Fluorodeoxyglucose positron emission tomography for detection of recurrent or metastatic breast cancer.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a noninvasive imaging technique capable of identifying primary tumors and metastases with high sensitivity and accuracy. The aim of this study was to evaluate the diagnostic accuracy of whole-body FDG-PET imaging for the detection of recurrent or metastatic breast cancer after surgery. Whole-body FDG-PET imaging was performed on 27 patients with suspected recurrent breast carcinoma. PET images were evaluated qualitatively for each patient and lesion. FDG-PET scans showed that there were 61 reference sites of malignant or benign lesions in 27 patients. In a patient-based analysis, FDG-PET scans correctly identified 16 of 17 patients with recurrent or metastatic disease and 8 of 10 without recurrence, resulting in a sensitivity, specificity, and accuracy of 94%, 80%, and 89%, respectively. In a lesion-based analysis, FDG-PET scans correctly identified 46 of 48 lesion sites with recurrent or metastatic disease and 11 of 13 without recurrence. The overall sensitivity, specificity, and accuracy for all lesion sites were 96%, 85%, and 93%, respectively. FDG-PET scans revealed unsuspected recurrent or metastatic diseases in 8 of 27 (30%) of patients and 11 of 20 (55%) distant metastatic lesions. In 13 patients treatment was altered by the outcome of the PET scan. We concluded that whole-body FDG-PET scan is a useful diagnostic imaging modality for detecting recurrent or metastatic breast carcinoma in patients suspected of having recurrent disease after primary surgery.

F-18-fluorodeoxyglucose positron emission tomography as a presurgical evaluation modality for I-131 scan-negative thyroid carcinoma patients with local recurrence in cervical lymph nodes.

BACKGROUND: F-18-labeled fluorodeoxyglucose-positron emission tomography (FDG-PET) has a supplementary role in localizing recurrent sites of differentiated thyroid carcinoma. We evaluated whether FDG-PET is feasible as a presurgical evaluation modality for I-131 scan-negative thyroid carcinoma patients. METHODS: Preoperative FDG-PET results were compared with the pathologic findings of lymph nodes specimens of 22 papillary thyroid patients. All patients had thyroidectomy and I-131 ablation therapy beforehand and showed negative I-131 scans on follow-up studies. RESULTS: In 85 cervical lymph node groups dissected, 56 lymph node groups revealed metastasis. The sensitivity and specificity of FDG PET for metastasis were 80% (45 of 56) and 83% (24 of 29), respectively. Among the pathologically positive 33 lymph nodes with normal size(< or =1 cm), FDG-PET detected 23 nodes. Serum thyroglobulin levels were elevated in 12 patients (sensitivity, 55%). CONCLUSION: FDG-PET accurately detected the recurred cervical lymph nodes of differentiated thyroid carcinoma patients who showed negative I-131 scan. FDG-PET is suitable for the presurgical evaluation of these patients.

Flow cytometric analysis of primary tumors and their corresponding metastatic nodes in breast cancer.

Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from one which is indolent to one which rapidly progresses. Although it is the metastasis rather than the primary tumor that ultimately overwhelms the patients, studies concerning the DNA pattern have focused on the primary tumors. This study was undertaken to identify heterogeneities between primary tumors and metastases, and to evaluate the prognostic significance of the ploidy pattern and the S-phase fraction (SPF) of metastatic nodes in axillary node positive patients. Seventy-four frozen specimens of the primary and corresponding metastatic nodes from 37 patients have been analyzed by flow cytometry and the SPF calculated. The results of ploidy pattern analysis in primaries revealed 25 diploidy (67.6%) and 12 aneuploidy (32.4%), while those in metastasis showed 17 diploidy (46.0%) and 20 aneuploidy (54.0%). The aneuploidy group in metastatic nodes had the poorer histological grade (85.0% vs. 15.0%, p = 0.02), and more mean metastatic nodes (5.75 +/- 2.10 vs. 3.05 +/- 1.56, p = 0.018), and more frequent lymphatic vessel invasion (65.0% vs. 11.8%, p = 0.031) than its counterpart. Decreased expression of ER (70.6% vs. 25.0% p = 0.006) and increased expression of c-erbB2 (65.0% vs. 23.5%, p = 0.012) were observed in the aneuploidy of metastatic nodes. The group with higher SPF in metastatic nodes had more metastatic nodes (5.47 +/- 2.31 vs. 4.00 +/- 1.78, p = 0.042), and the higher incidence of lymphatic vessel invasion (57.9% vs. 22.2%, p = 0.027), and poor histological grade (71.4% vs. 37.5%, p = 0.039). In conclusion, the cell populations in metastatic nodes revealed DNA pattern which differed from that of primary tumors. The ploidy pattern and SPF in metastatic nodes might be considered as discriminate measure for risk factors in breast cancer patients with positive axillary node.

