Anticatabolic and anabolic strategies in critical illness: a review of current treatment modalities.

Critically ill patients characteristically exhibit a pronounced catabolism in addition to a down-regulation of normal anabolic activity, leading to major complications from loss of body protein stores. The marked decrease in lean body mass and protein stores leads to the loss of essential structural and functional proteins required for restoring and maintaining homeostasis. The standard management of the catabolic response to injury and illness has centered on optimizing nutrient intake that modulates but does not reverse the process. Complications of ongoing catabolism therefore remain a major cause of morbidity. Addition of anticatabolic and anabolic agents that may counteract "the stress response to injury or illness" may be of significant clinical benefit. Agents currently available for clinical use, which will be described, can be divided into two groups. The first group are nutrients and nutrient metabolites, namely protein and the specific amino acids, glutamine, arginine, and branched chain amino acids, especially leucine. The second group are anabolic hormones, namely growth hormone, testosterone, and the testosterone analog oxandrolone. The pros and cons of these agents, as to their anabolic and anticatabolic value, are described.

The effect of glucagon on the pulmonary transvascular fluid filtration rate.

Administration of glucagon has been shown to decrease pulmonary vascular resistance, but its primary site of action is undetermined. Whether this is on the arterial or venous side of the capillary would be reflected in the microvascular hydrostatic pressure. We used the pulmonary flow of lymph, a sensitive index of the transvascular fluid filtration rate, to monitor the microvascular hydrostatic pressure. Eight unanesthetized sheep with a surgically created long-term fistula for monitoring pulmonary lymph were given a 3-mg bolus of glucagon after a baseline period. We found no change in pulmonary arterial or left atrial pressures but noted a significant increase in cardiac output and a decrease in pulmonary resistance. The flow of pulmonary lymph increased by 50 percent for 30 minutes after administration of glucagon, and the protein content of the lymph decreased by 15 percent, indicating a large increase in the microvascular hydrostatic pressure. From these data, we calculated a decrease in arterial resistance from 60 percent to 30 percent of the total and, subsequently, an increase of 6 cm H2O in the microvascular hydrostatic pressure. Administration of glucagon, therefore, decreases the arterial resistance while increasing microvascular pressure in the process.

Relation between pulmonary transvascular fluid filtration rate and measured Starling's forces after major burn.

Our purpose was to determine the reliability of the currently used measurements of pulmonary vascular hydrostatic and oncotic pressures in monitoring pulmonary water after a major burn. The flow of pulmonary lymph, a reliable indicator of the rate of filtration of pulmonary transvascular fluid (Qf), was measured before and for 72 hours after a third-degree burn over 40 to 55 percent of the total body surface in sheep. Changes in Qf were correlated with measured changes in pulmonary microvascular (Pmv), plasma colloid osmotic pressure (pi p), and interstitial colloid osmotic pressure (pi i), as measured in the pulmonary lymph. The periods from 0 to 24 hours (resuscitation), from 24 to 48 hours (early mobilization of fluid), and from 48 to 72 hours (early recovery) were compared with baseline. Regression equations and correlation coefficients for Qf vs Pmv, Qf vs Pmv minus pi p, and Qf vs Pmv minus (pi p -ph i), the oncotic gradient, were calculated. There were significant differences in slopes between the periods of time, with all three comparisons indicating that the response of the microcirculation to the same changes in pressure was different in each of the periods. The correlation between Qf and the comparisons of pressures was clearly best in the period from 48 to 72 hours. The comparison of Pmv minus pi p was not better than Pmv alone, while the comparison of Pmv minus the gradient (pi p -- pi i) was significantly better than either of the other comparisons in predicting Qf.

Changes in extravascular lung water during venovenous perfusion.

