas D, Fried JC. Oxygen consumption in sepsis and septic shock. Crit Ctrrr Mrtl 199 I;19:664-7 I . Meyer J. Traber LD, Nelson S, et trl. Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of nitric oxide synthesis. J Appl fhysiol ( i n press).
Downloaded from by guest on June 5, 2016
Nitric oxide and endotoxin shock Sir, - In their recent study reported in this journal, Wright, Rees. and Moncada investigated the role of nitric oxide in endotoxic shock under halothane anaesthesia.' The use of a nitric oxide donator combined with a nitric oxide synthase inhibitor is a very interesting approach and may offer new therapeutic strategies in the future. We agree with the authors' conclusion that the use of a vasoconstrictor or inhibition of a vasodilator may be deleterious in situations with a low cardiac output. However, the other conclusions drawn from this study are questionable for the following reasons. First, the administration of halothane alters the endothelium mediated vasodilatation in vitro, probably by affecting the nitric oxide pathway.' ' Second, the induction of the non-constitutive form of NO synthase requires protein synthesis.' This explains the time lag between activation and NO release observed in several studies.' Wright and colleagues observed their animals for only 3 h. Thus it is possible that the time point of maximum activity of the inducible NO synthase was not covered by their experimental protocol. The authors selectively inhibited the inducible form by dexamethasone in one of their experiments. However, dexamethasone did not influence the changes in regional blood flow after endotoxin administration despite maintenance of mean arterial pressure. Third, the authors did not report any fluid administration to their animals. Endotoxin administration is known to cause a relative hypovolaemia that requires fluid support for maintenance of haemodynamic stability.' It would have been helpful if the authors could have described their fluid resuscitation, which without any doubt may have influenced cardiovascular performance. Fourth, the data describing regional blood flow indicate that their model of endotoxin shock is a hypodynamic model. In contrast, clinical sepsis is very often characterised by a hyperdynamic state with an increased cardiac output and a decreased systemic vascular resistance.' We investigated the
