Ventilatory support following burns and smoke-inhalation injury.

The first major improvement in the treatment of burn injury came with the recognition of the importance of fluid resuscitation to prevent shock and renal failure. Subsequently, the use of topical antibiotics to control burn-wound infection and prevent invasive burn-wound sepsis led to the next significant reduction in morbidity and mortality of burn patients. Although progress has been made in the treatment of inhalation injury, the pathophysiology of the injury is still incompletely defined. A better understanding of pathogenic mechanisms will lead to the development of therapeutic agents and treatment regimens that will modulate the cascades of humoral mediators of organ dysfunction and reduce the morbidity and mortality associated with inhalation injury. The recognition of ventilator-induced lung injury has led to adoption of alternative ventilatory techniques such as high-frequency percussive ventilation, which has been shown to substantially reduce the morbidity associated with inhalation injury.

The use of perfluorocarbon-associated gas exchange to improve ventilation and decrease mortality after inhalation injury in a neonatal swine model.

Patients with tracheobronchial disease frequently require mechanical ventilation during therapy and experience iatrogenic complications such as barotrauma and volutrauma. The purpose of this study was to determine whether perfluorocarbon-associated gas exchange (PAGE) results in lower ventilatory pressures and more efficient ventilation than that provided by conventional ventilation after tracheobronchial mucosal injury caused by smoke inhalation in neonatal piglets. Ten piglets were used for this prospective, randomized study. After administration of a severe smoke inhalation injury, the piglets were randomly assigned to either the perfluorocarbon or control groups. Group 1 served as the control population and received standard (time-cycled, volume-limited) mechanical ventilation. Ventilator settings were adjusted to maintain physiological pH and PO2 at the lowest tidal volume, rate, and end-expiratory pressure possible throughout the study period. Group 2 was administered intratracheal perfluorocarbon as well as identical mechanical ventilation to attain the same physiological pH and PO2. Oxygenation index, peak and mean airway pressures, and arterial blood gas levels were measured throughout the study period and subjected to statistical analysis. Histological comparison of airway and parenchymal tissues confirmed identical patterns of smoke injury in both groups. Carbon monoxide levels were the same in both groups. There was significant barotrauma and volutrauma in the control group, but none in the PAGE group. All controls died from 13 to 17 hours after injury; one PAGE pig died at 23 hours with all others surviving past 24 hours (P = .0021). Peak, plateau, and mean airway pressures were all significantly higher (P < .05) past 12 hours after injury and continued to increase until death in the controls. Arterial blood gases showed significantly (P < .05) decreased pH, PO2, and elevated PcO2 levels in the control group past 12 hours after injury. The oxygenation index was significantly elevated (P < .05) in the control group past 12 hours after injury. PAGE shows potential for improving ventilation and survival immediately after severe smoke inhalation injury and may have clinical applications in other nonhomogeneous lung injuries.

Computer-assisted evaluation of hand and arm function after thermal injury.

Comprehensive care of the burned upper extremity requires accurate and complete evaluation of function, including two-point discrimination, active and passive range of motion, and grip strength. These evaluations, when performed serially during a course of therapy, are time-consuming and manpower-intensive. We tested the utility and accuracy of a commercially available computer-assisted impairment evaluation system when used to automate and standardize measurement of upper-extremity function. The function of 80 upper extremities was evaluated with both the conventional and the computer-assisted methods. The time required to perform a complete examination with each method was recorded, and measurements of grip strength and total active motion made with both methods were compared. Complete upper-extremity evaluation required an average of 20.3 minutes with the computer-assisted method, compared to 62.9 minutes with conventional means. Measurements of extremity function with computer-assisted and conventional methods had correlation coefficients of 0.984 for grip strength and 0.996 for total active motion. The computer-assisted impairment evaluation system was found to be a useful and accurate adjunct in the acute and rehabilitative management of burned upper extremities.

Predicting ventilation failure in children with inhalation injury.