The accumulation of extravascular lung water was related to changes in plasma colloid osmotic pressure and pulmonary hydrostatic pressures in 12 normal dogs and 13 dogs that had venovenous perfusion for 2 hours at 45 to 70 ml. per kilogram per minute. The venovenous perfusion system included a membrane oxygenator and a roller pump. Net intravascular filtration pressure was calculated from plasma colloid osmotic pressure and pulmonary hydrostic pressures. Rapid accumulation of extravascular lung water occurred in control and bypass animals when net intravascular filtration pressure exceeded zero. At lower filtration pressures, venovenous perfusion did not affect accumulation of extravascular lung water.

Topical ibuprofen decreases early postburn edema.

We determined the effect of topically applied ibuprofen on formation of second-degree burn edema and prostanoid production, a possible causative factor. Six adult sheep were given second-degree burns on both flanks with water at 80 degrees C while they were under general anesthesia. Lymph (QL), draining the flank areas, was used to monitor edema formation and prostanoid production. A 5% ibuprofen cream was applied at 2 and 5 hours after the burn and full-thickness biopsy specimens of burned hide were obtained at 8 hours for determination of water content. The QL increased sixfold in nontreated and 2.5 times in treated burn tissue. The lymph/plasma (L/P) protein ratio increased from 0.4 to 0.58 in both sides. Lymph TxB2 was increased from baseline of 200 pg/ml to 500 +/- 100 and 310 +/- 90 pg/ml in untreated and treated sides, respectively. Lymph 6-keto-PGF1 alpha increased from a baseline of 50 +/- 10 to 150 +/- 40 and 90 +/- 80 pg/ml in untreated and treated sides. The difference between PG content of lymph in treated and untreated sides was significant. Plasma prostanoids, except for a transient early rise, remained at preburn baseline. Lymph ibuprofen content on the treated side rose to 1.9 +/- 0.8 mcg/ml with no detectable plasma level. Water content of hide increased from a control value of 74 +/- 2% to 84 +/- 2% in untreated burn, while the value in the treated side was 76 +/- 4%, a significant difference between the two sides. We conclude that topically applied ibuprofen decreases both local edema and prostanoid production in burn tissue without altering systemic production.

The effect of complete burn wound excision and closure on postburn oxygen consumption.

We determined the effect of complete excision and closure of the burn wound on the postburn increase in oxygen consumption. Twelve sheep were given a 15% of total body surface full-thickness burn and were monitored for 7 days. By the third day, a 50% increase in O2 consumption, VO2, was noted, as was a significant increase in cardiac index and decrease in mixed venous PO2, compared to baseline. The hypermetabolic process persisted for the 7-day pre-excision period. On the seventh postburn day all sheep were anesthetized for 2 hours with halothane and placed on positive pressure ventilation, and then one half of these sheep underwent excision and closure. During anesthesia, VO2 decreased to 76 +/- 15 ml/min/M2, a value significantly lower than even the preburn awake baseline of 122 +/- 14 ml/min/M2 and the 7-day postburn value of 180 +/- 18 ml/min/M2. Quantitative cultures, before excision, revealed the wounds to be noninfected (less than 10(5) organisms per gram). In six animals, the burns were totally excised to fascia and closed with full-thickness defatted hide from other sheep obtained at the same time under sterile conditions. In these animals, the VO2 returned to preburn baseline by 24 hours postexcision and remained there for the 3-day postexcision study period. In the other six burned sheep, the 15% full-thickness burns remained. The hypermetabolic state returned to the 7-day postburn level on return to the awake state and persisted for the remainder of the study. We conclude that complete excision and wound closure can reverse the postburn increase in O2 consumption.

Effect of partial burn excision and closure on postburn oxygen consumption.