Effect of protease inhibitor on ischemia-reperfusion injury to rat liver.

Liver failure due to ischemia-reperfusion injury, believed to be closely related to the generation of oxygen-free radicals, is a serious problem during liver surgery. Gabexate mesilate, a synthetic protease inhibitor, suppresses the extracellular release of oxygen-free radicals in the microvascular endothelium. To determine its effects on ischemia-reperfusion injury to the liver, we performed experiments with rats. We divided the animals into two ischemia-reperfusion groups: an experimental group, which underwent ischemic injury for 30 minutes, along with the infusion of gabexate mesilate, and a control group, which underwent injury only. Each group was then divided into four subgroups: ischemic injury only and 60-, 120-, and 180-minute reperfusion injury. The test parameters were tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) in serum and superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) in liver and lung tissues. The experimental group had a significantly higher liver SOD and catalase levels and a significantly lower level of liver and lung MDA than the control groups. TNFalpha levels in the experimental groups were significantly lower during the early phase, but a comparison of IL-6 levels between the two groups yielded no differences. Levels of lung catalase and SOD were not significantly different between the two groups. We concluded that protease inhibitor suppressed liver ischemia-reperfusion injury, and that it was due to an increase of antioxidant or suppression of oxygen-free radicals. The roles of TNFalpha and IL-6 in liver reperfusion injury were not clear, though TNFalpha might have had an effect during the early phase. With liver ischemia-reperfusion injury, the mechanism of lung involvement might be different from that of liver involvement.

Detection of cancer in augmented breasts by positron emission tomography.

OBJECTIVE: To assess the diagnostic efficiency of positron emission tomography with 18-fluorine fluorodeoxyglucose in detecting breast cancer in augmented breasts. DESIGN: Retrospective study. SETTING: University hospital, Korea. SUBJECT: 9 cases or 8 patients with breasts augmented with paraffin or silicone. INTERVENTION: FDG-PET, mammography, and ultrasonography RESULTS: The mammogram detected the breast cancer in only 1 of 3 patients, and ultrasonography gave a false positive result in 1 patient with an augmented breast. In contrast, PET predicted all the cancers and 5/6 benign lesions. 2/3 breast cancers had axillary FDG uptake interpreted as showing metastatic involvement, and in 1 case with cancer with no axillary lymph node involvement there was no FDG uptake in the axilla, which correlated with the pathological finding. CONCLUSIONS: Although the high cost of PET makes its use as a screening test for all patients with augmented breasts unrealistic, it would be the best diagnostic choice if other methods failed.

Value of FDG PET in papillary thyroid carcinoma with negative 131I whole-body scan.