Despite advances in mechanical ventilatory support for patients with smoke inhalation injury, including the use of high-frequency flow-interruption ventilators such as the VDR, inhalation injury alone may increase mortality by as much as 20% in patients with thermal injury, and up to 60% when pneumonia occurs. Inhalation injury causes a primary large and small airway epithelial insult that results in ventilation abnormalities, rather than a primary alveolar lesion that results in oxygenation abnormalities as occur in multiple-system organ failure. Patients with inhalation injury requiring high ventilatory pressures experience complications of barotrauma and frequently succumb to necrotizing tracheobronchitis and oxygenation abnormalities after 2 to 4 weeks of mechanical ventilation. Ventilatory indexes obtained early in the postburn period allow the development of accurate predictive formulae that identify patients who will not be adequately supported by mechanical ventilation after smoke inhalation injury. Early identification of such patients will allow rapid conversion to other methods of ventilatory support that effect gas exchange, with minimal risk of further barotrauma, while inhalation injury healing occurs. Such predictors may be developed for other disease processes that are characterized by severe pulmonary ventilatory dysfunction.

Mobilization of renal carnosine and histidine to histamine during compound-48/80-induced shock.

Recently the presence of carnosine in the kidney has been established, and several potential roles for histamine have been proposed in renal metabolism. Histamine is known to occur in relatively high concentrations in renal tissue of several species and has been implicated in the autoregulation of renal blood flow and glomerular filtration. This study was designed to evaluate the effect of shock produced by compound 48/80 on the mobilization of renal carnosine to histamine and the effects of various blocking agents such as lodoxamide, diphenhydramine and cimetidine on this mobilization. Our results showed that compound-48/80-induced shock causes significant mobilization of renal carnosine and histidine to histamine and that this response can be blocked by administration of lodoxamide and diphenhydramine, but not cimetidine.

The presence and significance of carnosine in histamine-containing tissues of several mammalian species.

Histamine is known to exert profound effects on the cardiovascular system in many mammals. Carnosine (beta-alanyl-L-histidine) is a dipeptide previously known to be present only in a few tissues. It is our hypothesis that carnosine serves as a non-mast cell reservoir for histidine, available for histamine synthesis during periods of physiologic stress. To validate this hypothesis, we demonstrated the existence of carnosine in multiple histamine-rich tissues in several mammalian species; documented a metabolic link between carnosine and histidine, histamine and 3-methylhistamine (a degradation product of histamine) in unstressed animals, and showed that tissue carnosine is decreased simultaneously with an increase in tissue histamine during stress.

Effect of histamine antagonists on myocardial carcinine metabolism during compound 48/80-induced shock.

Carcinine (beta-alanylhistamine) is an imidazole dipeptide that exists in mammalian hearts, increases cardiac contractility, and is metabolically linked to carnosine (beta-alanylhistidine), a non-mast cell histidine and histamine precursor during stress. We have previously shown that tissue carnosine levels are regulated by H1 and H2 receptors. This study evaluated the effects of H1, H2, and mast cell degranulation blockers on metabolism of carcinine and related imidazoles during shock induced by compound 48/80, a mast cell degranulator. Fifty 125-g male Sprague-Dawley rats were divided into nine ip treatment groups: saline, 48/80, lodoxamide (LOD, mast cell degranulation inhibitor), diphenhydramine (DPH, H1 antagonist), cimetidine (CIM, H2 antagonist), LOD + 48/80, CIM + 48/80, DPH + 48/80, or DPH + CIM + 48/80. Heart tissue was analyzed at 30 min by HPLC. 48/80 caused decreases in myocardial carnosine (P less than 0.01) and histidine (P less than 0.0001) levels and concomitant increases in carcinine (P less than 0.01), histamine (P less than 0.01), and 3-methylhistamine (P less than 0.05) compared to those of controls. These changes were inhibited by LOD or DPH. Treatment with CIM significantly increased myocardial carcinine levels compared to 48/80 alone (P less than 0.001) without an additional effect on the other compounds. These data indicate that carcinine is involved in the cardiac response to stress via the carnosine-histidine-histamine pathway. Compound 48/80-induced shock increases histamine metabolism via this pathway resulting in mobilization of myocardial carnosine and histidine to carcinine and histamine; this effect is increased by H2 receptor blockade.