We studied the effect of partial excision and wound closure on the postburn hypermetabolic state. A 25% of total body surface burn was produced in seven sheep. Oxygen consumption (VO2) was significantly increased to 215 +/- 44 ml/min/M2 by day 3 compared with baseline of 125 +/- 21 ml/min/M2. The calculated increase was the result of the increased cardiac index as the average oxygen (AvO2) difference remained relatively constant. Body temperature was not significantly increased. Plasma and burn lymph thromboxane B2 were significantly increased. On day 7, 60% of the burn was completely excised to fascia and covered with a full-thickness graft from a donor animal. The VO2 decreased to below preburn levels during the period of anesthesia but returned completely to the preexcision hypermetabolic state by 2 hours after anesthesia and remained at this level for the remaining 2-day postexcision period. Quantitative cultures of burn hide at day 7 postburn and of the remaining 10% of total body surface burn at 2 days after excision revealed values less than 10(5) bacteria/gram eschar. No positive blood cultures were evident. We conclude that postburn hypermetabolism, once developed, may be perpetuated by a burn of lesser size. Partial excision, therefore, does not appear to significantly decrease the hypermetabolic state if a substantial inflammatory wound remains. Infection is not necessary to perpetuate the increased VO2.

Early burn excision attenuates the postburn lung and systemic response to endotoxin.

The lung and systemic physiologic response to endotoxin is markedly accentuated in the presence of a body burn. Our purpose was to determine whether early burn excision and closure would decrease this response. We compared the endotoxin (2 micrograms/kg)-induced response in 10 adult sheep with lung and soft-tissue lymph fistulas 3 days after a 15% total-body surface full-thickness burn that was excised immediately with that of sheep without burn excision and nonburned sheep. No infection was present in the burn wound. Early excision prevented the ongoing postburn lipid peroxidation and lung inflammation seen 3 days after burn before endotoxemia in animals with 15% total body surface burn wound not excised. Sheep that underwent excision demonstrated significantly less pulmonary hypertension and hypoxia after endotoxin than did either endotoxin-treated and intact burned sheep or endotoxin-treated nonburned sheep. Lung inflammatory changes as determined by neutrophil content of lung tissue and the increase in lung tissue malondialdehyde in the group that underwent burn excision after endotoxin were comparable to those seen with endotoxin alone, as was the lung lymph-flow response. Also, the systemic response was nearly identical to that seen with endotoxin alone with no increase in soft-tissue permeability as measured by lymph flow. Oxygen consumption (VO2) remained unchanged from baseline. In contrast, VO2 doubled in burn-intact animals initially after endotoxin, after which VO2 decreased to levels below baseline. An increase in soft-tissue vascular permeability was also noted. We can conclude that early burn excision and closure prevent the accentuated response to endotoxin that is seen when the burn wound is left intact, even if it is uninfected.

Early postburn lipid peroxidation: effect of ibuprofen and allopurinol.

We measured lipid peroxidation of plasma, lung, and liver in anaesthetized sheep after third-degree burns involving 30% of total body surface. Animals were resuscitated to baseline filling pressures with lactated Ringer's solution and killed 10 hours after burn. Six sheep were pretreated with ibuprofen (12.5 mg/kg) and five with allopurinol (50 mg/kg). We used conjugated dienes and malondialdehyde as measures of lipid peroxidation. Circulating conjugated dienes increased from a baseline of 0.48 +/- 0.06 to 0.64 +/- 0.05 after burn, while protein-rich burn tissue lymph flow increased up to eightfold. We also noted a significant increase in lung tissue malondialdehyde from 45 +/- 4 to 60 +/- 6 nmol/gm and liver malondialdehyde from 110 +/- 20 to 271 +/- 34 nmol/gm along with increased tissue neutrophil sequestration. Ibuprofen attenuated lung-tissue malondialdehyde but had no effect on lung inflammation, circulating lipid peroxides or burn edema, indicating that ibuprofen most likely decreased O2 radical release in lung tissue by the already-sequestered neutrophils. Allopurinol, possibly via xanthine oxidase inhibition, markedly attenuated burn QL and circulating lipid peroxides and prevented all pulmonary lipid peroxidation and inflammation, indicating that release of oxidant from burn tissue was in part responsible for local burn edema, as well as distant inflammation and oxidant release, the latter most likely from complement activation. Neither antioxidant decreased lipid peroxidation in the liver; this indicates that its mechanism of production was different from that seen in burn tissue, in plasma, or in the lung. An ischemic event resulting from a selective decrease in splanchnic blood flow may be the cause of the liver changes.

