Antithrombin in the treatment of burn trauma

Antithrombin (AT) is a natural anticoagulant with anti-inflammatory properties that has demonstrated value in sepsis, disseminated intravascular coagulation and in burn and inhalation injury. With high doses, AT may decrease blood loss during eschar excision, reducing blood transfusion requirements. There are no human randomized, placebo-controlled studies, which have tested the true benefit of this agent in these conditions. Two main forms of AT are either plasma-derived AT (phAT) and recombinant AT (rhAT). Major ovine studies in burn and smoke inhalation injury have utilized rhAT. There have been no studies which have either translated the basic rhAT research in burn trauma, or determined the tolerance and pharmacokinetics of rhAT concentrate infusions in burn patients. Advantages of rhAT infusions are no risk of blood borne diseases and lower cost. However, the majority of human burn patient studies have been conducted utilizing phAT. Recent Japanese clinical trials have started using phAT in abdominal sepsis successfully. This review examines the properties of both phAT and rhAT, and analyzes studies in which they have been utilized. We believe that it is time to embark on a randomized placebo-controlled multi-center trial to establish the role of AT in both civilian and military patients with burn trauma.     

Lorazepam conjugation is unimpaired in burn trauma

A previous clinical study documented impaired hepatic metabolism of diazepam (phase I reaction) after burn injury. In this study, using lorazepam as a marker of hepatic glucuronidation, we tested the hypothesis that after burn injury, phase II reactions may be less impaired than phase I reactions. Ten burned patients and 10 age-, weight-, and sex-matched control subjects were studied after a 2 mg bolus dose of lorazepam. Burned patients had received multiple medications, whereas control patients were not taking any medication. The burned patients were studied at a mean (+/- SE) of 22 (+/- 4.6) days after burn injury. The burned patients had increases in total volume of distribution (2.66 +/- 0.55 vs. 1.39 +/- 0.1 L/kg; P less than 0.02) and clearance (4.28 +/- 1.20 vs. 1.16 +/- 0.1 ml/min/kg; P less than 0.01), whereas the half-life was significantly reduced in the burned group (9.6 +/- 1.3 vs. 13.9 +/- 0.9 hours; P less than 0.025). The significantly increased clearance and decreased elimination half-life in burned patients indicates that the elimination kinetics of lorazepam are not impaired and in fact may be enhanced in burned patients.     

Protective role of heat stress in burn trauma

OBJECTIVE: This study was designed to determine whether cutaneous burn injury up-regulated expression of myocardial heat shock protein (HSP)70 and to determine a potential cardioprotective role of inducible HSP70 (iHSP70) in postburn myocardial contractile function. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: Adult Hartley guinea pigs. INTERVENTIONS: The first set of studies determined whether heat stress (increasing body temperature to 42 degrees C for 20 mins) in adult Hartley guinea pigs would increase expression of myocardial iHSP70. MEASUREMENTS AND MAIN RESULTS: Our model of heat stress increased expression of inducible HSP in the myocardium (Western blot), and this response persisted 1, 2, 4, and 24 hrs after the initial heat stress. We then determined whether burn trauma over 40% total body surface area (TBSA) increased myocardial expression of iHSP70. Time-matched sham and burned guinea pigs were killed 1, 2, 4, 12, 18, or 24 hrs postburn, and hearts were used either to examine myocardial iHSP70 expression by Western blot or to determine myocardial contractile function (Langendorff). Burn trauma produced a two-fold increase in myocardial iHSP70 that was evident as early as 1 hr postburn and persisted 24 hrs postburn; increased iHSP70 expression occurred despite only a modest and transient increase in body temperature after burn trauma. We then determined whether heat shock stress before burn trauma provided a protective or detrimental effect on cardiac function. Body temperature was increased to 42 degrees C for 20 mins, animals were allowed to recover, and body temperature returned to baseline; burn trauma was then produced (40% TBSA) either 1, 2, 4, or 24 hrs after the initial heat stress. Myocardial contraction and relaxation deficits were evident after burn trauma alone; however, heat stress 1 hr before burn trauma improved left ventricular developed pressure and positive or negative maximum change in pressure in time and shifted left ventricular function curves upward and leftward from those calculated for burn in the absence of heat stress, indicating improved ventricular performance. Increasing the time between the initial heat stress and burn injury decreased the cardioprotective effects of heat stress. Thus, organ protection was evident only when the time period between the initial heat stress and the second insult was brief (1 hr). CONCLUSIONS: Our finding that the amount of myocardial iHSP70 remained constantly elevated after heat stress while the cardio-protective effect afforded by a prior heat stress declined with time suggested that the initial heat stress evoked several compensatory/adaptive mechanisms that may include modulation of autonomic nervous system responses, changes in metabolic function, modulation of pro/anti-inflammatory cytokine responses, and heat stress-related alterations in antioxidant capacity.     