Effect of histamine receptor antagonists on mortality in compound 48/80-induced shock.

The roles of histamine and H1 and H2 receptors in shock are uncertain. We have found that treatment of aged rats with compound 48/80 (a mast cell degranulator) produced lethal (LD99) shock which was completely prevented by lodoxamide (LOD), a mast cell degranulation inhibitor. This study evaluated the effect of H1 and H2 receptors and age on mortality of 48/80-induced shock in rats. To assess survival, 65 young male (125 g), 65 mature male (250 g) and 30 aged male (500 g) SD rats were placed in groups and treated intraperitoneally with saline; 48/80; LOD + 48/80; the H1 blocker diphenhydramine (DPH) + 48/80; the H2 blocker cimetidine (CIM) + 48/80; or DPH and CIM + 48/80. Rats were observed for 30 min or until death. All 125 g rats survived. Of the 250 g rats, 50% of 48/80-treated and 100% of CIM + 48/80-treated rats died; all others survived. All 500 g 48/80- and CIM + 48/80-treated rats died; all other 500 g rats survived. For all ages, survival differences between saline-, 48/80-, and CIM + 48/80-treated rats were highly significant (P less than or equal to 0.0001). In addition, both 48/80 and CIM + 48/80 greatly reduced mean survival time in the 250 g and 500 g groups (P less than or equal to 0.0001) compared to all other treatments. Both LOD and DPH were protective against 48/80, and DPH was also protective against CIM + 48/80, for both absolute survival and mean survival time (P less than or equal to 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of H1 and H2 receptor blockers on mobilization of myocardial carnosine to histamine during compound 48/80-induced shock in young rats.

Histamine exerts profound effects on the cardiovascular system during shock mediated by H1 and H2 receptors. The source of histamine is uncertain. It is our hypothesis that carnosine serves as a nonmast-cell reservoir for histidine, utilized for histamine synthesis during shock. We have shown that treatment of older rats with compound 48/80, a mast cell degranulator, produces age-dependent lethal stress, which is prevented by lodoxamide (LOD), a mast cell degranulation inhibitor, is exacerbated by H2 receptor blockade, and is accompanied by increased mobilization of myocardial carnosine to histidine and histamine. This study was designed to evaluate the effects of H1 and H2 blockers on carnosine mobilization to histamine during 48/80-induced shock in young rats. Fifty male SD rats (125 g) were divided into nine groups: saline; LOD; H1 blocker diphenhydramine (DPH); H2 blocker cimetidine (CIM); 48/80; LOD + 48/80; DPH + 48/80; CIM + 48/80; and DPH + CIM + 48/80. All rats were sacrificed 30 min after final injections and hearts were analyzed via HPLC. There was a reduction in myocardial carnosine (P less than or equal to 0.01) and histidine (P less than or equal to 0.001) and a simultaneous increase in histamine (P less than or equal to 0.01, P less than or equal to 0.001) in animals receiving 48/80 or CIM + 48/80, respectively, compared to controls or groups pretreated with LOD, DPH, or DPH + CIM. These results indicate that 48/80-induced shock increases mobilization of myocardial carnosine and histidine to histamine, which supports a role for carnosine as a nonmast-cell histamine source.(ABSTRACT TRUNCATED AT 250 WORDS)

Existence of carcinine, a histamine-related compound, in mammalian tissues.

Carcinine (beta-alanylhistamine) was synthesized in vitro from histamine and beta-alanine. It was detected quantitatively using an HPLC method previously described for the quantification of the related compounds histamine, histidine, carnosine and 3-methylhistamine. Carcinine was identified in several tissue of the rat, guinea pig, mouse and human, and was then shown to be metabolically related in vivo to histamine, histidine, carnosine and 3-methylhistamine through radioisotopic labeling. The results demonstrate that carcinine may be concurrently quantitated using the same HPLC method as that used to measure histamine, histidine, carnosine and 3-methylhistamine. These findings suggest a role for carcinine in the carnosine-histidine-histamine metabolic pathway and in the mammalian physiologic response to stress.