Moderate smoke inhalation produces decreased oxygen delivery, increased oxygen demands, and systemic but not lung parenchymal lipid peroxidation.

We studied the first 24-hour lung and systemic physiologic response to a moderate smoke inhalation injury. In addition, we monitored oxidant-induced lipid peroxidation (LP), using malondialdehyde and conjugated dienes. Sixteen adult sheep with lung and soft tissue lymph fistulas were given 20 breaths of smoke while under anesthesia. Eight sheep were given a tidal volume of 5 ml/kg smoke, confining the inflammatory injury to airways only. Eight sheep were given 10 ml/kg smoke after which focal alveolar collapse and a carboxyhemoglobin level of 28% +/- 5% were noted in addition to airways injury. No significant lung or systemic physiologic changes were noted in the 5 ml/kg smoke exposure. However, plasma levels of malondialdehyde increased significantly, indicating that LP had occurred. With the 10 ml/kg smoke exposure, a 50% early decrease in oxygen consumption was noted. At 12 hours, oxygen consumption was then significantly increased by 30% over baseline. Fluid requirements to maintain filling pressures were also significantly increased, comparable to that seen after a 20% total body surface burn. A change in soft tissue permeability was noted with a twofold increase in systemic lymph, which could in part explain the fluid requirements. Lung lymph flow increased by only twofold, and lung water was not increased, whereas arterial partial oxygen pressure decreased from a baseline of 95 +/- 4 mm Hg to 60 +/- 5 mm Hg. Systemic LP was evident when both plasma malondialdehyde and conjugated dienes increased significantly. Liver tissue malondialdehyde at postmortem examination was double the normal level. However, lung parenchymal malondialdehyde was not increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of thromboxane synthetase accentuates hemodynamic instability and burn edema in the anesthetized sheep model.

Thromboxane A2 production is increased early after burn. We studied the effect of inhibiting thromboxane synthetase, using dazmegrel, on postburn hemodynamic stability and edema formation, the latter monitored by burn tissue lymph flow. Dazmegrel (3.4 mg/kg) was given to six anesthetized sheep, and a 40% of total-body-surface third-degree burn was produced. Lactated Ringer's solution was infused at a rate to restore filling pressures during a 12-hour study period. Data were compared to burn alone (n = 8), anesthesia alone (n = 6), and dazmegrel alone (n = 5) groups. The latter two groups showed no physiologic changes. Dazmegrel pretreatment prevented increased thromboxane A2, measured as thromboxane B2, but resulted in a significant increase in plasma prostacyclin, measured as 6-keto-PGF1 alpha. In addition, a marked vasodilatation and decrease in systemic vascular resistance were noted, as well as a 30% increase in fluid requirements and an increase in lymph flow compared with burn alone. The increase in prostacyclin more than likely accentuated the burn-induced permeability change. Of interest was that oxygen consumption was better maintained with dazmegrel postburn, even with the relative hypovolemia, indicating that postburn vasoconstriction impairs adequate O2 delivery to tissues and that thromboxane synthetase inhibition attenuates this process.

Effect of a body burn on endotoxin-induced lipid peroxidation: comparison with physiologic and histologic changes.

