Gordon, Goldsmith and Charipper, Proceedings of the Society for Experimental Biology and Medicine (1944),2200 demonstrated that PHT (15 mg), administered intraperitoneally ninety minutes prior to injury, prolonged the survival time and reduced the extent of lung hemorrhage in rats subjected to reduced barometric pressures (equivalent to an altitude of 39,000-49,000 feet).

2200. Gordon, A. S., Goldsmith, E. D. and Charipper, H. A., Effects of thiouracil and sodium 5,5-diphenylhydantoinate (Dilantin sodium) on resistance to lowered barometric pressures, Proc. Soc. Exp. Biol. Med., 56: 202-3, 1944.

Moss>, Bulletin of the New York Academy Of Medicine (1973),1374 demonstrated, in dogs, that PHT pretreatment provided protection against lung damage under conditions of hypoxia induced by hemorrhagic trauma. Six untreated dogs evidenced pulmonary edema, hemorrhage, congestion and atelectasis typical of shock lung. None of eight dogs pretreated with PHT (5 mg/kg, intramuscularly) one hour prior to the hemorrhage regimen showed evidence of shock lung. Their lungs appeared normal both grossly and microscopically.

1374. Moss, G., Shock, cerebral hypoxia and pulmonary vascular control: the centri-neurogenic etiology of the “respiratory distress syndrome”, Bull. N.Y. Acad. Med., 49: 689, 1973.

Stein and Moss, Surgical Forum (1973),1591 in a controlled study, found that pretreatment with PHT (5 mg/kg), two hours prior to hemorrhage, afforded statistically significant protection against "shock lung" in rats and dogs.

1591. Stein, A. A. and Moss, G., Cerebral etiology of the respiratory distress syndrome: diphenylhydantoin (DPH) prophylaxis, Surg. Forum, 24: 433-435, 1973.

Mentzer, Alegre and Nolan, Surgical Forum (1975),1981 studied the effects of PHT (1 mg/kg) on pulmonary vascular resistance and pulmonary vascular caliber in dogs. The authors conclude that PHT is a pulmonary vasodilator, that its effects are independent of myocardial performance or changes in systemic resistance, and that its mechanism of action is not mediated through adrenergic receptor sites.The authors suggest that PHT may have a beneficial effect in patients with alveolar hypoxia and pulmonary hypertension by reducing pulmonary vascular resistance.

1981. Mentzer, R. M., Alegre, C. and Nolan, S. P., Effects of diphenyihydantoin (Dilantin) on the pulmonary circulation, Surgical forum, 26: 217-9, 1975.

Das, Ayromlooi, Tobias, Desiderio and Steinberg, Pediatric Research (1980),1791 studied the effects of PHT on fetal rabbit lung ischemia in vivo. Normal levels of coenzyme A (CoA), acetyl CoA, and long-chain acetyl CoA were restored after treatment with PHT (7 mg/kg). NADH/NAD ratio was increased in hypoxic, untreated lung and restored to normal after treatment with PHT.

1791. Das, D., Ayromlooi, J., Tobias, M., Desiderio, D. and Steinberg, H., Effect of Dilantin (D) on hypoxic fetal rabbit lung, Pediatr. Res., 14: 640, 1980.

Flick, Hoeffel and Webster, Federation Proceedings (1982),2185 demonstrated that PHT (10 mg/kg) counteracts the increased vascular permeability which results from air emboli in sheep. Increases in leakage of lung lymph fluid and protein during emboli were 90% greater without PHT.

2185. Flick, M. F., Hoeffel, J. and Webster, R. O., Phenytoin attenuates increased lung microvascular permeability in sheep, Fed. Proc., 41(5): 1500, 1982.

Amy, LeGrand, Levitzky, Welch and Schechter, Journal of Trauma (1981),2291 demonstrated PHT's effects in preventing the development of shock lung in anemic animals following hemorrhagic shock. Untreated animals had grossly hemorrhagic lungs with diffuse interstitial and alveolar congestion, hemorrhage and edema. None of the animals receiving intravenous PHT (5 mg/kg), either one hour before or fifteen minutes after hemorrhage, had gross or histopathologic evidence of shock lung. The authors state that their findings suggest that PHT may be efficacious in preventing adult respiratory distress syndrome when administered as soon as possible to patients with major traumatic blood loss.

2291. Amy, B., LeGrand, P., Levitzky, M., Welsh, R. A., Schechter, F. C., Suppression of centrineurogenic shock lung by dilantin (DPH) administered early in established hemorrhagic shock, J. Trauma, 21(9) 7628, 1981.

Wohns and Kerstein, Critical Care Medicine (1982),2269 reported that PHT (5 mg/kg) protected dogs against the development of pulmonary edema during isolated cerebral hypoxia, but not during noncerebral systemic hypotension. They evaluated both pulmonary histology and gaseous exchange. The authors hypothesize that, because the development of neurogenic pulmonary edema is hypothatamically mediated, PHT may prevent cerebral hypoxia from triggering neurogenic pulmonary edema by stabilizing the hypothalamus.

2269. Wohns, R. N. W. and Kerstein, M. D., The role of Dilantin in the prevention of pulmonary edema associated with cerebral hypoxia, Crit. Care Med., 10(7): 436-43, 1982.

Flick, Webster, Hoeffel, Julien, Milligan, Kent and Lesser, Critical Care Medicine (1993),3591 conducted a placebo-controlled study to determine if the intravenous administration of phenytoin attenuates or prevents acute experimental lung injury. Hemodynamic, lung fluid balance and arterial blood variables were measured in injured and uninjured sheep, in untreated sheep, and in sheep after pretreatment with PHT. The authors found that intravenous phenytoin (10 - 15 mg/kg over one hour) attenuated the expected increase in lung vascular permeability caused by intravenous endotoxin infusion or venous air embolization, which is believed to injure the lungs indirectly by activating host-inflammatory responses. PHT had no effect on responses to intravenous oleic acid infusion, which is believed to injure lung directly; and PHT alone had no effects on uninjured sheep.

3591. Flick, M.R., Webster, R.O., Hoeffel, J.M., Julien, M., Milligan, S.A., Kent, B., and Lesser, M., Effect of phenytoin on acute lung injuries in unanesthetized sheep, Crit. Care Med. , 21(10):1562-71, 1993.