Effects of compound 48/80 and exogenous histamine on wound healing in mice.

Compound 48/80 has previously been shown to improve wound healing in rats, presumably through stimulation of histidine decarboxylase activity and mobilization of histamine from mast cells. In the present study, C57Bl/6 mice were wounded by dorsal skin incision followed by treatment with compound 48/80, exogenous histamine, or the combination of 48/80 plus histamine. Skin-breaking strength was significantly increased over saline-injected controls by the combined treatment with 48/80 and histamine. Neither 48/80 or histamine alone had any influence on wound healing. Histamine content of skin at the wound site was significantly reduced by 48/80 treatment, but was unaffected by 48/80 plus histamine or histamine given alone. In contrast, stomach and leg muscle histamine levels were significantly increased beyond those of unwounded, wounded saline- or 48/80-injected mice. These results were also confirmed in CD mice, and are in contrast to findings in rats in which treatment with 48/80 alone significantly improved wound healing of similarly injured animals.

Improved survival from compound 48/80-induced lethal stress and inhibition of myocardial histamine and carnosine mobilization by lodoxamide.

The precise roles of carnosine and histamine in the physiologic response of the cardiovascular system to stress are unknown. We have previously shown in skeletal and cardiac muscle that carnosine serves as a histidine reservoir available for subsequent histamine synthesis following trauma and sepsis. This study was designed to quantify the effect of histamine-releasing and blocking agents on the myocardial carnosine-histamine pathway as well as on survival during severe stress. Four groups of mature (9-month-old) Sprague-Dawley rats were treated with either (1) saline, (2) lodoxamide (L, mast cell degranulation inhibitor), (3) compound 48/80 (a mast cell degranulator which causes stress), or (4) L followed by 48/80, and observed until agonal or the end of 30 min. When either endpoint was reached the animals were sacrificed and their hearts were removed for tissue analyses of histidine, histamine, 3-methylhistamine, and carnosine via high-pressure liquid chromatography. All five L-pretreated animals survived challenge with 48/80 while all five animals given 48/80 alone died (P less than .005). This mortality correlated well with the increase in the myocardial levels of histidine (P less than or equal to .0005), histamine (P less than or equal to .0077), and 3-methylhistamine (P less than or equal to .0004) and the decrease in carnosine (P less than or equal to .009) experienced by the animals treated with 48/80 alone in comparison to the control, L-only- and L + 48/80-treated groups. A protective effect of L was shown against the deleterious effects of 48/80 which is associated with prevention of myocardial carnosine mobilization to histidine and histamine. These data support the role of carnosine as a nontoxic myocardial histidine reservoir which is mobilized in response to stress-induced increases in histamine requirements.

Gastrointestinal complications after cardiac surgery.

Gastrointestinal (GI) complications after cardiac surgical procedures are infrequent but severe. Thirty-three GI complications were identified in 25 patients who underwent cardiac surgery during a 7-year period (2.0% incidence). The mortality rate for patients having these GI complications was 44%. Acute acalculous cholecystitis was the most lethal complication (86%). Acute pancreatitis was the most common complication (eight patients). Most patients responded well to conservative measures. Five patients had upper GI hemorrhage and three had lower GI bleeding that required more than 2 U of packed red blood cells. All patient conditions were diagnosed endoscopically and none necessitated operation. Of the remaining patients, one was operated on because of perforated duodenal ulcer, one because of perforated diverticulitis, and one because of pseudo-obstruction of the colon, and one patient underwent diagnostic laparotomy and showed negative results for presumed acalculous cholecystitis. Liver failure was fatal in all three patients in whom it occurred. GI complications correlated significantly with advanced age, prolonged bypass times, valve surgery, and the female sex. We conclude that septic GI complications--particularly acute acalculous cholecystitis and perforated viscus--after cardiac surgery are uncommon but lethal. Clinical features are often subtle, and a high index of suspicion is necessary for an early diagnosis and the institution of appropriate treatment.