We determined the effect of a 15% total body surface (TBS), full-thickness burn on the physiologic, histologic, and oxidant-induced lipid peroxidation changes produced by endotoxin. The endotoxin-burn response was compared with that of endotoxin alone. Twenty-two adult sheep with chronic lung and flank lymph fistulas were studied. In 11 sheep a burn was produced under anesthesia and 3 days later they were given 2 micrograms/kg of endotoxin. Data were also compared with those of control sheep and those that were given burns alone. Circulating conjugated dienes increased with endotoxin alone but remained at baseline with endotoxin and burn injury. The lung lymph flow response was increased significantly in the endotoxin-burn group (sixfold) compared with that of endotoxin alone (fourfold). Histologic quantitation of lung neutrophil count was comparable in both groups 6 hours after injury, although mononuclear cells were much more evident in lungs in the endotoxin-burn group. Lipid peroxidation measured by malondialdehyde was significantly increased in the endotoxin group compared with the endotoxin-burn group, despite the greater increase in lymph flow and lung water in the burned group. Oxygen consumption (VO2) remained constant after endotoxin alone compared with baseline. However, VO2 increased twofold immediately after endotoxin in the endotoxin-burn group. This marked increase was followed by a significant decrease in VO2 from baseline. Flank soft-tissue nonburned increased lung lymph flow twofold to threefold with endotoxin and burn, indicating increased soft-tissue permeability, whereas it remained unchanged with endotoxin alone. Liver malondialdehyde increased from a control of 110 +/- 20 to 210 +/- 80 mmol/gm tissue with endotoxin alone and to 450 +/- 54 nmol/gm tissue with endotoxin and burn. We can conclude that burn injury accentuates both the pulmonary and systemic physiologic response to endotoxin, possibly as a result of mediators released from mononuclear cells already activated in the presence of the burn. The increased lung physiologic response does not appear to be caused by greater oxidant-induced lipid peroxidation, as was seen in the liver with the combined injury.

Early pulmonary and hemodynamic effects of a chest wall burn (effect of ibuprofen).

The cardiopulmonary effects of a third-degree scald burn involving the anterolateral chest wall was compared with a burn of equal size (30% of total body surface) to the flanks in anesthetized sheep with lung lymph fistulas. The chest-burn group was characterized by immediate decreases in cardiac output (6.5 to 3.0 L/min), central venous pressure (5 mm Hg to 0 mm Hg), pulmonary wedge pressure (10 mm Hg to 6 mm Hg), and urine output 1.5 ml/kg/hr to less than 0.5 ml/kg/hr. The temperature of pulmonary artery blood increased from 38 to 42 degrees C and plasma prostacyclin increased from 20 to 200 pg/ml. These changes were significantly different from those seen in the body sheep with burns. Initial fluid requirements necessary to restore filling pressures were 50% greater in the sheep with chest burns than in the sheep with body burns. An early decrease in static lung compliance was also seen after chest burn that was not the result of increased lung edema. A progressive decrease in compliance, urine output, and stroke output was also seen in the later postburn period (6 to 7 hours), which was significantly improved by a chest wall escharotomy. Postmortem analysis in the chest-burn group revealed a significantly increased malondialdehyde content, a reflection of increased oxygen radical-induced lipid peroxidation relative to the body burn. Pretreatment of the chest burn with ibuprofen, 12.5 mg/kg, prevented the initial vasodilator and lung compliance changes so that early cardiopulmonary status was identical to that seen with a body burn alone. Ibuprofen also decreased the lung tissue malondialdehyde content. We conclude that a burn involving the chest wall results in cardiopulmonary abnormalities, not seen after a body burn of a comparable size, which appear to be due to hyperthermia and an increased release of prostacyclin and O2 radicals.

Tissue inflammation without bacteria produces increased oxygen consumption and distant organ lipid peroxidation.