Criteria for assessment of endogenous intoxication in burn trauma

Registered in patients with burn trauma was the presence of endogenous intoxication (EI), which was determined by a higher value of coefficient CLP/AOS, a higher contents of medium-molecular peptides (MMP), a lower total and effective concentration of albumin (TAC and EAC) and by a reserve of the binding albumin ability. Intoxication coefficients, i.e. IC MMP/EAC and IC C/EAC showing the deposition and binding of toxic ligands, were acknowledged as the most informative EI parameters.     

Hypnotizability and trauma symptoms after burn injury

This study investigated the association of trauma symptoms and hypnotizability in 43 hospitalized survivors of burn injury. Three to 17 days after the injury, participants rated the frequency of intrusive and avoidance symptoms and were interviewed with the posttraumatic stress disorder module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-III-R. The Hypnotic Induction Profile was also administered at the postburn, hospital stage of recovery. Results indicated that when participants were divided into low, mid-range, and high hypnotizability categories, high hypnotizability was associated with more intrusive, avoidance, and arousal symptoms. Although causal relations cannot be assessed in this cross-sectional study, these results suggest that, as compared to the low and mid-range categories, high hypnotizables may experience a greater frequency of trauma symptoms after burn injury.     

Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinin-induced plasma extravasation in the knee joint of the rat.

Previous results from this laboratory demonstrated that plasma extravasation produced by intra-articular infusion of bradykinin in the rat is mediated by an action on the sympathetic terminals in the knee joint and that adrenal medullary epinephrine regulates the plasma extravasation provoked by bradykinin. Because the release of epinephrine is under cholinergic control, we have now evaluated the effect of nicotinic and muscarinic cholinergic agonists on bradykinin-induced plasma extravasation in the knee joint of the rat. We report that s.c. administration of nicotine and carbachol attenuated plasma extravasation induced by bradykinin; this attenuation was significantly antagonized by systemic injection of hexamethonium and atropine, respectively. The nicotine and carbachol effects were also significantly attenuated after removal of the adrenal medulla. These results indicate that both nicotine and carbachol can inhibit bradykinin-induced plasma extravasation and that this inhibition is mediated, at least in part, through activation of nicotinic and muscarinic receptors in the adrenal medulla. Finally, local perfusion of the knee joint with hexamethonium did not affect the inhibition of bradykinin-induced plasma extravasation produced by systemic nicotine. Intra-articular perfusion of atropine potentiated the inhibition of bradykinin-induced plasma extravasation by systemic carbachol, indicating that muscarinic receptors in the synovium also contribute to plasma extravasation. The inhibitory action of nicotine on plasma extravasation may contribute, in part, to the reported increased severity of arthritis in individuals who smoke.     

Hypnotizability and trauma symptoms after burn injury.

This study investigated the association of trauma symptoms and hypnotizability in 43 hospitalized survivors of burn injury. Three to 17 days after the injury, participants rated the frequency of intrusive and avoidance symptoms and were interviewed with the posttraumatic stress disorder module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-III-R. The Hypnotic Induction Profile was also administered at the postburn, hospital stage of recovery. Results indicated that when participants were divided into low, mid-range, and high hypnotizability categories, high hypnotizability was associated with more intrusive, avoidance, and arousal symptoms. Although causal relations cannot be assessed in this cross-sectional study, these results suggest that, as compared to the low and mid-range categories, high hypnotizables may experience a greater frequency of trauma symptoms after burn injury.     