UNLABELLED: The management of metastatic thyroid carcinoma patients with a negative 131I scan presents considerable problems. Fifty-four athyrotic papillary thyroid carcinoma patients whose 1311 whole-body scans were negative underwent 18F-fluorodeoxyglucose (FDG) PET; the purpose was to determine whether this procedure could localize metastatic sites. We also assessed its usefulness in the management of these patients. METHODS: Whole-body emission scan was performed 60 min after the injection of 370-555 MBq 18F-FDG, and additional regional attenuation-corrected scans were obtained. Metastasis was pathologically confirmed in 12 patients and was confirmed in other patients by overall clinical evaluation of the findings of other imaging studies and of the subsequent clinical course. RESULTS: In 33 patients, tumor had metastasized, whereas 21 patients were in remission. FDG PET revealed metastases in 31 patients (sensitivity 93.9%), whereas thyroglobulin levels were elevated in 18 patients (sensitivity 54.5%). FDG PET was positive in 14 of 15 metastatic cancer patients with normal thyroglobulin levels. In 20 of 21 patients in remission, FDG PET was negative (specificity 95.2%), whereas thyroglobulin levels were normal in 16 patients (specificity 76.1%). The sensitivity and specificity of FDG PET were significantly higher than those of serum thyroglobulin. In patients with negative 1311 scans, FDG PET detected cervical lymph node metastasis in 87.9%, lung metastasis in 27.3%, mediastinal metastasis in 33.3% and bone metastasis in 9.1%. In contrast, among 117 patients with 131I scan-positive functional metastases, 131I scan detected cervical lymph node metastasis in 61.5%, lung metastasis in 56.4%, mediastinal metastasis in 22.2% and bone metastasis in 16.2%. In all 5 patients in whom thyroglobulin was false-negative with negative antithyroglobulin antibody, PET showed increased 18F-FDG uptake in cervical lymph nodes, mediastinal lymph nodes, or both. Among patients with increased 18F-FDG uptake only in the cervical lymph nodes, the nodes were dissected in 11. Metastasis was confirmed in all, even in normal-sized lymph nodes. CONCLUSION: FDG PET scan localized metastatic sites in 131I scan-negative thyroid carcinoma patients with high accuracy. In particular, it was superior to 131I whole-body scan and serum thyroglobulin measurement for detecting metastases to cervical lymph nodes. FDG PET was helpful for determining the surgical management of these patients.

Recombinant human growth hormone decreases lung and liver tissue lipid peroxidation and increases antioxidant activity after thermal injury in rats.

The combination of increased oxidant with decreased endogenous polypeptide and protein antioxidant activity corresponds to a decrease in cellular energetics and cell membrane lipid peroxidation. Providing large doses of growth hormone has been shown to preserve cell mass and organ function after burn injury. The role of growth hormone in oxidant injury has not been defined. We determined whether growth hormone altered the degree of lung and liver lipid peroxidation and the activity of glutathione and catalase in lung and liver tissue after burn injury. Four groups of 40 rats each were studied for 48 hours, with 1 group receiving a 20% full-thickness burn, 1 group treated with growth hormone after 20% full-thickness burn injury, a control group, and a growth hormone alone-treated group. We found increased lipid peroxidation, measured as malondialdehyde, in lung and liver tissue, and a decrease in glutathione and catalase activities during the 48-hour post-burn period. The addition of growth hormone prevented the lipid peroxidation and significantly increased tissue glutathione and catalase activities with respect to control values. Growth hormone alone also increased endogenous antioxidant levels. We conclude that growth hormone given after burn injury decreases oxidant stress by producing a significant increase in the endogenous antioxidants glutathione and catalase.

Expression of phospholipase C-gamma 1 and its transcriptional regulators in breast cancer tissues.

BACKGROUND: PLC-gamma 1 is activated through direct interaction with growth factor receptor tyrosine kinase but little is known about the mechanisms controlling PLC-gamma 1 expression and its biological significance. MATERIALS AND METHODS: Using immunoblotting, we evaluated PLC-gamma 1 protein overexpression in twenty breast cancer tissues. The expression of binding protein to GES1, GES2 and GES3, located in transcriptional regulator (GPE1) was found by electrophoretic mobility shift assay (EMSA). We also determined whether there was any correlation between prognostic factors (numbers of metastatic axillary nodes, histologic grade, c-erbB2, p53, and E-cadherin) and the overexpression of PLC-gamma 1 protein. RESULT: On immunoblotting, 17 of 20 breast cancer tissues showed overexpression of PLC-gamma 1, a result of which was corresponded to that of immunohistochemistry. The binding proteins to GES1, GES2 and GES3 were overexpressed only when PLC-gamma 1 protein overexpression was apparent. Positive expression of E-cadherin only was significantly associated with PLC-gamma 1 protein overexpression (x = 0.607, p = 0.045). CONCLUSION: GPE1 binding proteins might be the transcriptional regulator in PLC-gamma 1 overexpression and the relationship between expression of PLC-gamma 1 and E-cadherin would require further elucidation.

Diagnostic value of positron emission tomography for detecting breast cancer.