An inflammatory focus was produced by implantation of gauze below the hide in the flanks of six sheep with flank lymph fistulas. Physiologic and metabolic parameters were monitored in the unanesthetized animals for 7 days, after which the gauze was removed and monitoring continued for another 5 days. Animals were then killed. Lung and liver tissue was inspected and analyzed for lipid peroxide content. Data were compared with those of six controls in which gauze was not implanted. We noted a transient significant increase (on day 1 only) in wound lymph, thromboxane B2, and 6-keto-PGF1 alpha from baseline values of 190 +/- 70 and 20 +/- 10 pg/ml to 1000 +/- 240 and 420 +/- 70 pg/ml, respectively. Plasma values were also significantly increased on day 1. Body temperature increased by 1 degree C and cardiac index increased by 30% during this period, whereas oxygen consumption, VO2, was not significantly increased. The VO2 and cardiac index increased by 50% over baseline, beginning on day 5, whereas systemic vascular resistance decreased. Body temperature was not increased. These changes corresponded with an increase in wound lymph monocyte count from 0% to 15% of total. The VO2 and cardiac index remained increased after gauze removal. No bacteria were found in the wound. Postmortem analysis revealed a marked monocyte-macrophage infiltration in both lung and liver. Lung water, represented as water content over dry weight, was normal. Lung and liver lipid peroxidation, measured by the by-product malondialdehyde content, increased 300% and 90% over control values, respectively. We conclude that a local, nonbacteria-induced wound inflammation increases VO2, with the increase not corresponding to increase in body temperature. Distant organ changes, namely, changes in lung and liver, were also evident 5 days after gauze removal.

Effect of thermal injury on endotoxin-induced lung injury.

We studied the effects of a burn injury on the response of the lung to endotoxin. Seventeen unanesthetized sheep with lung lymph fistulas were studied. Eight were given Escherichia coli endotoxin (1.5 micrograms/kg) alone and nine were given the same dose 72 hours after a 25% total body surface burn injury. At this time after burn, all physiologic parameters were at baseline levels. A characteristic two-phase lung injury was seen after administration of endotoxin with an initial hypertension phase, characterized by pulmonary artery hypertension, and a second or permeability phase, characterized by an increase in protein-rich lymph flow. all eight animals that underwent only endotoxin administration survived, whereas four of the nine burned animals died during the permeability phase in pulmonary edema. Major physiologic differences between the groups were noted during the permeability phase, including a more severe hypoxia, pulmonary hypertension, and increased postburn lymph flow. Major biochemical changes included significant increases in lymph thromboxane, thromboxane B2, and beta-glucuronidase activity in the burn group. We conclude that the lung is more sensitive to endotoxin after burn, probably as a result of an increased release of products of arachidonic acid metabolism and products of leukocyte activation caused by the body burn.

Effect of hydroxyl radical scavenging on endotoxin-induced lung injury.

The release of oxygen radicals, in particular the hydroxyl radical, from sequestered neutrophils produces acute lung injury after a number of insults. Our purpose was to determine whether hydroxyl radical, OH., is responsible for the lung injury from endotoxin characterized by (1) pulmonary leukostasis, (2) increased thromboxane production leading to pulmonary hypertension and hypoxia, and (3) increased protein permeability. This hypothesis was tested by infusion of a selective OH. scavenger, dimethyl thiourea (0.75 gm/kg), into unanesthetized sheep before endotoxin and comparison of the response to that seen with endotoxin alone. Pulmonary vascular integrity was measured by the use of lung lymph flow, QL, and lymph protein transport. Thromboxane A2 was measured as TxB2 and prostacyclin as 6-keto-PGF1 alpha. We found no difference in the degree of leukopenia and hypoxia after endotoxin or the levels of TxB2, 6-keto-PGF1 alpha, and pulmonary hypertension with dimethyl thiourea, compared with endotoxin alone. The permeability injury was also identical, with a twofold to threefold increase in protein-rich lymph seen in both groups. It appears that OH. does not play a major causative role in either phase of endotoxin lung injury.

Role of thermal injury-induced hypoproteinemia on fluid flux and protein permeability in burned and nonburned tissue.