Upper airway mucus deposition in lung tissue of burn trauma victims

Previous study in an ovine model of smoke inhalation and burn (S + B) injury has shown distal migration of upper airway mucus. This study examines the localization of an upper airway gland specific mucus, mucin 5B (MUC5B) in lung autopsy tissues of burn-only injury and in victims of S + B injury. We hypothesize that victims with S + B injury would exhibit increased distal migration of MUC5B than that seen in victims of burn-only injury. Autopsy lung tissue from victims of burn injury alone (n = 38) and combined S + B injury (n = 22) were immunostained for MUC5B. No normal lung tissues were included in the study. Semiquantitative analysis of the extent of MUC5B in bronchioles and parenchyma was performed on masked slides. Irrespective of injury conditions, all victims showed MUC5B in bronchioles. Mucin 5B was seen in the parenchyma except in two burn victims. No statistically significant difference was seen in the mean bronchiolar and parenchyma MUC5B scores between S + B and burn-only victims (P > 0.05). No strong statistical correlation of MUC5B scores with days postinjury or to the number of ventilatory days was evident. The percentage of pneumonia, identified histologically, was also similar between study groups. This study did not confirm our results in an ovine model of S + B injury. In contrast, virtually all pediatric burn victims, regardless of concomitant inhalation injury, showed MUC5B in their bronchioles and parenchyma. Increased mucus synthesis and/or impaired mucociliary function may contribute to the pulmonary pathophysiology associated with burn injury.     

Hypnotherapy in management of pain and reexperiencing of trauma in burn patients

This study examined the effects of hypnosis on both pain and reexperiencing of trauma in burn patients. Forty-four patients hospitalized for burn care were randomly assigned to either hypnotherapy or a control group. Direct and indirect hypnotic suggestions were used to reduce pain and reexperiencing of trauma. All patients received routine burn care. Pain reports were quantified by using a self-report numeric rating scale ranging from 0 to 5. The number of recalled vivid, troubling events of the trauma in 24-hour intervals was used for rating the reexperiencing of trauma. The hypnotherapy group showed significantly lower pain ratings than the control group and reported a significant reduction in pain from baseline. There was a significant reduction in trauma reexperience scores in the hypnotherapy group but not the control group. The findings support the efficacy of hypnotherapy in the management of both pain and reexperiencing of trauma in burn patients.     

Characteristics of anesthesia in trauma surgery in children with severe burn injuries

The authors analyze total anesthesia in 347 children with thermal injuries, subjected to traumatic operations involving massive blood loss. A characteristic feature of total anesthesia in children subjected to early necrectomies was a lower dose or refusal from cholinolytics for premedication, endotracheal multicomponent narcosis with ketamine, fentanyl (promedole) in the minimal doses in parallel with inhalation anesthesia by fluothane traces and a nitrous oxide-oxygen mixture with at least 50% oxygen. The optimal initial dose of nondepolarized myorelaxants in burnt children is 30-50% higher than the recommended dose and is determined by the size and depth of injury. For controlled myoplegia, the doses of nondepolarized myorelaxants for subsequent injections should be 1.5-2.5 times lower than the initial dose. The duration of pancuronium and arduan effects depended on hepatorenal function. Tracrium provided regulated myorelaxation in children with burns even in cases with hepatorenal dysfunction. A high rate of massive blood loss and early development of multiple organ failure in children with thermal injuries prompted us to develop infusion-transfusion therapy for traumatic operations involving massive blood loss. The volume of blood loss is estimated from the area of necrotic tissues removed and the type of necrectomy. Qualitative composition of transfusion mixture and the rate of transfusion is determined by the rate and volume of blood loss, level of hemoglobin and hematocrit, and metabolic disorders during the operation. Prolonged ventilation of the lungs is recommended for children with thermal injuries after operations involving blood loss of 1 circulating blood volume or more. These measures decreased the incidence and severity of complications involving the hemodynamics, oxygen status and metabolism in tissues, and improved the reparation.     

