Yeo-Kyu Youn

Oxidants and the pathophysiology of burn and smoke inhalation injury

A skin burn is a common traumatic injury that results in both local tissue damage and a systemic mediator-induced response. There is evidence of both local and systemic oxidant changes manifested by lipid peroxidation in animal burn models and also in burned man. Both increased xanthine oxidase and neutrophil activation appear to be the oxidant sources. Animal studies have also demonstrated decreased burn edema, and also decreased distant organ dysfunction with the use of antioxidants, suggesting a cause-and-effect relationship, which needs to be tested in man. Smoke inhalation injury, a chemical injury to the airways caused by incomplete products of combustion, is frequently seen in conjunction with a body burn. Lipid peroxidation, both in lung and in distant organs, is also seen with this injury. The combined body burn and smoke inhalation injury lead to a marked increase in mortality rate and also an increase in the degree of generalized oxidant release and lipid peroxidation. Although data in man are limited, the available information, along with that from animal research on burns and smoke inhalation, indicates oxidants may well play a key role, and antioxidants may be of clinical therapeutic use.

FLUID RESUSCITATION WITH DEFEROXAMINE PREVENTS SYSTEMIC BURN-INDUCED OXIDANT INJURY

We studied the effect of deferoxamine (DFO) infused after burns on hemodynamic stability as well as local and systemic inflammation and oxidant-induced lipid peroxidation. Eighteen anesthetized sheep were given a 40% of total body surface burn and fluid resuscitated to restore oxygen delivery (DO2) and filling pressures to baseline values. Animals were resuscitated with lactated Ringers (LR) alone or LR plus 1,500 ml of a 5% hetastarch complexed with DFO (8 mg/ml). Animals were killed 6 hours postburn. The sheep resuscitated with LR and LR plus hetastarch demonstrated significant lung inflammation and significant increases in lung and liver malondialdehyde (MDA) from controls of 47 +/- 6 and 110 +/- 7 nMol/gm to 63 +/- 13 and 202 +/- 59 for LR and 67 +/- 4 and 211 +/- 9 for LR + hetastarch, respectively. The group resuscitated with hetastarch alone required 15% less fluid. VO2 returned to baseline values in both groups by 2 hours. Resuscitation with the 5% hetastarch-DFO decreased total fluids by 30% over LR and prevented the increase in lung and liver MDA. In addition, postburn VO2 increased by 25% above baseline values. Burn tissue edema, measured as protein-rich lymph flow, was significantly increased with the administration of DFO compared with the other groups. We conclude that DFO used for burn resuscitation prevents systemic lipid peroxidation and decreases the vascular leak in nonburn tissues while also increasing O2 utilization. Resuscitation with hetastarch-DFO may accentuate burn tissue edema, possibly by increased perfusion of burn tissue.

Relationship between hepatic blood flow and tissue lipid peroxidation in the early postburn period.

Objectives:To determine the effect of a body burn on effective or nutrient liver blood flow and the relationship between blood flow and oxidant-induced lipid peroxidation. Design:Anesthetized sheep were given a 40% of total body surface, third-degree burn, after which animals were fluid resuscitated to return ventricular filling pressures and cardiac output to baseline values. Animals, for the 6-hr study period, were resuscitated with lactated Ringers solution alone or lactated Ringers solution plus 1500 mL of 5% hydroxyethyl starch or lactated Ringers solution plus hydroxyethyl starch on which was complexed the iron chelator deferoxamine to prevent oxidant release. Effective liver blood flow was measured using the galactose infusion technique. Liver tissue lipid peroxidation was monitored using malondialdehyde content. Results:We found that effective liver blood flow was decreased by 50% in the 4− to 5-hr postburn period, even when animals were resuscitated to baseline cardiac output values with lactated Ringers solution. Tissue malondialdehyde content increased in the group treated with lactated Ringers solution from a control value of 110 ± 7 to 202 ± 59 nmol/g of tissue. Resuscitation with hydroxyethyl starch restored postburn effective liver blood flow to control values, but malondialdehyde content was still increased two-fold. Resuscitation with hydroxyethyl starch and deferoxamine resulted in an increase in effective liver blood flow postburn to a value 80% above controls. In addition, lipid peroxidation was prevented. Conclusions:Effective liver blood flow is markedly decreased after burn injury, even with apparently adequate volume resuscitation, when using lactated Ringers solution. Liver lipid peroxidation persists even when effective liver blood flow is maintained, indicating that the oxidant process is not solely related to blood flow. Infusion of the antioxidant deferoxamine during resuscitation not only prevents the lipid peroxidation, most likely by a nonblood-flow-related process, but also results in an increase in blood flow above normal rates, suggesting that postburn liver oxygen needs exceed normal values.