Positron emission tomography (PET) is an imaging method that employs radionuclide and tomography techniques. PET has high sensitivity for detecting breast cancer, both the primary tumor and axillary node metastasis. From June 1995 to November 1996 a total of 27 patients underwent breast operations based on PET results at Seoul National University Hospital. Whole-body PET images were obtained beginning 60 minutes after injection of 370 MBq (10 mCi) 18F-fluorodeoxyglucose. Regional scans were also obtained with transmission images. We compared the PET results with those from the physical examination and mammography. All cases were histologically confirmed. The diagnostic accuracy of PET was excellent for the primary tumor mass (97%) compared with that of the physical examination (78%) and mammography (67%). For axillary lymph node metastasis, PET had outstanding detection accuracy (96%) compared with the physical examination and mammography (74% and 60%, respectively). Whole-body PET scans made it possible to see all of the metastatic lesions at a glance in cases of metastatic or recurrent breast cancer. There was a probable correlation between the standard uptake value (SUV) and the number of axillary lymph node metastases, but in this study statistical significance was not proved because of the small number of cases. PET also could detect breast cancer in paraffin-augmented breasts. We concluded that PET is a highly sensitive, accurate diagnostic tool for breast cancer and that SUV, after more studies, could be used as an important prognostic factor.

Increased early postburn fluid requirements and oxygen demands are predictive of the degree of airways injury by smoke inhalation.

The combination of burn and smoke inhalation was studied to determine if early hemodynamic and metabolic abnormalities would correspond with the degree of subsequent smoke-induced airways injury. Adult sheep (n = 45) given an 18% total body surface third-degree burn alone or with smoke exposures of 12 breaths of 5, 10, or 20 mL/kg tidal volume were continuously monitored with airways assessed at 4 or 24 hours. With increased smoke exposure (20 mL/kg tidal volume), oxygen consumption (VO2) in the first several hours and net positive fluid balance, especially in the first 6 hours, increased by 100% and 300%, respectively, over that seen with burn alone. The degree of increase in fluid requirement, net fluid retention, and VO2 with smoke, compared with burn alone, correlated best with the degree of airways damage quantitated at 24 hours, r = 0.83, 0.85, and 0.89, respectively. Airways damage at 4 hours did not predict the damage seen at 24 hours. Systemic changes were not caused by gas-phase toxins, such as carbon monoxide, because smoke filtered of particles had the same blood carbon monoxide control as whole smoke, but the systemic response was equal to burn alone, and there was no airways injury. The cause of the systemic changes is likely the result of the intense airways inflammation.

Effect of graded increases in smoke inhalation injury on the early systemic response to a body burn.

OBJECTIVE: To study the early (first 24 hrs) effect of increasing lung exposure to smoke on the hemodynamic response to a modest body burn. DESIGN: A prospective randomized study. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty-two adult yearling female sheep. INTERVENTIONS: Adult sheep (n = 32) were given an 18% of body surface burn; 24 sheep were then exposed to cotton toweling smoke using 12 breaths of a tidal volume of 5, 10, or 20 mL/kg. Animals were awakened, resuscitated to baseline oxygen delivery, and then killed at 24 hrs. MEASUREMENTS AND MAIN RESULTS: Vascular pressure, cardiac output, and oxygen consumption and delivery were measured, as well as blood gases, lung and soft tissue lymph flow, and fluid balance. We found that a 5-mL/kg tidal volume smoke exposure x 12 breaths did not produce significant airway inflammation or alter the cardiopulmonary response to a burn alone. Oxygen consumption (VO2) remained at baseline and the net 24-hr positive fluid balance of 1.5 L was comparable to a burn alone. Increasing the smoke exposure to 10 mL/kg tidal volume, which produced a moderate airway injury, resulted in a significant increase in early fluid requirements, a 40% early increase in VO2, a doubling of positive fluid balance, as well as a marked increase in burn edema. However, gas exchange was not impaired. The 20-mL/kg tidal volume exposure resulted in an early 100% increase in VO2, a three-fold increase in fluid requirements at 1 to 4 hrs, compared with burn alone, in addition to a severe airway inflammation with mucosal slough and resulting impaired gas exchange. CONCLUSIONS: The addition of a smoke exposure which produces airway inflammation and injury significantly increases early post burn systemic metabolic demands and fluid requirements, as well as the degree of burn edema and positive fluid balance compared with a burn alone. The magnitude of the accentuated response appears to correspond with the degree of airway inflammation and not with alveolar dysfunction.

The effect of acute nonbacterial dependent peritonitis on lung and liver oxidant stress and antioxidant activity.