We studied the role of hypoproteinemia, induced by a major burn injury, on the edema process in burned and nonburned tissues including the lung in the adult sheep. We used lymph flow (QL) and the lymph-plasma (L/P) protein ratio as indicators of the rate of fluid and protein flux across the microcirculation and into the interstitium. We compared the response after a full-thickness burn to 30% of total body surface plus resuscitation by means of lactated Ringer's solution (n = 8) with a comparable degree of hypoproteinemia produced by plasmapheresis with vascular hydrostatic pressure and cardiac output kept constant. We measured lung QL and soft tissue (prefemoral) QL from both the burned and nonburned areas. A twofold increase in QL and a decrease in the L/P ratio was seen in both lung and nonburned tissue in both burn and plasmapheresis animals, indicating the postburn response to be due to hypoproteinemia with no increase in protein permeability. The QL in burned tissue was increased five to ten times with an increase in the L/P ratio. Four burned sheep were resuscitated with pooled plasma. Restoration of plasma proteins eliminated the increase in QL in lung and nonburned tissue but had no effect on the burn response. In summary, burn-induced hypoproteinemia plays a major role in the edema process in nonburned tissues and is corrected by restoration of plasma proteins. Edema in burned tissue does not appear to be related to this process.

Response of the pulmonary microcirculation to fluid loading after hemorrhagic shock and resuscitation.

We compared the response of the pulmonary microcirculation to fluid overload before and 24 hours after hemorrhagic shock, resuscitated with either blood or crystalloid, to determine whether vascular permeability was altered, making the lung more susceptable to fluid overload after shock and whether this response differed depending on the type of resuscitation fluid. Fourteen unanesthetized sheep with chronic lung lymph fistula were given a fluid challenge (one half of blood volume) before and 24 hours after hemorrhagic shock. Seven sheep were resuscitated after whock with shed blood and seven sheep were resuscitated with Ringer's lactate alone equal to 2.5 times the amount of shed blood. Pulmonary vascular pressures and lung lymph flow Ql were at baseline in both groups 24 hours after resuscitation except for the decreased plasma oncotic pressure pi p in the crystalloid group. Interstitial oncotic pressure, pi i was also lowered in this group such that the gradient (pi p-pi i) remained at baseline. In the blood group, pulmonary vascular pressures and QL increased transiently after fluid loading before and after shock with the mean time for QL to return to baseline being 5.5 and 5.9 hours for the preshock and postshock periods, respectively. In the crystalloid group, fluid loading after shock produced an increase in pulmonary vascular pressures resulting in a significant increase in QL over the preshock fluid response with the mean time for QL to return to baseline being 10.1 hours. However, changes in the value of (pi p-pi i) were identical to those seen before shock. Therefore we noted that 24 hours after shock, lung permeability was not significantly altered but crystalloid resuscitation did make the lung more susceptible to volume overload.

Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin.

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.

The lung inflammatory response to thermal injury: relationship between physiologic and histologic changes.

We studied the effect of a body burn on lung physiologic, biochemical, and histologic changes in a 2-day postburn period. A 15% of total-body-surface third-degree burn was produced in 24 adult sheep with lung and burn lymph fistulas. Eight sheep were killed at 12 hours and eight at 48 hours. At 12 hours we noted increased lung tissue lipid peroxidation, lung congestion, and neutrophil sequestration, in addition to a 30% decrease in lung compliance. Lung permeability and water content were not increased. Increased release of lipid peroxides and prostanoids were noted from burn tissue, as evidenced by increased plasma levels of malondialdehyde and conjugated dienes that remained elevated for about 8 hours and were decreased with wound removal. The lung inflammatory response was still present at 48 hours, the cells being primarily neutrophils. Nevertheless, the lipid peroxidation process, as measured by lung tissue malondialdehyde, had resolved. There was no evidence of burn tissue infection, measured by quantitative culture, to explain the persistent increase in lung inflammatory cells. Excision and closure of the burn wound at 3 hours postburn in eight sheep attenuated the lipid peroxidation and compliance changes but did not decrease the neutrophil sequestration. We conclude that burn injury results in a local wound oxidant release that leads to lipid peroxidation, both in wounds and in lung, as well as lung inflammation. The lipid peroxidation process may be attenuated by removal of the wound. The neutrophil sequestration is not altered, however, indicating this response occurs very early after injury, probably as a result of oxidant-initiated complement activation.