Oxygen Consumption Early Postburn Becomes Oxygen Delivery Dependent with the Addition of Smoke Inhalation Injury

We determined the relationship between oxygen delivery, DO2, and oxygen consumption, VO2, in sheep after a moderate smoke inhalation injury and 15% TBSA third-degree burn compared with burn alone and controls. Comparison was made beginning three hours after injury when carboxyhemoglobin levels were back to baseline values. We decreased DO2 between three and eight hours by 25% by either removing blood (controls) or decreasing the resuscitation fluid infusion rate. Lung oxidant, measured as tissue malondialdehyde (MDA) levels, and histologic changes were also assessed. Animals were killed at 24 hours. We found that in controls and animals with a burn alone, a 25% decrease in DO2 was compensated for by an increase in O2 extraction, maintaining VO2 constant. Correlation of DO2 to VO2 was r2 = 0.3, indicating independence of VO2 from DO2. With the combined injury, VO2 decreased in proportion to DO2, since O2 extraction did not increase. The correlation of DO2 to VO2 was r2 = 0.9, indicating delivery-dependent consumption, a pathologic process most likely caused by increased inflammatory mediators from the combined injury. Lung lipid peroxidation was markedly increased in the combined injury, 148 +/- 18 nmol MDA/gram of tissue compared with burn alone, 64 +/- 5 nmol/g, or controls, 45 +/- 4 nmol/g. However, no decrease in arterial O2 tension or increase in lung water was noted, i.e., the sheep did not have ARDS, which is known to impair O2 extraction. We conclude that a pathologic O2 delivery-dependent consumption develops with the combination of burn and inhalation injury, increasing the potential for tissue hypoxemia. This change corresponds with increased lung tissue oxidant change.

Relationship between liver oxidant stress and antioxidant activity after zymosan peritonitis in the rat

Objective.To determine the effect of a severe nonbacterial-dependent peritonitis on the degree and time course of liver oxidant stress and antioxidant activity. Design.Prospective, randomized, controlled study. Setting.Animal laboratory. Subjects.Thirty-eight male Sprague-Dawley rats were injected with zymosan 0.75 mg/g body weight, mixed in mineral oil, and fluid resuscitated. Interventions.None. Measurements and Main Results.Oxygen consumption (Vo2), base deficit, and blood gases were determined. Liver tissue oxidized and reduced glutathione, malondialdehyde catalase, xanthine oxidase, and xanthine dehydrogenase were measured and data were compared with both a pair-fed and an ad libitum fed group over a 24-hr period. We noted a 30% mortality rate with animals dying between 20 and 24 hrs. Peak decrease in Vo2 occurred at 12 hrs, corresponding with a metabolic acidosis. Marked liver oxidant stress was seen at 4 hrs with oxidized glutathione increased from a control value of 0.2 ± 0.1 to 1.1 ± 0.2 mg/g of tissue, while reduced glutathione decreased from a control value of 1.8 ± 0.1 to 0.3 ± 0.1 mg/g. By 24 hrs, oxidized glutathione activity was no longer increased, but reduced glutathione concentrations were still markedly decreased. Tissue catalase was also significantly decreased at the 24-hr period. Liver malondialdehyde was increased at 24 hrs when the peak decrease in antioxidants was evident. Liver xanthine oxidase activity increased significantly from 15 ± 3 to 45 ± 8 μmol uric acid/ min/g by 4 hrs and remained increased, with the initial increase predating evidence of impaired perfusion. Pair-fed animals demonstrated no changes in oxidant or antioxidant activity. Conclusions.We conclude that a marked increase in liver oxidant stress and decrease in antioxidant activity occurs in the first several hours after the onset of nonbacterial peritonitis. An early increase in liver xanthine oxidase activity may be a source of the oxidants. Decreased liver antioxidant activity persists well after the oxidant stress resolves. (Crit Care Med 1993; 21:894–900)

EFFECT OF DOBUTAMINE ON OXYGEN CONSUMPTION AND FLUID AND PROTEIN LOSSES AFTER ENDOTOXEMIA

ObjectiveTo determine the effect of a dobutamine infusion on the relationship between oxygen consumption (&OV0616;o2) and oxygen delivery (&U1E0A;o2) after endotoxin administration, as well as the rate of fluid and protein loss from permeability-injured tissue. MethodsUnanesthetized adult sheep with lung and soft-tissue lymph fistulas were given 5 μg/kg Escherichia coli endotoxin alone, or E. coli endotoxin plus a continuous infusion of dobutamine (10 to 15 μg/kg.min) beginning at 3 hrs. Lymph flow reflected the vascular permeability and surface area perfused. Data were compared with dobutamine alone and with controls. Filling pressures were maintained at baseline. ResultsDobutamine alone produced a 75% increase in &U1E0A;o2, a transient 10 ± 4% increase in &OV0616;o2, but no increase in lung or soft-tissue lymph flow. Beginning at 3 hrs after endotoxin alone, a significant increase in protein-rich lung and soft-tissue lymph flow was noted, but only a transient 14 ± 5% increase in &OV0616;o2. Plasma proteins were slightly decreased. With the addition of dobutamine at 3 hrs postendotoxin, &U1E0A;o2 increased by >50% for the 3-hr infusion period, while &U1E0A;o2 increased for a 30-min period by 25 ± 8%, which was not different than endotoxin alone. Lung and soft-tissue lymph flow did not increase further, but plasma proteins did decrease significantly compared with controls and with endotoxin alone. ConclusionIncreasing &U1E0A;o2 with dobutamine postendotoxin does not increase the surface area perfused or the edema process, at least in lung and soft tissue. Therefore, no microvessels in these tissues are reopened with dobutamine when normal filling pressures are present. Dobutamine administration does not increase &OV0616;o2 more than the increase seen with endotoxin alone. (Crit Care Med 1991; 19:525)