BACKGROUND: The role of oxidant release and tissue antioxidant defenses on inflammation-induced organ injury is not clearly defined. METHODS: We determined the effect of acute zymosan peritonitis in rats on lung and liver tissue oxidant stress and antioxidant defenses during a 5-day period. Oxidant activity was measured as tissue malondialdehyde and oxidized glutathione (GSSG). Antioxidant activity was measured as tissue-reduced glutathione (GSH) and catalase activity. Rats were maintained hydrated with subcutaneous crystalloid. Animals were killed at 4, 12, and 24 hours and 5 days. RESULTS: Acute peritonitis was evident at 12 and 24 hours but was resolving at 5 days. Peritoneal fluid cultures were negative after 24 hours. A 50% mortality rate was noted between 20 and 30 hours, with no deaths after 30 hours. We noted a significant increase in lung GSSG and malondialdehyde at 4 hours that persisted for the 5 days, as did histologic evidence of a progressing severe lung inflammation. No increased conversion of lung xanthine dehydrogenase to xanthine oxidase was noted. Lung GSH and catalase activity were maintained at control despite negligible food intake. In contrast, liver GSSG was increased significantly only at the 4-hour period, corresponding with a transient conversion of xanthine dehydrogenase to xanthine oxidase from 10% to 31%. Tissue malondialdehyde did not increase despite the initial oxidant stress. However, tissue GSH and catalase values decreased by more than 50% after 24 hours and remained decreased at 5 days. CONCLUSIONS: We conclude that early lung and liver oxidant stress is initiated by acute peritonitis. Lung oxidant changes persist and lung dysfunction progresses, even though antioxidant activity is maintained and acute peritonitis is resolving. Liver lipid peroxidation did not develop despite oxidant release, probably because of a large antioxidant reserve. However, a severe and sustained decrease in liver antioxidants results, increasing the potential damage from a subsequent oxidant insult.

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 mumol 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.

Pentoxifylline does not prevent endotoxin induced lung and liver lipid peroxidation in the adult sheep.

Our purpose was to determine the effect of pentoxifylline pretreatment on endotoxin-induced (5 microgram/kg) lung and systemic oxidant activity, measured as lipid peroxidation. We used the awake adult sheep with lung and soft tissue lymph fistulae to monitor microvascular changes as well as to monitor oxygen delivery and consumption. Oxidant activity was monitored using the level of plasma conjugated dienes, a measure of circulating lipid peroxides, and lung and liver malondialdehyde content, a measure of tissue lipid peroxidation. Sixteen sheep were given endotoxin, eight of which were pretreated with pentoxifylline (20 mg/kg bolus) followed by a 6 mg/kg/hr infusion. We found that the degree of early endotoxin-induced pulmonary hypertension and hypoxia and later increased pulmonary microvascular permeability was not attenuated with pentoxifylline. In addition, a comparable increase in circulating conjugated dienes, lung neutrophil sequestration, and a three-fold increase in lung malondialdehyde was seen in both groups. Soft tissue QL also increased to the same degree in both groups. Liver MDA increased from a control of 110 +/- 20 nM/g tissue to 165 +/- 32 nM/g with endotoxin alone and to 260 +/- 55 nM/g with pentoxifylline pretreatment, a significant increase over both control and endotoxin alone groups. Pentoxifylline, however, did improve hemodynamic stability, required significantly less fluid, and prevented the hyperdynamic state seen at 4-5 hr post endotoxin. We conclude that pentoxifylline attenuates the initial endotoxin-induced hemodynamic instability, and later hyperdynamic state. However, pentoxifylline pretreatment does not appear to prevent endotoxin-induced oxygen radical release in the unanesthetized sheep.

Burn edema is accentuated by a moderate smoke inhalation injury in sheep.