Cardiomyocyte intracellular calcium and cardiac dysfunction after burn trauma

OBJECTIVE: To examine the effects of pharmacologic agents designed to limit burn-mediated calcium overload on cardiomyocyte [Ca2+] and cardiac contractile function. DESIGN: Experimental, comparative study. SETTING: Cellular biology and physiology laboratory. SUBJECTS: Adult Sprague Dawley rats. INTERVENTIONS: Rats were given third-degree burn injury over 40% of the total body surface area, were fluid resuscitated, and then were divided randomly to receive one of five treatments: vehicle (normal saline); amiloride (50 mg/kg) to inhibit H+-Na+ exchange and subsequent Na+-Ca2+ exchange; dantrolene (10 mg/kg, 30 mins, 6 and 22 hrs postburn) to inhibit sarcoplasmic reticulum Ca2+ release; diltiazem (10 mg/kg given over first 6 hrs postburn); or amlodipine (0.07 mg/kg, 24 hrs preburn and 30 mins postburn) to block calcium slow channels. Appropriate controls (sham burns given the appropriate pharmacologic agent) were included in each group. Twenty-four hrs postburn, left ventricular function (Langendorff), cardiomyocyte [Ca2+]i and [Na+]i measured by fura-2-AM or sodium-binding benzofurzan isophthalate loading of cardiomyocytes, and myocyte secretion of tumor necrosis factor-alpha (enzyme-linked immunosorbent assay) were assessed in shams and burns from each experimental group. This time point was selected based on our previous work confirming maximal ventricular contractile defects and maximal cytokine secretion 24 hrs postburn. MEASUREMENTS AND MAIN RESULTS: Burn trauma increased myocyte [Ca2+]i and [Na+]i, promoted tumor necrosis factor-alpha secretion by cardiomyocytes, and impaired left ventricular function. All pharmacologic agents reduced the burn-mediated Ca2+/Na+ accumulation in cardiomyocytes and ablated burn-mediated tumor necrosis factor-alpha secretion by myocytes; in contrast, dantrolene and amiloride provided significantly greater cardioprotection than pharmacologic agents that specifically targeted Ca2+ slow channels (diltiazem and amlodipine). CONCLUSION: Our data suggest that the calcium antagonists used in this study provide cardioprotection by modulating several aspects of the overall inflammatory cascade rather than solely limiting cardiomyocyte accumulation of calcium.     

Role of p38 mitogen-activated protein kinase in lung injury after burn trauma

This study was undertaken to evaluate the effect of SB203580, a specific p38 mitogen-activated protein (MAP) kinase inhibitor, on burn-induced lung injury as well as the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in rats to characterize the role of p38 MAP kinase in lung injury after burn trauma. Sprague-Dawley rats were divided into three groups: 1) sham group, or rats who underwent sham burn; 2) control group, or rats given third-degree burns over 30% total body surface area (TBSA) and lactated Ringer solution for resuscitation; and 3) SB203580 group, or rats given burn injury and lactated Ringers solution with SB203580 inside for resuscitation. Pulmonary injury was assessed at 24 h by pulmonary capillary permeability determined with fluorescein isothiocyanate-labeled albumin and lung histologic analysis. TNF-alpha and IL-1beta protein in bronchoalveolar lavage fluid and serum were measured by enzyme-linked immunosorbent assay and p38 MAP kinase was activity determined in lung by Western blot analysis. These studies showed that significant activation of p38 MAP kinase at 24 h postburn compared with control. Burn trauma resulted in increased pulmonary capillary leakage permeability, elevated levels of TNF-alpha and IL-1beta in bronchoalveolar lavage fluid and serum, and worsened histologic condition. SB203580 inhibited the activation of p38 MAP kinase, reduced the levels of TNF-alpha and IL-1beta, and prevented burn-mediated lung injury. These data suggest that p38 MAP kinase activation is one important aspect of the signaling event that may mediate the release of TNF-alpha and IL-1beta and contributes to burn-induced lung injury.     

Rapid modulation of micro-opioid receptor signaling in primary sensory neurons

Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the micro-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[(35)S]thio)-triphosphate (GTPgamma[(35)S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTPgamma[(35)S] binding and inhibited both prostaglandin E(2) (PGE(2))-stimulated adenylyl cyclase activity and BK/PGE(2)-stimulated neuropeptide release. The effect of BK was blocked by the B(2) antagonist HOE 140 [D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin], but not by the B(1) antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH(2), and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of micro-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that micro-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of phospholipase C-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.     

Effect of acute burn trauma on phagocytic activity of the reticuloendothelial system in rats

The effect of acute burn trauma on phagocytic activity of the reticuloendothelial system measured in vivo with technetium 99m sulfur colloid was examined in rats subjected to acute burn trauma. After the scald injuries (10-second, full-thickness burns) were induced, a reduction in phagocytic activity by the spleen took place with an accompanying increase in the uptake of colloid material by the lungs. Uptake of colloid material by the liver was essentially unchanged. These uptake changes, observed within hours after the inducement of acute burn trauma and apparently continuing for 7 days after burn injury, may explain, in part, the development of septicemia in patients with burns because altered phagocytic activity of the reticuloendothelial system can result in subsequent overabundance of microorganisms and bacteria in the blood.