We determined the lung and systemic response of a moderate smoke inhalation injury combined with a 15% total body surface third-degree burn compared with a burn alone and inhalation alone. Adult sheep were prepared with chronic lung and bilateral prefemoral soft tissue lymph fistula. The burn was confined to one side. Physiologic parameters, lymph flow (QL), and lymph/plasma protein ratio were monitored. Oxidant changes were measured as lipid peroxidation by circulating and lymph-conjugated dienes and lung tissue malondialdehyde. Animals were resuscitated with lactated Ringer's solution during the 24-hour study period to restore and maintain vascular filling pressures and cardiac index. We found net 24-hour fluid balance for burn-inhalation injuries to be 4.1 +/- 1.2 L compared with burn alone of 2.9 +/- 0.9 L and inhalation alone of 2.4 +/- 0.5 L, a significant difference. Protein-rich burn tissue QL increased by fivefold to sixfold with burn alone compared with more than tenfold with burn-inhalation injury. A twofold increase in both lung and nonburn soft tissue QL was also seen in the combined injury not seen with burn alone. Arterial blood gases decreased only at 12 hours. Plasma conjugated dienes were increased in all groups, whereas burn lymph values were increased only in combined insult. In addition, lung malondialdehyde content at 24 hours was 155 +/- 11 nmol/gm with burn-inhalation injury compared with 62 +/- 8 nmol/L for burn alone, 55 +/- 9 nmol/L in inhalation alone, and 45 +/- 4 nmol/L for controls. However, no alveolar flooding was noted in any group. We conclude that a modest smoke inhalation (carboxyhemoglobin of 25%) added to a 15% total body surface burn markedly increases the degree of burn edema, as well as nonburn soft tissue and lung QL, compared with burn alone, indicating increased plasma to interstitial fluid transport in these tissues as well. Increased burn tissue lipid peroxidation products corresponded with the increased burn fluid losses. The increased lung lipid peroxidation also indicates further lung oxidant activity as well.

Lung oxidant changes after zymosan peritonitis: relationship between physiologic and biochemical changes.

Our purpose was to determine the effect of non-bacteria-dependent systemic inflammation on the degree and time course of lung oxidant activity and antioxidant defenses, comparing these changes with lung, physiologic, and histologic alterations. Adult male rats were given intraperitoneal zymosan (0.7 mg/g body weight) and were fluid resuscitated. Oxidant changes were measured as lung tissue oxidized glutathione (GSSG) and malondialdehyde (MDA) content, antioxidant defenses as tissue reduced glutathione (GSH), and catalase. Animals were killed at 4, 12, and 24 h, and at 5, 10, and 30 days. Lung data were compared with that found in liver. We noted a 45% mortality in the first 18 to 36 h with all remaining animals surviving. In the first 24 h, we noted a doubling of lung MDA and an 80% conversion of tissue GSH to GSSG compared with less than 5% in control animals, indicating a severe oxidant stress. These findings corresponded with marked increase in lung neutrophils. Arterial pressure (PaO2) was significantly decreased from a control of 95 +/- 4 mm Hg to 80 +/- 5 mm Hg and 75 +/- 4 mm Hg at Days 5 and 10, respectively, but returned toward control by 30 days. Lung GSSG and MDA remained significantly increased for the 30-day period, whereas amounts of the antioxidants, catalase, and GSH returned to control after 24 h. The ongoing oxidant stress corresponded with marked mononuclear cell infiltration and interstitial thickening, which persisted over the 30-day period even after peritonitis had completely resolved.(ABSTRACT TRUNCATED AT 250 WORDS)

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 Ringer's solution alone or lactated Ringer's solution plus 1500 mL of 5% hydroxyethyl starch or lactated Ringer's 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 Ringer's solution. Tissue malondialdehyde content increased in the group treated with lactated Ringer's 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 Ringer's 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.

The role of mediators in the response to thermal injury.

Inflammatory mediators play a major role in both the local burn wound and the systemic response to burn injury. Oxidant and arachidonic acid metabolites are involved in the initial burn edema process. The mediators as well as the cytokines released from activated macrophages also result in an early generalized inflammatory response. The later postburn hyper-metabolism is initiated and perpetuated by these same mediators, especially the cytokines, tumor necrosis factor, interleukin-1, and interleukin-2. Circulating endotoxin from the wound or the gut also appears to be involved. The postburn septic response is now recognized to be the result of inflammation; infection is not necessary. Mediator induced priming of the inflammatory cells by the burn itself results in an exaggerated response to infection in the postburn period. Defining the specific mechanism of injury and mediators involved can result in a major improvement in burn care, especially since many mediator inhibitors are already available for clinical use. It is essential that the clinician understand this pharmacologic manipulation in order to be able to optimally utilize these future advances.